Intensive Care Medicine: Annual Update 2008

INTENSIVE CARE MEDICINE EImE ANNUAL UPDATE JEAN-LOUIS VINCENT INTENSIVE CARE MEDICINE ANNUAL UPDATE 2008 Editor Je...

Author: Jean-Louis Vincent

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INTENSIVE CARE MEDICINE

EImE

ANNUAL UPDATE JEAN-LOUIS VINCENT

INTENSIVE CARE MEDICINE ANNUAL UPDATE 2008 Editor

Jean-Louis Vincent MD, PhD, FCCM, FCCP Head, Department of Intensive Care Erasme Hospital, Universite libre de Bruxelles Brussels, Belgium

With 238 Figures and 90 Tables

~ Springer

JEAN-LoUIS VINCENT, MD, PHD, FCCM, FCCP Head, Department of Intensive Care Erasme Hospital Universite libre de Bruxelles Route de Lennik 808 1070 Brussels Belgium

ISBN 978-0-387-77382-7

Printed on acid-free paper.

© 2008 Springer Science + Business Media Inc.

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed in Germany 987654321 springer.com

v

Table of Contents

I Genetic Factors Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients? C. KIRWAN, I. MACPHEE, and B. PHILIPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

Genetic Susceptibility in ALI/ARDS: What have we Learned? R. CARTIN-CEBA, M.N. GONG , and O. GAJIC

13

Racial Disparities in Infection and Sepsis: Does Biology Matter? EB. MAYR, S. YENDE, and D.C. ANGUS

24

II Cardiac Issues B-type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care P.E. OISHI, J.-H. Hsu, and J.R. FINEMAN

33

Cardiac Dysfunction in Septic Shock I. CINEL, R. NANDA, and R.P. DELLINGER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome H. SCHMIDT, U. MULLER-WERDAN, and K. WERDAN

55

Quantification of Improved Left Ventricular Performance during Cardiac Resynchronization Therapy B. LAMIA and M.R. PINSKY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit J. POELAERT, E. OSIPOWSKA, and C. VERBORGH

76

Pharmacological Support of the Failing Right Ventricle P.E WOUTERS, S. REX, and C. MISSANT

88

Perioperative Cardioprotection H.-J. PRIEBE

101

III Cardiopulmonary Resuscitation Improving the Quality of Cardiac Arrest Resuscitation Care C]. DINE and B.S. ABELLA

113

Pediatric Cardiopulmonary Arrest and Resuscitation A. TOPJIAN, R.A. BERG, and V.M. NADKARNI

121

VI

Table of Contents

Early Cooling in Cardiac Arrest: What is the Evidence? 1. HAMMER, C. ADRIE, and J.-E TIMSIT

137

IV Emergencies Management of Severe Accidental Hypothermia G.J. PEEK, P.R. DAVIS, and J.A. ELLERTON

147

Initial ICU Management of Skin Sloughing Diseases: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome T.L. PALMIERI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 160

V Poisonings Pathophysiology of Caustic Ingestion M. OSMAN and D.N. GRANGER

171

Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity B. MEGARBANE, N. DEYE, and EJ. BAUD

179

VI Acute Respiratory Failure Epidemiology of Acute Respiratory Failure and Mechanical Ventilation H.S. SURI, G. LI, and O. GAJIC

193

Esophagectomy and Acute Lung Injury D.P. PARK, D. GOUREVITCH, and G.D. PERKINS

203

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe? P. PELOSI and P.R.M. Rocco 214 Regional Lung Function in Critically III Neonates: A New Perspective for Electrical Impedance Tomography I. FRERICHS, J. SCHOLZ, and N. WEILER

224

Extracorporeal Lung Assist for Acute Respiratory Distress Syndrome: Past, Present and Future R. Konr, U. STEINSEIFER, and R. ROSSAINT

235

VII Ventilatory Support Protective Mechanical Ventilation: Lessons Learned from Alveolar Mechanics S. ALBERT, B. KUBIAK, and G. NIEMAN

245

Mechanical Ventilation for Acute Asthma Exacerbations D. DE MENDOZA, M. LUJAN, and J. RELLO

256

Hypercapnia: Permissive, Therapeutic or Not at All? P. HASSETT, M. CONTRERAS, and J.G. LAFFEY

269

The Cardiopulmonary Effects of Hypercapnia T. MANCA, L.c. WELCH, and J.1. SZNAJDER

282

High Frequency Oscillation for Acute Respiratory Failure in Adults S.D. MENTZELOPOULOS, C. Roussos, and S.G. ZAKYNTHINOS

290

Table of Contents

Airway Pressure Release Ventilation : Promises and Potentials for Concern J. GUTIERREZ MEJIA, E. FAN, and N.D. FERGUSON

301

Post-operative Non-invasive Ventilation S. JABER, G. CHANQUES, and B. JUNG

310

VIII Tracheostomy Choice of Tracheostomy Tube: Does One Size Fit All? J. ORAM and A. BODENHAM

323

What's New in Percutaneous Dilational Tracheostomy? T.A. TRESCHAN, B. PANNEN, and M. BEIDERLINDEN

331

IX Infections Novel Therapies in the Prevention of Ventilator-associated Pneumonia P.J. YOUNG and M.C. BLUNT

343

Management of Ventilator-associated Pneumonia M. FERRER, M. VALENCIA, and A. TORRES

353

Flucytosine Combined with Amphotericin B for Fungal Infections P.H.J. VAN DER VOORT

365

X Cellular Mechanisms in Sepsis Apoptosis in Critical Illness: A Primer for the Intensivist Z. MALAM, J.C. MARSHALL

375

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis: A Putative Role for Hypoxia Inducible Factor 385 T. REGUEIRA, S.M. JAKOB, and S. DJAFARZADEH Gram-positive and Gram-negative Sepsis: Two Disease Entities? S. LEAVER, A. BURKE GAFFNEY, and T.W. EVANS

395

Methicillin-resistant Staphylococcus aureus-induced Sepsis: Role of Nitric Oxide P. ENKHBAATAR, 1. TRABER, and D. TRABER 404

XI Sepsis Therapies The Cardiovascular Management of Sepsis B.C. CREAGH-BROWN, J. BALL, and M. HAMILTON

413

Terlipressin in Septic Shock: When and How Much? C. ERTMER, A. MORELLI, and M. WESTPHAL

423

Blood Purification Techniques in Sepsis and SIRS P.M. HONORE, O. JOANNES-BoYAU, and B. GRESSENS

434

Glutathione in Sepsis and Multiple Organ Failure U. FLARING and J. WERNERMAN

444

Selenocompounds and Selenium: A Biochemical Approach to Sepsis X. FORCEVILLE and P. VAN ANTWERPEN

454

VII

VIII

Table of Contents

XII Metabolic Alterations The Role of Hypoxia and Inflammation in the Expression and Regulation of Proteins Regulating Iron Metabolism S. BRANDT, J. TAKALA, and P.M. LEPPER

473

Hyperammonemia in the Adult Critical Care Setting K. DAMS, W. MEERSSEMAN, and A. WILMER

481

Magnesium in the ICU: Sine qua non F. ESEN and L. TELCI

491

Strict Glycemic Control: Not If and When, but Who and How? M.J. DE GRAAFF, P.E. SPRONK, and M.J. SCHULTZ

502

Cortisol Metabolism in Inflammation and Sepsis B. VENKATESH and J. COHEN

514

XIII Fluid Management Assessment of Perioperative Fluid Balance M.T. GANTER and C.K. HOFER

523

Fluid Resuscitation and Intra-abdominal Hypertension I.E. DE LAET, J.J. DE WAELE, and M.L.N.G. MALBRAIN

536

XIV Acute Kidney Injury Six Truths about Acute Kidney Injury that the Intensivist should be Aware of E.A.J. HOSTE

551

Role of Poly(ADP-Ribose) Polymerase in Acute Kidney Injury R. VASCHETTO, F.B. PLOTZ, and A.B.J. GROENEVELD

559

From Hemodynamics to Proteomics : Unraveling the Complexity of Acute Kidney Injury in Sepsis 568 M. MATEJOVIC, P. RADERMACHER, and V. THONGBOONKERD

XV Hemodynamic Assessment and Management Towards Optimal Central Venous Catheter Tip Position W. SCHUMMER, Y. SAKR, and C. SCHUMMER

581

From Arterial Pressure to Cardiac Output M. CECCONI, A. RHODES, and G. DELLA Roccx

591

Hemodynamic Monitoring: Requirements of Less Invasive Intensive Care Quality And Safety A. VIEILLARD-BARON

602

Minimally Invasive Cardiac Output Monitoring: Toy or Tool? G. MARX and T. SCHUERHOLZ

607

Bioreactance: A New Method for Non-invasive Cardiac Output Monitor ing P. SQUARA

619

Goal-directed Hemodynamic Therapy for Surgical Patients P. MORGAN and A. RHODES

631

Table of Contents

XVI Tissue Oxygenation Use of Mixed Venous Oxygen Saturation in ICU Patients M. LEONE, V. BLASCO, and C. MARTIN Early Optimization of Oxygen Delivery in High-risk Surgery Patients S.M. LOBO, E. REZENDE, and F. SUPARREGUI DIAS

641 , 654

The Influence of Packed Red Blood Cell Transfusion on Tissue Oxygenation S. SUTTNER and J. BOLDT

665

Recent Advancements in Microcirculatory Image Acquisition and Analysis R. BEZEMER, M. KHALILZADA, and C. INCE

677

The Beneficial Effects of Increasing Blood Viscosity B.Y. SALAZAR VAZQUEZ, P. CABRALES, and M. INTAGLIETTA

691

XVII Anticoagulants in Organ Failure Protein C and Antithrombin Levels in Surgical and Septic Patients Y. SAKR, N.C.M. YOUSSEF, and K. REINHART

703

Thrombophilia as a Risk Factor for Outcome in Sepsis J.-J. HOFSTRA, M. SCHOUTEN, and M. LEVI

713

The Effects of Activated Protein C on the Septic Endothelium S.E. ORFANOS, N.A. MANIATIS, and A. KOTANIDOU

721

Improvement in Hemodynamics by Activated Protein C in Septic Shock X. MONNET, H. KSOURI, and J.-L. TEBOUL

730

XVIII Acute Bleeding Gastrointestinal Hemorrhage on the Intensive Care Unit S.J. THOMSON, M.L. COWAN, and T.M. RAHMAN

739

Recombinant Activated Factor VII: The Delicate Balance between Efficacy and Safety S. BELISLE, J.-F. HARDY, and P. VAN DER LINDEN

751

XIX Hepatic Disease ICU Management of the Liver Transplant Patient G. DELLA ROCCA, M.G. COSTA, and P. CHIARANDINI

763

Liver Support with Fractionated Plasma Separation and Adsorption and Prometheusw K. RIFAI, C. TETTA, and C. RONCO

777

Artificial Liver Support: Current Status F. SALIBA, P. ICHAI, and D. SAMUEL

785

XX Neurological Crises Encephalopathy in Sepsis A. POLITO, S. SIAMI, and T. SHARSHAR

801

IX

X

Table of Contents

Multimodality Monitoring in Patients with Elevated Intracranial Pressure D.B. SEDER, J.M. SCHMIDT, and S. MAYER

811

Managing Critically III Patients with Status Epilepticus S. LEG RIEL, J.P. BED os, and E. AZOULAY

822

XXI Analgesia and Sedation Sedation with Inhaled Anesthetics in Intensive Care EJ. BELDA, M. SORO, and A. MEISER Sedation or Analgo-sedation in the ICU: A Multimodality Approach E MEURANT, A. BODART, and J.P. KOCH

" 839 850

XXII Outcomes Time to Use Computerized Physician Order Entry in all ICUs J. ALI and A. VUYLSTEKE

865

Quality of Life in Locked-in Syndrome Survivors M.-A. BRUNO, E PELLAS, and S. LAUREYS

881

Post-traumatic Stress Disorder in Intensive Care Unit Survivors J. GRIFFITHS, A.M. HULL, and B.H. CUTHBERTSON

891

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907

XI

List of Contributors

ABELLA BS Department of Emergency Medicine University of Pennsylvania 3400 Spruce Street, Ground Ravdin Philadelphia, PA 19104 USA ADRIE C Department of Intensive Care Delafontaine Hospital Rue Dr P Delafontaine 2 93205 Saint Denis France ALBERT S Department of Surgery Suny Upstate Medical Univer sity 750 East Adams Street Syracuse, NY 13210 USA

ALI J Department of Anesthesia and Critical Care Papworth Hospital Cambridge, CB23 3RE United Kingdom AL-SUBAI E N General Intensive Care Unit St. James' Wing St. George 's Hospital Blackshaw Road London, SW17 OQT United Kingdom

ANGUS DC CRISMA Department of Critical Care Medicine University of Pittsburgh School of Medicine 605 Scaife Hall 3550 Terrace Street Pittsburgh, PA 15261 USA AZOULAY E Department of Intensive Care Hopital Saint-Louis 1 Avenue Claude Vellefaux 75010 Paris France BALL J General Intensive Care Unit St George's Hospital Blackshaw Road London, SW17 OQT United Kingdom BAUD FJ Medical Intensive Care and Toxicology Hopital Lariboisiere 2, Rue Ambroise Pare 75010 Paris France BEDOSJP Department of Intensive Care Medicine H6pital Andre Mignot 177 rue de Versailles 78150 Le Chesnay Fran ce

XII

List of Contributors BEIDERLINDEN M

BODART A

Department of Anesthesiology University Hospital Moorenstr. 5 40225 Dusseldorf Germany

Intensive Care Unit Kirchberg Hospital Rue E.Steighen, 9 2540 Luxemburg Luxembourg

BELDA FJ Department of Anesthesia and Critical Care Hospital Clinico Universitario Blasco Ibanez 17 46010 Valencia Spain

Department of Anesthesia and Intensive Care Leeds General Infirmary Gt. George St Leeds, LSI 3EX United Kingdom

BELISLE S Department of Anesthesiology Institut de Cardiologie 5000 Rue Belanger Est Montreal, QB HIT lC8 Canada BERG RA

Department of Pediatrics University of Arizona School of Medicine 1501 N Campbell Avenue, Tucson, AZ 85724 USA BEZEMER R

Department of Physiology Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Netherlands BLASCO V

BODENHAM A

BOLDT

J

Department of Anesthesiology and Intensive Care Medicine Klinikum der Stadt Ludwigshafen Bremserstr. 79 67063 Ludwigshafen Germany BRANDT S Department of Anesthesiology University Hospital Inselspital 3010 Bern Switzerland BRUNO MA

Coma Science Group Cyclotron Research Centre and Neurology Department University of Liege - Sart Tilman (B30) 4000 Liege Belgium BURKE GAFFNEY A

Department of Anesthesia and Intensive Care Hopital Nord Chemin des Bourrely 13915 Marseille France

Department of Critical Care Royal Brompton Hospital Sydney Street London, SW3 6NP United Kingdom

BLUNT MC

La Jolla Bioengineering Institute 505 Coast Boulevard South Suite # 405 La Jolla, CA 92037 USA

Department of Critical Care Queen Elizabeth Hospital Gayton Road King's Lynn, Norfolk, PE30 4ET United Kingdom

CABRALES

P

list of Contributors CARTIN-CEBA

R

Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Mayo Clinic 200 First Street SW Rochester, MN 55905 USA CECCONI

M

Department of Anesthesia and Intensive Care Medicine University Hospital PIe S.M. Misericordia 15 33100 Udine Italy CHANQUES

G

Department of Anesthesia and Critical Care Saint Eloi University Hospital 80 avenue Augustin Fliche 34295 Montpellier France CHiARANDlNI

P

Department of Anesthesia and Intensive Care Medicine Azienda Ospedaliero Universitaria S.M. della Misericordia PIe S.M. Misericordia 15 31100 Udine Italy CINEL

I

Division of Critical Care Cooper University Hospital One Cooper Plaza Dorrance Building, Suite 393 Camden, NJ 08103 USA COHEN

J

Department of Intensive Care Royal Brisbane & Ipswich Hospitals University of Queensland Queensland 4029 Australia

CONTRERAS

M

Department of Anesthesia Clinical Sciences Institute National University of Ireland Galway Ireland COSTA MG Department of Anesthesia and Intensive Care Medicine Azienda Ospedaliero Universitaria S.M. della Misericordia P.le S.M. Misericordia 15 31100 Udine Italy

ML Department of Gastroenterology St George's Hospital Blackshaw Road London, SW17 OQT United Kingdom COWAN

CREAGH -BROWN BC

General Intensive Care Unit St George's Hospital Blackshaw Road London, SW17 OQT United Kingdom BH Health Services Research Unit Health Sciences Building University of Aberdeen Aberdeen United Kingdom

CUTHBERTSON

DAMS

K

Medical Intensive Care Unit University Hospital Herestraat 49 3000 Leuven Belgium DAVIS PR Department of Emergency Medicine Defense Medical Services Southern General Hospital Glasgow, G51 4TF United Kingdom

XIII

XIV

List of Contributors DE GRAAFF MJ Department of Intensive Care Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam Netherlands DE LAET IE Department of Intensive Care ZNA Stuivenberg Lange Beeldekensstraat 267 2060 Antwerp Belgium DELLA ROCCA G

DINE

CJ

Division of Pulmonary, Allergy and Critical Care University of Pennsylvania 3400 Spruce Street, Ground Ravdin Philadelphia, PA 19104 USA DJAFARZADEH S Department of Intensive Care University Hospital Inselspital 3010 Bern Switzerland

Department of Anesthesia and Intensive Care Medicine Azienda Ospedaliero Universitaria S.M. della Misericordia PIe S.M. Misericordia 15 31100 Udine Italy

ELLERTON JA Birbeck Medical Group Bridge Lane Penrith Cumbria CAll 8HW United Kingdom

DELLINGER RP

Department of Anesthesiology University of Texas Medical Branch 610 Texas Ave Galveston, TX 77555 USA

Division of Critical Care Cooper University Hospital One Cooper Plaza Dorrance Building, Suite 393 Camden, NJ 08103 USA DE MENDOZA D

Critical Care Department Joan XXIII University Hospital Carrer Mallafre Guasch 4 43007 Tarragona Spain DE WAELE

JJ

Department of Intensive Care University Hospital De Pintelaan 185 9000 Ghent Belgium DEYE N Medical Intensive Care and Toxicology Hopital Lariboisiere 2, Rue Ambroise Pare 75010 Paris France

ENKHBAATAR P

ERTMER C Department of Anesthesiology and Intensive Care University Hospital Albert-Schweitzer-Str, 33 48149 Muenster Germany ESEN F Department of Anesthesiology and Intensive Care Medical Faculty of Istanbul University of Istanbul Capa Klinikleri 34093 Istanbul Turkey EVANS TW

Department of Critical Care Royal Brompton Hospital Sydney Street London, SW3 6NP United Kingdom

List of Contributors FAN

E

Department of Pulmonary and Critical Care Medicine Johns Hopkins University 1830 East Monument Street Baltimore, MD 21205 USA FERGUSON ND

Department of Critical Care Toronto Western Hospital 399 Bathurst Street, F2-150 Toronto, ON, M5T 2S8 Canada FERRERM

Pulmonology Service Institut Clinic del Torax Hospital Clinic Villarroel 170 08036 Barcelona Spain FINEMAN JR Cardiovascular Research Institute University of California San Francisco 513 Parnassus Avenue San Francisco, CA 94143 USA FLARING

U

Department of Anesthesia and Intensi ve Care Astrid Lindgren's Children Hospital Karolinska University Hospital Huddinge 14186 Stockholm Sweden FORCEVILLE X

Department of Intensive Care Centre Hospitalier de Meaux Hopital Saint Faron 6-8 Rue Saint Fiacre 77104 Meaux France

FRERICHS

I

Department of Anesthesiology and Intensive Care Medicine University Medical Center of Schleswig-Holstein Schwanenweg 21 24105 Kiel Germany GAJIC

a

Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Mayo Clinic 200 First Street SW Rochester, MN 55905 USA GANTER MT

Institute of Anesthesiology University Hospital Raemistr. 100 8091 Zurich Switzerland GONG MN

Department of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Mount Sinai Hospital 1190 Fifth Avenue New York, NY 10029 USA GOUREVITCH D

Department of Surgery University Hospital Birmingham NHS Foundation Trust Birmingham, B15 2TT United Kingdom GRANGER DN

Department of Molecular and Cellular Physiology Louisiana State University Health Sciences Center 1501 Kings Highway Shreveport, LA 71103-3932 USA

XV

XVI

List of Contributors

GRESSENS B Department of Intensive Care St-Pierre Para-Universitary Hospital Avenue Reine Fabiola 9 1340 Ottignies-Louvain-La-Neuve Belgium

HASSETT P Department of Anesthesia Clinical Sciences Institute National University of Ireland Galway Ireland

GRIFFITHS J Nuffield Department of Anesthetics John Radcliffe Hospital Headley Way Oxford OX3 9DU United Kingdom

HOFER CK Institute of Anesthesiology and Intensive Care Medicine Triemli City Hospital Birmensdorferstr. 497 8063 Zurich Switzerland

GROENEVELD ABJ Department of Intensive Care Vrije Universiteit Medical Centre De Boelelaan 1117 1081 HV Amsterdam Netherlands GUTIERREZ MEJIA J Department of Critical Care Toronto Western Hospital 399 Bathurst Street, F2-150 Toronto, ON, M5T 258 Canada HAMILTON M General Intensive Care Unit St George's Hospital Blackshaw Road London, SW17 OQT United Kingdom HAMMER L Department of Intensive Care Grenoble University Hospital BP 217 38043 Grenoble France HARDY JF Department of Anesthesiology Institut de Cardiologie 5000 Rue Belanger Est Montreal, QB HIT lC8 Canada

HOFSTRA II Department of Medicine Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam Netherlands HONORE PM Department of Intensive Care St-Pierre Para-Universitary Hospital Avenue Reine Fabiola 9 1340 Ottignies-Louvain-La-Neuve Belgium HOSTE EAJ Surgical Intensive Care Unit , 2k12-C Ghent University Hospital De Pintelaan 185 9000 Gent Belgium Hsu JH Department of Pediatrics Kaohsiung Medical University Hospital No. 100, Tzyou 1st Road Kaohsiung 807 Taiwan HULL AM Consultant Psychiatrist Murray Royal Hospital Perth, PH2 7BH United Kingdom ICHAi' P Department of Hepatobiliary Surgery Hopital Paul Brousse 12, Av. P.V. Couturier 94800 Villejuif France

List of Contributors INCE

C Department of Physiology Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Netherlands

KIRWAN C Department of Intensive Care St George 's University of London Rm 30, Jenner Wing Cranmer Terrace London, SW17 ORE United Kingdom

INTAGLIETTA M UCSD-Bioengineering 9500 Gilman Dr. La Jolla, CA 92093-0412 USA

KOCH JP

S Anesthesia and Critical Care Department Saint Eloi University Hospital 80 avenue Augustin Fliche 34295 Montpellier France JABER

JAKOB SM Department of Intensive Care University Hospital Inselspital 3010 Bern Switzerland

0 Department of Intensive Care Haut Leveque University Hospital University of Bordeaux II Avenue de Magellan 33604 Pessac France

JOANNES-BoYAU

JUNG B

Department of Anesthesia and Critical Care Saint Eloi University Hospital 80 avenue Augustin Fliche 34295 Montpellier France KHALILZADA

M

Department of Physiology Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Netherlands

Intensive Care Unit Kirchberg Hospital Rue E. Steighen, 9 2540 Luxemburg Luxemburg Kozr R Surgical Intensive Care Medicine University Hospital Pauwelsstr. 30 52074 Aachen Germany

A 1st Department of Critical Care University of Athens Medical School Evangelismos General Hospital 45-47 Ipsilandou St 10675 Athens Greece KOTANIDOU

KSOURI H Department of Intensive Care Centre Hospitalier Universitaire de Bicetre 78, rue du General Leclerc 94270 Le Krernlin-Bicetre France KUBIAK B

Department of Surgery Suny Upstate Medical University 750 East Adams Street Syracuse, NY 13210 USA LAFFEY JG

Department of Anesthesia Clinical Sciences Institute National University of Ireland Galway Ireland

XVII

XVIII List of Contributors

LAMIA B Department of Critical Care Medicine University of Pittsburgh Medical Center 606 Scaife Hall 3550 Terrace Street Pittsburgh, PA 15261 USA

LI G Pulmonary Department Guang An Mem Hospital Beijing China

LAUREYS S Coma Science Group Cyclotron Research Centre and Neurology Department University of Liege .:-Sart Tilman (B30) 4000 Liege Belgium

LOBO SM Division of Critical Care Medicine Department of Internal Medicine Medical School-FUNFARME and Hospital de Base Rua Antonio de Godoy 3548 Centro Sao Jose do Rio Preto - SP 15015-100 Brazil

LEAVER S Department of Critical Care Royal Brompton Hospital Sydney Street London, SW3 6NP United Kingdom

LUJAN M Department of Pneumology Corporacio Sanitaria Pare Tauli Pare Pauli sin 08208 Sabadell Spain

LEG RIEL S Department of Intensive Care Hopital Saint-Louis 1 Avenue Claude Vellefaux 75010 Paris France

MACPHEE I Department of Intensive Care St George's University of London Rm 30, Jenner Wing Cranmer Terrace London, SW17 ORE United Kingdom

LEONE M Department of Anesthesiology and Intensive Care Medicine Hopital Nord Chemin des Bourrely 13915 Marseille France LEPPER PM Department of Intensive Care University Hospital Inselspital 3010 Bern Switzerland LEVI M Department of Medicine Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam Netherlands

MALAM Z Division of Critical Care Room 4-007, Bond Wing St. Michael's Hospital 30 Bond Street Toronto, ON M5W 1B8 Canada MALBRAIN MLNG Department of Intensive Care ZNA Stuivenberg Lange Beeldekensstraat 267 2060 Antwerp Belgium MANCA T Pulmonary and Critical Care Medicine Feinberg School of Medicine, Northwesten University 240 E. Huron, McGaw Pavilion M-300 Chicago, IL 60611 USA

List of Contributors MANIATIS NA M. Simou Laboratory University of Athens Medical School Evangelismos General Hospital 3 Ploutarchou St 10675 Athens Greece

JC Division of Critical Care Room 4-007, Bond Wing St. Michael's Hospital 30 Bond Street Toronto, ON M5W IB8 Canada MARSHALL

MARTIN C Department of Anesthesiology and Intensive Care Hopital Nord Chemin des Bourrely 13915 Marseille France MARX G Department of Anesthesia and Intensive Care Medicine Friedrich Schiller University Erlanger Allee 101 07747 lena Germany MATEJOVIC M

151 Medical Department, ICU Chalres University Medical School and Teaching Hospital Alej svobody 80 30460 Plzen Czech Republic SA Neurological Intensive Care Unit Departments of Neurology and Neurosurgery Neurological Institute Columbia University Medical Center 710 West 1681h Street Box 39 New York, NY 10032 USA MAYER

MAYR FB CRISMA Department of Critical Care Medicine University of Pittsburgh School of Medicine 605 Scaife Hall 3550 Terrace Street Pittsburgh, PA 15261 USA MEERSSEMAN

W

Medical Intensive Care Unit University Hospital Herestraat 49 3000 Leuven Belgium MEGARBANE B Medical Intensive Care and Toxicology Hopital Lariboisiere 2, Rue Ambroise Pare 75010 Paris France MEISER

A

Anesthesiology Department St Josef-Hospital Gudrunstr. 56 44791 Bochum Germany SD Intensive Care Medicine Evangelismos Hospital 45-47 Ipsilandou Street 10675 Athens Greece MENTZELOPOULOS

MEURANT

F

Intensive Care Unit Kirchberg Hospital Rue E. Steighen, 9 2540 Luxemburg Luxembourg MISSANT C Department of Acute Medical Sciences Katholieke Universiteit Leuven Minderbroederstraat 19 - bus 7003 3000 Leuven Belgium

XIX

XX

List of Contributors MONNET X Department of Intensive Care Centre Hospitalier Universitaire de Bicetre 78, rue du General Leclerc 94270 Le Krernlin-Bicetre France

NIEMAN G Department of Surgery Suny Upstate Medical University 750 East Adams Street Syracuse, NY 13210 USA

A Department of Anesthesiology and Intensive Care University of Rome "La Sapienza" Via Barnaba Oriani 2 00197 Rome Italy

Pediatric Critical Care University of California 513 Parnassus Avenue, Box 0106 San Francisco, CA 94143 USA

MORELLI

MORGAN P

General Intensive Care Unit St. James' Wing St. George's Hospital Blackshaw Road London, SW17 OQT United Kingdom MULLER-WERDAN U Department of Medicine III Martin-Luther-University Halle- Wittenberg Klinikum Krollwitz Ernst-Grube-Str. 40 060097 Halle/Saale Germany NADKARNI VM

Department of Anesthesia and Critical Care Medicine The Children's Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, PA 19104 USA R Division of Critical Care Cooper University Hospital One Cooper Plaza Dorrance Building, Suite 393 Camden, NJ 08103 USA

NANDA

OISHI PE

ORAM

J

Department of Anesthesia and Intensive Care Leeds General Infirmary Gt. George St Leeds, LSI 3EX United Kingdom ORFANOS SE

2nd Department of Critical Care Medicine Attikon Hospital I, Rimini St. 12462 Haidari Greece OSIPOWSKA E

Department of Anesthesiology University Hospital of Brussels Laarbeeklaan 101 1090 Brussels Belgium OSMAN M

Department of Pediatric Surgery Ain Shams University School of Medicine Abbasya Square Cairo Egypt PALMIERI TL Dept of Surgery UC Davis Regional Burn Center and Shriners Hospital for Children 2425 Stockton Blvd., Suite 718 Sacramento, CA 95817 USA

List of Contributors

PANNEN B Department of Anesthesiology University Hospital Moorenstr. 5 40225 Dusseldorf Germany PARK DP Birmingham Heartlands Hospital Bordesley Green East Birmingham, B9 5SS United Kingdom PEEK GJ Cardiothoracic Surgery Glenfield Hospital Groby Road Leicester LE3 9QP United Kingdom PELLAS F Neurorehabilitation Medicin e Hopital Caremeau CHU 30029 Nimes France PELOSI P Department of Anesthesiology Ospedlae di Circolo e Fondazione Macchi Viale Borri 57 21100 Varese Italy PERKINS GD Warwick Medical School University of Warwick Coventry, CV4 7AL United Kingdom PHILIPS B Department of Intensive Care St George's University of London Rm 30, Jenner Wing Cranmer Terrace London, SW17 ORE United Kingdom

PINSKY MR Department of Critical Care Medicine University of Pittsburgh Medical Center 606 Scaife Hall 3550 Terrace Street Pittsburgh, PA 15261 USA PLOTZ FB Department of Pediatric Intensive Care Vrije Universiteit Medical Centre De Boelelaan 1117 1081 HV Amsterdam Netherlands POELAERT J Department of Anesthesiology University Hospital of Brussels Laarbeeklaan 101 1090 Brussels Belgium POLITO A Respiratory Muscle Laboratory Hopital Raymond Poincare Boulevard Raymont Poincare 104 92380 Garches France PRIEBE HJ Department of Anesthesiology University Hospital Hugstetter Str. 55 79106 Freiburg Germany RADERMACHER P Dept of Anesthesia University Hospital Parkstrasse 89073 Ulm Germany RAHMAN TM Department of Gastroenterology St George's Hospital Blackshaw Road London, SW17 OQT United Kingdom

XXI

XXII

List of Contributors REGUEIRA

T

REINHART

K

Department of Intensive Care Medicine University Hospital Inselspital 3010 Bern Switzerland Dept of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 103 07743 lena Germany RELLO

J

Critical Care Department Joan XXIII University Hospital Carrer Mallafre Guasch 4 43007 Tarragona Spain REX

S

Department of Anesthesiology University Hospital of the RWTH Pauwelsstrasse 30 52074 Aachen Germany REZENDE

E

Intensive Care Department Hospital do Servidor Publico Estadual Rua Pedro de Toledo 1800 Sao Paulo 040039901 Brazil RHODES

A

General Intensive Care Unit St. James' Wing St. George's Hospital Blackshaw Road London, SW17 OQT United Kingdom RIFAI

K

Department of Gastroenterology, Hepatology, and Endocrinology Medical School Carl Neuberg Strasse 1 30625 Hannover Germany

Rocco PRM Laboratory of Pulmonary Investigation Carlos Chagas Filho Biophysics Institute Federal University Rio de Janeiro Brazil RONCO

C

Department of Nephrology, Dialysis and Renal Transplantation San Bortolo Hospital Viale Rodolfi 37 36100 Vicenza Italy ROSSAINT R

Surgical Intensive Care Medicine University Hospital Pauwelsstr. 30 52074 Aachen Germany Roussos C Intensive Care Medicine Evangelismos Hospital 45-47 Ipsilandou Street 10675 Athens Greece SAKR

Y

Dept of Anesthesiology and Intens ive Care Friedrich-Schiller University Erlanger Allee 103 07743 lena Germany SALAZAR V A.ZQUEZ BY

UCSD-Bioengineering 9500 Gilman Dr. La Jolla, CA 92093-0412 USA SALIBA

F

Department of Hepatobiliary Surgery Hopital Paul Brousse 12, Av. P.v. Couturier 94800 Villejuif France

List of Contributors SAMU E L

D

Department of Hepatobiliary Surgery Hopital Paul Brousse 12, Av. P.V. Couturier 94800 Villejuif France SCHMIDT

H

SCHMIDT

JM

Department of Medicine III Martin-Luther-University Halle-Wittenberg Klinikum Krollwitz Ernst-Grube-Str. 40 060097 Halle/Saale Germany Neurological Intensive Care Unit Neurological Institute Columbia University Medical Center 710 West 168th Street Box 39 New York, NY 10032 USA SCHOLZ

J

Department of Anesthesiology and Intensive Care Medicine Universit y Medical Center of Schleswig-Holstein Schwanenweg 21 24105 Kiel Germany SCHOUTEN

M

Department of Medicine Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam Netherlands SCHUERHO LZ

T

Department of Anesthesia and Intensive Care Medicine Friedrich Schiller University Erlanger Allee 101 07747 lena Germany

SCH U LTZ

MJ

Department of Intensive Care Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam Netherlands C Dept of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 101 07747 lena Germany

SCHUMMER

W Dept of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 101 07747 lena Germany

SCHUMMER

DB Neurological Intensive Care Unit Departments of Neurology Neurological Institute Columbia University Medical Center 710 West 168th Street, Box 39 New York, NY 10032 USA

SEDER

SHARSHAR

T

Respiratory Muscle Laboratory Hopital Raymond Poincare Boulevard Raymont Poincare 104 92380 Garches France SIAM I S

Respiratory Muscle Laboratory Hopital Raymond Poincare Boulevard Raymont Poincare 104 92380 Garches France SORO

M

Department of Anesthesia and Critical Care Hospital Clinico Universitario Blasco Ibanez 17 46010 Valencia Spain

XXIII

XXIV

List of Contributors SPRONK PE Department of Intensive Care Academic Medical Center Meibergdreef 9 Il05 AZ Amsterdam Netherlands SQUARA

P

ICU CERIC Clinique Ambroise Pare 27, Bd Victor Hugo 92200 Neuilly-sur-Seine France

STEINSEIFER

U

Chair of Applied Medical Engineering University Hospital Pauwelsstr. 30 52074 Aachen Germany

SUPARREGUI DIAS F

Intensive Care Unit Hospital Sao Lucas da PUCRS Av. Ipiranga 6690 Porto Alegre 90610-000 Brazil SURI HS

Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Mayo Clinic 200 First Street SW Rochester, MN 55905 USA SUTTNER S

Department of Anesthesiology and Intensive Care Medicine Klinikum der Stadt Ludwigshafen Bremserstr. 79 67063 Ludwigshafen Germany

SZNAJDER JI

Pulmonary and Critical Care Medicine Feinberg School of Medicine, Northwesten University 240 E. Huron, McGaw Pavilion M-300 Chicago, IL 606Il USA

TAKALA J

Department of Intensive Care University Hospital Inselspital 3010 Bern Switzerland

TEBOUL JL

Department of Intensive Care Centre Hospitalier Universitaire de Bicetre 78, rue du General Leclerc 94270 Le Kremlin-Bicetre France TELCI L

Department of Anesthesiology and Intensive Care Medical Faculty of Istanbul University of Istanbul Capa Klinikleri 34093 Istanbul Turkey TETTA

C

International Research and Development Fresenius Medical Care Deutschland GmbH 61346 Bad Homburg Germany THOMSON SJ

Department of Intensive Care St George's Hospital Blackshaw Road London, SW17 OQT United Kingdom

THONGBOONKERD

V

Medical Molecular Biology Unit Office for Research and Development Faculty of Medicine Siriraj Hospital Mahidol University Bangkok Thailand TIMSIT JF

Department of Intensive Care Grenoble University Hospital BP 217 38043 Grenoble France

List of Contributors TOPJIAN A

Department of Anesthesia and Critical Care Medicine The Children's Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, PA 19104 USA TORRES A

Department of Pneumonology Institut Clinic del Torax Hospital Clinic Villarroel 170 08036 Barcelona Spain TRABER

D

Department of Anesthesiology University of Texas Medical Branch 610 Texas Ave Galveston, TX 77555 USA

VAN DER LINDEN

P

Department of Anesthesiology CHU Brugmann 4 Place Arthur Van Gehuchten 1020 Brussels Belgium PHJ Department of Intensive Care Onze Lieve Vrouw Gasthuis P.O. Box 95500 1090 HM Amsterdam Netherlands

VAN DER VOORT

VASCHETTO R

Faculty of Medicine University of Eastern Piedmont Novara Italy

VENKATESH B

TRABER

Department of Intensive Care Princess Alexandra & Wesley Hospitals University of Queensland 4066 Queensland Australia

TRESCHAN TA

Department of Anesthesiology University Hospital of Brussels Laarbeeklaan 101 1090 Brussels Belgium

L Department of Anesthesiology University of Texas Medical Branch 610 Texas Ave Galveston, TX 77555 USA

Department of Anesthesiology University Hospital Moorenstr. 5 40225 Dusseldorf Germany VALENCIA

M

Department of Pneumonology Institut Clinic del Torax Hospital Clinic Villarroel 170 08036 Barcelona Spain VAN ANTWERPEN

P

Pharmacy Institute Service de Chimie Pharmaceutique Organique BId du Triomphe Campus Plaine CP205/05 1050 Brussels Belgium

VERBORGH

C

VIEILLARD-BARON A

Department of Intensive Care Hopital Ambroise Pare 9 avenue Charles-de-Gaulle 92104 Boulogne France VUYLSTEKE A

Department of Anesthesia and Critical Care Papworth Hospital Cambridge, CB23 3RE United Kingdom

XXV

XXVI

List of Contributors

WEILER N Department of Anesthesiology and Intensive Care Medicine University Medical Center of Schleswig-Holstein Schwanenweg 21 24105 Kiel Germany WELCH LC Pulmonary and Critical Care Medicine Feinberg School of Medicine, Northwesten University 240 E. Huron, McGaw Pavilion M-300 Chicago, IL 60611 USA WERDAN K Department of Medicine III Martin-Luther-University Halle-Wittenberg Klinikum Krollwitz Ernst-Grube-Str. 40 060097 Halle/Saale Germany WERNERMAN J Department of Anesthesia and Intensive Care Karolinska University Hospital Huddinge 14186 Stockholm Sweden WESTPHAL M Department of Anesthesiology and Intensive Care University Hospital Albert-Schweitzer-Str, 33 48149 Muenster Germany WILMER A Medical Intensive Care Unit University Hospital Herestraat 49 3000 Leuven Belgium

WOUTERS PF Department of Anesthesiology Ghent University Hospital De Pintelaan 185 9000 Ghent Belgium YENDE S CRISMA Department of Critical Care Medicine University of Pittsburgh School of Medicine 605 Scaife Hall 3550 Terrace Street Pittsburgh, PA 15261 USA YOUNG PJ Department of Critical Care Medicine Queen Elizabeth Hospital Gayton Road King's Lynn, PE30 4ET United Kingdom YOUSSEF NCM Dept of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 103 07743 lena Germany ZAKYNTHINOS SG Department of Intensive Care Evangelismos Hospital 45-47 Ipsilandou Street 10675 Athens Greece

XXVII

Common Abbreviations

ALI ARDS BAL CBP CNS COPD CT CVP DIC DO z

EEG EKG HIV ICU IL LPS MAP MOF MRI NF-KB NO NOS PAC PAF PAl PAOP PARP PEEP RBC ROS ScvOz SIRS SOFA SvOz TLR TNF VILI VO z

Acute lung injury Acute respiratory distress synd rome Bronchoalveolar lavage Cardiopulmonary bypass Central nervous system Chronic obstructive pulmonary disease Computed tomography Central venous pressure Disseminated intravascular coagulation Oxygen delivery Electroencephalogram Electrocardiogram Human immunodeficiency virus Intensive care unit Interleukin Lipopolysaccharide Mean arterial pressure Multiple organ failure Magnetic resonance imaging Nuclear factor-kappa B Nitric oxide Nitric oxide synthase Pulmonary artery catheter Platelet activating factor Plasminogen activator inhibitor Pulmonary artery occlusion pressure Poly(ADP-ribose) polymerase Positive end-expiratory pressure Red blood cell Reactive oxygen species Central venous oxygen saturation Systemic inflammatory response syndrome Sequential organ failure assessment Mixed venous oxygen saturation Toll-like receptor Tumor necrosis factor Ventilator-induced lung injury Oxygen uptake

Section I

I Genetic Factors

1

3

Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients? C. KIRWAN, 1. MACPHEE, and B. PHILIPS

Introduction Drugs are administered to patients using dosing regimens established from animal data, clinical trials, and population studies . However, there may be enormous variation in dose requirement, efficacy, and adverse effects between individuals within a given population. Although this may partly be attributed to factors such as age, concomitant drug interactions, co-morbidities, and the underlying disease itself, genetic factors are estimated to account for 15- 30 % of between individual differences and for some drugs the impact of genetics may be much higher [1,2]. Genetic variation may influence all aspects of pharmacokinetics and pharmacodynamics and although the clinical relevance of pharmacogenetics remains uncertain, the idea is developing that some drug therapies may be individualized in the future. Historically genetic variations have needed to be dramatic to be noticed. For example, the inherited deficiency of gluose-6-phosphate dehydrogenase results in severe hemolysis if such patients are exposed to primaquine. This was clearly inherited as large population variation was observed between African (deficiency is common) and Caucasian (deficiency rare) patients . With the development of the Human Genome Project it has become possible to look for less dramatic genetic variations which if understood may have significant impact on the use and administration of drugs to individuals. This chapter will define pharmacogenetics and pharmacogenomics, describe how the science has evolved over the last few years, and attempt to highlight the possible impact the developments will have in the management of critically ill patients .

Pharmacogenetics or Pharmacogenomics? Historically, pharmacogenetics is the older term and emerged as individual variation in the pharmacokinetic and pharmacodynamic response to drugs became apparent [3- 5]. In general, pharmacogenetics identifies gene polymorphisms, which generate phenotypes of clinical importance. To be clinically relevant, these polymorphisms need to be either sufficiently common in the population or, if rare, of sufficient medical impact (e.g., the deletion of expression for pseudo-cholinesterase and the metabolism of succinylcholine) to alter clinical management. The development of the Human Genome Project [6] has coined the new term, pharmacogenomics. This term incorporates pharmacogenetics but has a rather broader meaning, describing the wider influence of DNA sequence variation on pheno type and the effect on drug handling and efficacy. Pharmacogenomics also includes

4

C. Kirwan, I. MacPhee, and B. Philips Table 1. Areas of pharmacology in which genetic polymorphism may alter a patient's risk of toxicity or therapeutic benefit Process

Target

Drug Example

Absorption

ATP-binding cassette B1 (ABCB1)

Phenytoin

Metabolism [Phase 1]

CYP2D6 CYP2C9

Codeine Wafarin

Metabolism [Phase 2]

Uridine diphosphate-glucuronosyltransferase (UGT1 A1) Thiopurine S- methyltransferase (TPMT)

Irinotecan Azathioprine

Excretion

Sodium lithium countertransport (SLC) transporters

Lithium

DNA repair

XRCC1

Oxaliplatin

Cellular target

~ rad re n o rece ptor

Asthma therapy

the application of genomic technologies to new drug discovery and further characterization of older drugs. Unlike other factors influencing drug response, inherited determinants generally remain stable throughout a person's lifetime ( Table 1).

Pharmacogenetics, Pharmacogenomics, and Drug Metabolism Phase I reactions (oxidation, reduction, and hydrolysis) and phase II conjugation reactions (acetylation, glucuronidation, sulfation, and methylation) are influenced by a number of genetic polymorphisms. Early discoveries include the metabolism of drugs such as succinylcholine and isoniazid or hydralazine. Four allelic genes coding for plasma cholinesterase cause wide variation in activity and therefore rate of hydrolysis of succinylcholine [7] and a common genetic variation in the phase II, N-acetylation, pathway causes large differences in the half-life and plasma concentrations of drugs metabolized by N-acetyltransferase including isoniazid, hydralazine, and procainamide. Currently, more than 30 families of enzyme complexes responsible for drug metabolism have been described in humans and numerous variations exist in the genes encoding the many enzymes and proteins. Several reviews illustrate the ways these variants may be clinically important [2, 8 -10] but the real clinical significance for most remains unstudied and uncertain. A clinical effect is most likely to be notable for drugs metabolized under predominately monogenic control and for those which possess narrow toxic or therapeutic ratios [2, 11-13], although significant haplotypes and frequent linkage disequilibria are also recognized. Although a number of different types of polymorphisms have been shown to influence drug response, single nucleotide polymorphisms (SNPs) are likely to be the most profitable in terms of pharmacogenomics analysis. SNPs are the most common variant class in the human genome with one occurring at approximately every 1000 base pairs. It is because these genetic variations are so common and technology exists for their rapid genotyping that SNPs are capable of revealing genomic variation on a scale which is not yet possible with other types of DNA polymorphism. One important clinical example found by this technique concerns the thiopurine methyltransferase (TPMT) gene. Approximately 100 SNPs have been identified on the TPMT gene but four in particular markedly increase the risk of bone marrow

Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients?

failure after administration of 6-mercaptopurine or azathioprine [14]. Other examples where data from SNP stud ies has suggested a clinical effect are found in the fields of gastroesophageal reflux, epilepsy, and human immunodeficiency virus (HIV) [15-17].

Clinically Relevant Genetic Polymorphisms in Critical Care Pharmacogenetics is a new science to critical care. The heterogeneity of patients and complexity of drug regimens makes investigation fraught with difficulty. The following is a selection of some of the more important systems that may have clinical significance. The Cytochrome P4S0 Isoenzymes

Approximately 12 cytochrome P450 (CYP) isoenzymes of families CYP1, CYP2, CYP3 are collectively respons ible for most phase I reactions in the human liver. Collectively they account for over 60 % of all drug elimination [18]. Alleles of the CYP enzymes are allocated a number. The wild type is allocated the number *1 and the terminology for an individual homozygous for the wild type allele (e.g., CYP3A4) would be CYP3A4 *1/*1. CYP3A Midazolam, a benzodiazepine commonly used in anesthesia and intensive care medicine, is exclusively metabolized by CYP3A. Enzymes in the CYP3A sub-family (CYP3A4 and CYP3A5) are the most abundant CYPs in the human liver. CYP3A4 is the most predominant form expressed in liver cells but CYP3A5 may contribute to more than 50 % of the hepatic CYP3A activity in the one third of the population that express both enzymes [19]. There is a large genetic variability in both of these enzymes and many different alleles have been described. A number are rare and many alleles of CYP3A4 have little or no significance on endogenous substrate metabolism [20, 21]. CYP3A5 is, however, more significant. Polymorphic CYP3A5 expression is strongly correlated with a single nucleotide change, designated CYP3AS *3 [22]. Volunteers who are homozygous (CYP3AS *3/*3) for the CYP3A allele showed marked loss of enzyme activity and thus midazolam clearance, when given midazolam in the presence of itraconazole (CYP3A4 and CYP3A5 inhibitor) [19, 23] and can be considered funct ional non-expressers. For patients undergoing solid-organ transplant, the CYP3AS *3/*3 genotype confers a lower dose requ irement of tacrolimus for both loading and maintenance. Patients with CYP3AS *1/*1 or *1/*3 have a delay in achieving target blood tacrolimus concentrations and genotyping may help in the initial dosing of tacrolimus after transplantation [24]. CYP2B6 CYP2B6 is one of the most polymorphic CYP genes in the liver with over 100 SNPs described, numerous complex haplotypes, and distinct ethnic frequencies. Its expression in the liver is highly variable with some individuals expressing more than 100 fold more enzyme than others [18]. CYP2B6 has not been extensively investigated but clinical substrates include cyclophosphamide, anti retrov irals, synthetic opioids (e.g., methadone), and propofol [25].

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C. Kirwan, I. MacPhee, and B. Philips

CYP2C9 Warfarin therapy is complicated by significant interpatient variability in sensitivity leading to significant risk of both under and overdosing and potential harm to each patient. Consequently, warfarin regimens require regular prothrombin time (PTT) testing, especially on the initiation of therapy. This difficulty in predicting individual requirements may be, in part, attributable to inherited differences in metabolism [26,27] . Warfarin is hydroxylated to an inactive metabolite by CYP2C9 [27]. Carriers of CYP2C9 variants have significantly lower dose requirements for warfarin relative to individuals with wild-type genotypes . The presence of these variants in conjunction with clinical factors has been found to account for 26 % of the interpatient variation in warfarin dosing requirements [28, 29]. CYP2C19 CYP2C19 was originally identified as the enzyme responsible for the metabolism of phenytoin and has since had the metabolism of the proton pump inhibitors attributed to it. Alleles conferring reduced enzyme activity are observed with high frequency in a number of races including up to 23 % of Asians and 8 % of Caucasians and black Africans. Seven variants associated with reduced activity have been identified with CYP2C19*2 and *3 being the most common. Patients homozygous for the wild type gene have a poorer response to standard proton pump dosing than patients with the variant genes. This difference is measurable in terms of gastric pH with higher pH values being observed in patients with reduced CYP2C19 activity. CYP2D6 CYP2D6 is the most widely studied enzyme of all the CYP450 isoenzymes and many drugs are substrates, including dihydrocodeine, tramadol, tricyclic antidepressants, some ~-blockers, antipsychotics, and antiarrhythmics. Before genotyping became readily achievable, phenotypic description based on the metabolism of sparteine divided people into extensive metabolizers, poor metabolizers, and ultrarapid metabolizers. Approximately 7 to 10 % of European Caucasians are poor metabolizers compared with 1 % of Chinese and Japanese. Alleles CYP2D6*3, *4 and *5 produce inactive enzyme [18]. However, CYP2D6 activity is generally lower in Chinese than Europeans because of the CYP2D6*10 allele, expressed in 50 % of the Chinese population. Conversely in black Ethiopians, gene duplication gives rise to the ultrarapid metabolizer phenotype in 29 % of the population. Not all of these variations will confer significant clinical effect but there are some important examples. Tramadol has an active metabolite and possibly greater opioid effect (including adverse effects) in patients with the poor metabolizer phenotype, but may be less efficacious or even ineffective in patients with the ultralipid metabolizer phenotype. Similarly, metoprolol efficacy may be enhanced with the poor metabolizer phenotype as may the effect of antipsychotics when given in standard doses [18]. Adrenoreceptors

Polymorphisms in the receptor genes of both ~- and a -adrenoceptors have been shown to affect cardiac function and response to drugs [30, 31]. A polymorphism in the ~1 receptor gene with the substitution of glycine (Gly389) for arginine (Arg389), if found in association with a genetic variant of the a 2-adrenoceptor (deletion of 4 consecutive amino acids [a2cDeI322-325]), is strongly linked to the development of congestive heart failure both in transgenic mouse models and humans [30, 31]. The

Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients? ~lArg389 genotype has an enhanced response to ~-adrenoceptor agonists conferring a 200 % increase in agonist stimulated activity [30, 31]. The u2cDel322-325 has a substantially decreased agonist function, with the normal negative feedback mechanisms to the release of norepinephrine inhibited. This combined effect may account for the associated increased risk of heart failure secondary to sustained adrenergic activation . The implication to critical illness and the use of adrenergic agonists or antagonists is yet to be studied. A variety of polymorphisms of the ~2-adrenoceptor with potential clinical importance have been observed. The normal desensit ization and hypo-responsiveness of the ~2-adrenoceptor with continuous exposure of vascular endothelium to agonists is exaggerated in patients with a substitution of Gly for Arg at position 16 [32]. This polymorphism has strong linkage disequilibrium with position 27, where a substitution of glutamic acid (Glu) for glutamine (GIn) confers enhanced vasodilatation in response to agonists. Individuals homozygous for Arg16 show rapid desensitization to agonist mediated vasodilatation and those homozygous for Glu27 show enhanced agonist-mediated vasodilatation [32]. These are not uncommon alleles. Of 400 volunteers (ethnicity unclear) in America, 25 % were homozygous for Arg16 and Gln27, 12 % for Gly16 and Glu27, and 8 % for Gly16 and Gln27 [32]. Again, the impact of the alleles on patient outcome in critical care remains uncertain. A perhaps rarer (0.5-2.3 % population) but better understood polymorphism of the ~2-adrenoceptor is the substitution of isoleucine (He) for threonine (Thr) at position 164. This allele has been known for some time to be associated with decreased survival from heart failure. More recently it has been shown that Hel64 confers a markedly decreased response in vivo to ~2 agonists, blunt ing vasodilatation and indirectly enhancing u j-adrenoceptor sensitivity [33].

Other Polymorphisms with Potential Clinical Importance in Critical Care One of the most serious adverse reactions to heparin is heparin-induced thrombocytopenia (HIT) with the potential to cause severe thromboembolic complications and death. Heparin induced antibodies recognize and bind to heparin-platelet factor 4 complexes and subsequently activate platelets via the platelet Fc y-receptor to mediate HIT. A single-nucleotide polymorphism commonly occurs in the platelet Fe yreceptor gene affecting platelet aggregation [34] and an association between the platelet-Fe y-receptor gene and the risk for HIT has been reported by some investigators [34, 35], although not all [36]. The largest of these studies included 389 patients with a history of HIT, 351 patients with a history of thrombocytopenia or thrombosis due to other causes, and 256 healthy blood donors [35]. The results suggested that the codon 131 genotype of the platelet Fc v-receptor increases the risk of HIT and worsens its clinical outcome. In the future , it may be possible to genotype candidates for heparin therapy to ident ify those at risk for drug-induced thromboembolic complications, in whom more intensive patient surveillance or alternative anticoagulant therapy may be used. Digoxin is a substrate for P-glycoprotein (P-gp), an adenosine triphosphatedependent drug efflux pump. Recently, P-gp has been implicated in a number of pharmacokinetic interactions [37]. For example, an increase in serum digoxin concentration after the initiation of amiodarone and quinidine therapy occurs secondary to inhibition of P-gp in both the intestines and renal tubules, increasing digoxin absorption and decreasing total-body digoxin clearance respectively. P-gp is encoded by the multidrug resistance gene (ABCBl or MDR-l), located on the long

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C. Kirwan, I. MacPhee, and B. Philips

arm of chromosome 7. Sixteen SNPs have so far been identified in the ABCBl gene [38]. Most of the polymorphisms do not change the encoded amino acid or occur in non-coding introns. However, one polymo rphism (g.3435>/T) has been associated with the expression of P-gp in the intestines [39]. A study of healthy volunteers showed those with the TIT genotype had a twofold lower expression of P-gp than those with the CIC genotype [40]. This should result in higher blood or tissue concentrations of digoxin (and other drugs that are P-gp substrates) in individuals with the TIT genotype . This was confirmed in a study where subjects with the TIT genotype had plasma digoxin levels 38 % greater than the maximum concentration in subjects with the CIC genotype; this difference was significant [40]. Thus, patients with the TIT genotype may require lower dosages of drugs that are P-gp substrates to maintain therapeutic concentrations. Alternatively the CIC homozygote, through increased expression of P-gp, may have sub-therapeutic concentrations of P-gp substrates and consequently experience underdosing. However, there is some controversy as to the reproducibility of this genotype-phenotype association. The main phenotypic characteristic of ABCBl knockout mice is the loss of the blood-brain barrier to drugs [41]. Genetically determined low levels of P-gp expression may predispose to neurotoxicity. Morphine is conjugated with glucuronic acid by the enzyme UDP-glucuronosyltransferase 2B7 (UGT2B7), to form the active and potent metabolite , morphine-Sglucuronide (M6G) and the inactive metabolite morphine-s -glucuronide (M3G) [42]. Following glucuron idation, metabolites are eliminated by glomerular filtration. Allelic variants in the genes encoding for UGT2B7 [43], opioid receptors (OPRMl gene) [44], or the transporter proteins for transport across the blood brain barrier (ABCBl gene) [45] influence the pharmacokinetics and pharmacodynamics and, thus, the clinical efficacy of morphine. Furthermore, genetic variability in the nonopioid system, such as the catecholamine metabolizing enzyme, catechol-O-methyltransferase (COMT), although not directly involved in morphine metabolism , can also modify the efficacy of morphine [46]. Response to steroids may similarly be affected by polymorphisms. Mutations of the glucocorticoid receptor gene (GR-gene) have been associated with cort icosteroid resistan ce possibly having wide ranging effects on metabolism, immune function, and response to stress [47].

Population Variations in Pharmacogenetics (Table 2) Some genotype frequencies appear to be highly dependent on the ethnicity of the population studied. This broad picture of expression can allow some pharmacogenetic therapeutic assumptions to be made without individual knowledge of phenotype but, perhaps more importantly, it gives the clinician an indication to look more closely within certain populations for specific pharmacogenetic polymorphisms when certain drugs are being considered. This is demonstrated very clearly as part of the investigation into polymorphisms of P-gp. Ameyawand colleagues [48] examined 1280 subjects from 10 ethnic groups. The frequency of the 3435T allele in the ABCBl gene (associated with lower expression of P-gp) was significantly influenced by ethnicity. The T allele frequency was 0.16 in the African-Americans, 0.52 in the Caucasians, and 0,47 in the Chinese. In support of this, a study of another P-gp substrate, tacrolimus, revealed that African-Americans had lower plasma concentrations of tacrolimus than white subjects given equal dosages [49].

Are Pharmacogenetics and Pharmacogenomics Important for Critically 11/ Patients? Examples of population variation in clinically important pharmacogenetic polymorphisms Drug Metabolizing Enzyme

Example of Drug Metabolized

Frequency of Poor Metabolism Phenotype Variant

N- acetyltransferase 2 (NAT2)

Procainamide

52 % White American 17 % Japanese

Uridine diphosphate - glucuronosyltransferase (UGT1A1)

Irinotecan

10.9 % Whites 4 % Chinese 1 % Japanese

Thiopurine S-methyltransferase (TPMT)

Azathioprine

1:300 Whites 1:2500 Asians

Catechol-O-methyltransferase (COMT)

Levodopa

25 % Whites

Challenges to Implementing Pharmacogenetics in Critically III Patients The concept that all drug dosing regimens would benefit from routine genotyping is likely to remain unfounded. The number of variables affecting pharmacokinetics and pharmacodynamics means that for most drugs the value of genotyping will be low. The most obvious question perhaps is why bother with genotyping when therapeutic monitoring is possible. Pharmacogenetics is most likely to have a role when considering drugs for which speed of reaching therapeutic concentrations is important (e.g., tacrolimus, phenytoin) or for drugs with narrow therapeutic ranges and high toxicity. There may be legal and ethical considerations to genomic-based therapeutics and pharmacogenetics but specific directed genotyping , perhaps based on ethnicity may be warranted. For clinical trials pharmacogenetics may prove a fundamental tool. The main difficulty remains in quantify ing the contribution of genetic variation to inter-individual differences in drug metabolism in critically ill patients. All studies will be confounded by other factors that influence drug absorption, elimination and action , including pre-existing disease and interaction with co-administered medications. Undoubtedly the stress response to critical illness contributes to altered drug effect, for example, through altered protein binding. The liver and especially the kidneys are often affected by critical illness and both of these have fundamental roles in the metabolism and excretion of drugs. Data from patients with chronic renal failure suggest the presence of a circulating cytokine that inhibits the metabolic action of the CYP3A enzymes [50] with the possibility that patients with certain phenotypes will be more affected than others [19]. This effect could be further complicated by some of the treatments we instigate. The cytokine is suggested to be somewhere between 10 and 15 kDa in size and not altered or removed by hemodialysis [50] but so far, no study has been done to see if it passes through the membrane of hemofiltration or hemodiafiltration. As a consequence of these difficulties, the majority of studies examining the influence of genetic variation on drug effect have focused on patients outside the intensive care unit (lCU) and typically in non-hospitalized individuals. However, if validated, the effective use of some drugs whose efficacy and safety appear to be affected by polymorphisms may be improved by pharmacogenetic studies.

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C. Kirwan, I. MacPhee, and B. Philips

Conclusion The practical value of pharmacogenetics to clinical medicine is still debatable for most drugs . However, as the human genome project develops, more polymorphisms of potential importance will be revealed, particularly for drugs where precise dosing is important for efficacy and to avoid toxicity or where rapidity in achieving target therapeutic concentrations is required. Nevertheless, the long-term prospects for critical care pharmacogenetics are still unclear. The application of pharmacogenetics to the understanding of differences in drug actions in non-acutely ill populations could provide insight into how to investigate these effects in patients requiring critical care. It would seem logical to investigate drugs with narrow toxic and therapeutic ranges, and in which genetic variation correlates highly with either drug tolerance or risk of toxicity. It may also be worth concentrating on disease processes and treatments, common to critical care, which may exaggerate the effect of some polymorphisms (e.g., acute renal failure and renal support). For drugs that are well tolerated and efficacious over a broad range of serum concentrations, in depth studies of pharmacogenetics are unlikely to yield benefit but for others there may be benefit and it may not be long before bedside genotyping is available to aid in clinical prescribing. References 1. Evans WE, Reiling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429:464-468 2. Weinshilboum R (2003) Inheritance and drug response. N Engl J Med 348:529-537 3. Evans WE, Johnson JA (2001) Pharmacogenomics: the inherited basis for inter individual differences in drug response. Annu Rev Genomics Hum Genet 2:9- 39 4. Evans WE, Reiling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487-491 5. McLeod HL, Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41:101-121 6. Lander ES, Linton LM, Birren B, et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860-921 7. Kalow W (1956) Familial incidence of low pseudocholinesterase level. Lancet 2:576 8. Evans WE, McLeod HL (2003) Pharmacogenomics - drug disposition , drug targets , and side effects. N Engl J Med 348:538- 549 9. Roses AD (2000) Pharm acogenetics and the practice of medicine. Nature 405:857-865 10. Wilkins MR, Roses AD, Clifford CP (2000) Pharmacogenetics and the treatment of cardiovascular disease. Heart 84:353-354 11. Higashi MK, Veenstra DL, Kondo LM, et al (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287:1690-1698 12. Kalow W (1997) Pharmacogenetics in biological perspective. Pharmacol Rev 49:369- 379 13. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225 - 229 14. Evans WE (2004) Pharm acogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 26:186-191 15. Lanfear DE, Marsh 5, Cresci 5, Spertus JA, McLeod HL (2004) Frequency of compound genotypes associated with beta-blocker efficacy in congestive heart failure. Pharmacogenomics 5:553-558 16. Quirk E, McLeod H, Powderly W (2004) The pharmacogenetics of antiretroviral therapy: a review of stud ies to date. Clin Infect Dis 39:98- 106 17. Siddiqui A, Kerb R, Weale ME, et al (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCBI. N Engl J Med 348:1442 -1448 18. Gardiner SJ, Begg EJ (2006) Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharm acol Rev 58:521- 590

Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients? 19. Kuehl P, Zhang J, Lin Y, et al (200l) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383-391 20. He P, Court MH, Greenblatt DJ, Von Moltke LL (2005) Genotype -phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 77:373-387 21. Ng FL, Holt DW, MacPhee IA (2007) Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation. Expert Opin Pharmacother 8:2045-2058 22. Hustert E, Haberl M, Burk 0, et al (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11:773-779 23. Yu KS, Cho JY, lang IJ, et al (2004) Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther 76:104-112 24. Reiling MV, Hoffman JM (2007) Should pharmacogenomic studies be required for new drug approval? Clin Pharmacol Ther 81:425-428 25. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M (2007) Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 8: 743-759 26. Furuya H, Fernandez-Salguero P, Gregory W, et al (1995) Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 5:389- 392 27. Takahashi H, Kashima T, Nomizo Y, et al (1998) Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes . Clin Pharmacol Ther 63:519-528 28. Freeman BD, McLeod HL (2004) Challenges of implementing pharmacogenetics in the criti cal care environment. Nat Rev Drug Discov 3:88-93 29. Tabrizi AR, Zehnbauer BA, Borecki 1B, McGrath SD, Buchman TG, Freeman BD (2002) The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coli Surg 194:267- 273 30. Mialet Perez J, Rathz DA, Petrashevskaya NN, et al (2003) Beta l -adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 9: 1300-1305 31. Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002) Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347:1135-1142 32. Dishy V, Sofowora GG, Xie HG, et al (200l) The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 345: 1030-1035 33. Dishy V, Landau R, Sofowora GG, et al (2004) Beta2-adrenoceptor Thr164I1e polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo. Pharmacogenetics 14:517-522 34. Burgess JK, Lindeman R, Chesterman CN, Chong BH (1995) Single amino acid mutation of Fc gamma receptor is associated with the development of heparin-induced thrombocytopenia. Br J Haematol 91:761-766 35. Carlsson LE, Santoso S, Baurichter G, et al (1998) Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism. Blood 92:1526-1531 36. Arepally G, McKenzie SE, Jiang XM, Poncz M, Cines DB (1997) Fc gamma RIIA H/R 131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis. Blood 89:370-375 37. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM (1999) Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quin idine. Circulation 99:552- 557 38. Cascorbi I, Gerloff T, [ohne A, et al (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDRl gene in white subjects . Clin Pharmacol Ther 69:169-174 39. Min DI, Lee M, Ku YM, Flanigan M (2000) Gender-dependent racial difference in disposition of cyclosporine among healthy African American and white volunteers . Clin Pharmacol Ther 68:478-486

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C. Kirwan, I. MacPhee, and B. Philips 40. Hoffmeyer 5, Burk 0 , von Richter 0, et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variat ions and correlation of one allele with Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473- 3478 41. Schinkel AH, Smit H, van Tellingen 0 , et al (1994) Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drug s. Cell 77:491-502 42. Coffman BL, Rios GR, King CD, Tephly TR (1997) Human UGT2B7 catalyzes morph ine glucuronidation. Drug Metab Dispos 25:1-4 43. Duguay Y, Baar C, Skorpen F, Guillemette C (2004) A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther 75:223- 233 44. Klepstad P, Rakvag TT, Kaasa S, et al (2004) The 118 A > G polymorphism in the human muopioid receptor gene may increase morphine requirements in patient s with pain caused by malignant disease. Acta Anaesthesiol Scand 48:1232-1239 45. Meineke I, Freudenthaler S, Hofmann U, et al (2002) Pharmacokinetic modelling of morphine , morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Clin Pharmacol 54: 592-603 46. Rakvag TT, Klepstad P, Baar C, et al (2005) The Va1l58Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients . Pain 116:73 -78 47. DeRijk RH, Schaaf M, de Kloet ER (2002) Glucocortico id receptor variants : clinical implication s. J Steroid Biochem Mol Bioi 81:103-122 48. Ameyaw MM, Regateiro F, Li T, et al (2001) MDRI pharmacogenetics: frequen cy of the C3435T mutat ion in exon 26 is significantly influenced by ethnicity. Pharm acogenetics 11: 217-22 1 49. Mancinelli LM, Frassetto L, Floren LC, et al (2001 ) The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther 69:24-31 50. Michaud J, Dube P, Naud J, et al (2005) Effects of serum from patien ts with chronic renal failure on rat hepati c cytochrome P450. Br J Pharmacol 144:1067-1077

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Genetic Susceptibility in ALIIARDS: What have we Learned? R. CARTIN-CEBA, M.N . GONG, and O. GAJIC

Introduction Since its initial description in 1967 [1], and subsequent defin ition in 1992 by the American-European Consensus Conference [2], acute lung injurylacute respiratory distress syndrome (ALI/ARDS) and all the different facets of this devastating illness - etiology, pathophysiology, epidemiology, management, and genetics - have become better understood. Recent reports from the United States document that this syndrome affects 190,000 patients annually with a mortality exceeding 35 % [3]. The incidence in European countries and Australia varies significantly, but is generally lower, rang ing from 16 to 34 cases per 100,000 person-years at risk [4-6]. While several environmental risk factors clearly predispose to the development of ALI/ARDS [7], the expression of the syndrome and its attributable morbidity and mortality are highly variable. A growing interest in genetic epidemiology and genomics in critical illness is illustrated in a prophetic statement by Villar et al. back in 2001: "Critical care medicine in the 21'1 Century: from CPR (cardiopulmonary resuscitation) to PCR (polymerase chain reaction)"[8] . The exponential growth of genomic studies has had a positive impact on the understanding of genetic determinants in the development and outcome of critical care syndromes as well as on the understanding of underlying pathophysiologic mechanisms. Most studies have focused on the genetic background of sepsis-septic shock and ALII ARDS. In ALI/ARDS, multiple biologically plausible candidate genes have been identified. However, ALI/ARDS is a complex syndrome where alterations in single genes are unlikely to explain the abnormal processes involved in alveolar permeability edema and inflammation that characterize this syndrome. Unfortunately, most of the studies have been limited by design/analysis, definition of an appropriate phenotype and controls, and ethnic/racial disparities. For the intensivist taking care of patients with ALII ARDS, the main questions regarding genomics in this disease are: 1) Can a genetic marker identify patients who are more susceptible to develop ALIIARDS? 2) Can a genetic marker identify patients who are more or less likely to respond to a specific therapy? 3) Can a genetic marker identify patients who are more likely to do poorly so that a prognosis can be discussed with the patient and family? Researchers interested in ALII ARDS look for potential new insights into the pathogenesis of this syndrome, so that more effective treatment approaches may be developed. The aim of this chapter is to review the advances in knowledge about candidate genes implicated in the development and prognosis of ALII ARDS. We will also describe the challenges and limitations of genetic epidemiology study designs and outl ine important steps that future studies ought to consider in order

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R. Cartin-eeba, M.N. Gong, and O. Gajic

to provide the answers to the clinical and research questions related to critical illness.

Basic Principles of Genomic Association Studies Related to Critical Care Syndromes Rather than a disease of a single etiology, ALIIARDS is a heterogeneous syndrome and, as such, presents important challenges for genomic association studies . Most of the initial molecular studies in ALIIARDS were focused on protein biomarkers, of which several have been associated with the development and prognosis of ALII ARDS, including surfactant protein B [9], tumor necrosis factor (TNF)-a [10], interleukin (IL)-6 and IL-l [11], von Willebrand's factor antigen [12], and plasminogen activator inhibitor (PAI)-1 [13]. The main objectives of trying to identify genetic markers in ALI/ARDS are: Assessment of susceptibility (which patients exposed to common triggers of ALI/ARDS will develop the syndrome); prognostication of outcomes (which patients will have worse outcomes); and what intervention can be made based on the genetic abnormalities (what abnormal pathway can be intervened on in a successful manner to improve outcomes of this critical disease). Many questions related to the objectives outlined above are still unanswered: Why do some patients with sepsis develop ALIIARDS while others do not? Why do some patients with ALI/ARDS develop multiple organ failure (MOF) and others do not? Can we predict patients at high risk of developing ALI/ARDS and/or poor outcome based on the genetic background? What is the interaction between the environment and the genome for the developing of ALIIARDS? Why are some pat ients more susceptible to adverse reactions of treatments, such as ventilator-associated lung injury (VALI)? Given the problems and questions outlined above, a genomic approach was hindered by the Human Genome Project that was finished in 2001 [14]. The number of genes existing in the human DNA code was found to be around 25,000 [14]. This project helped to identify around 10 million common single nucleotide polymorphisms (SNPs). SNP is a DNA variant that represents a variation in a single base and is used to describe the genetic variation between individuals. In 2003, the Hap Map project [15] was started in order to determine the SNPs that contain the most patterns of human genetic variation, which is estimated to decrease the number of significant SNPs to about 300,000 to 600,000. Gene expression and function has been studied by approaching one gene and analyzing its phenotype (either diseased or not) in diseases with classic Mendelian inheritance. This process is not adequate for analysis of complex and heterogeneous syndromes such as ALIIARDS, where multiple interactions exist between different genes and environmental exposures. Furthermore, as a syndrome that has emerged only recently with the advance of life support interventions, ALIIARDS is not known to be a disease that presents as a familial cluster or familial aggregation; therefore, linkage mapping studies have not yet been possible or have very limited value in the search of candidate genes in ALIIARDS. Lastly, the advanced age of most patients with ALIIARDS limits the availability of parents and even siblings for family based association studies . Given these limitations, candidate gene-based unrelated casecontrol studies are the most common approach utilized in the search of genetic susceptibility to ALI/ARDS. In such stud ies, a genetic variant is genotyped in a population for which phenotypic information is available (ALI/ARDS) . If a correlation is

Genetic Susceptibility in ALIIARDS: What have we Learned?

observed between genotype and phenotype, there is said to be an association between the variant and the disease. This method usually consists in comparing SNPs of genes with potential biological plausibility between unrelated cases of ALII ARDS and adequate controls . The most common candidate genes used are related to the mechanisms and the pathophysiological pathways known to be present in ALII ARDS, such as inflammation, water-ion transport and membrane permeability, regulation of cell proliferation, immune responses, coagulation, cell motility and chemotaxis. Clinical observations and the presence of biomarkers of the disease that connect different biological pathways related to ALIIARDS have been the main source for potential gene candidates in ALI/ARDS [16]. Most of the gene candidates associated with ALI/ARDS have also been associated with sepsis and septic shock, which confirms the close linkage between these two common critical syndromes. Once the candidate genes are selected, two different approaches can be made in order to document a significant association of the gene and its phenotype. The approach most commonly used focuses on the association between ALIIARDS and specific polymorphisms (most commonly SNPs) in the candidate gene that has a biological relationship with the pathophysiological mechanisms of the disease. The second approach examines all common SNPs in the gene as a haplotype (haplotypes are closely related variants that are inherited as a unit), regardless of whether the SNPs have any pathophysiological significance with ALII ARDS [17]. The most common candidate genes that have been implicated in ALI/ARDS and their presumed functional roles are summarized in Table 1. The candidate gene approach has been moderately successful in the discovery of genetic predisposition of ALII ARDS; however, this complex syndrome possibly has many susceptibility loci in which the discovery of one association from a candidate gene, even if true , may only reveal a small part of the genetic predisposition [18]. For that reason, genome wide studies might become the preferred method to determine associations given their capability to provide analysis of millions of SNPs, taking advantage of linkage disequilibrium and allowing the discovery of wide-spread genetic variation [19]. The technical aspect of this approach is becoming more realistic. The main caveat with genome-wide testing in ALII ARDS has to do with power and multiple testing. With genome wide testing, many SNPs will have low pretest probability and the risk of false positives from multiple testing is quite substantial. Given our current biost atistical methods in adjusting for multiple comparisons, the fact that ALIIARDS is not an epidemiologically common disease and the likelihood that an estimated relative risk will be modest (except maybe in subgroups of patients), it is difficult to have an adequately large sample size in a reasonable amount of time to perform a genome-wide association study with hundreds of thou sands of SNPs [20, 21]. If we consider that in ALI/ARDS there are possible geneenvironment interactions, the sample size requirements will increase further. Such a large sample size will also make it extremely difficult for the results to be validated in another population. Besides the approaches described above, another approach that may be more realistic for ALI/ARDS is a candidate pathway-based association study where particular focus is placed on SNPs that blanket only those genes in a particular pathway (inflammation or coagulation, for example) that are highly likely to be important in ALI/ARDS. Utilizing this approach, the number of SNPs examined is limited and, therefore, the likelihood of false positives diminishes. Such studies have already been done in other diseases such as age-related macular degeneration [22] and lung cancer [23].

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R. Cartin-(eba, M.N. Gong, and O. Gajic Table 1. Candidate genes implicated in acute lung injury (AlI)/acute respiratory distress syndrome (ARDS) CandidateGene

Gene symbol

Presumed funcAssociation in ALIIARDS tional role in ALII ARDS pathogenesis

Tumor necrosis factor a and ~

TNF-a and TNF- ~

Inflammation/ Immune response

-308GA in TNF-a polymorphism, but not the TNFBI2, was associated with increased mortality in ARDS [38].

Mannosebinding lectin-2

MBL-2

Inflammation/ Immune response

MBL-2 codon 54BB genotype conferred increased severity of illness, increased development of ARDS, more multiple organ failures after development of ARDS, and increased mortality in ARDS [39].

Inflammation/ Immune response

Haplotypes located in the 3' end of the MIF gene were associated with ALI [40].

MIF Macrophage migration inhibitory factor Angiotensin converting enzyme

ACE

Vascular permeability, vascular tone, fibroblast activity

The D allele is associated with increased mortality and/or susceptibility to ARDS [41, 42].

Clara cell protein 16

CC16

Chemotaxis

CC16 -26G>A polymorphism does not affect the susceptibility to or the outcome from ARDS [43].

Myosin light chain kinase

MYLK

Chemotaxis /cell motility

ALI-specific risk conferring haplotypes of the MYLK gene [44].

Pre-Bxell colony enhancing factor

PBEF

Inflammation/ Immune response

C-1543T variant allele and related haplotype are associated with better outcomes [45]. T-l001G variant allele was associated with development of ARDS [45].

Vascular endothelial growth factor

VEGF

Vascular permeability

+936TT and +936U+TT genotypes of the VEGF gene are significantly associated with an increased risk of mortality from ARDS [46].

Interleukin 6

IL-6

Inflammation/ Immune response

C allele and CC genotype frequencies were significantly reduced in ARDS [47].

Interleukin 10

IL-l0

Inflammation/ Immune response

-1082GG genotype associated with lower 60-day mortality in ARDS [48].

Surfactant protein-B

5FTPB

Vascular permeability and surface tension

Intron 4 SP-B gene variant increases susceptibility to ARDS in women [49].

Inhibitor K~-a

IKB-a

Inflammation/ Immune response

Haplotype GTC of the IKB-a gene was associated with increased susceptibility to ARDS [50].

Genetic Susceptibility in AWARDS: What have we Learned?

limitations of Genomic Association Studies Related to Critical Care Syndromes As stated in the introduction, ALII ARDS is a very complex syndrome where alterations in single genes are unlikely to explain all the abnormal processes involved in alveolar permeability, alveolar edema, and inflammation seen in this devastating disease, and presents important challenges for genomic associations. We want to accentuate that because ALIIARDS is not yet known to be a syndrome that presents as a familial trait, linkage mapping may not yet be possible or have very limited value in the search of candidate genes in ALIIARDS. All studies thus far have utilized the candidate gene-based association approach . It is important to emphasize that the biologic plausibility of the candidate gene in the pathogenesis of ALIIARDS is important and must have evidence supporting the importance of the gene product or function specifically in ARDSIALI [17). Some of the reasons why genetic studies of ALIIARDS are challenging include: 1) Significant phenotypic variance in critically ill patients ; 2) incomplete gene penetrance; 3) complex gene-environment interactions; and 4) a high likelihood for locus heterogeneity [24]. Most of the limitations arise from study design. An adequate study design that fulfills quality criteria to be applied in genetic epidemiology is mandatory for genetic studies in critical care medicine [25). Case control studies have been the most sensitive and powerful of all the armamentarium of study designs for detecting common and low-penetrant susceptibility genes in complex diseases such as ALII ARDS [26,27]. Rather than being epiphenomena, we know that genes are stable and not prone to time variation; therefore, less prone to biaslmisclassification in ascertainment and less equivocal with regards to the sequence of exposure and outcome. This factor is a major advantage of genes over other biomarkers in ALI. But gene expression can change with environmental stimuli or age. So, while genes may be 'fixed', the association between the exposure and the outcome may not be fixed. Just as important as whether an association exists or not, is the patient population and circumstances in which the association exists. The main problem in studies emerges in the selection of both cases and controls.

Selecting the Right Cases A major issue with syndromes in complex diseases is the misclassification that occurs with inaccurate phenotyping, which has lead to inconsistent findings for association tests. This is one of the keys in a well designed case-control study. Unfortunately, because ALIIARDS is a syndrome with no definitive markers, its diagnosis still relies on a clinical evaluation with potential biases in the diagnosis between different observers. In comparison to a pathological hallmark of diffuse alveolar damage, the criteria used for the diagnosis of this syndrome [2] are neither sensitive nor specific [28]. The three assets for the diagnosis of ALI/ARDS have to be adequately evaluated. First, radiologic consistency needs to be present and this can be ascertained by adequate training of the observers and by paying particular attention to radiographs from patients with chronic pulmonary disease such as pulmonary fibrosis. In patients with chronic lung disease, the presence of ALIIARDS could be overestimated based on the severity of the chronic lung disease. Second, because the PaOiFi0 2 ratio becomes an increasingly unreliable assessment of shunt when the Fi0 2 is below 0040, the ratio should be considered only when the Fi0 2 is greater than

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R. (artin-(eba, M.N. Gong, and O. Gajic DAD [3, 29]. Moreover, particular emphasis should be placed in non-intubated patients where the real FiOz is not reliable [3]. Finally, the assessment of left ventricular hypertension is very cumbersome in some patients, particularly nowadays when the use of pulmonary catheters is decreasing. Therefore, a standardized and structuralized method for assessment of congestive heart failure is mandatory. The same concerns should be applied to controls as it is important to make sure that they do not have ALIIARDS. In addi tion , it is of paramount importance to make sure that the precipitants to the development of ALI/ARDS and the management of the disease (infection, pancreatitis), injury (trauma, surgery), or intervention (transfusion of blood products) are accounted for and similar among cases and controls. For example, patients with severe sepsis or septic shock who develop ALIIARDS, should have had the same treatment to prevent ARDS as did the controls. There should not be a difference in time to first dose of antibiotics, time to source control, or time to early goal directed therapy [30] between the two groups . This will allow for a more robust finding that the susceptibility for the development of the disease or the outcome is influenced by the genetic background.

Selecting the Right Controls This is probably as or more important than the selection of the cases. It is clear from an epidemiology standpoint that the controls should have a similar chance of developing the disease, with the only difference being that they did not do so. Otherwise, confounding becomes a major player in the study and the results will most often be invalid. This is a very difficult task in critically ill patients. As stated above for the cases, it is important to use at-risk individuals who have a similar chance of developing the condition of interest as the cases. To give a different example than that presented for the cases, if we compare patients who develop ALIIARDS after trauma, the controls should have had similar injury scores and should have had similar interventions such as surgery or blood product transfusions in order to allow for meaningful comparison. One limitation in the selection of at-risk individuals is the fact that because these individuals are not randomly selected from the population, if the genotype of interest is associated with critical illness, then the genotype frequency may deviate from that predicted by the Hardy Weinberg equilibrium. Therefore, it is mandatory to take precautions to prevent biased results such as blinding of personnel, repeat genotyping, or validation of genotyping in a different population [17].

Other Limitations Statistical limitations Many studies are underpowered by the limited number of patients included. Particu lar emphasis needs to be instituted in power calculations for genotyping studies . Another problem resides in the classic cut-off in biomedical studies where alpha has been set as 0.05. It is well known that we may find statistical significance in an association by chance alone if multiple comparisons of different genetic loci susceptibility to a disease are performed. Therefore, there is an increased chance of finding false positive results with multiple comparisons. An emerging approach that may be more appropriate for ALI/ARDS studies will not be to correct for multiple comparisons but to calculate a post-test probability for false positive using a semi-Bayesian or Bayesian approach that takes into account the pre-test probability inherent in the

Genetic Susceptibility in AWARDS: What have we Learned?

candidate gene approach [31, 32). However, all these approaches are controversial and, in reality, different approaches may be appropriate for different diseases and study designs. Ultimately, it will come down to balancing the incidencelprevalence of the condition and the risk of false negative and positive results. None of these approaches preclude the need to confirm findings in another population. Publication bias There is a major publication bias regarding genotyping results. Many genotyping results that do not show a positive association with ALIIARDS remain unpublished. It is important to have the information regarding negative studies to facilitate excluding candidate genes in future genotyping studies . Racial and ethnic disparities Most of the stud ies performed regarding the association of particular genotypes and ALI/ARDS are significantly limited by the fact that they have included only Caucasians in their studies. Many of the polymorphisms found to be associated with ALII ARDS susceptibility or outcome are known to vary in frequency among major racial groups. Racial limitation is one of the main concerns regarding the external validity of these studies; however, utilizing diverse samples is not necessarily the answer. Because of population stratification, all analyses should be restricted to one major racial group. Having a racially diverse cohort is not nearly as important as having a large racially homogeneous cohort and having different populations within major racial groups to confirm associations found within one population . Within major racial groups, the need to adjust for population stratification is not as necessary especially if there is a great deal of mixture within the group as is usually the case in a country like the United States [33, 34). Gene-environment interaction Not taking into account the gene-environment interaction contributes greatly to the inconsistent findings from genetic association studies of complex disease [35]. As stated repeatedly, ALIIARDS is a complex disease and the gene under study may have no influence on the risk of the disease unless there is concomitant exposure to a particular environmental insult. Such cases have been seen in ARDS where an association was found only when there was a direct pulmonary injury such as pneumonia but no indirect pulmonary injury such as extra-pulmonary sepsis or massive transfusion. Because many of the polymorphisms found in ARDS are common, it is likely that these variants may be detrimental in some situat ions and benign or even beneficial in others (17) . Accurate phenotyping of cases and controls and adequate sample size will be instrumental in detecting gene-environmental interactions in ALIIARDS.

Future Considerations in Genomic Association Studies Related to Critical Care Syndromes Both refinements in study designs and new potential genome targets are likely to improve our under standing of genetic epidemiology as well as of the pathophysiology of ALIIARDS and related syndromes. Table 2 presents the details of an ideal case-control study to assess genetic associations in ALIIARDS utilizing the genecandidate approach.

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R. Cartin-Ceba, M.N. Gong, and O. Gajic Table 2.Characteristics of an ideal case-control study to determine the genetic association in acute lung injury (AU)/acute respiratory distress syndrome (ARDS) utilizing the candidate-gene approach. Gene candidates

Selection of cases

Selection of controls

Statistical issues

Racial/Ethnic diversity GeneEnvironment interaction

Biological plausibility in the development of ALII ARDS

Strict selection of cases by rigorous case definition of ALII ARDS stratified according to underlying risk factors

Choosing controls with similar risk of developing ALIIARDS stratified according to underlying risk factors

Adequate (la rge) sample size that may allow adjustment for multiple comparisons as well as for interaction with environmental factors

Large homogeneous cohort of a major racial group and having different populations within major racial groups to confirm association found within one population

In depth examination of the role of different environmental exposures

Table 3. Potential new candidate genes relevant to the pathogenesis ofacute lung injury (AU)/acute respiratory distress syndrome (ARDS) Inflammation/Immune response/ Chemotaxis

Coagulation

Vascular permeability

Interleukin 13 (lL-13)

Plasminogen activator inhibitor type 1 (PA/-7)

Heat shock protein 70 (HSP-70)

Interleukin 1B (lL -Ib)

Plasminogen activator, urokinase receptor (PLAUR)

(ADRB2)

Interleukin 1 receptor antagonist

Tissue factor/thromboplastin (F3)

Aquaporin 1 (AQP-I)

Proteinase-activated receptor 2

Actin related protein complex 4

(lL-IRA)

Cell differentiation antigen 14

Beta-2 adrenergic receptor

(CD-14)

(PAR-2)

Cyclooxygenase II (COX2)

Tissue-type plasminogen activator Endothelial differentiation (PLAT) sphingolipid G-protein receptor 1 (£OG-7)

Cortactin (EMSI)

Thrombospondin 1 (TSP-I)

Vitronectin (VNT)

Fibrinogen alpha (FGA)

Chemokine (C-C motif) ligand 2 (CCL-2)

Complement component 5 receptor 1 (C5AR) Complement component 3 (0) Annexin l/lipocortin 1 (ANXA I) Chemokine (C-X-C motif) receptor (CXCR-4)

Interleukin 8 receptor (lLR8)

(ARPC4)

Genetic Susceptibility in AWARDS: What have we Learned?

Multiple potential gene candidates have been proposed in the literature, yet specific studies in ALIIARDS have not been performed ( Table 3). Although genome-wide studies in complex diseases such as diabetes type-l [36] and rheumatoid arthritis [37] have proven useful, further improvements in biostatistical and analytic techniques will be needed before efficient genome-wide approaches to complex critical care syndromes, such as ALIIARDS, will be possible. The main goal is to identify genetic markers that will allow us to predict outcomes in ALII ARDS more accurately (risk assessment). On the other hand, these genetic markers may also help us to identify possible targets for a therapeutic approach if the biological defect is amenable for intervention.

Conclusion ALII ARDS is a challenging syndrome not only for the intensivist taking care of the

patient at the bedside, but also for the researcher trying to find the best way to predict outcomes and to find targets for appropriate interventions in order to improve overall prognosis . Alterations in single genes are unlikely to explain the abnormal processes involved in the development of this syndrome. Rather, a multiple geneenvironment interaction related to the maintenance of membrane permeability, cellular response to injury and inflammation will be more plausible. Candidate genebased association studies have been used to identify genomic associations in ALII ARDS with some success. However, significant limitat ions stem from inadequate study designs with small sample sizes and suboptimal characterization of phenotypic variance of critically ill patients and environmental exposures. Future studies using more optimal study designs and refined analytic techniques will hopefully fulfill the promise of human genome discovery and help improve our understanding of ALII ARDS and related critical care syndromes. References 1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults.

Lancet 2:319- 323 2. Bernard GR, Artigas A, Brigham KL, et al (1994) The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes , and clinical tr ial coordination. Am J Respir Crit Care Med 149:818- 824 3. Rubenfeld GD, Caldwell E, Peabody E, et al (2005) Incidence and outcome s of acute lung injury. N Engl J Med 353:1685-1693 4. Luhr OR, Antonsen K, Karlsson M, et al (1999) Incidenc e and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 159:1849-1861 5. Hughes M, MacKirdy FN, Ross J, Norrie J, Grant IS (2003) Acute respiratory distress syndrome: an audit of incidence and outcome in Scottish intensive care units. Anaesthesia 58:838-845 6. Bersten AD, Edibam C, Hunt T, Moran J (2002) Incidence and mortality of acute lung injury and the acute respiratory distre ss syndrome in three Australian States. Am J Respir Crit Care Med 165:443 - 448 7. Wheeler AP, Bernard GR (2007) Acute lung injury and the acute respiratory distre ss syndrome: a clinical review. Lancet 369:1553-1564 8. Villar J, Mendez S, Slutsky AS (2001) Critical care medicine in the 21st century: from CPR to PCR. Crit Care 5: pl25-l30 9. Bersten AD, Hunt T, Nicholas TE, Doyle IR (2001) Elevated plasma surfactant prote in-B predicts development of acute respiratory distress syndrome in pat ients with acute respiratory failure. Am J Respir Crit Care Med 164:648 -652

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R. Cartin-Ceba, M.N. Gong, and O. Gajic 10. Marks JD, Marks CB, Luce JM, et al (1990) Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis 141:94-97 11. Meduri GU, Headley S, Kohler G, et al (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-l beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 107:1062-1073 12. Ware LB, Conner ER, Matthay MA (2001) von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury. Crit Care Med 29:2325-2331 13. Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA (2003) Elevated levels of plasminogen activator inhibitor-l in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol, 285:L20 -28 14. Lander ES, Linton LM, Birren B, et al (2001) Initial sequencing and analysis of the human genome . Nature 409:860-921 15. The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789- 796 16. Flores C, Ma SF, Maresso K, Ahmed 0, Garcia JG (2006) Genomics of acute lung injury. Semin Respir Crit Care Med 27:389- 395 17. Gong MN (2006) Genetic epidemiology of acute respiratory distress syndrome: implications for future prevention and treatment. Clin Chest Med 27:705- 724 18. Wang WY, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practic al concerns . Nat Rev Genet 6:109-118 19. Hirschhorn IN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95-108 20. Gail MH, Pfeiffer RM, Wheeler W, Pee D (2007) Probability of detecting disease-associated single nucleotide polymorphisms in case-control genome-wide association studies . Biostatistics [Epub ahead of print] 21. Nannya Y, Taura K, Kurokawa M, Ogawa S (2007) Evaluation of genome-wide power of genetic association studies based on empirical data from the HapMap Project. Hum Mol Genet 16:3494-3505 22. Dinu V, Miller PL, Zhao H (2007) Evidence for association between multiple complement pathway genes and AMD. Genet Epidemiol 31:224-237 23. Engels EA, Wu X, Gu J, Dong Q, Liu J, Spitz MR (2007) Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer. Cancer Res 67:6520-6527 24. Meyer NJ, Garcia JG (2007) Wading into the genomic pool to unravel acute lung injur y genetics. Proc Am Thorac Soc 4:69- 76 25. Stuber F (2003) Genomics and critical care: do the right thing! Crit Care Med 31:1869-1870 26. Khoury MJ, Yang Q (1998) The future of genetic studies of complex human diseases: an epidemiologic perspective. Epidemiology 9:350- 354 27. Burton PR, Tobin MD, Hopper JL (2005) Key concepts in genetic epidemiology. Lancet 366:941- 951 28. Esteban A, Fernandez-Segoviano P, Frutos- Vivar F, et al (2004) Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings. Ann Intern Med 141 :440-445 29. Gowda MS, Klocke RA (1997) Variability of indices of hypoxemia in adult respiratory distress syndrome. Crit Care Med 25:41 - 45 30. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368-1377 31. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a posit ive report is false: an approach for molecular epidemiology studies. J Nat! Cancer Inst 96:434-442 32. Wakefield J (2007) A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am J Hum Genet 81:208-227 33. Wacholder S, Rothma n N, Caporaso N (2000) Population stratificat ion in epidemiologic studies of common genetic variants and cancer : quantification of bias. J Nat! Cancer Inst 92: 1151- 1158 34. Wang Y, Localio R, Rebbeck TR (2004) Evaluating bias due to population stratification in case-control association studies of admixed populations. Genet Epidemiol 27:14-20

Genetic Susceptibility in AWARDS: What have we Learned? 35. Andrieu N, Goldstein AM (1998) Epidemiologic and genetic approaches in the study of geneenvironment interaction: an overview of available methods. Epidemiol Rev 20:137-147 36. Smyth DJ, Cooper JD, Bailey R, et al (2006) A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region . Nat Genet 38:617-619 37. Plenge RM, Seielstad M, Padyukov L, et al (2007) TRAFI-C5 as a risk locus for rheumatoid arthritis - A genomewide study. N Engl J Med 357:1199-1209 38. Gong MN, Zhou W, Williams PL, et al (2005) -308GA and TNFB polymorphisms in acute respiratory distress syndrome. Eur Respir J 26:382-389 39. Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Christiani DC (2007) Polymerphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome. Crit Care Med 35:48-56 40. Gao L, Flores C, Fan-Ma S, et al (2007) Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations. Transl Res 150:18-29 41. Adamzik M, Frey UH, Rieman K, et al (2007) ACE IID but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS. Eur Respir J 29:482 - 488 42. [erng JS, Yu CJ, Wang HC, Chen KY, Cheng SL, Yang PC (2006) Polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome. Crit Care Med 34:1001-1006 43. Frerking I, Sengler C, Gunther A, et al (2005) Evaluation of the -26G> A CC16 polymorphism in acute respiratory distress syndrome. Crit Care Med 33:2404- 2406 44. Gao L, Grant A, Halder I, et al (2006) Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am J Respir Cell Mol Bioi 34:487-495 45. Bajwa EK, Yu CL, Gong MN, Thompson BT, Christiani DC (2007) Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome. Crit Care Med 35:1290-1295 46. Zhai R, Gong MN, Zhou W, et al (2007) Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS. Thorax 62:718-722 47. Montgomery HE, Marshall R, Hemingway H, et al (1998) Human gene for physical performance. Nature 393:221- 222 48. Gong MN, Thompson BT, Williams PL, et al (2006) Interieukin-IO polymorphism in position -1082 and acute respiratory distress syndrome. Eur Respir J 27:674-681 49. Gong MN, Wei Z, Xu LL, Miller DP, Thompson BT, Christiani DC (2004) Polymorphism in the surfactant prote in-B gene, gender, and the risk of direct pulmonary injury and ARDS. Chest 125:203- 211 50. Zhai R, Zhou W, Gong MN, et al (2007) Inhibitor kappaB-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians. Crit Care Med 35:893-898

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Racial Disparities in Infection and Sepsis: Does Biology Matter? HB. MAYR, S. YENDE, and D.C. ANGUS

Introduction Health disparities refer to preventable differences in the indicators of health for different population groups. The National Institutes of Health (NIH) define disparities as differences in the incidence, prevalence, mortality, and burden of diseases and other adverse health conditions that exist among specific population groups . Many groups all over the world are affected by disparities, including racial and ethnic minorities, older adults, children , women, and residents of rural areas. Racial differences in health care have been widely documented in the United States [1], with differences in burden of chronic health conditions, access to medical care and procedures, and outcomes throughout all major medical specialties [2- 6]. These differences may account for reduced life expectancy in minorities. Thus, it is critical to understand the causes for racial disparities and, thereby, to develop appropriate strategies to reduce health inequities. Infectious disease is a leading cause of death, preceded only by cardiovascular disease and cancer. Severe sepsis, an important complication of infection, is the 10th leading cause of death and accounts for more than 120,000 deaths in the United States [7,8]. Among African Americans, human immunodeficiency virus (HIV) and pneumonia are important causes of potential life-years lost [9]. In this brief chapter, we will discuss racial differences in susceptibility and outcomes of infection and sepsis. For the purpose of illustration, we will focus on racial differences between African Americans and whites in the United States. We relate our findings to cardiovascular medicine because racial disparities have been studied extensively in this specialty. Finally, we will examine the role of biology to explain racial differences in infectious diseases.

What is Race? With the completion of the Human Genome Project, there is increased emphasis on genetics and race in clinical medicine. Despite its problematic history, racial categorization is ubiquitous in medicine and public health, a reflection of both contemporary societal concerns and a mandate from federal funding agdncies, The NIH also requires reporting of research findings by racial categories to ensure adequate inclusion of women and minorities in human research. Despite widespread use of self-reported race in the medical literature, conceptualizing race is controversial. For instance, racial categories can be considered biologically as differences in genetic makeup that confer differential health risks. However,

Racial Disparities in Infection and Sepsis: Does Biology Matter?

several studies have shown that racial groups cannot be divided into distinct categories based on a single gene. Rather, a set of genetic markers identifies membership to four anthropologic groups : Sub-Saharan African, European, East Asian, and Native American. Furthermore, genetic differences across self-reported racial categories often represent a mixture of these markers . For example, African Americans in the United States often have up to 50 % Caucasian admixture. Therefore, a single racial category, identified based on self-report or skin color, is genetically heterogeneous. For example, the distribution of functional polymorphisms within the Tolllike-receptor (TLR)-4 gene varies extensively in whites from different countries in Europe and North America [10]. Race is also often viewed as a social and cultural construct, with unequal distribution leading to differences in socioeconomic resources. These differences may lead to differences in chronic disease burden, access to health care, and differences in outcomes of diseases. Nonetheless, categorization by race is important to under stand why significant differences in health outcomes exist between different subpopulations.

Differences in Disease Susceptibility Several studies have shown important racial differences in prevalence of traditional cardiovascular disease risk factors. African Americans have the highest self-reported prevalence of diabetes and hypertension, and often have two or more cardiovascular disease risk factors compared to other racial groups. As a consequence, African Americans have a higher incidence of first myocardial infarction at all ages [11]. Similar differences in racial disparities in infection and sepsis susceptibility have been described . For example, non-whites have a two-fold higher risk of developing sepsis and are significantly younger when they become ill [7]. In addition, African Americans have a higher incidence of pneumonia compared to whites. The reasons for higher susceptibility to infection are unclear. Classic risk factors for susceptibility to infection, such as hypertension and hypercholesterolemia for cardiovascular disease, have not been described . However, health behaviors and chronic diseases are known to increase risk of community-acquired pneumonia (CAP), the most common infectious cause of hospitalization and the most common cause of sepsis in developed countries. One study reported a 20-fold increased likelihood of HIV in African Americans [12]. African Americans are also more likely to have diabetes and chronic renal failure compared to Caucasians [13]. The higher burden of chronic diseases in African Americans may be a potential explanation for higher risk of infection and sepsis [14].

Differences in Access to Health (are United States Census Bureau data from 200S reveal significant racial disparities in health insurance coverage. Almost one-fifth (19.6 %) of African Americans had no health insurance compared to 11.3 % of non-Hispanic Whites. According to a report by the American College of Physicians and the American Society of Internal Medicine, uninsured persons are more likely than insured persons to refrain from seeking needed care and to suffer the consequences of delayed or forgone care [15]. For example, those without health insurance were more likely to have hospitalizations

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that could be prevented and received a diagnosis of cancer at an advanced stage. Although many of the studies summarized in this report did not control for selection bias, other research confirms that these discrepancies persist after adjustment for demographic, clinical, and socioeconomic factors [16]. Differences in access to health care may play an important role in susceptibility to and outcomes from infection. For instance, vaccination, particularly influenza and pneumococcal vaccine, reduces risk of pneumonia and respiratory tract infection. Uninsured individuals often skip office visits to discuss disease prevention, screen for health conditions, and administer vaccines. In 2000-2001, the Centers for Disease Control (CDC) report showed that influenza and pneumococcal coverage levels varied across racial groups. The coverage of pneumococcal and influenza was 66 % and 57 % for non-Hispanic whites, 48 % and 33 % for non-Hispanic blacks, and 54 % and 32 % for Hispanics, respectively. These differences in vaccination rates may explain differences in susceptibility to infections. Patients with sepsis often require admission to the intensive care unit (ICU). In a population-based study, we recently showed that Americans without health insurance use services less often than those with insurance. However, among hospitalized patients, the uninsured are more likely to receive ICU care and the outcome was worse among those admitted to the ICU because they were sicker [17]. In patients requiring ICU admission, racial differences in preferences for end-of-life care have also been described by Barnato et al. For example, non-whites are more likely to choose life-sustaining treatments (64 % for African Americans vs. 57.5 % in nonHispanic whites) [18]. The reasons for these differences are not known, but may include local patient and community factors (e.g., preferences and/or mistrust) or provider factors (e.g., hospital resources, staffing, or process and outcomes of communication and decision making).

Differences in Quality of (are Disparities in the use of diagnostic and therapeutic interventions have been extensively studied in cardiovascular disease. Racial differences in angiography, angioplasty, coronary artery bypass graft (CABG) surgery, and thrombolytic therapy persist even after adjusting for differences in clinical risk factor profile and presentation [19]. Similarly, African Americans with an acute ischemic stroke are one-fifth as likely as whites to receive thrombolytic therapy with tissue-plasminogen activator (tPA), despite no significant differences in time-to-presentation or contraindications to treatment [20]. Differences in quality of care have also been reported in patients with CAP. Most studies show that African Americans tend to receive fewer diagnostic procedures and poorer quality of care [21]. For example, they are less likely to receive antibiotics within eight hours of presentation [22]. Yet, African Americans have similar short-term outcomes despite higher chronic disease burden, less likelihood of having health insurance, and poorer quality of care. In patients with sepsis too, case-fatality rates are similar between blacks and whites [12, 13]. Similar results have also been observed in cardiovascular disease, where disparities in quality of care are not accompanied by differences in outcomes. For instance, analyses of short-term mortality for African Americans with unstable angina, non-Q wave myocardial infarction, or acute myocardial infarction have found similar death rates.

Racial Disparities in Infection and Sepsis: Does Biology Matter?

Understanding reasons for differences in quality of care, once individuals seek medical care, is complex. Differences may occur due to racial differences in clinical risk factor profile and clinical manifestation of disease, bias by health care personnel, site of delivery of health care, and individual beliefs that lead to acceptance or denial of therapeutic measures. It is important to consider these factors and carefully interpret racial differences in processes of care, such as timing of antibiotics for pneumonia, especially when they are not associated with differences in outcomes.

Could Differences in Underlying Biology Contribute to Racial Disparities? Although inequalities exist in health behaviors, burden of clinical risk factors, access to health care, and the quality of health care [23], differences in outcomes cannot be explained based on these factors alone. Increasing evidence suggests that racial differences in biology could contribute to the existing disparities and perhaps require race-specific treatment strategies . In cardiovascular disease, there are a number of reported differences between African Americans and whites in the extent of atherosclerosis, markers of inflammation, hemostasis, and endothelial dysfunction [24] . For example, plasma fibrinogen, D-dimer, factor VIII and von-Willebrand factor levels, all associated with an increased risk of cardiovascular disease, are consistently higher in African Americans than whites. Racial differences in intrinsic fibrinolytic activity have also been shown. The implications of these findings are integral to understanding the development of acute coronary syndromes and the response to treatment of acute myocardial infarction. Detection and correct interpretation of biological differences may lead to better insight about mechanisms of disease and perhaps result in different pharmacologic management. The African American Heart Failure Trial (A-HeFT) [25], for instance, was the first trial that resulted in approval of a race-specific drug (isosorbide dinitrate/hydralazine hydrochloride or BiDiFM ) by the Food and Drug Administration (FDA). These results suggest that a better understanding of biological differences in subpopulations could ultimately lead to individualized therapies. Fewer data are available to address the question of underlying differences in biology in infections . In an experimental model of low-grade systemic inflammation, we compared the pro-inflammatory and pro-coagulant response in healthy African and Caucasian volunteers. Each volunteer received 2 ng/kg of lipopolysaccharide (LPS) intravenously. We observed an attenuated chemokine and pro-coagulant response in volunteers of African descent compared to Caucasians [26]. Whether these differences extend to other components of the innate immune response is yet unknown. However, this preliminary work suggests that racial differences in the host response to infection exist. Clinical studies also suggest differences in susceptibility to infection. For example, Esper et al. showed that African American patients with sepsis have a greater frequency of Gram-positive infection s compared with whites and other races, even after controlling for variables that influence the inciting organism, such as the source of infection [12]. Genetic variation may explain differences in host response to infection across racial groups . Strong support for the role of genetics in infection comes from an adoptee study. Sorensen et al. linked cause of death in adoptees to the cause of death in both natural and adoptive parents. Children were six-fold more likely to die due to infectious causes if the natural parent died of infection by 50 years of age, when

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compared to risk of death in children whose adoptive parent died due to infection [27]. Similarly, previous studies suggest that genetics may influence the outcome of sepsis [28]. Whether racial differences in genetic makeup explain differences in host response to infection and differences in susceptibility to infection and sepsis is not known. For example, TLR2 is an important candidate gene to explain racial differences in infection susceptibility, particularly increased susceptibility to Gram-positive infections in African Americans [29]. Whether differences in frequency of puta tive functional polymorphisms within the TLR2 gene explain differences in susceptibility to Gram-positive infection is not known.

Conceptual Model of Racial Disparities Health-related racial disparities are driven by various factors ( Fig. 1). The interaction between these factors is complex and each of these factors may influence susceptibility and outcomes of disease. Certain health behaviors clearly increase infection susceptibility. For example, alcohol abuse is a common behavioral condition that has been reported to alter immune function and increase susceptibility to infection [30]. Up to 25 % to 50 % of patients with bacterial pneumonia have a prior history of alcohol abuse [31]. Health behaviors again reflect socioeconomic characteristics, such as level of education. For example, less educated people are more likely to smoke [32]. Socioeconomic characteristics also directly influence access to quality care and thereby influence current health status. People with less income are less likely to have health insurance and often seek medical care considerably later than insured people. Thus, they present with greater disease severity and worse clinical characteristics. As discussed above, biology may interfere at different disease stages. It may influence disease susceptibility or the host response to infection [27]. Furthermore, it is intriguing to speculate that these differences in susceptibility to and outcomes from infection may occur because of to different selection pressures. For instance, it has been hypothesized that a strong pro-inflammatory response may reduce risk of infection, but once infection occurs, these individuals may have higher risk of severe

Socioeconomic characterist ics Educational level Household income

.:

Health behaviors Smoking Alcoholconsumption

il

/

Clinical characteristics Disease severity Chronic disease burden

Access t o high·quality care Current health status Insurance coverage Continuity of care Quality of care

Biology Genepolymorphisms

Fig. 1. Conceptual model of factors contributing to racial disparities in infection and sepsis.

Racial Disparities in Infection and Sepsis: Does Biology Matter?

sepsis and death. Conversely, a potent anti-inflammatory response may increase susceptibility to infection , but may lower risk of severe sepsis and death. Biological differences in the pro- and anti-inflammatory response across different ethnic groups may reflect selection pressu res to combat certain endemic infections. An understanding of these complex intera ction s within each domain and across domains, outlined in Figure 1, is critical to design future studies to explain differences in susceptibility to infections .

Design Challenges for Further Studies There are several challenges to examining racial disparities and these issues should be recognized while planning future studies . African Americans and other minorities are still underrepresented in large clinical trials [33], and we need adequately powered studies to effectively investigate racial differences. Large administrative databases analyzed retrospectively [7, 13] are useful to characterize populationbased incidence rates, but have limited information regarding chronic health condition s, health services, health behaviors, and health outcomes. Though such databases are commonly used to report racial differences in incidence of disease, the reasons for the racial disparities are not known. An altern ative approach is to use large population-based cohorts. These studies offer several advantages, including detailed inventory of chronic health conditions, health behaviors, and outcomes. Often, these cohorts have genetic and proteomic markers and, therefore, may provide insights into differences in biology. However, due to selection bias, such cohorts may not necessarily reflect the diversity of the true population. Furthermore, one cannot study disparities in incidence in these cohorts.

Conclusion Significant racial disparities in health care exist that ultimately result in a shortened life expectanc y. Differences in socioeconomic characteristics, chronic disease profile, and health behavior s fail to entirely explain these disparities. Progress requires acknowledgement of the fact that subpopulations may and do differ in disease mechani sm, prevalence, and therapeutic response. Understanding of all the factors, including putative biological differences, which contribute to existing health disparities, is necessary to develop targeted therapies and prevention strategies. References 1. Council of Ethical and Judicial Affairs (1990) Black-white dispar ities in health care. JAMA

263:2344 - 2346 2. Bradley EH, Herrin J, Wang Y, et al (2004) Racial and ethnic difference s in time to acute reperfusion therapy for patients hospi talized with myocardial infarction . JAMA 292:1563-1572 3. Todd KH, Samaroo N, Hoffman JR (1993) Ethnicity as a risk factor for inadequate emergency department analgesia. JAMA 269:1537-1 539 . 4. [azieh AR, Buncher CR (2002) Racial and age-related disparities in obtaining screening mammography: results of a statewide databa se. South Med J 95:1145-1148 5. Schneider EC, Cleary PO, Zaslavsky AM, Epstein AM (2ool) Racial dispa rit y in influenza vaccinat ion: does man aged care narrow the gap between African Americans and whites? JAMA 286:1455- 1460

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6. Tamayo-Sarver JH, Hinze SW, Cydulka RK, Baker DW (2003) Racial and ethnic disparities in emergency department analgesic prescription. Am J Public Health 93:2067- 2073 7. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546-1554 8. Angus DC, Wax RS (2001) Epidemiology of sepsis: an update. Crit Care Med 29:S109-116 9. Wong MD, Shapiro MF, Boscardin WJ, Ettner SL (2002) Contribution of major diseases to disparities in mortality. N Engl J Med 347:1585-1592 10. Arnott !D, Ho GT, Nimmo ER, Satsangi J (2005) Toll-like receptor 4 gene in IBD: further evidence for genetic heterogeneity in Europe. Gut 54:308 11. Clark LT (2005) Issues in minority health: atherosclerosis and coronary heart disease in African Americans. Med Clin North Am 89:977-1001 12. Esper AM, Moss M, Lewis CA, Nisbet R, Mannino DM, Martin GS (2006) The role of infection and comorbidity: Factors that influence disparities in sepsis. Crit Care Med 34:2576-2582 13. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL (2007) Occurrence and outcomes of sepsis: influence of race. Crit Care Med 35:763-768 14. McGee D, Cooper R, Liao Y, Durazo-Arvizu R (1996) Patterns of comorbidity and mortality risk in blacks and whites. Ann Epidemiol 6:381-385 15. American College of Physicians (2000) No Health Insurance? It's Enough to Make You Sick. American Society of Internal Medicine, Philadelphia 16. Kasper JD, Giovannini TA, Hoffman C (2000) Gaining and losing health insurance: strengthening the evidence for effects on access to care and health outcomes . Med Care Res Rev 57:298-318 17. Danis M, Linde-Zwirble WT, Astor A, Lidicker JR, Angus DC (2006) How does lack of insurance affect use of intensive care? A population-based study. Crit Care Med 34:2043 - 2048 18. Barnato AE, Berhane Z, Weissfeld LA, Chang CC, Linde-Zwirble WT, Angus DC (2006) Racial variation in end -of-life intensive care use: a race or hospital effect? Health Serv Res 41: 2219-2237 19. Lillie-Blanton M, Maddox TM, Rushing 0, Mensah GA (2004) Disparities in cardiac care: rising to the challenge of Healthy People 2010. J Am Coli Cardiol 44:503-508 20. Johnston SC, Fung LH, Gillum LA, et al (2001) Utilization of intravenous tissue-type plasminogen activator for ischemic stroke at academic medical centers: the influence of ethnicity. Stroke 32:1061-1068 21. Ayanian JZ, Weissman JS, Chasan-Taber S, Epstein AM (1999) Quality of care by race and gender for congestive heart failure and pneumonia. Med Care 37:1260-1269 22. Mortensen EM, Cornell J, Whittle J (2004) Racial variations in processes of care for patients with community-acquired pneumonia. BMC Health Serv Res 4:20 23. U.S. Department of Health and Human Services (2005) National Healthcare Disparities Report. Available at: http://www.ahrq.gov/quaIlNhdr05/nhdr05.htm; accessed December 2007. 24. Clark LT, Ferdinand KC, Flack JM, et al (2001) Coronary heart disease in African Americans. Heart Dis 3:97-108 25. Taylor AL, Ziesche S, Yancy C, et al (2004) Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 351:2049-2057 26. Mayr FB, Spiel AO, Leitner JM, et al (2007) Duffy antigen modifies the inflammatory response in human endotoxemia. Crit Care Med [Epub ahead of print] 27. Sorensen Tl, Nielsen GG, Andersen PK, Teasdale TW (1988) Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 318:727- 732 28. Mira JP, Cariou A, Grall F, et al (1999) Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 282:561-568 29. Yim JJ, Ding L, Schaffer AA, Park GY, Shim YS, Holland SM (2004) A microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene: functional implications and racial differences. FEMS Immunol Med MicrobioI40:163-169 30. Nelson S, Kolls JK (2002) Alcohol, host defence and society. Nat Rev Immunol 2:205-209 31. Torres A, Serra-Batlles J, Ferrer A, et al (I991) Severe community-acquired pneumonia. Epidemiology and prognostic factors. Am Rev Respir Dis 144:312-318 32. Pierce JP, Fiore MC, Novotny TE, Hatziandreu EJ, Davis RM (I989) Trends in cigarette smoking in the United States. Educational differences are increasing. JAMA 261:56-60 33. Mosenifar Z (2007) Population issues in clinical trials. Proc Am Thorac Soc 4:185-187

Section II

II Cardiac Issues

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B-Type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care P.E.

OISHI,

J.-H . Hsu, and J.R.

FINEMAN

Introduction In 1988, Sudoh and colleagues described a novel natriuretic peptide in porcine brain [1]. Subsequent studies found that brain natriuretic pept ide was most abundant in the heart , and thus it was termed B-type natriuretic peptide (BNP). The release of BNP is triggered in large part by myocyte stretch and BNP levels are easily quanti fied by several commercially available assays. Thus, over the past decade numerous investigators sought to determine the clinical utility of BNP and together have now firmly established a role for BNP as a biomarker for diagnosis, prognostication, and management of adults with cardiac disease [2]. Unfortunatel y, far fewer data are available on the role of BNP in the management of critically ill neonates, infants, and children. Potential uses for BNP in pediatric critical care are outlined in This chapter will provide a brief review of these data with the goal of helping clinicians make use of BNP in the care of these patients. Table 1. Potential uses for B-type natriuretic peptide (BNP) determinations in pediatric critical care.

Diagnoses that may be aided by BNP determinations in pediatric patients Congestive heart failure Persistent pulmonary hypertension of the newborn Hemodynamically significant patent ductus arteriosus Ventricular diastolic dysfunction in the acute phase of Kawasaki syndrome Hemodynamically significant pulmonary-to-systemic blood flow ratio Anthracycline-induced cardiac toxicity Tonic-clonic seizures (vs partial seizures or syncope) Sleep disordered breathing Sepsis Postoperative outcomes that may be associated with elevated BNP levels in neonates, infants, and children after cardiac surgery Duration of mechanical ventilation Level of inotropic support Residual anatomic lesions Inability to separate from extracorporeal life support Low cardiac output syndrome Intensive care unit length of stay Hospital length of stay Death

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Natriuretic Hormone System Beginning with the observation by de Bold et al. [3] that rats infused with atrial tissue extracts developed natriuresis and diuresis, much has been learned over the past three decades about the role of the natriuretic hormone system in the homeostatic control of fluid balance and vascular tone. The natriuretic hormone system comprises several related peptides that activate specific receptors, particularly in the kidneys, myocardium, and vasculature, which use cyclic guanosine 3',5'-monophosphate (cGMP) as a secondary messenger [4]. These peptides include atrial natriuretic peptide (ANP), BNP, C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), kaliuretic peptide, and urodilantin. The primary stimulus for the release of these peptides is an increase in intravascular or cardiac volume, which causes increased atrial stretch, ventricular wall stress, vascular sheer stress, intravascular volume, and/or intravascular sodium concentration [4]. The precise roles of individual natriuretic peptides depend upon their distribution and abundance within the cardiovascular system, as well as the specific stimulus for their release.

B-Type Natriuretic Peptide Although originally isolated in the brain, BNP is predominantly produced in the cardiac ventricles. However under pathologic conditions, such as fluid overload, the cardiac atrium can also become a significant source [1, 5]. Biosynthesis of BNP begins with a 134 amino acid precursor, preproBNP. Stimuli, such as myocyte stretch, trigger the cleavage of preproBNP to form proBNP, which is subsequently cleaved by a serine protease to the active C-terminal 32 amino acid hormone, BNP, and the inactive N-terminal proBNP (NT-proBNP). BNP binds to three known cell membrane receptors, termed natriuretic peptide receptors (NPR-A, NPR-B, and NPR-C). NPR-A and NPR-B are transmembrane receptors that activate particulate guanylate cyclase, which catalyzes the conversion of guanosine triphosphate to cGMP. The third receptor, NPR-C, is involved in clearance via endocytosis. Circulating BNP is also inactivated by cleavage by neutral endopeptidases found in vascular cells and renal tubules ( Fig. 1) [2, 6]. Animal studies suggest that approximately half of natriuretic peptide clearance is via the NPR-C receptor and half via endopeptidase degradation, but the relative contributions in humans are unclear. The mechanisms that mediate BNP release and metabolism in health and disease are incompletely understood. In addition, the effect of development on these mechanisms is unknown, but clearly may have great relevance in a pediatric population. Active BNP is stored in the atria in specific storage organelles [5]. Basal BNP levels result from continuous secretion from the atria. With acute myocardial distention, BNP release increases from this storage pool, in a manner independent of BNP synthesis. However, under acute, sub-acute, and chronic conditions of increased cardiac volume or pressure loading, increases in circulating BNP are maintained due to ventricular re-expression of the fetal gene program [7, 8]. In addition to volume and pressure loading, acute myocardial ischemia, a agonist stimulation, endothelin-I, and inflammatory mediators, such as tumor necrosis factor (TNF)-a and interleukin (IL) -l~, result in rapid ventricular expression of BNP [8]. The primary actions of BNP are vascular smooth muscle relaxation and anti-mitogenesis, mediated by cGMP, diuresis, caused by a shift of intravascular volume into the interstitium, and natriuresis, caused by antagonism of renin and aldosterone release [1,5,6].

B-Type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care

VJ

BNP ----+

•

/~

NPR-A NPR-B

Neut ral --+ Degradation endopeptidase

Guanylyl cyclase

,---.

GTP

cGMP

Degradation

Biologic activity: vascular relaxation, anti-mitogenesis, natriuresis, diuresis, increased vascular permeability, suppression of renin-angiotensin-aldosterone, decreased sympathetic tone

Target cell(blood vessels, kidneys, heart,adrenals, brain)

Fig. 1. A schematic representation of B-type natriuretic peptide (BNP) signaling. BNP binds to 3 natriuretic peptide receptors (NPR), types A, B, and C, on various target cells located in the vasculature, kidney, heart, adrenal glands, and brain. NPR-A and NPR-B are high-affinity receptors with an extracellular binding domain, a single membrane-spanning region, and an intracellular guanylyl cyclase domain. Guanylyl cyclase catalyzes the conversion of guanosine-S'-triphosphate (GTP) to guanosine-3;S'-cyclic monophosphate (cGMP). BNP is degraded by two mechanisms: Neutral endopeptidases degrade circulating BNp, and binding to NPR-C results in receptor internalization and degradation by endocytosis. NPR-C is then recycled to the cell membrane (not shown).

Of all the natriuretic peptides, BNP has emerged as the most useful biomarker for cardiac disease. Its major advantage over the other natriuretic peptides is the fact that it is produced predominantly in the ventricles, as opposed to the atrium (ANP) or the vascular endothelium (CNP) [2,9] . Both active BNP and the inactive byproduct of its production, NT-proBNP, are used as biomarkers . BNP levels may be better suited to follow dynamic alterations in myocardial performance given the shorter circulating half-life of BNP compared to NT-proBNP (20 min vs. 60-120 min) [9]. In addition, the kidneys excrete NT-proBNP, and thus renal funct ion, independent of myocardial funct ion, has a greater influence on NT-proBNP levels than on BNP levels. Limited data suggest that BNP levels are high at birth but fall during the first week of life, reaching levels below adult values by 2 weeks of age. Interestingly, although levels in boys tend to decreas e with age, girls have an elevation during the second decade of life that is associated with pub erty [10-12] .

BNP in Adult Cardiac Disease Plasma BNP is widely used as a biomarker for the diagnosis, risk str atification, and treatment of adults with a var iety of cardiac disease states , includ ing systolic and

3S

36

P.E. Oishi, J.-H. Hsu, and J.R. Fineman

diastolic heart failure, acute coronary syndromes, hypertrophic cadiomyopathies, aorti c stenosis, and perioperative cardiac dysfunction [2, 13]. For example, BNP levels aid in the distinction between dyspnea caused by congestive heart failure (CHF) and that caused by non-cardiac etiologies [14]. BNP levels are increased in adults with systolic ventricular dysfunction and/or CHF, and the levels are predictive of New York Heart Association (NYHA) functional class and mortality [2]. Furthermore, improved outcomes have been demon strated by adjusting inpatient treatment for decompensated CHF in response to BNP levels, and the changes in BNP in response to therap y were pred ictive of hospitalization and death [13, 15]. Lastly, in several adult studies BNP levels increased after cardiac surgery with the use of cardiopulmonary bypass (CBP), and were correlated with ventricular dysfunction and postoperative outcomes, including mortality.

BNP in Pediatric Cardiac Disease In comparison to the adult experience, there are far fewer data regarding BNP in pediatric cardiac disease. Several studies of infants and children with congenital heart disease after correction or palliation of their cardiac defects found that BNP levels were associated with long-term outcomes, including the severity of ventricular dysfunction and NYHA functional class [16-19]. Fewer data are available on other types of cardiac disease in children . Kurotobi and colleagues found that BNP levels correlated with left ventricular diastolic dysfunction during the acute phase of Kawasaki disease, in a study of 25 pediatric patients [20]. In a study of 44 patients after orthotopic heart transplant, Lan and colleagues found that BNP levels were initially elevated but fell to levels below 100 pglml by 14 weeks after transplant, independent of ventricular size [21]. As opposed to adults with CHF, BNP levels in infants and children with congenital heart disease are quite varied, and are dependent in part upon the age of the patient and the specific physiology associated with the cardiac defect. For example, in a study of infants and children with ventricular septal defects, Suda and colleagues found that BNP levels correlated with the pulmonary-to-systemic blood flow ratio and the mean pulmonary arterial pressure [22]. Likewise, Kunii and colleagues compared BNP levels between normal children (n = 253), including 11 neonates, and children with ventricular septal defects (n = 91), patent ductus arteriosus (n = 29), and atrial septal defects (n = 34). As in the study by Suda et al. [22], these authors [23] found that BNP levels correlated with the pulmonary-to-systemic blood flow ratio, and also the left ventricular end-diastolic volume, and the right ventricular to left ventricular pressure ratio. These investigators reported a BNP cut-off level of 20- 35 pg/ml as an appropriate indicator for the need for surgical intervention [23]. Koch and colleagues found, in a study of 288 pediatric patients with congenital cardiac defects, that normal BNP levels did not exclude cardiac pathology such as the presence of structural defects or ventricular hypertrophy, but rather were associated with the extent of ventricular impairment [24]. Furthermore, these same investigators recently demonstrated age-dependent differences in the metabolic clearance of BNP and NT-proBNP [25]. This variability hampers the generalization of adult data, in particular absolute therapeutic cut-off values, for the care of pediatric patients. In a recent study of infants and children with chronic left ventricular dysfunction , a BNP level at or above 300 pg/ml was found to be predictive of death, hospitalization, or listing for cardiac transplant [26]. However, similar studies validating specific lev-

B-Type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care

els that might be used clinically are sparse or completely lacking in the broad spectrum of pediatric cardiac diseases.

BNP as a Biomarker Following Cardiac Surgery As a cardiac hormone with a relatively short circulating half life, which is dynamically released in response to deranged myocardial performance, BNP appears perfectly suited for guiding the perioperative management of pediatric patients undergoing cardiac surgery for repair or palliation of congenital cardiac defects. Several investigators have studied alterations in BNP following cardiac surgery in pediatric patients . Sun and colleagues measured BNP levels before and after surgery in 27 patients undergoing biventricular repair and in 27 patients undergoing univentricular repair of congenital heart defects [27). Plasma BNP levels increased after bypass in patients with biventricular defects, but not in patients with univentricular defects [27). Ationu and colleagues measured perioperative BNP levels in nine children undergoing repair of congenital heart defects [28). Contrary to larger reports, BNP levels decreased at 12 h following surgery, which may relate to the inclusion of four patients who underwent total cavopulmonary connection [28). Finally, Costello and colleagues examined BNP levels before and following cardiac surgery in 25 infants and children with congenital heart disease undergoing complete or palliative repair with the use of CPB [29). However, these studies did not report a role for BNP in predict ing outcome after surgery. Shih and colleagues conducted the first study demonstrating that BNP predicted outcome after cardiac surgery in children [30). BNP levels were determined before and after surgery in 51 patients. These investigators found that BNP levels increased after surgery, peaking at 12 h, and that BNP levels 12 h following surgery were predictive of a requirement for mechanical ventilation beyond 48 h and the presence of low cardiac output syndrome within the first 48 h postoperatively. Further, the study found that 12-hour BNP levels of 540 pg/ml had a sensitivity of 88.9 % and a specificity of 82.5 % for predicting the need for mechanical ventilation beyond 48 hours, and that a 12-hour BNP of 815 pg/ml had a sensitivity of 87.5 % and a specificity of 90.2 % for predict ing the development of low cardiac output syndrome. This initial report excluded neonates, a high risk group, but a subsequent study by Hsu and colleagues examined BNP levels before and after surgery in 31 consecutive neonates undergoing repair or palliation of their cardiac defects [31). These authors found that 24-hour BNP levels were lower than preoperative BNP levels in 21 patients (75 %), and higher in 7 patients (25 %). Although absolute levels of BNP were not associated with outcomes, the change in BNP after surgery was predictive. In fact, an increase in postoperative BNP was associated with an increased incidence of low cardiac output syndrome (l00 % vs. 36 %), and fewer ventilator-free days (17 ± 13 days vs. 25 ± 3 days), and predicted the 6-month composite endpoint of death, an unplanned operation, or cardiac transplant (57 % vs, 0 %). Furthermore, an increase in BNP after surgery had a sensitivity of 100 % and a specificity of 87 % for predict ing a poor postoperative outcome. Interestingly, neither arterial-venous oxygen saturation differences (AVDO z) nor lactate levels (or their corresponding changes) were associated with post-operative outcomes in this study [31). In another study, Cannesson and colleagues measured perioperative BNPlevels in 30 neonates undergoing the arterial switch operation (ASO) for d-transposition of the great arteries [32). Contrary to the findings of Hsu [31), BNP levels increased

37

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P.E. Oishi, J.-H. Hsu, and J.R. Fineman

over the first 48 hours postoperatively. However, like the study by Hsu et al. these investigators found that postoperative BNP levels predicted adverse clinical outcomes, including prolonged mechanical ventilation, prolonged stay in the intensive care unit (ICU), low cardiac output syndrome, and the need for inotropic support. Berry and colleagues stud ied 20 neonates, infants, and children undergoing various stages of palliation for cardiac defects with single ventricle physiology [33]. These authors reported that BNP levels were highest in neonates undergoing a Norwood procedure compared with patients undergoing bidirectional cavopulmonary anastomosis or a Fontan procedure. More importantly, postoperative BNP levels were predictive of hospital length of stay and postoperative inotropic support. Most recently, Chikovani and colleagues studied the potential utility of BNP levels in the assessment of native myocardial performance in ten neonates and infants being supported with extracorporeallife support after cardiac surgery [34]. In particular, alterations in BNP during weaning trials off extracorporeallife support were determined and compared to other biochemical markers, including lactate and the AVDO z' This study did not find associations between long-term outcome and alterations in lactate and the AVDO z during trials off extracorporeal life support. However, an increase in BNP during the final trial off extracorporeal life support had a sensitivity of 80 % and a specificity of 100 % for predicting the need for an unplanned operat ion or death within 3 months . In a similar earlier study, Huang and colleagues studied fifteen pediatric patients requiring extracorporeallife support for cardiogenic shock [35]. Eleven of the fifteen patients developed shock after cardiac surgery. These investigators did not find an association between BNP levels during the course of extracorporeallife support and survival after extracorporeallife support. However, they did find that BNP levels on the first and fourth day following separation from extracorporeal life support were significantly higher in non-survivors than in survivors [35].

Respiratory Distress: Differentiating between Potential Etiologies Respiratory distress is a common feature in critically ill pediatric patients and yet it is a relatively non-specific sign. Thus, several studies have examined the utility of BNP measurements in differentiating between patients with respiratory distress of various etiologies. Reynolds and colleagues compared BNP levels obtained from neonates with persistent pulmonary hypertension of the newborn (PPHN), respiratory distress with normal pulmonary artery pressures, and normal controls [36]. These authors reported that BNP levels were significantly higher in neonates with PPHN (median, 1610 pg/ml) than in neonates with respiratory distress (median, 132 pg/ml) or normal controls. In addit ion, in the PPHN group the tricuspid regurgitation jet and the pulmonary to systemic blood pressure ratio correlated with BNP levels. Two studies examined whether BNP could aid diagnosis in pediatric patients presenting with acute respiratory distress. Cohen and colleagues measured NT-proBNP in infants presenting with CHF, lung disease not related to cardiac dysfunction, and healthy age-matched control patients [37]. They found that NT-proBNP levels were significantly higher in infants with CHF (median , 18,452 pg/ml) than infants with lung disease (median, 311 pg/ml) or healthy controls (median, 89 pg/ml). Likewise, Koulouri and colleagues studied 49 infants and children presenting with respiratory distress [38]; they found that BNP levels were greater in patients with CHF

B-Type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care

(693±501 pg/ml) as compared to patients with primary lung disease (45±64 pg/ml) , and that a BNP level of greater than 40 pg/ml was 84 % accurate for differentiating CHF from lung disease.

Patent Ductus Arteriosus Six recent studies, representing a combined total of 207 premature neonates, reported that BNP levels correlated with the degree of shunting across a patent ductus arteriosus and predicted hemodynamic significance as determined by echocardiography-based criteria [39- 44]. However, the precise cut-off value for BNP that was predictive varied widely. For example, Choi and colleagues reported that a BNP level of > 1110pg/ml was 100 % sensitive and 95 % specific for the presence of a hemodynamically significant patent ductus arteriosus, while Sanjeev and colleagues reported a 92 % sensitivity with a cut-off level of 70 pg/ml [39, 42].

BNP in Other Pediatric Illnesses Several adult studies indicate that BNP levels are elevated in the setting of sepsis and septic shock and are predictive of outcome. Similar data are not yet available in pediatric patients. Fried and colleagues reported that NT-proBNP levels were elevated in pediatric patients with sepsis, but that they could not distinguish between patients with sepsis and patients with acute left ventricular failure [45]. Novel applications of BNP in pediatric patients with very limited data include the detection of anthracycline-induced cardiotoxicity, the differentiation between types of seizures, and the stratification of disease severity in patients with sleep disordered breathing [46- 49]. These studie s are intriguing and warrant further investigations.

Exogenous Administration of BNP The exogenous administration of BNP may have therapeutic benefits, and in fact recombinant human BNP, nesiritide (Natrecor, Scios Inc, Freemont CA), recently gained Food and Drug Administration (FDA) approval for the treatment of CHF in adults. A review of the literature supporting a role for exogenous BNP therapy in pediatric critical care is beyond the intended scope of this chapter. However, the rationale for the use of exogenous BNP therapy is founded in part on the notion that the endogenous natriuretic hormone system is dysfunctional under disease conditions. Thus, it must be noted that no studies have so far adequately associated BNP levels or function with the response to exogenous BNP therapy. To date, the in vivo assessment of the natriuretic system is best characterized by determining the molar ratio of plasma cGMP-to-natriuretic peptide levels. However, cGMP is not only the secondar y messenger to natriuretic hormones, but to nitric oxide (NO) as well. A number of systems, in addit ion to the natriuretic hormone system, which impact cGMP levels, including endothelial and inducible NO synthase (NOS), soluble guanylate cyclase, and the phosphodiesterase system, are altered under disease conditions, such as CPB. Thus, alternative methods of assessing endogenous natriuretic hormone system function are required in order to elucidate

39

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P.E. Oishi, J.-H. Hsu, and J.R. Fineman

a potentially important association between endogenous function and exogenous therapy. However, even in the absence of such a proven association, further investigations on the efficacy and safety of exogenous BNP therapy for pediatric patients are warranted, given its unique effects on vascular tone and fluid homeostasis.

Conclusion The essential relationship between BNP production by the cardiac ventricle and increased myocyte stretch is the foundation for the potential use of BNP as a biomarker in any condition in which abnormal ventricular loading conditions are primarily involved in the pathophysiology. To date, plasma BNP determinations have not attained the same clinical prominence in pediatric patients as in adults. The growing utilization of BNP determinations in the care of adult patients likely stems from the ability to make clinical decisions, indeed to titrate therapy, in response to BNP levels [13]. Thus, a widespread use of BNP in pediatric patients is restrained by the scarcity of data that support BNP guided therapies. It is likely that this discrepancy between the adult and pediatric experience relates, in part, to the sheer number of investigations. However, compared to adult CHF, pediatric cardiac diseases resulting in ventricular dysfunction and CHF are far more heterogeneous. In fact, coronary artery disease is the leading cause of CHF in adults, whereas pediatric CHF may result from a wide spectrum of congenital cardiac defects and various cardiomyopathies. Moreover, clinically relevant cut-off values for plasma BNP levels within these various disease processes are not well established or are completely unknown. Nonetheless, the ability to readily quantify plasma BNP levels is attractive as few markers are so directly related to the pathobiology of the cardiac ventricle. This is particularly true in the management of critically ill pediatric patients, where we often employ surrogate markers of disease severity, such as serum lactate levels, that reflect global processes as opposed to organ specific functioning. Thus, future studies must begin to evaluate the utility of guiding therapy in response to plasma BNP values. Fortunately, the ease of measuring BNP levels should facilitate these studies. For now, the available data clearly demonstrate that BNP has emerged as a novel biomarker with great potential for the care of critically ill pediatric patients. References 1. Sudoh T, Kangawa K, Minamino N, Matsuo H (1988) A new natriuretic peptide in porcine brain. Nature 332:78-81 2. Silver MA, Maisel A, Yancy CW, et al (2004) BNP Consensus Panel 2004: A clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congest Heart Fail 10:1-30 3. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (1981) A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 28:89-94 4. Levin ER, Gardner DG, Samson WK (1998) Natriuretic peptides. N Engl J Med 339:321-328 5. McGrath MF, de Bold ML, de Bold AJ (2005) The endocrine function of the heart. Trends Endocrinol Metab 16:469-477 6. Yandle TG (1994) Biochemistry of natriuretic peptides. J Intern Med 235:561- 576 7. Zhang Y, Carreras D, de Bold AJ (2003) Discoordinate re-expression of cardiac fetal genes in N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension. Cardiovasc Res 57:158 -167 8. Hama N, Itoh H, Shirakami G, et al (1995) Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction . Circulation 92:1558-1564

B-Type Natriuretic Peptide: An Emerging Biomarker in Pediatric Critical Care 9. Costello JM, Goodman DM, Green TP (2006) A review of the natriuretic hormone system's diagnostic and therapeutic potential in critically ill children . Pediatr Crit Care Med 7:308-318 10. Koch A, Singer H (2003) Normal values of B type natriuretic peptide in infants, children, and adolescents. Heart 89:875- 878 II. Yoshibayashi M, Kamiya T, Saito Y, et al (1995) Plasma bra in natriuretic peptide concentrations in healthy children from birth to adolescence: marked and rap id increase after birth . Eur J Endocr inol 133:207- 209 12. Ationu A, Carter ND (1993) Brain and atrial natriuretic peptide plasma concentrations in normal healthy children . Br J Biomed Sci 50:92- 95 13. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM (2000) Treatment of heart failure guided by plasma aminoterminal brain natriuretic pept ide (NBNP) concentrations. Lancet 355:1126- 1130 14. Maisel AS, Krishna swamy P, Nowak RM, et al (2002) Rapid measurement of B-type natriuretic peptide in the emergenc y diagnosis of heart failure. N Engl J Med 347:161-167 15. Murdoch DR, McDonagh TA, Byrne J, et al (1999) Titrat ion of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodyn amic and neuroendocrine effects of tailored versus empiric al therapy. Am Heart J 138:1126-1132 16. Law YM, Keller BB, Feingold BM, Boyle GJ (2005) Usefulness of plasma B-type natriuretic peptide to identify ventricular dysfunct ion in pedi atric and adult patients with congenital heart disease. Am J Cardiol 95:474-478 17. Cowley CG, Bradley JD, Shaddy RE (2004) B-type natriuretic peptide levels in congenital heart disease. Pediatr Cardiol 25:336-340 18. Koch A, Kitzsteiner T, Zink S, Cesnjevar R, Singer H (2007) Impact of cardiac surger y on plasma levels of B-type natriuretic peptide in children with congenital heart disease. Int J Cardiol 114:339-344 19. Gessler P, Knirsch W, Schmitt B, Rousson V, von Eckardstein A (2006) Prognostic value of plasma N-term inal pro-brain natr iuretic peptide in children with congenital heart defects and open-heart surgery. J Pediatr 148:372-376 20. Kurotobi S, Kawakami N, Shimizu K, et al (2005) Brain natriuretic peptide as a hormonal marker of ventr icular diastolic dysfunction in children with Kawasaki disease. Pediatr CardioI26:425-430 21. Lan YT, Chang RK, Alejos JC, Burch C, Wetzel GT (2004) B-type nat riuretic peptide in children after cardiac transplantation. J Heart Lung Transplant 23:558- 563 22. Suda K, Matsumura M, Matsumoto M (2003) Clinical implication of plasma natriuretic peptides in children with ventric ular septal defect. Pediatr Int 45:249- 254 23. Kunii Y, Kamada M, Ohtsuk i S, et al (2003) Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease. Acta Med Okayama 57:191-197 24. Koch A, Zink S, Singer H (2006) B-type natr iuretic peptide in paediatric patients with congenital heart disease. Eur Heart J 27:861 - 866 25. Koch AM, Rauh M, Zink S, Singer H (2006) Decreasing ratio of plasma N-terminal pro-Btype natriuretic peptide and B-type natriuretic peptide according to age. Acta Paediatr 95: 805-809 26. Price JF, Thoma s AK, Grenier M, et al (2006) B-type natriuretic peptide predict s adverse cardiovascular events in pediatric outpatients with chronic left ventricular systolic dysfunct ion. Circulation 114:1063-1069 27. Sun LS, Dominguez C, Mallavaram NA, Quaegebeur JM (2005) Dysfunction of atr ial and Btype natriuretic peptides in congenital univentricular defects. J Thorac Cardiovasc Surg 129:1104-1110 28. Ationu A, Singer DR, Smith A, Elliott M, Burch M, Carter ND (1993) Studies of cardiopulmonar y bypa ss in children : implications for the regulation of brain natriuretic peptide. Cardiovasc Res 27:1538-1541 29. Costello JM, Backer CL, Checchia PA, Mavroudis C, Seipelt RG, Goodman DM (2004) Alterations in the natriuretic hormone system related to cardiopulmonary bypass in infants with congestive heart failure. Pediatr Cardiol 25:347- 353

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P.E. Oishi, J.-H. Hsu, and J.R. Fineman 30. Shih CY, Sapru A, Oishi P, et al (2006) Alterations in plasma B-type natriuretic peptide levels after repair of congenital heart defects: a potential perioperative marker. J Thorac Cardiovasc Surg 131:632-638 31. Hsu J, Keller R, Chikovani 0, et al (2007) B-type natriuretic peptide levels predict outcome after neonatal cardiac surgery. J Thorac Cardiovasc Surg 134:939-945 32. Cannesson M, Bionda C, Gostoli B, et al (2007) Time course and prognostic value of plasma B-type natriuretic peptide concentration in neonates undergoing the arterial switch operation. Anesth Analg 104:1059- 1065 33. Berry JG, Askovich B, Shaddy RE, Hawkins JA, Cowley CG (2007) Prognostic value of B-type natriuretic peptide in surgical palliation of children with single-ventricle congenital heart disease. Pediatr Cardiol [Epub ahead of print] 34. Chikovani 0, Hsu J, Keller R, et al (2007) B-type natriuretic peptide levels predict outcomes for children on extracorporeal life support after cardiac surgery. J Thorac Cardiovasc Surg 134:1179-1187 35. Huang SC, Wu ET, Ko WJ, et al (2006) Clinical implication of blood levels of B-type natri uretic peptide in pediatric patients on mechanical circulatory support. Ann Thorac Surg 81: 2267-2272 36. Reynolds EW, Ellington JG, Vranicar M, Bada HS (2004) Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics 114:1297-1304 37. Cohen S, Springer C, Avital A, Perles Z, Rein AJ, Argaman Z, Nir A (2005) Amino-terminal pro-brain-type natriuretic peptide : heart or lung disease in pediatric respiratory distress? Pediatrics 115:1347-1350 38. Koulouri S, Acherman RJ, Wong PC, Chan LS, Lewis AB (2004) Utility of B-type natriuretic peptide in differentiating congestive heart failure from lung disease in pediatric patients with respiratory distress . Pediatr Cardiol 25:341- 346 39. Choi BM, Lee KH, Eun BL, et al (2005) Utility of rapid B-type natriuretic peptide assay for diagnos is of symptomatic patent ductus arteriosus in preterm infants. Pediatrics 115:e255261 40. Flynn PA,da Graca RL, Auld PA, Nesin M, Kleinman CS (2005) The use of a bedside assay for plasma B-type natriuretic peptide as a biomarker in the management of patent ductus arteriosus in premature neonates. J Pediatr 147:38-42 41. Puddy VF, Amirmansour C, Williams AF, Singer DR (2002) Plasma brain natriuretic peptide as a predictor of haemodynamically significant patent ductus arter iosus in preterm infants. Clin Sci (Lond) 103:75-77 42. Sanjeev S, Pettersen M, Lua J, Thomas R, Shankaran S, L'Ecuyer T (2005) Role of plasma Btype natriuretic peptide in screening for hemodynamically significant patent ductus arterio sus in preterm neonates. J Perinatol 25:709-713 43. Holmstrom H, Omland T (2002) Natriuretic peptides as markers of patent ductus arteriosus in preterm infants. Clin Sci (Lond) 103:79-80 44. da Graca RL, Hassinger DC, Flynn PA, Sison CP, Nesin M, Auld PA (2006) Longitudinal changes of brain-type natriuretic peptide in preterm neonates. Pediatrics 117:2183-2189 45. Fried I, Bar-Oz B, Algur N, et al (2006) Comparison of N-terminal pro-B-type natriuretic peptide levels in critically ill children with sepsis versus acute left ventricular dysfunction . Pediatrics 118:e1165- 1168 46. Kaditis AG, Alexopoulos EI, Hatzi F, et al (2006) Overnight change in brain natriuretic peptide levels in children with sleep-disordered breathing . Chest 130:1377 -1384 47. Erkus B, Demirtas S, Yarpuzlu AA, Can M, Gene Y, Karaca L (2007) Early prediction of anthracycline induced cardiotoxicity. Acta Paediatr 96:506- 509 48. Aggarwal S, Pettersen MD, Bhambhani K, Gurczynski J, Thomas R, L'Ecuyer T (2007) B-type natriuretic peptide as a marker for cardiac dysfunction in anthracycline-treated children. Pediatr Blood Cancer 49:812-816 49. Rauchenzauner M, Haberlandt E, Foerster S, et al (2007) Brain-type natriuretic peptide secretion following febrile and afebrile seizures - a new marker in childhood epilepsy? Epilepsia 48:101-106

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Cardiac Dysfunction in Septic Shock 1.

CINEL,

R.

NANDA,

and R.P. DELLINGER

Introduction Clinically, we observe septic shock as increased capillary permeability, hypovolemia, decreased cardiac output, tachycardia, and hypotension. Sepsis-related systolic and diastolic dysfunction are often characterized by depressed ejection fraction, decreased contractility, and impaired relaxation. Mechanisms of cardiac dysfunction require understanding in order to better attack the clinical challenges of treating septic shock. The inflammatory cascade, autonomic dysregulation, adrenergic receptor downregulation, abnormal myocardial calcium utilization, biochemical uncoupling of mitochondrial energy production, and apoptosis have been implicated in sepsis-related cardiovascular dysfunction. The cellular and biochemical relationships that mitigate the pathophysiology of systolic and diastolic dysfunction in sepsis will be discussed in this chapter.

Mechanisms Leading to Cardiac Dysfunction in Sepsis Sepsis is, potentially, the systemic maladaptive response of the host organism to a serious systemic infection. It is a complex immunological, metabolic, and cardiovascular disorder that progresses gradually [1]. Tissue hypoperfusion is driven by some combination of loss of intravascular volume and increase in venous capacitance, arteriolar vasodilation, and cardiac depression ( Fig. 1) [2]. Various pathways have been shown to be associated with myocardial depression in sepsis, but a unifying cause has yet to be found. A major advance in understanding the early events of sepsis has been the identification of Toll-like receptors (TLRs). As a member of the pattern recognition receptors (PRRs), TLRs are the key elements of innate immune responses. It has been shown that TLRs and CD14, the binding protein for lipopolysaccharide (LPS), are expressed on cardiac myocytes [3]. TLRs recognize specific structures of microorganisms and their activation triggers the production of cytokines. Myocardial expression of inflammatory mediators is TLR4-dependent [4]. CD14- and TLR4-deficient mice are protected against LPS-induced inflammation and myocardial dysfunction [5, 6]. Competitive inhibition of functional TLR4 and TLR2 protects cardiac myocyte contractility against LPS and highlights the role of cardiac myocyte TLR expression in the contribution to sepsis-induced myocardial dysfunction [6, 7]. TLR-mediated signaling has been shown to activate the transcription factor, nuclear factor-kappa B (NF-KB), and to upregulate the expression of cytokines and inducible enzymes. This suggests an emerging role for TLRs in the pathogenesis of cardiovascular collapse during sepsis [8]. Recently, novel findings

44

I. Cinel, R. Handa, and R.P. Dellinger

+tJrJr+

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I

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Increased venous capacitance

At • AR

Increased ventricular complia nce

Decreased arteriola r resistance

Fig. 1. Cardiovascular changes associated with septic shock. PVR: peripheral vascular resistance; AO: aorta; VR: venous return; RA: right atrium; RV: right ventride; LA: left atrium; LV: left ventricle; AR: arteriolar resistance; VC: venous capacitance; PA: pulmonary artery; ~: blood flow (cardiac output); -+: contractility. From [2) with permission from Kim et al. reported that, despite smaller infarcts, cardiac function might not be preserved in TLR4-deficient mice [9]. These results indicate that pathogenesis of cardiac dysfunction is complex; while TLRs may be key to the development of cardiac dysfunction, there likely exist other mechanisms causing cardiac depression. The balance between the inflammatory and anti-inflammatory cytokines in sepsis is important in the development of depressed myocardium ( Fig. 2). Human volunteers given tumor necrosis factor (TNF)-a infusion demonstrate similar responses to those seen in clinical septic shock, such as hyperthermia, hypotension, and tachycardia [10]. In beating rat cardiac myocyte cultures, it has been demonstrated that serum from patients with septic shock produced early in vitro depression of cardiac myocyte contractility. These findings in the animal model correlated quantitatively and temporally with the depression of ventricular ejection fraction as seen in the same patients in vivo [11]. This depressant activity represents the synergistic activity of circulating cytokines such as TNF-a and interleukin OL)-I~. In the continuum of this concept, Parrillo's group showed that an anti-inflammatory cytokine, transforming growth factor-beta (TGF-~), preserved contractility of isolated cardiac myocytes in response to cardiodepressant concentrations of TNF-a, IL-l(3, the synergistic combination of the two cytokines, and human septic serum with known depressant activity [12J. The depressant role of IL-6, IL-8, and an anti-inflammatory cytokine, lL-10, in myocardial dysfunction was also demonstrated [13J. A number of important mediators such as endothelin-I (ET-l), nitric oxide (NO) , and mitogenactivated protein kinase (MAPK) pathways, have been proposed to affect myocardial performance during sepsis. The details of regulation of molecular signalization, such

Cardiac Dysfunction in Septic Shock

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Infectious insults Endothelium and myocardium

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Fig. 2. Potential mechanisms leading to cardiac dysfunction in sepsis. Pathogenic mechanisms during sepsis trigger imbalances between inflammatory-anti-inflammatory, oxidant-antioxidant, coagulant-anticoagulant, and apoptotic-antiapoptotic pathways which can lead to intrinsic myocardial dysfunction. TLR: Toll-like receptor; NF-KB: nuclear factor kappa-B; TNF: tumor necrosis factor; IL: interleukin; HMGB-l: high mobility group box-l ; RAGE: receptor for advanced glycation end products; ROCK: RhoA/Rho kinase; PARP-l : poly(ADP ribose) polymerase-l; iNOS: inducible nitric oxide synthase; COX-2: cyclooxygenase-2; ONOO-: peroxynitrite; Cyt C: cytochrome c.

as MAPKs, p38-MAPK, c-Iun N-terminal kinase phosphorylation (JNK), and apoptosis, in the septic myocardium have recently been clarified during early (hyperdynamic) and late (progressive hypodynamic) stages of sepsis [14].

Nitric Oxide The debate continues as to the beneficial or detr imental effects of NO on cardiac function . Historically, NO has been implicated in the reduction of calcium influx via cyclic GMP inhibition of the beta-adrenergic receptors that lead to depressed function. Additionally, NO is postulated to inhibit mitochondrial synthesis of ATP, the energy source needed for myocardial contractility. Conversely, NO has been shown to have vasodilative properties that, perhaps, contribute to beneficial effects in the presence of sepsis-induced cardiovascular changes, to include both afterload reduction in the presence of impaired ventricular systolic performance via arteriolar dilatation, and left and right ventricular dilatation to optimize the Frank-Starling curve principle of volume/pressure loading by increasing left ventricular end diastolic dimensions to enhance myocardial fibril contractile force. A beneficial role for NO

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has been suggested in experimental models of hypoxia-reoxygenation, where pretreatment with cyclic GMP or NO donors may protect myocytes from relaxation failure [15]. At a cellular level, inhibition of platelet aggregation, inhibition of leukocyte adhesion to the endothelium, and macrophage activation by NO may contribute to improved organ perfusion. It has recently been shown that inhaled NO decreases infarction size and improves left ventricular function in experimental myocardial ischemia-reperfusion models [16]. NO-induced toxicity of the mitochondrial oxidative phosphylation apparatus is postulated to be a contributor to organ dysfunction . Excessive NO produ ction during reperfusion appears to alter cardiac diastolic function due to an excess of peroxynitrite (ONOO-) formation [17]. In this context, some of the results may be explained by toxic ONOO--induced activation of matrix metalloproteinases [18].

Mitochondrial Dysfunction An early theory of cardiac depression in sepsis involved decreased oxygen delivery to the heart. This was disproved by two human studies evaluating coronary hemodynamics, which demonstrated that global cardiac perfusion in sepsis is normal or increased [19, 20]. All these observations helped to build the blocks for the concept of cytopathic hypoxia in septic myocardium. Cellular hypoxia (due to circulatory derangements) and dysoxia (due to mitochondrial dysfunction) may both place the cardiomyocyte at risk of energy depletion and cell death if energy demands continue to outstrip supply. Cardiac muscle is highly dependent on mitochondrial oxidative metabolism in the formation of ATP [21]. Muscle biopsies obtained from septic patients, showed a decrease in ATP and an increase in tissue NO in non-survivors verses survivors of septic shock. Increased tissue concentrations of NO were also found to have a correlation with increasing disease severity and higher simplified acute physiology scores (SAPS) [22]. Disruption of oxidative phosphorylation and ATP production has not been directly proven to occur in myocardial cells, but it is reasonable to infer that cardiac dysfunction from such a mechanism contributes to cardiac organ dysfunction from the lack of adequate fuel stores for contractility. Cardiomyocytes demonstrate mitochondrial ultra-structural damage in both septic animals [23] and patients [24]. Increased expression of mitochondrial uncoupling proteins, heat shock proteins (HSP), and the mitochondrial (membrane) permeability transition may also have roles to play in the development of mitochondrial dysfunction or may provide avenues to improve cardiac function [25]. It has been shown that the onset of the hypodynamic phase of sepsis coincides with maximal competitive cytochrome oxidase inhibition and decline in mitochondrial cytochrome c [26]. Logically, increasing the substrate availability of mitochondrial cytochrome c by overpowering competitive enzyme inhibition of cytochrome oxidase can overcome inhibition and restore enzyme velocity. Mitochondrial resuscitation with exogenous cytochrome c has demonstrated that exogenous cytochrome c gains access to cardiomyocyte mitochondria, repletes mitochondrial levels of cytochrome c, restores myocardial cytochrome oxidase activity, and improves cardiac function in early and late stages of sepsis [27].

Cardiac Dysfunction in Septic Shock

Apoptosis Most of the deleterious effects of endotoxin-induced apoptosis have been attributed to increased cell death of circulating lymphocytes, lymphoid tissue resident lymphocytes, and intestinal epithelial cells [28, 29). Alternatively, it has been shown that apopto sis contributes to cardiomyocyte loss leading to failure in the early phase of sepsis. Endotoxin has been shown to trigger p53 upregulation and TNF-a signaled apoptosis of myocardial cells, which is associated with multiple caspase activation and cytochrome c release from the mitochondria as a trigger to the onset of contractile dysfunction in the septic heart [30,31). Overexpression of Bcl-2, an anti-oxidant and anti-apoptotic gene, prevented myocardial dysfunction and improved survival rate in an endotoxemia model [31). Recently, it was confirmed that pre-apoptotic signaling of myocytes, such as caspase activation, has a role in endotoxin-induced cardiac dysfunction [32). In vivo blockade of caspase activity with broad-spectrum agents and effector caspase (i.e., caspase-J) inhibitors reduced endotoxin-induced heart caspase-3 activity and myocardial dysfunction [30). Furthermore, caspase-3 activation has been shown to be related to changes in calcium myofilament response, contractile protein cleavage, and sarcomere disorganization in endotoxininduced cardiomyocyte dysfunction. Targeting caspases in cardiomyocytes is suggested to be beneficial and would be potentially useful in the treatment of myocardial depression in sepsis [33). As a result, it seems plausible that a sequence of inflammatory factors gives rise to myocardial depression. An increased mortality at 3 and 7 days postsepsis is associated with a number of myocardial apoptotic cells. These are correlated with progressive left ventricular dysfunction, elevated concentrations of ET-l, and expression of pro-apoptotic proteins (e.g., Bax) and caspase-3 [14). The progression of sepsis from day 1 to days 3 through 7, produces distinct cardiodynamic characteristics with a more profound effect during later stages.

Calcium Utilization Cardiac myocyte contraction is dependent on the influx of calcium from the sarcoplasmic reticulum into the cytosol, facilitating the interaction of myosin with actin filaments to produce shortening of the cardiac muscle fiber. Troponins and tropomyosin act in the binding of calcium and regulation of filament interaction. Re-sequestration of calcium at the termination of contraction initiates cardiac relaxation. Disruption of calcium cycling is postulated to cause cardiac dysfunction [34). The ryanodine receptor, when activated, releases calcium from the sarcoplasmic reticulum, but in septic models these receptors have been shown to have a decreased density, consequently leading to a decrease in available calcium for muscle contraction [35). Endotoxin has been shown to depress cardiac function by altering calcium regulation in animal models [36). Inadequate availability of calcium for proper actin and myosin interaction contributes to inefficient cardiac myocyte contractions. Sensitization of calcium binding sites has been a novel concept in the development of new cardiac inotropes, such as levosimendan .

Systolic and Diastolic Cardiac Dysfunction in Sepsis Decreased cardiac filling is almost universally present in early severe sepsis due to capillary leak and venodilation. This clinical problem is correctable with adequate

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fluid resuscitation. Arteriolar vasodilation is associated with decreased tissue perfusion pressure and is corrected with targeted vasopressor therapy. Depression of contractility is targeted, when necessary, with inotropic therapy. The role of diastolic dysfunction has been recently recognized. Despite the presence of myocardial dysfunction in septic shock, the frequently observed increased cardiac output in the hyperdynamic state is achieved with some combination of increased diastolic ventricular dimension, tachycardia, and decreased systemic vascular resistance. However, both systolic and diastolic dysfunctions can be simultaneously present in severe sepsis and septic shock. The mechanisms of systolic dysfunction in sepsis occur on numerous levels. Following fluid resuscitation, septic shock patients can manifest a hemodynamic profile characterized by a decreased systemic vascular resistance and increased cardiac index, generally requiring continued volume resuscitation in order to maintain adequate stroke volume and mean arterial pressure due to venodilation and continued capillary leakage ( Fig. 3). In septic shock patients and in animal models, a depressed ejection fraction with the accompanied physiological response of increased left ventricular end-diastolic volume and increased cardiac index following adequate fluid resuscitation has been demonstrated [37]. This end-diastolic dilatation may be an adaptive response to the decreased ejection fraction allowing higher stroke volume with any given contractile state based on the Frank-Starling mechanism of enhanced contractility with increasing myocardial fiber stretch. Different patterns exist between survivors and non-survivors of septic shock. Survivors often exhibit reduced ejection fraction and increased left ventricular end-diastolic dimensions which can represent an adaptive response. It has been demonstrated through radionuclide scanning that non-survivors are unable to dilate the left ventricle in order to compensate for reduced stroke volume in the face of a depressed ejection fraction . It has been postulated that a less compliant ventricle is caused by infiltration of polymorphonuclear cells within the myocardial fibers [38]. Ionic derangements, impaired intracellular calcium trafficking, reduced myofilament calcium sensitivity, and ryanodine receptor activity may also account for some of the systolic abnormalities observed in sepsis [35]. Microcirculatory changes, such as increased capillary permeability, cause hypovolemia leading to a low preload state for left ventricular filling. This leads to lower

-

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Fig. 3.Relationship between venous return and cardiac function. Fluid resuscitated septic shock patients can manifest a hemodynamic profile characterized by a decreased systemic vascular resistance and increased cardiac index and generally require continued volume resuscitation in order to maintain adequate stroke volume and mean arterial pressure. From [611 with permission.

Cardiac Dysfunction in Septic Shock

stroke volumes that may contribute to depressed organ perfusion and hypotension . The mainstay treatment of resuscitation in septic shock-induced hypotension is believed to be aggressive fluid administration [1]. However, following volume resuscitation, the institution of vasopressor and inotropic support may be required to maintain mean arterial pressure. It has been demonstrated that volume repletion of septic shock patients improves stroke volume and cardiac output, as evidenced by increased left ventricular stroke work index [39]. Tachycardia is a predictable response to hypovolemic states that helps to maintain cardiac output. Excessive tachycardia leads to a decrease in diastolic filling time and decreased left ventricular end-diastolic volume. A decrease in heart rate following volume resuscitation is predictive of improved outcomes [40] . Atrial fibrillation in the setting of septic shock would be predicted to be particularly problematic with the loss of atrial kick contributing to a depressed stroke volume. It is well established that heart failure is associated with increased natriuretic peptide levels. Various forms of natriuretic peptides have also been demonstrated to be elevated in septic patients with higher levels correlating with worse outcome. However, elevated natriuretic peptides have been shown to have poor correlation with cardiac function . Right ventricular failure, renal failure, and central nervous system (eNS) disease, are a few settings in which different forms of natriuretic peptide can be elevated without relation to actual left ventricular function [41]. In septic shock, measurement of B-type natriuretic peptide (BNP) appears poorly predictive of cardiac dysfunction. Elevated troponins have been associated with higher levels of TNF-a and IL-6 [42J, implying some degree of sepsis-associated cardiac cell injury [43]. TNF-a and IL-l~, and other cytokines have been found to directly depress myocardial function [44J . Troponins can be used to predict prognosis and impaired systolic dysfunction [42]. Left ventricular diastolic dysfunction is defined by abnormalities of diastolic distensibility, filling, or relaxation, independent of the ejection fraction [45]. The inability of the left ventricular chamber to fill at low atrial pressures can result from either impairment in left ventricular compliance (passive mechanism) or from an alteration in left ventricular relaxation (active process). The transition between contraction and relaxation corresponds to the dissociation of actin-myosin crossbridges that begins during the early phase of left ventricular ejection and before aortic valve closure [46J . Thus, alterations leading to diastolic dysfunction may involve phenomena that occur not only during 'classic' diastole, but also earlier in the cardiac cycle, when intracellular calcium decreases. An example of this is disordered calcium trafficking leading to cardiac dysfunction. Left ventricular relaxation is greatly affected by the lack of homogeneity in left ventricular contraction. Both left ventricular segmental coordination and atrio-ventricular synchronization are essential to guarantee efficient relaxation in the diastolic phase [47J. In addition to the contraction-relaxation coupling, alterations in myocyte energetic balance have a role in left ventricular relaxation [46J . Myocardial relaxation was initially considered to be affected by afterload conditions only. Ventricles with altered contractile function consistently show a 'decreased afterload reserve' or the inability of the left ventricle to respond to elevations of afterload without appropriate increases in left ventricular end-systolic volume and pressure in order to maintain stroke volume [48]. However, it has been suggested that right ventricular loading can modify actin-myosin cross-bridge kinetics and favorably improve left ventricular function [49J. This introduced the concept of 'pre-

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load reserve' or that any excess fluid can induce a dramatic increase in left ventricular end-diastolic pressure. Preload reserve is reduced in patients with altered left ventricular diastolic properties, thus preventing a normal increase in the pressurevolume relationship in response to increases in afterload . Left ventricular filling mainly depends on the pressure gradient between the left atrium and the left ventricle, which is influenced by passive chamber properties (compliance), the active process of left ventricular relaxation, and end-diastole atrial contraction (atrial kick). Thus, impairment ofleft ventricular compliance (decreased left-atrial-left ventricular pressure gradient) , or the loss of atrial contraction, directly impairs diastolic filling. In sepsis-induced left ventricular diastolic dysfunction, the diastolic portion of the pressure/volume loop (compliance curve) is shifted to the left and upward. In systolic dysfunction , the end-systolic pressure/volume slope is shifted downward and to the right, indicating a reduction in contractility, with increased end-systolic and end-diastolic left ventricular volumes [45]. In combined systolic and diastolic dysfunction , as seen in sepsis, modest increases in left ventricular end-diastolic volume may result in large increases in left ventricular enddiastolic pressure . In addition to leukocyte infiltration, left ventricular compliance and function can be altered by other mechanisms . Delayed relaxation and impaired compliance are likely to be related to nitration of contractile proteins rather than alterations in calcium homeostasis in sepsis [50]. It has been demonstrated that contractile proteins such as myosin appear to be specifically nitrated by toxic peroxynitrite in the myocardium of patients who die of septic shock [51].

Beta-adrenergic Hyporesponsiveness and Hibernation in Septic Shock Models of septic shock have shown myocardial hyporesponsiveness to beta-adrenergic stimulation. Beta receptor hyporesponsivenes may be accounted for by dopamine resistance as ident ified in previous clinical studies [52]. This is supported by a similarly designed study using dobutamine which also showed a hyporesponsiveness to beta agonism in septic shock patients [53]. A downregulation in receptor density or responsiveness to surges or exogenous administration of catecholamines, suggests the need to explore other avenues of stimulus for improvement of cardiac function . Such explored alternatives include novel inotropic agents such as calcium sensitizing agents like levosimendan. Although the response of the myocardium to ischemia is strikingly similar to sepsis-associated myocardial depression, a key difference between sepsis-associated myocardial depression and ischemic myocardium is impaired oxygen utilization, not oxygen supply. Coronary perfusion does not seem to be affected, despite coexisting myocardial depression [19,20]. An interruption in oxidative phosphorylation within mitochondria dur ing sepsis and irreversible cytochrome oxidase inhibition as a mechanism has been termed cytopathic hypoxia [54]. During ischemia and hypoxia, reversibly hypocontractile cardiomyocytes maintain viability by downregulating oxygen consumption, energy requirements, and ATP demand. This adaptive response is known as myocardial hibernation [55]. Hibernating cardiomyocytes are reversibly hypocontractile and demonstrate characteristic metabolic and ultrastructural changes that maintain viability during hypoxia or a 'functionally hypoxic state' despite the presence of oxygen seen in sepsis [56]. Postmortem examinations of septic patients reveal histologic absence of injury and

Cardiac Dysfunction in Septic Shock

little cell death despite profound organ dysfunction [57]. Thus it is possible that sepsis-associated organ dysfunction may reflect underlying cellular hibernation where cells maintain viability by reducing oxygen consumption and energy requirements. However, hibernation, although potentially adaptive during ischemia and hypoxia, may be pathologic during sepsis and, if persistent, may ultimately result in death .

lactate: the New Fuel Classically lactate has been thought of as a byproduct of hypoxia or tissue hypoperfusion. Recently, the paradigm may be changing. The presence of lactate in the blood is a balance of consumption and production. Lactate is a product of pyruvate + NADH + H+. Two essential instances can increase lactate formation: 1) mitochondria being overwhelmed by pyruvate, and 2) any increase in glycolysis [58]. Pyruvate is oxidized in the mitochondria to NADH which yields 36 molecules of ATP for each molecule of pyruvate. Lactate itself is transformed into oxaloacetate and alanine which then can be utilized by the liver to produce glycogen and glucose via the Cori cycle. Thus, lactate can be transformed into glucose. Hypoxic lactate formation is a result of an imbalance between ATP and NADH/ NAD. The increase in NADH shifts to an accumulation of pyruvate which in turn produces hyperlactemia. It is important to recall that in anaerobic metabolism, the yield of ATP is only 2 molecules. Anaerobic metabolism parallels cardiogenic shock and hemorrhagic shock. In septic shock, two entities mimic anaerobic production of lactate: 1) catecholamine resistant circulatory shock, and 2) prior to volume resuscitation. Lactate format ion in aerobic metabolism is a situation of the mitochondria being overwhelmed by pyruvate. This occurs when there is excess of glucose or muscle/protein catabolism. Aerobic metabolism of pyruvate may play a larger role in the production of lactate in organs that preferentially receive oxygen in septic states, while organ beds that suffer from deprivation of perfusion or oxygen conserve glucose. This theory has been entitled the "lactate shuttle" [58]. Revelly et al. [59] were able to demonstrate, in a small cohort of cardiogenic shock and septic shock patients, an increase in lactate production with lactate clearance similar to that of healthy patients. Lactate production was also in concordance with hyperglycemia, indicating possible lactate conversion to glucose for metabolism. More recently, Levyet al. [60] were able to demonstrate that lactate deprivation is detrimental to cardiovascular performance, indicating that heart muscle is a vascular bed that is a highly oxidative metabolic machine in the septic shock/stressed states and utilizes lactate as a substrate for energy. In this animal model, beta-2 inhibition was accomplished with a beta-2 receptor blocker (ICI-1l8551) and dichloroacetate, a stimulant of pyruvate dehydrogenase. The result was a decrease in muscle lactate formation . Frank cardiovascular collapse followed when lactate was added to beta-2 inhibition , the hemodynamic response was not as fulminant with increase in aortic blood flow supporting lactate dependence for maintenance of hemodynamic stability [60].

Conclusion Mortality rates remain high in severe sepsis and despite advances in therapy much remain s to be done to advance our understanding of organ dysfunctions in sepsis.

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The roles of TLRs as a member of the pattern recognition receptors, inflammatoryanti-inflammatory cytokines, oxidant-antioxidant balance (with the importance of reactive nitrogen species, such as NO and peroxynitrite) are now recognized. Mitochondrial dysfunction , including the changes in cytochrome oxidase activity and mitochondrial permeability transition resulting in cytochrome c release, altered calcium regulation and, lastly, apoptosis (with the importance of caspase 3 and Bcl-2 or Akt balance) have been described in sepsis-induced cardiac dysfunction. Distinct cardiodynamic and molecular characteristics during early and late stages of sepsisinduced myocardial dysfunction and the presence of both systolic and diastolic dysfunctions simultaneously have been clarified. Understanding mechanisms behind precisely defined sepsis-induced cardiac dysfunction will likely lead to specific management tools that will improve clinical outcomes. References I. Cinel I, Dellinger RP (2007) Advances in pathogenesis and management of sepsis. Curr Opin in Infect Dis 20:345-352 2. Dellinger RP (2003) Cardiovascular management of septic shock . Crit Care Med 31:946-955 3. Frantz S, Kobzik L, Kim YD, et al (1999) Toll 4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104:271- 280 4. Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann DL, Vallejo JG (2001) In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4. J Infect Dis 183:1617 - 1624 5. Knuefermann P, Nemoto S, Misra A, et al (2002) CDl4 -deficient mice are protected against lipopol ysaccharide-induced cardiac inflammation and left ventricular dysfunction. Circulation 106:2608-2615 6. Baumgarten G, Knuefermann P, Schuhmacher G, et al (2006) Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia. Shock 25:43-49 7. Zhu X, Bagchi A, Zhao H, et al (2007) Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction . Crit Care Med 35:886- 892 8. Brown MA, Jones WK (2004) NF-kappaB action in sepsis: the innate immune system and the heart. Front Biosci 9:1201-1217 9. Kim SC, Ghanem A, Stapel H, et al (2007) Toll-like receptor 4 deficiency : smaller infarcts , but no gain in function. BMC Physiol 7:5 10. Van der Poll T, Romijn JA, Endert E, Borm 11, Buller HR, Sauerwein HP (1991) Tumor necro sis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol 261:E457-465 II. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W (1985) A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest 76:1539-1553 12. Kumar A, Kumar A, Paladugu B, Mensing J, Parrillo JE (2007) Transforming growth factorbetal blocks in vitro cardiac myocyte depression induced by tumor necrosis factor-alpha , interleukin-l beta, and human septic shock serum. Crit Care Med 35:358-364 13. [oulin 0, Petillot P, Labalette M, Lance! S, Neviere R (2007) Cytokine profile of human septic shock serum inducing cardiomyocyte contractile dysfunction. Physiol Res 56:291- 297 14. Chopra M, Sharma AC (2007) Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction. Life Sci 81:306-316 15. Schluter KD, Weber M, Schraven E, Piper HM (1994) NO donor SIN-l protects against reoxygenation-induced cardiomyocyte injury by a dual action. Am J Physiol 267:HI461-1466 16. Hataishi R, Rodrigues AC, Neilan TG, et al (2006) Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 291:H379-384 17. Xie YW, Kaminski PM, Wolin MS (1998) Inhibition of rat cardiac muscle contraction and

Cardiac Dysfunction in Septic Shock mitochondrial respiration by endogenous peroxynitrite formation during posthypoxic reoxygenation. Circ Res 82:891- 897 18. Wang W, Sawicki G, Schulz R (2002) Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res 53:165-174 19. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE (1986) The coronary circulation in human septic shock. Circulation 73:637- 644 20. Dhainaut JF, Huyghebaert MF, Monsallier JF, et al (1987) Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation 75:533- 541 21. Barth E, Albuszies G, Baumgart K, et al (2007) Glucose metabolism and catecholamines . Crit Care Med 35 (suppl 9):S508-518 22. Brealey D, Brand M, Hargreaves 1, et al (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219-223 23. Suliman HB, Welty-WolfKE, Carraway MS, Tatro L, Piantadosi CA (2004) Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc Res 64: 279-288 24. Soriano FG, Nogueira AC, Caldini EG, et al (2006) Potential role of poly (adenosine 5'diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit Care Med 34:1073-1079 25. Larche J, Lancel S, Hassoun SM, et al (2006) Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 48:377-385 26. Levy R1, Vijayasarathy C, Raj NR, Avadhani NG, Deutschman CS (2004) Competitive and noncompetitive inhibition of myocardial cytochrome c oxidase in sepsis. Shock 21:110-114 27. Piel DA, Gruber PJ, Weinheimer C], et al (2007) Mitochondrial resuscitation with exogenous cytochrome c in the septic heart. Crit Care Med 35:2120- 2127 28. Hotchkiss RS, Tinsley KW, Swanson PE, et al (1999) Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Nat! Acad Sci USA 96:14541-14546 29. Cinel I, Buyukafsar K, Cinel L, et al (2002) The role of poly (ADP-ribose) synthetase inhibition in preventing endotoxemia-induced intestinal epithelial apoptosis. Pharmacol Res 46: 119-127 30. Neviere R, Fauvel H, Chopin C, et al (2001) Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis. Am J Respir Crit Care Med 163:218-225 31. Lancel S, Petillot P, Favory R, et al (2005) Expression of apoptosis regulatory factors during myocardial dysfunction in endotoxemic rats. Crit Care Med 33:492-496 32. Carlson DL, Willis MS, White DJ, Horton JW, Giroir BP (2005) Tumor necrosis factor-alphainduced caspase activation mediates endotoxin -related cardiac dysfunction. Crit Care Med 33:1021-1028 33. Lancel S, Ioulin 0, Favory R, et al (2005) Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunct ion. Circulation 111:2596 - 2604 34. Ren 1, Ren BH, Sharma AC (2004) Sepsis-induced depressed contractile function of isolated ventricular myocytes is due to altered calcium transient properties. Shock 18:285-288 35. Dong LW, Wu LL, [i Y, Liu MS (2001) Impairment of the ryanodine-sensitive calcium release channel s in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. Shock 16:33- 39 36. Zhong J, Hwang T-C, Adams HR, Rubin LJ (1997) Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am J Physiol Heart Circ PhysioI273:2312-2324 37. Parrillo JE, Parker MM, Natanson C, et al (1990) Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 113:227- 242 38. Fernandes Junior C], Iervolino M, Neves RA, Sampaio EL, Knobel E (1994) Interstitial myocarditis in sepsis. Am J Cardiol 74:958-962 39. Rackow EC, Kaufman BS, Falk JL, Astiz ME, Weil MH (1987) Hemodynamic response to fluid repletion in patients with septic shock: evidence for early depression of cardiac performance. Circ Shock 22:11- 22 40. Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE (I987) Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis . Crit Care Med 15:923-929

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I. CineI, R. Nanda, and R.P. Dellinger 41. Boldt J, Suttner SW (2006) Physiology and pathophysiology of the natriuretic peptide system. In: Vincent JL (ed) Yearbook ofIntensive Care and Medicine, Springer-Verlag, Heidelberg, pp 101-109 42. Maeder M, Fehr T, Rickli H, Ammann P (2006) Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic pep tides. Chest 129:1349-1366 43. McLean AS, Huang SJ, Hyams S, et al (2007) Prognostic values of B-type natriuretic peptide in severe sepsis and septic shock. Crit Care Med 35:1019-1026 44. Ammann P, Maggiorini M, Bertel 0, et al (2003) Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coli Cardiol 41:2004-2009 45. Pirracchio R, Cholley B, De Hert S, Solal AC, Mebazaa A (2007) Diastolic heart failure in anaesthesia and critical care. Br J Anaesth 98:707- 721 46. Rabuel C, Mebazaa A (2006) Septic shock: a heart story since the 1960s. Intensive Care Med 32:799-807 47. Aurigemma GP, Gaasch WH (2004) Clinical practice . Diastolic heart failure. N Engl J Med 351:1097-105 48. Pennock GO, Yun DO, Agarwal PG, Spooner PH, Goldman S (1997) Echocardiographic changes after myocardial infarction in a model of left ventricular diastolic dysfunction. Am J Physiol 273:H2018-2029 49. De Hert SG, Gillebert TC, Ten Broecke PW, Mertens E, Rodrigus IE, Moulijn AC (1999) Contraction-relaxation coupling and impaired left ventricular performance in coronary surgery patients. Anesthesiology 90:748 -757 50. Tavernier B, Garrigue 0, Boulle C, Vallet B, Adnet P (1998) Myofilament calcium sensitivity is decreased in skinned cardiac fibres of endotoxin -treated rabbits. Cardiovasc Res 38: 472479 51. Rabuel C, Renaud E, Brealey 0, et al (2004) Human septic myopathy: induction of cyclooxygenase, heme oxygenase and activation of the ubiquitin proteolytic pathway. Anesthesiology 101:583 - 590 52. Levy B, Dusang B, Annane 0, Gibot S, Bollaert PE (2005) Cardiovascular response to dopamine and early prediction of outcome in septic shock: a prospective multiple-center study. Crit Care Med 33:2172-2177 53. Silverman HJ, Penaranda R, Orens JB, Lee NH (1993) Impaired beta-adrenergic receptor stimulation of cyclic adenosine monophosphate in human septic shock: association with myocardial hyporesponsiveness to catecholamines. Crit Care Med 21:31-39 54. Levy RJ, Vijayasarathy C, Raj NR, Avadhani NG, Deutschman CS (2004) Competitive and noncompetitive inhibition of myocardial cytochrome c oxidase in sepsis. Shock 21:110-114 55. Budinger GR, Duranteau J, Chandel NS, Schumacker PT (1998) Hibernation during hypoxia in cardiomyocytes. Role of mitochondria as the 02 sensor. J BioI Chern 273:3320-3326 56. Levy RJ, Piel DA, Acton PO, et al (2005) Evidence of myocardial hibernation in the septic heart. Crit Care Med 33:2752-2756 57. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138-150 58. Levy B (2006) Lactate and shock states; the metabolic view. Curr Opin Crit Care Med 12:315-321 59. Revelly JP, Tappy L, Martinez A, et al (2005) Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med 33:2235- 2240 60. Levy B, Mansart A, Montemont C, et al (2007) Myocardial lactate deprivation is associated with decreased cardiovascular performance, decreased myocardial energetics, and early death in endotoxic shock. Intensive Care Med 33:495- 502 61. Myburgh JA (2006) An appraisal of selection and use of catecholamines in septic shock - old becomes new again. Critical Care and Resuscitation 8:353-360

55

The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome H.

SCHMIDT,

U.

MULLER-WERDAN,

and K.

WERDAN

Link between Autonomic Dysfunction and Inflammation: The 'Cholinergic Anti-inflammatory Pathway' The development of multiple organ dysfunction syndrome (MODS) is characterized by activation of innate immunity, resulting in an inappropriate release of inflammatory mediators leading to cellular damage in parenchymal organs and to inflammatory, metabolic, and neuroendocrine disturbances [1]. There is increasing evidence that autonomic dysfunction may contribute substantially to the development of MODS since continuous communication between all vital organs through autonomic nervous system signals is a fundamental feature in healthy humans [2, 3]. An 'uncoupling' of these neurally mediated organ interactions in MODS and sepsis may potentially alter neural reflexes and thus cause a disruption of appropriate interorgan communication, thereby advancing single organ dysfunction into MODS. There may also be a diminished reactivity of the organ to reflex stimuli. Taking into consideration the interference of the mediators and toxins with cardiac cellular signal transduction, blunted or dysfunctional cellular responses possibly contribute to decreased reflex responses of the target organ, leading to an impairment in the autonomic balance of the heart. Tracey and colleagues [4, 5] recently described a mechanism for prevention of excessive cytokine spillover into the circulation, which is based on structures of the autonomic nervous system. The hypothesis behind this observation was that the central nervous system (eNS) adjusts many physiological variables, such as heart rate, blood pressure, and respiration, via innervated circuits. It would be very useful to control such a potentially deadly cytokine response [6, 7] as is seen in sepsis and MODS. The vagal nerve is most appropriate to adapt cytokine release in sepsis and MODS since it innervates a large number of the thoracic and abdominal organs and contains afferent fibers [8]. The afferents within the vagus nerve may be the sensory arm of the inflammatory reflex, which guide information concerning local infection to the central brain structures in which they are integrated and adapted and from which an efferent response will be sent to the target organs and cells [8- 10]. The central vagal signal is modulated by a muscarinergic-responsive brain network since intracerebroventricular administration of muscarinergic agonists may decrease serum levels of tumor necrosis factor (TNF)-a during endotoxemia [11]. As a result of this increased efferent vagal traffic, the prognostically relevant depression of heart rate variability (see below) is ameliorated [8]. The efferent arm of the above characterized inflammatory reflex is now called the 'cholinergic anti-inflammatory pathway' [8].

56

H. Schmidt, U. Miiller-Werdan, and K. Werdan

Baroreflex (Vagus 1) Chemoreflex (Sympat hetic 1) Figoreflex (Sympat hetic 1)

.........

Organ compartment of the reticuloendothelial system

TNF

IL-l HMGB l

Fig. 1. The cholinergic anti-inflammatory reflex. TNF: tumor necrosis factor; IL: interleukin; HMGB: high mobility group box protein; Ach: acetylcholine. (adapted from [4]).

The major neurotr ansmitter of the vagus is acetylcholine. It has been clearly shown that macrophages (but also lymphocytes and microglia) are able to express acetylcholine receptors, which mediate the signal intracellularly and thus blunt cytokine synthesis. The a 7 subunit of the nicotinic acetylcholine receptor is the receptor that is most promising in suppression of cytokines [8]. Signal transduction of the a7 subunit of the nicotinic acetylcholine receptor is influenced by ligand-gated ionchannel functionality [8]. Activation of the receptors elicits a blunted nucle ar translocation of nuclear factor kappa-B (NF-KB) and activation of the transcription factor, signal transducer and activator of transcription 3 (STAT3), via a Janus kinase (JAK)2-mechanism [1]. Figure 1 summarizes the interplay of the cholinergic antiinflammatory reflex and the major autonomic reflexes. The aforementioned data implicate an intact vagal-sympathetic balance as a prerequisite for inflammatory control. But how can this well-balanced situation be achieved? The sophisticated sympathetic-parasympathetic (vagal) balance is maintained by several reflex arches, constructed in the same pattern. In general, the basic elements of a cardiovascular reflex include four groups of neurons [12, 13]: • Sensory endings, detecting mechanical (baroreceptors), biochemical or metabolic (e.g., arterial chemoreceptors), and physicochemical (e.g., therrnoreceptors) changes. The afferent endings of these neurons project to the medulla oblongata, especially to the nucleus tractus solitarius. • Central neurons receive information from the afferent neurons and send it to sympathetic or parasympathetic (vagal) efferents.

The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome

• Neuron s from upper parts of the e NS can modulate the discharge chara cteristics of the central neurons. • Efferent sympathetic and vagal neurons ru n in a contralateral reticulospinal projection to innervate heart, blood vessels and respiratory muscles. The nucleus trac tus solitari us is the central integrating location in the medulla oblongata, receiving afferent neuron s both from arterial and card iopulmonary baroreceptors, from the central and peripheral arterial chemor eceptors . These examples reveal that unde r physiological condition s the sympathetic-vagal balance is a result of interactions and interferences of several antagonistic reflexes. When we look for the cardiovascular autonomic reflexes in patient s with MODS, as can been done by measuring heart rate variability, baroreflex sensitivity, and chemoreflex sensitivity ( Table 1), we find a dram atic reduction in sympathetic as well as vagal activity to the cardiovascular system. This card iovascular autonomic dysfunction (Table 2) indicates a bad progn osis for these MODS patient s, as can be shown best by a marker of vagal activity, the 'very low frequenc y (VLF)' domain of heart

Table 1. Major autonomic reflexes and their main impact on the autonomic nervous system Receptor

Location

Afferent nerve

Stimulus

Vaga l or sympathetic

I. Peripheral arterial chemoreceptors

carotid sinus, aortic arch

9th and 10th cranial nerve

Alterations in PaOlo pH, PaC0 2

Mainly sympathoexcitatory but also activation of the dorsal vaga l nucleus

II. Arterial baroreceptors

carotid sinus, aortic arch

9th and 10th cranial nerve

Changes in arterial blood pressure

Vagal activation and

III. Ergoreflexes

skeletal muscles

small fibers 10th cranial nerve

Products of muscle work

Mainly sympathoexcit atory

activation

sympathetic suppression

Pa0 2: arterial oxygen tension; PaC0 2: arterial carbon dioxide tension

Table 2. Autonomic dysfunction in a cohort of patients with multiple organ dysfunction syndrome(MODS) as assessed by 24-hour-electrocardiograph (EKG) as well as measurement of baro- and chemoreflex sensitivity [2]. HRV variable SDNN (msec) pNN50 (%) LF (rnsec') HF (msec') VLF (rnsec-l LF/HF (rnsec') Baroreflex sensitivity (ms/mmHg) Chemoreflex sensitivity (ms/mmHg)

Normal range G

V S+V V V SIV

MODS patients

p value

141 + 39 9+ 7 791 + 563 229 + 282 1782 + 965 4.61 + 2.33 > 6.1

.i .i .i .i .i .i .i .i .i .i .i .i .i .i

57.7 + 30.7 4.8 + 8.4 129.3 + 405.1 112.3 + 267.3 191.3 + 661.1 1.1 + 0.9 1.6 + 1.5

< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001

0.9 + 0.5

.i .i

0.5 + 0.4

< 0.0001

G: total variability; S: sympathetic nervous system; V: vagus; HRV: heart rate variability; HF: high frequency; LF: low frequency; VLF: very low frequency; SDNN: standard deviation of all normal-to-normal RR intervals; pNN50: percentage of differences of successive RR intervals differing > 50 msec

57

58

H. Schmidt, U. Miiller-Werdan, and K. Werdan

rate variability: patients in whom the the InVLF is < 3.9 have a mortality risk nearly 3-fold higher than patients with a InVLF > 3.9 [2]. This strong depression of cardiovascular autonomic function poses three questions: a) what are the mechanisms of cardiovascular autonomic dysfunction in MODS patients, b) can the strongly dampened vagus activity still exert its beneficial effects ('cholinergic anti-inflammatory reflex'; and c) does therapeutic improvement of vagal activity give these patients a better prognosis?

Heart Rate 'Stiffness' as a Measure of Cardiac Autonomic Dysfunction in Patients with MODS: Possible Mechanisms Godin et al. demonstrated that intravenously applied endotoxin can induce reversible heart rate 'stiffness' in healthy volunteers [14]. One can, therefore, speculate that endotoxin and pro-inflammatory mediators contribute to the impaired cardiac autonomic function seen in patients with MODS. The observed decrease in heart rate variability in patients with MODS must be due to a strongly impaired regulation of the heart rate by rate-increasing sympathetic and rate-decreasing vagal activity. The efferent sympathetic and vagal signals to the heart start in the brain, run through the autonomic nervous system, and finally use the binding of the neurotransmitters, norepinephrine and acetylcholine, to the cardiac adrenoceptors and muscarinergic receptors to trigger signal transduction pathways in the pacemaker cells, which results in a modulation of the pacemaker current, the latter mainly mediated by

Control

1:1 a

-8

1~1 b

-8

-60 mV -70 mV

'ii Vi o,

-80 mV -:: 0>

I

I

0

t (5)

2

-90 mV

I

3

11lg/m l LPS -60 mV -70 mV -80 mV -90 mV j

I

0

t (5)

2

G:'

.2VI

.30>

I

3

o1~1 LPS ~

1·4~: =:~ ~: i -60 mV

-

c

90 mV

-8

I

0

,

I

t (5)

2

I

3

0>

Fig. 2. Effects of endotoxin on If current in isolated human atrial myocytes from right atrial appendages, as measured by the whole-cell patch-damp technique. Representative current recordings from an untreated cell (a) and from two endotoxin-incubated cells ( b 1 ~g/mJ. c 10 ~g/ml) . Hyperpolarizing steps were applied from a holding potential of -40 to - 140 mV (10-mV increment). The three cells had comparable maximal conductance values (= 90 pS/pF). (adapted from [16)).

The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome

3

2

Fig. 3. Absolute mean current-density values of control and LPS-incubated myocytes (1 and lOllg/ml) (adapted from [16]).

Control (29) . 11l9/ml (9) • 10llg/ml (19)

O +----,---'--'--r--=---~--=--

-60

-70

-80

-90

Vm(mV)

HCN channel (hyperpolarization-activated cyclic nucleotide-gated channel) activity (Lcurrent; "f" = funn y, as the current is triggered by hyperpolarization). In principal, impairment can occur at any of the levels mentioned. The described experiment s by Godin et al. [14) cannot, however, provide the answer to whether heart rate 'stiffness' is due to an endotoxin-induced alteration of the brain, the autonomic nervous system, or the pacemaker cell itself. Having shown that endotoxin can redu ce beating rate variability in spontaneously beating neonatal rat heart cells in culture [15], we hypothesized that endotoxin-induc ed heart rate 'stiffness' is mediated - at least in part - by a direct interaction of endotoxin with the signal transduc tion pathways and ion channels by which the sympathetic and the vagal nerves exert their chronotropic effects. A likely target for endotoxin is the pacem aker current Ir which is mainly driven by the HCN channels (L, see above). Indeed, in our whole patch-clamp experiments with isolated human myocytes from right atrial appendages, endotoxin (1, 10 flg/ml) significantly impaired If by suppressing the current at membrane potentials positive to -80 mV and slowing down current activation, but without affecting maximal current conduction (Figs. 2, 3) [16). Furthermore, in endotoxin-incubated cells, the If respon se to ~-adrenergic stimulation (1 flM isoproterenol) was significantly larger compared with control cells (shift of half-maximal activation voltage to more positive potentials amounted to -10 and -14 mV in untreated and treated cells, respectively). Simulations using a spontaneously active sinoatrial cell model demonstrated that endotoxin-induced If impairment reduced the respons iveness of the model cell to fluctuations in autonomic input [16). In summar y, our experiments [16] demonstrate a direct impact of endotoxin on the cardia c pacem aker current, If. This endotoxin-induced If impairment may contribute to the clinically observed reduction in heart rate variability in MODS patients . These observation s indicate that autonomic dysfunction is not only triggered by an alteration in the autonomi c nervous system itself, but also by an impairment of the signal transduction path ways/ion channels mediating the autonomic ner vous signals in the target cell. In MODS, a reduction in heart rate variability correlates with an unfavorable prognosis [2). It has been propo sed that in early sepsis, an uncoupling of organ systems involved in heart rate regulation (e.g., autonomic system, sinus node, and systemic blood vessels) occur s [6).

59

60

H. Schmidt, U. Miiller-Werdan, and K. Werdan

~t;iA/I: ~

Cardiovascular control

Respiratorycontrol

Parasympathetic NS

1

LPS (Sepsis/MODS) Pacemakercurrent Ifunny I

!

Heart rate

~

variability I

Fig. 4. Possible cellular mediation ofdepressed heart rate variability in sepsis and MODS. LPS: lipopolysaccharide; NS: nervous system

Figure 4 summarizes the proposed mechanisms of reduced heart rate variability in

MODS.

(an We Increase the Depressed Vagal Activity in Patients with MODS and, Thereby, Improve Prognosis? Tracey [8] has made several suggestions of ways in which the impaired cholinergic anti-inflammatory reflex could be strengthened in a causal manner, including application of nicotinic patches, acupuncture, or application of vagus stimulation devices. However, no controlled clinical trials are available concerning these suggestions. We chose another approach, by looking in MODS patients for the effects of drugs, which have well-documented beneficial effects in patients with heart diseases like coronary heart disease and heart failure, to determine whether with these beneficial effects were accompanied by an increase in the reduced heart rate variability in these patients. We, therefore, analyzed, in retrospective case control studies, the mortality of MODS patients who were, at the initial phase of MODS, being treated or not with statins, beta-blo ckers, or angiotensin converting enzyme (ACE) inhibitors.

Statins 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitors ('statins') are known to possess, beside their cholesterol-lowering properties, 'pleiotropic' antiinflammatory and immunomodulatory characteristics. These properties seem to be beneficial in reducing cardiovascular events in patients with coronary artery disease and also, surprisingly, in preventing sepsis, exo- and endotoxic shock [17, 18]. Thus, Almog et al. [19] have recently shown that prior therapy with statins may be associated with a reduced rate of severe sepsis and intensive care unit (lCU) admission in patients admitted with acute bacterial infection. Kruger et al. [20] assessed the association between statin administration and mortality in bacteremic patients and found a significant survival benefit associated with statin therapy.

The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome

12

ro > .~

~

Q)

> .."

Cho leste ro l

10

- - '"j

~ -,-- , -'-

8 6

- 1_ ..

OJ

:; E 4

-'_,

(p=0.2)

P = 0.0007

Statins _- - 1_ ,"_.. _ , __

Heart rate var ia bility

- - -1-

:::l

U

Stati ns + Statins( ho I.(m mo lll) 3.4 ± 1.3 3.8 ± 1.3

Statins +

InVLF (ms 2)

2 0

Stat ins + Sta tin s 4.1 ± 1.4 3.1 ± 1.3 (p = 0.009)

0

5

10 15 20 Time (days)

Num ber of patien ts at risk 39 32 30 39 24 15

25

30

26 (28 days) for sta t ins + (- ) 11 (28 days) for sta t ins - (- - - )

Fig. 5. Impact ofstatin therapy onsurvival ofpatients with multiple organ dysfunction syndrome (MODS) [21]. Our recent study [21] analyzed the mortality data of 40 patients with MODS (inclusion criteria: ICU admission acute physiology and health evaluation [APACHE] II score 2: 20 at admission) receiving statin therapy and of 80 age- and sex-matched MODS patients without statin therapy. All baseline characteristics including clinical and demographic data, severity scores (APACHE II, sequential organ failure assessment [SOFA], simplified acute physiology score [SAPS] II), presence of chronic diseases, and laboratory test results were assess ed within 24 h of admission. All data were obtained from th e patients' charts and subsequently computerized. An independent observer checked the patients' charts concerning statin therapy and recorded the duration of statin administration. Statin administration was managed according to routine protocols used in the ICU by the study-independent staff. There were no differences in age, height, weight, or sex distribution between the statin and the non-statin groups. APACHE II and SOFA scores were not significantly different between the groups and cholesterol levels were comparable in both groups at admission. During the 28-day study period there were more deaths in the group without statin treatment than in the statin group ( Fig. 5). These results suggest that patients under statin treatment who develop MODS may have a lower 28-day mortality compared with MODS patients of equally pronounced disease severity who are not receiving statins. The parasympathetically mediated variables, pNN50 (the fraction of consecutive RR intervals that differ by more than 50 ms) and InVLF, were better preserved in the statin group than in the non-statin group (lnVLF 4.1 ± 1.4 vs. 3.1 ± 1.3, P = 0.02; (Fig. 5). Hence, statin therapy might potentially influence short-term mortality in MODS patients by restoring parasympathetic tone and reducing the inflammatory response via the cholinergic anti-inflamm atory pathway [4-11] . We speculate that two major mechanisms may contribute to this complex phenomenon: • Statins can modulate inflammatory responses and coagulation processes during septic episodes [17, 18].

61

62

H. Schmidt, U. Miiller-Werdan, and K. Werdan

• An intact vagal activity seems to be a prerequisite for functioning of the cholinergic anti-inflammatory reflex ( Fig. 1). Statins have been shown to augment baroreflex sensitivity, a major input of vagal activity (see above).

Beta-Blockers and Angiotension-converting Enzyme Inhibitors Administration of beta-blockers has been shown to increase heart rate variab ility in patients with coronary artery disease, chronic heart failure, and diabetes. These drugs mainly act indirectly by attenuating symp athetic tone, but direct parasympathet ic modulatory effects have also been described. Moreover, beta-blockers have been shown to increase baroreflex sensitivity [22], a major source of vagal activity, and to blunt increased chemoreflex sensitivity [23], thus reducing sympathetic tone. These effects might restore an appropriate sympathetic-vagal balance and thus prevent cytokine spillover. ACE inhibitors can reduce mortality rates in cardiac patients with reduced left ventricular function [24, 25]. Additionally, they are able to restore autonomic function (especially vagal activity) and have anti -inflammatory features in patients with chroni c heart failure and coronary artery disease [26, 27]. Moreover, blockade of angiotensi n II may be most beneficial, since angiotensin II enhances the afferent drive of the carot id chemoreceptors and thus has sympathoexcitator y effects [28]. Thus, ACE inhibitors and angioten sin receptor blockers could modify important features of autonomic function that characterize MODS.

Mortality and Therapeutic Interventions in MODS The aforementioned examples show that statins , beta-blockers, and ACE inhibitors have beneficial effects on autonomic dysfunction. Nevertheless, it is unclear whether these effects result in a decrease in mortality rates. Data concern ing mortality and therapeutic interventions in MODS with stat ins, beta-blockers, and ACE inhibitors are scare. We have recently condu cted a stud y analyzing the benefit of admin istration of beta-blockers and ACE inhibitors in patients with MODS [29, 30] and the data, as summarized in Figure 6, are very promi sing.

100 80

~ 60

.~ ~ (;

~

p = 0.001

P = 0.002

P = 0.0001

69

69

70

,---,

r----1

40

,---,

29

20

a

+ Statins

n = 38

+

~-Bl o cker

+

n= 40

ACEI

Fig. 6. Illustration of 28-day-mortality in a group of 78 patients with multiple organ dysfunction syndrome (age 64± 11 years, height 172±8cm, weight 77±13 kg, APACHE II score 28±7, SAPS II 60±17, SOFA score 11±4). The cohort was separated into subgroups with and without statin, beta-blocker, or ACE inhibitor (ACEI) administration [20, 29, 30].

The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome

Conclusion In MODS, a severe, prognostically relevant cardiac autonomic dysfunction exists as manifested by a strong attenuation of sympathetically and vagally mediated heart rate variability. The mechanisms underlying this attenuation are not restricted to the level of the autonomic nervous system and the brain, but also include the pacemaker cells of the heart themselves: Endotoxin blocks the pacemaker current, If, of the HCN channels in the sinus node cells of the heart, the channels which play an important role in transmitting sympathetic and vagal signals on heart rate variation. The vagal pathway, in particular, is attenuated in MODS resulting in an attenuation of the cholinergic anti-inflammatory reflex. Consequently, ameliorating the blunted vagal activity would be of help in suppressing the inflammatory state and, thereby, improving the prognosis of patients with MODS. Initial, preliminary data reveal therapeutic benefits (increased heart rate variability, mortality reduction) from administration of statins, beta-blockers and ACE inhibitors in patients with MODS. Acknowledgement: We are indebted to D. Menning for her technical help in preparing the manuscript. References 1. Godin PJ, Buchmann TG (1996) Uncoupling of biological oscillators . A complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 24:1107-1116 2. Schmidt H, Miiller-Werdan U, Hoffmann T, et al (2005) Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups . Crit Care Med 33:1994- 2002 3. Schmidt H, Moyer D, Hennen R, et al (2007) Autonomic dysfunction predicts both one- and two-month mortality in middle-aged patients with multiple organ dysfunction syndrome. Crit Care Med (in press) 4. Tracey KJ (2002) The inflammatory reflex. Nature 420:853- 859 5. Borovikova LV, Ivanova S, Zhang M, et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458-462 6. Libert C (2003) A nervous connection. Nature 421:328-329 7. Wang H, Yu M, Ochani M, et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384- 388 8. Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117:289- 296 9. Wang H, Liao H, Ochani M, et al (2004) Cholinergic agonists inhibit HMGBI release and improve survival in experimental sepsis. Nat Med 10:1216-1221 10. Saeed RW, Varma S, Peng-Nemeroff, T et al (2005) Cholinergic stimulation blocks endothelial cell activation and leukocyte recru itment during inflam mation. J Exp Med 201:1113-1123 11. Pavlov VA, Ochani M, Gallowitsch-Puerta M, et al (2006) Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Nat! Acad Sci USA 103:5219 - 5223 12. Abboud FM, Thames MD (1983) Interaction of cardiovascular reflexes in circulatory control. In: Sheperd IT, Abboud FM, Geiger SR (eds) Handbook of Physiology. Section 2: The Cardiovascular System. Vol. III, Chapter 19. American Physiological Society, Bethesda, pp 675-752 13. Eyzaguirre C, Fitzgerald RS, Lahiri S, Zapata P: Arterial chemoreceptors. In: Sheperd JT, Abboud FM, Geiger SR (eds) Handbook of Physiology. Section 2: The Cardiovascular System. Vol. III, Chapter 16. American Physiological Society, Bethesda, pp 557- 562 14. Godin PJ, Fleisher LA, Eidsath A, et al (1996) Experimental human endotoxemia increases cardiac regularity: results from a prospective, random ized crossover trial. Crit Care Med 24: 1117-1124

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IS. Schmidt H, Mtiller-Werdan U, Saworski J, Kuhn C, Heinroth C, Werdan K (1999) Beating rate variability of cardiomyocytes is narrowed by LPS but not by TNF-a? Intensive Care Med 25 (suppl 1):59 (abst) 16. Zorn-Pauly K, Pelzmann B, Lang P, et al (2007) Endotoxin impairs the human pacemaker current If. Shock [Epub ahead of print] 17. Merx MW, Liehn EA, Janssens U, et al (2004) HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation 109:2560-2565 18. Pruefer 0, Makowski J, Schnell M, et al (2002) Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin. Circulation 106:2104-2110 19. Almog Y, Shefer A, Novack V, et al (2004) Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 110:880 - 885 20. Kruger P, Fitzsimmons K, Cook 0, Jones M, Nimmo G (2006) Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med 32:75-77 21. Schmidt H, Hennen R, Keller A, et al (2006) Association of statin therapy and increased survival in patients with multiorgan dysfunction syndrome. Intensive Care Med 32:1248-1251 22. Parati G, Mutti E, Frattola A, et al (1994) Beta-adrenergic blocking treatment and 24-hour baroreflex sensitivity in essential hypertensive patients. Hypertension 23:992- 996 23. Agostoni P, Contini M, Magini A et al. (2006) Carvedilol reduces exercise-induced hyperventilation: A benefit in normoxia and a problem with hypoxia. Eur J Heart Fail 8:729-735 24. The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429-1435 25. The SOLVO Investigators. (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293- 302 26. Ferrario CM, Strawn WB (2006) Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 98:121-128 27. Routledge HC, Chowdhary S, Townend IN (2002) Heart rate variability - a therapeutic target? J Clin Pharmacy Ther 27:85- 92 28. Li YL, Xia XH, Zheng H, et al (2006) Angiotensin II enhances carotid body chemoreflex control of sympathetic outflow in chronic heart failure rabbits . Cardiovasc Res 71:129-138 29. Schmidt H, Hennen R, Keller A, et al (2005) B-blocker treatment, heart rate variability, and survival of intensive care patients. Intensive Care Med 31 (suppl 1):A310 (abst) 30. Schmidt H, Hoyer 0 , Rauchhaus M, et al (2007) ACE-inhibitor therapy and survival among patients with multiorgan dysfunction syndrome of 24 to 96 years. Intensive Care Med 33 (suppl):A722 (abst)

65

Quantification of Improved Left Ventricular Performance during Cardiac Resynchronization Therapy B. LAMIA and M.R.

PINSKY

Introduction Regional contraction asynchrony is the most common contractile abnormality seen clinically, accounting for much of the observed, clinically relevant increase in morbidity from heart disease. Regional myocardial dyssynchrony, characterized by regional wall motion abnormalities (RWMA), commonly occurs in patients with both normal [1-4] and abnormal [5-7] cardiac physiology. RWMA are monitored intraoperatively to detect regional myocardial ischemia [8-10]. The impact of RWMA on global left ventricular (LV) performance is difficult to quantify but it is important to have a quantitative measure of regional myocardial dysfunction to minimize subjective bias in the diagnosis of myocardial ischemia [2], and aid in the evaluation of treatments and titration of therapies used to restore regional myocardial function, including both revascularization and cardiac resynchronization therapy. LV ejection reflects the summed contraction of all cardiac muscle cells in which function is altered by LV volume, arterial impedance, coronary blood flow, and excitation-contraction coupling through the His-Purkinje system [4, 10, 11]. LV contraction is normally heterogeneous [3, 12]. The apex and base of the left ventricle differ in their onset of contraction and in their response to inotropes [1, 13]. The apex is slightly phase lagged in relation to the base region and somewhat more dynamic. This degree of dyssynchrony is necessary for proper mechanical functioning of the mitral valve apparatus and causes minimal cardiac dilation. However, if LV contraction becomes even more dyssynchronous among regions of the heart, then LV ejection effectiveness will decrease. LV ejection efficiency is defined as the ratio of external work (stroke work) to energy consumed (MV0 2 ) , and LV ejection effectiveness as the ratio of global LV contraction to phase-specific regional LV contraction. Increasing LV contraction asynchrony decreases LV ejection efficiency by decreasing LV ejection effectiveness, whereas aortic stenosis or akinetic myocardium, for example, may decrease LV ejection efficiency without changing LV ejection effectiveness.

Conceptual Framework Any form of contraction dyssynchrony whether induced primarily by electrical or mechanical abnormalities (e.g., left bundle branch block [LBBB] or myocardial infarction, respectively) usually causes cardiac dilation, decreasing LV ejection efficiency (stroke work/Mvo), The cause of this observable dilation is the mechanical inefficiency of myocardial contraction induced by dyssynchrony. Thus, for the same

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stroke work, MV0 2 is greater. Importantly, contraction dyssynchrony impairs overall efficiency independent of conduction defects [14]. Baller et al. [15] showed, using intact dogs, that right ventricular (RV) pacing was associated with a higher MV0 2 for the same stroke work, and thus lower LV ejection efficiency than seen with atrial pacing . Accordingly, increasing dyssynchrony decreases LV contraction efficiency. This effect is clinically important because: 1) RWMA are the most common cardiac abnormalities; 2) pacing for rate control normally increases contraction dyssynchrony; 3) patients requiring ventricular pacing usually have impaired ventricular pump function and reduced coronary reserve; 4) cardiac resynchronization therapy has been approved for the management of wide complex heart failure patients without clear titration end-points for therapy other than measuring developed pressure; and 5) inotropic agents used in patients with RWMA may improve or impair LV ejection effectiveness, presumably based on their effects of LV ejection synchrony. Changes in LV ejection synchrony are a primary determinant of both LV ejection effectiveness and the response of the patient to therapeutic interventions, such as pacing, cardiac resynchronization therapy, and pharmacotherapies. Cardiac resynchronization therapy improves LV function and reverses heart failure remodeling. Blanc et al. showed that LV pacing could improve LV ejection while decreasing LV filling pressure in 23 patients with severe heart failure, although the mechanisms were not defined [16]. Potential mechanisms include not only normalization ofventricular activation sequence, but also increased filling time, decreased mitral regurgitation, and optimizing mechanical atrio-ventricular delay [17]. Hemodynamic improvement following cardiac resynchronization therapy tends to be greatest in those subjects with most asynchronous myocardium at baseline [18], and when the pacing site is centered near the most delayed region of contraction [19]. In cardiac resynchronization therapy, selective ventricular multi -site pacing is used to optimize LV mechanical function. The clinical efficacy of cardiac resynchronization therapy is generally quantified in terms of its effects on LV systolic function and other hemodynamic indices, such as LV ejection fraction (LVEF), stroke volume, stroke work, maximum rate of LV pressure increase (dP/dtmax), and aortic pulse pressure [20 - 24]. Several clinical trials have documented that cardiac resynchronization therapy improves functional status and survival [25-32], but 20-30 % of patients do not benefit from this therapy [33]. Many factors may contribute to this variability in benefit from cardiac resynchronization therapy: • limited knowledge regarding the mechanisms underlying the beneficial effects of cardiac resynchronization therapy • lack of robust algorithms for identifying the optimal pacing site(s) that maximizes LV ejection effectiveness and/or minimizes contraction dyssynchrony • limited choices of pacing sites available in the clinical setting.

Clinical Applications of Left Ventricular Dyssynchrony Quantification In order to quantify contraction dyssynchrony, one must first measure myocardial movement accurately. A recent canine study using magnetic resonance imaging (MRI) has demonstrated that circumferential myocardial dynamics may characterize LV dyssynchrony in a more sensitive manner than longitudinal [34]. Although very accurate measures of dyssynchrony can be obtained using MRI, echocardiography tissue Doppler strain, and speckle tracking strain, only echocardiographic tissue Doppler and speckle strain analyses lend themselves to clinical applications. Clearly,

Quantification of Improved Left Ventricular Performance during CRT

tagged MRI has been traditionally used to assess myocardial movement and is excellent to provide spatial resolut ion of the impact of pacing site on contractile effectiveness [35] but does not easily lend itself to clinical practice . Echocardiographic Angle-corrected Tissue Doppler Strain Imaging

Echocardiographic tissue Doppler imaging uses a 3.0 MHz transducer to obtain digitized color-coded images from mid-LV short-axis levels. Color tissue Doppler video data can be analyzed off-line using custom software (TDI-Q, Toshiba Medical Systems Corporation, Tokyo, Japan) as described for a canine preparation [36]. Briefly, the myocardial vector (V) of motion toward a manually placed point of contraction center is calculated as:

V motion = V beam/cosine (ep) where ¢ is the angle of incidence of the ultrasound beam. Since Doppler velocity becomes inaccurate as the angle of incidence falls away from 0°, sectors are masked where the angle of incidence approaches 90° (e.g. > - 60°) as illustrated in Figure t Strain is calculated as the time integral of the velocity gradient that is calculated along radii of a distance (.~ r) toward the contractile center. Angle corrected , colorcoded Lagrangian strain is calculated as percent wall thickening toward the contraction center and displayed on a continuous scale from dark red to bright orange-yellow as positive strain corresponding to wall thickening . Regions of interest are manually drawn on 6 segment s of the mid-LV short-axis view (midseptum, anterosep tum, anterolateral, posterolateral, posterior, and inferior) linear polygons with transmural length ranging from 3 to 4 mm placed in the inner third of the wall at end diastole. This subendocardial region is selected to represent the major component of transmural thickening . A tracking algorithm is used with manual adjustment of the size and shape of the regions of interest to maintain its subendocardial location throughout the cardiac cycle. Time-strain curves are constructed and time-to-peak strain is determined from the onset of the QRS complex in all 6 segments, and dyssynchrony is defined as the maximum difference in time from earliest to latest segment among 6 segments ( Fig. 1). Since tissue Doppler techniques are limited by the Doppler angle of incidence, inducing missing regions of interest , if complete LV wall movement could be assessed then better characterization of LV contraction and synchrony could be achieved. A novel approach to quantify regional myocardial function from rout ine gray-scale two-dimen sional echocardiographic images, known as speckle tracking, calculates myocardial strain independent of angle of incidence. Speckle Tracking Strain from Routine Gray Scale Echocardiographic Images

The speckle-tracking analysis was introduced by Reisner and Leitman [37,38] and used to generate regional LV strain. In this technique, routine B-mode gray scale echocardiographic images are analyzed for frame-by-frame movement of stable patterns of natural acoustic markers, or speckles, present in ultrasound tissue images over the cardiac cycle. As with tissue Doppler imaging, the specific regions of intere st for analysis need not be manually defined. In the case of speckle tracking, however, a circula r region of interest is traced on the entire endocardial and epicardial border. In the analysis we report, this image came from a mid-LV short axis view. Speckles within the region of interest are tracked in subsequent

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Fig. 1. Tissue Doppler image (TOil in short-axis view taken at mid-left ventricular (LV) location. Strain waveforms were calculated from velocity data obtained at each of the six segments under four pacing modalities: a: right atrial (RA) pacing; b: right ventricular (RV) pacing; C: cardiac resynchronization therapy at apex; and d: cardiac resynchronization therapy at free-wall; line colors of waveforms correspond to the segments labeled in TO!. Each segment was paired with one another for a pair-wise evaluation of contraction synchrony. From [41] with permission

Quantification of Improved Left Ventricular Performance during CRT

Fig. 2. Asimplified diagram depicting the operation of speckle tracking echocardiography. The relative position of the speckles is tracked from frame to frame define tissue motion or deformation. This determines the motion of the trace of the endocardial and epicardial border. Radial strain was calculated as changes in length/initial length between endocardial and epicardial trace.

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frames. The location shift of these speckles from frame to frame, which represents tissue movement, provide s the spatial and temporal data. This determines the motion of the trace of the endocardial and epicardial border. Radial strain is calculated as change in length/initial length between endocardial and epicardial traces in a fashion similar but not identic al to tissue Doppler imaging. Nevertheless, we previously showed that the two techniques co-vary [39]. Using this approach, radial stra in using speckle tracking can be analyzed among the entire LV segments of a short axis image ( Fig. 2). Speckle tracking analysis of echocardiographic images are new and peer-reviewed publications have yet to be published. Thus, for our initial analysis we report on tissue Doppler imaging to create regional strain analysis.

Modeling Contraction Dyssynchrony Several studies have focused on deriving an algorithm to assess contraction dyssynchrony [35, 36, 39, 40]. Unfortunately, there is no general agreement regarding optimal pacing site(s) for cardiac resynchronization therapy. Recently, Johnson et al. [41] assessed the effects of LV pacing site (apex vs. free-wall) on restoration of radial contraction synchrony and global LV performance in a canine model of contraction dyssynchrony. In this study, ultrasound tissue Doppler imaging and hemodynamic (LV pressure-volume) data were collected in seven anesthetized, opened-chest dogs. Right atrial (RA) pacing served as control and contraction dyssynchrony was created by simultaneous RA and RV pacing to induce a LBBB-like contraction pattern. This method of creating dyssynchrony has been used previously and proven to model well clinical LBBB contraction patterns [34]. Cardiac resynchronization therapy was implemented by adding simultaneous LV pacing to the RV pacing mode at either the LV apex or the free-wall. Angle corrected, color-coded Lagrangian strain was calculated as percent wall thickening toward the contraction center as described above [36, 41]. Since tissue Doppler imaging cannot measure velocity at angles of incidence < 30°, we were limited to the regions shown in Fig. 1.

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Regional radial synchrony was analyzed by implementing a newly developed algorithm on time-strain curves constructed from color-coded strain data at the mid-LV level ( Fig. 3). This cross-correlat ion synchrony index (CC51) was developed in the time-domain via a pair-wise correlation analysis of radial stra in waveforms over systole for six myocardial segments. Details of the method have been described previously [41]. Only the systolic portion of the strain waveforms was used for all crosscorrelation analyses. Because strain data were acquired for 6 segments, 15 segment pair combinations were calculated for cross-correlation coefficients. The sum of all cross-correlation coefficients was used as an overall index of synchro ny. A value of

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Fig. 3. Example of cross-correlation method developed to analyze contraction synchrony. Top plots show regional myocardial strain waveforms for all six segments under a: right atrial (RAJ pacing and b: right ventricular (RV) pacing. End systole was determined by the time to latest peak strain (dashed line). The line colors of waveforms correspond to the segments labeled in Figure 1. The bottom plots show an example of the cross-correlation analysis applied to one segmental pair (mid-septum [MS)-posterior lateral [PLJ) over systole. With RA pacing ( Cthe two segments are contracting almost synchronously, as indicated by high cross-correlation value (0.96) over the systolic duration. In contrast, significant contraction dyssynchrony is evident with RV pacing (q manifested as septal to lateral contraction delay and a low cross-correlation value (-0.40) over the systolic duration. From (41) with permission.

Quantification of Improved Left Ventricular Performance during CRT

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Fig. 4. Mean values of synchrony index (i.e., sum of cross-correlation coefficients). Compared to the control condition (right atrial [RAl pacing), right ventriclar (RV) pacing resulted in marked decrease in synchrony and both modes of cardiac resynchronization (apex [CRTal and free-wall [CRTf]) therapy restored synchrony to the control level (i.e., RA pacing). Data are means ± SE; n = 7; < 0.01 V5. RA pacing. From [41] with permission.

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15 connotes perfect synchrony and lower values reflect progressively greater dyssynchrony. RV pacing significantly decreased radial synchrony as compared to RA pacing (from ILl ± 0.8 to 4.8 ± 1.2, P < 0,01, Fig. 4). This reduced synchrony was in proportion to reductions in indices of global LV performance (cardiac output: 2.0±0.3 vs. 1.4 ± 0.1 lImin; stroke work: 137 ± 22 vs. 60 ± 14 m]: p < 0.05]. However, the eeS1 alone did not predict well global LV performance, because although both apex and free wall cardiac resynchronization therapy significantly improved radial synchrony, only the apex cardiac resynchronization therapy improved global function (cardiac output: 2.1 ± 0.2 lImin; stroke work: 113 ± 13 m]; p < 0.01 vs. RV pacing) . Apex cardiac resynchronization therapy also appeared to be associated with an augmented global LV contractile state relative to RV pacing because it decreased LV end-systolic volume compared to RV pacing without any change in LV end-systolic pressure. Thus, eeS1 , although tracking mid-papillary myocardial synchrony, does not model completely global LV performance. The dissociation between changes in synchrony, as quantified by the sse1 and global LV performance with free-wall cardiac resynchronization therapy suggests that regional analysis from a single cross-sectional mid-papillary plan e may not be sufficient to adequately characterize contraction synchrony. How does contractile dyssynchrony impact on LV ejection effectiveness? The impact of asynchrony on MVO z should be predictable from the LV pressure-volume analysis. Suga et al. [42] demonstrated many years ago that MVO z is proportional to both the stroke work and the elastance-defined potential area, called the pressurevolume area, as illustrated in Fig. 5. With normal contraction, MVO z is proportional to the stroke work (light gray area) plus the elastance-defined internal work (dark gray area). With increasing dyssynchrony, the LV endsystolic pressure volume relationship is shifted to the right , with volume on the x-axis. MVO z should increase in proportion to the increase in 'area' defined by the parallelogram of the LV endsystolic pressure volume relationship with and without dyssynchronous contraction (hatched area).

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Fig. s. Proposed effect of asynchrony on myocardial oxygen consumption (MV0 2) based on the pressurevolume area analysis. See text for explanation. ESPVR: end-systolic pressure volume relationship

Human Data Echocardiographic imaging is the standard for bedside assessment of LV function and as described above can be used to quantify dyssynchrony as well. However, technical limitations in the acquisition of cardiac images often limit its complete application in clinical trials. Prior studies used longitudinal imaging by convenience since long axis views are often easier to obtain. Mid-axis cross sectional views, however, also describe regional contraction [43] and may add additional information about contraction synchrony. Thus, the addition of radial mechanical information to that acquired from long axis longitudinal image analysis is a logical extension of dyssynchrony analysis. Furthermore, radial strain may likely be complementary and potentially superior to assessment of longitudinal dyssynchrony if canine models can be used to predict human physiology [34]. Longitudinal dyssynchrony calculated from the apical 4 chamber view is defined as a cut-off delay 2: 65 msec between earliest and latest time to peak strain among segments [43]. Radial dyssynchrony calculated from the short axis view is defined as a cut-off delay 2: 135 msec between earliest and latest time to peak strain among segments [39]. Suffoletto et al. [39] demonstrated that a novel speckle tracking algorithm applied to routine gray-scale images can quantify radial LV dyssynchrony in heart failure patients and predict both immediate and long-term response to cardiac resynchronization therapy. This extends the ability of echocardiography to quantify mechanical LV dyssynchrony non-invasively [39]. The timing of speckle-tracking radial strain correlated well with similar measures by tissue Doppler radial strain to determine dyssynchrony. Because speckle-tracking strain is not dependent on Doppler angle, it is able to determine the timing of multiple other sites whose timing could not be determined by tissue Doppler imaging. Sites of latest radial mechanical

Quantification of Improved Left Ventricular Performance during CRT

activation identified by speckle tracking were associated with greater improvements in LV ejection fraction when LV lead position was concordant with these sites.

Conclusion Bedside echocardiography when coupled with tissue Doppler imaging and speckle tracking analysis can quant ify mechanical LV dyssynchrony. The potential use of this technique in directin g lead placement dur ing cardiac resyn chronization therapy and assessing response to treatments, including cardia c resynchronization therapy, is evolving. Clearly, tissue Doppler angle-corr ected radial strain imaging can quantify mechanical dyssynchron y and the effects of cardia c resynchronization therapy in region s moving to or away from the sensing prob e. Speckle tracking extends this analysis to the entir e myocard ium. By applying phase angle analysis of regional strain-time activity curves, one can quantify LV contraction synchrony and potentially predict which patients will benefit from cardia c resynchronization therapy and where such pacing should be don e for optimal improvement. Acknowledgement: This work was suppor ted in part by NIH grants HL671 81 HL07820. References 1. Pand ian NG, Skorton DJ, Collins SM, Falsetti HL, Burke ER, Kerber RE (1983) Heterogeneity of left ventricular segmental wall thi ckening and excursio n in 2-dimensional echocardiograms of normal hum an subjects. Am J Cardiol 51:1667 -1 673 2. Thys DM (1987) The intraoperat ive assessme nt of regional myocardial per formance: Is the cart before the horse? J Cardiothorac Anesth 1:273 - 275 3. LeWinter M, Kent R, Kroener J, Carew T, Covell J (1975) Regional differen ces in myocardi al performance in the left ventricle of the dog. Circ Res 37:191-199 4. Haendchen RV, Wyatt HL, Maurer G, et al (1983) Quantificatio n of regional cardiac functio n by two-dimensional echo cardiography I. Patterns of contraction on the norm al left ventricle. Circu latio n 67:1234- 1245 5. Xiao HB, Roy C, Gibso n DG (1994) Nature of ventricular activatio n in patients with dilated cardio myopathy: evidence for bilateral bun dle br anch block. Br Heart I 72:167- 174 6. Bonow RO (1990) Regional left ventric ular nonuniform ity: effects on left ventricular diastolic function in ischemi c heart disease, hyper tr ophic cardi omyopathy, and the norm al heart. Circulation 81:11I54-11I65 7. Little W, Reeves R, Arcin iegas J, Kath oli R, Roger s E (1982) Mecha nism of abn ormal interventicular septal moti on duri ng delayed left ventri cular activatio n. Circulatio n 65:14861491 8. Gallagher KP, Matsuzaki M, Koziol [A, Kemper WS, Ross J (1984) Regional myocard ial perfusion and wall th ickening during ischemi a in conscio us dogs. Am J Physiol 247:H727-H738 9. Buffingto n CW, Coyle RJ (1991) Altered load depend ence of post-ischemic myocardium. Anesthesiology 75:464-474 10. Miura T, Bhargava V, Guth BD, et al (1993) Increased afterloa d inten sifies asynchronous wall moti on and impairs ventric ular relaxation. J Appl Physiol 75:389- 396 11. Shroff SG, Naegelen D, Clark WA (1990) Relation between left ventricular systolic resistance and ventricular rate processes. Am J Physiol 258:H381-H394 12. Diedericks J, Leon e BJ, Poex P (1989) Regional differen ces in left ventricular wall moti on in th e anesthetized dog. Anesthesiology 70:82- 90 13. Freedma n RA, Alderman EL, Sheffield LT, Sapor ito M, Fisher LD (1987) Bundle branch block in patients with chronic coro nary artery disease: angiogra phic correlates and prog nostic significance. J Am Coli Cardiol 10:73 -80

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B. Lamia and M.R. Pinsky 14. Strum DP, Pinsky MR (2000) Esmolol-induced regional wall motion abnormalities do not affect regional ventricular elastances. Anesth Analg 90:252-261 15. Baller D, Wolpers HG, Zipfel J, Bretschneider HJ, Hellige G (1988) Comparison of RA, RV apex and AV sequential pacing on MV0 2 and cardiac efficiency. Pacing Clin Electrophysiol 11:394-403 16. Blanc H, Etienne Y, Gilard M, et al (1997) Evaluation of different ventricular pacing sites in patients with severe heart failure. Circulation 96:3273-3277 17. Auricchio A, Stellbrink C, Block M, et al (1998) Effect of pacing chamber and atrio-ventricular delay on acute systolic function of paced heart failure patients in PATH-CHF Study. Pacing Clin Electrophysiol 21:837 18. Sogaard P, Kim WY, Jensen HK, et al (2001) Impact of acute biventricular pacing on left ventricular performance and volume sin patients with severe heart failure. A tissue Doppler and three-dimensional echocardiographic study. Cardiology 95:173-182 19. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M (2002) Doppler myocardial imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing. J Am Coli Cardiol 39:489- 499 20. Gorcsan J 3rd, Kanzaki H, Bazaz R, Dohi K, Schwartzman D (2004) Usefulness of echocardiographic tissue synchronization imaging to predict acute response to cardiac resynchronization therapy. Am J Cardiol 93:1178-1181 21. Leclercq C, Faris 0, Tunin R, et al (2002) Systolic improvement and mechanical resynchronization does notrequire electrical synchrony in the dilated failing heart with left bundlebranch block. Circulation 106:1760- 1763 22. Verbeek XA, Auricchio A, Yu Y, et al (2006) Tailoring cardiac resynchronization therapy using interventricular asynchrony. Validation of a simple model. Am J Physiol Heart Circ Physiol 290:H968- 977 23. Verbeek XA, Vernooy K, Peschar M, Cornelussen RN, Prinzen FW (2003) Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block. J Am Coli Cardiol 42:558- 567 24. Verbeek XA, Vernooy K, Peschar M, Van Der Nagel T, Van Hunnik A, Prinzen FW (2002) Quantification of interventricular asynchrony during LBBB and ventricular pacing . Am J Physiol Heart Circ Physiol 283:H1370-1378 25. Abraham WT, Fisher WG, Smith AL, et al (2002) Cardiac resynchronization in chronic heart failure. N Engl J Med 346:1845-1853 26. Auricchio A, Stellbrink C, Butter C, et al (2003) Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am CoIl Cardiol 42:2109-2116 27. Auricchio A, Stellbrink C, Sack S, et al (2002) Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am CoIl Cardiol 39:2026-2033 28. Bristow MR, Saxon LA, Boehmer J, et al (2004) Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350: 2140-2150 29. Cazeau S, Leclercq C, Lavergne T, et al (2001) Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344:873- 880 30. Cleland JG, Daubert JC, Erdmann E, et al (2005) The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:1539-1549 31. Reuter S, Garrigue S, Barold SS, et al (2002) Comparison of characteristics in responders versus nonresponders with biventricular pacing fordrug-resistant congestive heart failure. Am J Cardiol 89:346- 350 32. Young JB, Abraham WT, Smith AL, et al (2003) Combined cardiac resynchronization and implant able cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 289:2685- 2694 33. Bax H, Abraham T, Barold SS, et al (2005) Cardiac resynchronization therapy: Part 1 - Issues before device implantation. J Am Coli Cardiol 46: 2153-2167 34. Helm RH, Leclercq C, Faris OP, et al (2005) Cardiac dyssynchrony analysis using circumferential versus longitudinal strain: implications for assessing cardiac resynchronization. Circulation 111:2760- 2767

Quantification of Improved left Ventricular Performance during CRT 35. Wyman BT, Hunter WC, Prinzen FW, Faris OP, McVeigh ER (2002) Effects of single- and biventricular pacing on temporal and spatial dynamics of ventricular contraction. Am J Physiol Heart Circ Physiol 282:H372- 379 36. Dohi K, Pinsky MR, Kanzaki H, Severyn D, Gorcsan J 3rd (2006) Effects of radial left ventricular dyssynchrony on cardiac performance using quantitative tissue Doppler radial strain imaging. J Am Soc Echocard iogr 19:475-482 37. Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z (2004) Global longit udi nal strain: a novel index of left ventri cular systolic function. J Am Soc Echocardiogr 17: 630 - 633 38. Leitman M, Lysyansky P, Sidenko S, et al (2004) Two-dimensional strain-a novel software for real-time quantitative echoca rdiographic assessment of myocardia lfuncti on . J Am Soc Echocardiogr 17:1021- 1029 39. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J 3'd (2006) Novel speckle-tr acking radial strain from routine black-and -white echocardiographic images to quantify dyssynchrony and predict response to cardi ac resynchronization therapy. Circulation 113:960-968 40. Yu CM, Fung JW, Zhang Q, et al (2004) Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the predict ion of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynch roni zation therapy. Circulation 110: 66-73 41. Johnson L, Kim HK, Tanabe M, et al (2007) Different ial effects of left ventricular pacing sites in a canine model of contrac tion dyssynchrony. Am J Physiol Heart Circ Physiol [Epub ahead of print] 42. Suga H, Hayashi T, Shirahata M (1981) Ventricular systolic pressure-volume area as predictor of cardiac oxygen consumption. Am J Physiol 240:H39-H44 43. Sade LE, Kanzaki H, Severyn D, Dohi K, Gorcsan J 3rd (2004) Quantificat ion of radial mechanical dyssynchrony in patients with left bundle branch block and idiopathic dilated cardiomyopathy witho ut conduction delay by tissue displacement imaging . Am J Cardiol 94: 514-518

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Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit J.

POELAERT,

E.

OSIPOWSKA,

and C.

VERBORGH

Introduction With the advent of newer technology, recognition of diastolic dysfunction has become a major feature of cardiac disease, in heart failure as in septic shock. Doppler echocardiography plays a pivotal role in the evaluation of both systolic and diastolic function. Preserved systolic function, in conjunction with diastolic dysfunction, is an early sign of cardiac failure. Therefore, early diagnosis of diastolic failure is warranted. In recent years, measurement of intra-myocardial tissue Doppler velocities and deformations of the myocardial wall have attracted the attention of many researchers. In this chapter, the most recent echocardiographic and Doppler applications, based on wave progression, pressure gradients, mitral valve leaflet and annular motion, and ventricular rotation will be discussed to give the critical care specialist a better insight into the diagnosis of diastolic dysfunction.

Definitions In the discussion of diastolic function, physiological and pathophysiological aspects of relaxation and compliance should be taken into account. Normal diastolic function of the left ventricle means that the left ventricle is able to relax and fill in a manner which is sufficient to obtain a normal stroke volume. In terms of definitions, normal diastolic pressures both at rest and during exercise are obligatory. Furthermore, relaxation is an active, energy consuming process as described below whereas compliance of the left ventricle is a passive component of diastole, related to distensibility of the myocardial tissue. The Cardiac Cycle

The energy necessary to circulate the blood through the cardiopulmonary vascular bed is provided by the heart, which acts as a double serial pump. The mechanical energy exerted by this pump is induced by an electrical impulse. Direct links between mechanical and electrical signals have to be understood because of the close relationship between concomitant pressure and flow changes involving the different cardiac chambers ( Fig. 1). In order to illustrate this relationship, the events in the left and right heart will be discussed step by step in the following paragraphs. The cardiac cycle can be divided into a systolic and diastolic phase; the systolic phase includes the time in which the heart pumps the blood into the circulation

Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit

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LV Inflow velocity

7

(mechanical act), wherea s diastole comprises all issues related to the filling of the ventricles. At the end of diastole, atrial contraction, marked by the P wave on the electrocardiograph (EKG), causes atrial pressure to rise. This increase in pressure manifests as the a wave of the right atrial or pulmonary capillary wedge pressure and coincides with acceleration of the blood flow from the atrium into the ventricle across the atrioventricular valve at the end-diastole. The corresponding flow velocity can be recorded by pulsed wave Doppler as the A wave. In the left ventricle at this moment, the mitral valve is maximall y opened in contrast to the aortic valve, which is closed during the entire diastole. After the QRS complex, marking the onset of electrical activation of the myocardium on the EKG, ventricular contraction (systole) follows. The intraventricular pressure rises and results in closure of the mitral valve. The isovolumic contraction period is the time between the closure of the mitral valve and the opening of the aortic valve. The latter open s when the pressure in the ventricle exceeds the pressure in the aorta and starts the ejection phase of systole. The isovolumic contraction time can be measured by Doppler echocardiography by placing the sample volume between the mitral valve and the left ventricular (LV) outflow tract (either in the four or five chamber views or in the deep transgastric view, both in the transverse plane). The time interval between the end of the A wave and the onset of LV eject ion is measured. Once the aortic valve is open , blood is ejected swiftly into the ascending aorta. The extent of opening of the cusps of the aortic valve is directly related to the volume flow across this valve, and hence to cardiac output. The time required for the ejection of blood across the aortic valve is called the ejection period. This time period is defined as the interval between the onset and the end of the systolic blood flow across the aortic valve and can be measured by Doppler echocardiography in the deep transgastric view, which permits flow to be measured without a significant intercept angle. The aortic blood flow velocity recorded by pulsed or continuous wave Doppler is determined by: i) LV preload; ii) LV afterload and hence also aortic valve resistance ; and iii) LV contractilit y.

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The slope of the aortic pressure rise and of the aortic flow velocity wave form is dependent on the force developed by the ventricular pump during ejection , and hence on the force of LV contraction. It has to be remarked that aortic pressure rises slower to its peak value than flow, even if the delay owing to the use of fluid filled catheters is taken into consideration. Eventually, LV pressure starts to decline and, once it has fallen below the pressure in the aorta, the aortic valve cusps close. Diastole then starts as routinely described in clinical textbooks. However, relaxation already starts during the major part of LV ejection and continues during the isovolumic relaxation period and the early filling phase of the left ventricle . The isovolumetric relaxation period is the first phase in diastole. It is characterized by an absence of volume change in the left ventricle and lasts till the moment when LV pressure falls below left atrial pressure and causes the mitral valve to open. Measurement of the isovolumetric relaxation time is again easily performed by Doppler echocardiography (placing the sample volume between the mitral valve and the LV outflow tract) or by Doppler myocardial imaging at the mitral annular level (as the time interval between the end of the systolic wave and the onset of the early diastolic wave). The opening of the mitral valve marks the onset of the early LV filling period and is associated with an abrupt increase in blood flow velocity which is inscribed in the Doppler recording as early filling velocity or E wave. This early E wave is physiologically characterized by a higher amplitude than the atrial contraction wave A. With advancing age, however, the E velocity decreases while the A velocity increases with a consequent fall in EtA ratio. In addition to the effect of age, relative changes in the early to late flow wave ratio are governed by LV preload and LV diastolic function characteristics. In order to diminish the impact of filling conditions on the E wave, new techniques, such as color M mode Doppler propagation flow velocity of the early filling and tissue Doppler imaging have been introduced into the praxis of echocardiography. The E wave is followed by a period of diastasis and the late LV filling phase, which is typified in Doppler echocardiography by the A wave. In contrast to the clinical definition described above, Brutsaert et al. defined diastole as the phase in the cardiac cycle where the myocardium develops no active tension; therefore, in this view, diastole is built up by diastasis and late filling only [I, 2]. The first part of diastole: Relaxation During the major part of ejection , isovolumic relaxation and early filling, relaxation is occurring as an active, energy consuming process. Gillebert et al. showed that about 82 % of peak isovolumic LV pressure is reached when contraction is switching towards relaxation [3]. The determining factors influencing relaxation are the prevailing loading conditions [4- 7], the degree of mechanical non-uniformity or incoordination during systole [8], and the rate of inactivation, this being the global process which leads to inactivation of force-generating sites (e.g., detachment of the cross-binding bridges). The end of relaxation is not yet clearly defined. Usually relaxation ends somewhere after the isovolumic relaxation; however, more recent research on calcium metabolism elucidated small concentrations of endoplasmic calcium during diastole [9, 10]. The duration of myocardial relaxation is governed by the elastic recoil, which is intrinsic load. At the end of systole, the left ventricle contracts below its equilibrium volume, through which restoring forces develop, which actually generate the elastic recoil. Several factors influencing this response have been identified;

Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit

rate accelerates myocardial relaxation mainly through decreased myofilament sensitivity [9). The smaller the end-systolic volume, the higher the elastic recoil and the larger the energy release by decompression of the elastic components such as titin and extracellular collagen. The golden standard for characterization of relaxation is the time-constant of isovolumic relaxation, L [l l ], which exemplifies the zero [12) or non-zero (13) asymptote in an empirical exponential model. Rapid relaxation is related to rapid LV pressure decay. When LV pressure becomes less than left atrial pressure, the mitral valve will open and the early filling phase will start, demonstrated by the E flow wave on Doppler echocardiography, quickly diminishing the pressure gradient between the left atrium and left ventricle. The relaxation phase is followed by a diastasis, a period of no flow. In this period there is a complete pressure equilibration between the pulmonary veins, over the left atrium, and the left ventricle. The left atrium also then behaves as a passive conduit between the pulmonary veins and the left ventricle. Compliance of the left ventricle In addition to normal relaxation, normal diastolic function also comprises normal compliance, permitting unrestricted passive filling. Little et al. described a noninvasive manner to calculate LV stiffness, KLV [14): KLV = P . L . (~ . _1)2 A 2 tdec

(1)

where p = density of blood; L = effective mitral valvular length; and A = mitral valve area. In conditions of increa sed LV stiffness, early filling velocities will increase, including a shorter time of deceleration. Comparisons between directly measured LV stiffness indices and Doppler derived stiffness estimations show good correlations (r = .94; SEE = .06 mmHg/ml; p < .05) [14). In addition to relaxation and compliance, external factors playa major role in the determination of the physiology and pathophysiology of diastole: Wall thickness of the left ventricle, ventricular interdependence and in particular the influence of the right ventricle , and finally pericardial constraint.

Diastolic Dysfunction This term relates to either relaxation and/or stiffness abnormalities, independent of the presence of systolic dysfunction and/or clinical symptoms. Although LV dysfunction may be present, diastolic dysfunction is more often present without disturbed LV ejection fraction (LVEF). Methods to Determine Diastolic Dysfunction

Echo-Doppler techniques are routinely used to diagnose the presence of diastolic dysfunction. Traditional Doppler-echocardiography relied on altered transmitral Doppler patterns ( Fig. 2). Reflecting the pressure gradient between the left atrium and ventricle, transmitral Doppler depicts how filling of the left ventricle occurs. Flow velocities are related to left atrial pressure and independently and inversely related to ventricular relaxation.

79

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J. Poelaert, E. Osipowska, and C. Verborgh

Normal

Impai red relaxation

E/A

>1

<1

Dect

<240 ms

> 240 ms

Pseudonormal

<1 160- 200 ms

Restrictive

» 1 < 160 ms

Fig. 2. Different Doppler patterns brought together: Upper line, transmitral Doppler pattern; middle line, pulmonary venous Doppler; lower line, myocardial Doppler pattern. Left column, normal; second column, reduced relaxation rate; third column, pseudonormalization; final column, low compliant ventricle.

Table 1. Physiological and pathophysiological factors interfering with the transmitral flow pattern. Physiological: • age: in particular characterized by a decreased relaxation with increasing age • preload: a decreased Ecould be related to low preload • heart rate: increasing heart rate will fuse the Eand A Pathophysiological • stiffness of left ventricle • compliance of left atrium

A normal filling pattern at the level of the mitral valve consists of two consecutive flow waves: An early filling wave (E) followed by a period of diastasis , whereafter the atrial contraction flow velocity (A) occurs. The latter is often characterized by a smaller amplitude (velocity) and area under the curve (effective flow). The E wave is also described by the deceleration time, the time between peak velocity and zero flow velocity ( Fig. 2). The deceleration time is normally < 220 ms. A final variable derived from the transmitral flow pattern is the E/A which is normally > 1. A number of physiological factors interfere with the normal values of E, A, deceleration time of E, and E/A (Table 1).

Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit Abnormal Transmitral Flow Patterns Three different phase of diastolic dysfunction have been recognized and described, comprising reduction of relaxation , pseudonormalization, and finally stiffening of the ventricle with reduced compliance ( Fig. 2). 1. Impaired relaxation: The early filling will gradually decrease with ageing or decreased preload as well as ischemic heart disease, increased afterload or myocardial disease resulting in prolonged deceleration time, and decreased E flow wave velocity. This decline represents the decrease in the relaxation rate and is compen sated for by an increased atrial contraction flow wave velocity. This pattern, characterized by a reduced E flow wave velocity in conjunction with an increased atrial contraction wave velocity, has been attributed to a reduced relaxation rate of the left ventricle. Besides a reduced E/A, this pattern is governed by a prolonged isovolumic relaxation time and a lengthened deceleration time. 2. Pseudonormalization: This phase of diastolic dysfunction is characterized by a nearly normal E/A ratio, actually not identifiably different from a normal pattern. It simply reflects the transition from reduced relaxation to the next phase of diastolic dysfunction. 3. Restricted filling: This phase illustrates the reduced compliance and increased stiffness of the left ventricle, as the early filling rate is abrupt and brisk. Therefore, the E/A is » 1 and often approaches 2. The high E flow wave velocity also suggests an increased left atrial pressure , whereas the A flow wave velocity is rather small, suggesting a small pressure difference between the left atrium and the low compliant left ventricle . From the discussion of the different phases of diastolic function, it is evident that two major shortcomings of using transmitral flow in the diagnosis of diastolic dysfunction are prominent: i) the pseudonormalization is indiscernible from a normal pattern and, therefore, transmitral flow analysis cannot help in the diagnosis of the correct phase of diastolic dysfunction; ii) The E flow wave velocity is strongly preload dependent and dependent on myocardial relaxation rate. Improved preload will shorten the isovolumetric relaxation time and the deceleration time, and augment the amplitude of the E flow wave. Again, differentiating between both clinical entities is, therefore, not possible. For all these reasons, researchers looked more closely at pulmonary venous Doppler patterns. Pulmonary Venous Doppler In an attempt to overcome all difficulties encountered with the transmitral flow pattern and assessment of diastolic function, pulmonary venous Doppler has been proposed. About 80 % of transthoracic echo-Doppler evaluations and all transesophageal investigations allow the visualization of pulmonary venous Doppler flow velocities, both in the right and left pulmonary veins ( Fig. 2). The pattern is characterized by at least three distinct flow waves: i) the atrial contraction wave (a) which is a reverse flow wave, normally smaller than 0.25 m/s; increased flow wave amplitudes suggest increased left atrial pressure ; ii) the antegrade systolic flow wave (5), which is sometimes observed as two consecutive flow waves (low preload); iii) an antegrade smaller diastolic flow wave (D), which occurs concurrently with the early filling wave at the trans mitral flow pattern. The systolic flow velocity wave is blunted in several conditions: Severe mitral regurgitation with systolic reverse flow, low left atrial and/or LV compliance, or ele-

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vated filling pressures. The atrial contraction wave is often diminished whenever restrict ive filling is present. Commonly, progressively decreasing diastolic dysfunction is expressed in relation to EtA as a parabolic distribution: determination of the phase of diastolic dysfunction an individual patient shows, remains difficult because of the interplay between relaxation and preload, which makes routine pulsed wave Doppler indices less preferable, in particular in a setting where preload conditions may change constantly and abruptly as in many critically ill patients. Nevertheless, in a series of vasopressor dependent patients with septic shock, it was possible to discern different patterns of diastolic dysfunction [15]. Tissue Doppler Echocardiography

This newer Doppler technique allows on-line assessment of myocardial motion. With classical Doppler echocardiography a high pass filter is active, eliminating low velocity signals; furthermore, the gain settings are increased to amplify the reflected signals. In myocardial Doppler echocardiography, however, this high pass filter is inactivated, resulting in display of low Doppler velocities. In contrast to commonly used Doppler echocardiography in which red blood cells reflect low amplitude high velocity Doppler signals, myocardial Doppler signals are characterized by high amplitudes and low velocities. The technique is hampered by shortcomings related to intrinsic characteristics of myocardial function (e.g., tethering of the interventricular septum, presence of regional wall motion abnormalities) and Doppler technology (translation and rotation of the myocardial tissue, angle misalignment). Nevertheless, assessment of regional LV systolic and diastolic funct ion is possible provided the sample volume is placed at the level of the mitral annulus and kinetic problems (severe hypokinesis, akinesis or dyskinesis, following either myocardial ischemia or infarction) in the annulus region are absent. Finally, myocardial Doppler echocardiography cannot account for translational motion that affects the total heart. Pulsed myocardial Doppler imaging

Myocardial Doppler echocardiography can visualize the signals in pulsed Doppler, as first described by Isaaz et al. [16] or color tissue Doppler [17], as used in most modern echocardiographs. The latter allows simultaneous assessment of myocardial velocities in different segments, useful in the assessment of regional wall motion ( Table 2), although the above mentioned restrictions should be kept in mind. A single pulsed display depicts three major waves ( Fig. 3): a systolic wave velocity (Sm); an early wave velocity (Em); and a late signal (Am), concomitant with the p wave on the EKG. The combined use of these signals with the commonly used Doppler patterns can describe the phase of diastolic dysfunction in a proper manner [18, Table 2. Differences between pulsed versus color tissue Doppler echocardiography. Pulsed Tissue Doppler Echocardiography

Color Tissue Doppler Echocardiography

High temporal resolution Low spatial resolution

High temporal resolution High spatial resolution Evaluation of multiple structures in one view

Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit

0.16

-0.16

v

\V o1 -5

f

f\

v

-10 I -

o I

2.50 to.14 s

I

--

5

~

v (crn/s) 5.26

v-9 .71 cm/s

cm/s

1\

''-/

\~

fI

f

V

V

-

--

0.8

0.2

f\

1.0

~

-

1.2

Em

Fig. 3. Typical color tissue Doppler image obtained from a transthoracic echocardiogram at the mitral annulus or the lateral wall.

Table 3. Various phases of diastolic dysfunction as identified by different Doppler patterns and techniques Descriptors of Diastolic Dysfunction in Relation to Respective Physiology EIA Dect E (ins) SID Ar (rn/s)

Em (m/s)

Normal Delayed relaxation Pseudonorma l filling Restrictive filling

> < < <

> 1 < 1 1- 2 > 2

< 220 > 220

140-200 < 140

> > < <

1 1 1 1

< < > >

0.35 0.35 0.40 0.40

0.08 0.08 0.08 0.08

Ar = reverse flow velocity at the level of a pulmonary vein, owing the atrial contraction; DT = deceleration time; EIA = ratio of early to late filling wave velocity; Em = early flow velocity with spectral Doppler tissue imaging; IVRT = isovolumetric relaxation time; SID = ratio of systolic to diastolic Doppler flow velocity in a pulmonary vein.

19], and are relatively easy to obtain [20]. Table 3 summarizes the use of the different signals to discriminate the various phases of diastolic dysfunction. Myocardial Doppler echocardiography permits the evaluation of longitudinal systolic function of the left and right ventricles . The apical-directed motion of the mitral or tricuspid annulus is directly related to the force of contraction of the respective ventricle. Nevertheless, at the level of the left ventricle, rotational and circumferential forces should not be ignored. In addition, it is to be expected that the systolic motion velocity of the myocardium is load dependent [21]. Less transparency exists on the load dependency of the diastolic myocardial velocities [22]. Although Em appeared to be load independent in settings of rapid

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infusion or preload alteration, Jacques et al. clearly demonstrated both afterload independency and preload dependency of Em in dogs with preserved LV function [23]. Em was consistently related to decreased LV end-diastolic filling pressures. However, Jacques et al. did not report the sample volume location . A recent stud y assessed the effects of acute loading changes in hemodialysis patients and in a rather small subset of critically ill patients [24]. Comparison between the septal and lateral mitral annulus signals suggests that the septal signals are apparently more sensit ive to preload alterat ions. The stability of the septal signals in criti cally ill patients can be questioned, particularly when considering ventilation-induced afterload shifts of the interventricular septum [25]. In ICU patients, many issues, with or without relation to each other, interplay with a correct interpretation of hemodynamics. This is also true for hemodynamic variables obtained by Doppler echocardiography. Load-diminishing effects (such as ultrafiltration) counterbalance the effects of inotropic drugs with respect to the evaluation of Em [26]. Furthermore, the influence of ultrafiltration itself on LV systolic and diastolic function during septic shock is largely unknown. The combination of lower preload (by ultrafiltration) and decreased LV function would render a less preload dependent Em, as suggested by Jacques et al. [23]. Although Em appears to be quite a robust variable in terms of assessment of diastolic dysfunction in cardiac failure in the critically ill, sorting out Doppler results with respect to hemodynamic assessment still seems very difficult [22]. Em is related to preload, LV -dP/dt and LV relaxation (r). Left atrial relaxation , left atrial dP/dt and LV end-diastolic pressure determine Am [27].

Strain Rate and Strain These techniques allow assessment of deformation rate (strain rate) or deformation (strain) of a three-dimensional structure in a two-dimensional manner. Strain , E, is defined as the deformation of an object normalized to the original shape. Compression of an object relates to a negative value of strain whereas expansion confers the reverse. A three-dimensional structure obliges definition of 3 normal and 6 shear strain components. Three axes perpendicular to each other should be considered: Radial, longitudinal and circumferential strain. Thus, strain can be defined as: E

= (L2 - Ll) ILl = [(y2 - x2) - (y1 - xl)] I (y1 - xl)

with L2 = the length of a bar after deformation, being y2 - x2; Ll bar before deformation, being y l - x l , as depicted in Figure 4 Strain rate is then strain over time: E

• •

= the length

(2)

of the

= ElM = [(y2 - y1) I M - (x2 - xl) M] I y1 - xl -= (v2 - v1) ILl (3)

L,

•

y,

•

Fig. 4. Unidimensional deformation of a line element from L1 towards L2.

Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit

Some practical issues: • intercept angle: as with other Doppler signals, tissue Doppler is also sensitive to the angle the Doppler beam applies to the reflecting bodies. Therefore, the intercept angle should be kept as low as possible (preferentially below 20°). • acquisition rate: Whereas commonly used Doppler echocardiography utilizes low pulse repetition frequencies (PRF), providing more lines along an image line with lower PRF, studies suggest a PRF setting of 200- 300 Hz, as some myocardial mechanical events are short-lived [27]. The value of these variables in the critically ill remains to be completely elucidated.

Evaluation of Filling Pressures Assessment of left sided filling pressures has always been an important goal for the echocardiographer dealing with ICU patients . For many years, intensivists have become accustomed to the physiology behind intracardiac pressures and their relationship with systolic function, preload , and afterload of both ventricles. Although the risks of invasive hemodynamic monitoring should not be exploited, it is clear that the drawbacks must be recognized [29]. In addition, the knowledgeable clinician could gain considerable time savings by using bedside transthoracic echocardiography to manage hemodynamic instability in comparison with invasive hemodynamic monitoring. The reader is referred to review articles in which echo-Doppler guided decision making regarding hemodynamic assessment is explained [30- 33]. In brief, echo-Doppler provides quick and instantaneous bedside information on the cause of hemodynamic instability: The intensivist has a considerable advantage as he/she can combine knowledge on invasive pressures with Doppler-derived flow information. The short axis is, in this perspective, the very first view to be analyzed as it allows immediate assessment of global systolic function , diagnosis of presence or absence of regional wall motion abnormalities, and it provides a rough idea of preload . Many researchers have invested large amounts of time to achieve non-invasive assessment of LV filling pressures from Doppler derived flow estimations. Rough estimations can be obtained from the diastolic dysfunction grading. The most prominent studied variable in this respect is the ratio of E and Em, which combines the influence of highly load-dependent transmitral driving pressure between the left atrium and ventricle and myocardial relaxation [34]. Myocardial Doppler imaging was utilized in the setting of ventilated ICU patients to relate pulmonary artery occlusion pressure (PAOP) with E/Em in two different studies. Both found a relationship between E/Em > 7 and PAOP > 13 mmHg, with the transthoracic [35] or the transesophageal (36) approach. One study exemplified a relationship between E/Em > 7 (lateral mitral valve annulus) and the PAOP > 13 mmHg with a sensitivity of 86 % and a specificity of 92 % (36). Therefore, E/Em can be safely used to indicate high filling pressures; however, in patients with normal LV diastolic function (23) or tethering of the interventricular septum (37), it is much more difficult to safely predict left sided filling pressures. Advanced evaluation of this index is necessary to elucidate thoroughly the drawbacks in critically ill patients .

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Conclusion Diagnosis of diastolic dysfunction is an important issue in view of the importance of early treatment of cardiac failure. Tissue Doppler echocardiography allows assessment of diastolic function and helps to solve the incapacity of transmitral and pulmonary venous Doppler flow patterns to determine the phase of diastolic dysfunction. However, thorough knowledge of the appropriate use and shortcomings of each technique must be recognized [38]. This knowledge is a critical point when learning and performing echocardiography and Doppler studies in general and in critically ill patients in particular. Meticulous background of the physiology and pathophysi ology of the heart, hemodynamics (preload, afterload , and contractility), and the circulation should be obtained to understand fully the power and the drawbacks of the different tools utilized with echo-Doppler. References 1. Brutsaert DL, Rademakers FE, Sys SU, Gillebert TC, Housmans PR (1985) Analysis of relaxation in the evaluation of ventricular function of the heart. Prog Cardiovasc Dis 28:143- 163 2. Brutsaert DL, Rademakers FE, Sys SU, Gillebert TC, Housmans PR (1984) The heart as an integrated muscle and pump system: triple control and subdivision of the cardiac cycle. Acta CardioI39:89-95 3. Gillebert T, Leite-Moreira A, De Hert S (1997) The hemodynamic manifestation of normal myocardial relaxation. A framework for experimental and clinical evaluation. Acta Cardiologica 52:223- 246 4. De Hert S, Gillebert T, Ten Broecke P, Mertens E, Rodrigus I, Moulijn A (1999) Contractionrelaxation coupling and impaired left ventricular performance in coronary surgery patients. Anesthesiology 90:748-757 5. Ishizaka S, Asanoi H, Wada 0, Kameyama T, Inoue H (1995) Loading sequence plays an important role in enhanced load sensitivity of left ventricular relaxation in conscious dogs with tachycardia-induced cardiomyopathy. Circulation 92:3560-3567 6. Leeuwenburgh BP, Steendijk P, Helbing WA, Baan J (2002) Indexes of diastolic RV function : load dependence and changes after chronic RV pressure overload in Iambs. Am J PhysioI Heart Circ Physiol 282:H1350-1358 7. Leite-Moreira A, Correia-Pinto J, Gillebert T (1999) Load dependence of left ventricular contraction and relaxation . Effects of caffeine. Basic Research in Cardiology 94:284- 293 8. Leite-Moreira A, Gillebert T (1994) Nonuniform course ofleft ventricular pressure fall and its regulation by load and contractile state. Circulation 90:2481 - 91 9. Varian KD, Janssen PM (2007) Frequency-dependent acceleration of relaxation involves decreased myofilament calcium sensitivit y. Am J Physiol Heart Circ PhysioI292:H2212-2219 10. Bombardini T (2005) Myocardial contractility in the echo lab: molecular, cellular and pathophysiological basis. Cardiovasc Ultrasound 3:27 11. Khour i SJ, Maly GT, Suh DD, Walsh TE (2004) A practical approach to the echocardiographic evaluation of diastolic function. J Am Soc Echocardiogr 17:290-297 12. Weiss JL, Frederiksen JW, Weisfeldt ML (1976) Hemodynamic determinants of the timecourse offall in canine left ventricular pressure . J Clin Invest 58:751-760 13. Nikolic S, Yellin EL, Tamura K, et al (1988) Passive properties of canine left ventricle: diastolic stiffness and restoring forces. Circ Res 62:1210-1222 14. Little WC, Ohno M, Kitzman DW, Thoma s JD, Cheng CP (1995) Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation 92:1933- 1939 15. Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA (1997) Left ventricular systolic and diastolic funct ion in septic shock. Intensive Care Med 23:553 - 560 16. Isaaz K, Thompson A, Ethevenot G, Cloez JL, Brembilla B, Pernot C (1989) Doppler echocardiographic measurement of low velocity motion of the left ventricular posterior wall. Am J Cardiol 64:66-75

Diastolic Dysfunction and Cardiac Failure in the Intensive Care Unit 17. McDicken WN, Sutherland GR, Moran CM, Gordon LN (1992) Colour Doppler velocity imaging of the myocardium. Ultrasound Med Bioi 18:651-654 18. Garcia MJ, Thomas JD, Klein AL (1998) New Doppler echocardiographic applications for the study of diastolic funct ion. J Am Coli Cardiol 32:865- 875 19. Miyatake K, Yamagishi M, Tanaka N, et al (1995) New method of evaluating left ventricular wall motion by color-coded tissue Doppler imaging: in vitro and in vivo studies. J Am Coli Card iol 25:717- 724 20. Ommen SR, Nishimura RA, Appleton CP, et al (2000) Clinical utility of Doppler echocardiography and tissu e Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 102:1788-1794 21. Ama R, Segers P, Roosen s C, Claessens T, Verdonck P, Poelaert J (2004) Effects ofload on systolic mitral annular velocity by tissue Doppler imaging . Anesth Analg 99:332- 338 22. Poelaert J, Roosens C (2007) Is tissue Doppler echoca rdiography the Holy Grail for the intensivist? Crit Care 11:135 23. Jacques DC, Pinsky MR, Severyn D, Gorcsan J, III (2004) Influence of Alterations in Loading on Mitral Annular Velocity by Tissue Doppler Echocardiography and Its Associated Ability To Predict Filling Pressures. Chest 126:1910- 1918 24. Vignon P,Allot V, LesageJ, Martaille J-F, Francois B, Gastinne H (2007)Diagnosis ofleft ventricular diastolic dysfunction in the setting of acute changes in loading conditions. Crit Care 11 :R43 25. Roosens CD, Ama R, Leather HA, et al (2006) Hemodynamic effects of different lung-protective ventilat ion strategies in closed-chest pigs with normal lungs. Crit Care Med 34:29902996 26. von Bibra H, Tuchnitz A, Klein A, Schneider-Eicke J, Schomig A, Schwaiger M (2000) Regional diastolic function by pulsed Doppler myocardial mapping for the detection of left ventricular ischemia during pharmacologic stress testing : a comparison with stress echocardiography and perfusion scintigraphy. J Am Coli Cardiol 36:444-452 27. Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS (2001) Hemodynamic determ inants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 37:278-285 28. D'hooghe J, Jamal F, Bijnen s B, et al (2000) Calculation of strain values from strain rate values: how should this be don e? In: IEEE International Ultrasonics Symposium Proceedings, pp 1269-1272 29. Weil M (1998) The assault on the Swan Ganz catheter. A case history of constrained technology, constrained bed side clinician s, and constrained monetary expenditures. Chest 113: 1379-1386 30. Michel-Cherqui M, Ceddaha A, Liu N, et al (2000) Assessment of systematic use of intraoperative transesophageal echocardiographic during card iac surgery in adults : a pro spective study of 203 patients. J Cardiothorac Vase Anesth 14:45-50 31. Pruszc zyk P, Torbicki A, Kuch-Wocial A, Szulc M, Pacho R (2001) Diagnostic value of transoesophageal echocardiography in suspected haemo dynamically significant pulmonary embolism. Heart 85:628-634 32. Poelaert J (2006) The failing heart under stres s: echocardiography is an essential monitoring tool in the intensive care unit. Semin Cardiotho rac Vase Anesth 10:111-115 33. Poelaert JI, Schupfer G (2005) Hemod ynamic monitoring utilizing transesophageal echocardiography: The relationships among pressure, flow, and function. Chest 127:379-390 34. Nagueh S, Mikati 1, Kopelen H, Middlet on K, Quinonens M, Zoghbi W (1998) Doppler estimation of left ventricular filling pressur e in sinus tachycardia . A new application of tissue Doppler imaging. Circulat ion 98:1644- 1650 35. Combes A, Arnoult F, Trouillet JL (2004) Tissue Doppler imaging estimation of pulmonary artery occlusion pressure in ICU patients. Intensive Care Med 30:75-81 36. Bouhemad B, Nicolas-Robin A, Benois A, Lemaire S, Goarin JP, Rouby JJ (2003) Echocardiographic Doppler assessment of pulmonary capillary wedge pressu re in surgical patients with postoperative circulatory shock and acute lung injury. Anesthesiology 98:1091-1100 37. D'Souza KA, Mooney DJ, Russell AE, MacIsaac AI, Aylward PE, Prior DL (2005) Abnormal septal motion affects early diastolic velocities at the septal and lateral mitral annulus, and impacts on estimat ion of the pulmonary capillary wedge pressure . J Am Soc Echocardiogr 18:445-453 38. Poelaert J, Mayo P (2007) Education and evaluation of knowledge and skills in echocardiography : how should we organi ze? Intensive Care Med 33:1684 - 1686

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Pharmacological Support of the Failing Right Ventricle P.E

WOUTERS,

S.

REX,

and C. MISSANT

Introduction After years of relative neglect, the role of the right ventricle in maintaining circulatory homeostasis is now generally recognized. Right ventricular (RV) dysfunction is a frequent cause of low output syndrome after cardiac surgery and appears to be associated with a higher mortality than left ventricular (LV) failure in the perioperative setting [1]. In the acute respiratory distress syndrome (ARDS) and in primary pulmonary hypertension [2] RV failure has an independent detrimental effect on clinical outcome. This pathophysiological condition remains a clinical challenge for which our current therapeutic approaches do not yet provide a satisfactory answer. Correct treatment obviously relies on a proper and timely diagnosis. Virtually no clinical signs, biochemical alterations, or hemodynamic variables are specific enough to allow an early differentiation between right- and left- or biventricular failure. However, echocardiography has substantially improved our ability to detect RV dysfunction by providing a direct window to the relative performance of, and interaction between, the two cardiac chambers. A simple assessment of the LV/RV size ratio has excellent predictive value for the diagnosis of RV dysfunction [3]. More advanced echo techniques such as myocardial velocity and deformation imaging and real time 3-D echocardiography provide interesting new tools to quantify RV function but their clinical role, e.g., in evaluating the effectiveness of therapeutic interventions, remains to be determined [4]. The majority of pharmacological studies on support of the failing heart have focused on the left ventricle and transposing such data to clinical RV failure is not valid. There are marked differences between the left and right ventricle with regard to embryology, anatomy and physiology. A fair understanding of the pathophysiology of RV failure is mandatory because the efficacy of any treatment will ultimately depend on how it affects right and left ventriculo-vascular coupling and how it changes the serial and parallel interaction between both ventricles (ventricular interdependence).

Pathophysiology of Right Ventricular Failure The normal right ventricle has only one fifth the muscle mass of the left ventricle. The maximum response to positive inotropic drugs, i.e., the contractile reserve of the right ventricle, is, therefore, limited and its sensitivity to acute afterload changes is extremely high. The right ventricle is also a more compliant chamber than the left ventricle with a flatter slope for the Frank-Starling relationship indicating reduced preload sensitivity.

Pharmacological Support of the Failing Right Ventricle

A

RV failureand dilatation

~ I RV out put

I Ca rdiacoutput

~----';"+---""l

B + + + + + + + + + + + + + +

Systemic hypotension

Fig. 1. Pathophysiological consequences of right ventricular (RV) failure. The left panel (A) illustrates the consequences of ventricular interdependence. Panel B highlights the vicious circles of self-aggravation (+). LV: left ventricular

The functional role of the RV pump in a spontaneously breathing subject with normal pulmonary vascular tone is negligible. This was shown in early experimental studies where complete destruction of the RV free wall had no immediate hemodynamic consequences. It is also illustrated by the clinical success of the Fontan approach to univentricular physiology. However, RV pump function becomes important whenever pulmonary vascular input impedance increases and the pressure gradient between the right and left atrium rises. In such condit ions, the RV pump is needed to propel blood across the pulmonary circulation. It is assisted in this function by the left ventricle via pressure transduction across the interventricular septum and, presumably, by fiber shortening of muscle bands connected to the RV free wall and/or encircling the entire heart [5]. The capacity of the thin-walled right ventricle to cope with acute rises in afterload is limited, however. If pressure overload persists or increases, the right ventricle will eventually distend and affect LV performance through serial (failure to produce antegrade filling of the left ventricle) and parallel (transseptal disturbance of diastolic and systolic function) ventricular interaction . At this stage, the clinical signs of heart failure become obvious and vicious circles of self aggravation rapidly lead to circulatory shock ( Fig. 1).

Therapeutic Options There are three primary approaches to treat the failing right ventricle: 1) pulmonary vasodilation; 2) systemic vasopressor therapy; and 3) positive inotropic support. In the vast majority of clinical situations where hemodynamic compromise is due to primary RV failure, there is an indication for a selective decrease in RV afterload.

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Indeed, RV failure rarely produces circulatory collapse in the presence of a normal pulmonary vascular tone (unless there is biventricular involvement). On the other hand, RV failure which occurs secondary to LV dysfunction (causing backward failure and venous pulmonary hypertension) is a common clinical scenario. Here, treat ment should focus on the left ventricle since any attempt to selectively increase RV performance may overload the left ventricle. The exact etiology of acute RV failure will also determine its responsiveness to treatment. Finally, right ventricles that have been subjected to chronic overload have a much higher contractile reserve - but possibly at the expense of a reduced coronary flow reserve and impaired diastolic function. Optimization of the ventilation mode and correction of biochemical changes that affect pulmonary vascular tone are of primary importance to control RV afterload but will not be considered in this chapter. Instead, we will focus on the pharmacological tools that are currently at our disposal. This covers a variety of vasodilators, positive inotropic drugs, and vasoconstrictors with different, often complementary, modes of action .

Pulmonary Vasodilators There are no vasodilators available that act only on the pulmonary vasculature; when administered intravenously, they almost invariably produce systemic vasodilatation and arterial hypotension. Systemic hypotension is extremely compromising for patients with RV failure since it reduces RV perfusion to critically low levels and promotes leftward septal shifting. Recently, Fattouch and co-workers demonstrated that treatment with intravenous vasodilators in the early postoperative period after mitral valve surger y had to be stopped in 62 % of patients due to severe systemic hypotension [6]. Another important limitation of intravenous vasodilators is their indiscriminate action on pulmonary vessels in ventilated as well as in non-ventilated lung areas. This effect often produces increased intrapulmonary shunting and deteriorate s oxygenation in patients with acute lung injury (ALI)/ARDS, despite marked improvements in pulmonary hemodynamics [7]. For these reasons, intravenously admin istered pulmonary vasodilator s should be used only with caution, i.e., starting at low doses and/or in combination with systemic vasopressors in patients with acute RV failure and/or ARDS. Selectivity for the pulmonary vasculature can be obtained, however, by adminis tering vasodilators via the airway. Several vasodilators have been shown to be effective when administered via a nebulizer or aerosol. The drugs are distributed primarily to the well-ventilated areas of the lung and their selective disposition redistributes pulmonary blood flow to improve ventilation-perfusion matching and oxygenation in patients with ARDS. Vasodilators with a short half-life produce very little spill-over in the systemic circulation and carry a lower risk for systemic arterial hypotension. Inhaled nitric oxide This endogenous substance plays a key role in the regulation of pulmonary vascular tone at the endothelial level. After inhalation, nitric oxide (NO) diffuses rapidly across the alveolo-capillary membrane into the subjacent smooth muscle of pulmonary vessels. By activating soluble guanylate cyclase, GTP is converted to cGMP, the second messenger involved in smooth muscle relaxation. The physiological actions of cGMP are constrained to the area of synthesis due to hydrolysis by cyclic nucleo-

Pharmacological Support of the Failing Right Ventricle

tide phosphodiesterase (PDE), in particular PDE-5 [8]. After diffusion into the bloodstream, NO rapidly reacts with oxyhemoglobin to form methemoglobin and nitrate and with deoxyhemoglobin to form iron-nitrosyl-Hb. Inhaled NO has long been considered the drug of choice to achieve selective pulmonary vasodilation. It has been successfully used in ARDS and in perioperative pulmonary hypertension of various etiologies, in particular in congenital heart surgery, in cardiac transplantation, and during placement of LV assist devices. Concentrations of up to 80 ppm inhaled NO have been used for the treatment of pulmonary hypertension but recent data have shown that concentrations exceeding 20 ppm do not add further hemodynamic benefit. In ARDS, oxygenation can be improved in most cases with low concentrations, i.e., 5-10 ppm or lower [9]. Despite marked effects on pulmonary hemodynamics and oxygenation, there is still no evidence that treatment with inhaled NO improves survival in these patients. The inhaled administration of NO is technically cumbersome and require s sophisticated mon itoring to avoid toxicity from NO z formation and methemoglobinemia. Clinical studies show a considerable number of non-responders [9], and sudden discontinuation of inhaled NO can cause rebound pulmonary hypertension and deter iorate oxygenation. Importantly, since its approval by the Food and Drugs Administration (FDA) for the treatment of persistent pulmonary hypertension in newborns, costs for treatment with inhaled NO have increased. Inhaled prostacyclin Prostacyclin (PGIz) is synthesized in pulmonary endothelial cells through the arachidonic acid pathway. It causes both vascular smooth muscle relaxation and potent inhibition of platelet aggregation . PGIz acts via binding to a specific prostanoid receptor (IP), and activates adenylate cyclase to increase intracellular cyclic adenosine monophosphate (cAMP) levels. cAMP is hydrolyzed preferentially by PDE-3. PGIz has a short half-life of only 3- 6 mins due to spontaneous hydrolysis to its inactive metabolite , 6-ketoprostaglandin-Fl a [10]. Numerous studies in patients with ARDS and in cardiac surgical patients with perioperative pulmonary hypertension have demonstrated that inhaled PGIz exerts selective pulmonary vasodilation. Interestingly, when compared to inhaled NO, PGIz seems to be more potent in decreasing pulmonary vascular resistance (PVR) but less effective in improving oxygenation. The optimal dosing of PGIz is still to be defined. A practical approach is to start with a dose of 50 rig/kg/min and, after stabilization of the patient, to down-titrate the dose to achieve the minimal effective concentration. According to the available data, PGIz and its metabolites seem to be remarkably safe and non-toxic. Inhaled PGIz was shown to inhibit platelet aggregation in cardiac surgical patients as indicated by in vitro tests; however, bleeding time, chest tube drainage and transfusion requirements were not increased [11]. Systemic effects normally seen with the intravenous use of PGIz (arterial hypotension, facial flushing, headache , jaw pain, and diarrhea) have not been observed in any of the published studies . As with inhaled NO, sudden discontinuation of PGIz can result in rebound pulmonary hypertension and in ARDS, the rate of non -responders seems to be comparable with inhaled NO. Owing to its low toxicity, PGIz can be administered without technically sophisticated monitoring. The solution must be protected from ambient light and is stable at room temperature only for 12 h. Due to the short halflife, PGIz necessitates continuous nebulization. As with inhaled NO, there is no hard evidence that treatment with inhaled PGIz improves survival.

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Inhaled iloprost Iloprost is the carbacyclin analog of PGIz• In contrast to PGlz• iloprost is stable at room temperature and does not need to be protected from light. The half-life of inhaled iloprost has been described in humans to be 6-9 mins, while its pulmonary vasodilating effects were found to last 20-60 mins, allowing intermittent nebulization [12]. Although bolus administration of iloprost produces a transient spill-over into the systemic circulation, effects on systemic vascular tone are much smaller than the effects on pulmonary vascular resistance [12]. As with PGlz, aerosolized iloprost has been shown to decrease RV -afterload and consequently improve cardiac output to a greater extent than inhaled NO [13]. Inhaled iloprost improved symptoms, pulmonary hemodynamics, and prognosis in patients with idiopathic pulmonary arterial hypertension. A randomized controlled trial also showed beneficial effects with inhaled iloprost in cardiac surgery [14]. The optimal dosage for inhaled iloprost to treat acute RV failure after cardiac surgery remains unknown, as no dose response curves are available for this particular situation . In our clinical routine, an adequate vasodilator response can be achieved with 25 ~g. Type 5 phosphodiesterase inhibitors Sildenafil is the prototype of an orally-active, potent and selective inhibitor of PDE5. It increases the intracellular concentration of cGMP, thereby producing relaxation and antiproliferative effects on vascular smooth muscle cells [15]. As PDE-5 is abundant in the pulmonary endothelium, sildenafil may have a preferent ial effect on the lung vasculature. Oral sildenafil was found to increase the pulmonary vasodilator effects of both inhaled NO [16] and inhaled iloprost [17] suggesting a certain level of non-specifity for PDE-inhibitors. The drug has become an important treatment option in patients with chronic pulmonary hypertension [15]. In acute pulmonary hypertension, inhalation of sildenafil resulted in selective pulmonary vasodilation in animal experiments [18]. However, as the drug is currently only available as an oral formula, research should focus on the effects of enteral sildenafil in the setting of perioperative pulmonary hypertension. Only case reports or small series have described the use of sildenafil in critically ill patients. In a group of eight adults with pulmonary hypertension after mitral valve repair or placement of a LV assist device, sildenafil facilitated weaning from pulmonary vasodilators [19]. Whether systemic administration of sildenafil produces selective pulmonary vasodilation is still debated. In congenital heart surgery, intravenous sildenafil caused a significant decrease in systemic arterial pressures and a worsening of arterial oxygenation [20]. Sildenafil was recently reported to enhance contractility in the hypertrophied right ventricle, suggesting that it acts as an inodilator [21]. While prospective data in larger groups of patients are missing, caution is warranted in the use of sildenafil to treat perioperative RV dysfunction subsequent to pulmonary hypertension. Endothelin antagonists Endothelin-l (ET-l) plays a prominent role as a vasoconstrictor and mitogen for smooth muscle [22]. The pulmonary circulation is an important site of production and clearance of ET-l. Increased circulating levels of ET-l have been detected in patients with primary pulmonary hypertension as well as in experimental models of pulmonary hypertension, suggesting that over-activation of the ET-l system is involved in the pathogenesis and maintenance of pulmonary hypertension. In cardiac surgery, circulating ET-l plasma levels are increased in patients undergoing

Pharmacological Support of the Failing Right Ventricle

cardiopulmonary bypass (CPB) and may contribute to the increase in PVR after CPB [23]. ET-l binds to two subtypes of receptors, ETA and ETB: ETA-receptors can be found in vascular smooth muscle cells whereas ETB-receptors are located in both vascular smooth muscle cells and in endothelial cells. Activation of ETA- and ETBreceptors on vascular smooth muscle cells mediates the vasoconstrictive and mitogenic effects of ET-l, whereas stimulation of endothelial ETB-receptors induces NO and prostacyclin release and promotes ET-1 clearance [22]. Several clinical trials have shown that orally administered non selective ETA/B receptor blockade by bosentan or selective ETA-receptor blockade by sixtasentan are effective treatments for patients with chronic pulmonary hypertension [15]. Preliminary studies also show promise for the use of inhaled ET-IA receptor blockers in experimental models of pulmonary hypertension due to ARDS [24]. In a recent trial, sixtasentan was found to improve pulmonary hemodynamics after CPB and to decrease systemic vascular resistance dose-dependently [25]. Data on the use of ETl-receptor antagonists in patients with acute RV failure are still lacking. Nesiritide Brain natriuretic peptide (BNP) was first isolated from the porcine brain and later found in the human heart. BNP is bound to special natriuretic peptide receptors that mediate the biological activities of natriuretic peptides by synthesis and intracellular accumulation of cGMP. Recent studies have demonstrated that plasma BNP levels are increased in states of left and right ventricular overload [26]. BNP has been reported to have various biochemical effects, such as diuretic and natriuretic activities, potent vasodilator effects both for pulmonary and systemic circulations, and suppression of aldosterone secretion. These findings suggest that BNP may play an important role in maintaining cardiopulmonary homeostasis in RV overload through a reduction in preload and afterload. It is important to note that BNP has been shown to counteract the vasoconstricting properties of endothelin and may act as an endogenous inhibitor of this predominant vasoconstrictor. BNP may thus represent a compensatory and protective mechanism under conditions such as severe right heart failure due to pulmonary hypertension. Whereas recombinant human BNP (nesiritide) showed promising effects in patients with perioperative LV dysfunction and in patients with secondary pulmonary hypertension [27], data on the use of nesiritide in patients with perioperative RV failure due to pulmonary hypertension are confined to case reports. As nesiritide has been demonstrated to lower systemic blood pressures, its systemic use in patients with RV failure may be associated with the drawbacks of other intravenous vasodilators, i.e., deterioration in hemodynamic status due to lack of pulmonary selectivity. Adrenomedullin The peptide adrenomedullin was discovered in 1993 and subsequently demonstrated to be a potent long-lasting pulmonary vasodilator [28]. Like ET-l, adrenomedullin is synthesized in, and cleared by, the lung and can act as a hormone as well as an autocrine/paracrine mediator. Adrenomedullin and ET-l appear to function as physiological antagonists because of their opposing pharmacodynamic effects but also interact at the cellular level in complex ways. Adrenomedullin inhibits the production and actions of ET-l but, conversely, ET-l appears to increase the production of adrenomedullin. In patients with primary pulmonary hypertension, plasma levels of adrenomedullin are elevated. The exogenous administration of adrenomedullin,

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either intravenously or by inhalation, has been shown to induce hemodynamic improvement in experimental models of pulmonary hypertension and in humans with pulmonary hypertension [29). While these data suggest that adrenomedullin treatment may become an interesting new option for treatment of pulmonary hypertension and RV dysfunction in ARDS, further studies with regard to safety and efficacy are required.

Systemic Vasopressors The rationale for using systemic vasopressors to treat the failing right ventricle is: 1) to improve coronary perfusion pressure; and 2) to restore interventricular pressure gradients and counteract leftward septal shifting. On the other hand, systemic vasopressors may also increase pulmonary vascular resistance. The result of any therapeutic regimen will ultimately depend on how the drugs affect the ratio between pulmonary and systemic vascular resistance. It may be a delicate clinical task to optimize this ratio because the drug(s) and doses required to achieve an optimal result will vary between patients and depend also on the exact underlying cause of RV failure. For example, when acute pressure overload is caused by a mechanical obstruction, vasoconstrictors will have little additional effect on RV afterload and the beneficial actions on coronar y perfusion and ventricular interdependence will dominate. In reactive acute pulmonary hypertension, the response of the pulmonary circulation to vasopressors may be exaggerated and completely offset the benefits of systemic vasoconstriction. Vasopressors are sometimes infused through a left atrial line (after cardiac surgery) in an attempt to target vasoconstriction primarily to the systemic vascular bed but a risk/benefit analysis of this popular clinical practice has not been prospectively studied . When it is suspected that LV function is not normal, systemic vasopressors should be used with great caution and their effects on LV performance need to be monitored closely. Phenylephrine Phenylephrine is a pure ol-adrenergic agonist that produces arteriolar vasoconstriction in the systemic and pulmonary vascular bed. In an animal model of acute pulmonary hypertension, the net effect of phenylephrine was a decreased cardiac output and stroke volume [30) because pulmonary arterial elastance was increased with no change in RV contractility. Similar results have been described in patients with chronic pulmonary hypertension [31). Vasopressin Vasopressin is a potent non-adrenergic systemic vasoconstrictor that operates via the G protein-coupled VI receptors on vascular smooth muscle cells. In addition, it appears that vasopressin causes endothelial dependent vasodilatation in the pulmonary circulation, but only in preconstricted pulmonary arter ies. Theoretically, the combination of systemic vasoconstriction and pulmonary vasodilation would provide the ideal therapy for RV failure. Surprisingly, in an experimental model of acute pulmonary hypertension, vasopressin increased pulmonary artery pressure and PVR and significantly decreased RV contractility [30]. In recent case reports, much lower doses of vasopressin were shown to be effective in the managemen t of hypotension caused by RV failure in patients with chronic pulmonary hypertension [32).

Pharmacological Support of the Failing Right Ventricle Positive Inotropic Drugs The currently available positive inotropic agents fit into three categories according to their primary mechanism of action, Le., sympathomimetic agents, PDE-3 inhibitors and calcium sensitizers. Alternatively, the available drugs can be classified as inodilators and inopressors, according to their overall pharmacodynamic profile. PDE-3 inhibitors and levosimendan, the only clinically available calcium sensitizer, are obligatory inodilators but for sympathomimetics the effect depends on which receptor subtype(s) they activate . Very few studies have examined positive inotropic drugs in a comparative fashion with regard to efficacy in treating RV failure. In clinical practice there is no consensus and preference for specific drugs and/or combinations seems to vary widely between institutes. Clinicians who prefer to use inodilators count on the combined effect of stimulating contractility and reducing RV afterload. Lack of selectivity for the vasodilator component often produces systemic hypotension for which a vasopressor is then needed. In theory, inodilators are more effective when LV failure is involved. Inopressors are more effective in isolated RV failure but a pronounced vasoconstrictive effect on the pulmonary vasculature may limit their efficacy. Sympathomimetic drugs The mechanism of action, the recommended clinical doses and the limitations of this class of inotropes are well known and do not need to be addressed here . Pharmacodynamic differences between the drugs in this group are related to their receptor specificity. Epinephrine and norepinephrine are powerful inoconstrictors because they stimulate both a\- and ~I-adrenergic receptors. Norepinephrine has more vasoconstrictor effects whereas epinephrine is the more powerful inotrope. Because the right ventricle has limited contractile reserve (except for conditions of chronic pressure overload) the effect of ~I-receptor stimulation on RV performance should not be overestimated. High doses of epinephrine - particularly when RV dysfunction is caused by a mechanical obstruction - often produce a hypercontractile but empty left ventricle and severe tachyarrhythmia with no evidence for improvement of the hemodynamic condition; in this case, norepinephrine may be the better choice. Dopam ine is an inodilator at low doses but acts like an inoconstrictor at doses exceeding 5 ug/kg/rnin (dose-dependent activation of aI -receptors). In an animal model of acute pulmonary embolism, dopamine increased cardiac output and reduced PVR [33]. In hypoxic pulmonary hypertension, however, dopamine failed to increase cardiac index, and significantly increased pulmonary artery pressure and PVR [34]. Dobutamine is an inodilator because of its combined ~I- and ~2 effects. In an animal study on pressure load-induced RV failure, dobutamine up to 5 ug/kg/min, significantly increased RV contractility and cardiac output, and decreased PVR. Higher doses of 10 ug/kg/rnin had limited incremental effect on RV contractility, did not change RV afterload, and produced severe tachycardia [35]. It is important to realize that dobutamine also stimulates aI-receptors at higher doses and this effect may predominate in patients receiving chronic beta-blockade [36]. Isoproterenol is also a non -selective ~-agonist but it is direct-acting and has stronger chronotropic and vasodilator effects than dobutamine. Isoproterenol decreased PVR and improved cardiac output in an animal model of acute pulmonary hypertension [37] and has been recommended for treating acute RV failure in

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post-cardiac transplant patients. In our experience, the risk for systemic hypotension is too high and addition of a vasopressor is often mandatory. Phophodiesterase type 3 inhibitors Selective PDE-3 inhibitors, like milrinone and enoximone, increase contractility and produce arterial and venous dilation by raising the intracellular concentrations of cAMP. In animal models of acute pulmonary hypertension, milrinone significantly reduced PVR and increased cardiac output and RV contractile function, but at the expense of profound systemic vasodilation and hypotension [38]. To avoid hypotension, milrinone has been administered by inhalation [11]. Recent studies in animal models of pulmonary hypertension [39] and in patients after cardiac surgery [40] have confirmed the efficacy of inhaled milrinone. As expected from its additive effect on intracellular c-AMP levels, inhaled milrinone was shown to potentiate and prolong the selective pulmonary vasodilating effect of inhaled prostacyclin [11]. Additive pulmonary vasodilating effects were also reported with sildenafil and NO [38,41]. Calcium sensitizers Levosimendan, is increasingly being studied and used for the treatment of RV failure. Its primary effect is to enhance the sensitivity of myocardial fibers to calcium and to stabilize the conformation of the Ca2+-troponin C complex [42]. Compared to other positive inotropic drugs, levosimendan increases contractility at a much lower oxygen cost [43]. Levosimendan also produces vasodilatation by opening ATP-sensitive potassium channels in vascular smooth muscle cells, especially in the coronary and mesenteric arteries and arterioles [44]. Experimental studies show that levosimendan also exerts vasodilatory effects on the pulmonary vasculature due to local NO production by inducible NO synthase [45]. The combination of its positive inotropic effect and pulmonary vasodilation render this drug extremely interesting for the treatment of RV failure. Several experimental studies have examined the effect of levosimendan on RV contractility and afterload in a variety of models for RV failure. In an animal model of combined temporary pulmonary artery constriction and repetitive episodes of RV ischemia (to reflect the clinical setting of myocardial stunning), we showed that levosimendan optimizes RV ventriculo-vascular coupling. The effects on RV contractility were moderate but RV afterload was lowered effectively ( Fig. 2). Importantly, levosimendan did not impair RV diastolic function and increased right coronary artery blood flow [46]. Identical effects on RV contractility and RV afterload have been reported in other animal models of acute loading-induced RV failure [35]. No clinical studies on isolated RV failure have been reported yet, however, studies in congestive and advanced heart failure indicate that levosimendan improved RV contractility and myocardial efficiency [47]. In a pilot study in patients with ARDS and septic shock, levosimendan reduced PVR and improved cardiac index and RV ejection fraction, measured with cardiac magnetic resonance imaging (MRI) [48]. Levosimendan also has an acetylated biologically active metabolite (OR-1896) with a half life of 80-96 h. This metabolite has Ca2+-sensitizing and weak PDE-3 inhibiting properties and exerts positive inotropic effects similar to levosimendan [49]. It is likely that this metabolite causes the hereto unexplained sustained hemodynamic effects observed after discontinuation of levosimendan .

Phannacological Support of the Failing Right Ventricle 2.5 2.0

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Fig. 2. Effect of levosimendan on right ventriculo-vascular coupling (right ventricular [RVj end-systolic elastance/arterial elastance [EmaxlEa]) in pigs subjected to RV ischemia/reperfusion (I/R). BL: baseline; T15: start of the levosimendan (L) infusion; T60: end of the levosimendan (L) infusion; C: control group; AUC: area under the curve. From [46] with permission

Conclusion RV failur e occurs frequently in acute medicine and is asso ciated with a poor prognos is. It remains a particular challenge for the clinician to recognize this specific pathophysiological condition and to select appropriate therapeutic strategies. General rules for treatment of LV failure cannot simply be transposed and applied to treat the failing right ventricle. The conceptual framework of ventricular interdependence is an important guide to understand the pathophysiology of RV failure and predict th e effects of individual drugs. Selective pulmonary vasodilation, systemic vasocon striction, and po sitive inotropic support are the three primary clinical strategies to be considered. The clinical conditions, the exact cause of the RV failure, and patient-related factors such as chronic drug intake and the presence of RV hypertrophy will determine which of the three strategies needs more emphasis. An important hemodynamic target is to maximize the ratio between systemic and pulmonary vascular resistance. Inhaled administration of NO has long been the only clinical therapy to produce selective pulmonary vasodilation; however, recent studies show a number of vasodilators can produce a similar effect at a presumably lower toxic-totherapeuti c ratio when nebulized and administered via the airway. Calcium sensitizers have recently been proposed to be ideally suited for the treatment of RV failure because the y increase contractility at lower oxygen cost and simultaneously produce pulmonary vasodilation. Animal studies have shown promising results and have generated high expectations from clinical st udies which focus on RV failure and are now due . References Davila-Roman VG, Waggoner AD, Hopkins WE, Barzilai B (1995) Right ventricular dysfunction in lowoutput syndrome after cardiac operations: assessment by transesophageal echocardiography. Ann Thorac Surg 60:1081-1086 2. Monchi M, Bellenfant F, Cariou A, et al (1998 ) Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med 158:10761.

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P.F. Wouters, S. Rex, and C. Missant 3. Mansencal N, Joseph T, Vieillard-Baron A, et al (2003) Comparison of different echocardiographic indexes secondary to right ventricular obstruction in acute pulmonary embolism. Am J Cardiol 92:116-119 4. Missant C, Rex S, Claus P, Mertens L, Wouters PF (2007) Load-sensitivity of regional tissue deformation in the right ventricle: isovolumic versus ejection-phase indices of contractility. Heart [Epub ahead of print) ~. Santamore WP, Gray LJr (1995) Significant left ventricular contributions to right ventricular systolic function . Mechanism and clinical implications. Chest 107:1134-1145 6. Pattouch K, Sbraga F, Bianco G, et al (2005) Inhaled pros tacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement. J Cardiac Surg 20:171176 7. Melot C, Lejeune P, Leeman M, Moraine n, Naeije R (1989) Prostaglandin E1 in the adult respiratory distress syndrome . Benefit for pulmonary hypertension and cost for pulmonary gas exchange. Am Rev Respir Dis 139:106-110 8. Ichinose F, Roberts JD, Zapol WM (2004) Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation 109:3106 - 3111 9. Dellinger RP, Zimmerman JL, Taylor RW, et al (1998) Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 26:15-23 10. Olschewski H, Rose F, Schermuly R, et al (2004) Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther 102:139-153 11. Haraldsson S.A., Kieler-Jensen N, Ricksten SE (2001) The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Anesth Analg 93:1439-1445 12. Olschewski H, Rohde B, Behr J, et al (2003) Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest 124:1294- 1304 13. Hoeper MM, Olschewski H, Ghofrani HA, et al (2000) A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coli Cardiol 35:176-182 14. Rex S, Schaelte G, Metzelder S, et al (2007) Inhaled iloprost to control pulmonary artery hypertension in patients undergoing mitral valve surgery : a prospective, randomized-controlled trial. Acta Anaesthesiol Scand 51:1258-1267 15. Galie N, Torbicki A, Barst R, et al (2004) Guidelines on diagnosis and treatm ent of pulmo nary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 25:2243- 2278 16. Atz AM, Lefler AK, Fairbrother DL, Uber WE, Bradley SM (2002) Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crises. J Thorac Cardiovasc Surg 124:628- 629 17. Ghofrani HA, Wiedemann R, Rose F, et al (2002) Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 136:515-522 18. Ichinose F, Erana-Garcia J, Hromi J, et al (2001) Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 29:1000-1005 19. Trachte AL, Lobato EB, Urdaneta F, et al (2005) Oral sildenafil reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 79:194-197 20. Schulze-Neick I, Hartenstein P, Li J, et al (2003) Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 108 (Suppl 1): 11167-11173 21. Nagendran J, Archer SL, Soliman D, et al (2007) Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116:238- 248 22. Motte S, McEntee K, Naeije R (2006) Endothelin receptor antagonists. Pharmacol Ther 110: 386-414 23. Dorman BH, Kratz JM, Multani MM, et al (2004) A prospective, randomized study of endothelin and postoperative recovery in off-pump versus conventional coronary artery bypass surgery. J Cardiothorac Vase Anesth 18:25 - 29 24. Kaisers U, Busch T, Wolf S, et al (2000) Inhaled endothelin A antagonist improves arte rial oxygenation in experimental acute lung injury. Intensive Care Med 26:1334-1342

Pharmacological Support of the Failing Right Ventride 25. Ikonomidis IS, Hilton EI, Payne K, et al (2007) Selective endothelin-A receptor inhibition after cardiac surgery: a safety and feasibility study. Ann Thorac Surg 83:2153-2160 26. Phua J, Lim TK, Lee KH (2005) B-type natriuretic peptide: issues for the intensivist and pulmonologist. Crit Care Med 33:2094-2013 27. Mentzer RM, Oz MC, Sladen RN, et al (2007) Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA Trial. J Am ColI CardioI49:716-726 28. Nagaya N, Nishikimi T, Uematsu M, et al (2000) Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart 84:653- 658 29. Nagaya N, Kyotani S, Uematsu M, et al (2004) Effects of adreno medullin inhalation on hemo dynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation 109:351- 356 30. Leather HA, Segers P, Berends N, Vandermeersch E, Wouters PF (2002) Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension. Crit Care Med 30:2548-2552 31. Rich S, Gubin S, Hart K (1990) The effects of phenylephrine on right ventricular performance in patients with pulmonary hypertension. Chest 98:1102-1106 32. Price LC, Forrest P, Sodhi V, et al (2007) Use of vasopressin after Caesarean section in idiopathic pulmonary arterial hypertension. Br J Anaesth 99:552- 555 33. Ducas I, Stitz M, Gu S, Schick U, Prewitt RM (1992) Pulmonary vascular pressure-flow characteristics . Effects of dopamine before and after pulmonary embolism. Am Rev Respir Dis 146:307 -31 2 34. Cheung PY, Barrington KI (2001) The effects of dopamine and epinephrine on hemodynamics and oxygen metabolism in hypoxic anesthetized piglets. Crit Care 5:158-166 35. Kerbaul F, Rondelet B. Demester JP, et al (2006) Effects of levosimendan versus dobutamine on pressure load-induced right ventricular failure. Crit Care Med 34:2814-2819 36. Tarnow I, Komar K (1988) Altered hemodynamic response to dobutamine in relation to the degree of preoperative beta-adrenoceptor blockade. Anesthesiology 68:912-919 37. Ducas I, Duval D, Dasilva H, Boiteau P, Prewitt RM (1987) Treatment of canine pulmonary hypertension: effects of norepinephrine and isoproterenol on pulmonary vascular pressureflow characteristics. Circulation 75:235 - 242 38. Deb B, Bradford K, Pearl RG (2000) Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension. Crit Care Med 28:795-799 39. Hentschel T, Yin N, Riad A, et al (2007) Inhalation of the phosphodiesterase-3 inhibitor rnilrinone attenuate s pulmonary hypertension in a rat model of congestive heart failure. Anesthe siology 106:124-131 40. Lamarche Y, Perrault LP, Maltais S, Tetreault K, Lambert J, Denault AY (2007) Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg 31:10811087 41. Lobato EB, Beaver T, Muehlschlegel J, Kirby DS, Klodell C, Sidi A (2006) Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combina tion during thromboxane-induced acute pulmonary hypertension. Br J Anaesth 96:317-322 42. Haikala H, Kaivola I, Nissinen E, Wall P, Levijoki I, Linden IE (1995) Cardiac troponin C as a target protein for a novel calcium sensitizing drug , levosimendan. I Mol Cell Cardiol 27:1859-1866 43. Lilleberg I, Nieminen MS, Akkila I, et al (1998) Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart I 19:660- 668 44. Pollesello P, Mebazaa A (2004) ATP-dependent potassium channels as a key target for the treatment of myocardial and vascular dysfunction. Curr Opin Crit Care 10:436-441 45. Grossin i E, Caimmi PP, Molinar i C, Teodori G, Vacca G (2005) Hemodynamic effect of intracoronary admini stration of levosimendan in the anesthetized pig. I Cardiovasc Pharmacol 46:333- 342 46. Missant C, Rex S, Segers P, Wouters PF (2007) Levosimendan improves right ventriculovascular coupling in a porcine model of right ventri cular dysfunction. Crit Care Med 35:707-715 47. Parissis IT, Paraskevaidis I, Bistola V,et al (2006) Effects ofIevosimendan on right ventricular function in patients with advanced heart failure. Am I Cardiol 98:1489-1492

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P.F. Wouters, S. Rex, and C. Missant 48. Morelli A, Teboul JL, Maggiore SM, et al (2006) Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 34:2287 - 2293 49. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikainen PJ (2002) Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther 40:465-471

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Perioperative Cardioprotection H.-J.

PRIEBE

Introduction The per ioperative period induces large, unpredictable and unphysiological changes in sympathetic tone, cardiovascular performance, coagulation and inflammatory response (to name just a few). These changes induce, in turn, unpredictable alterations in coronary plaque morphology, funct ion , and progression. Simultaneous perioperative alterations in homeostasis and coronary plaque characteristics may trigger a mismatch of myocardial oxygen supply and demand by numerous mechanisms. If not alleviated in time, this will ultimately result in myocardial infarction, irrespe ctive of its etiology (morphological, hemodynamic, inflammatory, or coagu lation-induced). Thus, not sur prisingly, in patients with coronary artery disease, the incidence of perioperative cardiac morbidity and mortality remains high and is associated with adverse outcome [1]. Consequently, the quest for perioperative cardioprotective strategies continues.

Preoperative Coronary Revascularization The effect of prophylactic preoperative coronary revascularization (interventional and surgical) on long-term outcome was studied in a randomized trial of 510 patients undergoing vascular surgery [2]. Within the group of patients undergoing preoperative coronary revascularization, percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) were not randomized. Approximately 21/ 2 years following surgery, mortality was comparable between groups. It is noteworthy that during and after coronary revascularization, but before the planned surgery, 4 patients died and 17 suffered a myocardial infarction. Previous non -randomized studies which postulated a benefit of preoperative coronary revascularization on outcome did not account for this considerable risk of coronary angiography and revascularization in high-risk patients. It is also noteworthy that two years after randomization, the majority of patients in both groups were taking beta-blockers (approx. 80 %), aspirin (approx. 85 %), statins (approx. 70 %), and angiotensin-con verting-enzyme inhibitors (approx. 55 %). The study had several limitations: (i) only 8.3 % of the init ially screened population was studied (selection bias) ; (ii) the indication for coronary angiography was made by cardiology consultants (referral bias); (iii) during the study, cardiology consultants were aware of recognized risk factors (e.g., stroke, insulin-dependent diabetes, renal failure) and of find ings on stress imag ing (treatment bias); (iv) only patients with clinically significant but stable coronary artery disease were included;

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Fig. 1. Postoperative incidence of all-cause death or myocardial infarction. Modified from [3]

and (v) the majority of patients had single or two-vessel disease. Patients with severe coronary-artery disease, poor left ventricular function and severe aortic valve stenosis were excluded. The effectiveness of prophylactic preoperative coronary revascularization was recently investigated in 101 patients with extensive stress-induced ischemia and angiographically documented multivessel coronary artery disease undergoing major vascular surgery [3]. The patients were randomly assigned to preoperative coronary revascularization (n = 49) or not (n = 52). Again, PCI (drug-eluting stent: n = 30; bare metal stent: n = 2) and CABG (n = 17) were not randomized. All patients received perioperative beta-blocker therapy with the aim of maintaining heart rate between 60 and 65 beats/min. Dual antiplatelet therapy with aspirin and clopidogrel was continued perioperatively in all patients who had undergone PCI. At 30-day and l-year follow-ups, there were no significant differences between groups in all-cause mortality or myocardial infarction (Fig. 1). It is again noteworthy that at the time of randomization, the majority of patients in both groups were taking beta-blockers (approx. 70 %), aspirin (58-76 %), angiotensin-convertingenzyme inhibitors (42-57 %), and statins (58-69 %) . Although there were no statistically significant differences between groups in outcomes at 30-days and 1 year postoperatively, when closely looking at the findings it appears that there was a clear trend for better outcome at 30 days postoperatively in patients without compared to those with preoperative coronary revascularization (all-cause mortality 11.5 % vs. 22.5 %; combined death and myocardial infarction 32.7 % vs. 42.9 %) which, however, had disappeared by 1 year (all-cause mortality 23.1 % vs. 26.5 %; combined death and myocardial infarction 44.2 % vs. 49.0 %). In other words, over time the medically only treated patients seemed to 'catch-up' with the revascularized patients in terms of adverse outcomes. Thus, in addition to maintaining aggressive postoperative cardioprotective medication, it may be prudent to closely follow-up non-revascularized high-risk cardiac patients during the months following vascular surgery for the development of ischemic symptoms and perform coronary revascularization when medically indicated. Because of the small number of patients included in this trial, these findings can obviously only be considered preliminary.

Perioperative Cardioprotection

Following PCI with or without coronary stent placement, severe perioperative hemorrhage (due to perioperative continuation of dual anti-platelet therapy with clopidogrel and aspirin) as well as lethal coronary artery thromboses in the territory of the stented coronary artery (due to preoperative discontinuation of dual anti -platelet therapy) have been reported during subsequent surgery [4]. The considerable risk associated with preoperative PCI seems to be dependent on the time interval between stent placement and surgery « 3-6 months vs > 3-6 months), the type of PCI (with vs. without stent placement), and the type of stent (bare-metal vs. drugeluting) [4-6] .

Pharmacological Cardioprotection Intensive Medical Therapy

In view of the increasing rate of coronary stent placements in patients with stable coronary artery disease, the increasing evidence for a highly beneficial effect of optimized medical therapy on outcome in patients with stable coronary artery disease, and the markedly elevated perioperative risks associated with surgery in patients with coronary stents [6, 7], a critical evaluation of the benefits of PCI in addition to optimal medical therapy, in general, is needed . The Clinical Outcomes Utilization Revascularization and Aggressive Drug Evaluation (COURAGE) randomized trial compared the effect of combined PCI and optimal medical therapy with optimal medical therapy alone on the risk of death and non -fatal myocardial infarction [8]. Included were patients with stable coronary artery disease, those with an initial Canadian Cardiovascular Society (CCS) class IV angina who subsequently stabilized under medical therapy, and those with a coronary artery stenosis of at least 70 % in at least one proximal epicardial artery and objective electrocardiographic (EKG) evidence of myocardial ischemia, or at least one coronary artery stenosis of at least 80 % accompanied by classic angina . Excluded were patients with persistent CCS class IV angina , a highly positive stress test, refractory heart failure or cardiogenic shock, an ejection fraction of less than 30 %, revascularization within the previous 6 months, and a coronary anatomy unsuitable for PCI. All patients randomized to either group received daily anti -platelet therapy with aspirin and clopidogrel, anti-ischemic therapy with long-acting metoprolol, amlodipine and isosorbide mononitrate alone or in combination, and secondary prevention with angiotensin-converting enzyme inhibitors. In addition, all patients were aggressively treated with modification of life style and/or medication to lower serum concentrations of low-density lipoprotein (LDL) cholesterol, and to increase serum concentrations of high -density lipoprotein (HDL) cholesterol. The main finding of this trial was the following: PCI in addition to intensive medical therapy did not reduce myocardial infarction or mortality during a follow-up period of 2.5-7.0 years ( Fig. 2). The 4.6-year cumulative rates of myocardial infarction and death were 19 % in the combined PCI and med ical therapy group and 18.5 % in the medical therapy alone group, with a mortality rate of approximately 8 % in both groups (no significant differences) . At 5 years, 74 % and 72 % of patients in the combined PCI and medical therapy group and in the medical therapy group, respectively, were free of angina. Several limitations of this study need to be considered before drawing final conclusions . Of the 35,539 patients who were initially screened, only 3,071 (8.6 %) met all inclusion criteria, and 2,287 (6.4 %) consente d to participate in the study (com -

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bined PCI and medical therapy group: n = 1,149; medical therapy alone group: n = 1,138). The low number of patients enrolled in the study compared to the number initially screened is of concern. Patients with severe ventricular dysfunction, a highly positive stress test, or clinical instability were excluded. Drug-eluting stents were used in only 31 (2.7 %) of the 1,149 pat ients in the PCI group, because they were not available until the late phase of patient recruitment. Although there are presently no good data to indicate that drug-eluting stents compared to bare-metal stents reduce the incidence of myocardial infarction and death in patients with stable coronary artery disease, on-label use of drug -eluting stents seems to reduce the rate of repeat revascularization [9, 10]. It is, thus, conceivable that more frequent use of drug-eluting stents might have resulted in a lower rate of repeat revascularization and angina and, in turn, better outcome in the combined PCI and medical therapy group. In addition, approximately one :third of patients in the medical group required coronary revascularization for control of angina and acute coronary syndromes during the median follow-up of 4.6 years. With PCI being effective in ameliorating angina and in treating acute coronary syndromes, it cannot entirely be excluded that the relatively high cross-over rate from the combined PCI and medical therapy group to the medical therapy alone group might have biased the results in favor of medical therapy alone, which might have contributed to the comparable degree of symptom control and cardiovascular event rate at 5 years. However, during the same time period additional revascularization was also necessary in 21.1 % of patients in the PCI group.

Perioperative (ardioprotection This is the first trial that routinely used stents in combination with what is presently considered optimal medical therapy. Despite the limitations, this study strongly suggests that even in the presence of objective evidence of baseline myocardial ischemia and extensive coronary artery disease, PCI added to intensive medical therapy does not necessarily reduce the incidence of major cardiovascular events as compared to intensive medical therapy alone during the subsequent few years. The findings may partly be explained by differences in atherosclerotic plaque morphology associated with stable coronary artery disease versus acute coronary syndromes [1, 11]. Myocardial ischemia and anginal symptoms are usually associated with stable plaques. These plaques tend to have thick fibrous caps, small lipid cores, considerable amounts of smooth muscle cells and collagen but few macrophages [12]. They ultimately undergo inward (constrictive) remodeling with narrowing of the coronary lumen that is readily detected by coronary angiography. As the potential for acute rupture is relatively low, stable plaques are less likely to cause acute coronary syndromes. By contrast, vulnerable plaques tend to have thinner fibrous caps, larger lipid cores, fewer smooth muscle cells, more macrophages, and less collagen . They undergo outward (expansive) remodeling with less narrowing of the coronary lumen. As a result, vulnerable plaques do not usually cause significant coronary stenosis and clinical symptoms before rupture and subsequent precipitation of an acute coronary syndrome. In other words, coronary lesions that cause acute coronary syndromes are not necessarily severely stenotic (and not necessarily readily detectable by coronary angiography), and severely stenotic lesions (readily detectable by coronary angiography) that cause anginal symptoms are not necessarily unstable. As stable plaques are less likely to trigger an acute coronary event, it should not come as a total surprise that focal management of even severe coronary artery stenoses by coronary artery revascularization (be it by PCI or surgically) does not reduce the incidence of major cardiovascular events. Following PCI, vulnerable plaques will continue to exist unchanged. Presumably by improving endothelial function and plaque stability, lipid lowering therapy more successfully reduces the incidence of cardiac events than the severity of the stenosis [13]. A meta-analysis showed that PCI is ineffective in reducing major cardiovascular events as compared to medical management [14). This may reflect reduced plaque vulnerability due to aggressive medication and intervention for cardiac risk factors. Short-term pre-treatment with atorvastatin in patients with acute coronary syndromes undergoing early invasive strategy conferred an 88 % risk reduction of 30-day major adverse cardiac events [15).

Specific Cardiac Drugs Beta-blockers Numerous cardiovascular and other effects (anti-arrhythmic, anti-inflammatory, altered gene expression and receptor activity, protection against apoptosis) of betablockers may account for their possible cardioprotective effect in the operative and non-operative setting [16). The benefit of perioperative atenolol in patients with, or at risk for, coronary artery disease undergoing major non-cardiac surgery under general anesthesia was examined in a ran domized, double-blind, placebo -controlled study [17). Over the two year follow-up period, overall mortality after hospital discharge was significantly lower in the atenolol (10 %) than in the placebo group (21 %, P = 0.019). The combined cardiovascular outcomes were similarly reduced in

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the atenolol group. The study has been criticized on numerous grounds. Most importantly, in-hospital cardiac morbidity and mortality were not included in the analysis. If this is done, statistical significance is lost. A subsequent randomized, placebo-controlled, non-blinded study looked at the benefit of perioperative bisoprolol in patients with documented coronary artery disease (diagnosed by new wall motion abnormalities on dobutamine stress echocardiography) undergoing major vascular surgery [18]. Outcome parameters included cardiac death and non-fatal myocardial infarction during the first 30 days following surgery. In the bisoprolol group, perioperative cardiac events were l O-fold lower compared to the 'standard care' group (3.4 % vs, 34 %; P = 0.001). This investigation also has several limitations. Most importantly, the study was terminated before the a priori calculated number of patients was reached, no aspect of the study was blinded, and a 90 % relative reduction in 3D-day adverse outcome by beta-blockers is entirely unrealistic. In view of the small sample size, it is highly likely that the results occurred by chance alone. In a non-randomized, non-blinded observational cohort study in 272 vascular surgery patients with documented coronary artery disease, high-dose perioperative beta-blocker therapy and perioperative tight heart rate control were associated with a reduced incidence of myocardial ischemic episodes, reduced release of cardiac troponin T, and with improved long-term outcome [19]. Despite suggestive evidence for a cardioprotective effect of perioperative betablocker therapy, a recent meta-analysis failed to provide convincing evidence for a reliable cardioprotective effect of perioperative beta-blocker therapy [20]. In addition, three subsequently published double-blind, randomized, placebo-controlled trials also failed to demonstrate a cardioprotective effect of perioperative betablocker therapy [21-23]. Thus, the repeated recommendations for perioperative beta-blockade in patients with suspected or documented coronary artery disease are mainly based on the findings of two prospective, randomized controlled trials of highly questionable methodology and data analysis in a little over 300 patients [17, 18] and on a non-randomized observational cohort study [19]. The recent update of the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on perioperative cardiovascular evaluation [24] lists several class I indications for perioperative beta-blocker therapy (i.e., conditions for which there is evidence for and/or general agreement that the therapy is useful and effective): (i) continuation of beta-blockers in patients receiving beta-blockers to treat angina, symptomatic arrhythmias, hypertension or other ACC/AHA class I guideline indications; (ii) patients undergoing vascular surgery at high cardiac risk owing to the finding of myocardial ischemia on perioperative testing. In patients at lower perioperative cardiac risk, perioperative beta-blocker therapy may actually worsen outcome [25]. Although the available evidence supports the recommendation to consider perioperative beta-blocker therapy in selected patients at high cardiac risk, a large trial is essential to document the effectiveness and safety of periop erative beta -blockade before widespread use. Such a trial, POISE (PeriOperative ISchemic Evaluation), funded by the Canadian Institute of Health Research, is now underway [26]. Until the results are available, it seems fair to conclude that at this time, the evidence for a cardioprotective effect of perioperative beta-blocker therapy is weak at best [27, 28].

Perioperative Cardioprotection

Statins Statins possess anti -inflammatory actions and reverse endothelial dysfunction. Their numerous pleiotropic effects may result in improved endothelial function and coronary plaque stabilization. This may explain the possible perioperative cardioprotective effect of statins. Perioperative use of statins may be associated with reduced perioperative mortality in patients undergoing non-cardiac and cardiac surgery [29- 33]. A recent meta-analysis assessed whether stat ins provide perioperative cardioprotection [34]. The analysis included 18 studies with concurrent control groups: two randomized trials (n = 177), 15 cohort studies (n = 799 632), and one case-control study (n = 480). Statins were associated with a statistically significant reduction in perioperative mortality and acute coronary syndromes. However, these findings were largely based on observational studies . Evidence from the randomized trials was entirely inconclusive. The results of a large randomized trial are necessary to provide an ultimate answer. At present it seems reasonable to recommend perioperative statin therapy in those patients with a medical indication for such therapy independent of surgery. There is suggestive evidence that chronic statin therapy should not be discontinued postoperatively in high-risk patients [35]. Alpha-2 adrenoceptor agonists Alpha-2 adrenoceptor agonists have been shown to improve cardiovascular morbidity and mortality following non -cardiac and cardiac surgery [36, 37]. The mechanism of the protective effect is likely to be manifold. Alpha-2 adrenoceptor agonists attenuate perioperative hemodynamic instability, inhibit central sympathetic discharge, reduce peripheral norepinephrine release, and dilate post-stenotic coronary vessels. Aspirin (acetylsalicylic acid) Early postoperative administration of aspirin improved outcome following coronary artery bypass surgery [38]. Aspirin is known to reduce cardiac events in patients with acute coronary syndromes and in patients not known to have coronary artery disease. It eliminates the diurnal variation in plaque rupture. Aspirin will, of course, reduce platelet aggregability, but its ability to reduce future myocardial infarction appears greatest in individuals with serologic evidence of increased inflammation. Thus, the anti-inflammatory effect of aspirin may be additive to its antithrombo tic effect in patients with plaque instability. This effect may be of particular relevance in the perioperative setting.

Pharmacological Protection: Summary The overall evidence suggests that coronary revascularization is of no benefit in patients with stable coronary artery disease who are on optimal cardiac medication . Consistent with the results of the COURAGE trial [8], lack of benefit by preoperative coronary revascularization [2, 3] may partly be explained by the long-term aggressive medical therapy in revascularized as well as non-revascularized patients. All of this adds further evidence for a benefit of aggressive perioperative medical therapy in patients with stable coronary artery disease, and for the lack of added benefit from preoperative coronary revascularization. Aggressive peri operative medical therapy may well be one of the most important, if not the most important cardioprotective intervention.

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Miscellaneous Preventive Measures Postoperative myocardial ischemia has been shown to be associated with postoperative anemia [39], hypothermia [40,41], and pain [42,43] . All of these activate sympathetic tone with adverse effects on cardiovascular function and coagulation. The result will be an increase in myocardial oxygen consumption in the presence of a decrease in oxygen delivery. As peri operative myocardial ischemia is a predictor of adverse short- and long-term cardiac outcome, maintenance of an appropriate hemoglobin concentration, normothermia, and adequate pain control are essential preventive measures.

Conclusion The etiology of peri operative cardiac morbidity and mortality is multifactorial. With the many and diverse etiologic factors involved, it is highly unlikely that one single intervention will successfully improve cardiac outcomes following non-cardiac surgery. A multifactorial, step-wise approach is indicated [44- 46]. Based on increasing knowledge of the nature of atherosclerotic coronary artery disease, and in view of the poor positive predictive value of non-invasive cardiac stress tests and the considerable risk of coronary angiography and coronary revascularization in high-risk pat ients [4], the paradigm is shifting from an emphasis on extensive non-invasive preoperative risk stratification to an emphasis on a combination of selective noninvasive testing (to reliably identify those patients who truly benefit from preoperative intervention, such as cancellation of surgery, preoperative coronary revascularization, initiation or optimization of cardioprotective medication), and aggressive pharmacological perioperative therapy [45- 50]. Based on increasing knowledge of the nature of atherosclerotic coronary artery disease [1], perioperative plaque stabilization by pharmacological means (statins, aspirin, beta-blockers) may be as important in the prevention of perioperative myocardial infarction as is an increase in myocardial oxygen supply (by coronary revascularization) or a reduction in myocardial oxygen demand (by beta-blockers or alpha-2-agonists) . References 1. Priebe H-J (2005) Perioperative myocard ial infarction - aetiology and prevention. Br J Anaesth 95:3 - 19 2. McFalls EO, Ward HB, Moritz TE, et al (2004) Coronary -artery revascularization before elective major vascular surgery. N Engl J Med 351:2795 -2804 3. Poldermans D, Shouten 0, Vidakovic R, et al (2007) A clinical randomized trial to evaluate the 4. 5. 6. 7. 8.

safety of a noninvas ive approach in high-risk patients undergoing major vascular surgery. The DECREASE-V pilot study. J Am Coll Cardiol 49: 1763 -1769 Kertai MD, Bogar L, Gal J, Poldermans D (2006) Pre-operative coronary revascularization: an optimal therapy for high-risk vascular surgery patients? Acta Anaesthesiol Scand 50:816 -827 Vicenzi MN, Meislitzer B, Heitzinger B, Halaj M, Fleisher LA, Metzler H (2006) Coronary artery stenting and non-cardiac surgery - a prospective outcome study. Br J Anaesth 96:686-893 Spahn DR, Howell SJ, Delabays A, Chasssot PG (2006) Coronary stents and perioperative antiplatelet regimen : dilemma of bleeding and stent thrombosis. Br J Anaesth 96:675 -677 Howard-Alpe GM, de Bono J, Hudsm ith L, Orr WP, Foex P, Sear JW (2007) Coronary artery stents and non-cardiac surgery. Br J Anaesth 98:560-574 Boden WE, O'Rourke RA, Teo KK, et al (2007) Optimal medical therapy with or without PCl for stable coronary disease. N Engl J Med 356: 1503 - 1516

Perioperative (ardioprotection 9. Kastrati A, Mehilli J, Pache J, et al (2007) Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 356:1030-1039 10. Mauri L, Hsieh W, Massaro JM, Ho KKL, D'Agostino R, Cutlip DE (2007) Stent thrombosis in randomized clinical trials of drug-eluting stents . N Engl I Med 356:1020-1029 II. Hochman IS, Steg PG (2007) Does preventive PCI work? N Engl J Med 356:1572-1574 12. Waxman S, Ishibashi F, Muller JE (2006) Detection and treatment of vulnerable plaques and vulnerable patients : novel approaches to prevention of coronary events. Circulation 114: 2390- 2411 13. Sdringola S, Loghin C, Boccalandro F, Gould KL (2006) Mechanisms of progression and 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

regression of coronary artery disease by PET related to treatment intensity and clinical events at long-term follow-up. I Nucl Med 47:59-67 Katritsis DG, loannidis IP (2005) Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis. Circulation 111:2906- 2912 Patti G, Pasceri V, Colonna G, et al (2007) Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention . Results of the ARMYDA-ACS Randomized Trial. J Am Coli Cardiol 49:1272-1278 London MJ, Zaugg M, Schaub MC, Spahn DR (2004) Perioperative B-adrenergic receptor blockade. Physiologic foundations and clinical controversies. Anesthesiology 100:170- 175 Mangano DT, Layug EL, Wallace A, Tateo I (1996) Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery: Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 335:1713- 1720 Poldermans D, Boersma E, Bax 11, et al (1999) The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 341:1789-1794 Feringa HHH, Bax 11, Boersma E, et al (2006) High-dose B-blockers and tight heart rate control reduce myocardial ischemia and troponin T release in vascular surgery patients. Circulation 114 (suppl I): 1-344-349 Devereaux PJ, Beattie WS, Choi PT, et al (2005) How strong is the evidence for the use of perioperative B blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ 331:313-321 POBBLE Trial Investigators (2005) Perioperative B-blockade (POBBLE) for patients undergoing infra renal vascular surgery: results of a randomized double -blind controlled trial. I Vase Surg 41:602- 609 luul AB, Wetterslev J, Gluud C, et al (2006) Effect of perioperative B blockade in patients with diabetzes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMI 332:1482 Yang H, Raymer K, Butler R, Parlow J, Roberts R (2006) The effect of perioperative B-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart I 152:983- 990 Fleisher LA, Beckman JA, Calkins H, et al (2006) ACC!AHA 2006 Guideline update on perioperative cardiovascular evaluation for non-cardiac surgery: focused update on perioperative beta-blocker therapy. J Am Coli Cardiol 47:2344 -2355 Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM (2005) Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl I Med 353: 349-361 Devereaux PJ, Yang H, Guyatt GH, et al (2006) Rationale, design and organization of the perioperative ischemic evaluation (POISE) trial: a randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery. Am Heart J 152:223-230 McCullough PA (2006) Failure of beta-blockers in the reduction of perioperative events: where did we go wrong? Am Heart J 152:815-818 Bolsin S, Colson M, Conroy M (2007) B blockers and statins in non-cardiac surgery. Routine use to prevent perioperative cardiac complications is not evidence based. BMJ 334:1284-1285 Boushra NN, Muntazar M (2006) Review article: the role of statins in reducing perioperative cardiac risk: physiologic and clinical perspectives. Can J Anesth 53:1126-1147 Hindler K, Shaw A, Samuels J, Fulton S, Collard C, Riedel B (2006) Improved postoperative outcomes associated with preoperative statin therapy. Anesthesiology 105:1260-1272 Kersten JR, Fleisher LA (2006) Statins. The next advance in cardioprotection? Anesthesiology 105:1079-1080

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32. Collard CD, Body SC, Shernan SK, et al (2006) Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 132:392-400 33. Powell BD, Bybee KA, Valeti U, et al (2007) Influence of preoperative lipid-lowering therapy on postoperative outcome in patients undergoing coronary artery bypass grafting. Am J Cardiol 99:785- 789 34. Kapoor AS, Kanji H, Buckingham J, Devereaux PJ, McAlister FA (2006) Strength of evidence for per ioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ 333:1149 35. Le Manach Y, Godet G, Coriat P, et al (2007) The impact of postoperative discontinuation or continuation of chromic statin therapy on cardiac outcome after major vascular surgery. Anesth Analg 104:1326-1333 36. Wallace AW, Galindez D, Salahieh A, et al (2004) Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery. Anesthesiology 101:284-293 37. Wijeysundera DN, Naik JS, Beattie S (2003) Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med 114:742-752 38. Mangano DT, for the Multicenter Study of Perioperative Ischemia Research Group (2002) Aspirin and mortality from coronary bypass surgery. N Engl J Med 347:1309-1317 39. Nelson AH, Fleisher LA, Rosenbaum SH (I993) Relationship between postoperative anaemia and cardiac morbid ity in high-risk vascular patients in the intensive care unit. Crit Care Med 21:860-866 40. Frank S, Beattie C, Christopherson R, et al (1993) Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology 78:468-476 41. Frank S, Fleisher L, Breslow M, et al (1997) Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA 277: 1127- 1134 42. Beattie WS, Buckley DN, Forrest JB (1993) Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth 40:532-541 43. Mangano DT, Siliciano D, Hollenberg M, et al (I992) Postoperative myocardial ischemia therapeutic trials using intensive analgesia following surgery. Anesthesiology 76:343- 353 44. Cohn SL, Goldman L (2003) Preoperative risk evaluation and perioperative management of patients with coronary artery disease. Med Clin N Am 87:111 -136 45. Grayburn PA, Hillis LD (2003) Cardiac events in patients undergoing noncardiac surgery : shifting the paradigm from noninvasive risk stratification to therapy. Ann Intern Med 138:506-511 46. Mukherjee D, Eagle KA (2003) Perioperative cardiac assessment for noncardiac surgery: eight steps to the best possible outcome. Circulation 107:2771-2774 47. Wesorick DH, Eagle KA (2005) The preoperative cardiovascular evaluation of the intermediate-risk patient : new data, changing strategies. Am J Med 118:1413.el- 9 48. Poldermans D, Bax JJ, Schouten 0 , et al (2006) Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coli Cardiol 48:984-989 49. Eagle KA, Lau WC (2006) Any need for preoperative cardiac testing in intermediate-risk patients with tight beta-adrenergic blockade? J Am Coli Cardiol 48:970-972 50. Auerbach A, Goldman L (2006) Assessing and reducing cardiac risk of noncardiac surgery. Circulation 113:1361-1376

Section III

III Cardiopulmonary Resuscitation

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Improving the Quality of Cardiac Arrest Resuscitation Care C.l. DINE

and B.S. ABELLA

Introduction Sudden cardiac arrest is defined as the cessation of mechanical cardiac activity as confirmed by the absence of signs of circulation [1]. Sudden cardiac arrest is one of the leading causes of mortality in the hospital as well as in the community setting. There are similar rates of sudden cardiac arrest in North America and Europe, leading to over 700,000 deaths in both regions combined annually [2-4] and, although overall cardiovascular mortality is decreasing, the proportion of deaths from sudden cardiac arrest ha s remained constant with a high mortality rate [5]. In fact, the survival rate from out-of-hospital sudden cardiac arrest has been reported to vary between 5 to 18 %, depending on the original arrest rhythm and other factors [6]. Poor quality cardiopulmonary resuscitation (CPR) is believed to be a significant factor in the observed low survival rates, since multiple studies have documented a several-fold survival benefit of well-performed CPR [7-10]. Several studies have shown that the quality of CPR parameters - chest compression rate and depth, ventilation rate and fraction of time without chest compressions, for instance - often did not meet CPR consensus guideline recommendations [11]; this has been demonstrated during both in -hospital and out-of-hospital cardiac arrest. For example, one study showed significant compression pauses especially during transport of the car diac arrest patients by using the impedance changes in electrocardiograph (EKG) signals to measure chest compressions and ventilations [12]. Such measurable defi ciencies in CPR performance highlight the necessity to monitor CPR quality and the need to improve CPR performance in order to increase chances for survival from sudden cardiac arrest. The identification of deficiencies in CPR performance has led to recent changes in the international consensus CPR guidelines as promulgated by the International Liaison Committee on Resuscitation (ILeOR) [13]. Some of the more important of these recommendations focus on improving the quality of CPR by simplifying CPR instruction, increasing the number of chest compressions delivered per minute (by changing the compression-to-ventilation ratio from 15:2 to 30:2), and reducing interruptions in chest compressions during CPR. The guidelines also recommended con tinued emphasis on CPR education and quality improvement efforts to attempt to increase the survival of sudden cardiac arrest victims. These changes highlight the large potential to improve CPR quality. This chapter will review a variety of methods and new technologies that may play a role in achieving high quality CPR performance, and recent investigations using these methods will be discussed

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Improving Bystander Cardiopulmonary Resuscitation A number of studies have shown the importance of starting CPR as soon as possible after the onset of sudden cardiac arrest, given that survival falls 10-15 % for every minute in which cardiac arrest care is not initiated ( Fig. 1) [14, 15]. Since professionals trained in Basic Life Support (BLS) or Advanced Cardiac Life Support (ACLS) are rarely the first responders at a sudden cardiac arrest, bystander CPR is an important determinant in providing prompt high quality CPR during out-of-hospital cardiac arrest .

Telephone-directed Instructions An important approach for immediate CPR education is the use of emergency telephone dispatchers to provide instructions to lay witnesses at the scene of a sudden cardiac arrest. However, the performance of bystander CPR even when being instructed over the telephone has been poor [16]. Examination of the deficiencies in bystander CPR led one group of investigators to modify telephone instructions used by a British dispatch service to emphasize key CPR parameters such as chest compression rate. The rate of chest compressions was improved but still below the recommended 100 per minute as recommended by ILCOR and the depth of chest compressions decreased to 2.0 em [17]. This study highlights the complexity of telephone CPR instructions and their limitations to improve care. Further methods to improve bystander instructions as well as novel mechanisms to improve lay public CPR, such as, for example, the use of automated external defibrillators (AEDs) with feedback capability for CPR performance, are being investigated (see below).

Compression-only Resuscitation A major obstacle to effective resuscitation care is the lack of bystander participation - less than 25 % of sudden cardiac arrest victims receive bystander CPR, which may be due to lack of training or unwillingness of trained individuals to perform CPR. Previous investigations have shown that some of the resistance of bystanders to performing CPR relates to the fear of mouth-to-mouth contact [18]. This has led to an interest in whether providing chest compressions only (without rescue ventilations) would be equally beneficial when compared with performing standard CPR with ventilations included [19-23] . A Japanese investigative group performed a prospec50

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Fig. 1. Schematic of survival from sudden cardiac arrest. Note that early delivery of bystander cardiopulmonary resuscitation (CPR) may change the survival curve dramatically (dashed line), given the typically later arrival of trained Emergency Medical Systems (EMS) firstresponders (rectangle).

Improving the Quality of Cardiac Arrest Resuscitation Care

tive, multicenter, observational study of 4,068 adult out-of-hospital cardiac arrests where paramedics assessed bystander CPR on arrival at the scene. The technique of bystander CPR was compared to the primary endpoint of favorable neurological outcomes 30 days after cardiac arrest. The group showed that 10.8 % of patients received compression-only resuscitation, 17.5 % received conventional CPR, and 71.7 % received no bystander CPR. Not only did any attempt at resuscitation result in more favorable neurological outcomes, but the compression-only resuscitation also resulted in a significantly higher proportion of patients with a favorable neuro logical outcome when compared to conventional CPR [24]. Future studies will be required to determine whether compression-only CPR should be recommended for all bystander resuscitation care.

Device Adjuncts to Manual Cardiopulmonary Resuscitation Audio Prompts on Automated External Defibrillators

Given concerns regarding inadequate CPR performed by bystanders and trained first-responders, one simulation study aimed at improving layperson CPR quality by providing audio prompts incorporated into an AED. Twenty-four laypersons were asked to provide CPR on a manikin with and without audio prompts. The investigators demonstrated that performance levels met guideline criteria for CPR when an audio prompt was given to an untrained layperson and subjects felt more confident about the CPR they were providing [25]. Audiovisual Feedback Defibrillators

Another real-time method to improve resuscitation quality is the provision of audiovisual feedback of any deviations from resuscitation guidelines, either via a freestanding CPR-sensing device or a defibrillator outfitted with CPR-sensing technology. New defibrillators are capable of identifying and recording deficiencies in CPR quality and provide automated feedback to result in real time adjustment in CPR performance. These technologies had previously been studied in manikin simulations with encouraging results [26, 27], and recent investigations have compared resuscitation events using real time CPR detection and audiovisual feedback incorporated into a clinical monitor/defibrillator to those without feedback. The variability of multiple CPR parameters including chest compression rate and ventilation rate was decreased by providing real time feedback [28]. Inspiratory Impedance Threshold Valve (lTV)

The lTV is a small device placed at the end of the endotracheal tube or face mask during CPR delivery. It is used to prevent inflow of respiratory gases during active decompression (when the chest wall recoils) while the patient is not being actively ventilated to augment the negative intrathoracic pressure and, therefore, amplify venous blood return to the right heart. Early animal investigations showed improved 24 h survival and neurological recovery when an lTV was compared to a sham valve [29]. More recent small human trials demonstrated improved systolic blood pressures during a sudden cardiac arrest and improved short-term survival rates [30,

31] .

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Mechanical Cardiopulmonary Resuscitation Devices A number of mechanical CPR devices have been developed in an attempt to overcome suboptimal chest compressions and CPR interruptions during manual delivery. Although these devices can reliably produce consistent compressions and eliminate the factor of human error, data regarding their clinical utility are conflicting at this point . Further investigation into mechanical CPR devices is needed to assess the appropriate use of these devices in resuscitation. Autopulse

One of the newer of these devices is a battery-powered compression band that is applied across the anterior chest wall and affixed via a backboard (Autopulse, Zoll Medical Corporation, Chelmsford, MA). In an observational cohort study, this device has been investigated in out-of-hospital sudden cardiac arrest on Emergency Medical Services ambulances and was shown to engender improved survival when compared with historical control sudden cardiac arrest events with manual CPR [32]. However, in a multicenter, randomized control trial using this compression device for out-of-hospital arrests, use of the Autopulse was associated with worse neurological outcomes and a trend toward worse survival when compared to manual CPR [33]. Further investigations into the appropriate use of Autopulse are needed to resolve these conflicting data. Lund University Cardiac Arrest System (LUCAS)

LUCAS is a gas-driven sternal compression device that incorporates a suction cup for active decompression . While currently not approved by the Food and Drug Administration (FDA) for clinical use in the United States, LUCAS is currently approved and being used in Europe during clinical resuscitation. The report of the first 100 consecutive cases treated with LUCAS during out-of-hospital sudden cardiac arrest documented that the 3D-day survival was 25 % in the setting of ventricular fibrillation and 5 % in asystole if the CPR was started within the first 15 minutes from cardiac arrest [34] - these survival characteristics are similar to when conventional CPR is performed in the study locale.

Training and Education An important area that may yield improvements in CPR quality is that of improvements in human factors and resuscitation skills. The lack of adequate resuscitation training and education for health care professionals was recently highlighted by a cross-sectional survey study. Of 289 Canadian medical residents' who responded to a questionnaire on resuscitation skills confidence, almost half (49.3 %) felt inadequately trained to lead cardiac arrest teams and over half (55.3 %) expressed fear that that they may have made errors during past resuscitation care [35]. Only 5.9 % reported having had received debriefing of any kind following a cardiac arrest and only 1.3 % reported having obtained any feedback from colleagues or instru ctors. This survey highlights the need for further education in resuscitation - incorporating different techniques, including simulation , feedback, and debriefing. These tools can serve as an important component of resuscitation quality improvement, espe-

Improving the Quality of Cardiac Arrest Resuscitation Care

Human feedback

Code team: • Debriefing • Training • Simulation

Obj ect ive feedback

Human factors observation

Chart/nursing arrest flow sheet

1

Objective CPRquality data collection

Synthesis into complete resuscitation transcript/ dataset

Fig. 2. Overview of cardiopulmonary resuscitation (CPR) quality improvement techniques and how they might fit into the framework of clinical resuscitation care. Note that this model involves two distinct feedback loops to improve quality - one relies on human feedback via education/debriefing, and the other depends on devices to provide objective information during or after a sudden cardiac arrest event.

cially when coupled with robust data collection that can then feed into educational programs ( Fig. 2). Simulation

Given the trend towards reduction in exposure of physicians-in-training to critically ill patients in the United States, simulation and «mock codes" are being used more commonl y to provide necessary instruction. In the medical domain , simulation methodology has historically focused on resuscitation, and many different tools are now being employed and developed, ranging from on-line simulation to integrated clinical simulators that use high-fidelity whole body manikins [36). The Resuscitation Council in the United Kingdom and the European Resuscitation Council Advanced Life Support Provider course has now integrated simulation training [37). Incorporating simulation into advanced life-support training combines repetitive practice opportunities with multiple learning strategi es while also providing feedback. One study measured the impact of medical simulator sessions on adherence to resuscitation guidelines by internal medicine residents . Those that had simulator training showed significantly better performance even after adjust ing for clinical experience, which, by itself, had no impact on performance of advanced cardiac life support [38). Simulation can also address and teach other skills that are necessary for a successful resuscitation, skills that are difficult to teach by mechanisms other than modeling or simulation. For example, a simulation study of 16 teams comprised of three health-care workers assessed whether the teams could successfully convert ventri cular fibrillation to sinus rhythm by providing two shocks within the first two

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minutes or by two shocks during the first five minutes if uninterrupted basic life support was started within 60 seconds [39]. Only six of the teams were successful. Several variables between the successful and the unsuccessful teams were compared including leadership, task distribution, information transfer, and conflicts. Although all teams demonstrated the necessary theoretical knowledge, the successful teams had significantly higher ratings of leadership and task distribution. Debriefing

Following a sudden cardiac arrest, an important opportunity for learning exists among the participating health care providers. During the time immediately following a sudden cardiac arrest event, participants are primed to discuss and learn from the recent event. This provides a key moment to provide real-time and relevant verbal feedback to a provider of CPR. Studies have demonstrated that providing verbal debriefing can impact the quality of subsequent simulated cardiac events. In fact, even when combining real time audiovisual feedback as described earlier with debriefing using the data obtained from the CPR detection device, not only was CPR quality improved, but return of spontaneous circulation was significantly increased [40].

Other Cardiopulmonary Resuscitation Techniques Various different CPR techniques have received attention over the past few years. For example, one research group recently investigated whether CPR quality could be augmented by providing sustained abdominal pressure using an inflatable contoured cuff device on pigs during CPR after inducing ventricular fibrillation. This resulted in a significant increase in coronary perfusion pressure throughout the duration of abdominal pressure and was immediately reversible upon deflating the device. The increase in coronary perfusion pressure was similar to that seen with vasopressor drugs [41]. Given this animal study and new information about the potential consequences of vasopressors, such as post-resuscitation myocardial depression , further investigation into sustained abdominal compression to enhance CPR may be warranted.

Conclusion Sudden cardiac arrest is a major cause of mortality worldwide resulting in over 700,000 deaths each year in Europe and in the United States combined. Studies have demonstrated improved outcomes when resuscitation care, and especially CPR, is well-performed. Therefore, given the presently dismal survival rate, further investigations to improve the quality of resuscitation are necessary. So far, methods to improve the training of bystanders as well as medical professions by providing real time audiovisual feedback during CPR performance have been most promising with a potential to increase the rate of return of spontaneous circulation. Innovative methods to teach CPR, such as integrating simulation into training classes or incorporating real-time audiovisual feedback, may enable better instruction to be given to health care providers . Several new mechanical devices have been developed in an attempt to eliminate human error from resuscitation events and allow the health

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119

care providers to focus on other aspects of the resuscitation. Through further investigation of such devices and methods of instruction ( Fig. 2), CPR quality during actual delivery may be improved in coming years, and this, in turn, will hopefully lead to improvements in saving lives from this enormous clinical problem of sudden cardiac arrest. References 1. Eisenberg MS, Mengert TJ (2001) Cardiac resuscitation. N Engl J Med 344:1304-1313 2. Zipes DP, Wellens HJ (1998) Sudden cardiac death. Circulation 98:2334-2351 3. Myerburg RJ, Kessler KM, Castellanos A (1993) Sudden cardiac death epidemiology, transient risk, and intervention assessment. Ann Intern Med 119:1187 -1197 4. Priori SG, Aliot E, Blomstrom-Lundqvist C, et al (2001) Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J 22:1374-1450 5. Myerburg RJ, Interian A Ir, Mitrani RM, Kessler KM, Castellanos A (1997) Frequency of sudden cardiac death and profiles of risk. Am J Cardiol 80:IOF-19F 6. Ali B, Zafari, AM (2007) Narrative review: Cardiopulmonary resuscitation and emergency cardiovascular care: Review of the current guidelines. JAMA 147:171-179 7. Van Hoeyweghen RJ, Bossert LL, Mullie A, et al (1993) Quality and efficiency of bystander CPR. Belgian Cerebral Resuscitation Study Group. Resuscitation 26:47-52 8. Gallagher EJ, Lombardi G, Gennis P (1995) Effectiveness of bystander cardiopulmonary resuscitation and survival following out-of-hospital arrest. JAMA 274:1922-1925 9. Berg RA, Sanders AB, Kern KB, et al (2001) Adverse hemodynamic effects of interrupting chest compressions for rescue breathing during cardiopulmonary resuscitation for ventricular fibrillation cardiac arrest. Circulation 104:2465-2470 10. Dowie R, Campbell H, Donohoe R, Clarke P (2003) "Event tree" analysis of out-of-hospital cardiac arrest data: confirming the importance of bystander CPR. Resuscitation 56:173-181 11. Abella BS, Alvarado JP, Myklebust H, et al (2005) Quality of cardiopulmonary resuscitation during in-hospital cardiac arrest. JAMA 293:305 -310 12. Olasveengen TM, Wik L, Steen PA (2007) Quality of cardiopulmonary resuscitation before and during transport in out-of-hospital cardiac arrest. Resuscitation [epub ahead of print] 13. ECC Committee, Subcommittee and Task Forces of the American Heart Association (2005) 2005 American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 112 (24 suppl):IVI -203 14. So HY, Buckley TA, Oh TE (1994) Factors affecting outcome following cardiopulmonary resuscitation. Anaesth Intensive Care 22:647- 58 15. Mitchell RG, Brady W, Guly UM, Pirrallo RG, Robertson CE (1997) Comparison of two emergency response systems and their effect on survival from out of hospital cardiac arrest. Resuscitation 35:225- 229 16. Cheung S, Deakin CD, Hsu R, Petley GW, Clewlow F (2007) A prospective manikin-based observational study of telephone cardiopulmonary resuscitation. Resuscitation 72:425- 35 17. Deakin CD, Cheung S, Perley GW, Clewlow F (2007) Assessment of the quality of cardiopulmonary resuscitation following modification of a standard telephone-directed protocol. Resuscitation 72:436- 334 18. Shibata K, Taniguchi T, Yoshida M, Yamamoto K (2000) Obstacles to bystander cardiopulmonary resuscitation in Japan. Resuscitation 44:187-193 19. Berg RA, Kern KB,Sanders AB,Otto CW, Hilwig RW, EwyGA (1993) Bystander cardiopulmonary resuscitation. Is ventilation necessary? Circulation 88:1907-1915 20. Babbs CF, Kern KB (2002) Optimum compression to ventilation ratios in CPR under realistic, practical conditions: a physiological and mathematical analysis. Resuscitation 54:147-157 21. Sanders AB, Kern KB, Berg RA, Hilwig RW, Heidenrich J, Ewy GA (2002) Survival and neuro logic outcome after cardiopulmonary resuscitation with four different chest compressionventilation ratios. Ann Emerg Med 40:553- 562 22. Heidenreich JW, Sanders AB, Higdon TA, Kern KB, Berg RA, Ewy GA (2004) Uninterrupted chest compression CPR is easier to perform and remember than standard CPR. Resuscitation 63:123-130

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frequency combined with an inspiratory impedance device improves CPR efficiency in swine model of cardiac arrest. Resuscitation 61:75-82 24. SOS-KANTO study group (2007) Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational stud y. Lancet 369:920 - 926 25. Williamson LJ, Larsen PD, Tzeng YC, Galletly DC (2005) Effect of automat ic externa l defibrillator audio prompt s on cardiopulmonary resuscitation performance. Emerg Med J 22:140-

143 26. Wik L, Thowsen J, Steen PA (2001) An automated voice advisory manikin system for training

in basic life support without an instructor. A novel approa ch to CPR training. Resuscitation

50:167- 172

27. Handley AJ, Handley SA (2003) Improving CPR performance using an audible feedback system suitable for incorporation into an automated external defibrillator. Resuscitation 57: 57-62 28. Abella BS, Edelson DP, Kim S, et al (2007) CPR quality improvement using in-hospital cardiac arrest using a real time audiovisual feedback system. Resuscitation 73:54-61 29. Lurie KG, Zielinski T, McKnite S, Aufderheide TP, Voelckel W (2002) Use of an inspiratory

impedance valve improves neurologically intact survival in a porcine model of ventricular fibrillation. Circulation 105:124- 129 30. Pirrallo RG, Aufderheide TP, Provo TA, Lurie KG (2005) Effect of an inspir atory impedan ce threshold device on hemodynamics during conventional manual cardiopulmonary resuscitation. Resuscitation 66:13-20 31. Aufderheide TP, Pirrallo RG, Provo TA, Lurie KG (2005) Clinical evaluation of an inspiratory impedance threshold device during standard cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest . Crit Care Med 33:734-740 32. Ong ME, Ornato JP, Edwards DP, et al (2006) Use of an automated, load-distributing band chest compression device for out-of-hospital cardiac arrest resuscitation. JAMA 295:26292637 33. Hallstrom A, Rea TD, Sayre MR, et al (2006) Manual chest compression vs use of an auto34. 35. 36. 37. 38.

mated chest compression device during resuscitation following out-of-hospital cardiac arrest : a randomized trial . JAMA 295:2661- 2664 Steen S, Sjoberg T, Olsson P, YoungM (2005) Treatment of out-of-hospit al cardiac arrest with LUCAS, a new device for automatic mechanical compressions and active decompression resuscitation. Resuscitation 67:25- 30 Hayes CW, Rhee A, Detsky ME, Leblanc VR, Wax RS (2007) Residents feel unprepared and unsupervised as leaders of cardiac arrest teams in teaching hospitals: a survey of internal medicine residents . Crit Care Med 35:1668-1672 Perkins GD (2007) Simulation in resuscitation training. Resuscitation 73:202- 211 Nolan JP (2001) Advanced life support training. Resuscitation 50:9-11 Wayne DB, Butter J, Siddal VJ, et al (2005) Simulation-based training of internal medicine residents in advanced cardiac life support protocols: A randomized trial. Teach Learn Med

17:202-208 39. Marsch SC, Muller C, Marquardt K, Conrad G, Tschan F, Hunziker PR (2004) Human factors

affect the quality of cardiopulmonary resuscitation in simulated cardiac arrest s. Resuscitation

60:51-56

40. Edelson DP, Litzinger B, Arora V, et al (2007) Resuscitation with actual performance inte-

grated debriefing (rapid) improves trainee cpr quality and initial patient survival. Arch Intern Med (in press) 41. Lottes AE, Rundell AE, Geddes LA, Kemeny AE, Otlewski MP, Babbs CF (2007) Sustained abdom inal compression dur ing CPR raises coronary perfusion pressure s as much as vasopressor drug s. Resuscitation 75:515-524

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Pediatric Cardiopulmonary Arrest and Resuscitation A. TOPPAN, R.A. BERG, and V.M. NADKARNI

Introduction In this chapter we will briefly review the current state-of-the-art in pediatric cardiac arrest: Epidemiology, the four phases of cardiac arrest, mechanisms of blood flow during cardiopulmonary resuscitation (CPR), interventions, post-arrest supportive care, special resuscitation circumstances (pediatric ventricular fibrillation [VFj, post-congenital heart surgery, extracorporeal membrane oxygenation [ECMO)CPR), and innovative implementation of training programs.

Epidemiology of Pediatric Cardiac Arrest Cardiovascular disease is the most common cause of disease-related death, resulting in approximately one million deaths per year in North America. Approximately 16,000 American children (8 to 20/100,000 children/year) suffer a cardiac arrest each year. Bystander CPR is only provided to approximately 30 % of pre-hospital pediatric cardiac arrest victims [1). Dependent on the setting of pediatric cardiac arrest, initial return of spontaneous circulat ion occurs in 5- 64 % of cases, with approximately half of those surviving their arrest event living to hospital discharge and approximately 75 % of survivors having a favorable neurologic outcome [2,3). Critical factors that influence survival outcomes include the environment in which arrest occurs, the pre-existing condition of the child, the duration of no flow prior to resuscitation, the initial electrocardiograph (EKG) rhythm detected, and the quality of the basic and advanced life support interventions provided. Long-term survival from pediatric out-of-hospital cardiac arrest is generally reported as < 5 %, while survival from arrest in a pediatric ICD is 15- 27 %.

Pediatric Out-of-hospital Arrests Outcomes following pediatric out-of-hospital arrests are much worse than in-hospital arrests [1,2,4-13) (Table 1). Survival to hospital discharge typically occurs in less than 10 % of these children, and many have severe neurological sequelae. These poor outcomes are in part because of prolonged periods of 'no flow' and in part because of specific diseases (e.g., traumatic cardiac arrest and sudden infant death syndrome [SIDS)). Many pediatric out-of-hospital cardiac arrests are not witnessed, and only 30 % of children are provided with bystander CPR. Therefore, the 'no flow' period is typically quite prolonged before emergency medical service (EMS) personnel provide CPR.

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A. Topjian, R.A. Berg, and V.M. Nadkarni Table 1. Summary of representative studies of outcome following out-of-hospital pediatric cardiac arrest Author, year

Setting

Osmond, 2006 [6]

Out-of-hospital cardiac arrest, Canada

Donoghue, 2005 [75]

Number of patients

Return of spontaneous circulation

Survival to discharge

Favorable neurological survival

S03

Not reported

10 (2%)

Not reported

Out-of-hospital cardiac arrest systematic review

5693

Not reported

689 (12 %) 228 (4 %)

Berg M, 2005 [4]

Out-of-hospital cardiac arrest, shockable rhythm

13

13 (100 %)

0(0 %)

0 (0%)

Young, 1999 [1]

Meta-analysis, out-ofhospital cardiac arrest

1568

Not reported

132 (8%)

Not reported

Sirbaugh, 1999 [10]

Out-of-hospital cardiac arrest

300

33 (11 %)

6 (2%)

1 « 1 %)

Suominen, 1998 [12]

Out-of-hospital cardiac arrest after trauma

41

10 (24%)

3 (7%)

2 (5%)

Suominen, 1997 [11]

Out-of-hospital cardiac arrest

50

13 (26 %)

8 (16%)

6 (12 %)

Schindler, 1996 [9]

Out-of-hospital cardiac arrest

80

43 (54%)

6 (8%)

0(0 %)

Kuisma, 1995 [7]

Out-of-hospital cardiac arrest

34

10 (29%)

5 (15 %)

4 (12%)

Dieckmann, 1995 [5] Out-of-hospital cardiac arrest

65

3 (5%)

2 (3 %)

1 (1.5 %) 34 (16 %)

Lopez-Herce, 200S [8]

Mixed in-hospital and out-of-hospital cardiac arrest

213

110 (52%)

45 (21 %)

Tunstall-Pedoe, 1992 [13]

Mixed in-hospital and out-of-hospital cardiac arrest

3765

1411 (38%)

706 (19 %) Not reported

Pediatric In-hospital Arrests Pediatric CPR and advanced life support can be remarkably effective [1,3,8,13-23] ( Table 2). Almost two-thirds of in-hospital pediat ric cardiac arrest patients can be initially successfully resuscitated (i.e., attain sustained return of spontaneous circulation). Approximately 25- 50 % of initial survivors survive to hospital discharge. The l -year survival rates of 10-44 % are substantially better than reported outcomes following out-of-hospital pediatric CPR. Almost three-fourths of survivors to discharge have good neurological outcomes. In a recently published Utstein style report of in-hospital pediatric cardiac arrests derived from the American Heart Association's multicenter National Registry of Cardiopulmonary Resuscitation (NRCPR), 95 % of arrests were witnessed and/or monitored and only 14 % occurred on a general pediatric ward, 52 % attained sustained return of spontaneous circulation , 36 % survived for 24 hours, and 27 % survived to hospital discharge. Outcomes for these children were substantially superior to outcomes for adults in this registry

Pediatric Cardiopulmonary Arrest and Resuscitation Table 2. Summary of representative studies of outcome following in-hospital pediatric cardiac arrest Author, year

Setting

Meaney, 2006 [16] All ICU patients < 21 Samson, 2006 [19]

In-hospital cardiac arrest, (initial VFNT rhythm)

Number Return of of spontaneous patients circulation 464 272 (104)

Survival to dis- Good neurocharge logical survival

50%

(22 %)

(14 %)

(70 %)

(35 %)

(33 %)

Nadkarni, 2006 [3] In-hospital cardiac arrest

880

459 (52 %)

236 (27 %)

154 (18 %)

Reis, 2002 [18]

129

83 (64 %)

21 (16 %)

19 (15 %)

Extracorporeal Life In-hospital cardiac Support Organiza- arrest resuscitation by tion, 2005 [15] ECMO

232

N/A All needed ECMO

88 (38 %)

Not reported

Suominen, 2000

In-hospital cardiac arrest

118

74(63 %)

Parra, 2000 [17]

Pediatric (ICU cardiac arrest

32

24 (63 %)

14 (44 %)

Chamnanvanakij,

In-hospital intubated NICU patients with chest compressions for bradycardia

39

33 (85 %)

CPR 20 (51 %) CPR 5 (13 %) Cardiac arrest (6 lost to follow-up) 10%

Sionim, 1997 [20]

In-hospital PICU cardiac arrest

205

Not reported

28 (14 %)

Torres, 1997 [22]

In-hospital cardiac arrest

92

Not reported

Zaritsky, 1987 [23] In-hospital cardiac arrest

53

Not reported

Cardiac arrest

Not reported

[21]

2000 [14]

In-hospital cardiac arrest

l-year survival Not reported

21 (18 %)

8 (25 %)

Not reported

l-year survival 7 (8%)

9 (10 %) 5 (9%)

Young, 1999 [1]

Meta-analysis In hospital cardiac arrest

544

Not reported

129 (24 %)

Not reported

lopez-Herce, 2005 [8]

Mixed in-hospital and out-of-hospital cardiac arrest

213

110 (52 %)

45 (21 %)

34 (16 %)

Tunstall-Pedoe,

Mixed in-hospital and out-of-hospital cardiac arrest

3765

1411 (38 %)

706 (19 %)

Not reported

1992 [13]

VF: ventricular fibrillation; VT: ventricular tachycardia; NICU: neonatal intensive care unit; PICU: pediatric intensive care unit; (ICU: cardiac intensive care unit; ECMO: extracorporeal membrane oxygenation; CPR: cardiopulmonary resuscitation (27 % sur vival to discharge versus 18 %, respectively; adjusted odds ratio, 2.3 [95 %CI, 2.0 - 2.7]). Importantly, 65 % of these children had favorable neurological outcome, defined as Pediatric Cerebral Performance Category of 1, 2 or 3, or no change from admission baseline.

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Mechanism of Blood Flow to Vital Organs during Cardiac Arrest The major role of CPR is to supply vital organs and tissues with blood flow, oxygen and nutrients. Minimally interrupted flow of oxygen and nutrients is necessary to sustain viability and promote restoration of normal function. A combination of direct cardiac compression and thoracic pump mechanisms appears to be important in blood flow generation during CPR. Coronary Blood Flow during CPR

During card iac arrest (asystole or VF) coronary flow ceases. During chest compression, aortic pressure rises at the same time as right atrial pressure. During the decompression phase of chest compression, the right atrial pressure falls faster and lower than the aortic pressure generating a pressure gradient that perfuses the heart with oxygenated blood during 'diastole'. Coronary perfusion pressure below 15 mmHg during CPR is a poor prognostic factor for a return of spontaneous circulation [24]. The importance of negative intrathoracic pressure on coronary perfusion pressure and myocardial blood flow during CPR has been recently discovered. Dur ing the decompression phase, negative intrathoracic pressu re can be enhanced by briefly impeding air flow to the lungs (e.g., with an inspiratory impedance threshold device), which promotes venous return, cardiac output and mean aortic pressure. The application of this concept has been shown in animal and adult human trials of CPR to improve vital organ perfusion pressures, myocard ial blood flow, and survival rates, but has not yet been explored in children [25-27]. Phases of Resuscitation

Interventions to improve outcome from pediatric cardiac arrest should be targeted to optimize therapies according to the etiology, timing, duration, intensity, and 'phase' of resuscitation as suggested in Table 3. There are at least four phases of cardiac arrest: 1) pre-arrest; 2) no flow (untreated cardiac arrest); 3) low flow (CPR); and 4) post -resus citation. The pre-arrest phase represents the greatest opportunity to impact patient survival by preventing pulseless cardiopulmonary arrest. This phase includes recognition and treatment of pre-existing conditions (e.g., neurological, cardiac, respiratory, infectious, or metabolic problems), developmental status (e.g., premature neonate, mature neonate, infant, child, or adolescent) , and precipitating events (e.g., respiratory failure or shock) . Interventions during the pre-arrest phase focus on prevention. Since early recognition, prevention, and anticipation of cardiac arrest is better than treatment, Medical Emergenc y Teams (Rapid Response Teams) are being trained to recognize and intervene when cardiac arrest is impending [28, 29]. Interventions during the no flow phase of pulseless cardiac arrest focus on early recognition of cardiac arrest and prompt initiation of basic life support. The goal of effective CPR is to optimize coronary and cerebral perfusion and blood flow to critical organs during the low flow phase. Basic life support with near continuous effective chest compressions (e.g., push hard, push fast, allow full chest recoil, minimize interruptions, and don't over ventilate) is the emphasis in this phase. For VF and pulseless ventricular tachycardia (VT), rapid determination of EKG rhythm and prompt defibrillation when appropriate are important. For cardiac arrests due to

Pediatric Cardiopulmonary Arrest and Resuscitation Table 3. Phases of cardiac arrest and resuscitation Phase

Interventions

Pre-arrest (Protect)

• Optimize community education regarding child safety • Optimize patient monitoring and rapid emergency response • Recognize and treat respiratory fa ilure and lor shock to prevent cardiac arrest

Arrest (no-flow) (Preserve)

• Minimize interval to BLS and ALS (organized response) • Minimize interval to defibrillation, when indicated

Low-flow (CPR) (Resuscitate)

• • • • •

Post-resuscitation Short-term

• • • • •

'Push Hard; 'Push Fast' Allow full chest recoil Minimize interruptions in compressions Avoid overventilation Titrate CPRto optimize myocardial blood flow (coronary perfusion pressures and exhaled COL) • Consider adjuncts to improve vital organ perfusion during CPR • Consider ECMO if standard CPR/ALS not promptly successful Optimize cardiac output and cerebral perfusion Treat arrhythmias, if indicated Avoid hyperglycemia, hyperthermia, hyperventilation Consider mild post-resuscitation systemic hypothermia Debrief to improve future responses to emergencies

• Early intervention with occupational and physical therapy Post-resuscitation Longer-term rehabili- • Bioengineering and technology interface tation (Regenerate) • Possible future role for stem cell transplantation CPR: cardiopulmonary resuscitation; BLS: basic life support; ALS: advanced life support; ECMO: extracorporeal membrane oxygenation asphyxia and/or ischemia, provision of adequate myocardial perfusion and myocardial oxygen delivery with ventilation titrated to blood flow is important. The post-resuscitation phase is a high-risk period for brain injury, ventricular arrhythmias, and extension of reperfusion injuries. Injured cells can hibernate, die, or partially or fully recover funct ion. Myocardial dysfunction and severe hypotension are common during the post-resuscitation phase [30]. Interventions, such as systemic hypothermia, during the immediate post-resuscitation phase strive to min imize reperfusion injury and support cellular recover y. The post -arrest phase may have the most potential for innovative advance s in the understanding of cell injury and death , inflammation, apoptosis and hibernation, ultimatel y leading to novel interventions. Thoughtful attention to management of temperature (avoid hyperthermia), glucose (normoglycemia ), blood pressure (normotension), coagulation, and optimal ventilation (avoid hyperventilation) may be particularl y important in this phase . The specific phase of cardiac arrest and resuscitation should dictate the timing, intensity, duration and focus of interventions. Emergin g data suggest that interventions that can improve short-term outcome during one phase may be deleterious during another. For instance, intense vasoconstriction during the low flow phase of card iac arrest may improve coronary perfusion pressure and probability of return of spontaneous circulation. The same intense vasoconstriction during the post -resuscitation phase may increa se left ventricular afterload and worsen myocardial strain

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A. Topjian, R.A. Berg, and Y.M. Nadkami and dysfunction . Current understanding of the physiology of cardiac arrest and recovery only enables the titration of blood pressure, global oxygen delivery and consumption, body temperature, inflammation, coagulation, and other physiologic parameters to attempt to optimize outcome. Future strategies will likely take advantage of emerging discoveries and knowledge of cellular inflammation, thrombosis, reperfusion, mediator cascades, cellular markers of injury and recovery, and transplantation technology.

Interventions during Cardiac Arrest (No-Flow) and CPR (Low Flow) Phases Airway and Breathing During CPR, cardiac output and pulmonary blood flow are approximately 10-25 % of that during normal sinus rhythm. Consequently, much less ventilation is necessary for adequate gas exchange from the blood traversing the pulmonary circulation during CPR. Animal and adult data indicate that over-ventilation during CPR is common and can substantially compromise venous return and cardiac output. Most concerning, these adverse hemodynamic effects during CPR combined with the interruptions in chest compressions typically contribute to worse survival outcomes. In animal models of sudden VF cardiac arrest, acceptable Pa0 2 and PaC0 2 persist for four to eight minutes during chest compressions without rescue breathing. Adequate oxygenation and ventilation can continue without rescue breathing because the lungs serve as a reservoir for oxygen during the low flow state of CPR, and chest compressions alone with an open airway can provide about 33 % of normal minute ventilation. Several retrospective studies of witnessed VF cardiac arrest in adults also suggest that outcomes are similar or better after bystander-initiated CPR with either chest compressions alone or chest compressions plus rescue breathing [31]. Animal studies of asphyxia-precipitated cardiac arrests have established that rescue breathing is a critical component of successful CPR [32]. Asphyxia results in significant arterial hypoxemia and acidemia prior to resuscitation in contrast to VE In this circumstance, rescue breathing can be life-saving.

Circulation Basic life support with minimally interrupted effective chest compressions is generally not provided. The most critical elements are to "push hard" and "push fast". Because there is no flow without chest compressions, it is important to minimize interruptions in chest compressions. To allow good venous return in the decompression phase of external cardiac massage, it is important to allow full chest recoil, and to avoid overventilation. The latter can prevent venous return because of increased intrathoracic pressure. Open chest CPR Excellent standard closed chest CPR generates approximately 10- 25 % of baseline myocardial blood flow and a cerebral blood flow that is approximately 50 % of normal. By contrast, open chest CPR can generate a cerebral blood flow that approaches normal. Although open chest massage improves coronary perfusion pressure and increases the chance of successful defibrillation in animals and humans, surgical thoracotomy is impractical in many situations. Open chest CPR is often provided to children after open-heart cardiac surgery and sternotomy. Earlier institution of open

Pediatric Cardiopulmonary Arrest and Resuscitation

chest CPR may warrant reconsideration in selected special resuscitation circumstances such as penetrating trauma and tamponade.

Ratio of Compressions to Ventilation Ideal compression-ventilation ratios for pediatric patients are unknown. Recent physiologic estimates [33] suggest the amount of ventilation needed during CPR is much less than the amount needed during a normal perfusing rhythm because the cardiac output during CPR is only 10- 25 % of that during normal sinus rhythm. The best ratio depends upon many factors including the compression rate, the tidal volume, the blood flow generated by compressions , and the time that compressions are interrupted to perform ventilations. A chest compression to ventilation ratio of 15:2 delivered the same minute ventilation as CPR with a chest compression to ventilation ratio of 5:1 in a manik in model of pediatric CPR, but the number of chest compressions delivered was 48 % higher with the 15:2 ratio [34, 35]. The benefits of positive pressure ventilation (increased arterial content of oxygen and carbon dioxide elimination) must be balanced against the adverse consequence of impeding circulation.

Drug Administration Intraosseous vascular access has largely replaced the need for endotracheal drug administration. Absorption of drugs into the circulation after endotracheal administration depends on dispersion over the respiratory mucosa, pulmonary blood flow, and the matching of the ventilation (drug dispersal) to perfusion. Although animal studies indicate that epinephrine can improve initial resuscitation success after both asphyxial and VF cardiac arrests, no single medication has been shown to improve survival to hospital discharge outcome from pediatric cardiac arrest. Medications commonly used for CPR in children are vasopressors (epinephrine or vasopressin), calcium chloride, sodium bicarbonate, and anti-arrhythmics (amiodarone or lidocaine). During CPR, epinephrine's a-adrenergic effect increases systemic vascular resistance, increasing diastolic blood pressure which in turn increases coronary perfusion pressure and blood flow and increases the likelihood of the return of spontaneous circulation . Epinephrine also increases cerebral blood flow during CPR because peripheral vasoconst riction directs a greater proportion of flow to the cerebral circulation . The ~-adrenergic effect increases myocardial contractility and heart rate and relaxes smooth muscle in the skeletal muscle vascular bed and bronchi although this effect is of less importance. Epinephrine also increases the vigor and intensity of VF, increasing the likelihood of successful defibrillation. High-dose epinephrine (0.05- 0.2 mg/kg) improves myocardial and cerebral blood flow during CPR more than standard-dose epinephrine (0.01- 0.02 mg/kg), and may increase the incidence of initial return of spontaneous circulation [36, 37]. However, prospective and retrospective studies indicate that use of high-dose epinephrine in adults or children does not improve survival and may be associated with a worse neurological outcome [38, 39]. A randomized, blinded controlled trial of rescue high-dose epinephrine versus standard-dose epinephrine following failed initial standard-dose epinephrine for pediat ric in-hospital cardiac arrest demonstrated a worse 24-hour survival in the high-dose epinephrine group (1127 vs 6123, P < 0.05) [40].

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Post-resuscitation Interventions Temperature management

Mild induced hypothermia is the most celebrated goal-directed post-resuscitation therapy for adults. Two seminal articles [41, 42] established that induced hypothermia (32- 34°C) could improve outcome for comatose adults after resuscitation from VF cardiac arrest. In both randomized, controlled trials, the inclusion criteria were patients older than 18 years who were persistently comatose after successful resuscitation from non-traumatic VE Interpretation and extrapolation of these studies to children is difficult. Fever following cardiac arrest, brain trauma, stroke, and other ischemic conditions is associated with poor neurological outcome. Hyperthermia following cardiac arrest is common in children [43]. It is reasonable to believe that mild induced systemic hypothermia may benefit children resuscitated from cardiac arrest. However, benefit from this treatment has not been rigorously studied and reported in children or in any patients with non- VF arrests. Emerging neonatal trials of selective brain cooling and systemic cooling show promise in neonatal hypoxic-ischemic encephalopathy, suggesting that induced hypothermia may improve outcomes [44, 45]. Post-resuscitation Myocardial Support

Post-arrest myocardial stunning occurs commonly after successful resuscitation in animals, adults, and children. Post-arrest myocardial stunning is pathophysiologically similar to sepsis-related myocardial dysfunction and post-cardiopulmonary bypass (CPB) myocardial dysfunction, including increases in inflammatory mediator and nitric oxide (NO) production. Optimal treatment of post-arrest myocardial dysfunction has not been established. The hemodynamic benefits seen in animal stud ies of post-arrest myocardial dysfunction, in pediatric studies of post-CPB myocardial dysfunction, and in pediatric sepsis-related myocardial dysfunction support the use of inotropic/vasoactive agents in this setting [46- 51], although there are no data demonstrating improvements in outcome. Blood Pressure Management

Laurent and colleagues [30] demonstrated that 55 % of adults surviving out-of-hospital cardiac arrests required in-hospital vasoactive infusions for hypotension unresponsive to volume boluses. It is rational to presume that blood pressure variability should be minimized as much as possible following resuscitation from cardiac arrest. A brief period of hypertension following resuscitation from cardiac arrest may diminish the no-reflow phenomenon. In animal models, brief induced hypertension following resuscitation results in improved neurological outcome compared to normotension. In a retrospective human study, post-resuscitative hypertension was associated with a better neurological outcome after controlling for age, gender, duration of cardiac arrest, duration of CPR, and preexisting diseases [39]. Glucose Control

Hyperglycemia following adult cardiac arrest is associated [52] with worse neurological outcome after controlling for duration of arrest and presence of cardiogenic shock. In animal models of asphyxial and ischemic cardiac arrest, administration of

Pediatric Cardiopulmonary Arrest and Resuscitation

insulin and glucose, but not admini stration of glucose alone, improved neurological outcome compared to administration of normal saline [53]. Data for evidence-based titration of specific endpoints is not available.

Post-resuscitation Outcomes and Quality of Life Neuropsychological Issues

Information about neurological outcomes and predictors of neurological outcome after both adult and pediatric cardiac arrests is limited. Barriers to assessment of neurological outcomes of children after cardiac arrests include the constantly changing developmental context that occurs with brain maturation. Prediction or prognosis for future neuro-psychological status is a complex task, particularly after an acute neurological insult. There is little information about the predictive value of clinical neurological examinations, neurophysiological diagnostic studies (e.g., electroencephalogram [EEG], or somatosensory evoked potentials), biomarkers, or imaging (computed tomography [CT], magnetic resonance imaging [MRI], or positron emission tomography [PET]) on eventual outcome following cardiac arrest or other global hypoxic-ischemic insults in children. CT scans are not sensitive in detecting early neurological injury. The value of MRI studies following pediatric cardiac arrest is not yet clear. However, MRI with diffusion weighting should provide valuable information about hypoxic/ischemic injury in the subacute and recovery phases. Emerging data suggest that a burst-suppression pattern on post-arrest EEG is sensitive and specific for poor neurological outcome [54]. One study showed that somatosensory evoked potential (SSEP) was highly sensitive and specific in pediatric patients after cardiac arrest [55]. However, SSEP is not standardized in the pediatric population and is difficult to interpret. Many children who suffer a cardiac arrest have substantial pre-existing neurological problems. For example, 17 % of the children with in-hospital cardiac arrests from the NRCPR were neurologically abnormal before the arrest [3]. Thus, comparison to pre-arrest neurological function of a child is difficult and adds another dimension/barrier to the assessment and prediction of post-arrest neurologi cal status. Biomarkers are emerging tools to predict neurological outcome. In an adult study, serum levels of neuron-specific enolase (NSE) and S100b protein showed prognostic value. NSE > 33 f!g/l and S100b > 0.7 f!g/l were highly sensitive and specific for poor neurological outcome (death or persisting unconsciousness) [56]. The validation of these biomarkers in pediatric post- arrest patients requires further study.

Special Resuscitation Circumstances Pediatric Ventricular Fibrillation

VF is an uncommon, but not rare, EKG rhythm during out-of-hospital pediatric cardiac arrests . Two studies reported VF as the initial rhythm in 19-24 % of out-ofhospital pediatric cardiac arrests , but these studies excluded SIDS deaths. In studies that include SIDS victims, the frequency drops to the range of 6-10 % [57]. The incidence of VF varies by setting and age. In special circumstances, such as tricyclic antidepressant overdose, cardiomyopathy, post-cardiac surgery, and prolonged QT syndromes, VF is a more likely rhythm during cardiac arrest. Commotio cordis, or mechanically-initiated VF due to relatively low-energy chest wall impact during a

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A. Topjian, R.A. Berg, and V.M. Nadkarni narrow window of repolarization (10-30 msec before the T wave peak in swine models) is reported predominantly in children 4-16 years old. Out-of-hospital VF cardiac arrest is uncommon in infants, but occurs more frequently in children and adolescents. The variance of VF by age was highlighted in a study documenting VF/VT in only 3 % of children 0- 8 years old in cardiac arrest versus 17 % of children 8- 19 years old [58). Although VF is often associated with underlying heart disease and generally considered the 'immediate cause' of cardiac arrest, 'subsequent' VF can also occur during resuscitation efforts. Asphyxia-associated VF is also well documented among pediatric near-drowning patients [59). Traditionally, VF and VT have been considered 'good' cardiac arrest rhythms, resulting in better outcomes than asystole and pulseless electrical activity. Among the first 1,005 pediatric in-hospital cardiac arrests in the NRCPR [19), 10 % had an initial rhythm of VF/VT; an additional 15 % had subsequent VF/VT (i.e., some time later during the resuscitation efforts). Of note, survival to discharge was much more common among children with an initial shockable rhythm than among children with shockable rhythms occurring later during the resuscitation. These data suggest that outcomes after initial VF/VT are 'good', but outcomes after subsequent VF/VT are substantially worse, even compared to asystole/pulseless electrical activity rhythms. Termination of ventricular fibrillation: Defibrillation Defibrillation (defined as termination of VF), is necessary for successful resuscitation from VF cardiac arrest. The goal of defibrillation is return of an organized electrical rhythm with pulse. When prompt defibrillation is provided soon after the induction of VF in a cardiac catheterization laboratory, the rates of successful defibrillation and survival approach 100 %. When automated external defibrillators are used within 3 mins of adult witnessed VF, long-term survival can occur in more than 70 % [60, 61). In general, mortality increases by 7 %-10 % per minute of delay to defibrillation. Early and effective, near-continuous chest compressions can attenuate the incremental increase in mortality with delayed defibrillation. Provision of high quality CPR can improve outcome and save lives. Because pediatric cardiac arrests are commonly due to progressive asphyxia and/or shock, the initial treatment of choice is prompt CPR. Therefore, rhythm recognition is relatively less emphasized compared with adult cardiac arrests. The earlier that VF can be diagnosed, the more successfully we can treat it.

Post-operative Congenital Heart Disease Considerations The post-operative cardiac patient may require resuscitation due to a persistent low cardiac output state, but is also likely to experience an acute decompensation such as a respiratory event, an arrhythmia, a feed-associated vagal episode, aortopulmonary shunt occlusion, pulmonary hypertensive crisis, or a coronary event. Although the incidence of cardiac arrest is higher in children admitted to a cardiac intensive care unit (lCU) compared to those admitted to a pediatric lCU, the outcome of these patients is better - 44 % survival in the cardiac lCU versus 15- 27 % in the pediatric lCU. Likely explanations for the disparity in survival rates are that the populations' arrest etiologies, arrest interventions, and post-arrest management are inherently different.

Pediatric Cardiopulmonary Arrest and Resuscitation

131

Mechanical Circulatory Support ECMO is commonly used for circulatory support in pediatric cardiac surgical patients with refractory low cardiac output, persistent hypoxemia, arrhythmias, cardiac arrest, or failure to wean from CPB. Some centers report using ECMO to support neonates early after surgical palliation for hypoplastic left heart syndrome to avoid hypoxemia and potential cardiac arrest during the low cardiac output syndrome [15]. According to the 2004 Extracorporeal Life Support Organization registry, survival to hospital discharge was 41 %. Following a stage 1 palliation for hypoplastic left heart syndrome (2002 to 2006, n = 269), 33 patients (13 %) required CPR and of these patients 21 (63 %) were stabilized with ECMO. In particular, patients with shunted single-ventricle circulation supported with ECMO show survival to hospital discharge ranging from 39 to 64 % [62]. Perhaps the ultimate technology to control post-resuscitation temperature and hemodynamic parameters is ECMO. In addition, the concomitant administration of heparin may optimize microcirculatory flow. Reports of the use of veno-arterial ECMO to reestablish circulation and provide controlled reperfusion following cardiac arrest have been published, but prospective, controlled studies are lacking. Nevertheless, these series have reported extraordinary results with the use of ECMO as a rescue therapy for pediatric cardiac arrests, especially from potentially reversible acute post-operative myocardial dysfunction or arrhythmias [17,63-67]. In one study [64], 11 children who suffered cardiac arrest in the pediatric ICU after cardiac surgery were placed on ECMO during CPR after 20-110 minutes of CPR. Prolonged CPR was continued until ECMO cannulae, circuits, and personnel were available. Six of these 11 children were long-term survivors without apparent neurological sequelae. Most remarkably, Morris et al. [67] reported 66 children who were placed on ECMO during CPR over 7 years. The median duration of CPR prior to establishment of ECMO was 50 minutes, and 35 % (23/66) of these children survived to hospital discharge. It is important to emphasize that these children had brief periods of 'no flow', excellent CPR during the 'low flow' period, and a well-controlled post -resuscitation phase. CPR and ECMO are not curative treat ments; they are simply cardiopulmonary supportive measures that may allow tissue perfusion and viability until recovery from the precipitating disease process.

Quality of CPR and Resuscitation Interventions Despite evidence-based guidelines, extensive provider training, and provider eredentialing in resuscitation medicine, the quality of CPR is typically poor. CPR guidelines recommend target values for selected CPR parameters related to rate and depth of chest compressions and ventilations, avoidance of CPR-free intervals, and complete release of sternal pressure between compressions [68]. Slow compression rates, inadequate depth of compression, and substantial pauses are the norm. An approach to "Push Hard, Push Fast, Minimize Interruptions, Allow Full Chest Recoil and Don't Over-ventilate" can markedly improve myocardial , cerebral, and systemic perfusion, and will likely improve outcomes [69]. Recent technology has been developed that monitors quality of CPR and implements a force sensor and accelerometer into a defibrillator monitor to quantitatively provide verbal feedback to the CPR administrator on the frequency and volume of ventilations. Recent studies show that rescuers can use feedback obtained from the defibrillator electrode pads placed on the

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chest to improve compliance with these guidelines. Quality of post-resuscitative management has also been demonstrated to be critically important to improve resuscitation survival outcomes [70].

III

Special Issues in Simulation, Advanced Education, and Implementation of Programs 'Just-in-time' and 'just-in-place' training concepts were developed based on studies and recent review by experts for resuscitation training. Psychomotor skills and team function are the primary skills necessary during resuscitation; however, it is well recognized that these skills are subject to decay within six weeks after resuscitation training [71]. 'Just-in-time' and 'Just-in-place' refresher training seems reasonable to enhance operational performance and improve patient safety based on the facts that psychomotor skills decay over time. This can incorporate some of the advantages of simulation such as abilities to plan and shape training opportunities, safe environment for both patients and students, unexpected exposure to rare but complicated and important clinical events, and opportunity to repeat performance [72]. DeVita et al. evaluated the efficiency of the code team (crisis management team) training with adult high fidelity simulation manikins [73]. These authors measured the survival of the manikin in a simulated scenario and the task completion rate as outcomes in three simulated training sessions. The team performance showed improvement in overall simulation survival rate and task completion rate from 0 % to 90 %, and 31 % to 89 %, respectively. Hunt et al. successfully used simulated trauma stabilization "mock codes" to identify deficiencies in stabilization of children with trauma presenting to the hospital emergency departments [74]. Evaluation-tool inter-rater reliability was excellent, and 57 % of the stabilization tasks needed improvement (estimating a child's weight, preparing for intraosseous needle placement, ordering fluid boluses, applying warm measures, and ordering dextrose for hypoglycemia). Such simulations are likely to drive resuscitation implementation in the future .

Future Directions and Potential Obstacles Exciting new epidemiological studies, such as the NRCPR for in-hospital cardiac arrests and the large-scale, multicenter Resuscitation Outcome Consortium funded by the National Heart, Lung and Blood Institute (NHLBI), are providing new data to guide our resuscitation practices and generate hypotheses for new approaches to improve outcomes. It is increasingly clear that excellent basic life support is often not provided. Innovative technical advances, such as directive and corrective realtime feedback, can increase the likelihood of effective basic life support. In addition, team dynamic training and debriefing can substantially improve self-efficacy and operational performance. Induced hypothermia is a promising neuro-protective and cardio-protective post-arrest intervention. Mechanical interventions, such as ECMO or other CPB systems, are already commonplace interventions during prolonged inhospital cardiac arrests. Technical advances are likely to further improve our ability to provide such mechanical support. Clinical trials are necessary for appropriate evidence-based recommendations for treatment of pediatric cardiac arrests. It is likely that the evolution of systems such

Pediatric Cardiopulmonary Arrest and Resuscitation

as cardiac arrest centers, similar to trauma, stroke , and myocardial infarction centers, is likely to facilitate the administration of appropriate intensive care to patients who require specialized post-resuscitation care.

Conclusion Outcomes from pediatric cardiac arrest and CPR appear to be improving . The evolution of practice to understand the pathophysiology and timing, intensity, duration, and variability of the hypoxic-ischemic insult leads to goal directed therapy gated to the phase of cardiac arrest encountered. Exciting discoveries in basic and applied science laboratories are on the immediate horizon for study in specific sub-populations of cardia c arrest victims. By strategically focusing therapies to specific phases of cardiac arrest and resuscitation and to evolving pathophysiology, there is great promise that critical care interventions will lead the way to more successful cardiopulmonary and cerebral resuscitation in children. References I. Young KD, Seidel JS (1999) Pediatric cardiopulmonary resuscitation: a collective review. Ann Emerg Med 33:195-205 2. Donoghue AJ, Nadkarn i VM, Elliott M, Durbin D (2006) Effect of hosp ital characteristics on outcomes from pediat ric cardiopulmonary resuscitation: a report from the national registr y of card iopulmonary resuscitation. Pediatrics 118:995-1001 3. Nadkarni VM, Larkin GL, Peberdy MA, et al (2006) First documented rhythm and clinical outcome from in-hosp ital cardiac arre st among children and adults. JAMA 295:50-57 4. Berg MD, Samson RA, Meyer RJ, Clark LL, Valenzuela TD, Berg RA (2005) Pediatric defibrillation doses often fail to terminate prolonged out-of-hospital ventricular fibrillation in children . Resuscitation 67:63 - 67 5. Dieckmann RA, Vardis R (1995) High-dose epinephrine in pediatric out-of-hospital cardiopulmonary arrest . Pediatrics 95:901-913 6. Gerein RB, Osmond MH, Stiell IG, Nesbitt LP, Burns S (2006) What are the etiology and epidemiolog y of out-of-hospital pediatric cardiopulmonary arre st in Ontario, Canada? Acad Emerg Med 13:653-658 7. Kuisma M, Suominen P, Korpela R (1995) Paediatric out-of-hospital cardiac arrests - epidemiology and outcome. Resuscitation 30:141-150 8. Lopez-Herce J, Garcia C, Dominguez P, et al (2005) Outcome of out-of-hospital cardiorespiratory arrest in children . Pediatr Emerg Care 21:807 - 815 9. Schindler MB, Bohn D, Cox PN, et al (1996) Outcome of out-of-hospital cardiac or respirator y arre st in children. N Engl J Med 335:1473 -1479 10. Sirbaugh PE, Pepe PE, Shook JE, et al (1999) A prospective, population-based study of the demographics, epidemiology, management, and outcome of out-of-hospital pediatric cardiopulmonary arre st. Ann Emerg Med 33:174-184 II. Suominen P, Korpela R, Kuisma M, Silfvast T, Olkkola KT (1997) Paediatric cardiac arrest and resuscitation provided by physician-staffed emergenc y care units. Acta Anaesthesiol Scand 41:260 - 265 12. Suominen P, Rasanen J, Kivioja A (1998) Efficacy of cardiopulmonary resuscitation in pulseless paediatric trauma patients . Resuscitation 36:9-13 13. Tunstall-Pedoe H, Bailey L, Chamberlain DA, Marsden AK, Ward ME, Zideman DA (1992) Survey of 3765 cardiopulmonary resuscitations in British hosp itals (the BRESUS Study): methods and overall results. BMJ 304:1347 -1351 14. Chamnanvanakij S, Perlman JM (2000) Outcome following card iopulmonary resuscitation in the neonate requiring ventilator y assistance . Resuscitation 45:173-180 15. Hintz SR, Benitz WE, Colby CE, Sheehan AM, Rycus P, Van Meurs KP (2005) Utilization and

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outcomes of neonatal cardiac extracorporeallife support: 1996- 2000. Pediatr Crit Care Med 6:33-38 Meaney PA, Nadkarni VM, Cook EF, et al (2006) Higher survival rates among younger patients after pediatric intensive care unit cardiac arrests. Pediatrics 118:2424-2433 Parra DA, Totapally BR, Zahn E, et al (2000) Outcome of cardiopulmonary resuscitation in a pediatric cardiac intensive care unit . Crit Care Med 28:3296-3300 Reis AG, Nadkarni V, Perondi MB, Grisi S, Berg RA (2002) A prospective investigation into the epidemiology of in-hospital pediatric cardiopulmonary resuscitation using the international Utstein reporting style. Pediatrics 109:200 - 209 Samson RA, Nadkarni VM, Meaney PA, Carey SM, Berg MD, Berg RA (2006) Outcomes of inhospital ventricular fibrillation in children. N Engl J Med 354:2328 -2339 Sionim AD, Patel KM, Ruttimann UE, Pollack MM (1997) Cardiopulmonary resuscitation in pediatric intensive care units. Crit Care Med 25:1951-1955 Suominen P, Olkkola KT, Voipio V, Korpela R, Palo R, Rasanen J (2000) Utstein style reporting of in-hospital paediatric cardiopulmonary resuscitation. Resuscitation 45:17- 25 Torres A [r, Pickert CB, Firestone J, Walker WM, Fiser DH (1997) Long-term functional outcome of inpatient pediatric cardiopulmonary resuscitation. Pediatr Emerg Care 13:369-373 Zaritsky A, Nadkarni V, Getson P, Kuehl K (1987) CPR in children. Ann Emerg Med 16:1107-1111 Parad is NA, Martin GB, Rivers EP, et al (1990) Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 263:1106-1113 Lurie K, Zielinski T, McKnite S, Sukhum P (2000) Improving the efficiency of cardiopulmonary resuscitation with an inspiratory impedance threshold valve. Crit Care Med 28 (11 suppl) :N207- 209 Lurie KG, Coffeen P, Shultz J, McKnite S, Detloff B, Mulligan K (1995) Improv ing active compression-decompression cardiopulmonary resuscitation with an inspiratory impedance valve. Circulation 91:1629-1632 Yannopoulos D, Aufderheide TP, Gabrielli A, et al (2006) Clinical and hemodynamic compar ison of 15:2 and 30:2 compression-to-ventilation ratios for cardiopulmonary resuscitat ion. Crit Care Med 34:1444- 1449 Brilli RJ, Gibson R, Luria JW, et al (2007) Implementation of a medical emergency team in a large pediatric teaching hospital prevents respiratory and cardiopulmonary arrests outside the intensive care unit. Pediatr Crit Care Med 8:236-246 Tibballs J, Kinney S (2004) A prospective before-and-after trial of a medical emergency team. Med J Aust 180:308 Laurent I, Monchi M, Chiche JD, et al (2002) Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coli Cardiol 40:2110-2116 Hallstrom AP, Cobb LA, Johnson E, Copass MK (2003) Dispatcher assisted CPR: implementation and potential benefit. A 12-year study. Resuscitation 57:123-129 Berg RA, Hilwig RW, Kern KB, Ewy GA (2000) "Bystander" chest compressions and assisted ventilation independently improve outcome from piglet asphyxial pulseless "cardiac arrest". Circulation 101:1743-1748 Idris AH, Staples ED, O'Brien DJ, et al (1994) Effect of ventilation on acid-base balance and oxygenation in low blood- flow states. Crit Care Med 22:1827-1834 Kinney SB, Tibballs J (2000) An analysis of the efficacy of bag-valve-mask ventilation and chest compression during different compression-ventilation ratios in manik in-simulated paediatric resuscitation. Resuscitation 43:115-120 Srikantan SK, Berg RA, Cox T, Tice L, Nadkarni VM (2005) Effect of one-rescuer compres sion/ventilation ratios on cardiopulmonary resuscitation in infant, pediatric, and adult mani kins. Pediatr Crit Care Med 6:293- 297 Brown CG, Martin DR, Pepe PE, et al (1992) A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med 327:1051-1055 Lindner KH, Ahnefeld FW, Bowdler 1M (1991) Comparison of different doses of epinephrine on myocardial perfusion and resuscitation success during cardiopulmonary resuscitation in a pig model. Am J Emerg Med 9:27-31 Callaham M, Madsen C, Barton C, Saunders C, Daley M, Pointer J (1992) A randomized clini-

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39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61.

cal trial of high-dose epinephrine and norepinephrine versus standard-dose epinephrine in prehospital cardiac arrest. JAMA 268:2667- 2672 Behringer W, Kittler H, Sterz F, et al (1998) Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med 129:450-456 Perondi MB, Reis AG, Paiva EF, Nadkarni VM, Berg RA (2004) A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest . N Engl J Med 350:1722-1730 Hypothermia After Cardiac Arrest Study Group (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest . N Engl J Med 346:549- 556 Bernard SA, Gray TW, Buist MD, et al (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557- 563 Hickey RW, Kochanek PM, Ferimer H, Graham SH, Safar P (2000) Hypothermia and hyperthermia in children after resuscitation from cardiac arrest. Pediatrics 106:118-122 Gluckman PD, Wyatt JS, Azzopardi D, et al (2005) Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365: 663-670 Shankaran S, Laptook A, Wright LL, et al (2002) Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics 110:377- 385 Hoffman TM, Wernovsky G, Atz AM, et al (2003) Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 107:996 -1002 Innes PA, Frazer RS, Booker PD, et al (1994) Comparison of the haemodynamic effects of dobutamine with enoximone after open heart surgery in small children. Br J Anaesth 72: 77-81 Laitinen P, Happonen JM, Sairanen H, Peltola K, Rautiainen P (1999) Amrinone versus dopamine and nitroglycerin in neonates after arterial switch operation for transposition of the great arteries . J Cardiothorac Vase Anesth 13:186-190 Laitinen P, Happonen JM, Sairanen H, et al (1997) Amrinone versus dopamine -nitroglycer in after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vase Anesth 11:870-874 Abdallah I, Shawky H (2003) A randomised controlled trial comparing milrinone and epinephrine as inotropes in paediatric patients undergoing total correction of Tetralogy of Fallot. Egyptian Journal of Anaesthesia 19:323-329 Ceneviva G, Paschall JA, Maffei F, Carcillo JA (1998) Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics 102:e19 Langhelle A, Tyvold SS, Lexow K, Hapnes SA, Sunde K, Steen PA (2003) In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway. Resuscitation 56:247- 263 Berger PB (2005) A glucose-insulin-potassium infusion did not reduce mortality, cardiac arrest, or cardiogenic shock after acute MI. ACP J Club 143:4-5 Nishisaki A, Sullivan J 3rd, Steger B, et al (2007) Retrospective analysis of the prognostic value of electroencephalography patterns obtained in pediatric in-hospital cardiac arrest survivors during three years. Pediatr Crit Care Med 8:10-1 7 Schellhammer F, Heindel W, Haupt WF, Landwehr P, Lackner K (1998) Somatosensory evoked potentials : a simple neurophysiological monitoring technique in supra-aortal balloon test occlusions. Eur Radiol 8:1586-1589 Piazza 0, Cotena S, Esposito G, De Robertis E, Tufano R (2005) S100B is a sensitive but not specific prognostic index in comatose patients after cardiac arrest. Minerva Chir 60:477 - 480 Smith BT, Rea TD, Eisenberg MS (2006) Ventricular fibrillation in pediatric cardiac arrest. Acad Emerg Med 13:525- 529 Appleton GO, Cummins RO, Larson MP, Graves JR (1995) CPR and the single rescuer: at what age should you "call first" rather than "call fast"? Ann Emerg Med 25:492-494 GrafWD, Cummings P, Quan L, Brutocao D (1995) Predicting outcome in pediatric submer sion victims. Ann Emerg Med 26:312-319 Caffrey SL, Willoughby PJ, Pepe PE, Becker LB (2002) Public use of automated external defibrillators . N Engl J Med 347:1242-1247 Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG (2000) Outcomes of

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62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75.

rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 343: 1206-1209 Thiagarajan RR, Laussen PC, Rycus PT, Bartlett RH, Bratton SL (2007) Extracorporeal membrane oxygenation to aid cardiopulmonary resuscitation in infants and children. Circulation 116:1693-1700 Dalton HJ, Siewers RD, Fuhrman BP, et al (1993) Extracorporeal membrane oxygenation for cardiac rescue in children with severe myocardial dysfunction. Crit Care Med 21:1020-1028 del Nido PJ, Dalton HJ, Thompson AE, Siewers RD (1992) Extracorporeal membrane oxygenator rescue in children during cardiac arrest after cardiac surgery. Circulation 86 (suppl): 1I300-1I304 Tecklenburg FW,Thomas NJ, Webb SA, Case C, Habib DM (1997) Pediatric ECMO for severe quinidine cardiotoxicity. Pediatr Emerg Care 13:111-113 Thalmann M, Trampitsch E, Haberfellner N, Eisendle E, Kraschl R, Kobinia G (200!) Resuscitation in near drowning with extracorporeal membrane oxygenation. Ann Thorac Surg 72: 607-608 Morris MC, Wernovsky G, Nadkarni VM (2004) Survival outcomes after extracorporeal cardiopulmonary resuscitation instituted during active chest compressions following refractory in-hospital pediatric cardiac arrest. Pediatr Crit Care Med 5:440-446 Abella BS, Alvarado JP, Myklebust H, et al (2005) Quality of cardiopulmonary resuscitation during in-hospital cardiac arrest. JAMA 293:305-310 Edelson DP,Abella BS, Kramer-Johansen J, etal (2006) Effects of compression depth and preshock pauses predict defibrillation failure during cardiac arrest. Resuscitation 71:137- 145 Sunde K, Pytte M, Jacobsen D, et al (2007) Implementation of a standardised treatment pro tocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 73:29-39 Stross JK (1983) Maintaining competency in advanced cardiac life support skills. JAMA 249:3339- 3341 Grenvik A, Schaefer JJ 3rd, DeVita MA, Rogers P (2004) New aspects on critical care medicine training. Curr Opin Crit Care 10:233-237 DeVita MA, Schaefer J, Lutz J, Dongilli T, Wang H (2004) Improving medical crisis team performance. Crit Care Med 32 (suppl):S61- 65 Hunt EA, Hohenhaus SM, Luo X, Frush KS (2006) Simulation of pediatric trauma stabilization in 35 North Carolina emergency departments: identification of targets for performance improvement. Pediatrics 117:641- 648 Donoghue AJ, Nadkarni V, Berg RA, et al (2005) Out-of-hospital pediatric cardiac arrest : an epidemiologic review and assessment of current knowledge. Ann Emerg Med 46:512-522

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Early Cooling in Cardiac Arrest: What is the Evidence? L. HAMMER, C.

ADRIE,

and

J.-F.

TIMSIT

Introduction Cardiac arrest is a major cause of unexpected death in developed countries, with surv ival rates ranging from less than 5 % to 35 % [1, 2]. In patients who are initially resuscitated, anoxic neurological injury is an important cause of morbidity and mortality [3]. For successful resuscitation, rapid return to spontaneous circulation is mandatory, but overcoming post-resuscitation tissue injury is necessary as well [4, 5]. Various treatment strategies have been used to attenuate ischemic-related patho physiological damage and behavioral deficits. Prolonged therapeutic hypothermia is the only post-resuscitation therapy clinically demonstrated to improve the outcome of cardiac arrest survivors [6-9] . Therapeutic hypothermia is recommended by the International Liaison Committee on Resuscitation (1LCOR) [8]. The ideal therapeutic time window for the application of therapeutic hypothermia is not known. It is generally believed that the earlier the hypothermia is initiated, the more effective it is likely to be. The purpose of this chapter is to review the physiological rationale for early cooling, the results of available clinical trials in the field, and the main practical approaches available to perform cooling in emergency.

Pathophysiology The extent of anoxic brain damage is related mainly to the duration of ischemia. Several studies have shown that hypothermia by itself may have an organ-protective effect in various pathologic inflammatory situations such as acute hemorrhage [10] or cardiopulmonary bypass (CPB) [11]. Hypothermia may also delay the induction of pro-inflammatory cytokines [12] and attenuate the rise of the anti-inflammatory interleukin (1L)-10 [10]. Many experimental studies suggest that an earlier induction of hypothermia may more efficiently blunt the inflammatory response observed during the post-resuscitation phase related to whole-body ischemia-reperfusion syndrome [13, 14]. However, apoptosis and the excitotoxic cascade take place over a period of up to 48 h, which may (partly) explain Why hypothermia can be neuroprotective even if initiated some time after injury [15]. The length of this therapeutic window will depend on which destructive mechanisms are activated and on the relative contribution of these mechani sms (neuroexcitotoxic cascade activation, reperfusion, inflammation, apoptosis, etc.) to the overall injury [16].

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"Is sooner better"? Animal studies and some clinical data strongly suggest that the protective effects of hypothermia may increase significantly when the treatment is initiated in the very early stages after the occurrence of injury [17- 23]. In a dog model of cardiac arrest, delays in cooling as little as 15 min after reperfusion, negated the beneficial effect of mild hypothermia [17]. Cooling in a mouse model of cardiac arrest is highly protective against cardiac and neurological injury when induced during ischemia (i.e., during cardiac arrest) and maintained for 1 h after reperfusion (i.e., return of spontaneous circulation). Delaying hypothermia even by several minutes into reperfusion after cardiac arrest abrogates protection [18]. In a rat model of cardiac arrest, Takata et al. demonstrated that excessive glutamate release was prevented or mitigated if hypothermia was initiated before cardiac arrest or at the onset of resuscitation but not in larger stages. The authors observed also that histological injuries were significantly decreased by hypothermia if this was initiated before injury (94 % reduction), at the onset of resuscitation (65 % reduction), or immediately after direct-current recovery (± 5 mins after start of resuscitation, 29 % reduction) [19]. In a dog model of ventricular fibrillation (VF) cardiac arrest, Nozari et al. demonstrated that early induction of mild hypothermia (during cardiopulmonary resuscitation [CPR]) preserved the organism, enabling intact survival after up to 60 minutes of VE A 20-min versus 10-min delay in cooling negates the beneficial effects of hypothermia [20]. In a rat model of cerebral ischemia, delays in achieving target temperature of 15 min and 30 min preserved the beneficial effect of hypothermia, but with delays of 45 min there was no attenuation of infarct volume [21]. Using the same model, Colbourne and Corbett showed that hypothermia (32 DC), when initiated 4 h after ischemia, rescued 12 % of hippocampal CAl neurons while mild hypothermia (34 DC) initiated 1 h after ischemia saved 60 % of CAl neurons [22]. In a model of ischemic myocytes, Shao et al. showed that myocyte injury was decreased when hypothermia was initiated early before reperfusion, even if the duration of ischemia was extended [23]. These observations tend to show that the therapeutic time window for the application of therapeutic hypothermia, at least for very brief periods (4 h), is very short. The theoretical advantages of cooling before or just after return of spontaneous circulation may include decreasing reperfusion-related injury. However, longer durations of hypothermia (> 24 h) have been subsequently shown to reduce post-ischemic neuronal death even when its application was delayed for prolonged periods of time, up to 8 h in one clinical study [7, 24-26]. Indeed, despite a relatively late and slow surface cooling technique (8 h to achieve target temperature), this clinical trial performed in Europe documented neurological benefits with prolonged mild hypothermia (24 h) in survivors of out-of-hospital cardiac arrest [7]. In a neonatal rat model of cerebral ischemia, Wagner et al. demonstrated that prolonged hypothermia (26 h), even when started 2 h after the hypoxic-ischemic insult, significantly reduced the final size of cerebral infarction by 23 % at 6 weeks after the injury and improved long-lasting behavioral outcome [24]. In another rat model of asphyxial cardiac arrest, Hicks et al. showed that immediate or delayed induction (60 min) of prolonged hypothermia (24 h) were equally effective for improving functional recovery after the onset; mortality was increased in normothermic rats (33 %) compared to hypothermic rats (0 %) [25]. In an in vitro model of simulated global brain ischemia, the neuroprotective effect of prolonged post-ischemic hypothermia was both optimal and equivalent when initiated between 1 and 8 h after reoxygenation [26]. These results suggest the need for further in vivo

Early Cooling in Cardiac Arrest: What is the Evidence?

studies to define the therapeutic window within which prolonged hypothermia is optimally neuroprotective after cardiac arrest. All these experimental data suggest that therapeutic hypothermia should be instituted during CPR. When hypothermia is begun after return of spontaneous circulation, it should be given for a longer period of time.

Human Data about Pre-hospital Hypothermia Evidence and Safety Because experimental studies have shown that delays in cooling negate the beneficial effect of mild hypothermia [17- 23], some have suggested that hypothermia should be initiated as soon as possible after resuscitation or, preferably, during CPR attempts [18-20,27]. Early hypothermia does not seem to be deleterious. Indeed, no human studies have shown significant adverse effects if cooling is started during acute myocardial infarction or cardiac arrest [28-31]. In a recent study in patients with acute myocardial infarction, Ly et al. reported no hemodynamic instability or arrhythmias when hypothermia was induced before reperfusion therapy [29]. Several studies have demonstrated that lowering myocardial temperature reduces metabolic demand and may cause a profound reduction in infarct size [28, 30]. Another study has also shown that hypothermia improves defibrillation success in a swine model of VF cardiac arrest [31]. When therapeutic hypothermia is induced with rapid infusion of a large volume of ice cold fluid (30-40 mllkg), volume overload is not associated with adverse effects; indeed, in studies with this cooling protocol, no patients developed pulmonary edema [32-34]. In another study, Polderman et al. demonstrated that only few patients (6 %) required a moderate increase in positive end-expiratory pressure (PEEP) levels, which indicated a very low rate of pulmonary edema [35]. In a pilot, randomized clinical trial of pre-hospital induction of mild hypothermia with a rapid infusion of cold normal saline, Kim et al. suggested that the rate of pulmonary edema was not significantly different between the cooling group and the control group [36]. We also conducted a pilot study in which we retrospectively evaluated the efficacy and safety of an immediate pre-hospital cooling procedure implemented just after the return of spontaneous circulation by infusion of large volume ice-cold saline. Ninety-nine patients were studied. Rapid infusion of fluid was not associated with evidence of pulmonary edema (23 % in the cooling group vs. 14 % in the control group, p = 0.34) [37].

Efficacy To date there are no data confirming the potential benefit of immediate cooling in cardiac arrest. A randomized controlled trial assessing long term survival after prehospital induction of hypothermia with cold intravenous fluid is about to start (www.Clinicaltrials.gov identifier NCT00391469). Few data are available regarding the safety and effectiveness of hypothermia in a prehospital setting. The first clinical study was performed by Virkunnen et al. in 2004 [38]. This study was a pilot study in which hypothermia was induced, just after return of spontaneous circulation, with 30 mllkg ice-cold Ringer's solution in 13 prehospital cardiac arrest patients. The results suggested that induction of therapeutic hypothermia very early after return of spontaneous circulation was feasible. The

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mean infused volume was 2188 ± 754 ml and the treatment decreased core temperature by 1.9°C. This study was a small clinical trial (n = 13) without detailed assessment of metabolic side effects [38]. A more recent study was performed by Kim et al. in 125 randomized pre-hospital cardiac arrest patients treated by paramedics [36]. The patients were randomized to receive either standard care alone or with induction of mild hypothermia using a rapid infusion of 2 1of 4 °C normal saline as soon as possible after return of spontaneous circulation. This treatment decreased core temperature by 1.2 "C, In this study, there was no difference in the overall survival rate between the early cooling and the control groups (33 % vs. 29 %, P = 0.75). However, there was a trend toward improved survival rate to discharge in the group with early field cooling when the initial rhythm was VF (66 % vs. 45 %, P = 0.15). Most patients randomized in the cooling group (51/63, 81 %) did not receive the intended volume, the infusion being stopped at the discretion of emergency department personnel by the time of hospital arrival. Only 12 patients (19 %) received the full 2 1of cold fluids with a mean temperature decrease approaching 1.6- 1.7 "C, The rate of pulmonary edema was not significantly different between the two groups, but was much higher than rates observed in previous studies (50 %) [32-37] . In our study, the median core temperature decrease was 1.3°C at 70 minutes [37].

Methods of Cooling In routine practice, many methods should be used in order to rapidly decrease body temperature. Cooling during the post-resuscitative period is a very difficult task ( Table 1). Average or median times to achieve cooling to 33°C range between 2 to 8 h after cardiac arrest in most trials [6, 7, 33, 39-46]. Various cooling techniques have been used, either external, such as ice bags [6, 39, 44, 45] or cooling blankets [7,40,41], or internal, such as specialized central venous catheters [42,44], intravenous infusion of cooled fluids [32-36, 38], or extracorporeal veno-venous cooling techniques [43, 47]. The external surface cooling methods (ice-packs, cooling blankets or mattresses) that have been used so far in clinical trials after cardiac arrest have been associated with very slow cooling rates, ranging from 0.3 to 1.5°C/h. [6,7,44,48] . Other devices for surface cooling with cold metal have been shown to be effective for rapid induction of mild hypothermia in adult human-sized swine during spontaneous circulation, without signs of skin damage [49]. These methods (ice-pack, cold metal), independent of energy supply during use, could be initiated in the out-of-hospital setting. The advantages of using an infusion of cold fluid include the low technical requirement and the rapidity of temperature decrease. Five feasibility trials have investigated the efficacy and safety of large volume infusion of cold fluids in more than 200 adult cardiac arrest survivors. These studies reported cooling rates between 1.1 °C and 2 °C within the first 30 min with no clinically relevant adverse effects of the infusion, especially no pulmonary edema, even in patients with cardiac shock [32,33,35,36,38] . Independence from energy supply during use represents another advantage, making this method particularly suitable for emergency use outside the hospital. This technique of induction of hypothermia could possibly be applied during CPR [50]. However, infusion of cold fluid is not enough to maintain mild therapeutic hypothermia, even with repeated administrations of cold fluids - an additional cooling method is necessary [32, 34]. Recent new devices for surface cooling including water-circulating adhesive pads have been shown to lower patient temperature at a median cooling rate of 1.2 °C/h

Early Cooling in Cardiac Arrest: What is the Evidence? Table 1. Cooling rates for the main invasive and non-invasive cooling techniques. Study

External

Zeiner, 2000 [41 ] Feldberg, 2001 [40] HACA, 2002 [7] Bernard, 2002 [6] Oddo, 2006 [39] Haugk, 2007 [46] Arrich, 2007 [44] Belliard, 2007 [45]

Number of patients (cooling method)

27 (cooling blanket and mattress) 9 (cooling blanket) 123 (cooling blanket and mattress) 43 (pre-hospital, ice packs) 55 (ice pack, cooling mattress) 27 (adhesive hydrogel-coated cooling pads) 92 (cold fluids, ice packs, surface cooling) 32 (ice packs)

Rapid infusion ice cold fluid

Bernard, 2003 [33] Virkkunen, 2004 [38] Kim, 2005 [32] Kliegel, 2007 [34] Kim, 2007 [36]

Endovascular device

AI-Senani, 2004 [42] Arrich, 2007 [44]

0.9 1.2 1.3

22 13 (pre-hospital) 17 (± paralysis) 20 (± endovascular cooling) 125 (pre-hospital)

1.7 1.9 2 2 1.2

13 326

0.8 1.1

High-volume hemofiltration

Laurent, 2005 [43]

Cooling rate ("C/h)

22

Delay to reach the target temperature (from collapse to target temperature - minutes) 297 391 500 145 > 300 284 181 572 130

235

< 240

in cardiac arrest survivors [46]. More invasive techniques include endovascular cooling devices or extracorporeal veno-venous cooling with a heat exchanger delivering cooling rates from 0.9 °C/h to 3.5 °C/h [28,42-44,47]. These techniques, dependent on an energy supply, exclude the use of invasive cooling methods early after successful resuscitation outside the hospital. Whatever the technique used, it should be remembered that associated paralysis is mandatory. Kim et al. reported that some patients who did not receive neuromuscular blockade for maintenance cooling had a rapid rise in temperature after a successful induction. [32].

Conclusion On the basis of the published evidence, the ILCOR has made the recommendation that unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32-34 °C for 12 to 24 h when the initial rhythm was VE Such cooling may also be beneficial for other rhythms or in-hospital arrest . Cooling should probably be initiated as soon as possible after return of spontaneous circulation but appears to be successful even if delayed [8]. Perhaps even greater benefits could be achieved, or required cooling periods reduced, if cooling were initiated in the very early stages after cardiac arrest in a pre-hospital setting. Clinical studies are required to determine the optimal window of hypothermia therapy at later times.

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L. Hammer, C. Adrie, and J.-F. Timsit References 1. Eisenberg MS, Horwood BT, Cummins RO, Reynolds-Haertle R, Hearne TR (1990) Cardiac arrest and resuscitation: a tale of 29 cities. Ann Emerg Med 19:179-186 2. Bernard S (1998) Outcome from prehospital cardiac arrest in Melbourne, Australia. Emerg Med 10:25- 29 3. Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P (1994) Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT 1 Study Group. Lancet 343:10551059 4. Cummins RO, Ornato JP, Thies WH, Pepe PE (1991) Improving survival from sudden cardiac arrest: the "chain of survival" concept. A statement for health professionals from the Advanced Cardiac Life Support Subcommittee and the Emergency Cardiac Care Committee, American Heart Association. Circulation 83:1832-1847 5. Safar P (1988) Resuscitation from clinical death : pathophys iologic limits and therapeutic potentials. Crit Care Med 16:923-941 6. Bernard SA, Gray TW, Buist MD, et al (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557- 563 7. Group HACAS (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arr est. N Engl J Med 346:549- 556 8. Nolan JP, Morley PT, Hoek TL, Hickey RW (2003) Therapeutic hypothe rmia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation. Resuscitation 57:231- 235 9. Holzer M, Bernard SA, Hachimi-Idrissi S, Roine RO, Sterz F, Mullner M (2005) Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data metaanalysis. Crit Care Med 33:414-418 10. Gundersen Y, Vaagenes P, Pharo A, Valo ET, Opstad PK (200l) Moderate hypothermia blunts the inflammatory response and reduces organ injury after acute haemorrhage. Acta Anaesthesiol Scand 45:994-1001 11. Vazquez-jimenez JF, Qing M, Hermanns B, et al (2001) Moderate hypothermia during cardiopulmonary bypass reduces myocardial cell damage and myocardial cell death related to cardiac surgery. J Am Coli Cardiol 38:1216-1223 12. Kimura A, Sakurada S, Ohkuni H, Todome Y, Kurata K (2002) Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit Care Med 30:1499-1502 13. Adrie C, Adib-Conquy M, Laurent I, et al (2002) Successful cardiopulmonary resuscitation after cardiac arrest as a "sepsis-like" syndrome. Circulation 106:562- 568 14. Negovsky VA, Gurvitch AM (1995) Post-resuscitation disease - a new nosological entity. Its reality and significance. Resuscitation 30:23- 27 15. Ning XH, Chen SH, Xu CS, et al (2002) Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis. J Appl Physiol 92:22002207 16. Polderman KH (2004) Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence. Intensive Care Med 30:556-575 17. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H (1993) Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 21:1348-1358 18. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB (2004) Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation 109:2786-2791 19. Takata K, Takeda Y, Sato T, Nakatsuka H, Yokoyama M, Morita K (2005) Effects of hypothermia for a short period on histologic outcome and extracellular glutamate concentration during and after cardiac arrest in rats. Crit Care Med 33:1340-1345 20. Nozari A, Safar P, Stezoski SW,et al (2006) Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation 113:26902696 21. Markarian GZ, Lee JH, Stein DJ, Hong SC (1996) Mild hypothermia: therapeutic window after experimental cerebral ischemia. Neurosurgery 38:542-550

Early Cooling in Cardiac Arrest: What is the Evidence? 22. Colbourne F, Corbett D (1995) Delayed post ischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci IS: 7250-7260 23. Shao ZH, Chang WT, Chan KC, et al (2007) Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling. Am J Physiol 292:HI995-2003 24. Wagner BP, Nedelcu J, Martin E (2002) Delayed postischemic hypothermia improves longterm behavioral outcome after cerebral hypoxia-ischemia in neonatal rats. Pediatr Res 51: 354-360 25. Hicks SD, DeFranco DB, Callaway CW (2000) Hypothermia during reperfusion after asphyxial cardiac arrest improves functional recovery and selectively alters stress-induced protein expression. J Cereb Blood Flow Metab 20:520-530 26. Lawrence EJ, Dentcheva E, Curtis KM, Roberts VL, Siman R, Neumar RW (2005) Neuroprotection with delayed initiation of prolonged hypothermia after in vitro transient global brain ischemia. Resuscitation 64:383- 388 27. Safar P, Xiao F, Radovsky A, et al (1996) Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 27:105- 113 28. Dixon SR, Whitbourn RJ, Dae MW, et al (2002) Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am CoIl Cardiol 40:1928-1934 29. Ly HQ, Denault A, Dupuis J, et al (2005) A pilot study : the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 150:933.e9-e13 30. Hale SL, Kloner RA (1997) Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia. Am J Physiol 273:H220-227 31. Boddicker KA, Zhang Y, Zimmerman MB, Davies LR, Kerber RE (2005) Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation 111:3195-3201 32. Kim F, Olsufka M, Carlbom D, et al (2005) Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest. Circulation 112:715-719 33. Bernard S, Buist M, Monteiro 0, Smith K (2003) Induced hypothermia using large volume, ice-cold intravenous fluid in comatose surv ivors of out-of-hospital cardiac arrest : a preliminary report. Resuscitation 56:9- 13 34. Kliegel A, [anata A, Wandaller C, et al (2007) Cold infusions alone are effective for induction of therapeutic hypothermia but do not keep patients cool after cardiac arrest. Resuscitation 73:46-53 35. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR (2005) Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med 33:2744-2751 36. Kim F, Olsufka M, Longstreth WT, et al (2007) Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 115:3064-3070 37. Hammer L, Savary D, Debaty G, et al (2007) Immediate pre-hospital hypothermia protocol in comatose survivors of out-of-hospital cardiac arrest : a preliminary report. Intensive Care Med 33:S105 (abst) 38. Virkkunen I, Yli-Hankala A, Silfvast T (2004) Induction of therapeutic hypothermia after cardiac arrest in prehospital patients using ice-cold Ringer's solution : a pilot study. Resuscitation 62:299- 302 39. Oddo M, Schaller MD, Feihl F, Ribordy V, Liaudet L (2006) From evidence to clinical pract ice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 34:1865-1873 40. Felberg RA, Krieger DW, Chuang R, at al (2001) Hypothermia after cardiac arrest : feasibility and safety of an external cooling protocol. Circulation 104:1799-1804 41. Zeiner A, Holzer M, Sterz F,et al (2000) Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group. Stroke 31:86-94 42. Al-Senani FM, Graffagnino C, Grotta JC, et al (2004) A prospective, multicenter pilot study to

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43. 44. 45. 46. 47. 48. 49. 50.

evaluate the feasibility and safety of using the CoolGard System and Icy catheter following cardiac arrest. Resuscitation 62:143-150 Laurent I, Adrie C, Vinsonneau C, et al (2005) High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study. J Am Coli CardioI46:432-437 Arrich J (2007) Clinical application of mild therapeutic hypothermia after cardiac arrest. Crit Care Med 35:1041-1047 Belliard G, Catez E, Charron C, et al (2007) Efficacy of therapeutic hypothermia after out-ofhospital cardiac arrest due to ventricular fibrillation . Resuscitation 75:252 - 259 Haugk M, Sterz F, Grassberger M, et al (2007) Feasibility and efficacy of a new non -invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation 75:76- 81 Holzer M, Behringer W, [anata A, et al (2005) Extracorporeal venovenous cooling for induction of mild hypothermia in human-sized swine. Crit Care Med 33:1346-1350 Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L (2001) Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 51:275-281 Bayegan K, [anata A, Frossard M, et al (2007) Rapid non-invasive external cooling to induce mild therapeutic hypothermia in adult human-sized swine. Resuscitation [Epub ahead of print] Bernard SA, Rosalion A (2007) Therapeutic hypothermia induced during cardiopulmonary resuscitation using large-volume, ice-cold intravenous fluid. Resuscitation [Epub ahead of print]

Section IV

IV Emergencies

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Management of Severe Accidental Hypothermia G.]. PEEK, P.R. DAVIS, and ].A. ELLERTON

Introduction Doctors working in intensive care, emergency medicine, pre-hospital care, cardiac surgery and ECMO (extracorporeal membrane oxygenation) programs may be called upon to assist in the management of victims of severe environmental hypothermia. We focus on the triage of hypothermic patients who would potentially benefit from transfer to a tertiary centre. Often decisions made at the scene can result in a patient being transferred long distances to a ho spital that does not have the ideal facilities to cope with such a severely hypothermic patient. The International Commission for Alpine Rescue (http://www.ikar-cisa.org), International Society for Mountain Medicine (http:www.ismmed.org), and the Union Internationale des Associations d'Alpinisme medical committee (International Mountaineering and Climb ing Federation; http://www.uiaa.ch) have been instrumental in gathering data and publishing guidance for the pre-hospital triage and management of victims of deep hypothermia in the mountains [1]. The principles guiding the resuscitation of victims of accidental hypothermia in the maritime or mountain environment may be applied to everyday emergency practice, even in an urban setting [2].

Definitions Hypothermia is defined as a body core temperature (Teo) below 35°C. It is classified as mild (Teo 35-32 °C), moderate (Teo 32-30 °C) or severe (Teo < 30°C).

Pathophysiology Hypothermia commonly results from an injury in a cold environment, immersion in cold water or a prolonged exposure to low temperatures. Muscular activity and the catabolic processes of the body produce heat; heat is lost by radiation, convection, conduction, and evaporation (vaporization), particularly of water vapor from the skin and lungs. Thermoregulation is a balance between heat production and heat loss, allowing enzyme systems to operate optimally within a narrow temperature range. In mild hypothermia, thermoregulatory mechanisms operate fully in an attempt to combat the situation. If the condition is unchecked however, the thermoregulatory system diminishes until it fails, leading to death from cardiorespiratory failure . Hypothermia causes characteristic changes (the Osborn J wave) in the electrocardiograph (EKG) and severe hypothermia can cause life-threatening dysrhythmias, or

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asystole. The typical sequence is a progression from sinus bradycardia through atrial fibrillation (AF) to ventricular fibrillation (VF) and ultimately asystole. Rough patient handling or sudden changes in posture may provoke VF at any time in the severely hypothermic pat ient. Initial tachypnea is replaced by a decrease in respiratory rate and tidal volume, and bronchorrhea predisposes to aspiration pneumonia. The oxyhemoglobin dissociation curve undergoes a leftwards shift impairing tissue oxygen delivery. The central nervous system is progressively depressed with a corresponding decrease in conscious level. Mild incoordination progresses through agitation and irritation to lethargy, and eventually coma. In hypothermia, the decreased cerebral oxygen requirements may protect the brain against anoxic or ischemic damage after cardiac arrest [3]. Cold diuresis occurs due to impaired renal concentration and an increased central intravascular volume due to peripheral vasoconstriction. Volume losses may be such that significant fluid resuscitation is required whilst managing the recovering victim. Adrenoceptors become dysfunctional in severe hypothermia, so vasoactive drugs (e.g., epinephrine) are ineffective and may accumulate to toxic thresholds, then exerting their toxic effects upon rewarming and reperfusion [4]. There is a plasma shift to the extravascular space, and the consequent hemoconcentration may lead to disseminated intravascular coagulation (Die). Reversible platelet dysfunction occurs and the clotting time is prolonged due to derangement of the extrinsic pathway [5, 6]. The immobile hypothermic pat ient is prone to rhabdomyolysis and acute tubular necrosis may occur through myoglobinuria and renal hypoperfusion. In the initial stages, increased insulin secretion and glycogenolysis mobilizes glucose reserves, but hypoglycemia supervenes as reserves are used up. Acidosis occurs due to respiratory depression and hypercarbia, and lactic acid production through shivering and poor tissue perfusion. Hepatic function is depressed leading to accumulation of drugs that normally undergo hepatic metabolism or detoxification. Finally, the extremities are vulnerable to frostbite as a result of the peripheral vasoconstriction, hypoperfusion, and hemoconcentration leading to 'sludging' of the red cells within the small blood vessels.

Consequences of Hypothermia in Trauma Patients From the late 1980s, the 'lethal triad' of hypothermia, acidosis, and coagulopathy has been identified as a major cause of morbidity and mortality in the critically injured patient. Patients are more likely to die in the intensive care unit (lCU) from persistent acidosis and uncorrected coagulopathy, rather than in the operating room (OR) from failure to definitively repair a bowel injury, or to achieve intermedullary fixation of a comminuted long bone fracture. Even in urban settings when transport times are less than fifteen minutes more than 50 % of patients with penetrating injury are hypothermic upon admission to the emergency room [7]. Compared to the normothermic, mortality of hypothermic patients increases by as much as 50 % in case matched trauma studies [8]. Also at especially high risk for hypothermia are the very young and very old, patients with burns, the head injured patient (the thermostat mechanisms in the hypothalamus may be deranged) and the patient with a high spinal injury causing disruption to the sympathetic chain. These patients become poikilothermic. Prevention of further heat loss and rewarming (where appropriate) are, therefore, essential components of good trauma care [9].

Management of Severe Accidental Hypothermia

Etiological Classification of Hypothermia Acute Hypothermia Severe cold stress overwhelms thermogenesis and rapid cooling ensues, but before the energy reserves are used and the intravascular fluid changes occur. This kind of hypothermia occurs for instance in the avalanche victim or during cold water immersion. Here, the cold shock response occurs in the first 3 to 4 minutes. This initiates peripheral vasoconstriction, the gasp reflex, hyperventilation and tachycardia, and may lead to submersion and drowning , or cause vagal arrest of the heart. In survivors of the cold shock, hypothermia may take up to 30 minutes to develop [10]. Survival time prediction is based on the interrelationship between the thermoregulatory response, clothing and insulation, sea temperature and sea conditions [11].

Sub-acute Hypothermia This could affect a climber isolated in the mountains. There is slow but continuous heat loss and the energy reserves become gradually depleted. The rate of onset is related to the patient's physical and mental condition, his/her equipment and the severity of the environmental conditions. Complex fluid shifts occur between the various body compartments, leading to hypovolemia, and necessitating fluid resuscitation during rewarming.

Sub-chronic Hypothermia The classic example is of the elderly patient, immobilized through a fractured neck of femur sustained in a fall at home. Hypothermia is slow in onset but complicated by depletion of energy reserves, rhabdomyolysis, acute renal failure, metabolic acidosis, and hypovolemia due to fluid compartment shifts. Resuscitation is challenged by cardiovascular instability, and by co-morbidities such as respiratory tract infection, which lead to high mortality. Rewarming should be slow and gentle in these patients.

Pre-Hospital Care (Fig. 1) In the field the core temperature should be measured using an epitympanic low reading thermometer [1].

Staging of Hypothermia in the Field According to Clinical Features The 'Swiss' (Swiss Society of Mountain Medicine) method is the most practicable as it is not based solely on the measurement of core temperature and can be performed by non-medical personnel [1]: Stage I Stage II Stage III Stage IV Stage V

Patient alert and shivering Patient drowsy and not shivering Patient unconscious, but with vital signs present Absent vital signs; apparent death Death due to irreversible hypothermia

(Teo 35- 32°C) (Teo 32-28°C) (Teo 28-24°C) (Teo 24-l3 °C) (Teo < l3°C)

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Rescue examine Yes +.- - - - - - - - - - - -

1

Responsive?

1 1

No

Pronounce Lethal injury? ---+ Yes ---+ life ext inct

1 1

No

Respiration?

1\

Yes

No

j

j

N10

Central pulse? Check 60 s

Yes

7

j

Intubate Vetilate

Remove all wet clothing insulate Provide food & drink if able to swallow Allow spontaneous endogenous heating

j

~

No

1

ALS Max 3 attempts at defibri llation Wit hhold vasoactive drugs CPR only if uninterrupted to definitivecare

1

Remove all wet clothing (Cut around pat ient) Insulate Ca reful pat ient handling

j Rewarm wit h heat packs, inhaled warm gases, warming devices Heati ng optional Consider transfer to hospital (casesof inj ury, intoxication)

~

7

Yes Assume cardiacoutput RS I, intubate and venti late

Shivering?

<;

1

Rewa rm wit h heatpacks, inhaled warm gases, warming devices

7

Crit ical Ca reTransfer to hospital with ICU and preferably ECCfacility

Fig. 1. Algorithm for pre-hospital care of patient with severe accidental hypothermia. ALS: advanced life support; CPR; cardiopulmonary resuscitation; RSI; rapid sequence induction of anesthesia; ICU: intensive care unit; ECC: extracorporeal circulation

Management of Severe Accidental Hypothermia

Severely hypothermic patients have been successfully resuscitated even after several hours of asystolic cardiac arrest. The current record for the lowest core temperature from which a victim has been resuscitated in accidental hypothermia is 13.7°C [12]. Clearly the principal clinical challenge is in differentiating a stage IV from a stage V victim. The key being that in stage V the thorax and abdomen are not compressible, the cardiac rhythm is always asystole (stage IV, maybe asystole or VF), the core temperature is lower than 13°C, and the serum potassium is greater than 12 mmol/l, Of course, one cannot resuscitate all hypothermic casualties; hypothermia is a consequence of death whatever its cause and it would be inappropriate to attempt to rewarm these casualties. It is important to remember that an obvious lethal injury is a contraindication to resuscitation. As a clinical example, in avalanche victims the burial time and presence of an air pocket are important prognostic factors as well. Patients buried for more than 35 minutes with no air pocket do not survive. However, when burial time exceeds 35 minutes, and the patient has an air pocket, managing severe hypothermia may become the key challenge in the extracted victim. Extrication should be careful and gentle as rough handling may provoke VF or asystole. In the absence of vital signs, if the victim is in presumed cardiac arrest, and has a core temperature of > 32°C then resuscitation follows Advanced Life Support (ALS) guidelines. If successful then the patient is transported to a critical care facility; if there is failure to respond after 20 minutes resuscitation then life may be pronounced extinct. In the case of prolonged burial when the victim's core temperature has dropped below 32°C, stage IV hypothermia must be assumed provided that there is an air pocket around the face of the victim and that the airway is clear from obstruction due to ice or vomitus. ALS is commenced, and the patient transported to definitive care where active internal rewarming can be performed. If, however, the airway is obstructed, then resuscitation is contraindicated, and life may be pronounced extinct

Resuscitation Guidelines According to Clinical Staging of Hypothermia Stage I Provide shelter and insulate from wind, rain or snow. Give hot sweet drinks and food. Encourage shivering or exercise to generate heat. Evacuation should be considered if there is the suspicion of an occult injury or co-morbidity that may have precipitated the hypothermic condition, such as a toxicological ingestion. Stage II This patient is not shivering, and is vulnerable to a dysrhythmia if handled roughly or inappropriately. He/she should be nursed horizontally in the side position to protect the airway (unless of course there is the suspicion of a spinal injury), and he/she should be warmed. If the gag-reflex is present and the patient can swallow without risk of aspiration, then give hot sweet drinks and food. Disposition is to a hospital with an intensive care facility (lCU). Avalanche victims who were completely buried and the maritime victim who has been submersed, but survived, are at risk of late respiratory complications such as pulmonary edema, acute respiratory distress syndrome (ARDS), or aspiration pneumonitis [13]. Stage III This patient will have a reduced level of consciousness, and will be on the cusp of VF or asystole if handled inappropriately. It is prudent to intubate and ventilate the patient, both to protect the airway and to optimize ventilation. Intravenous access can be challenging due to peripheral vasoconstriction, but is essential for

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rapid sequence induction of anesthesia. There are risks to intubation in that VF may be provoked by laryngoscopy and the time required to perform the procedure may prolong extrication and evacuation. Measures to rewarm and insulate against further loss of heat must be employed. Disposition is to an institution capable of active rewarming - preferably with cardiopulmonary bypass (CPB) or ECMO facilities. Stage IV This patient is severely hypothermic and apparently dead. Deep tendon reflexes are absent, and the pupils are fixed and dilated. Cardiopulmonary resuscitation (CPR) must be instituted immediately with the caveat that once commenced it must be continued uninterrupted through to definitive care [14, 15]. The rationale for this is that at very low temperatures it may be difficult to confirm ventilation or cardiac activity and initiation of CPR may trigger VE To then cease CPR would be a fatal insult to the patient. These patients should be transported to a hospital with CPB or ECMO facilities; going to a hospital without these facilities wastes valuable time. In more isolated settings, such as parts of Alaska, other management guidelines have been published to reflect the practicalities of evacuation to a medical centre with re-warming facilities [16]. Advanced Life Support in Hypothermia

Intubate and ventilate, employing protective ventilatory strategies (high positive endexpiratory pressure [PEEP], low tidal volume). Palpate the carotid pulse and observe the EKG trace if possible, for up to 60 seconds before concluding that there is no cardiac output. If the victim is pulseless, or even if there is any doubt, then start chest compressions immediately. The ratio of ventilations to chest compressions is the same as for a normothermic patient. Intravenous fluids should be warmed. Ringer's lactate (Hartmann's solution) should be avoided because the hepatic metabolism of lactate may be diminished and lead to increased lactic acidosis [17]. Epinephrine has been shown experimentally to improve coronary perfusion pressure in hypothermic cardiac arrest in pigs, but not survival [18, 19]. Epinephrine should be withheld in both the field and in the hospital until the core temperature exceeds 30°C, because: a) the adrenoceptor is less responsive at low temperatures; and b) decreased drug metabolism may lead to potentially toxic plasma concentrations of any drug given repeatedly. Amiodarone is similarly affected [20]. Once 30°C is reached during rewarming, the intervals between doses should be doubled until core temperature approaches normal when standard protocols should be used. Arrhythmias other than VF tend to resolve spontaneously as the core temperature increases. Bradycardia is usually physiological and does not require pacing unless persistent after rewarming. Defibrillation may be attempted pre-hospital, but must be limited to three shocks, even if VF or ventricular tachycardia (VT) persists, until the core temperature is greater than 30°C [21,22]. Afterdrop

This is a continued fall in the core temperature after removal from the cold stress, and it may occur during rewarming . It is important because further cooling of the heart lowers the threshold for VF [23]. It is caused by conductive heat loss along tissue thermal gradients (i.e., between the core of a muscle where the temperature is greater than at the cooler periphery of the skin) [24, 25] and convective heat loss through changes in peripheral blood flow as cold peripheral tissue becomes increasingly reperfused as rewarming proceeds [26].

Management of Severe Accidental Hypothermia

Circum-rescue Collapse

There are many examples of victims being rescued (usually from cold water immersion) in an apparently stable and conscious condition, only to undergo a secondary or circum-rescue collapse, with symptoms ranging from syncope through to ventricular fibrillation and cardiac arrest [27]. Deaths have been described just before, during, or soon after rescue, as well as up to 24 hours later [28- 30]. Vertical extrication leads to potentially fatal fluid shifts [27]; these can be prevented by lifting the casualty horizontally. Insulation and Rewarming

General measures include mitigating against the cold stress, gentle patient handling and removal of all layers of wet and damp clothing, usually by cutting. In the field, the victim should be insulated from the ground and from the wind, rain, or snow. Rewarming can be endogenous (encouraging the patient to shiver or exercise and so produce their own heat) , passive external (blankets in a warm room, allowing endogenous heat production to gradually warm the patient - suitable only for conscious victims with mild hypothermia), active external (heat packs, convective warming blankets), or active internal (warmed intravenous fluids, warmed humidified air/oxygen mixes, gastric, pleural, peritoneal or bladder lavage with warmed fluids and ultimately extra corporeal blood warming (see below). Pre-hospital Rewarming It is imperative to prevent any further cooling of the victim in the field. The heart

must not be allowed to cool any further - the threshold for VF will be lowered. Active warming must, therefore, commence in the field, with the caveat that patient handling is safe and controlled. The most practical method of active warming in the field is to place heat packs on the skin near to major blood vessels (neck, thoracic inlet, axillae, abdomen and groin) [31). Warmed, humidified air/oxygen mixes have little thermal advantage [32,33]. Arterio -venous anastomosis warming can be useful in a base camp setting or aboard ship [34]; the arms, forearms , lower legs, and feet are immersed in water at 42 or 45°C, giving rewarming rates between 6.1 and 9.9°C per hour respectively [35]. The arteriovenous anastomoses in the fingers and toes act as the heat exchanger in this elegant technique. Whole-body immersion in hot water is contraindicated. This form of rapid surface warming will cause massive vasodilatation and hypotension, and is likely to provoke dysrhythmias and cardiovascular collapse. In-Hospital Critical Care (Fig. 2)

The in-hospital management of hypothermia follows the primary survey - resuscitation - secondary survey approach. Cardiovascular stability will only be achieved through stopping the fall in core temperature and establishing rewarming. Correction of metabolic and electrolyte disturbances and intravenous fluid replacement runs concurrently. Esophageal or urinary bladder electronic temperature probes are more accurate than rectal probes. The reduction in the core temperature does not dictate the method or rapidity of rewarming - the presence or absence of a perfusing rhythm is the critical deciding

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Critical care

! !

Management of traumatic injury & control of major hemorrhage

/

Concurrent rewarming

<,

Hemodynamic instability

Hemodynamic stability

"No perfusingrhythm"

"Perfusing rhythm"

Rapid rewarming >2°Cper hour

Moderate rewa rming 1 to 2 °Cper hour

Extra corporeal circulation

Heatpacks

or (if ECC not available) thoracicand bladder lavage

Resistive heatingsystems

!

! !

Forced-air warming Inhaled warm gases

Concurrent management of electrolyte and metabolic derangements

/

Fig. 2. Algorithm for in-hospital care of patients with severe accidental hypothermia

factor. Even in the patient with severe hypothermia, but with a perfusing rhythm, forced-air rewarming has been shown to be an effective method leading to eventual discharge with a very good functional recovery [36, 37). However, in the presence of a cardiorespiratory arrest and severe hypothermia, the priority is to restore a perfusing rhythm. The rate of rewarming must be rapid - in excess of 2°C per hour - and achieved by invasive means . In an institution without CPB or ECMO facilities, the options for extracorporeal warming of blood are limited to veno-veno hemofiltration [38, 39), or else pleural, peritoneal and bladder lavage with warmed fluids that internally warm the heart and major blood vessels. When the triage of patients is performed at the incident scene, it makes little sense to evacuate such patients to a hospital facility that does not have CPB or ECMO as these techniques remain the gold standard for rewarming the hypothermic victim [40-43) . Once a spontaneous circulation has been restored, it is recommended that standard strategies for post resuscitation care be employed. There is no evidence to support the routine use of steroids, nor of antibiotics, unless there is coexistent sepsis [44). Principals of Extracorporeal Rewarming

Rewarming rates can be as high as lQoC per hour. Survival to discharge with excellent neurological function is possible even after 1 or 2 hours of asystolic cardiac

Management of Severe Accidental Hypothermia

arrest. Success rates may be as high as 64 % in patients who are not asphyxiated prior to becoming hypothermic; in contrast, submersed patients who have drowned and then become hypothermic, or avalanche victims who have asphyxiated before becoming hypothermic have a very poor prognosis [45). The rate of rewarming is a function of the temperature of the blood and the blood flow rate in the device. In elective cardiac surgery, it is well known that large temperature gradients between the blood in the circuit and the patient's core temperature cause a worse neurological outcome [46]. A gradient of 5-10 0C is commonly used and allows thorough heating of the patient both centrally and peripherally and reduces the possibility of an afterdrop. Alpha stat acid base management should be employed during rewarming (where no correction for temperature is made during blood gas analysis). In all cases the blood temperature should never exceed 40°C as higher temperatures cause denaturing of cellular and humoral elements of the blood.

Extracorporeal Rewarming Devices These can be divided into devices applicable for patients with a cardiac output and those that also support the circulation. Patients with cardiac output I) Veno-venous rewarming circuit: A simple circuit consisting of 3/8" tubing (for adults), a centrifugal pump head and a heat exchanger, e.g., ECMO Therm (Medtro nic). Access is percutaneous veno -venous and the circuit can run without heparin; it also makes an excellent rapid transfusion device (M Hines, Wake Forest, Personal communication) . Avoiding full heparinization is obviously beneficial in trauma patients [47). II) Continuous veno-venous hemofiltration: Unfortunately the blood flow rate of these devices is very limited, e.g., 180 ml/rnin for the Gambro Prisma, which limits the thermal transfer capability. Both these devices could be used for patients who suffer a cardiac arrest as long as cardiac massage is continued. However, the rewarming will be extremely slow as thermal transfer will be limited by the low cardiac output achievable with external cardiac massage, usually only 20 % of normal [39]. If the patient is presenting in cardiac arrest then one of the following devices should be used. Patients in cardiac arrest I) Cardio-pulmonary bypass: An adult circuit can be used to support patients larger than 40 kg. Smaller patients will need to go to a pediatric cardiac surgical unit. Blood flow rates of up to 2.4 l/m 2/min allow full support of gas exchange and cardiac output. The circuit is relatively complex. Blood is usually drained into a venous reservoir from where it flows to the pump, of either centrifugal or roller type. The blood is then propelled through an oxygenator, which is usually made from polypropylene hollow fibers with an integral heat exchanger. There is often an arterial line filter to remove particulate debris before the blood is returned to the arterial system of the patient. If applicable, a system of suction tubes collecting in a cardiotomy reservoir also allows shed blood from the surgical field to be recirculated. The circuit has many areas where blood is stationary and it therefore requires complete anticoagulation with heparin 300 units/kg to give an activated clotting time (ACT) of

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500-1000 seconds. This is obviously a disadvantage in patients who have suffered trauma, particularly intracerebral bleeding. The circulation is usually accessed via direct cannulation of the heart and great vessels via a median sternotomy. This approach has the advantage of great speed, and the ability to decompress the left ventricle which may become distended once CPB is initiated, especially in the patient who has resistant VE This is achieved by placing a vent either in the left atrium, left ventricle, or pulmonary artery according to preference. Often VF will revert spontaneously once the heart is decompressed. The other advantage of trans-thoracic cannulation is seen in small children where the femoral vessels are unusable for access. In this situation the right carotid and jugular vein are usually used if extra-thoracic access is employed. Ligation of the carotid and jugular during cardiac arrest has a much higher incidence of right-sided brain lesions in babies being cannulated for ECMO compared to those who were not in cardiac arrest [48]. In older children and adults the femoral vessels can be used for cannulation either percutaneously or by cutdown [49]; typical adult femoral cannulae would be a 28F venous cannula and a 21F or 23F arterial return. Even patients with a core temperature < 14°C can be rewarmed in 1-2 hours on CPB. Thorough warming is confirmed by measuring the bladder or peripheral temperatures before discontinuing CPB; these should usually be in excess of 35°C. After weaning from bypass, heparin is reversed with protamine and coagulopathy is corrected by transfusion of platelets, plasma and cryo-precipitate as appropriate. Anti-fibrinolytics such as tranexamic acid or aprotinin can also be helpful for post bypass hemorrhage as can recombinant activated factor seven (Novoseven, NovoNordisk). II) extracorporeal membrane oxygenation: ECMO uses modified CPB technology to provide prolonged cardio-respiratory support in the ICU. It has several advantages over CPB for resuscitating patients with severe hypothermia. • The circuit is designed to eliminate areas of stasis so there is no venous reservoir and no suction apparatus. This allows much lower doses of heparin to be used than are needed for CPB. Only 100 units/kg of heparin are given prior to cannulation and then 30- 60 units/kg/h are given to maintain an ACT of 160-200 seconds. If there is recent trauma or ongoing bleeding micro-dose heparin (10 units/kg/min) or even heparin free ECMO can be used for short periods of time [48]. Aprotinin infusion is a useful adjunct to reduce bleeding on ECMO. • ECMO can be used to provide prolonged respiratory support; for instance, in the immersion victim or trauma patient there may be significant lung injury which requires extra-corporeal gas exchange after rewarming. • ECMO causes a much smaller inflammatory response than CPB [50]. It would be usual to opt for veno-arterial ECMO in a hypothermic patient in cardiac arrest but it is possible to use veno-venous bypass and cardiac massage [43]. If the left heart is distended then a vent can be inserted in the same way as during CPB; the tubing is simply connected into the venous side of the circuit. Care must be taken not to allow any air to enter the circuit via the vent as the ECMO circuit is not designed to have air in it, and can easily pump this air back to the pat ient if a roller pump is being used. The oxygenator is usually constructed from heparin coated poly-methyl pentene (PMP) and can be used safely for short periods without intravenous heparin, partie-

Management of Severe Accidental Hypothermia

ularly in the presence of a coagulopathy. Older circuit designs use solid silicone membrane lungs, which are very effective but have a higher priming volume and cause slightly more blood activation than the PMP devices [51]. The same issues pertain to ECMO cannulation as those discussed above for CPB. To summarize, avoidance of carotid and jugular ligation is sensible in patients who are arrested, and the femoral vessels are the ideal choice in any patient where they are large enough (usually from the age of 2). Trans-thoracic cannulation is preferred initially in younger patients in cardiac arrest, moving to cervical cannulation to allow hemostasis after 12-24 hours. The rewarming approach is the same as for CPB keeping the temperature gradient between the blood and core temperature 5- 10°C and never allowing the blood temperature above 40°C. This will allow rewarming rates of 5-1O°C per hour. It is worth attempting defibrillation once rewarming has been initiated, particularly if the heart has been decompressed. However, if it is unsuccessful, further attempts should be postponed until the core temperature is above 30°C. If the VF is resistant at this temperature, administration of magnesium and amiodarone can be helpful to facilitate cardioversion.

Conclusion For doctors in tertiary care centers, the most important task is to identify patients who can benefit from transfer to their facility. Hospitals without CPB or ECMO should encourage transfer of patients in cardiac arrest directly from the scene to units that do have these facilities. This will drastically reduce journey times and time-to-definitive treatment by eliminating the need for a secondary transfer. In determining the correct disposition for the patient, a balance has to be struck between the journey time entailed in a critical care transfer, the risk of further cooling of the patient (perhaps provoking a fatal dysrhythmia, or lowering to a core temperature from which resuscitation is impossible), the vulnerability of the patient during the transfer, and the advantages offered by advanced tertiary care facilities. The old adage 'not dead until warm and dead' remains pertinent. If the heart has stopped send the patient to a hospital with CPB or ECMOl References 1. Elsensohn F (2001) Consensus Guidelines on Mounta in Emergency Medicine and Risk Reduc-

tion. Casa Editrice Stefanoni, Lecco 2. Soar J, Deakin CD, Nolan JP,et al (2005) European Resuscitat ion Council Guidelines for Resuscitation. Section 7d. Hypothermia. Resuscitation 67 (Sl) :S144-146 3. Holzer M, Behringer W, Schorkhuber W, et al (1997) Mild hypothermia and outcome after CPR. Hypothermia for Cardiac Arrest (HACA) Study Group. Acta Anaesthesiol Scand Suppl l l l :55- 58 4. Reuler JB (1978) Hypoth ermia: pathophysiology, clinical settings, and management. Ann Intern Med 89:519-527 5. Valeri CR, Cassidy G, Khuri S, et al (1987) Hypothermia induced reversible platelet dysfunction . Ann Surg 205:175-181 6. Staab DB, Sorensen VJ, Fath JJ, et al (1994) Coagulation defects resulting from ambient temperature-induced hypothermia. J Traum a 36:634-638 7. Johnson JW, Gracias VH, Schwab CW, et al (2001) Evolution in damage control for exsanguinating penetrating abdominal injury. J Trauma 51:261- 271 8. Steineman S, Shackford SR, Davis JW (1990). Implications of admission hypothermia in trauma patients. J Trauma 30:200- 202

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GJ. Peek, P.R. Davis, and J.A. Ellerton 9. Rousseau JM, Marsigny B, Cauchy E, et al (1997). Hypothermie en traumatologie. Ann Fr Anesth Reanim 16:885 -894 10. Giesbrecht GG (2001) Prehospital treatment of hypothermia . Wilderness Environ Med 12:24-31 11. Tikuisis P (1997) Prediction of survival time at sea based upon observed body cooling rates. Aviat Space Environ Med 68:441-448 12. Gilbert M, Busund R, Skagseth A, et al (2000) Resuscitation from accidental hypothermia of 13.7°C with circulatory arrest. Lancet 355:375-376 13. Brugger H, Falk M, Adler-Kastner L (1997) Avalanche emergency. New aspects of the pathophysiology and therapy of buried avalanche victims . Wien Klin Wochenschr 109:145-159 14. Giesbrecht GG (2000) Cold stress, near drowning and accidental hypothermia: a review. Aviat Space Environ Med 71:733 -752 15. Steinman AM (1986) Cardiopulmonary resuscitation and hypothermia. Circulation 74:IV29 -32 16. Department of Health and Social Services, Division of Public Health, Section of Community Health and EMS, State of Alaska. Cold Injuries Guidelines 2003. Available at: http://www. chems .alaska.gov/EMS/documentslAKColdlnj2005.pdf. Accessed Dec 2007 17. Aun CST (1997) Thermal disorders. In: Oh TE (ed) Intensive Care Medicine 4th edn. Butterworth Heinemann, Oxford 18. Krismer AC, Lindner KH, Kornberger R, et al (2000) Cardiopulmonary resuscitation during severe hypothermia in pigs: does epinephrine or vasopressin increase coronary perfusion pressure? Anesth Analg 90:69- 73 19. Kornberger E, Lindner KH, Mayr VD, et al (2001) Effects of epinephrine in a pig model of hypothermic cardiac arrest and closed-chest cardiopulmonary resuscitation combined with active rewarming. Resuscitation 50:301 - 308 20. Stoner J, Martin G, O'Mara K, et al (2003) Amiodarone and bretylium in the treatment of hypothermic ventricular fibrillation in a canine model. Acad Emerg Med 10:187- 191 21. Southwick FS, Dalglish SPH [r (1980) Recovery after prolonged asystolic cardiac arrest in profound hypothermia: a case report and literature review. JAMA 243:1250 -1253 22. Ujhelyi MR, Sims H, Dubin SA, et al (2001) Defibrillation energy requirements and electrical heterogeneity during total body hypothermia. Crit Care Med 29:1006-1011 23. Covino BG, Beavers WR (1957) Effect of hypothermia on ventri cular fibrillatory threshold. Proc Soc Exp Bioi Med 95:631-634 24. Golden FS, Hervey GR (1977) The mechanism of the after-drop following immersion hypothermia in pigs. J Physiol 272:26P-27P 25. Webb P (l986) Afterdrop of body temperature dur ing rewarming : an alternative explanation. J App Physiol 60:385- 390 26. Giesbrecht GG, Bristow GK (1992) A second post-cooling afterdrop: more evidence for a convective mechanism. J Appl Physiol 73:1253-1258 27. Golden FS, Hervey GR, Tipton MJ (1991) Circum-rescue collapse: collapse, sometimes fatal, associated with rescue of immersion victims . J Roy Nav Med Serv 77:139-149 28. Crisfill JW,McCance RA, Ungley CC, Widdowson EM (1956) The hazards to men in ships lost at sea, 1940 - 44. Spec Rep Ser Med Res Counc (GB) 32:1-44 29. Keatinge WR (1965) Death after shipwreck. BMJ 25:1537 -1541 30. Golden F St C (1973) Death after rescue from immersion in cold water. J R Nav Med Serv 59:5-7 31. Hamilton RS, Paton BC (1996) The diagnosis and treatment of hypothermia by mountain rescue teams: a survey. Wilderness Environ Med 7:28-37 32. Mekjavic IB, Eiken 0 (1995) Inhalation rewarming from hypothermia: an evaluation in -20°C simulated field conditions. Aviat Space Environ Med 66:424-429 33. Ducharme MB, Kenny GP, Johnston CE, et al (1996) Efficacy of forced-air and inhalation rewarming in humans during mild (Teo = 33.9°C) hypothermia. In: Shapiro Y, Moran DS, Epstein Y (eds) Environmental Ergonomics: Recent Progress and New Frontiers . Freund Publishing Co, London, pp 147-150 34. Vanggaard L, Gjerloff CC (1979) A new simple technique of rewarming in hypothermia. Int Rev Army Navy Air Force Med Serv 52:427-430 35. Vanggaard L, Eyolfson D, Xu X et al (1999) Immersion of distal arms and legs in warm water (AVA rewarming) effectively rewarms hypothermic humans. Aviat Space Environ Med 70: 1081-1088

Management of Severe Accidental Hypothermia 36. Kornberger E, Schwarz B, Lindner KH, et al (1999) Forced air surface rewarming in patients with severe accidental hypothermia. Resuscitation 41:105- 1Il 37. Roggla M, Frossard M, Wagner A, et al (2002) Severe accidental hypothermia with or without hemodynamic instabilit y: rewarming without the use of extracorporeal circulation. Wien Klin Wochenschr Il4:315-320 38. Spooner K, Hassani A (2000) Extracorpore al rewarming in a severely hypothermic patient using veno-venou s haemofiltration in the accident and emergen cy department. J Accid Emerg Med 17:422- 424 39. Hughes A, Riou P, Day P (2007) Full neurolog ical recovery from profound (18.0 °C) acute accidental hypothermia: successful resuscitat ion using active invasive rewarming techniques. Emerg Med J 24:5Il-512 40. Walpoth BH, Walpoth-Aslan BN, Mattle HP, et al (1997) Outcome of survivors of accidental deep hypothe rm ia and circulatory arrest treated with extracorporeal blood warm ing. N Engl J Med 337:1500-1505 41. Silfvast T, Pettila V (2003) Outcome from severe accidental hypothermia in Southern Finland - a lO-year review. Resuscitation 59:285- 290 42. Moser B, Voelckel W, Gardetto A, et al (2005) One night in a snowbank: a case report of severe hypothermia and card iac arrest. Resuscitation 65:365- 368 43. Tiruvoipati R, Balasubramanian SK, Khoshbin E, et al (2005) Successful use of veno-venous extracorporeal membrane oxygenation in accidental hypothermic cardiac arrest . ASAIO J 51:474-476 44. Safar P (1993) Cerebral resuscitation after cardiac arrest: research initiative s and future directions. Ann Emerg Med 22:324- 349 45. Farstad M, Anderson KS, Koller ME, et al (2001) Rewarming from accidental hypothermia by extracorporeal circulat ion. A retrospect ive study. Eur J Cardiothorac Surg 20:58-64 46. Grigore AM, Grocott HP, Mathew JP, et al (2002) The rewarming rate and increased peak tempe rature alter neurocognitive outcom e after cardiac surgery. Anesth Analg 94: 4-10 47. Kirkpatr ick AW, Garraway N, Brown DR, et al (2003) Use of a centr ifugal vortex blood pump and hepar in-bonded circuit for extracorporeal rewarming of severe hypothermia in acutely injured and coagulopathic patients. J Trauma 55:407-412 48. Peek GJ, Firmin RK (2000) Cannulation for Extracorporeal Organ Support . In: Zwischenberger J, Steinhorn RH, Bartlett RH (eds) Extracorporeal Life Support in Cardio-pulmonary Critical Care, 2nd Edition. Extracorporeal Life Support Organisation, Ann Arbor, pp 253-265 49. Van Meurs K, Lally KP, Peek GJ, Zwischenberger JB (2005) Extracorporeal Life Support in Cardio-pulmonary Critical Care, 3rd Edition. Extracorporeal Life Support Organ isation , Ann Arbor 50. Peek GJ, Firmin RK (1999) The inflammatory and coagulative response to prolonged extra corporeal membrane oxygenation, a review. ASAIO J 45:250-263 51. Khoshbin E, Roberts N, Harvey C, et al (2005) Poly-methyl pentene oxygenators have improved gas exchange capability and reduced transfusion requirements in adult extracorporeal membrane oxygenation . ASAIO J 51:281- 287

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Initial leu Management of Skin Sloughing Diseases: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome T.L. PALMIERI

Introduction Case Presentation: A 48 year old woman with metastatic breast cancer develops signs of an upper respiratory infection, fever, and malaise two weeks after starting dilantin for seizures from brain metastases. In the ensuing 48 hours, she develops skin eruptions on her face, which progress to her upper extremities and trunk. She develops lesions of the mouth as well as bullae overher trunk and extremities. She is admitted to the intensive care unit (lCU) hypotensive, tachycardic, and acidotic with sloughing of the skin of her head, trunk, both arms, and legs. The above case is a common initial presentation for a patient with a skin sloughing disorder who initially gets adm itted to an leu. The diagnostic possibilities , listed in Table 1, range from infectious to immunologic diseases. The diagnosis and treatment of pat ients with exfoliative disorders requires an integrated team approach to permit wound healing while supporting vital organ funct ion. The purpose of this chapter is to describe the initial evaluation and management of patients with skin sloughing disorders, particularly the most severe skin-sloughing disorder, toxic epidermal neerolysis. Stevens-Johnson syndrome Toxic epidermal necrolysis Staphylococcal scalded skin syndrome Viral exanthem Morbilliform drug eruption Acute graft-versus-host disease Drug reaction Toxic erythroderma Epidermolysis bullosa Burn injury

Table 1. Differential diagnosis of skin-sloughing

disorders

Toxic Epidermal Necrolysis Epidemiology

Toxic epidermal necrolysis, first described by Lyell in 1956 [l], is a life-threatening mucocutaneous disorder with an incidence of 0.4-1.2 cases per million; StevensJohnson syndrome has an incidence of 1.2-6 cases per million [1-4]. Toxic epider-

InitiallCU Management of Skin Sloughing Diseases Table 2. Characteristics of exfoliating disorders Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Prodrome

None

Fever, malaise

Fever, malaise

Acute phase

4-8 days

4-8 days

1- 2 days

Skin lesion

Symmetric target lesion, extremities, no blisters

Varia ble location, vesicles < 20% BSA

Diffuse detachment, vesicles > 30 % BSA

Nikolsky's Test

Negative

Positive

Positive

Histopathology

Dermoepidermal separaDermoepidermal separation, Dermoepidermal separation, epidermal necrosis tion, mononuclear infiltrate dermal infiltrate

Mortality

0- 5 %

0- 40 %

20-80%

mal necrolysis is the most extensive form of the exfoliative disorders, which include erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolys is. All of the syndromes involve dermoepidermal separation and appear to be caused by an immunologic reaction to foreign antigens. They are distinguished from each other primarily by the extent of cutaneous involvement. In general, toxic epidermal necrolysis is defined as > 30 % body surface area (BSA) desquamation, while Stevens-Johnson syndrome has less than 10 % BSA desquamation. Those patients with a 10-29 % BSA involvement are considered to have a Stevens-Johnson syndrome/ toxic epidermal necrolysis 'overlap'. The characteristics of erythema multi forme, Stevens- Johnson syndrome, and toxic epidermal necrolysis are listed in Table 2. The relative frequencies of Stevens-Johnson syndrome, Stevens-Johnson syndrome/toxic epidermal necrolysis overlap, and toxic epidermal necrolysis are 3:2: 1 respectively [5]. Toxic epidermal necrolysis is associated with a prodromal phase consisting of fever and malaise, similar to a viral illness, beginning shortly after exposure to the inciting agent [6]. The syndrome may involve the mucosal surfaces of the oropharynx, eyes, gastrointestinal tract, and tracheobronchial tree, resulting in dysfunction of multiple organ systems. Overall mortality ranges from 20- 75 %; however, in a recent multicenter review of 199 patients treated in USA burn centers, mortality was 32% [7-10]. The pathogenesis of toxic epidermal necrolysis involves a cell-mediated immune reaction characterized by the destruction of the basal epithelial cells from the accumulation of CD8 positive cells and macrophages in the superficial dermis [11, 12]. Toxic epidermal necrolysis has been compared to graft-versus-host disease in which the donor T cells attack the recipient cells that bear a perceived foreign histocompatibility antigen [13]. Cytotoxic T-cells thus recognize drug metabolites complexed to major histocompatibility complex (MHC)-I molecules on the surface of the keratinocytes . This results in migration of the T-cell into the epidermis, keratinocyte injury, and epidermal necrolysis. Apoptosis factor C95, otherwise known as Fas, has also been implicated in the causation of toxic epidermal necrolysis [14]. Drug exposure is the most common causative factor in toxic epidermal necrolysis, accounting for 80 % of all cases [15, 16]. Dilantin and sulfonamide antibiotics are involved in 40 % of all cases [10]. However, other agents, such as nonsteroidal anti-inflammatory agents, penicillins, cephalosporins, and other antibiotics have also been implicated. Upper respiratory tract infections and viral illnesses have also

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been associated with the development of toxic epidermal necrolysis [17, 18). Patient groups at risk for toxic epidermal necrolysis, due to the drugs used to treat the disease, include patients with seizure disorder, metastatic cancer (with brain metastases), urinary tract infection, allogeneic bone marrow recipients, and human immunodeficiency virus (HIV). Toxic epidermal necrolysis has been associated with human leukocyte antigen (HLA) haplotypes A29, B12, and DR7.

Physical Signs On physical examination, patients with toxic epidermal necrolysis have evidence of epidermal necrosis with large areas of epidermal detachment. Nikolsky's sign, the separation of the epidermis with moderate digital pressure, is a common physical finding ( Fig. 1). Diagnosis of toxic epidermal necrolysis is made by obtaining a biopsy of the periphery of the lesion (i.e., at the edge of the desquamation) to identify the level of dermoepidermal separation.

Fig. 1. Nikolsky's sign: Skin separation with moderate digital pressure, associated with toxic epidermal nee-

rolysis and Stevens-Johnson syndrome.

Treatment The treatment of toxic epidermal necrolysis first and foremost involves stopping the inciting agent. Skin biopsy at the border between the blistered area and adjacent uninvolved skin should be performed on admission, to distinguish toxic epidermal necrolysis from infectious (staphylococcal scalded skin syndrome, viral exanthem) or immunologic disorders. These biopsies need to be evaluated by a dermatopathologist experienced in distinguishing the level of epidermal separation.

Initial ICU Management of Skin Sloughing Diseases

Airway Management Immediate management of the patient with toxic epidermal necrolysis requires a systematic evaluation, since any organ system can be involved. Airway management can be extremely challenging in patients with toxic epidermal necrolysis. Oropharyngeal involvement is common, often resulting in epiglottal swelling , dysphagia, and the need for endotracheal intubation for airway protection [19]. Alveolar lining cells may desquamate, causing airway obstruction, interstitial edema, and bronchopneumonia in up to 50 % of cases [20]. Intubation with an appropriately-sized endotracheal tube, bronchoscopy to clear obstruction from sloughing epithelium, administration of humidified oxygen, and aggressive pulmonary toilet are the mainstays of therapy. The use of steroids in toxic epidermal necrolysis has not been shown to be beneficial in airway management, and may be harmful [10). Securing an endotracheal tube can be challenging in patients who have exfoliated the skin of the face, as tape will not adhere to the moist surfaces, and may desquamate what appears initially to be intact skin. Endotracheal tubes should be secured with tracheostomy ties and monitored closely for damage to underlying tissue as facial edema progresses. Resuscitation Fluid resuscitation and fluid maintenance also differ from the 'typical' ICl) patient. Patients with toxic epidermal necrolysis require fluid resuscitation due to the loss of the epidermal barrier in addition to normal evaporative fluid losses . Fluid loss from partial thickness skin loss may be massive, and these losses must be replaced to avoid hypovolemic shock and organ failure. Thus, the fluid requirements include normal maintenance fluids plus the evaporative losses from the open wounds. The extent of evaporative fluid losses from the wounds can be calculated from the following equation: (25 + percent total BSA desquamation)

x BSA

The percent total BSA desquamated can be estimated by one of two methods: The 'ru le of nines', in which each extremity is a multiple of 9 (each arm including the hand is 9 %, each leg including the foot is 18 %, anterior trunk 18 %, posterior trunk 18 %, and head 9 %) , or by using the area of the patient's palm and fingers, which represents 1 % of the patient's total BSA. Only those areas that are blistered and/or are denuded should be included in the estimate. Initial resuscitation fluid should generally consist of lactated Ringer's solution due to the risk of acidosis from large volumes of normal saline. Fluids should be adjusted to maintain urine output of 30- 50 ml/h. The fluid resuscitation formula is merely a starting point. Patients with large areas of pulmonary or gastrointestinal desquamation will likely require even greater amounts of fluid. Initial fluid requirements will decrease as wound coverage is achieved, and careful management of intravenous fluids is required to avoid over or under-resuscitating patients. Nutrition Maintenance of adequate nutrition, using the enteral route when available, provides the substrate for wound healing. Parenteral nutrition has been associated with increased mortality in patients with toxic epidermal necrolysis [10]. However, if patients manifest gastrointestinal dysfunction, as evidenced by diarrhea or severe

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ileus, parenteral nutrition may be indicated. Adequacy of nutrition should be estimated by weekly resting energy expenditure, respiratory quotient measurement, and urinary urea nitrogen levels. Adjustments should be made to feeding rate and composition based on these measurements. Ophthalmologic care

Ocular involvement is common in toxic epidermal necrolysis, with up to half of the survivors having severe long-term sequelae [21]. Ophthalmologic consultation should be obtained early in the course of the disease in order to diagnose and treat pseudomembranous or membranous conjunctivitis. Daily ophthalmologic examination and removal of conjunctival lesions is frequently needed in patients with eye involvement. Wound Management

A wide range of regimens for toxic epidermal necrolysis wound care have been proposed. To date , there is no objective evidence that prophylactic intravenous antibiotics are helpful in preventing wound infections, and their routine use is not recommended. Reported dressing modalities include xenograft, Biobranew, allograft, Xeroform ®gauze, 0.5 % silver nitrate soaks , and Acticoatw, To date, there are no prospective, randomized trials which prove the superiority of any given regimen, although single center studies exist [9, 22- 25]. What does appear to make a difference is protocol-driven and consistent care. Adequate debridement of devitalized tissue with placement of temporary wound coverage is the key to patient survival. Because toxic epidermal necrolys is involves separation of the dermal-epidermal junction, it is similar to a partial thickness (second degree) burn wound, which can heal without operative intervention provided that appropriate supportive therapy is given. Each wound care modality has advantages and disadvantages, which will be briefly listed below. Xenograft, or pig skin, is a biologic dressing which can be placed directly on a debrided wound. It may improve re-epithelialization and decrease the pain associated with toxic epidermal necrolys is, decrease fluid requirements, and is relatively easy to place. The disadvantage is the expertise and resources required to adequately debride and replace the skin (experienced burn surgeons or burn nurses), the cost, and the ability to monitor the progress of the wound. Wounds need to be carefully monitored for signs of infection, which may necessitate removal of the xenograft. The xenograft comes off when the patient has healed the underlying wound, usually within 7 - 10 days. Biobrane w is a woven synthetic nylon polymer, which is placed after debridement of devitalized tissue. It can be secured with either staples or steristrips, and becomes incorporated into the wound. It generally will separate from the patient's skin at 7- 10 days, when the underlying wound is healed. The disadvantages of this substance are the cost, expertise needed for placement, and infection. Because it is a synthetic, infections of Biobranew, such as toxic shock syndrome, can be lethal, and thus the wounds need to be monitored closely for purulent drainage or separation of the Biobranev prior to wound healing. Xeroformv gauze is bismuth and petroleum impregnated fine mesh gauze. The bismuth provides some antimicrobial action, while the petroleum acts to maintain a moist wound healing environment. The gauze needs to be changed 1- 2 times daily unless it has been incorporated into the patient's wound. Hence, the major disadvan-

Initial leU Management of Skin Sloughing Diseases

tage to this is the need for continual dressing changes as well as infection . Xeroform®, however, is helpful for scattered desquamated areas and areas with lesions, but not as yet denuded. The 0.5 % silver nitrate solution is ideal for patients with a suspected infectious process, as it provides antimicrobial activity against Gram-positive and some Gramnegative organisms as well as yeast. Because silver nitrate solution is hypotonic, it can lead to electrolyte disturbances, such as hyponatremia and hypomagnesemia, and close monitoring of electrolytes is necessary. Other disadvantages include the need for twice daily dressing changes, permanent staining of objects (such as bedding, floor, ceiling) from oxidation of the solution, and the potential for methemoglobinemia. Acticoatw, which incorporates silver into fine mesh gauze, can be placed on a cleaned and debrided wound for up to 72 h, at which time it is replaced after wound cleansing. This decreases the frequency of dressing changes and the concomitant pain . The silver provides for antimicrobial coverage including both Gram-positive and Gram-negative organisms . However, Acticoatw has several limitations. First, the silver component, although necessary for the antimicrobial action , also delays wound healing, which is the key to survival in toxic epidermal necrolysis. Second, availability and cost may be prohibitive in some centers. Finally, the potential exists for the development of a biolayer from the wound surface which would prevent the silver from accessing the wound .

Systemic Therapies Multiple medication regimens have been advocated for toxic epidermal necrolysis. Steroid administration, thought by many to decrease the inflammatory response, has not improved survival in toxic epidermal necrolysis after the development of desquamation; in fact, it may increase the risk of subsequent infection [12,26,27]. The use of immunoglobulins in the treatment of toxic epidermal necrolysis was recommended due to its inhibition of CD95 in an experimental model [14]. A multicenter retrospective study suggested that high-dose immunoglobulins may be helpful [28]. However, other clinical studies have not demonstrated benefit of immunoglobulin administration [29,30]. Further prospective multicenter studies evaluating immunoglobulin use in toxic epidermal necrolysis are needed . Other regimens which have been advocated, but not proven, to benefit patients with toxic epidermal necrolysis, include cyclosporine and plasmapheresis [31, 32].

Prognosis and Outcomes Mortality after toxic epidermal necrolysis has been related to multiple factors. A simplified toxic epidermal necrolysis scoring system, SCORTEN, is one method that has been validated as an accurate predictor of mortality from toxic epidermal necrolysis [33, 34]. SCORTEN risk factors (age > 40 years, presence of malignancy, total BSA of sloughed epidermis > 10 %, blood urea nitrogen level > 28 mg/dl, serum glucose > 252 mg/dl, serum bicarbonate < 20 mEq/l, and heart rate > 120 beats/minute) are collected within the first 24 h of admission, with each item contributing a maximum of 1 point. Mortality rates vary based on the SCORTEN level: a SCORTEN of 0 has virtually no mortality, while a SCORTEN of 6 is associated with a > 90 % mortality. The predicto rs of mortality in a multicenter review of patients with toxic epidermal necrolysis correlate with SCORTEN parameters: Mortality was related to age,

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total BSA desquamation, increasing APACHE II score, parenteral nutrition prior to burn center transfer, and number of complications. Delay in transfer to a burn center, presence of malignancy, intubation, and number of infectious complications also appeared to playa role in mortality [10]. Outcome after toxic epidermal necrolysis is varied . Mortality is due primarily to sepsis, multisystem organ failure, and cardiopulmonary complications [10]. Twothirds of patients are able to return home, while a small number are cared for in a rehabilitation center or a skilled care facility. Long-term sequelae include abnormal pigmentation, loss of nail plates, phimos is in men, vaginal synechiae in women, dysphagia, conjunctival scarring, lacrimal duct damage with decreased tear production, ectropion, and symblepharon [35]. Close follow-up and referral to appropriate specialists is needed to optimize long-term outcomes.

Conclusion The management of toxic epidermal necrolysis involves the integration of critical care with wound management techniques. Although much has been learned about the care of the patient with toxic epidermal necrolysis, future randomized prospective trials are needed to determine what therapeutic interventions, such as immunoglobulin or immunosuppressive agents, may be efficacious. Similarly, the ideal wound management technique is subject to debate and requires further study. In summary, toxic epidermal necrolysis is a potentially lethal disorder involving desquamation of a large body surface area in response to a foreign antigen . Optimal therapy, involving stopping the inciting agent, diagnosis via skin biopsy, airway management, fluid resuscitation, appropriate debridement of devitalized tissue, wound coverage, and long-term supportive care in a burn center are necessary to optimize patient outcome. References 1. Lyell A (1956) Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 68:355- 361 2. Becker DS. (1998) Toxic epidermal necrolysis. Lancet 351:1417- 1420 3. Chan HC, Stern RS, Arndt KA, et al (1990) The incidence of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis. Arch DermatoI126:43-47 4. French LE (2006) Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome: our current understanding . Allergol Int 55:9-16 5. Roujeau JC (1994) The spectrum of Stevens-Johnson Syndrome and toxic epidermal necrolysis: A clinical classification. J Invest Dermatol 102:28S-30S 6. Correia 0, Chosidow 0 , Saiag P, et al (1993) Evolving patterns of drug- induced toxic epidermal necrolysis. Dermatology 186:32- 37 7. Heimbach DM, Engrav LH, Marvin JA, Harnar TJ, Grube BJ (1987) Toxic epidermal necrolysis: a step forward in the treatment. JAMA 257:2171- 2175 8. Kelemen JJ 3'd, Cioffi WC, McManus WF, Mason AD Jr, Pruitt B Jr (1995) Burn Center care for patients with toxic epidermal necrolysis. J Am Coll Surg 180:273-278 9. Zoltie N, Verlende P, O'Neill TJ, Mc Kenzie AW (1994) Lyell's syndrome on a burns unit. Burns 20:368-370 10. Palmieri TL, Greenhalgh DG, Saffle JR, et al (2002) A multicenter review of toxic epidermal necrolysis treated in U.S. Burn Centers at the end of the twentieth century. J Burn Care Rehabi! 23:87- 96 11. Hermes B, Haas N, Henz BM (1996) Plasmaphere sis and immunopathogenic aspects of toxic epidermal necrolysis. Hautarzt 47:749-753

Initial leu Management of Skin Sloughing Diseases 12. Breathnach SM McGibbon DH, Ive FA, Black MM (1982) Carbamazepine and toxic epidermal necrolysis: report of three cases with histopathological observations. Clin Exp Dermatol 7:585-591 13. Peck GL, Elias PM, Graw RG Ir (1972) Graft-versus-host reaction and toxic epidermal necrolysis. Lancet 2:1151-1153 14. Viard I, Wehrli P, Bullani R, et al (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490-493 15. Rojeau JC, Kelly JP, Rzany B, et al (1995) Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600-1607 16. Guillaume JF, Roujeau JC, Revuz J, et al (1987) The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell syndrome). Arch Dermatol 123:1166-1170 17. Halebian P, Corder V, Herndon D, Shires GT (1983) A burn center experience with toxic epidermal necrolysis . J Burn Care Rehabil 4:176-183 18. Schulz JT, Sheridan RL, Ryan CM, MacKool B, Tompkins RG (2000) A lO-year experience with toxic epidermal necrolysis. J Burn Care Rehabil 21:199-204 19. Wahle D, Beste D, Conley SF (1992) Laryngeal involvement in toxic epidermal necrolysis. Otolaryngol Head Neck Surg 6:796-799 20. Lebargy F, Wolkenstein P, Gisselbrecht M, et al (1997) Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study. Intensive Care Med 23:1237- 1244 21. Wilkins J, Morrison L, White CR (1990) Oculocutaneous manifestations of the erythema multiforme/Stevens-Johnson syndrome : descriptive and therapeutic controversy. Chest 98:331- 336 22. Marvin JA, Heimbach DM, Engrav LH, Harnar TJ (1984) Improved treatment of the StevensJohnson syndrome. Arch Surg 119:601- 605 23. McGee T, Munster A (1998) Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to a regional burn center. Plast Reconstr Surg 102:1018-1022 24. Bradley T, Brown RE, Kucan JO, Smoot EC, Hussmann J (1995) Toxic epidermal necrolysis: a review and report of the successful use of Biobrane for early wound coverage. Ann Plast Surg 35:124-132 25. Birchall N, Langdon R, Cuono C, McGuire J (1987) Toxic epidermal necrolysis: an approach to management using cryopreserved allograft skin. J Am Acad Dermatol 16:368-372 26. Halebian PH, Madden MR, Finkestein JL, et al (1986) Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 204:503-511 27. Engelhardt SL, Schurr MJ, Helgerson RB (1997) Toxic epidermal necrolysis: an analysis of referral patterns and steroid usage. J Burn Care Rehabil 18:520-524 28. Prins C, Vittorio C, Padillar S, Hunzikar P et al (2003) Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson Syndrome: A retrospective, multicenter study. Dermatology 207:96- 99 29. Brown KM, Silver GM, Halerz M, et al (2004) Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 25:81-88 30. Bachot N, Revuz J, Roujeau JC (2003) Intravenous immunoglobulin treatment for StevensJohnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 139:33 - 36 31. Renfro L, Grant-Kels JM, Daman LA (1989) Drug-induced toxic epidermal necrolysis treated with cyclosporine. Int J Dermatol 28:441 - 444 32. Egan C, Grant W, Morris S, Saffle J, Zone J (1999) Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 40:458-461 33. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. (2000) SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest DermatoI115:149- 153 34. Trent JT, Kirsner RS, Romanelli P, Kerdel FA (2004) Use of SCORTEN to accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Dermatol 140:890- 892 35. Spies M, Hollyoak M, Muller MJ, Goodwin CW, Herndon DN (2000) Exfoliative and necrotizing diseases of the skin. In: Herndon DN (ed) Total Burn Care, 2nd edn. W.B.Saunders, New York, pp 492- 496

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Section V

V Poisonings

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Pathophysiology of Caustic Ingestion M.

OSMAN

and D.N.

GRANGER

Introduction A 2005 report from the American Association of Poison Control Centers indicates that there were over 200,000 exposures to caustic substances in the form of household and industrial products, including acids (sulfuric acid, hydrochloric acid), alkalis (potassium hydroxide, sodium hydroxide), and other agents. While the majority of cases involved exposure of a body surface, such as the face, eyes, and extremities, ingestion of the caustic agent was the leading cause of death [1]. Of the different types of ingested caustics, the most commonly involved are: A. strong alkalis, such as sodium hydroxide and potassium hydroxide, which exist in different forms, including granular, paste, or liquid. The most common household forms of the alkalis include washing detergents, drain cleaners, soaps, cosmetics, and clinitest tablets. Alkalis are found in high concentrations in button batteries, which can cause severe injury if they leak after ingestion of the battery. B. strong acids can be found in battery fluids (sulfuric acid), toilet bowel cleaners (sulfuric and hydrochloric acids), antirust compounds (oxalic and hydrochloric acids) and slate cleaners (hydrochloric acid) [2]. Many medications can cause damage to the esophageal mucosa on contact. This can occur when patients take pills without water or in a recumbent position, or if there is a predisposing factor to esophageal injury. Examples for medications causing this type of mucosal injury to the esophagus include potassium chloride, tetracycline, aspirin, and doxycycline. It is noteworthy that potassium hydroxide ingestion can cause perforations of the brachial artery, left atrium, and aorta. [3] The majority of caustic ingestions in the United States involve strong alkalis with concentrations exceeding 50 %. The Federation Caustic Poison Act of 1927 was the first major government effort for poison prevention in the United States that aimed to decrease the incidence of caustic ingestion, which mostly occurs in children. This was followed by the Poison Prevention Packaging Act and the Hazardous Substances Act in the 1970s. Both restricted the concentration of household cleaning agents to less than 10 %, and also mandated the use of child resistant containers and warning labels. However, these measures have not totally prevented the occurrence of serious injuries from ingestion of caustic products [4].

Factors Affecting the Extent and Severity of Gastrointestinal Injury due to Caustic Ingestion (Fig. 1). Physical Form (solid, liquid, or gel) The form of an ingested corrosive determines the pattern and distribution of injury in the gastrointestinal tract. Liquid alkalis cause diffuse and circumferential burns

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while solids tend to produce localized burns especially at sites of anatomic constrictions [5). The amount of ingested caustic is also dependent on the physical form. While the liquid form is easily swallowed, the crystallized corrosive tends to cause marked oral pain, which limits further swallowing. Granular automatic dishwashing powder has also been associated with severe injury to the gastrointestinal tract [6]. Contact Time

Logically, the longer the contact-time between the caustic compound and tissue, the more profound the injury. For example, exposure of rat esophagus to caustic soda for a period of 10 min causes damage to the esophagus and if prolonged to 120 min, leads to perforation [7]. Concentration

As expected, the damage induced by a caustic solution is positively correlated to its concentration in solution. For example, exposure of rat esophagus to 1.83 % caustic soda largely causes epithelial necrosis, while 7.33 % produces additional submucosal damage, and a concentration of 14.33 % further extends the damage to the muscle and adventitial layers [7]. pH, pKa, and Titratable Acid/alkaline Reserve

Alkalis are known to cause liquifactive necrosis, with greater penetration into the tissue layers, while acids induce a coagulative necrosis that limits tissue penetration [8]. Potential injury to tissues by a corrosive cannot be predicted based solely on pH. There are many other determinants of the ability of a corrosive to damage tissues, including solution strength. The term 'strength' refers to the willingness of the alkali to dissociate in aqueous solution, and is expressed by the equilibrium constant, pKa, which is the pH at which the alkali is 50 % dissociated to its conjugate acid. Strong alkalis are compounds that have a pKa greater than 14 or are capable of complete dissociation in water [9]. Titratable acid or alkaline reserve (TAR) is a better indicator of the ability of a caustic to injure the tissue. It is defined as the amount of acid or alkali that needs to be added to the caustic in order to reach neutral pH. Higher TAR values generally Physical form Stomach contents

Transit time

pH, pKa, and TAR

Contact time

Quantity

Concentration

Fig. 1. Summary of the factors affecting the extent and severity of gastrointestinal injury dueto caustic ingestion. TAR: titratable acid/alkaline reserve

Pathophysiology of Caustic Ingestion

translate into more tissue damage. For example, a 1 % ammonia solution with a pH 9.6 and TAR of 10 wiJI cause more tissue injury than a 1 % bleach solution with pH 9.5 and TAR 1.0 [10]. The difference between TAR and pH is similar to the difference between heat capacity and temperature; the two latter measures are used to express thermal injury potential in thermal non-chemical burns. For example, dry air at 60°C is less injurious than water at the same temperature, but with greater heat capacity [9]. While TAR has received considerable attention as a predictor of the potential of a compound/solution to elicit caustic injury, the results of a recent report question the predictive value of this parameter [11].

Quantity The quantity of caustic that gains access to esophageal and gastric tissue is usually dictated by whether the ingestion is accidental or intentional. Oropharyngeal irritation and/or the strong odor of the caustic may halt the ingestion process via protective reflexes. Consequently, larger quantities of alkali are often ingested because these solutions generally are tasteless and odorless, while acid causes immediate pain that limits further ingestion [2]. Solid forms of caustic agents are more difficult to swallow, with focal proximal injuries resulting from the adherence of the solid to the mucous membrane [12].

Transit Time It was once been believed that acids mainly injure the stomach and spare the esoph-

agus because of the alkaline nature of the oropharynx and the rapid transit of the acid through the esophagus. However, it has been shown that highly concentrated sulfuric or hydrochloric acids are capable of producing severe injury to the esophagus [13]. Animal studies have revealed that ingestion of liquid alkaline caustic causes regurgitation into the esophagus, which is followed by propulsion of the alkali back into the stomach. These regurgitations are repeated over several minutes, producing extensive injury to the esophagus and stomach before the alkali finally passes to the duodenum [14]. Acids may also elicit pylorospasm, which results in prolonged pooling of the caustic in the stomach [15].

Stomach Contents The presence of food in the stomach decreases the severity of caustic injury, as an empty stomach has no buffering or dilutional effect [15].

Caustic Agents Alkalis Chemical and physical properties The term alkali is taken from the Arabic word 'qili' which means soda ash, the residues from burning a plant. An alkali is considered in the context of biological systems as a substance that generates an aqueous solution in which hydroxyl (OH-) ions exceed hydrogen ions (H +) . Alkalis are defined as substances having a pH more than 7.0. Since pH is a logarithmic value, a l -unit rise in pH translates into a lO-fold

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rise in OH- concentration. According to modern acid-base theories, an alkali is defined as a proton acceptor or electron pair donor [9]. It has been proposed that the production of reactive oxygen species (ROS) and subsequent lipid peroxidation is a major mechanism that contributes to the initial esophageal injury and subsequent strictures produced by alkali exposure. The levels of malonaldehyde, a metabolic end-product of lipid peroxidation, and glutathione, an endogenous free radical scavenger, were measured in esophageal tissue after exposure to a caustic burn. Significantly lower concentrations of glutathione and higher levels of malonaldehyde were detected in the injured esophageal tissues, compared to uninjured control tissue. Malonaldehyde concentration remained elevated for 72 h after alkali exposure [16]. Tissue effects Alkalis cause liquefactive necrosis, which involves dissolution of proteins, destruction of collagen, and saponification of fat. This causes the tissues to soften or liquefy, facilitating the penetration of the alkali deeper into the tissues and the burn penetrates deeper until the excess OH- ions are consumed [17]. Heat is produced from the dissolution of the ingested solid alkali as well as the reaction of alkali with tissue, but this heat production has a secondary role in caustic tissue injury [18, 19]. Acids

Chemistry An acid is a compound that, when dissolved in water, donates protons to water molecules, forming the hydronium ion, H30+ [20]. Tissue effects Acids, through the generation of hydronium ions, cause coagulative necrosis, which reflects the desiccation, denaturation, and precipitation of cellular protein [21, 22]. The resulting coagulative crust or eschar serves to limit further penetration of the acid deeper into the tissue layers. Despite the protective role of the eschar, acids are still able to produce a full thickness esophageal burn, with resultant perforation of the wall and fatal complications [23]. Comparison of the tissue effects of acids and alkalis on the esophagus suggests that alkalis lead to more serious injuries. However, this does not apply to strong acids and bases, both of which can lead to rapid full thickness burns. Indeed, one study has shown that the ingestion of strong acids is associated with a longer hospital stay, and increased incidence of systemic complications, such as renal failure, hemolysis, liver dysfunction, and disseminated intravascular coagulation (DIC) [24]. Button Battery

Button batteries contain high concentrations (up to 45 %) of either sodium or potassium hydroxides. The pH of the surrounding medium has a major influence on the rate of leakage of these batteries. An acidic medium enhances leakage by accelerating the corros ive dissolution of the crimp region of the battery. In alkaline medium, on the other hand, iron oxides and hydroxides precipitate along the crimp area, slowing the corrosion process. Therefore, batteries arrested in the stomach are more likely to be corroded and disassembled than those in the intestine [25]. Batteries containing mercuric oxide, are more likely to leak, but the incidence of complica-

Pathophysiology of Caustic Ingestion

tions is decreased due to the reduction of the released mercuric oxide into elemental nontoxic mercury. This reaction occurs in the presence of gastric acid and iron released from the corrosion of the steel battery canister [26].

Hydrofluoric acid Chemistry Hydrofluoric acid is produced by the reaction of calcium fluoride with sulfuric acid. A product of this reaction is a gas that can be converted to a liquid state by cooling and storage at either low temperature or under pressure (boiling point = 19.4 C). This liquid is a highly corrosive inorganic acid that is commonly used as an industrial cleaner [27]. Exposure to this chemical leads to local tissue injury, as reflected by: 1) ingestion causing corrosive injury to the gastrointestinal tract; 2) topical exposure causing destruction of skin and soft tissue; and 3) exposure to fumes leading to injuries of the eye and/or respiratory system [28]. Tissue effects Hydrofluoric acid remains in a relatively non-ionized form in tissues due to its electronegativity and it does not readily dissociate from the hydrogen ion. Consequently, hydrofluoric acid can readily penetrate cell membranes, and once inside the cells, the fluoride ion reacts with calcium and magnesium to form insoluble complexes. It may also combine with other metallic ions to form soluble and dissociable salts that can release fluoride ions [29]. The insoluble calcium and magnesium salts lead to depletion of calcium stores, which interfere with cell metabolism [30]. Increased cell membrane permeability to potassium ions also occurs secondary to the binding of calcium; this stimulates free nerve endings to cause pain. The disturbance in the cellular metabolism finally leads to cellular death and liquefactive necrosis of soft tissues [29]. The effects of fluoride ions on cellular enzymes can also lead to systemic complications . Inhibition of Na+, K+ ATPase and dysfunctional calcium dependent potassium channels can promote potassium release from red blood cells and consequently hyperkalemia [31]. Fluoride-induced activation of myocardial adenylate cyclase and increased intracellular cyclic AMP concentration can increase the potential for refractory arrhythmias [32].

Bleach Bleach is a household laundry product of which the active component is 5.25 % sodium hypochlorite. Ingestion of small amounts is common in children, causing oral mucosal and gastrointestinal injuries that are usually minor, with rare serious complications [33]. Systemic complications are recorded when larger amounts are ingested . For example, metabolic acidosis and hypernatremia have been reported after ingestion of 500 ml of sodium hypochlorite containing bleach. Excessive absorption of hypochlorous acid and sodium appear to underlie these systemic responses [34].

Glacial acetic acid Glacial acetic acid is the concentrated form of acetic acid. It is commonly used in the preparation of Hindustan - Surinam food. Most of the reported ingestions are suicidal but some are accidental. Glacial acetic acid is a very aggressive corrosive and

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causes severe damage to the esophageal wall, penetrating into deeper layers and possibly causing perforation [35]. Moreover, glacial acetic acid is known to cause severe systemic complications such as hepatic and renal insufficiency, hemolysis, and DIC [36].

Site of Gastrointestinal Injury following Caustic Ingestion While it was long postulated that acid spares the esophagus more than alkali, this concept has been largely disproved [36]. One study reported esophageal damage in 87.8 % of patients who ingested acid [23]. Another study described the occurrence of second to third degree esophageal burns in 17 out of 34 patients with acid ingestion, with one mortality secondary to esophageal perforation after ingestion of sulfuric acid [37]. A third study reported esophageal damage in 44 % of patients ingesting acid [38]. Alkalis on the other hand are known to produce more uniform and severe injury to the esophagus than the acids [39]. Gastric injury is also very common following acid ingestion. This is more pronounced in the distal part of the stomach, most likely due to the "magenstrasse" flow of the acid along the lesser gastric curvature, with pooling of the acid in the pyloric region caused by acid-induced pylorospasm [40]. The duodenum may be spared from acid-induced injury as a result of the pylorospasm and the alkaline intraluminal pH. However, it has been reported that 34.6 % of patients that ingest acid suffer from grade I to grade II duodenal injury [41] .

Changes in the Esophagus after Caustic Ingestion Within the first two days after caustic ingestion, thrombosis of the blood vessels followed by cell necrosis of the epithelium, submucosa, and muscularis are observed. An ulcer develops within the first 72 to 96 h after necrosis, with sloughing of the superficial mucosa. The period with the highest risk of perforation is from 3 days to 2 weeks. During that period, invasion of the necrotic areas with granulation tissue and subsequent deposition of collagen occurs [42]. Three to six weeks after caustic ingestion, contraction of collagen fibers leads to shortening and stricture of the esophagus [43]. In addition to stricture formation, impaired esophageal motility, manifest as absence of peristalsis and low amplitude aperistaltic contractions, and gastroesophgeal reflux are common long-term consequences of caustic ingestion [44]. Furthermore, the incidence of squamous cell carcinoma in the esophagus is increased 20 to 40 times after caustic injury, often developing at the stricture sites decades after the caustic ingestion [43].

Conclusion Despite the high incidence and severe complications of caustic ingestions, relatively little effort has been made to define the cellular and molecular basis of this injury process. Consequently, few therapeutic options are available to limit the gastrointestinal injury associated with this condition. Since many ingested caustic agents appear to mediate irreversible damage (and ultimately necrosis) to gastrointestinal tissue via processes such as protein denaturation or saponification of membrane

Pathophysiology of Caustic Ingestion

lipids, drug-based prevention or attenuation of tissue injury may be an unachievable goal. Nonetheless, agents that can slow the injury process and allow endogenous reparative processes to replace the injured tissue should be identified and tested. The effective therapeutic strategies of the future are likely to target regrowth and/or reconstruction of damaged tissue, using technologies such as tissue engineering, stem cell therapy, and/or growth factor administration. In the absence of such therapies, a renewed focus on prevention strategies to reduce the number of cases of caustic poisoning is warranted. References 1. Lai MW, Klein-Schwartz W, Rodgers GC, et al (2006) 2005 Annual Report of the American Association of Poison Control Centers' National Poisoning and Exposure Database. Clin Toxicol 44:803- 932 2. Loeb-Abram PM, Eisenstein M (1998) Caustic injury to the upper gastrointestinal tract. In: Feldman M, Scharschmidt BF, Sieisenger MH, Fordtran JS (eds) Sieisenger and Fordtran's Gastro intestinal and Liver Disease, 6th edition. W. B. Saunders Company, Philadelphia, pp 335-342 3. Gorman RL, Khing-Maung-Gyi MT, Klein-Schwartz W, et al (1992) Initial symptoms as predictors of esophageal injury in alkaline corrosive ingest ions. Am J Emerg Med 10:189-194 4. Dale Browne J, Thompson IN (2005) Caustic ingestion. In: Cummings CW, Haughey BH, Thomas JR, Harker LA, Flint PW (eds) Cummings Otolar yngology: Head and Neck Surgery, 4th ed. Mosby, New York, pp 1869-1 872 5. Zargar SA, Kochhar R, Nagi B, Mehta S, Mehta SK (1992) Ingestion of strong corrosive alkalis: spectru m of injury to upper gastrointestinal tract and natural history. Am J Gastroenterol 87:337- 341 6. Kynaston JA, Patrick MK, Shepherd RW, Raivadera PV, Cleghorn GI (1989) The hazards of automatic-dishwasher detergent. Med J Aust 151:155 7. Mattos GM, Lopes DD, Mamede RC, Ricz H, Mello-Filho FV, Neto JB (2006) Effects of time of contact and concentration of caustic agent on generation of injuries. Laryngoscope 116: 456 - 460 8. Havanond C (2002) Is there a differenc e between the management of grade 2b and 3 corrosive gastric injuries? J Med Assoc Thai 85:340 - 344 9. Sivilotti MLA, Ford M (2000) Alkali ingestions. In: Ford M, Delaney KA, Ling L, Erickson T (eds) Clinical Toxicology, 1st ed. W. B. Saunders Company, Philadelph ia, pp 1002-1007 10. Hoffman RS, Howland MA, Kamerow HN, Goldfrank LR (1989) Comparison of tit ratable acid/alkaline reserve and pH in potentially caustic hou sehold products. J Toxicol Clin Toxicol 27:241 -261 11. Boldt GB, Carroll RG (1996) Titratable acid/alkaline reserve is not predictive of esophageal perforation risk after caustic exposure. Am J Emerg Med 14:106-108 12. Kirsh MM, Ritter F (1976) Caustic ingestion and subsequent damage to the oropharyngeal and digestive passages . Ann Thorac Surg 21:74-82 13. Penn er GE (1980) Acid ingestion : Toxicity and treatment. Ann Emerg Med 9:374-379 14. Ritter FN, Newman MH, Newman DE (1968) A clinical and experimental study of corrosive burns of the stomach. Ann Otol Rhin Lary ngol 77:830- 842 15. Clifton JC II (2001) Acid ingestions. In: Ford M, Delaney KA, Ling L, Erickson T (eds) Clinical Toxicology, l st ed. W. B. Saunders Company, Philadelphia, pp 1009 -1018 16. Gunel E, Caglayan F, Caglayan 0 , Akillioglu 1 (1999) Reactive oxygen radical levels in caustic esophageal burns. J Pediatr Surg 34:405- 407 17. Homan CS, Maitra SR, Lane BP, Thode HC, Sable M (1994) Therapeutic effects of water and milk for acute alkali injury of the esophagus. Ann Emerg Med 24:14-20 18. Homan CS, Maitra SR, Lane BP, Thode HC Jr, Finkelshteyn J, Davidson L (1995) Effective treatment for acute alkali injury to the esophagus using weak-acid neutralization therapy: an ex-vivo study. Acad Emerg Med 2:952-958 19. Rumack BH, Burrington JD (1977) Caustic ingestions: a rational look at diluent s. Clin Toxicol 11:27- 34

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M. Osman and D.N. Granger 20. Bronsted IN (1923) Some remarks on the concept of acids and bases. Reel Trav Chim Pays Bas 42:718-728 21. Cardona JC, Daly JF (1971) Current management of corrosive esophagitis: An evaluation of results in 239 cases. Ann Otol Rhinol Laryngol 80:521-526 22. Rubin MM, [ui V, Cozzi GM (1989) Treatment of caustic ingestion. J Oral Maxillofac Surg 47: 286-290 23. Zargar SA, Kochhar R, Nagi B, Mehta S, Mehta SK (1989) Ingestion of corrosive acids: Spectrum of injury to upper gastrointestinal tract and natural history. Gastroenterology 97:702-707 24. Poley JW, Steyerberg EW, Kuipers EJ, et al (2004) Ingestion of acid and alkaline agents: outcome and prognostic value of early upper endoscopy. Gastrointest Endosc 60:372- 377 25. Litovitz TL, Schmitz BF (1992) Ingestion of cylindrical and button batteries : An analysis of 2382 cases. Pediatrics 89:747-757 26. Barber TE, Menke RD (1984) The relationship of ingested iron to the absorption of mercuric oxide. Am J Emerg Med 2:500- 503 27. Anderson WJ, Anderson JR (1988) Hydrofluoric acid burns of the hand : Mechanism of injury and treatment. J Hand Surg 13A:52-57 28. Sadove R, Hainsworth D, Van Meter W (1990) Total body immer sion in hydrofluoric acid. South Med J 83:698-700 29. Edinburg M, Swift R (1989) Hydrofluoric acid burns of the hands: A case report and suggested management. Aust NZ J Surg 59:88- 91 30. Kirkpatrick JJ, Enion DS, Burd DA (1995) Hydrofluoric acid burns: A review. Burns 21: 483-493 31. Klasaer AE, Scalzo AJ, Blume C, Johnson P, Thompson MW (1996) Marked hypocalcemia and ventricular fibrillation in two pediatric pat ients exposed to a fluoride-containing wheel cleaner. Ann Emerg Med 28:713-718 32. Mullett T, Zoeller T, Bingham H, et al (1987) Fatal hydrofluoric acid cutaneous exposure with refractory ventricular fibrillation. J Burn Care Rehabil 8:216- 219 33. Cardona J, Boussemart T, Berthier M, Oriot D (1993) [Accidental bleach ingestion in children: Results of a survey of 11 anti-poison centres. Proposals for management.] Pediatrie 48:705-709 34. Ward MJ, Routledge PA (1988) Hypernatraemia and hyperchloraemic acidosis after bleach ingestion. Hum Toxicol 7:37-38 35. Davids PH, Bartelsman JF, Tilanus HW, van Lanschot JJ (2001) [Consequences of caustic damage of the esophagus). Ned Tijdschr Geneeskd 145:2105-2108 36. Muhletaler CA, Gerlock AJ [r, de Soto L, Halter SA (1980) Acid corrosive esophagitis: Radiographic findings. Am J Roentgenol 134:1137 -1140 37. Hawkins DB, Demeter MJ, Barnett TE (1980) Caustic ingestion: Controversies in management: A review of 214 cases. Laryngoscope 90:98- 109 38. Bautista Casasnovas A, Estevez Martinez E, Varela Cives R, Villanueva Jeremias A, Tojo Sierra R, Cadranel S (1997) A retrospective analysis of ingestion of caustic substances by children: Ten-year statistics in Galicia. Eur J Pediatr 156:410-414 39. Gumaste VV, Dave PB (1992) Ingestion of corrosive substances by adults. Am J Gastroenterol 87:1-5 40. Waldeyer W (1908) Die Magenstrasse. Sitzungsber K Preuss, aka d Wissench Gesammtsitz 29: 595-606 41. Zargar SA, Kochhar R, Mehta S, Mehta SK (1991) The role of fiberoptic endoscopy in the management of corrosive ingestion and modified endoscopic classification of burns. Gastrointest Endosc 37:165-169 42. Johnson EE (1963) A study of corrosive esophagitis. Laryngoscope 73:1651 -1696 43. Hopkins RA, Postlethwait RW (1981) Caustic burns and carcinoma of the esophagus . Ann Surg 194:146-148 44. Bautista A, Varela R, Villanueva A, Estevez E, Tojo R, Cadranel S (1996) Motor function of the esophagus after caustic burn. Eur J Pediatr Surg 6:204- 207

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Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity B. M EGARBAN E, N.

DEYE,

and EJ.

BAUD

Introduction Cardiovascular toxicity is a potential complication following accidental or inten tional overdose with various classes of drugs. The term 'cardio-toxic drug' is not limited to cardiovascular drugs but also includes various other toxicants, such as antidepressants , meprobamate, Hl-antihistaminic agents, nivaquine, cocaine, organo phosphates, cyanide, and plants ( Table 1). Despite improvement in critical care, drug-induced card iovascular failure still remains a leading cause of death. The mortality rate remains high in poisonings with compounds that include membrane sta bilizing agent s in addition to their main pharmacological activity [1]. Of 847,483 exposures in adults reported to the Ameri can Association of Poison Control Centers in 2005, cardi ovascular drugs were involved in 5.8 % of cases; however, they accounted for approximately 19 % of the total 1,261 poisoning fatalities , representing

Table 1. Cardio-toxic drugs causing severe acute heart failure that may require extracorporeal life support Pharmacological class

Membrane stabilizing agent

Vaughan Williams class 1 anti-arrhythmic drugs Some ~-b loc ke rs Tricyclic or tetracyclic antidepressants Some serotonin-reuptake inhibitors Dopamine and norepinephrine uptake inhibitor Anticonvulsive drugs Neuroleptics Analgesics Anti-malarial drugs Festive drugs

Other toxicants

Calcium-channel blockers

Other cardio-toxic drugs

Toxicants quinidine, lidocaine, mexiletine, cibenzoline, tocainide, procainamide, disopyramide, f1 ecainide, propafenone, ... prop ranolol, acebutolol, nadoxolol, pindolol, penbutolol, labetalol, metoprolol, oxprenolol imipramine, desipramine, amitritptyline, clomipramine dosulepin, doxepin, maprotiline venlafaxin, cit alopram bupropion carbamazepine, phenytoin phenothiazines, including thioridazin dextropropoxyphene chloroquine, quinine cocaine nifedipine, nicardipine, verapamil, diltiazem, nimodipine, amlodipine, nitrendipine, bepridil perhexiline meprobamate, colchicine, beta-blocker without membrane stabilizing activity, Hl-antihistaminic drugs, organophosphates, aconite, yew, scombroid fish ...

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the fifth toxicant category responsible for death, following analgesics, sedative drugs, antidepressants, and stimulants [2]. In this register, calcium channel blockers and beta-blockers accounted for 40 % of cardiovascular drug exposures, while calcium channel blockers represented the first cause of cardiovascular agent-related death. The usefulness of temporary mechanical assistance for drug-induced cardiac failure is debated [3- 5]. Recently, promising results have been obtained using percutaneous cardiopulmonary support in cardiac arrest refractory to prolonged resuscitation [6-9] as well as in ventricular tachycardia refractory to anti-arrhythmia agents and cardioversion attempts [10]. Furthermore, several case reports, including one small series of poisoned patients (N = 7), have suggested the need to define the place of extracorporeal life support (ECLS) in drug-induced cardiac failure [11- 13].

Features of Drug-induced Cardiac Toxicity Severe cardiotoxicity may be evident at the time of presentation or during the course of poisoning by the sudden onset of hypotension, high degree atrio-ventricular block, asystole, pulseless ventricular tachycardia, or ventricular fibrillation. Other critical manifestations include mental status deterioration, seizures, metabolic acidosis from hyperlactacidemia, and acute respiratory failure. Neurological features are generally consecutive to cerebral hypoperfusion. Cardiovascular effects generally occur within 6 hours after a massive ingestion; however, this time span depends on several parameters including the type of drug, the pharmaceutical formulation (immediate versus sustained release), and the dose (the greater the dose the shorter the delay). Delays may range from a few minutes and even seconds for cyanide to less than 3 hours for class IC anti-arrhythmic agents, 24 hours for verapamil, and 72 hours for colchicine. Therefore, intensive cardiac monitoring, including clinical parameters (blood pressure, heart rate , respiratory rate , Sp02' and Glasgow coma score) and electrocardiogram (EKG), is mandatory as soon as the patient is admitted to the emergency room or to the intensive care unit (ICU). The EKG is essential to identify drug-induced cardio-toxicity: enlarged QRS complexes (> 0.12 s) are observed with membrane stabilizing agents, narrowed QRS with meprobamate, and severe sinus bradycardia or high-degree atrioventricular block with beta-blockers or calcium-channel blockers. The prognostic factors for poisonings involving cardio-toxic drugs have been poorly investigated, except for digitalis, colchicine, theophylline, and antidepressants. Prognostic factors are specific for a toxicant or a class of toxicants. Interestingly, the prognostic value of toxicant blood concentration remains to be determined. In cardiac glycoside poisoning, outcome assessment has shown that mortality increases in patients exhibiting five prognostic factors [14]: 1) advanced age, 2) heart disease, 3) male sex, 4) high -degree atrioventricular block, and 5) hyperkalemia. In tricyclic antidepressant poisonings, determination of the maximal limb-lead QRS duration predicts the risk of seizures and ventricular arrhythmias, whereas serum drug levels are not of predictive value [15]. In chloroquine poisoning, bad prognostic factors related to severe cardio-circulatory failure are: 1) an ingested dose > 4 g, 2) systolic blood pressure < 100 mmHg, and 3) QRS duration> 0.10 s [16, 17]. In beta-blocker poisonings, the most important factors associated with the development of cardiovascular morbidity are the ingestion of a beta-blocker with membrane stabilizing agents properties as well as concomitant ingestion of another cardio-toxic drug [18, 19].

Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity

Mechanisms of Drug-induced Cardiac Toxicity Drug-induced cardiac toxicity mainly results in hypotension of variable pathogenesis, including hypovolemia, myocardial depression , cardiac arrhythmias, and systemic vasodilatation [3, 5, 20]. The major mechanism of toxic heart failure is decreased systolic myocardial contractility. However, numerous other mechanisms may also playa role, including diastolic dysfunction (cardiac glycosides), alteration in the geometry of heart contraction (membrane stabilizing agents, drug-induced ventricular arrhythmia), myocarditis (ethylene glycol, organophosphates), anoxia (carbon monoxide, cyanide), or acute coronary syndrome (adrenergic agents including cocaine). Overdoses with calcium channel blockers, beta-blockers, or membrane stabilizing agents result in myocardial negative inot ropic effects as well as arterial vasodilatation. Cardiac toxicity is generally reversible following the elimination of the responsible toxicant (,functional toxicity'). However, in some rare situations , drugs may induce irreversible injur ies resulting in significant cardiac sequellae, such as myocardial necrosis due to cocaine-related coronary vasoconstriction. Determination of the mechanisms of drug-induced cardiovascular shock is man datory to improve management. Shock does not always result from a decrease in cardiac contractility. A large number of cases of drug-induced shock result from a combination of relative hypovolemia and arterial vasodilatation, like with dihydropyridines, including nifedipine, polycyclic antidepressants, and chloroquine. Therefore, in drug-induced shock apparently refractory to conventional treatment, it is mandatory to perform a bedside hemodynamic study. Echocardiography coupled with Doppler requires extensive training to achieve valuable conclusions and remains operator-dependent. Right heart catheterization is often performed and must be completed by the simultaneous measurement of arterial and mixed venous blood gases providing insights into oxygen transfer, delivery, and consumption. Evaluation of the microcirculatory consequences of cardiac toxicity, i.e., the ability of the macrocirculation to meet metabolic cellular demands, is essential for optimal patient management. This evaluation is routinely based on the measurement of urine output, plasma lactate, serum creatinine concentrations, coagulation tests, as well as liver enzymatic tests. However, in beta-blocker-induced shock, there may be a misleading moderate increase in lactate concentration, probably related to the protective effect of beta-blockers on glycolysis and lactate production in comparison with other cardio-toxic poisonings, although there is a severe impairment of the microcirculation. In the near future , new devices allowing the non- or minimally invasive assessment of the microcirculation, including continuous mixed venous oxygen saturation (SV02) measurement and near-infrared spectroscopy (NIRS), may become useful indicators of cardiac toxicity.

How to Optimize Conventional Management of Drug-induced Cardiac Toxicity Management of drug-induced cardiac toxicity focuses on restoring hemodynamic function, and involves multiple additive pharmacological therapies [5,20,21]. Nonspecific supportive cares aims to correct hypoxia, hypotension, acid/base and electrolyte disorders . Tracheal intubation and mechanical ventilation are required in cases of coma, severe collapse, or cardiac arrhythmia. In cases of cardiac arrest, standard basic and advanced life support should be immediately provided. With the

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exception of torsades de pointes, cardioversion is indicated for life-threatening ventricular arrhythmia. Multidose activated charcoal is not helpful unless sustainedrelease preparations have been ingested. Due to large distribution volumes and high protein binding ratios, extracorporeal elimination enhancement techniques are not feasible options. For hypotension, treatment should be individualized according to each drug class; however, an initial strategy of rapid intravenous saline infusion is indicated in most circumstances [3, 20, 21]. Vasopressors are required for refractory hypotension. The vasopressor of choice depends on the type of intoxication. In the emergency room or in the absence of close cardiac monitoring, the authors believe that epinephrine should be the first-line catecholamine. Sodium bicarbonate is required if ventricular conduction is delayed, for example in membrane stabilizing agent poisonings (Fig. 1). Administration of intravenous sodium bicarbonate to achieve a systemic pH of 7.5-7.55 reduces QRS prolongation and reverses hypotension in patients with moderate to severe tricyclic antidepressant poisoning [22]. Studies also suggest

-

Suspicionof severemembrane stabilizing agent poisoning (SBP <100 mm Hg or QRS 2: 0.12s)

~

Support ive tr eatment: Fluid loading SOO - 1,000 ml (if SPB <100 mm Hg) 8.4% sodium bicarbonate 250- 750 ml (if QRS >0.12 s) Consider int ubat ion + mechanical ventilation (if severe) Charcoa l (if feasible + repeated if sustained-releasepreparations)

Adequate vasopressor: epinephrine or norepinephrine (0.5-10 mg/h)

Monit or hemodynamic status (echocardiography, pulmonary artery catheterization) ~

Persist ent cardiac arrest

,--I

Cardiac failure

+

- - ,

Vasoplegia

~ Refracto ry heart failure despite optimal medical t reatment suggested by: SBP<90 mmHg despite adequate fluids, 350 mI 8.4% bicarbonate, epinephrine infusion rate >3 mg/h, associated with respiratory (Pa Oi Fi0 2 <150 mm Hg) or renal failure (oliguria or serum creatinine concentration >90 prnol/ l)

1

Percut aneous extr acorporeallife support

Increasing doses of vasoactive drugs

Fig. 1. Proposed algorithm for the treatment of membrane-stabilizing agent poisoning. This algorithm is based on case series and reports (SBP: systolic blood pressure, QRS: QRS duration on EKG).

Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity

this approach is beneficial to reduce any antidepressant-associated EKG Brugada syndrome [23]. However, the exact indications and dosing recommendations remain to be clarified. Administration of sodium bicarbonate may resolve arrhythmias even in the absence of acidosis; thus, conventional anti-arrhythmic drugs should be used only if this therapy fails. Class lA and l C anti-arrhythmic drugs should be avoided since they worsen sodium channel blockade, further slow conduction velocity, and depress contractility. Class II agents (beta-blockers) may also precipitate hypotension and cardiac arrest. There is limited evidence for any benefit from magnesium infusion. In addition to supportive treatments, a number of antidotes and specific treat ments have been investigated. In chloroquine poisoning, combining early mechanical ventilation with diazepam and epinephrine administration is effective in the treatment of cardiovascular failure [16]. For cardiac glycoside poisonings, digoxinspecific Fab fragments represent the treatment of life-threatening events, if atropine fails as the first-line anti-arrhythmic therapy to correct bradycardia [14]. Thus, digitalis-induced heart failure due to ventricular arrhythmias may only be observed if Fab fragments are not administered early or are unavailable. Furthermore, during digitalis intoxication, the pacemaker has limited preventive and curative effects, is difficult to handle, and exposes patients to risk of iatrogenic accidents. The future of immunotherapy in the treatment of other cardio-toxic drug toxicity remains uncertain: desipramine-specific Fab fragments were shown to be efficient in experimental models; however, conclusions of clinical trials are still pending [24]. Similarly, colchicine-specific Fab fragments were effective in experimental models; however, only one life-threatening human case has benefited from this treatment which is still not commercially available [25]. In calcium channel blocker poisoning, first-line drug therapy remains the catecholamines ( Fig. 2) [20,21 ,26] . Despite controversial clinical efficacy, calcium salts are still recommended, initially by some authors [20] and only in shock refractory to conventional vasopressors by others [26]. The optimal dosage and agent (i.e., calcium gluconate or chloride) is still unclear; repeated intravenous boluses of 1 g every 15-20 min up to a total of 4 doses is usually recommended, followed by an infusion of 20 - 50 mg/kg/h in patients with a beneficial hemodynamic response. Serum calcium concentration should be measured at least twice daily and maintained at normal levels, given the lack of evidence for a benefit of supraphysiological levels. Glucagon, administered as a 5- 10 mg intravenous bolus over 1 min followed by an infusion of 1- 10mg/h, may also have beneficial effects on hemodynamic parameters [26]. Finally, based on animal data and single case reports, insulin/glucose therapy should be used early as adjunctive treatment, mainly if vasopressors fail to improve hemodynamic function or conduction disturbances ( Fig. 2) [27]. The proposed protocol consists of 1 IV/kg intravenous bolus of insulin followed by an infusion of 0.5- 1.0 IV /kg/h, with a highly concentrated glucose infusion to maintain euglycemia. For beta-blocker poisoning, glucagon is widely used, despite a lack of clinical studies to support its beneficial effects [28]. Therefore, glucagon should not be the first choice, based on limited clinical data and restricted availability in comparison to other inotropic agents. In France, a 5 rng/h glucagon regimen costs 95 euros, whereas an equivalent 30 IVlh insulin regimen costs only 0.84 euros. Thus, we recommend the following order for antidote administration if initial supportive measures fail: dobutamine, glucagon, epinephrine ( Fig. 3). Isoproterenol is life-saving in sotalol-related bradycardia, as QT interval prolongation may cause torsade de

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Suspicion of calcium-channel-blockerpoisoning (HR <50/min and/or SBP <100 mm Hg)

~

Symptomatic therapies: Atropine 0.5 mg IVbolus (if HR <50 I min) Fluid loading 500-1 ,000 ml (ifSPB <100 mm Hg) Consider intubation + mechanical ventilation (if severe) Charcoal (if feasible + repeated if sustained-release preparations)

Adequate vasopressor: epinephrineor norepinephrine (0.5- 10 mg/h)

1

Calcium salts (chloride or gluconate) Repeat 19 IV bolus 115- 20 min to a total of 4 doses followed by 20-50 mg/ kg/h continuousinfusion

Monitor hemodynamic status (echocardiography, pulmonary artery catheterization)

Monitor serum ionized calcium concentration

~

Glucagon2- 5 mg IVbolusfollowed by 2 -1 0 mg/h continuousinfusion

High-doseinsulin {1 IU/kg IVbolus + 0.5 IU/ kg/h infusion) - + adequateglucose infusion

Monitor serum glucose and potassium concentration

Ventricular pacing Intra-aortic balloon pump Percutaneous extracorporeal life support Phosphodiesterase inhibitors, aminopyridinesor vasopressin, and analogs

Fig. 2. Proposed algorithm for the treatment ofcalcium-channel-blocker poisoning. This algorithm is based on case series and reports (HR: heart rate, SBP: systolic blood pressure).

pointes or favor sustained ventricular tachycardia or fibrillation. Sodium bicarbonate is recommended in the presence of QRS interval enlargement on the EKG in poisonings involving beta-blockers with membrane stabilizing activity. Interestingly, in beta-blocker and calcium channel blocker poisonings, various other antidotes have shown promise, including phosphodiesterase inhibitors (milrinone), vasopressin analogs, levosimendan, as well as potassium-channel-antagonists used as non-depolarizing neuromuscular blocking agents (4-aminopyridine and 3,4diaminopyridine) [3, 21, 26]. However, these agents have only proved interesting in animal studies or in single human cases. Moreover, their availability limits their utilization .

Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity

Suspicion of beta-blocker poisoning (HR <SO/min and/or SBP <100 mm Hg)

~

Symptomatic therapies: Atropine 0.5 mg IV bolus (if HR <SO/ min) Fluid loading 500-1 ,000ml (ifSPB <100 mm Hg) 8.4% sodium bicarbonate 250-750 ml (if QRS >0.12s) Consider intubation + mechanicalventilation (if severe) Charcoal (if feasible + repeated if sustained-release preparations)

Dobutamine(5- 20 Ilg/kg/minl Isoproterenol (1 - 5 mg/h) in sotalol

:....................•

~

High-dose Glucagon 2-5 mg IV bolusfollowed by insulin 2- 10 mg/h continuousinfusion (1 IUlkg IV : 7 bolus + . . ~. : ... 0.5IU/kg/h infusion) Adequate vasopressor: + adequate epinephrineor norepinephrine (0.5 - 10 mg/h) glucose infusion : ....................•

II

Monitor serum glucose and potassium

==

Monitor hemodynamic status (echocardiography, pulmonary artery catheterization)

Ventricular pacing Intra-aortic balloon pump Percutaneous extracorporea l life support Phosphodiesterase inhibitors

Fig. 3. Proposed algorithm for treatment of beta-blocker poisoning. This algorithm is based on case series and reports (HR: heart rate, SBP: systolic blood pressure).

Extracorporeal Life Support for the Poisoned Failing Heart Despite the recommendations for optimal supportive and antidotal treatments, management of cardio-toxic poisoning remains difficult. Prognostic factors predictive of refractoriness to conventional treatment are still lacking. In a series of 137 consecutive cases of severe poisoning with membrane stabilizing agents requiring catecholamine administration for shock in addition to specific treatment admitted in our ICU, the mortality rate was 28 % [5]. Ventricular arrhythmia, sudden cardiac arrest, and refractory cardiovascular failure may cause death, despite aggressive resuscitative measures and vasopressors [3, 5, 16 -19, 21]. Thus , there is clearly a need for more aggressive treatment in the subset of patients not responding to optimal conventional treatment. In these patients, high-dose titrated vasopressors, ventricular pacing (transvenous or transthoracic), intra-aortic balloon pump (IABP), or percutaneous cardiopulmonary bypass (CPB) should be considered as lifesaving measures [3]. However, data allowing analysis of the benefit of these exceptional therapies are still limited. The place for IABP appears limited due to the need for an

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intrinsic cardiac rhythm for synchronization and diastolic augmentation. Consistently, IABP does not work in patients with cardiac arrest. When dealing with cardio-toxic drugs, this is a major limitation as the major effects of poisoning are ventricular tachycardia and fibrillation as well as electromechanical dissociation and refractory asystole. Extracorporeallife support is an arterio-venous technique providing circulatory support but requiring blood bypass from the right to the left system with extracorpOteal blood oxygenation. In contrast, extra-corporeal membrane oxygenation (ECMd) is a veno-venous method that improves PaOz without providing any support to the circulatory system. In drug-related heart failure, only extracorporeallife support is indicated. The use of extracorporeal life support for reversible cardiac toxicity has a sound basis, but clinical experience is still limited in toxicology with insufficient evidence to provide a high grade recommendation (grade C) [3,4] . Two published experimental studies in membrane-stabilizing agent-poisoned dogs and swine support the hypothesis that extracorporeallife support is life-saving in comparison with advanced cardiac life-support-treated animals [29,30]. The purpose of extracorporeal life support is to take over the heart function during refractory cardiac shock until recovery can occur, thus minimizing myocardial work, improving organ perfusion, and maintaining the renal and biliary elimination of the toxicant . However, only a limited number of cases of shock result from cardiogenic shock refractory to conventional treatment. In terms of the different mechanisms of shock that may be observed in poisoned patients, extracorporeallife support should not be considered in shock related to arterial vasodilatation. Based on the review of case reports, CPB may be beneficial in cardio-toxic poisonings .to treat hemodynamic instability not responding to convent ional measures, provided that the patient has not sustained hypoxic cerebral damage due to resistant hypotension prior to its use [4, 11-13]. Peripheral circulatory assist devices are particularly useful in comparison to conventional bypass support using sternotomy [4]. CPB is a surgical procedure with a number of potentially life-threatening complications and its use is restricted to the operating room. Interestingly, in the international life support registry report of 2004, poisonings were not individualized as a cause of cardiac failure in adults [31]. Moreover, there is no clear definition of drug-induced refractory heart failure. Prognostic factors, able to predict refractoriness to conventional treatments of cardio -toxic poisonings, are still unknown, except for digitalis [14]. Although, criteria for unresponsive membrane-stabilizing agent poisonings have recently been proposed (Fig. 1), there is still an urgent need to clarify prognostic factors in order to advance understanding regarding the Indications for extracorporeal life support and its efficiency. We recently demonstrated that emergent extracorporeallife support is feasible in a medical ICU [9]. However, femoral cannulation for extracorporeal life support remains an invasive technique, with potential severe risks (bleeding at the cannulation site requiring multiple transfusion, cannulated limb ischemia, femoral nerve palsy. extensive deep venous thrombosis, as well as various technical problems) [7, 9, 11, 13, 32]. Pulmonary edema may require emergency decompression of the left atrlum during extracorporeallife support [33]. However, to our knowledge, emergehcy decompression of the left atrium during extracorporeal life support has not been reported in poisoned patients treated with this technique.

Extrilcorportal Life-Support for Acute Drug-induced Cardiac Toxicity

Extracorporeal Life Support Management for Acute Poisonings in the Medical ICU The development of peripheral extracorporeal life support has enabled extracorporeal life support to be performed outside the operating room with cardiopulmonary perfusion to be started early in the ICU or the emergency room, where poisoned patients are admitted [6,8-10] . However, a number of pre-requisites should be considered for the use of extracorporeal life support in a medical ICU. There is a need to establish a close collaboration with a department of cardiac surgery [9]. Depending on local facilities, cardiac surgeons may decide to perform extracorporeal life support inside the department of cardiac surgery or directly in the medical ICU. The latter solution requires training of intensivists regarding the surgical approach of the femoral vessels in the Scarpa triangle, while additional physicians and nurses have to be trained in the priming and handling of extracorporeallife support equipment. Facilities must exist for coagulation tests and an emergency blood supply should be available. Cardiac surgeons must be available on a 24-hour a day basis, in order to: 1)- discuss the indications for extracorporeal life support; 2)- insert the cannulae and start extracorporeal life support; 3)- provide local hemostasis; 4)- cope with local complications, including local bleeding and lower limb ischemia; 5)- address any complication related to the pump and the membrane oxygenation; and 6)- withdraw the cannulae and perform vascular repair in cases offavorable outcome [5,9] . The femoral vessels are most frequently cannulated in adults; in infants, other vessels may also be used, including the carotid artery and the internal jugular vein. The preferred method for cannulat ion remains a matter of debate. Percutaneous cannulation of femoral vessels is usually performed. A blind approach may cause laceration resulting in severe occult local bleeding. Furthermore, due to the size of the arterial cannula of about 15-17 F gauge, occlusion of the vessel lumen by the cannula may result in arterial ischemia. A peripheral femoro -fernoral shunt has been shown to prevent this severe complication of extracorporeal life support [13, 32]. Circulation in the cannulated limb was provided by a tube inserted distally into the superficial femoral artery and connected to the side port of the extracorporeal life support arterial line. Extracorporeal life support results in blood flows ranging from 1.5 to 6 lImin, thus providing a complete supplementation of a failing or even arrested heart. Extracorporeal blood flow is adjusted to mainta in an adequate systemic blood flow and oxygen supply as monitored by mean arterial pressure, urine output, plasma lactate concentrations, and central venous oxygen saturation. The doses of inotropic agents used before extracorporeal life support are progressively tapered following extracorporeal life support setup. During cardiac assistance, complete electromechanical dissociation is often observed . Dobutamine (10 Ilg/kg/min) +/- vasopressors are often infused to facilitate left ventricular decompress ion, minimizing the risks of pulmonary and left ventricle blood stasis as well as intracardiac clotting. Heparin is infused as early as possible to maintain a target activated clotting time 2.0- 2.5 times higher than control at full flow. Patients are mechanically ventilated with 5-6 mllkg tidal volume and 10 cmH20 positive end-expiratory pressure (PEEP). The lowest possible fraction of inspired oxygen is used and guided by pulse oximetry and radial arterial blood gas determination. Echocardiography is used twice daily to assess venous cannula position, to exclude significant aortic regurgitation , and to assess progressive recovery of myocardial contractility. Serial routine biological tests and EKG findings should be checked daily. Neurological status is

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assessed using serial electroencephalograms during extracorporeal life support while the patient remains unresponsive. The prerequisites to wean from extracorporeallife support are echocardiography assessment of myocardial function (left ventricular ejection fraction> 50 %) and a radial PaOz/Fi02 ratio> 150 mmHg. The pump flow is tapered, given a clotting time > 2.5 times higher than a control, to check there is no deterioration in hemodynamic status. If the patient's cardiovascular status remains stable, extracorporeallife support is withdrawn by the cardiac surgeons . If irreversible damage to myocardial function is diagnosed , the patient is transferred under extracorporeallife support to the cardio-surgical ward, to be considered for a ventricular assist device. Extracorporeal life support may be withdrawn in some cases based on evidence of severe neurological injury or unresponsive multiple organ failure.

Conclusion Cardio-toxic poisoning may induce life-threatening cardiac dysfunction resulting in multiple organ failure and leading to death. Supportive treatment is usually efficient, but the usefulness of CPB remains a matter of debate. However, due to the persistent high mortality rates associated with poisonings involving cardio-toxicants, there is a need for more aggressive treatment in the subset of patients not responding to conventional treatment. Determination of prognostic factors predictive of refractoriness to conventional treatment remains mandatory. To date, only experimental studies and a few case reports support the hypothesis that peripheral extracorporeal life support may be life-saving. Further studies on a larger scale are needed to clarify the indications and usefulness of extracorporeal life support in this context. References 1. Henry JA, Cassidy SL (1986) Membrane stabilizing activity: a major cause of fatal poisoning .

Lancet 1:1414-1417 2. Lai MW, Klein-Schwartz W, Rodgers GC, et al (2006) 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila) 44:803- 932 3. Albertson TE, Dawson A, De Latorre F, et al (2001) TOX-ACLS : toxicologic-oriented advanced cardiac life support. Ann Emerg Med 37:S78-S90 4. Purkayastha 5, Bhangoo P, Athanasiou T, et al (2006) Treatment of poisoning induced cardiac impairment using cardiopulmonary bypass: a review. Emerg Med J 23:246-250 5. Baud FJ, Megarbane B, Deye N, Leprince P (2007) Clinical review: Aggressive management and extracorporeal support for drug -induced cardiotoxicity. Crit Care 11:207 6. Massetti M, Tasle M, Le Page 0, et al (2005) Back from irreversibility: extracorporeallife support for prolonged cardiac arrest. Ann Thorac Surg 79:178-183 7. Nichol G, Karrny-Iones R, Salerno C, Cantore L, Becker L (2006) Systematic review of percutaneous cardiopulmonary bypass for cardiac arrest or cardiogenic shock states. Resuscitation 70:381-394 8. Chen JS, Ko WJ, Yu HY, et al (2006) Analysis of the outcome for patients experiencing myocardial infarction and cardiopulmonary resuscitation refractory to conventional therapies necessitating extracorporeallife support rescue. Crit Care Med 34:950-957 9. Megarbane B, Leprince P, Deye N, et al (2007) Emergency feasibility in medical intensive care unit of extracorporeal life support for refractory cardiac arrest . Intensive Care Med 33: 758-764 10. Tsai FC, Wang YC, Huang YK, et al (2007) Extracorporeallife support to terminate refractory ventricular tachycardia. Crit Care Med 35:1673-1676

Extracorporeal Life-Support for Acute Drug-induced Cardiac Toxicity 11. Bosquet C, Jaeger A (200l) [Therapeutiques d'exception au cours des defaillances circulatoires et respiratoires d'origine toxique]. Reanimation 10:402 -411 12. Megarbane B, Leprince P, Deye N, et al (2006) Extracorporeallife support in a case of acute carbamazepine poison ing with life-threatening refractory myocardial failure. Intensive Care Med 32:1409-1413 13. Massetti M, Bruno P, Babatasi G, Neri E, Khayat A (2000) Cardiopulmonary bypass and severe drug intoxication. J Thorac Cardiovasc Surg 120:424- 425 14. Taboulet P, Baud FJ, Bismuth C (1993) Clinical features and management of digitalis poison ing - rationale for immunotherapy. J Toxicol Clin ToxicoI31:247-260 15. Boehnert MT, Lovejoy FH, Jr. (1985) Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313:474- 479 16. Riou B, Barriot P, Rimailho A, Baud FJ (1988) Treatment of severe chloroquine poisoning . N Engl J Med 318:1-6 17. Clemessy JL, Taboulet P, Hoffman JR, et al (1996) Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med 24:1189-1195 18. Love IN, Howell JM, Litovitz TL, Klein-Schwartz W (2000) Acute beta blocker overdose: factors associated with the development of cardiovascular morb idity. J Toxicol Clin Toxicol 38:275-281 19. Love IN, Litovitz TL, Howell JM, Clancy C (1997) Characterization offatal beta blocker ingestion: a review of the American Association of Poison Control Centers data from 1985to 1995. J Toxicol Clin Toxicol 35:353- 359 20. Zimmerman JL (2003) Poisonings and overdoses in the intensive care unit: general and specific management issues. Crit Care Med 31:2794-2801 21. Megarbane B, Donetti L, T. Blanc T, et al (2006) ICU management of severe poisoning with medication s or illicit substances. Reanimation 15:343- 353 22. Bradberry SM, Thanacoody HK, Watt BE, Thomas SH, Vale JA (2005) Management of the cardiovascular complications of tr icyclic antidepressant poisoning: role of sodium bicarbon ate. Toxicol Rev 24:195-204 23. Monteban-Kooistra WE, van den Berg MP, Tulleken JE, et al (2006) Brugada electrocardio graphic pattern elicited by cyclic antidepressants overdose. Intensive Care Med 32:281- 285 24. Heard K, Dart RC, Bogdan G, O'Malley GF, et al (2006) A preliminary study of tricyclic antidepressant (TCA) ovine FAB for TCA toxicity. Clin Toxicol (Phila) 44:275-281 25. Baud FJ, Sabouraud A, Vicaut E, et al (1995) Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragment s. N Engl J Med 332:642-645 26. Salhanick SD, Shannon MW (2003) Management of calcium channel antagonist overdose. Drug Saf 26:65- 79 27. Megarbane B, Karyo S, Baud FJ (2004) The role of insulin and glucose (hyperinsulinaemial euglycaemia) therapy in acute calcium channel antagon ist and beta -blocker poisoning. Toxicol Rev 23:215-222 28. Bailey B (2003) Glucagon in beta-blo cker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol 4: 595-602 29. Freedman MD, Gal J, Freed CR (1982) Extracorporeal pump assistance - novel treatment for acute lidocaine poisoning . Eur J Clin Pharmacol 22:129-135 30. Larkin GL, Graeber GM, Hollingsed MJ (1994) Experimental amitr iptyline poisoning: treatment of severe cardiovascular toxicity with cardiopulmonary bypass. Ann Emerg Med 23:480-486 31. Conrad SA, Rycus PT, Dalton H (2005) Extracorporeal Life Support Registry Report 2004. ASAIO J 51:4-10 32. Babatasi G, Massetti M, Verrier V, et al (200l) [Severe intoxication with cardiotoxic drugs : value of emergency percutaneous cardiocirculatory assistance]. Arch Mal Coeur Vaiss 94: 1386-1392 33. Aiyagari RM, Rocchini AP, Remenapp RT, Graziano IN (2006) Decompression of the left atrium during extracorporeal membrane oxygenation using a trans septal cannula incorporated into the circuit. Crit Care Med 34:2603 - 2606

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Epidemiology of Acute Respiratory Failure and Mechanical Ventilation H.S . SUR1, G. Lr, and O. GAlle

Introduction Acute respiratory failure, and the need for mechanical ventilation, remains one of the most common reasons for admission to the intensive care unit (leU). The burden of acute respiratory failure is high in terms of mortality and morbidity as well as the cost of its principal treatment, mechanical ventilation. Very few epidemiologic studies have evaluated the prevalence and outcome of acute respiratory failure and mechanical ventilation in general. Most of the published literature has focused on specific forms of acute respiratory failure, particularly acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) . In this chapter, we provide a brief review of the pathophysiology of acute respiratory failure, its definition and classification, and then present the incidence and outcomes of specific forms of acute respiratory failure from epidemiologic studies.

Definition and Classification Normal respiration requires the integrated function of several components of the respiratory system (Fig. 1). Dysfunction of any component results in the impairment of normal gas exchange and may lead to acute respiratory failure and the need for mechanical ventilation. According to the underlying pathophysiologic mechanism, acute respiratory failure is usually divided into four patterns: Types I-IV ( Ta ble 1). Type I and type II respiratory failure are also referred to as hypoxemic and hyper-

Nervoussystem

---.

/ Vascu lature

Musculature

Respiratory system Airways Alveolar units

Fig. 1. Vital components of the respiratory system

--

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u and O. Gajic

Table 1. Pathophysiological classification of acute respiratory failure with corresponding clinical syndromes. Type I

Type II

Type III

Type IV

Mechanism

VIO mismatch

Alveolar hypoventilation

Atelectasis Shunt (Os/Ot)

Hypoperfusion Metabolic acidosis

Anatomic compon ents

Alveolar unit failure CNS dysfunction Pulmonary vascular Neuromuscular failure failure Airway dysfunction

Regional alveo- All tissues lar unitcollapse Respiratory muscles

Clinical syndromes

Pulmonary edema ALI, CPE Pneumonia Trauma ILD*

Perioperative

Shunt (Os/Ot)

Coma NMD* COPD*·** Asthma

Shock

* may occur as acute exacerbations - acute on chronic respiratory failure; ** type I and type II respiratory failure frequently co-exist; ILD: interstitial lung disease; NMD: neuromuscular disorder; COPD: chronic obstructive pulmonary disease; ALI: acute lung injury; CPE: cardiogenic pulmonary edema; CNS: central nervous system

capnic respiratory failure, based on a predominant gas exchange abnormality. In many disease states however, more than one pathophysiologic mechanism is operational and clinical criteria that incorporate setting, acuity, and severity are used more often ( Table 1). Acute episodes (exacerbations) of respiratory failure in patients with chronic compensated respiratory insufficiency are usually referred to as 'acute on chronic' respiratory failure. A consensus definition of acute respiratory failure is not available and most studies have used the combination of mechanical ventilation (of variable duration) with or without evidence of severe hypoxemia on arterial blood gas analysis. While some studies utilized a more strict definition than others, the essential component in all has been the need for mechanical ventilation. The indications for mechanical ventilation , however, are mostly based on clinical observations (increased respiratory rate, use of accessory muscles, paradoxical chest wall movements, changes in mental state), none of which has sufficient accuracy or precision. Therefore, the epidemiology of acute respiratory failure has so far been restricted to 'treated' acute respiratory failure, possibly explaining the wide variations in the reported incidence and outcomes of acute respiratory failure and associated clinical syndromes. Since the availability of intensive care and mechanical ventilation vary greatly in different parts of the world, the burden of acute respiratory failure may be severely underestimated depending on the access to leu services.

Incidence and Outcome of Acute Respiratory Failure The incidence of acute respiratory failure varies according to the definition used and the population studied (Table 2). Two European studies , one conducted in Germany [I] and the other in Sweden, Denmark, and Iceland [2], estimated very similar incidences, 88.6 and 77.6 cases per 100,000 person-years. Both studies used an identical definition (intubation and mechanical ventilation for > 24 h regardless of arterial blood gas findings) and employed a multicenter approach with large patient cohorts over a short period (8 weeks). On the other hand, Behrendt reported a much higher

Epidemiology of Acute Respiratory Failure and Mechanical Ventilation Table 2. Comparison of selected epidemiological studies of acute respiratory failure Incidence

Mortality %

Study

Design

Definition of ARF

Age of population

Setting, duration and year of study

[4]

Esteban

Prospective observationa I

Need of mechanical ventilation > 12 hours

Adult

361 International 33 % of ICU admissions ICUs, 1 month, 1998

Vincent

Prospective

Pa02 /Fi02 ratio < 200 and the need of mechanical respiratory support

> 12

40 International ICUs, 1 month, 1995

56 % of ICU

Sweden, Denmark Iceland & Norway, 8 weeks, 1997

41 % 77.6 per 100,000

Multicenter, 2 months

Not studied

[7]

observatio-

Luhr [2]

Prospective observationaI

Intubation and mechan- > 15 years ical ventilation ;:: 4 hours regardless of Fi02

Prospective observationaI

Mechanical ventilation > 24 hours and Fi02 > 0.5 for at least 24 hours.

Lewandowski

Prospective Observetional

Intubation and median- > 14 years ical ventilation ;:: 24 hours regardless of Fi0 2

Behrendt

Retrospective

ICD-9-CM for respiratory failure and mechanical ventilation

Vasilyev

[38]

[1] [3]

nal

years

All ages

admissions

30.7 %

31 %

person-years

44.4 %

1991-1992

> 5

years

42.7% Berlin (Germany), 88.6 per 100,000 8 weeks, 1991 person-years United States, 1 year 1994

35.9 % 137.1 per 100,000 person-years

incidence of acute respiratory failure in the USA, 137.1 per 100,000 patient-years. This incidence was estimated based on the ICD-9-CM disease codes for diagnoses and treatment in patients > 5 yrs old observed over a l- year period [3]. The significant variation between the US and European incidences may in part be explained by the differences in study design ( Table 2) and in part by incons istent indications and access to mechanical ventilation in different countries. Acute respiratory failure is often accompanied or followed by a failure of other vital organs, and death most often occurs becau se of multiorgan failure (MOF) and the withdrawal of mechan ical ventilati on when the chances for a meaningful recovery of the patient's qual ity of life are deemed to be exceedingly low. Imprecision of clinical prognostic criteria, variations in available resources, and patient and provider preferences limit the interpretation of mortality data from different epidemiologic studies. Reported mortality rates for acute respir ator y failure from the 1990s are remarkably similar, approximately 40 % in spite of differences in study designs and the definit ions applied (Table 2). Lewandowski and coworkers [1] studied 476 patients from 72 ICUs in Berlin, Germany and reported mortality rates of 36-58 % depending on the lung injury score (LIS). In a large prospective study from Scandinavia, Luhr and coworkers reported an all-cause 90-day mortality of 41 % [2]. In a large, prospective international cohort involving 361 ICUs, Esteban and coworkers reported an ICU mortality of 30.7 %. Mortality increased significantly in patients with sepsis, shock, ARDS, or liver failure [4]. Vincent and coworkers used sequential organ failure

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assessment (SOFA) score criteria and the need for mechanical ventilation to define acute respiratory failure and estimated an overall ICU mortality of 31 %. The mortality was much lower (7 %) when the lung was the only organ involved [5]. Recently, Flaatten and coworkers reported the mortality from acute respiratory failure at different time points after disease onset . Mortality was again the lowest in single organ acute respiratory failure and rose with each add itional organ failure. Higher mortality rates were found 90 days after the onset compared to at ICU or hospital discharge [6]. MOF following an ICU admission , presence of circulatory shock on ICU admission , older age, and pre-existing comorbidities (cirrhosis, malignancy and chronic renal failure) were independent risk factors for the mortality rate reported in several studies [4, 7- 9].

Epidemiology of Specific Clinical Syndromes Acute Lung Injury (ALI)

ALI and its more severe form, ARDS, are clinical syndromes defined as an acute onset of hypoxemic respiratory failure with diffuse pulmonary infiltrates in the absence of left atrial hypertension as the principal cause of acute pulmonary edema. ALI is a major cause of acute respiratory failure in the ICU and is associated with high morbidity and mortality. Since it was first described by Ashbaugh and colleagues [10] and than redefined in 1994 [11], there have been significant advances in the understanding of etiology, pathophysiology, and the epidemiology of ALI. Clinical risk factors for ALI are usually divided into direct (pulmonary) and indirect (extrapulmonary). Pneumonia, aspiration, lung contusion; and inhalation injury are the principal pulmonary risk factors, while sepsis, shock, trauma, pancreatitis, and multiple transfusions represent the most important extrapulmonary risk factors. In recent years, transfusion-related ALI (TRALI) and novel viral pathogens (severe acute respiratory syndrome [SARSj) have emerged as important risk factors for ALI. The reported incidence of All has varied significantly. The 1972 report of the National Heart and Lung Institute Task Force on Respiratory Diseases, estimated 150,000 cases of ARDS per year yielding the annual incidence of 75 per 100,000 person-years . Subsequent studies reported an incidence of All ranging from 16 to 34 cases per 100,000 person-years in European countries [2, 12] and Australia [13], and a much higher incidences of ALI in the USA, 78 per 100,000 persons-years (190,600 cases per year) [13-15]. While a significant minority of patients with All is treated with non-invasive ventilation (NIV), the majority of studies included only patients treated with invasive ventilation. A recently completed, retrospective, community cohort study in Olmsted County, Minnesota included patients treated with NIV and found an even higher incidence of ALI, 156 per 100,000 person-years (personal communication, Rodrigo Cartin -Ceba), Mortality from ALI varies greatly depending upon the age of the patient, underlying chronic illnesses, ALI risk factors, and non-pulmonary organ dysfunctions [15]. Two decades ago, the mortality rate from ALI ranged from 50 -70 % [4, 8, 16, 17], but has since declined and more recently has been estimated to be about 30- 50 % [2, 13, 15,23]. Advances in general supportive care [9] and the use of new mechanical ventilation strategies [16] may account for most of the change. Both the incidence of and mortality from All increase exponentially with age [1-3, 15, 18]. MOF [7, 19,20], liver failure, severe sepsis [8,9, 15, 17], aspiration [15], presence of infection and neurological failure on ICU admission [7], and pree-

Epidemiology of Acute Respiratory Failure and Mechanical Ventilation

xisting cirrhosis [2, 8, 17, 21], bone marrow transplantation, human immunodeficiency virus (HIV) [17], hematologic [7, 22] or active malignancy [17, 22], and Charlson comorbidity score [23] have been associated with a higher mortality. Persistent severe hypoxemia and cardiovascular failure also predict poor outcomes [21, 23].

Non-survivors of ALI die predominantly of MOE A landmark study published in

1985 reported that only 16 % of deaths were caused by respiratory failure [24]. Similar results (16 % and 9 %) were reported by two stud ies conducted in recent years [13, 25]. MOF, septic shock , and underlying comorbidities are the most common

causes of death in patients with ALI. Survivors of ALI often have a prolonged recovery and significant short and longterm disability. While lung function usually returns to normal within several months [9], neuromuscular and neurocognitive sequelae may persist much longer [26, 27]. The most important predictors of prolonged disability are the use of systemic steroids during the ICU stay, presence of a complicating illness acquired dur ing the ICU stay, and the rate of resolut ion of ALI and MOF [27]. Neuropsychologi cal sequelae are also common and about 27 % of long-term survivors develop posttraumatic stress disorder [28]. With a decline in mortality from ALI, more survivors are at risk of prolonged morbidity ('chronic critical illness') contributing to substantial increases in the utilization of health care resources. Cardiogenic Pulmonary Edema

Cardiogenic pulmonary edema is a common cause of acute respiratory failure. In about 10 % of the mechanically ventilated patients in an international cohort study, cardiogenic pulmonary edema was the principal reason for instituting mechanical ventilation [4]. Other epidemiologic studies reported similar rates of cardiogenic pulmonary edema [2, 29] with mortality ranging from 28 -48 % [1,4] . In the past two decades, NIV, both continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) ventilation, have received a great deal of interest in the management of patients presenting with acute cardiogenic pulmonary edema . Randomized trials comparing either CPAP or BiPAP with standard medical therapy, found similar improvements in arterial blood gases and breathing rates, reduced need for intubation, and improved outcome [30]. Acute Exacerbation of Chronic Obstructive Pulmonary Disease

According to the World Health Organization, chronic obstructive pulmonary disease (COPD) ranks fourth among all causes of death with an age-adjusted mortality rate of 39.9 per 100,000 person-years. The 20th century pandemic of cigarette smoking is taking its toll, evident by the increase in the annual hospitalization rate for acute exacerbation of COPD from 9.7 in 1988 to 24.4 % in 2005. Moreover, about 10 % of all hospitalizations are directly or indirectly attributable to COPD [31]. Many patients with acute exacerbation of COPD require admission to the ICU for acute respiratory failure. In an international cohort study [4], acute exacerbation of COPD was a principal indication for initiating mechanical ventilation in 13 % of patients with acute respiratory failure. The hospital mortality rate of COPD patients admitted with acute exacerbation varies between 2.5 - 30 %, depending on the methodology of the data collection and the patient population. Seneff et al. [32] reported a hospital mortality rate of 24 %

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H.S. Suri, G. Li, and O. Gajic in 362 admissions for acute exacerbation of COPD selected from the acute physiol ogy chronic health evaluation (APACHE) III database of 17,440 admissions in a prospective multicenter trial. Mortalities rose to 30 % at hospital discharge and doubled to 59 % at the l-year follow-up. Invasive mechanical ventilation was instituted in 170 of 362 patients with a mortality rate of 47 %. After controlling for the severity of illness , mechanical ventilation at ICU admission was not asso ciated with either hospital mortality or subsequent survival. Development of non-respiratory organ dysfunction was the most important predictor of hospital mortality, while the abnormalities in gas exchange (PaC0 2, pH , Pa0 2) indicative of advanced dysfunction were strongly associated with six month mortality. Esteban et al. [4] reported a hospital mortality of 28 % in patients receiving mechanical ventilation for acute exacerbation of COPD. Liu et al. [33] retrospectively studied a cohort of 138 patients with COPD requiring invasive mechanical ventilation for acute respiratory failure. The cause of acute respiratory failure was acute exacerbation of COPD in 55 % and pneumonia in 44 % of patients. The hospital mortality rate was 39.9 % in all patients and 31.1 % in the acute exacerbation of COPD subgroup. Respiratory acidosis was corrected (pH> 7.30) in 69.9 % of survivors but only in 21.8 % of non-survivors. In a recent study, 205 conse cutive patients hospitalized with acute exacerbation of COPD were followed prospectively for 3 years [31]. The in-hospital mortality rate was 8.3 %. The overa1l6-month mortality was 24 %, with 1-,2-, and 3-year mortality rates of 33 %, 39 %, and 49 %, respectively. More severe gas exchange abnormalities and longer hospital stays were associated with the hospital mortalities. Long-term mortality was associated with longer disease duration, lower serum albumin, low body mass index, and lower Pa02' MOF and sepsis were the most common immediate causes of death in patients with acute exacerbation of COPD admitted to the ICU. In another prospective study of 250 patients with acute exacerbation of COPD [34], invasive mechanical ventilation was started in 60 % and NIV was tried in 40 % of patients and was successful in 54 % of them. Median duration of ventilation was 6 days. After several clinical tr ials reported improved outcomes [35], NIV has become the principal init ial mode for providing mechanical ventilation to patients with acute exacerbation of COPD [36]. Since the indications for NIV are more liberal than those of invasive ventilation, it is difficult to directly compare the outcomes of mechanically ventilated patients treated with the two modes. In a study by Girou et al., however, adjusted odds of death (0.37; 95 % confidence interval [CI], 0.18-0.78) suggested that the mortality in patients with similar severity of illness treated with NIV was significantly lower.

Asthma Severe status asthmaticus is a rare cause of acute respiratory failure requmng mechanical ventilation (1.5 % of patients in the international cohort study) [4]. Patients in status asthmaticus who require invasive mechanical ventilation are at high risk of severe complications (pneumothorax, cardiopulmonary arrest) and mortality. Afessa et al. reported the incidence and outcomes of status asthmaticus in a US inner city hospital, from 1995 to 1998 [37]. Forty-eight out of 132 hospital admissions required mechanical ventilation (36 %). Mechanically ventilated patients had significant mortality (21 %) and high complication rates. Sixteen patients developed non-pulmonary organ failure and four developed pneumothorax requiring chest tube drainage. Interestingly, all patients who died in this study were female .

Epidemiology of Acute Respiratory Failure and Mechanical Ventilation Pneumonia

Pneumonia is a common cause of hypoxemic acute respiratory failure. Approximately 14- 23 % of acute respiratory failure episodes requiring mechanical ventilation are due to pneumonia. ICU mortality rates from acute respiratory failure due to pneumonia range from 37- 44 % [1, 2, 4, 38]. In many patients with pneumonia, however, complications such as septic shock and ALI, or acute worsening of underlying chronic lung disease (COPD) are the principal reasons for instituting mechanical ventilation . Compared to other ALI risk factors, pneumonia is associated with higher mortality (see ALI paragraph above). Interstitial Lung Diseases

The majority of patients with interstitial lung disease and acute respiratory failure admitted to the ICU require invasive mechanical ventilation . Interstitial lung disease is, however, an uncommon cause of acute respiratory failure (less than 2 % of patients in the international cohort study [4]). In a retrospective review [39] of 75 patients with interstitial lung disease who were mechanically ventilated at Mayo Clinic from 2003 to 2005, acute respiratory failure was the most common cause of ICU admiss ion (77 %), followed by sepsis (11 %) and cardiopulmonary arrest (4 %). Seventeen patients were initially treated with NIV but eventually all patients required invasive mechanical ventilation. Hospital mortality was 49 %. Patients with idiopathic pulmonary fibrosis tended to have a higher mortality rate than non -idiopathic pulmonary fibrosis forms of interstitial lung disease. Conventional lung protective mechanical ventilation was not associated with improved outcome. Worsening hypoxemia and higher positive end-expiratory pressure (PEEP) settings were associated with increased mortality. In an earlier study, Saydain and coworkers observed the clinical course of 38 patients with idiopathic pulmonary fibrosis admit ted to the ICU. Acute respiratory failure was the most common reason for ICU admission. While 49 % of the patients survived to hospital discharge, 12 of 13 survivors (92 %) died within 2 months after hospital discharge [40]. Neuromuscular Diseases

Patients with neuromuscular disease are frequently treated with both acute and chronic mechanical ventilation. Neuromuscular disease accounted for 2 % of patients receiving mechanical ventilation in the international cohort study [4]. Compared to other causes of acute respiratory failure, patients with neuromuscular disease had higher costs and length of ICU stay and 68 % required tracheostomy [4]. Hospital mortality was 15 %. Epidemiologic studies looking at the outcomes of acute respiratory failure due to specific forms of neuromuscular disease are scarce. Recently, Ali et al. [41] reported on the outcomes of 54 patients with Guillain-Barre syndrome who required mechanical ventilation. All but six patients (89 %) required tracheostomy. Forty-six patients (85 %) survived to hospital discharge, and 39 (72 %) were alive at the l-year follow-up Trauma

According to the international cohort study [4], in 7.3 % of patients mechanical ventilation was employed because of trauma. Hospital mortality for these patients was

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20 %. In a retrospective incident study of acute respiratory failure in the USA [3], acute respiratory failure related to trauma was more common in the younger age group and trauma without MOF was associated with a very low mortality rate. In a Scandinavian study, approximately 9 % of cases of acute respiratory failure were caused by trauma [2]. Of the 508 cases of acute respiratory failure in the Berlin study, 19 were due to trauma with mortality of 20 % [1]. Complicating coma, shock, and ALI are common indications for mechanical ventilation in patients with trauma. About 8-15 % of cases of ALI are related to trauma [2,4, 15] with mortality lower than that for other ALI risk factors (24 %, see above) [15].

Shock Shock is characterized by global hypoperfusion leading to lactic acidosis, hyperventilation and hypoperfusion of respiratory muscles, resulting in type IV respiratory failure. Up to 30 % of oxygen consumption in shock may be used by the respiratory muscles contributing to a global imbalance between oxygen delivery and consumption . Pulmonary edema, ALI, and anemia often contribute towards respiratory distress. Work of breathing may ultimately overcome respiratory reserve leading to the development of acute respiratory failure. Early use of mechanical ventilation in severe shock may be justified to limit the work of breathing and decrease oxygen consumption by respiratory muscles. Septic shock, in particular, is commonly associated with acute respiratory failure and ALI. In the international cohort study, septic shock was a primary indication for mechanical ventilation in 9 % of patients with mortality of 55 % [4]. Coma

Coma is a non-specific syndrome of widespread central nervous system impairment resulting from various metabolic and structural etiologies. It usually results in type II respiratory failure due to upper airway dysfunction and hypoventilation. Intubation and invasive mechanical ventilation are usually required to protect the airway and maintain gas exchange. In the study by Esteban et al. [4], 16 % of patients required mechanical ventilation because of coma. Reported ICU mortality was 36 % in patients with coma who received mechanical ventilation.

Conclusion and Future Considerations Advances in mechanical ventilation have dramatically changed the management and outcome of patients with acute respiratory failure. With increased access to mechanical ventilation , the burden of acute respiratory failure may grow beyond the health care budget of even the richest societies. Inconsistent use of standardized definitions for acute respiratory failure and, in particular, indications for mechanical ventilation, present the major impediment to the meaningful understanding of clinical research results and will have to be overcome in future studies. Population studies are needed to determine the risk factors, prevalence, and the attributable outcomes of various forms of acute respiratory failure in the community. Such studies will help identify the best strategies for the prevention and treatment of acute respiratory failure, will pinpoint important uncertainties that need to be tested in clinical trials, and will allow informed decisions regarding allocation of scarce resources so

Epidemiology of Acute Respiratory Failure and Mechanical Ventilation

that bedside practitioners may best improve the quality-adjusted survival of their patients . References 1. Lewandowski K, Metz J, Deutschmann C, et al (1995) Incidence, severity, and mortality of acute respiratory failure in Berlin, Germany. Am J Respir Crit Care Med 151 :1121-1125. 2. Luhr OR, Antonsen K, Karlsson M, et al (1999) Incidence and mortality after acute respiratory failure and acute respiratory distre ss syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 159:1849-1861 3. Behrendt CE (2000) Acute respiratory failure in the United States: incidence and 31-day survival. Chest 118:1100-1105 4. Esteban A, Anzueto A, Frutos F, et al (2002) Character istics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 287:345- 355 5. Vincent JL, Sakr Y, Ranieri VM (2003) Epidemiology and outcome of acute respiratory failure in intensive care un it pat ients. Crit Care Med 31 (suppI4):S296-299 6. Flaatten H, Gjerde S, Guttormsen AB, et al (2003) Outcome after acute respiratory failure is more dependent on dysfunct ion in other vital organs than on the severity of the respiratory failure. Crit Care 7:R72 7. Vincent JL, Akca S, De Mendonca A, et al (2002) The epidemiology of acute respiratory failure in critically ill pat ients. Chest 121 :1602- 1609 8. Doyle RL, Szaflarski N, Modin GW, Wiener-Kronish JP, Matthay MA (1995) Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 152:1818-1824 9. Suchyta MR, Orme JF, [r., Morris AH (2003) The changing face of organ failure in ARDS. Chest 124:1871-1879 10. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults. Lancet 2:319-323 11. Bernard GR, Artigas A, Brigham KL, et al (1994) The American-European Consensus Conference on ARDS. Definitions, mechan isms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818-824 12. Hughes M, MacKirdy FN, Ross J, Norr ie J, Grant IS (2003) Acute respiratory distress syndrome : an audit of incidence and outcome in Scottish intensive care units. Anaesthesia 58:838-845 13. Bersten AD, Edibam C, Hunt T, Moran J (2002) Incidence and mortality of acute lung injur y and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 165:443-448 14. Goss CH, Brower RG, Hudson LD, Rubenfeld GD (2003) Incidence of acute lung injury in the United States. Crit Care Med 31:1607- 1611 15. Rubenfeld GD, Caldwell E, Peabody E, et al (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353:1685- 1693 16. The Acute Respiratory Distress Syndrome Network. (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301-1308 17. Zilberberg MD, Epstein SK (1998) Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome. Am J Respir Crit Care Med 157:1159-1164 18. Stauffer JL, Fayter NA, Graves B, Cromb M, Lynch JC, Goebel P (1993) Survival following mechanical ventilation for acute respiratory failure in adult men. Chest 104:1222-1229 19. Kraus PA, Lipman J, Lee CC, et al (1993) Acute lung injury at Baragwanath ICU. An eightmonth audit and call for consensus for other organ failure in the adult respiratory distress syndrome. Chest 103:1832-1836 20. Squara P, Dhainaut JF, Artigas A, Carlet J (1998) Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study. Intensive Care Med 24:1018-1028 21. Monchi M, Bellenfant F, Cariou A, et al (1998) Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med 158: 1076-1081

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H.S. Suri, G. Li, and O. Gajic 22. Peters SG, Meadows JA, 3rd, Gracey DR (1988) Outcome of respiratory failure in hematologic malignancy. Chest 94:99- 102 23. Yilmaz M, lscimen R, Keegan MT, et al (2007) Six-month survival of patients with acute lung injury: Prospective cohort study. Crit Care Med 35:2303 - 2307 24. Montgomery AB, Stager MA, Carrico CT, Hudson LD (1985) Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 132:485-489 25. Ferring M, Vincent JL (1997) Is outcome from ARDS related to the severity of respiratory failure? Eur Respir J 10(6):1297- 1300 26. Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson LV (1999) Neuropsychological sequelae and impaired health status in surv ivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 160:50-56 27. Herridge MS, Cheung AM, Tansey CM, et al (2003) One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683-693 28. Schelling G, Stoll C, Haller M, et al (1998) Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 26: 651-659 29. Esteban A, Anzueto A, Alia I, et al (2000) How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med 161: 1450-1458 30. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito JA (2005) Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta -analysis. JAMA 294:3124-3130 31. Gunen H, Hacievliyagil SS, Kosar F, et al (2005) Factors affecting survival of hospitalized patients with COPD. Eur Respir J 26:234-241 32. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA (1995) Hospital and I-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA 274:1852-1857 33. Liu H, Zhang TT, Ye J (2007) Analysis of risk factors for hospital mortali ty in patients with chronic obstructive pulmonary diseases requiring invasive mechanical ventilation. Chin Med J (Engl )120:287-293 34. Afessa B, Morales IJ, Scanlon PD, Peters SG (2002) Prognostic factors, clinical course, and hospital outcome of patients with chronic obstructive pulmonary disease admitted to an intensive care unit for acute respiratory failure. Crit Care Med 30:1610-1615 35. Ram FS, Picot J, Lightowler J, Wedzicha JA (2004) Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev CD004104 36. Girou E, Brun-Buisson C, TaiIIe S, Lemaire F,Brochard L (2003) Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA 290:2985-2991 37. Messa B, Morales I, Cury JD (2001) Clinical course and outcome of patien ts admitted to an ICU for status asthmaticus. Chest 120:1616-1621 38. Vasilyev S, Schaap RN, Mortensen JD (1995) Hospital survival rates of patients with acute respiratory failure in modern respiratory intensive care units. An international, multicenter, prospective survey. Chest 107:1083 -1088 39. Fernandez-Perez ER, Tenad H, Daniels CE, Ryn TH, Gajic 0 (2006) Ventilator settings and outcome in pat ients with interstitial lung disease requiring mechanical ventilation in the intensive care unit. Chest 130:152s (abst) 40. Saydain G, Islam A, Messa B, Ryu JH, Scott JP, Peters SG (2002) Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 166:839 - 842 41. Ali MI, Fernandez-Perez ER, Pendern S, Brown DR, Wijdicks EF, Gajic 0 (2006) Mechanical ventilation in patients with GuiIlain-Barre Syndrome . Respir Care 51:1403-1407

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Esophagectomy and Acute Lung Injury D .P. PARK, D . GOUREVITCH, and G.D. PERKINS

Introduction Esophagectomy is a complex surgical procedure, with significant associated morbidity and mortality. Pulmonary complications are particularly common. This chapter will discuss the incidence, pathophysiology and treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following esophagectomy. This topic is important not only in improving our postoperative care for patients undergoing upper gastrointestinal surgery, but because ALI and ARDS following esophagectomy may provide an excellent model for the study and understanding of these syndromes across all areas of critical care.

Esophagectomy Esophagectomy is a major surgical intervention involving resection of all or part of the esophagus and subsequent restoration of continuity to the gastrointestinal tract. Surgery is usually performed for the treatment of carcinoma of the esophagus; other indications may include Barrett's esophagus associated with severe dysplasia, fixed rigid strictures, corrosive strictures and the iatrogenic perforated esophagus. Esophagectomy is reported to have an in-hospital mortality rate of approximately 10 % [1-4], and is associated with a high risk of major postoperative complications. There is no established optimal surgical approach, and a number of different procedure s are currently performed. Choice of operation is largely determined by the position of the lesion, and the preference and experience of the surgeon. The most common approach in the UK has been the Ivor-Lewis resection, a two stage operation which necessitates a laparotomy and a right-sided thoracotomy. Extensive two field lymph node dissection of abdominal and thoracic lymph nodes is combined with the procedure. A period of one lung ventilation is required in order to facilitate appropriate surgical access. Esophageal resections involving thoracotomy can also be performed via a left thoraco-abdorninal incision. Alternatively a transhiatal approach may be employed in an attempt to avoid opening the chest . This usually involves a left cervical incision and a midline laparotomy with mobili zation of the intrathoracic esophagus between the two incisions (the Orringer technique) . Minimally invasive approaches to esophageal resection using laparoscopic and video assisted thoracoscopic surgery (VATS) are also increasingly used. The optimal surgical approach for esophagectomy continues to be debated amongst surgeons. It might be expected that a thoracotomy would carry a higher risk of pulmonary complications, and this was found to be the case in a recent meta -

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D.P. Park, D. Gourevitch, and G.D. Perkins

analysis looking at studies comparing transhiatal with transthoracic operations ; however, there was no difference in five-year mortality [1]. Complications are common following esophagectomy by whichever technique and surgical approach, affecting almost two thirds of all patients. In a recent report of a large multicenter database from hospitals across England and Wales the risk of a technical complication relating directly to the surgery itself was 20 %, including the development of an anastomotic leak, abscess, or wound infection [4]. The most common 'medical' complications involved the respiratory system, and affected 41 % of patients, although cardiac complications were also frequent, with an incidence of 16 %. In particular, post-esophagectomy respiratory complications include the development of pneumonia, pleural effusion, atelectasis and ALIIARDS.

Acute Lung Injury/Acute Respiratory Distress Syndrome ARDS is a condition characterized by severe disturbance in pulmonary gas exchange. It was first described by Ashbaugh and colleagues in 1967 [5], who documented twelve patients with respiratory distress, diffuse infiltrates on chest radiograph, refractory cyanosis, and decreased lung compliance. Further work on and understanding of the condition has always been hampered by a difficulty in precise diagnosis, and in particular in distinguishing ARDS from other pathologies affecting the lungs such as pneumonia, atelectasis and cardiac failure. Not only are these conditions common in a critical care setting, but there may be considerable interaction between them, and different pathologie s may coexist within the same patient. Several further attempts have been made at a workable definition. In 1994, an American-European Consensus Committee (AECC) defined ARDS as a syndrome of acute onset, in which bilateral infiltrates were present on chest radiography without clinical evidence of left atrial hypertension, and gas exchange is impaired such that the ratio of the partial pressure of oxygen in arterial blood to the faction of inspired oxygen (PaO/FiO z) is 200 or less [6]. In addition a syndrome of 'acute lung injury' was defined to include those patients with less severely impaired gas exchange, where the PaOz/FiO z is 300 or less. The AECC definition has the advantage that it can be readily applied at the bedside, but its limitations include variability in the interpretation of chest radiographs and clinical assessment of cardiac status. In addition there is no standardization of the respiratory support offered when quantifying hypoxemia, leading to the description of a very heterogeneous group of patients . ALII ARDS is characterized at a cellular level by intense alveolar inflammation and damage to the alveolar-capillary barrier leading to increased permeability and the influx into the alveoli of a protein rich edema fluid. Extensive hyaline membrane formation takes place in the flooded alveoli. The inflammatory response is mediated by a complex cascade of cytokines and other inflammatory substances. Cytokines may be produced locally by lung epithelial cells, inflammatory cells, and fibroblasts. Inflammatory mediators thought to play an important role include interleukin (IL)1, IL-6, and IL-8, tumor necrosis factor (TNF)-a, a range of oxidants, proteases, and platelet activating factor (PAF). Anti-inflammatory substances, such as IL-I receptor antagonist (IL-Ira) , IL-IO and 11, and soluble TNF receptor are also present [7]. The subsequent course of the condition is highly variable. Some individuals undergo rapid resolution of the edema with an associated recovery in respiratory function. Others develop granulation tissue within the airspaces and ultimately

Esophagectomy and Acute Lung Injury

fibrosis and scarring of lung tissue. Pulmonary hypertension and right heart failure may develop following damage to pulmonary capillaries. Many survivors of ARDS experience considerable long-term pulmonary, musculoskeletal, and neuropsychological disability, and carry a significant financial burden [8). The precise incidence of ALIIARDS has been difficult to establish with certainty. A recent single center prospective cohort study using the AECC definition found ALI to be present in 78.9 cases per 100,000 person years whilst 58.7 cases per 100,000 person years met the stricter criteria for ARDS [9). The mortality rate for ARDS is between 34 and 58 %, with this figure falling in recent studies compared to those from a decade ago [8). Most patients with ALI/ARDS do not die from the lung injury itself, and it is likely that the improvement in mortality relates to better treatment and supportive care for associated conditions such as sepsis. The causes of ALIIARDS may be divided into those involving direct and indirect lung injuries. A direct lung injury is most frequently due to pneumonia or aspiration of gastric contents. Common indirect etiologies include sepsis and major trauma with shock and multiple transfusion.

Incidence and Outcome of ALI/ARDS following Esophagectomy Determining the incidence of ALIIARDS following esophagectomy is made difficult because in most of the large reported series on outcome it is grouped with other conditions under a composite heading such as 'respiratory failure' or 'pulmonary complications'. Table 1 gives a selection of studies on esophageal surgery that have documented the incidence of respiratory complications. It is clear that despite differences in definition respiratory complications are very common after esophagectomy, Table 1. Selected large studies giving overall mortality and incidence of pulmonary complications after esophagectomy Study

Recruit- Study design ment dates

Number of patients

Definition of pulmonary complications

Incidence of pulrnonary complications

Overall mortality

Hulscher et al [1 ]

19691999

7243

Not further defined

Randomized studies (transhiatal 43.8%, transthoracic 37.7%) All studies (transhital, 12.7%, transthoracic 18.7 %)

7.5 %

Worldwide meta-analysis

Ferguson 1980and 2000 Durkin [2]

USsingle center retrospective

292

Bailey et al [3]

19912001

US multicenter prospective observational study

1777

McCulloch et al [4]

1993 2003

UK multicenter prospective observational study

365

Reintubation for 27 % isolated respiratory failure, pneumonia

7%

Unplanned relntu- 16.2 % bation Mechanical ventila- 22% tion over 48 hours

9.8 %

Not further defined

40.5%

14%

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D.P. Park, D. Gourevitch, and G.D. Perkins Table 2. Selected studies giving incidence of ALI/ARDS after esophageetomy Number of patients

Study

Recruitment dates

Study design

Gockel et al [48]

1985- 2004

German single center 424 case series

Schilling et al [40]

1994 -1998

Swiss retrospective case series

Tandon et al [10]

1996- 1999

Ryan et al [20] Schilling et al [28]

Definition of Incidence of ALI/ARDS ALI/ARDS

Mortality after ALI/ARDS

Not given

6.5 % (ARDS)

Not given

118

AECC

16.9 % (ARDS)

Not given

UK single center prospective

193

AECC

23.8 % (ALI) 14.5 % (ARDS)

ARDS mortality 50 %

1999- 2005

Irish sing le center retrospective

200

Not given

7% (ARDS)

Not given

Not given

Prospective observetional study Switzerland

AECC

33 % (ARDS)

Not given

18

with an incidence ranging between 12.7 % and 40.5 % in the five large studies quoted in Table1 They are also associated with a greatly increased risk of postoperative mortality, quantified in the study by Ferguson et al. as a rise from 7 % to 32 % [2]. A number of studies have looked specifically at the incidence of ALI/ARDS following esophagectomy ( Table 2). The incidence quoted varies widely, reflecting the different definitions in use (several of the studies listed predate the AECC definition), the impact of different operative techniques. Prospective studies are likely to be most reliable, and in the largest of these, Tandon et al. found an incidence of ARDS of 14.5 %, with a mortality of 50 % [10].

Risk Factors for the Development of ALi/ARDS Factors which might predispose to the development of pulmonary complications following esophagectomy have been extensively studied, and will IlPW be summarized. Not all of these studies have specifically looked for the inc.idenc!l gf ALI/A~.DS, and these patients are included within wider categories such as 'respiratory failure' and 'length of mechanical ventilation: Table 3 gives some of the more recent studies which have looked at preoperative measures of patient fitness to predict postoperative pulmonary complications. Increasing age and poor respiratory function by a variety of measures have commonly been found to be associated with a worse respiratory outcome. That this is not more frequently the case may reflect the strict case selection which takes place for such major surgery. With increasing understanding of the importance of genetics in the incidence and outcome of both cancer and ALI/ARDS, work has been done to try to identify a genetic predisposition for the development of pulmonary complications following esophagectomy. Lee et al. [11] investigated the role of an angiotensin converting enzyme (ACE) insertion/deletion polymorphism in the development of these complications. These researchers reported that possession of the DID genotype was

Esophagectomy and Acute Lung Injury Table 3. Selected studies relating preoperative measures of patient fitness to pulmonary complications Study

Number Date of proceof dures patients

Definition of pulmonary complication

Patient factors found to predict pulmonary complications

Ferguson et al [2]

292

1980-2000

Reintubation for respiratory failure Pneumonia

Age, FEV1

Kuwano et al [49]

178

1989- 1993

Respiratory failure Pneumonia

FEV1, FVC

Law et al [13]

421

1990-2001

Pneumonia Respiratory failure

Age

61

1994- 2000

Length of mechanical ventilation

Age, pulmonary function

168

1996 - 1999

ARDS (AECC)

Low BMI, cigarette smoking

Avendano et al [50] Tandon et al [10]

FEV 1: forced expiratory volume in one second; FVC: forced vital capacity; BMI: body mass index

associated with the development of pulmonary complications postoperatively, especially in association with other risk factors such as age, hypoalbuminemia, and poor pulmonary function. A higher incidence of infectious complications, including pneumonia, following esophagectomy was also found to be related to genetic polymorphisms in the promoter region of the TNF-a gene [12]. It is likely that further studies in this area will yield increasing evidence of a genetic link to outcome. Intra-operative variables have also been addressed in a number of studies . Law et al. [13] found that the length of operation was associated with the development of pulmonary complications, whilst Tandon et al. [10] reported that the experience of the surgeon, the duration of the operation and of one lung ventilation , and cardiorespiratory instability (as measured by perioperative hypoxemia, hypotension, fluid and blood requirements, and the need for inotropic support) were all correlated with the development of ARDS. The surgical approach used for esophagectomy might be expected to have a profound effect on the incidence of subsequent pulmonary complications. A meta-analysis of 50 studies (three of which were randomized) carried out by Hulscher et al. [1] in 2001 found no difference in five-year survival between transthoracic and transhiatal procedures , but a significantly higher risk of pulmonary complications in the transthoracic group (RR 1.47, CI 1.29-1.68). Hulscher et al. [14] also performed a randomized trial of 220 patients comparing a transhiatal approach with a transthoracic esophagectomy with extended en bloc lymphadenectomy. Their results agreed with the meta-analysis in showing an increase in pulmonary complications (57 % vs 27 %, p< 0.001), but they also reported a trend towards a survival advantage at five years in the transthoracic group. Esophagectomy is increasingly being undertaken with the assistance of a thoracoscope to allow a 'minimally invasive approach'. Early case series have not demonstrated the expected benefits of reducing postoperative respiratory morbidity, and the first published study directly comparing minimally invasive and open esophagectomy in 34 patients showed no difference in respiratory complications [15]. The procedure has a steep learning curve, and experience of the surgeon is likely to be

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of great importance. One of the largest case series published to date (222 patients) from a high volume center quoted a postoperative ARDS rate of 1.8 % and pneumonia in 7.7 % [16]. Annual hospital case load also has a marked effect on the incidence of pulmonary complications. A recent meta-analysis has suggested that as with many other complex surgical operations, mortality rates following esophagectomy are lower in units performing larger numbers of procedures [17]. Unsurprisingly, as pulmonary complications are a major determinant of mortality, these have also been shown to be less common at high volume institutions. Thus, for example, Dimick et al. looked at 366 patients undergoing esophageal resection in Maryland between 1994 and 1998, and found that 11.8 % suffered from pulmonary failure at institutions with an annual case load of less than 34, but only 2.9 % at high volume hospitals (p = 0.001) [18]. A similar reduction of operative mortality for hospitals with larger numbers of cases has also been found in the UK [4]. This has led to guidance being issued in 2001 that the provision of esophagectomy should be a centralized service, and there is evidence that the implementation of this strategy has led to a fall in mortality [19].

Postoperative measures have also been investigated to look for variables predictive of pulmonary complications. In a retrospective study of 200 patients undergoing esophagectomy for malignant disease, Ryan et al. [20] looked at serum albumin levels on postoperative days one, three, and seven. They found that patients with an albumin of less than 20 gIl on day one were twice as likely to develop postoperative complications. The incidence of ARDS increased from 5 % to 22 % between the two groups. The relationship between the use of neoadjuvant chemotherapy and the development of pulmonary complications was addressed in a recent Cochrane review [21], and a meta-analysis by Urschel and Vasan [22] looked for a link with chemoradiotherapy. No evidence of an association was found in either case. The area remains controversial however, and meta-analysis is made more challenging by an insufficient number of appropriately powered studies, and no standardization for the histology of the tumor or the chemotherapy or radiotherapy regime. A recent prospective observational study of 200 patients, found increased numbers of patients with respiratory failure and ARDS in a group of patients receiving chemoradiotherapy before surgery as compared to those receiving surgery alone [23].

The Nature of ALI/ARDS following Esophagectomy Is the lung injury developed following esophagectomy similar to that of ALIIARDS from other causes? This question will be addressed with a discussion of the likely etiologies of ALII ARDS in this setting, and then a brief summary of our understanding of its pathophysiology. The perioperative course of esophagectomy involves many insults which might be expected to give rise to 'classic' ALIIARDS. Procedures involving a transthoracic approach require the patient to undergo a period of one-lung ventilation. Traditionally this has been carried out with near normal tidal volumes, exposing the ventilated lung to the risk of ventilator-induced lung injury (VILI). VILI is recognized as important in the pathogenesis of ALI/ARDS, and a protective lung ventilation strategy has been shown to reduce mortality in patients with established ARDS [24]. One-lung ventilation is also commonly performed with a high Fi0 2, in order to

Esophagectomy and Acute Lung Injury

maintain arterial oxygenation. Hyperoxic ventilation has been implicated in the pathogenesis of ALI/ARDS [25], as has the ischemialreperfusion injury to which the collapsed lung is exposed. Evidence for the role of one-lung ventilation in patients undergoing esophagectomy is provided by a study which measured levels of the inflammatory cytokine, 1L-6, part of the inflammatory cascade triggered during ALIIARDS. It was found that 1L-6 levels were higher in patients receiving prolonged one-lung ventilation, and reduced by temporary ventilation of the collapsed lung [26]. The use of an intraoperative protective ventilation strategy has also been shown to reduce the subsequent rise in inflammatory cytokines, and lead to earlier extubation [27]. Other well described causes of ALII ARDS which may occur during the operation itself or in the postoperative period include multiple blood transfusions, the development of prolonged hypotension, and the need for large volume fluid replacement. Later complications, including the development of pneumonia or sepsis (from, for example, an anastomotic leak), may also lead to ALI/ARDS, as may aspiration following gastroplasty. The peak incidence of radiographic criteria for ALIIARDS has been found to be on the seventh postoperative day [28], perhaps suggesting a significant role for some of the causes of ALII ARDS occurring later in the postoperative course. There are thus many potential explanations for why an esophagectomy patient may develop 'classic' ARDS. There is also some evidence that the pathology is similar at a cellular level. The presence of cytokines and other mediators in the plasma and alveoli of patients post-esophagectomy, which are also seen in patients with ALI/ARDS from other causes, has been well described [29-32]. Simply finding inflammatory cytokines after a major surgical insult clearly has to be interpreted with caution; however, in some cases a significant association was found between the levels of these mediators and the subsequent development of ALIIARDS. For example, a study by Tsukada et al. [32] showed higher levels of the inflammatory cytokine, 1L-8, in bronchoalveolar lavage (BAL) specimens after surgery, with the highest levels in those patients going on to develop pulmonary complications. Further work by the same group found that levels of BAL fluid granulocyte colony stimulating factor (G-CSF) were associated with the development of pulmonary complications following esophagectomy [33]. BAL fluid G-CSF levels have previously been demonstrated to correlate with both the presence of ARDS and the severity of pulmonary neutrophilia [34]. An increase in vascular permeability is characteristic of ALII ARDS. This has been shown in large animal models [35], and also in human patients with ARDS [36]. Demonstrating a similar increase following esophagectomy has been more problematic, although work in this area has only been on very small numbers of patients. One study by Rocker et al. [30], which looked at serial changes in nine patients after surgery, showed an increased pulmonary capillary permeability to transferrin at eight hours, but this finding was not confirmed in a second study comparing 20 patients undergoing esophagectomy with healthy volunteers [29]. A further recent study of patients with a variety of insults including eight patients who had undergone transhiatal surgery was also unable to correlate pulmonary vascular permeability to lung injury score [37]. It is, however, likely that Rocker's serial approach is a more sensitive technique.

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Prevention and Treatment Options for ALI/ARDS after Esophagectomy The treatment of ALIIARDS on the critical care unit remains largely supportive. The use of a protective ventilation strategy remains the only intervention that has been shown to reduce mortality in ARDSIALI in a large randomized controlled trial [24]. Both the use of methylprednisolone in established ARDS and a conservative fluid strategy have been shown to reduce the number of ventilator free days in the first month, but neither improved mortality at 60 days [38, 39]. A number of small studies have been carried out specifically on esophagectomy patients to attempt to improve outcomes from postoperative lung injury. It has previously been recognized that ALIIARDS following esophagectomy has the potential to provide an excellent model for our understanding of the condition in a wider context [30]. We have seen that there is a high incidence of ALI/ARDS following these procedures, and the pathophysiology of lung injury in this setting appears to be similar to that of 'classic' ARDSIALI. Most triggers for ALI/ARDS are highly unpredictable, making prophylactic or early therapy difficult or impossible to administer, and running a clinical trial would be equally challenging. In contrast, elective surgery provides a timed insult of relatively uniform severity to a population which can be recruited in advance. In addition, patients undergoing esophagectomy are a largely homogeneous group. Individuals tend to be suffering from the same disease, are of similar age, mostly male, have often suffered from weight loss, and have smoking or ex-smoking as a risk factor in common. Given the advantages of this model, it is perhaps surprising that it has not been utilized more frequently. A number of groups have conducted small trials, including Schilling et al. [40], who published a study of 38 consecutive patients undergoing esophagectomy treated perioperatively with ketoconazole. This drug is a thromboxane synthase inhibitor, which it was postulated would reduce the activity of the inflammatory cascade associated with the development of lung injury and reduce the vasoactive alterations associated with surgical mesenteric traction and endotoxin release. A statistically significant reduction was recorded in the incidence of ARDS, from 16.9 % to 2.6 %, but the study was not randomized, and a historical control group was used for comparison. More recently Zingg et al. [41] administered high dose N-acetylcysteine to 22 patients undergoing esophagectomy including a thoracotomy, hypothesizing that its anti-oxidant effects would lead to an improvement in postoperative pulmonary complications. They reported that N-acetylcysteine improved postoperative oxygenation, and reduced overall pulmonary complications, although the numbers were small. This group also used a set of historical controls. Several randomized controlled trials have been carried out in Japan using methylprednisolone administered shortly prior to surgery at a dose of 10- 30 mg/kg. Although these trials are probably too small to show a mortality benefit, a reduction in the incidence of postoperative pulmonary complications, and a reduction in the levels of inflammatory cytokines and improvement in postoperative oxygenation have been demonstrated [42]. Further investigations currently in progress include phase WIll trials to look at the effectiveness of long acting beta agonists and statins in preventing postoperative ALII ARDS. Beta agonists have been shown to reduce extravascular lung water in patients with established ARDS [43], whilst statins are known to have anti-inflammatory properties and have been found to reduce endothelial permeability in an endotoxemic sepsis model of ALIIARDS following the administration of endotra-

Esophagectomy and Acute Lung Injury

cheal lipopolysaccharide [44]. High dose N-acetylcysteine is also being trialled in patients undergoing esophage ctomy with a focus on reducing pulmonary morbidity and improving long term health outcom es. Non-pharmacological aspects of perioperative management have also been suggested to impro ve outcome following esophagectomy. The use of an algorithm restricting intraoperative fluid therap y was found to reduce pulmonary complica tions and shorten the recovery per iod in hospital in a retrospective study of 112 patients [45], and low rates of postoperative morbidity (including respiratory complications) were reported when fluid restriction was used as part of a multi-modal regime including early extubation, early enteral nutrition, minimal opioids, and intraoperative epidural lidoca ine [46]. Advocates of a 'fast tra ck' approach maintain that through close attention to physioth erapy, nut rition, analgesia , restrictive fluid management, and early extubation it is possible to minimize postoperative complications and reduce the need for intensive care support [47].

Conclusion Esophagectomy is a complex surgical pro cedure which continues to carry a risk of significant mortalit y and morbidity. The optimal surgical approach is still a subject of debat e. The most common postoperative complications affect the respiratory system, and ALlI ARDS is prominent among st these. It seems likely that this is similar in nature to 'classic' ALlI ARDS from other causes. Much is known about factors predispo sing to pulmonary complications following esophage ctomy, but fewer studies have looked specifically at which of these may increase the risk of ALIIARDS. Esophagectomy leading to ALlI ARDS may provide a useful model for studies in the pre vention and early treatment of the condi tion in oth er sett ings, and a number of inter ventional trial s are cur rently underway. References I. Hulscher ), Tijssen ), Obertop H, van Lanschot ) (2001) Transthoracic versus transhiatal

resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 72:306 -3 13 2. Fergu son M, Durk in A (2002) Preoperative predict ion of the risk of pulmonar y complications after esophagectomy for cancer. ) Thorac Cardi ovasc Surg 123:661 -669 3. Bailey S, Bull D, Harp ole D, et al (2003) Outcomes after esophagectomy: a ten -year prospective cohort. Ann Thora c Surg 75:217 - 222 4. McCulloch P, Ward ), Tekkis P (2003) Mortality and morbidity in gastro- oesophageal cancer sur gery: initia l results of ASCOT multi center pro specti ve cohort study. BM) 327:1192-1197 5. Ashb augh D, Bigelow D, Petty T, Levine B (1967) Acute respiratory distr ess in adults. Lancet 2:319-323 6. Bern ard G, Artigas A, Brigham K, et al (1994) The American-European Consensus Conference on ARDS. Definition s, mechanisms, relevant outcomes, and clinical tr ial coordination. Am) Respir Crit Care Med 149:818 - 824 7. Ware L, Matthay M (2000) The acute respirator y distr ess syndro me. N Engl I Med 342: 1334 - 1349 8. Rubenfeld GD, Herri dge MS (2007) Epidemiology and outcomes of acute lung injury. Chest 131: 554 - 562 9. Rubenfeld G, Caldwell E, Peabody E, et al (2005) Incidence and outcomes of acute lung injury. N Engl I Med 353:1685- 1693 10. Tand on S, Batchelor A, Bullock R, et al (2001) Peri-oper ative risk factors for acute lung injury after elective oesophagectomy. Br) Anaesth 86:633-638

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D.P. Park, D. Gourevitch, and G.D. Perkins 11. Lee J, Lo A, Yang S, Tsau H, Chen R, Lee Y (2005) Association of angiotens in-convert ing enzyme insertion/deletion polymorphism with serum level and development of pulmonary complications following esophagectomy. Ann Surg 241:659-665 12. Azim K, McManus R, Brophy K, Ryan A, Kelleher D, Reynolds J (2007) Genetic polymerphisms and the risk of infection following esophagectomy. positive association with TNFalpha gene -308 genotype . Ann Surg 246:122 -128 13. Law S, Wong K, Kwok K, Chu K, Wong J (2004) Predictive factors for postoperative pulmonary complications and mortality after esophagectomy for cancer. Ann Surg 240:791-800 14. Hulscher J, van Sandick J, de Boer A, et al (2002) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669 15. Nguyen N, Follette D, Wolfe B, Schneider P, Roberts P, Goodnight JJ (2000) Comparison of minimally invasive esophagectomy with transthoracic and transhiatal esophagectomy. Arch Surg 135:920- 925 16. Luketich J, Alvelo-Rivera M, Buenaventura P, et al (2003) Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg 238:486-495 17. Metzger R, Bollschweiler E, Vallbohmer D, Maish M, DeMeester T, Holscher A (2004) High volume centers for esophagectomy: what is the number needed to achieve low postoperative mortality? Dis Esophagus 17:310-314 18. Dimick J, Pronovost P, Cowan J, Lipsett P (2003) Surgical volume and quality of care for esophageal resection: do high-volume hospitals have fewer complications? Ann Thorac Surg 75:337-341 19. AI-Sarira A, David G, Willmott S, Slavin J, Deakin M, Corless D (2007) Oesophagectomy practice and outcomes in England. Br J Surg 94:585-591 20. Ryan A, Hearty A, Prichard R, Cunningham A, Rowley S, Reynolds J (2007) Association of Hypoalbuminemia on the First Postoperative Day and Complications Following Esophagectomy. J Gastrointest Surg 11:1355- 1360 21. Malthaner R, Collin S, Fenlon D (2006) Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 3:CD001556 22. Urschel J, Vasan H (2003) A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 185:538-543 23. Reynolds J, Ravi N, Hollywood D, et al (2006) Neoadjuvant chemoradiation may increase the risk of respiratory complications and sepsis after transthoracic esophagectomy. J Thorac Cardiovasc Surg 132:549-555 24. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distre ss syndrome. N Engl J Med 342:1301-1308 25. Altemeier W, Sinclair S (2007) Hyperoxia in the intensive care unit: why more is not always better. Curr Opin Crit Care 13:73-78 26. Ojima H, Kuwano H, Kato H, et al (2007) Relationship between cytokine response and temporary ventilation during one-lung ventilation in esophagectomy. Hepatogastroenterology 54:111-115 27. Michelet P, D'[ourno X, Roch A, et al (2006) Protective ventilation influences systemic inflammation after esophagectomy: a randomized controlled study. Anesthesiology 105: 911-919 28. Schilling M, Gassmann N, Sigurdsson G, et al (1998) Role of thromboxane and leukotriene B4 in patients with acute respiratory distress syndrome after oesophagectomy. Br J Anaesth 80:36-40 29. Reid P, Donnelly S, MacGregor I, et al (2000) Pulmonary endothelial permeability and circulating neutrophil-endothelial markers in patients undergoing esophagogastrectomy. Crit Care Med 28:3161 -3165 30. Rocker G, Wiseman M, Pearson D, Shale D (1988) Neutrophil degranulation and increased pulmonary capillary permeability following oesophagectomy: a model of early lung injury in man. Br J Surg 75:883-886 31. Sato N, Koeda K, Kimura Y, et al (2001) Cytokine profile of serum and bronchoalveolar lavage fluids following thoracic esophageal cancer surgery. Eur Surg Res 33:279-284

Esophagectomy and Acute Lung Injury 32. Tsukada K, Hasegawa T, Miyazaki T, et al (2001) Predictive value of interleukin-8 and granulocyte elasta se in pulmonar y compl ication after esophagectomy. Am J Surg 181:167-1 71 33. Tsukada K, Miyazaki T, Katoh H, et al (2004) Interferon-gamma and granulocyte colonystimulating factor in bronchoalveolar lavage fluid after oesophagectomy. Dig Liver Dis 36: 572-576 34. Aggarwal A, Baker C, Evans T, Haslam P (2000) G-CSF and lL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distres s syndrome. Eur Respir J 15:895-901 35. Brigham K, Bowers R, Haynes J (1979) Increa sed sheep lung vascular permeability caused by Escherichia coli end otoxin. Circ Res 45:292- 297 36. Sinclair D, Braud e S, Haslam P, Evans T (1994) Pulmonary endo thelial permeability in patient s with severe lung injur y. Clinical corr elates and natur al histor y. Chest 106:535- 539 37. Groeneveld A (2007) Increased permeabilit y-oedema and atelectasi s in pulmonary dysfunc tion after trauma and surg ery: a pro spective cohort study. BMC Anesthesio l 7:7 38. Steinberg K, Hudson L, Goodman R, et al (2006) Efficacy and safety of corticostero ids for persistent acute respirator y distre ss syndr ome. N Engl J Med 354:1671- 1684 39. Wiedemann HP, Wheeler AP, Berna rd GR, et al (2006) Comparison of two fluid-m anagement strategies in acute lun g injury. N Engl J Med 354:2564- 2575 40. Schilling M, Eichenberger M, Maure r C, Sigurdsso n G, Buchler M (2001) Ketoconazole and pulmonary failur e after esop hagectomy: a prospective clinical trial. Dis Esophagus 14:37- 40 41. Zingg U, Hofer C, Seifert B, Metzger U, Zollinger A (2007) High dose N-acetylcysteine to prevent pulm onar y complications in parti al or total transthoracic esoph agectomy: results of a prospect ive observational study. Dis Esophagus 20:399-405 42. Raimondi A, Guimarces H, Amaral J, Leal P (2006) Periop erative glucocorticoid administration for preventi on of system ic organ failure in patient s undergoing esophageal resection for esophageal carcinoma. Sao Paulo Med J 124:112-11 5 43. Perkins G, McAuley D, Thickett D, Gao F (2006) The bet a-agonist lung injury trial (BALT!): a randomized placebo-controlled clinical tr ial. Am J Respir Crit Care Med 173:281- 287 44. Jacobson J, Barna rd J, Grigo ryev D, Ma S, Tuder R, Garcia J (2005) Simvastatin attenuates vascular leak and inflammatio n in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 288:L1026 -1032 45. Kita T, Mamm oto T, Kishi Y (2002) Fluid man agement and postoperative respiratory dist urbances in patients with tr ansthoracic esophagectomy for carcinoma. J Clin Anesth 14: 252 - 256 46. Neal J, Wilcox R, Allen H, Low D (2003) Near-total esoph agectomy: the influence of standardized mult imoda l man agement and intrao perative fluid restr iction. Reg Anesth Pain Med 28:328- 334 47. Low D (2007) Evolutio n in peri operative management of patients undergoing oesophagectomy. Br J Surg 94:655 - 656 48. Gockel I, Exner C, Iunginger T (2005) Morbidity and mortality after esophagectomy for esophageal carcinom a: a risk analysis. World J Surg Oncol 3:37 49. Kuwano H, Sumiyoshi K, Sonoda K, et al (1998) Relation ship between preoperative assessment of organ function and postoperative morbidity in patients with oesophageal cancer. Eur J Surg 164:581 - 586 50. Avenda no C, Flume P, Silvestri G, King L, Reed C (2002) Pulmo nary complicatio ns after esopha gectomy. Ann Thorac Surg 73:922 - 926

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Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe? P. PELOSI and P.R.M. Rocco

Introduction In the early phases of acute respiratory distress syndrome (ARDS) the evolution of systemic and pulmonary inflammation during mechanical ventilation determines the physiological progression (resolving or unresolving) and outcome of the disease [1- 3]. In order to achieve partial or total resolution of ARDS, an innate or treatment-induced downregulation of systemic inflammation may be required [1]. Glucocorticoids, as end-effectors of the hypothalamic-pituitary-adrenal (HPA) axis, are the most important physiologic inhibitors of inflammation [4] affecting genes involved in stress-related homeostasis [5]. Recent studies have shown that systemic inflammation-induced glucocorticoid receptor resistance and/or insensitivity is an acquired, generalized process central to the pathogenesis of unresolving ARDS that is potentially reversed by quantitatively adequate and prolonged glucocorticoid supplementation [1,2,6]. This chapter will review the mechanisms of action of corticosteroids and the results of experimental and clinical studies on the use of corticosteroids in ARDS.

ARDS: A Static or Progressive Disease? ARDS is thought to be a uniform expression of a diffuse and overwhelming inflammatory reaction of the pulmonary parenchyma to a variety of serious underlying diseases [7- 9]. However, despite recent advances in the understanding of the pathophysiology of ARDS and improved life support, mortality rates persist at 30- 60 % [10]. The alveolar capillary barrier consists of type I and type II alveolar epithelial cells and capillaries and serves as a minimal tissue barrier to alveolar air. Between the endothelial and epithelial sides, the extracellular matrix plays an important role in the biomechanical behavior of the lung parenchyma, regulating hydration and water homeostasis, maintaining structure and function, modulating the inflammatory response, and influencing tissue repair and remodeling [11 - 13]. Traditionally, ARDS has been divided into three stages in which an initial inflammatory phase (exudative) is followed by fibre-proliferation, which can lead to established interstitial and intra-alveolar fibrosis, the final phase. The histological features of the exudative phase are: a) hyaline membranes; b) alveolar collapse; and c) swollen type I pneumocytes with cytoplasmic vacuoles. In the early phase of ARDS, damage to the alveolar capillary barrier and the increase in its permeability cause accumulation of a fluid rich in proteins which may gradually become organized leading to hyaline membrane that further destroys the alveolar structure [14, 15]. In this phase, there

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe?

is also an intense alveolar inflammatory process with local accumulation and activation of neutrophils and macrophages which can release oxidants, proteases and inflammatory mediators, including cytokines and leukotrienes [16, 17], and promote coagulation and fibrinolysis alterations [18]. During recovery from ARDS, the increased endothelial and epithelial permeability is solved by fluid clearance from the lung and elimination of the soluble and insoluble materials from the interstitium and alveolar spaces [19]. However, at the same time, a certain amount of fibrosing alveolitis can develop with deposition and accumulat ion of collagen in the lung [20, 21]. The proliferative phase has been described to begin as early as the third day but as most prominent in the second and third weeks after symptom onset. However, ten years ago, Chesnutt et al. [22] reported a high concentration of pro collagen type III in the bronchoalveolar lavage (BAL) fluid of ARDS patients only one hour after the onset of the disease. These results suggested that the fibrosing alveolitis may develop even in the early phase and that pro collagen type III could be used to identify patients at risk of death. Other investigators confirmed these findings reporting that fibroproliferation is an early and not a late response to lung injury [23, 24]. In this setting, careful limited administration of corticosteroids could promote faster resolution of injured tissue [25].

Mechanisms of Action of Corticosteroids Cortisol is the predominant corticosteroid secreted by the adrenal cortex in humans. In healthy subjects, cortisol is secreted according to a diurnal pattern under the influence of corticotropin released from the pituitary gland . Corticotropin secretion, in turn, is under the influence of hypothalamic corticotropin-releasing hormone (CRH), and both hormones are subject to negative feedback control by cortisol itself [26,27]. Corticosteroids are mainly transported in the blood complexed to transcortin (corticosteroid-binding globulin) and albumin , although a small portion is in a free, metabolically active state. The free corticosteroid molecules cross the plasma membrane into the cytoplasm, where they bind to a specific receptor, the glucocorti coid receptor. The glucocorticoid receptor is located in the cytoplasm of nearly all human cells. After hormone binding, the glucocorticoid receptor complex migrates to the cell nucleus and inhibit s inflammatory gene transcription, including nuclear factor kappa -B (NF-KB) and activator protein (AP)-I , which are activated by extracellular inflammatory signals received by cell surface receptors. When not bound to its ligand, glucocorticoid receptor is sequestered in the cytoplasm as an inactive complex with two molecules of heat shock protein (HSP)-90, and other cytosolic proteins. Upon binding glucocorticoids, glucocorticoid receptor undergoes conformational changes which allows it to dissociate from the HSP-90 molecules. The hormone-bound glucocort icoid receptor translocates to the nucleus, where it transiently associates with HSP-56, and later dissociates from it and binds as a dimer to conserve palindromic DNA sequences, named glucocorticoid response elements (GRE). NF-KB is the central tran scription factor that drives the inflammatory response to insults, and its activation is an essential step in the experimental development of neutrophilic lung inflammation. NF-KB consists of two subunits arranged as homodimers or heterodimers. The most common form of activated NF-KB consists of a p65 and p50 heterodimer ( Fig. 1). Under basal conditions, NF-KB is retained in the cytoplasm in an inactive state by a related inhibitory protein known as IKBa. Currently the most commonly accepted mechanism leading to the activation of NF-KB

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P. Pelosi and P.R.M. Rocco Inflammatory signa ls

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Glucocorticoid

~ GRa

~~.. " , Glucocorticoid

~

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1,~E

NF-KB

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receptor

binding site

-=~~~:=-'--== KB binding site

Gene

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Pro-inflammatory cytokines

~

Chemokines

~ Adhesion molecules

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i

I-KB Gene t Pro-inflammatory cytokines t Adhesion molecules t Chemokines

Fig. 1. Mechanisms ofaction ofcorticosteroids. GR: glucocorticoid receptor, GRE: glucocorticoid response elements, NF-KB: nuclear factor kappa-B (NF-KB consists of a p65 and p50 heterodimer); IKBa: inhibitory protein. Continuous lines indicate activating mechanisms, while dashed lines indicate inhibitory mechanisms.

involves the activation of the recently described IKB kinase, which rapidly phosphorylates IKBa in response to various pro- inflammatory signals. The released NF-KB then translocates into the nucleus and binds to promoter regions of target genes to initiate the transcription of multiple cytokines forming a positive regulatory loop that amplifies and perpetuates the inflammation. Activated glucocorticoid receptors mediate transcriptional interference via the following mechanisms: a) by physically interacting with the p65 subunit and forming an inactive glucocorticoid receptor- aNF-KB complex; b) by inducing the transcription of the inhibitory protein IKBa gene, which traps NF-KB in inactive cytoplasmic complexes catabolized by the ubiquit in-proteosoma pathway; c) by blocking degradation of IKBa via enhanced synthesis of interleukin (IL)-lO; d) by impairing tumor necrosis factor (TNF)-a-induced degradation of IKBa; and e) by competing for limited amounts of glucocorticoid receptor coactivators. Glucocorticoid receptors may also interact directly with protein transcription factors in the cytoplasm and nucleus and, thereby, influence the synthesis of certain proteins independent of an interaction with DNA in the cell nucleus. The inhibitory effects of corticosteroids on cytokine synthesis are particularly important. Corticosteroids inhibit NF-KB and consequently the expression of the NF-KB-dependent pro-inflammatory gene ( Fig. 1). Thus, they inhibit the transcription of several cytokines that are relevant to ARDS and fibrogenesis. Glucocorticoids also stimulate apoptosis of T-cells, eosinophils , and monocytes, inhibit neutrophil activation, and are important in maintai ning endothelial integrity and vascular permeability. The various corticosteroid preparations available for systemic use differ in their relative anti -inflammatory capacity, potential for sod ium retention, and plasma and biologic half-lives. In general, short-acting preparations, such as prednisone and prednisolone, are preferable to longer-acting agents, such as dexamethasone, because tapering to an alternate-day schedule cannot be accomplished with drugs with prolonged (i.e., > 24 h) biologic half-lives. In addition, hydrocortisone and cor-

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe?

217

tisone are rarely used to treat inflammatory and immunologically mediated diseases because of the considerable mineralocorticoid activity that accompanies their use. Methylprednisolone may be better concentrated in the lungs than prednisolone because it has a larger volume of distribution, longer mean residence time, and greater retention in the epithelial lining fluid of the alveoli.

What Recent Animal Research has Taught Us about Corticosteroids Several studies using animal models of sepsis and lung injury have shown that corticosteroids decrease morbidity and mortality if given simultaneously with or before the experimental insult [27]. Pre-treatment with corticosteroids was also shown to increase the survival rate in acute lung injury (ALI) induced by aspiration pneumonitis and oleic acid-induced pulmonary edema [28]. In a rat model of butylatedhydroxytoluene-induced ARDS, the timing of corticosteroid administration had strikingly different effects. Early administration of steroids resulted in increased collagen deposition, increased lung damage, and inhibition of type II pneumocyte proliferation. Late administration, on the other hand, prevented excessive collagen deposition [29]. Systemic methylprednisolone or dexamethasone at doses of 20 or 4 mg/kg/day, respectively, improved pulmonary inflammation and mechanics in animals with ALI [30]. Dexamethasone (a single dose of 2.5 mg/kg) significantly reduced inflammatory cell protein content in BAL fluid, and improved lung compliance 24 h after injury induced by oleic acid [31]. However, prophylactic treatment with methylprednisolone (60 mg/kg/h) 30 min before injury did not attenuate oleic acid-induced ALI [32]. Corticosteroid at a dose of 10 mg/kg, starting on day 5 after infection with reovirus, and given daily until the end of the time course of the disease, also did not attenuate the infiltration of inflammatory leukocytes, cytokine/ chemokine expression, or the development of fibrotic changes in the lungs [33]. Rocco et al. [34] in a paraquat-induced ALI model observed that corticosteroids acted differently depending on the degree of ALI, leading to a complete maintenance of normal tissue mechanics and collagen content in a mild lesion, whereas they minimized the changes in tissue impedance and extracellular matrix components in a severe lesion. Early beneficial effects of corticosteroids on extracellular matrix remained unchanged 30 days after lung injury. Rocco et al. [35] also tested the hypothesis that corticosteroids may act differently depending on the etiology of ALI and observed that in models of pulmonary and extra pulmonary ALI with similar degrees of mechanical compromise, one low-dose steroid therapy early in the course of lung injury attenuated lung mechanics and morphometric changes, cytokine levels in BAL fluid only in pulmonary ALI, but avoided changes in collagen fiber content in both ALI groups [35]. Overall, animal research on corticosteroids suggests that : a) low dose corticosteroids may inhibit inflammatory and fibrotic responses from the early phases of ALI; b) short-term courses of corticosteroids may be effective; and c) corticosteroids are more effective in pulmonary compared to extrapulmonary ARDS.

Prospective Randomized Trials on Corticosteroids in ARDS Corticosteroid therapy at high doses has been studied in early ARDS in three main different situations in prospective randomized controlled trials: 1) Prevention in

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P. Pelosi and P.R.M. Rocco

high risk patients [36]; 2) early treatment with high-dose, short-course therapy [37-39]; and 3) specific groups of patients: At risk of fat embolism syndrome [40] or with acquired immune deficiency syndrome (AIDS) and Pneumocystis carinii pneumonia [41, 42]. Weigelt et al. [36] included 81 patients at high risk of ARDS randomized to methylprednisolone (30 mg/kg i.v, every 6 h for 48 h) or placebo. Twenty-five steroid-treated patients (64 %) and 14 placebo-treated patients (33 %) developed ARDS. There were no differences in ventilatory requirements or days of intensive care. Bone et al. [37] randomized 79 patients to receive methylpredniso lone (30 mg/kg i.v.) or placebo every 6 h for a total of four doses within 2 h of the onset of sepsis and/or ARDS. They found an increased incidence of ARDS and 14day mortality in the steroid group. Bernard et al. [38] randomized 99 adult patients within 30 h of the onset of ARDS to receive high-dose methylprednisolone (30 mgt kg i.v.) or placebo. Corticosteroids had no effect on oxygenation, hemodynamics, ARDS reversal, or mortality. In addition, there was a trend toward increased infections in the corticosteroid group, as well as significant treatment-related hyperglycemia. Similarly, Luce et al. [39] failed to demonstrate any benefit of corticosteroid on ARDS development or subsequent death. Corticosteroids have been shown to reduce mortality in patients at risk offat embolism syndrome [40] or in patients with AIDS and P. carinii pneumonia [41, 42]. The failure of high dose corticosteroids in the early phase of ARDS could be due to different factors: a) The population studied, which varied in terms of case mix and patient management; b) negative effects due to the profound immunodepression or other side effects induced by high doses of steroid could counterbalance the positive effects, so that the overall effect may be neutral or even deleterious; c) corticosteroid therapy might be ineffective if many of the patients, who were considered to have ARDS based on clinical definitions, did not develop activation of inflammatory cascades in their lungs. Meduri [43] hypothesized that if endogenous glucocorticoid inadequacy and/or peripheral tissue resistance were important pathophysiologic factors in a deregulated, protracted systemic inflammatory response in ARDS, then prolonged glucocorticoid therapy might be useful, not as an anti-inflammatory treatment per se, but as hormonal supplementation necessary to compensate for the host's inability to produce appropriate elevated amounts of cortisol in relation to the degree of peripheral glucocorticoid resistance. In a recent prospective , match-control trial, Lee et al. [44] compared 20 patients with ARDS after major thoracic operations treated with metylprednisolone (2 mg/kg bolus i.v, followed by 2 mg/kg per day, in four doses) with a control group. The corticosteroid treated group showed a reduced duration of intensive care unit (ICU) stay and mechanical ventilation, associated with a marked reduction in hospital mortality (90 % vs 4 %). The effectiveness of prolonged glucocorticoid supplementation at low dosages in ARDS has been investigated in four randomized trials in community-acquired pneumonia (CAP) [45], early ARDS [46], and unresolving ARDS [47,48]. Table 1 shows the main outcome results reported by these studies . Overall, prolonged glucocorticoid treatment was associated with a significant reduction in makers of systemic inflammation (IL-6 or C-reactive protein [CRP]), more rapid improvement in gas exchange, and a sizable reduction in duration of mechanical ventilation and ICU length of stay in all four randomized clinical trials . Two trials [45, 46] demonstrated a significant reduction in hospital mortality, and one trial showed a reduction in ICU mortality [46], while the last reported no significant effect [48]. Three key aspects related to the study designs, must be considered for the correct interpretation of the results and clinical relevance of the most recent trials [46, 48]:

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe? Table 1. Corticosteroids versus placebo in four randomized trials in ALI!ARDS patients Phase of ALI!ARDS

ALI, CAP

Early ARDS

Unresolving ARDS

Unresolving ARDS

Reference

[45]

[46]

[47]

[48]

Number of patients

46

91

24

180

Median duration of mechen- 5 vs 13 ical ventilation (days) (p = 0.09)

5 vs 9.5 (p = 0.002)

11 .5 vs 23 (p = 0.001 )

14.1 vs 23.6 (p = 0.006)

Median duration of ICU stay (days)

10 vs 18 (p = 0.01)

7 vs 14.5 (p= 0.007)

NA

17 vs 20* (p = 0.29)

Incidence of ventilatorassociated pneumonia

O%vs13 % (p = 0.23)

14 % vs 57 % (p = 0.004)

37 %vs12 % (p = 0.7)

7 % vs 15 % (p = 0.05)

Hospital mortality (%)

o vs 30

24 vs 43 (p = 0.07)

13 vs 63 (p = 0.03)

29.2 vs 28.6 (p = 1.0)

(p = 0.009)

NA = not available; ALI: acute lung injury; CAP: community acquired pneumonia; ARDS: acute respiratory distress syndrome. *median duration of ICU stay in survivors.

1) The prevention of complications associated with glucocorticoid treatment with infection surveillance; 2) the avoidance of paralysis; and 3) the rebound inflammation with physiological deterioration associated with premature removal of treatment.

Corticosteroids in Community-acquired Pneumonia

In a multicenter trial , Confalonieri et al. [45) randomized 46 patients with severe CAP admit ted to the ICU to receive hydrocortisone infusion (i.v, 200-mg bolus followed by infusion at a rate of 10 mg/hour for 7 days) or placebo. Patients treated with cortico steroids had, compared with control subjects , a significant improvement in PaOz/FiO z and chest radiograph score associated with a significant reduction in CRP levels, multiple organ dysfunction syndrome (MODS) score, and delayed septic shock. Hydrocortisone treatment was also associated with a significant reduction in length of hospital stay and mortality. Corticosteroids in Early ARDS

Meduri et al. [46) studied 91 ARDS patients randomly assigned (2:1 fashion) to methylprednisolone infusion (l mg/kg/day) versus placebo. The duration of treatment was up to 28 days. A significant reduction in the rate of nosocomial infections , duration of mechanical ventilation, ICU stay, and ICU mortality (20.6 % vs. 42.9 %; P = 0.03) was found in the treated group. However, the results reported in this study are clearly open to discussion: a) Small sample size; b) non-conventional randomization; c) larger number of patients in the treatment group associated with a protocol violation and/or discontinued intervention; d) treatment group characterized by a significantly high percentage of pneumothorax (22 %) . Interestingly, most patients included in this study were suffering from pulmonary ARDS, which has been shown to be more responsive to corticosteroids in animal experiments. However, the major aspects related to this paper are: a) surveillance bronchoscopy with bilateral BAL fluid at 5- to 7-day intervals in intubated patients (without contraindication); and b) a systematic diagnostic protocol if patients developed fever or had an increase in immature neutrophil count (2: 10 %) or minute ventilation (2: 30 %). Infection sur-

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P. Pelosi and P.R.M. Rocco

veillance identified 56 % of nosocomial infections in patients without fever. This finding underscores the need to incorporate a strict infection surveillance program when treating ICU patients with prolonged glucocorticoid treatment. Finally, among patients who received methylprednisolone, 4 % developed prolonged neuromuscular weakness and delayed weaning, a lower incidence than that reported in the recent ARDSnet study [48], and probably related to the limited use of neuromuscular blocking agents. In conclusion , even if these recent data are extremely interesting, they are not convincing enough to recommend the routine use of corticosteroids in the early phases of ALIIARDS.

Corticosteroids in Resolving ARDS

VI

A large uncontrolled series of patients with late ARDS treated with corticosteroids was studied by Meduri [43]. The results suggested that the early removal of high dose corticosteroid treatment in the previous randomized trials, which used shortterm corticosteroid treatment, might have reversed any early beneficial effect of treatment or overturned the ability to detect a beneficial effect. In order to determine the effects of prolonged steroid therapy on lung function and mortality in non-resolving ARDS, Meduri et al. [47] randomized 24 patients with ARDS who had been mechanically ventilated for more than 7 days to treatment with methylprednisolone (2 mg/kg administered i.v, followed by 2 mg/kglday from day 1 to day 14 and then by progressively lower doses until day 32 of the study) or placebo. Significant changes were observed in PaOz/FiOz ratio, lung injury score (LIS), mean pulmonary artery pressure, and MODS score in the corticosteroid-treated group versus the placebo group. ICU survival was 100 % in the steroid group versus 37 % in the placebo group, and overall survival was 87 % versus 37 %. Recently, the ARDSnet Clinical Trials Network published the results of an 8-year long trial that randomly assigned 180 patients with ARDS of at least seven days' duration to methylprednisolone versus placebo [48]. The study found no difference in mortality rate at 60 days (primary end point), while secondary variables improved significantly. However, the mortality in patients randomized after day 14 of ARDS was increased in the treatment group. This study, however, suffered from some important methodological problems: The two groups were not exposed to the same risk for morbidity-mortality: a) lack of infection surveillance and concurrent use of neuromuscular blocking agents; b) premature discontinuation of treatment after 48 hours of unassisted breathing.

Conclusion In conclusion, in patients with ARDS: a) The use of low-dose corticosteroids should be preferred, when necessary; b) corticosteroids should not be given 14 days after the onset of ARDS; c) limited data suggest that early corticosteroid treatment at low doses could be useful to reduce the time on mechanical ventilation and the length of ICU stay. However, there are currently no clear convincing data to support the widespread use of corticosteroids in early or late phases of ALIIARDS.

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe? References 1. Meduri GU, Muthiah MP, Carratu P, Eltorky M, Chrousos GP (2005) Nuclear factor-kappaBand glucocorticoid receptor alpha- mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids. Neuroimmunomodulation 12:321- 338 2. Meduri GU, Yates CR (2004) Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS. Ann N Y Acad Sci 1024:24-53 3. Parsons PE, Eisner MD, Thompson BT, et al (2005) Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 33:1-6 4. Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids-new mechanisms for old drugs. N Engl J Med 353:1711 - 1723 5. Galon J, Franchimont D, Hiroi N, et al (2002) Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 16:61-71 6. Meduri GU, Tolley EA, Chrousos GP, Stentz F (2002) Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome . Evidence for inadequate endogenous glucocorticoid secretion and inflammationinduced immune cell resistance to glucocortico ids. Am J Respir Crit Care Med 165:983-991 7. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress syndrome. Lancet 2:319- 323 8. Bernard GR, Artigas A, Bringham KL, et al (1994) The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination . Am J Respir Crit Care Med 149:818-824 9. Villar J, Mendez-Perez L, Lopez J, et al (2007) An early PEEP/FiOz trial identifies different degrees of lung injury in ARDS patients. Am J Respir Crit Care Med 176:795-804 10. Esteban A, Ferguson ND, Meade MO et al (2007) Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit Care Med [Epub ahead of print] 11. Pelosi P, Rocco PR, Negrin i D, Passi A (2007) The extracellular matrix of the lung and its role in edema formation. An Acad Bras Cienc 79:285- 297 12. Souza-Fernandes AB, Pelosi P, Rocco PR (2006) Bench to Bedside Review: the role of glycosaminoglycans in respiratory disease . Crit Care 10:237 13. Moriondo A, Pelosi P, Passi A, et al (2007) Proteoglycan fragmentation and respiratory mechanics in mechanically ventilated healthy rats. J Appl Physiol 103:747-756 14. Ware LB, Matthay MA (2005) Clinical practice . Acute pulmonary edema. N Engl J Med 253:2788- 2796 15. Guidot DM, Folkesson HG, Jain L, Sznajder [I, Pittet IF, Matthay MA (2006) Integrating acute lung injury and regulation of alveolar fluid clearance . Am J Physiol Lung Cell Mol Physiol 291:L301-L306 16. Matthay MA, Zimmerman GA (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Bioi 33:319-327 17. Suter PM (2006) Lung inflammation in ARDS: friend or foe? N Engl J Med 354:1739-1742 18. Ware LB, Camerer E, Welty-Wolf K, Schultz MJ, Matthay MA (2006) Bench to bedside: target ing coagulation and fibrinolysis in acute lung injury. Am J Physiol Lung Cell Mol Physiol 291:L307-L311 19. Calfee CS, Matthay MA (2007) Non ventilatory treatments for acute lung injury and ARDS. Chest 131:913-920 20. Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342: 1334-1349 21. Martin C, Papazian L, Payan MJ, Saux P, Gouin F (1995) Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. Chest 107:196-200 22. Chesnutt AN, Matthay MA, Tibayan FA, Clark JG (1997) Early detection of type III pro collagen peptide in acute lung injury. Pathogenetic and prognostic significance. Am J Respir Crit Care Med 156:840- 845

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P. Pelosi and P.R.M. Rocco 23. Rocco PRM, Negri EM, Kurtz PM, et al (2001) Lung tissue mechanics and extracellular matrix in acute lung injury. Am J Respir Crit Care Med 164:1067-1071 24. Marshall RP, Bellingan G, Webb S, et al (2000) Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome. Am J Respir Crit Care Med 162: 1783-1788 25. Meduri GU, Marik PE, Pastores SM, Annane D, Calfee CS, Matthay MA (2007) Corticosteroids in ARDS: a counterpoint. Chest 132:1093-1094 26. Cooper MS, Stewart PM (2003) Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348:727- 734 27. Fernandes ABS, Zin WA, Rocco PRM (2005) Corticosteroids in acute respiratory distress syndrome. Braz J Med BioI Res 38:147- 159 28. Shiue ST, Thrall RS (1991) Effect of corticosteroid therapy on the acute injury and recovery stage of oleic acid induced lung injury in the rat. Experiment Lung Res 17:629-638 29. Jones RL, King RG (1975) The effects of methylprednisolone on oxygenation in experimental hypoxemic respiratory failure. J Trauma 15:297- 303 30. Cheney FW, Hung TH, Gronka R (1979) Effects of methylprednisolone on experimental pulmonary injury. Ann Surg 190:236-242 31. Volpe BT, Lin W, Thrall RS (1994) Effect of intratracheal dexamethasone on oleic acidinduced lung injury in the rat. Chest 106:583-587 32. Kuwabara K, Furue S, Tomita Y, et al (2001) Effect of methylprednisolone on phospholipase A2 activity and lung surfactant degradation in acute lung injury in rats . Eur J Pharmacol 433:209-216 33. London L, Majeski E, Altman-Hamamdzic S, et al (2002) Respiratory reovirus l/L induction of diffuse alveolar damage: pulmonary fibrosis is not modulated by corticosteroids in acute respiratory distress syndrome in rats . Clin Immunol 103:284- 295 34. Rocco PRM, Souza AB, Faffe DS, et al (2003) Effect of corticostero id on lung parenchyma remodeling at an early phase of acute lung injury. Am J Respir Crit Care Medicine 168: 677-684 35. Rocco PRM, Leite-junior JHP, Bozza PT, et al (2006) Effects of corticosteroid on lung parenchyma remodeling in pulmonary and extra pulmonary acute lung injury. Proc Am Thorac Soc 3:838 (abst) 36. Weigelt JA, Norcross JR, Borman KR, Snyder WH (1985) Early steroid therapy for respiratory failure. Arch Surg 120:536-540 37. Bone RC, Fisher Ir CJ, Clemmer TP, Slotman GJ, Metz CA (1987) Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome. Chest 92:10321036 38. Bernard GR, Luce JM, Sprung CL, et al (1987) High dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 317:1565-1570 39. Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF (1988) Ineffectiveness of high -dose methylprednisolone in preventing parenchymal lun g injury and improving mortality in patients with septic shock . Am Rev Respir Dis 138:62- 68 40. Schonfeld SA, Ploysongsang Y, DiLisio R, et al (1983) Fat emboli sm prophylaxis with corticosteroids: a prospective study in high risk patients. Ann Intern Med 99:438-443 41. Bozzette SA, Sattler FR, Chiu J, et al (1990) A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 323:1451 -1457 42. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L (1990). Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: A double-blind, placebo -controlled trial. N Engl J Med, 323:1444-1450 43. Meduri GU (1999) A historical review of glucocorticoid treatment in sepsis: disease pathophysiology and the design of treatment investigation. Sepsis 3:21-28 44. Lee HS, Lee JM, Kim MS, Kim HY, Hwangbo B, Zo JI (2005) Low dose steroid therapy at an early phase of postoperative acute respiratory distress syndrome. Ann Thorac Surg 79:405410 45. Confalonieri M, Urbino R, Potena A, et al (2005) Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 171: 242-248

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: Friend or Foe? 46. Meduri GU, Golden E, Freire AX, et al (2007) Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 131:954-963 47. Meduri GU, Headley S, Golden E, et al (1998) Effect of prolonged methylprednisolone therapy in unre solving acute respiratory distre ss syndrome. A randomized controlled trial. JAMA 280:159- 165 48. Steinb erg KP, Hud son LD, Goodma n RB, et al (2006) Efficacy and safety of cort icoster oids for persistent acute respiratory distre ss syndrome. N Engl J Med 354:1671- 1684

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Regional Lung Function in Critically III Neonates: A New Perspective for Electrical Impedance Tomography I.

FRERICHS,

J.

SCHOLZ,

and N. WEILER

Introduction Electrical impedance tomography (ElT) is an emerging, radiation-free, medical imaging modality considered to become a bedside monitoring tool of regional lung function in intensive care patients [1- 9]. This method could be used not only in adult but also in neonatal and pediatric patients. The perspective of EIT in the latter patient group is mainly based on: 1) the lack of information on regional lung function at the bedside; and 2) deficits in available diagnostic and monitoring techniques to provide this information. Bedside monitoring of regional lung function is needed because most critically ill neonates require either invasive or non-invasive ventila tory support, their lung tissue is immature and prone to development of irreversible damage and chronic lung disease, pathological processes in the lungs are not uniform, and therapeutic measures (e.g., surfactant or ventilator therapy) may exhibit regionally heterogeneous effects. At present, only global information on lung function is available, which is derived from, e.g., arterial, capillary, and venous blood gas analyses, pulse oximetry, transcutaneous measurement of partial pressures of O2 and CO2 as well as airway pressure and flow measurements. Imaging modalities, like computed tomography (CT) or magnetic resonance imaging (MRI), which are routinely used in adult critically ill patients, play no relevant role in the setting of a neonatal intensive care unit (ICU). Usually, only chest radiography is used to obtain information on regional lung status in preterm and term critically ill neonates. However, chest X-ray examinations expose the infants to increased ionizing radiation load . They provide only momentary information on lung tissue structure, which means that the functional impact of disease can only be assessed indirectly. Chest radiography is not suitable for monitoring changes in lung function during long periods of time . Other techniques, like inert gas washout are not routinely used [8, 10, 11]. EIT has the potential to become a useful monitoring tool of regional lung function mainly because of its radiation-free measuring principle and its ability to detect changes in regional air content in lungs [5, 12-15] with high temporal resolution and excellent reproducibility, especially during mechanical ventilation [16]. Thus, EIT has the capacity to provide frequent measurements of ventilation and aeration distribution which might be used as feed-back information in the acute management of critically ill neonates and assessment of response to treatment. This chapter briefly presents the basic characteristics of EIT and summarizes the main results of EIT studies so far performed in preterm and term neonates.

Regional Lung Function in Critically III Neonates

Measuring Principle of EIT EIT is a fully non -invasive method with no known hazards. It generates cross-sectional scans of the studied part of the body by measuring the electrical properties of underlying biological tissues. Biological tissues conduct electrical current because they contain ions which act as charge carriers. Different tissues have different electrical properties. Lung tissue is characterized by low electrical conductance (i.e., high electrical resistance) . Neonatal lungs exhibit lower electrical resistance than adult lungs [17, 18]. Under in vivo condit ions, current flow through the lung tissue is time-dependent because it typically changes in the course of the respiratory cycle depending on the lung air content . The larger the volume of air in the lungs, the longer is the current flow path through the stretched tissue. Therefore, the electrical resistance of inflated lung tissue to electrical current flow is much higher than in the deflated lung. A twofold to threefold increase in electrical resistance occurs during deep inspiration [19,20] . To determine the electrical properties of tissues contained in the studied body segment, EIT applies very small alternating currents (usually in the range of 50 to 500 kHz) to the body surface. The resulting voltages are then measured and electrical impedance (i.e., electrical resistance to alternating current) is calculated. In contrast to other techniques utilizing the same measuring principle (e.g., impedance cardiography), EIT is able to generate cross-sectional scans of the body. Therefore, EIT has to probe the body by applying electrical currents and measuring the resultant voltages at multiple locations. Only in this way, can EIT determine the distribution of electrical impedance within the bod y. When an EIT examination is performed on the chest, an array of electrodes is placed on the chest circumference ( Fig. 1). Conventional self-adhesive electrocardio-

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Fig. 1. Electrical impedance tomography (Ell) measurement in a prone preterm neonate. An array of 16 X-ray translucent electrodes is placed on the chest circumference in one transverse plane.

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Fig. 2. Measuring principle of electrical impedance tomography (Ell). Rotating application of very small electrical current (n is performed between pairs of adjacent surface electrodes and resulting voltages (U) are measured between pairs of remaining passive electrode pairs. One complete measuring cycle is completed after 208 (16 x 13) voltages have been collected. From [8) with permission graph (EKG) electrodes can be used, although X-ray translucent electrodes may be convenient in a clinical setting. Most ElT devices apply electrical currents through a pair of adjacent electrodes and the voltages are measured between all other adjacent electrodes pairs ( Fig. 2). This process is cyclic, i.e., electrical current is applied and voltages are measured repeatedly between all pairs of electrodes in a rotating way. The acquired boundary voltage data are then processed to generate EIT scans. This process is called image reconstruction. All EIT scans shown in this review have been generated using the so-called back-projection image reconstruction procedure [19,21]. This reconstruction algorithm projects the measured voltages along curved equipotential lines, it is robust and relatively insensitive to noise, possible unequal spacing of electrodes, and noncircular form of the chest cross-section. Such scans can be generated with a high time resolution of several tens of scans per second. The acquired series of scans are usually processed in an online or offline evaluation procedure and functional ElT scans enabling the visualization of regional ventilation, aeration, and regional filling and emptying behavior of lungs are then generated and quantitative parameters calculated [22- 28].

Regional Lung Ventilation in Preterm and Term Neonates with no Lung Pathology Surprisingly little is known about the topographical distribution of inspired air in the lungs of preterm and term neonates. However, to make conclusions regarding the effect of therapy and/or mechanical ventilation on regional lung ventilation in critically ill neonates and small infants suffering from lung disease it is essential to know how lung ventilation is distributed under normal physiological conditions and during spontaneous breathing. Unfortunately, only a few studies have been carried

Regional Lung Function in Critically III Neonates

out in neonates and small infants to study the physiological aspects of regional lung ventilation . This may be explained by the lack of adequate techniques applicable in healthy babies. Studies in neonates are generally difficult because infants do not cooperate. Therefore, our knowledge of spatial distribution of lung ventilation in neonates is limited to data obtained in sedated or anesthetized infants [29, 30] and in infants with lung [29, 31] or other disease [30]. Most of the data have been acquired during mechanical ventilation [3D, 31]. The applied examination techniques required the use of face masks, endotracheal intubation, sedation , all of which modified the respiratory mechanics and the natural breathing pattern. Large age heterogeneity was noted among the studied infants [29, 3D, 32]. EIT has given us the possibility to study the distribution of lung ventilation in healthy spontaneously breathing neonates free of any lung disease. We have examined the effect of the breathing pattern and body position on the spatial distribution of lung ventilation using this technique [33, 34]. We have determined a very high variability in the regional ventilation distribution depending on the depth of the breaths , breathing rate, and end -tidal volume. This almost breath -by-breath variability of regional lung ventilation in neonates can be seen in Fig. 3, showing an EIT measurement performed in a preterm neonate lying on the right side. Initially (phase 1), the neonate breathed spontaneously at approximately 48 breaths/min; by the end of the scanning period (phase 3) the rate was about 76 breaths/min. The average inspiratory-to-expiratory amplitude of relative impedance change representing the tidal volume was lower in phase 1 than phase 3. The minimum, end-expiratory values were also lower in phase 1. The functional EIT images of regional ventilation generated from the enhanced measurement phases showed lower ventilation of the dependent lung region during phase 1, a reduction in the right-to-left imbalance in ventilation in phase 3, and a reversal of the ventilation distribution pattern

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with higher ventilation in the dependent lung during the sigh (phase 2). The results of our study indicated that the postulated reversal of the adult ventilation distribution pattern in infants [32] was only discernible in those phases of spontaneous breathing when the neonates were breathing at low end-expiratory and tidal volumes. At higher lung volumes, inspired air was distributed homogeneously between the right and left lungs. During sighs, the distribution pattern was similar to adults. Thus, EIT was able to determine that the known variability of the neonatal breathing pattern with fast, slow, small, and deep breaths [35] resulted in a high variability of the ventilation distribution pattern in neonatal lungs. Our study also confirmed that the topography of ventilation distribution depended on body position. EIT also provided the surprising finding that head position had an impact on the distribution of ventilation in the chest cross section (Fig. 4) [34]. In spontaneously breath ing neonates, reduced distribution of inspired air into the left lung was noted in the prone posture whereby this effect was enhanced by turning the infant's head to the left side. To a lesser extent this effect of the head position was also observed during mechanical ventilation [34]. These studies and studies aimed at assessing the maturational changes of neonatal lung tissue using EIT [17, 18] have provided new insights into neonatal lung physiology.

Regional Lung Ventilation during Mechanical Ventilation in Infants with Lung Disease Only a small number of EIT studies have been performed in critically ill preterm and term infants [22, 28, 36-39] . The design of these studies was mainly observational, nevertheless, they showed that EIT measurements are feasible in this group of patients. The neonatal leu is an extremely electrically noisy environment. Noise can be detected in acquired EIT data, however, its effect does not deteriorate the quality of measurements to a large degree. Offline data processing can be applied to attenuate this effect [22]. EIT examinations performed in mechanically ventilated critically ill infants indicate that changes in distribution of regional lung ventilation in response to a change in ventilator mode (controlled, assisted, invasive or non-invasive ventilation, weaning from mechanical ventilation) or settings (inspiration-to-expiration time, peak

Regional Lung Function in Critically III Neonates

Fig. s. Electrical impedance tomog-

raphy (EIT) measurement in a supine infant suffering from prematurity, inguinal hernia, and hydrocele ventilated in a pressure-controlled mode with a tidal volume (Vr) of 26 ml at a rate of 15 breaths/min. During the measurement, positive end-expiratory pressure (PEEP) was increased from 2 to 3 cmH 20 . The tracings of relative impedance change (reI. ~Z) (middle) show the breath-by-breath variation of the EIT signal in anterior (x) and posterior regions (+ ) of the right lung. Large impedance fluctuations are related to ventilation and reflect the changes in pulmonary air content. Small impedance fluctuations (discernible during expirations) are related to cardiac action and lung perfusion and occur at a frequency corresponding with the heart rate. Functional Ell images of regional lung ventilation (top), generated from the enhanced sections of measurement at each PEEP level, do not reveal any significant effect of PEEP on distribution of respired air in lungs. Functional EIT image of regional shift in lung aeration (bottom) shows an increase in regional air volume with PEEP predominantly in posterior region s. From [81 with permission

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inspiratory and positive end-expiratory pressure, respiratory rate, tidal volume) are discernible [8, 36, 37, 40]. Fig. 5 shows an example of an ElT measurement performed in an infant (postnatal age: 10 weeks; body weight: 2500 g; gestational age: 30 weeks; birth weight: 900 g) ventilated in a pressure -controlled mode. Two types of functional ElT scans have been generated from this short EIT measurement segment in the course of which posit ive end-expiratory pressure (PEEP) was increased by 1 cmH20. These scans show that the distribution of ventilation in the chest crosssection was not affected by this change and that regional aeration was increased, especially in the dependent lung regions. The uniqueness of the information that can be obtained by ElI is illustrated by a measurement performed in another infant (postnatal age: 13 weeks; body weight: 2850 g; gestational age: 36 weeks; birth weight: 2520 g) shown in Fig. 6. This infant was ventilated in an assisted mode of ventilation allowing spontaneous breathing. A chest X-ray film was obtained shortly before the shown EIT measurement was started, showing massive lung congestion affecting mainly the right lung. Because

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Fig. 6. EIT measurement in a supine infant ventilated in an assisted mode of mechanical ventilation. The infant suffered from tetralogy of Fallot, stenosis of the left pulmonary artery, and hereditary dysmorphism. Functional EIT (f-EIT) scans show the distribution of air in the lungs elicited by ventilator-generated (top) and spontaneous breaths (bottom). The scans are autoscaled. The tracing of relative impedance change averaged over the whole thoracic cross-section reflects the changes in overall lung volume during an interval of 15 s. Large fluctuations reveal the changes in air content during ventilator-generated breaths. Small fluctuations originate from spontaneous breaths. SIMV: synchronized intermittent mandatory ventilation. From (36) with permission

mechanical ventilation and spontaneous breathing activity were clearly separated in the frequen cy domain, EIT data could easily be filtered in the bands of mechanical and spontaneous breathing rates. Two functional EIT scans showing the ventilation distribution during ventilator-generated and spontaneous breaths were generated from the band-pass filtered data. This type of offline data analysis revealed that ventilation distribution during mechanic al breaths differed from the spontaneous breaths. On the background of the known more pronounced edema of the right lung, the EIT findings may be interpreted as follows: During spont aneous breaths, the less affected left lung was better ventilated (the lower EIT scan shows higher ventilation-related variation of electrical impedance in the left lung region) and , during ventilator-generated breaths, the left lung was overinflated resulting in seemr>

Fig. 7. Functional Ell scans of regional lung ventilation and fractional lung ventilation determined by EIT

in two newborn piglets. The measurements were carried out before and after induction of acute lung injury and after endotracheal administration of surfactant. Six experimental phases are presented: NL, normal lung; IL, injured lung; IL-R, injured lung after a recruitment maneuver; BS, 1 min before surfactant administration; 510, 10 min after surfactant administration; and 560, 60 min after surfactant administration. In animal 2 (bottom), an additional recruitment maneuver was performed immediately after surfactant administration. In animal 4 (top), no recruitment maneuver was performed. Anterior-to-posterior profiles of local ventilation, shown below the corresponding functional EIT scans, visualize the distribution of ventilation in the right and left halves ofthe chest (dark and light blue bars). The fractional ventilation in each region of interest relative to the total ventilation in the whole chest cross-section was expressed as a percentage. The numbers inthe left and right upper corners ofthese diagrams specify the fractional ventilation in the right and left halves of the thoracic cross-section, respectively. From (46) with permission

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ingly better ventilation of the right lung (the upper EIT scan shows higher ventilation-related variation of electrical impedance in the right lung region) . This information is not accessible by other diagnostic tools which means that such heterogeneous distribution of air in the lungs may not be identified and the risk of overinflation and volutrauma and air leak is increased. Many prematurely born infants suffer from respiratory distress syndrome (RDS). Surfactant administration is the standard therapy which has significantly reduced mortality and incidence of air leak in these infants [41-43]. However, arrested acinar development still occurs and chronic lung disease develops in infants with RDS treated with exogeneous surfactant [41, 42, 44, 45]. This indicates that our understanding of the mechanisms of this disease is limited and treatment not optimum, especially regarding the application of surfactant and the ventilatory management before, during, and after surfactant administration. Thanks to its ability to assess regional ventilation and aeration, EIT could be a useful tool to monitor infants before, during, and after surfactant treatment and to standardize the applied therapeutic procedures. EIT has been used to identify the effects of surfactant treatment on regional lung ventilation and mechanics in a few clinical and experimental cases [3, 37]. A recent experimental study in newborn piglets has shown that changes in ventilation distribution caused by acute lung injury (ALI) and subsequent surfactant treatment can be identified by ElT [46]. Lung volume recruitment performed immediately after endotracheal administration of surfactant led to a more homogeneous ventilation distribution which is in accordance with other experimental studies [47]. Fig. 7 shows the functional ElT scans and ventilation distribution profiles obta ined in two animals after development of ALI and surfactant treatment with and without lung volume recruitment. The findings illustrate how ElT could be used to monitor the redistribution of regional lung ventilation resulting from surfactant treatment and changes in ventilator settings.

Conclusion ElT is able to assess new and in part unique phenomena regarding regional lung function both in experimental and clinical settings. EIT has revealed that body and head position as well as breathing pattern exert a significant effect on the distribution of lung ventilation in spontaneously breathing preterm and term neonates. Changes in regional lung ventilation, aeration, and lung mechanics resulting from changed ventilator settings, surfactant treatment, and body position have been identified by EIT in critically ill infants. These findings constitute another piece of evidence that EIT could provide valuable information for clinical decision making in the future. However, EIT is not yet ready for routine clinical use at present. Proof of clinical efficacy and acceptance has to be provided. Larger prospective experimental and clinical studies need to be initiated to establish guidelines regarding EIT data collection, analysis, and interpretation. Further technological development of EIT hardware and software is equally important and needs to be pursued in parallel.

Regional Lung Function in Critically III Neonates ~elerences I. Arnold JH (2004) Electrical impedance tomography: on the path to the Holy Grail. Crit Care

Med 32:894-895 2. Frerichs I (2000) Electrical impedance tomography (EIT) in applications related to lung and ventilation: a review of experimental and clinical activities . Physiol Meas 21:Rl- 21 3. Frerichs I, Dargaville PA, Dudykevych T, Rimensberger PC (2003) Electrical impedance tomography: a method for monitoring regional lung aeration and tidal volume distribution? Intensive Care Med 29:2312-2316 4. Hedenstierna G (2004) Using electr ic impedance tomography to assess regional ventilation at the beds ide. Am J Respir Crit Care Med 169:777-778 5. Hinz J, Hahn G, Neumann P, et al (2003) End-expiratory lung impedance change enables bedside monitoring of end-expiratory lung volume change . Intensive Care Med 29:37- 43 6. Luepschen H, Meier T, Grossherr M, Leibecke T, Karsten J, Leonhardt S (2007) Protective ventilation using electrical impedance tomography. Physiol Meas 28:S247- 260 7. Odenstedt H, Lindgren S, Olegard C, et al (2005) Slow moderate pressure recruitment maneuver minimizes negative circulatory and lung mechanic side effects: evaluation of recruitment maneuvers using electric impedance tomography. Intensive Care Med 31:17061714 8. Pillow J), Frerichs I, Stocks J (2006) Lung function tests in neonates and infants with chronic lung disease: global and regional ventilation inhomogeneity. Pediatr PulmonoI41:105-I21 9. Wolf GK, Arnold JH (2005) Noninvasive assessment of lung volume: respiratory inductance plethysmography and electrical impedance tomography. Crit Care Med 33:S163-169 10. Aurora P, Gustafsson P, Bush A, et al (2004) Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis . Thorax 59:1068-1073 11. Schibler A, Hall GL, Businger F, et al (2002) Measurement oflung volume and ventilation distribution with an ultrasonic flow meter in healthy infants . Eur Respir J 20:912-918 12. Frerichs I, Hinz I, Herrmann P, et al (2002) Detection of local lung air content by electrical impedance tomography compared with electron beam CT. J Appl Physiol 93:660-666 13. Hinz J, Neumann P, Dudykevych T, et al (2003) Regional ventilation by electrical impedance tomography: a comparison with ventilation scintigraphy in pigs. Chest 124:314-322 14. Kunst PW, Vonk Noordegraaf A, Hoekstra OS, Postmus PE, de Vries PM (1998) Ventilation and perfusion imaging by electrical impedance tomography: a comparison with radionuclide scanning. Physiol Meas 19:481- 490 IS. Victorino JA, Borges JB, Okamoto VN, et al (2004) Imbalances in regional lung ventilation: a validation study on electrical impedance tomography. Am J Respir Crit Care Med 169: 791-800 16. Frerichs I, Schmitz G, Pulletz S, et al (2007) Reproducibi lity of regional lung ventilation distribution determined by electrical impedance tomography during mechanical ventilation. Physiol Meas 28:S261-267 17. Brown BH, Primhak RA, Smallwood RH, Milnes P, Narracott AJ, Jackson MJ (2002) Neonatal lungs - can absolute lung resistivity be determined non-invasively? Med BioI Eng Comput 40:388-394 18. Brown BH, Primhak RA, Smallwood RH, Milnes P, Narracott AI, Jackson MJ (2002) Neonatal lungs : maturational changes in lung resistivity spectra. Med Bioi Eng Comput 40:506-511 19. Barber DC (1990) Quantification in impedance imaging . Clin Phys Physiol Meas 11 (suppl A):45-56 20. Geddes LA, Baker LE (1967) The specific resistance of biological material-a compendium of data for the biomedical engineer and physiologist. Med Bioi Eng 5:271- 293 21. Barber DC (1989) A review of image reconstruction techniques for electrical impedance tomography. Med Phys 16:162-169 22. Dun lop S, Hough J, Riedel T, Fraser JF, Dunster K, Schibler A (2006) Electrical impedance tomography in extremely prematurely born infants and during high frequency oscillatory ventilation analyzed in the frequency domain. Physiol Meas 27:1151- 1165 23. Frerichs I, Dudykevych T, Hinz J, Bodenstein M, Hahn G, Hellige G (2001) Gravity effects on regional lung ventilation determined by functional EIT during parabolic flights. J Appl PhysioI91 :39-50

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I. Frerichs, J. Scholz, and N. Weiler 24. Frerichs I, Hahn G, Hellige G (1999) Thoracic electrical impedance tomographic measurements during volume controlled ventilation-effects of tidal volume and positive end-expiratory pressure . IEEE Trans Med Imaging 18:764-773 25. Frerichs I, Hahn G, Schroder T, Hellige G (1998) Electrical impedance tomography in monitoring experimental lung injury. Intensive Care Med 24:829-836 26. Hahn G, Sipinkova I, Baisch F, Hellige G (1995) Changes in the thoracic impedance distribution under different ventilatory conditions. Physiol Meas 16:A16I-173 27. Meier T, Luepschen H, Karsten J, et al (2007) Assessment of regional lung recruitment and derecruitment during a PEEP trial based on electrical impedance tomography. Intensive Care Med [Epub ahead of print) 28. Smallwood RH, Hampshire AR, Brown BH, Primhak RA, Marven S, Nopp P (1999) A comparison of neonatal and adult lung impedances derived from EIT images. Physiol Meas 20: 401-413 29. Helms P, Hulse MG, Hatch OJ (1982) Lung volume and lung mechanics in infancy lateral or supine posture? Pediatr Res 16:943-947 30. Larsson A, Jonmarker C, Lindahl SG, Werner 0 (1989) Lung function in the supine and lateral decubitus positions in anaesthetized infants and children. Br J Anaesth 62:378-384 31. Heaf DP, Helms P, Gordon I, Turner HM (1983) Postural effects on gas exchange in infants. N Engl J Med 308:1505-1508 32. Davies H, Kitchman R, Gordon I, Helms P (1985) Regional ventilation in infancy. Reversal of adult pattern. N Engl J Med 313:1626-1628 33. Frerichs 1, Schiffmann H, Oehler R, et al (2003) Distribution of lung ventilation in spontaneously breathing neonates lying in different body positions . Intensive Care Med 29:787- 794 34. Heinrich S, Schiffmann H, Frerichs A, Klockgether-Radke A, Frerichs I (2006) Body and head position effects on regional lung ventilation in infants: An electrical impedance tomography study. Intensive Care Med 32:1392-1398 35. Thach B (2001) Fast breaths, slow breaths, small breaths, big breaths: importance of vagal innervation in the newborn lung. J Appl Physiol 91:2298-2300 36. Frerichs I, Hahn G, Schiffmann H, Berger C, Hellige G (1999) Monitoring regional lung ventilation by functional electrical impedance tomography during assisted ventilation . Ann N Y Acad Sci 873:493- 505 37. Frerichs I, Schiffmann H, Hahn G, Hellige G (2001) Non-invasive radiation -free monitoring of regional lung ventilation in critically ill infants. Intensive Care Med 27:1385 - 1394 38. Hampshire AR, Smallwood RH, Brown BH, Primhak RA (1995) Multifrequency and parametric EIT images of neonatal lungs. Physiol Meas 16:A175-189 39. Taktak A, Spencer A, Record P, Gadd R, Rolfe P (1996) Feasibility of neonatal lung imaging using electrical impedance tomography. Early Human Development 44:131-138 40. Frerichs I, Schiffmann H, Hahn G, Dudykevych T, Just A, Hellige G (2005) Funktionelle elektrische Impedanztomographie - eine Methode zur bettsetigen Ueberwachung der regionalen Lungenfunktion. Intensivmed 42:66- 73 41. Ainsworth SB, Milligan OW (2002) Surfactant therapy for respiratory distress syndrome in premature neonates : a comparative review. Am J Respir Med 1:417 -433 42. Rodriguez RJ (2003) Management of respiratory distress syndrome: an update . Respir Care 48:279-286 43. Suresh GK, Soli RF (2005) Overview of surfactant replacement trials. J Perinatol 25 (suppl 2): S40-44 44. Couser RJ, Ferrara TB, Wheeler W, et al (1993) Pulmonary follow-up 2.5 years after a randomized, controlled , multiple dose bovine surfactant study of preterm newborn infants. Pediatr Pulmonol 15:163- 167 45. Mercier CE, Soli RF (1993) Clinical trials of natural surfactant extract in respiratory distress syndrome. Clin Perinatol 20:711 -735 46. Frerichs I, Dargaville PA,van Genderingen H, Morel DR, Rimensberger PC (2006) Lung volume recruitment after surfactant administration modifies spatial distribution of ventilation. Am J Respir Crit Care Med 174:772-779 47. Krause M, Olsson T, Law AB, et al (1997) Effect of volume recruitment on response to surfactant treatment in rabbits with lung injury. Am J Respir Crit Care Med 156:862 - 866

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Extracorporeal Lung Assist for Acute Respiratory Distress Syndrome: Past, Present and Future R.

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Introduction In the most severe cases of acute respiratory distress syndrome (ARDS), additional strategies seem necessary to prevent additional lung injury, life threatening hypoxemia, and fatal outcomes. In the context of clinical algorithms (Fig. 1) and prospective trials, inhaled vasodilators, partial liquid ventilation, high frequency ventilation, and prone position have been used for this purpose. An alternative approach is the application of extracorporeal gas exchange devices to facilitate oxygenation and decarboxylation without the harm associated with aggressive mechanical ventilation strategies. Depending on technical modifications, blood flow rates, and the route of extra corporeal blood flow these techniques are called extracorporeal lung assist (ECLA), extracorporeal membrane oxygenation (ECMO), or interventionallung assist (ILA). The purpose of this chapter is to review the basic principles of extracorporeal devices in the treatment of ARDS. Furthermore, we intend to present an overview on the current developments and clinical application of ECLA. Finally we would like to present some possible future developments in this area.

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R. Kopp, U. Steinseifer, and R. Rossaint

Clinical History of Extracorporeal Lung Assist With the first successful applicat ion of a modified cardiopulmonary bypass (CPB) system for a young patient with ARDS, ECLA/ECMO was introduced in 1972 into clinical practice [1]. Promising results in different case reports led to the first prospective randomized controlled study in the early 1970s [2]. Ninety pat ients with severe ARDS were randomized to convent ional therapy with mechanical ventilation or to additional ECMO-therapy. Mortality in both groups was high without significant differences (90 % vs. 92 %). A veno-arterial perfusion with reduced pulmonary blood flow, no adjustment of mechanical ventilation after starting ECMO, high dose heparinization with a blood loss of 2.5 lid, and termination of ECMO after 5 days independent of lung function are possible reasons for the disappointing results in this trial. Gattinoni et al. developed an alternative approach, called extracorporeal CO2 removal (ECC0 2R), using a veno-venous perfusion route and a blood flow of only 20- 30 % of cardiac output combined with low frequency mechanical ventilation and additional oxygen insufflation [3]. Forty-three patients with severe ARDS accord ing to the entry criteria of the first ECMO study were treated with ECC0 2R and demonstrated a mortality of 51.2 %. Confirmation of these results in a subsequent prospective randomized trial failed, but an injurious ventilation strategy, a low blood flow despite ongo ing hypoxia, and a high loss of blood (4.7 lid) were profound technical problems in the ECMO group [4]. Despite these negative results, several ARDS centers use enhanced ECMO therapy combined with a lung protective ventilation strategy ( Fig. 2) for the most severe ARDS patients with life-threatening hypoxemia. In different case series , survival rates were similar to overall survival rates in ARDS (Table 1). A prospective controlled study (CESAR Trial) comparing enhanced ECMO therapy with conventional management for severe ARDS has recently been completed [5].

Fig. 2. Picture and schematic drawing of veno-venous extracorporeal membrane oxygenation (ECMO).

Extracorporeal Lung Assist for Acute Respiratory Distress Syndrome Table 1. Outcome of patients with severe ARDS receiving extracorporeal membrane oxygenation (ECMO) Number of patients

Mortality

Hemmila et al. 2004 [1 2] Henzler et al. 2004 [23 ] Mols et al. 2001 [24] Linden et al. 2000 [25] Ullrich et al. 1999 [26] Peek et al. 1997 [27] Lewandowski et al. 1997 [28]

255 15 62 17 13 50 49

48% 33 % 45 % 24 % 38 % 34 % 45 %

Total

461

44%

Case study

Further Development of Extracorporeal Lung Assist The development of oxygenators with silicone or microporous membranes increased short- and long-term hemocompatibility compared to the bubble oxygenators used in the 1960s. This was a milestone for the technical evolution from short-term CPB to long-term ECLA. Because of a highe r gas transfer rate and, therefore, a smaller surface area, microporous membrane oxygenators are the preferred devices in most European ECMO centers. A severe complication of microporous membranes is 'plasma leakage' when large amounts of blood plasma pass over the membranes. Because of the dramatically reduced gas transfer affected oxygenators have to be changed [6). Risk factors are increased blood concentrations of lipids or phospholipids, liver failure, younger patient age, and the number of oxygenators already replaced. Newly developed fibers combine a microporous texture with a thin closed layer on the surface to prevent plasma leakage and to extend the running-time of the oxygenators ( Fig. 3) [7). Oxygenators with a plasma resistant polymethylpentene fiber have been successfully used for long-term ECMO [8).

-

.....

~

~

~ .....

-~ -,.~'4

.~

~~

Fig. 3. Characteristics of microporous polypropylene membranes (left) and polymethylpentene composite membranes (right).

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R. Kopp, U. Steinseifer, and R. Rossaint

For microporous capillary fibers, different techniques of heparin coating of the blood contacting surfaces have been developed reducing coagulation activation and increasing hemocompatibility [9]. With the implementation of these heparin -coated ECMO circuits, systemic heparin ization could be reduced to 150- 220 IU/kg/d leading to an activated clotting time (ACT) of 120-150 sec: this resulted in decreased blood loss as well as less bleeding complications [10]. Today, different surface modifications are commercially available. Roller pumps have been standard for ECMO therapy, although continuous mechanical stress can result in rupture and embolism of tube particles . This requires the regular change of tubes in roller pumps. By using centrifugal pumps, these complications can be avoided. Blood depositions on centrifugal pumps may increase damage to blood cells however, leading to regular exchange of pumps. Newly developed impeller-pumps provide a decreased filling volume, uncoupling of pump and control unit, and extended monitoring of the ECMO circuit. In the past, a blood pump was necessary to overcome flow resistance of cannulae and oxygenators and to achieve sufficient blood flow. Using newly designed oxygenators and cannulae with reduced pressure drop, mean arterial blood pressure becomes sufficient to achieve adequate extracorporeal blood flow. Mathematical analysis demonstrated that for arterio-venous pumpless ILA total extracorporeal CO2-removal is possible with a blood flow of 10-15 % cardiac output, a gas flow 2: 5 l/rnin, and an adequate diffusing capacity of the oxygenator [11]. Oxygen transfer is limited due to the oxygenated blood coming into the membrane lung.

Veno-venous Extracorporeal Membrane Oxygenation Today Clinical Practice In most ARDS centers, application of ECMO is limited to the most severe cases of ARDS with imminent hypoxemia defined by 'fast entry criteria' (Fig. 1) and sometimes addit ional criteria (e.g., Murray Score 2: 3.0 or pH < 7.20). Because ECMO is a complex and invasive technique with a number of complications, absolute contraindications have to be considered: Cerebral damage, acute severe head injury, terminal chronic or malignant disease, severe hemorrhage, and disseminated intravascular coagulation (Die). Older age, immune suppression, mild to moderate acute head injury, left-ventricular failure, and heparin-induced thrombocytopenia (HIT) are relative contraindications. In most cases of lung failure, a veno-venous perfusion route is used with the femoral vein and the jugular vein cannulated using a percutaneous Seldinger technique [12]. ECMO centers use different perfusion routes (jugular-femoral , femoral-jugular, and femoral-femoral). With the veno-venous perfusion route, lung perfusion remains normal. In our center, a femoral cannula is usually placed for blood drainage from the lower body including desaturated blood from liver veins and blood returns to the vena cava near the right atr ium via the right jugular vein. Blood flow is adjusted to 30 - 50 % of cardiac output providing sufficient oxygenation and decarboxylation. For low extracorporeal blood flows, two cannulae with one oxygenator and one pump are sufficient, but in case of increased cardiac output a second oxygenator and blood pump with three cannulae are often used to achieve sufficient gas exchange. With this technique a lung protective ventilation strategy is possible even in the most severe ARDS cases, avoiding further ventilator-associated lung injur y (VALl).

Extracorporeal Lung Assist for Acute Respiratory Distress Syndrome

In case of life-threatening hypoxemia the patient can be connected to the ECMO in the referring hospital before interhospital transfer [13]. This technique is also used for intrahospital transfer with ECMO for diagnostic or surgical procedures outside the intensive care unit (ICU). After recovery of lung function, extracorporeal blood and gas flow is reduced . When sufficient gas exchange by the lung has been demonstrated, ECMO is weaned and the cannulae are removed usually without surgical intervention. The heparin coating of all blood contacting surfaces allows the reduction of systemic heparinization leading to an ACT of 120-150 sec and subsequently decreased blood loss as well as fewer bleeding complications.

Complications Accumulating mechanical damage of erythrocytes and platelets leads to an increased plasma hemoglobin concentration and a decrease in platelets. These complications are reduced by optimizing blood flow and avoiding clot formation especially in pump and oxygenator housing. Activation of the coagulation system as well as platelets on the ECLA surfaces can result in Die. In patients with HIT, alternative methods of anticoagulation are necessary. Heparin-bonded surfaces are contraindicated and hirudin, argatroban, or perhaps systemic prostacyclin have to be used for systemic anticoagulation. Formation of blood clots in the pump, oxygenator, or cannulae, as well as spallation of plastic, carries the risk of embolism. Dislocation of cannulae and tubes as well as rupture of components results in life-threatening failure of ECMO. The incidence of 'plasma leakage' of the oxygenators is reduced when using modern composite membranes. ECMO therapy is highly demanding in terms of personnel, technical requirements, and monitoring and , therefore , its use is restricted to dedicated clinical centers [14).

Arteria-venous Pumpless Interventional Lung Assist A new approach is the combination of an oxygenator with a reduced pressure drop and an arterio-venous pumpless perfusion route driven by the patient's mean arterial pressure ( Fig. 4). The feasibility and safety of this technique has been demonstrated in initial clinical studies; the mean blood flow was 0.5 - 1.0 lImin with a commercially available oxygenator (Medtronic Affinity) [15) and 2.0 ± 0.44 11m with a specially designed low resistance membrane lung (Novalung ILA) (16). Decreasing hypercapnia demonstrated adequate carbon dioxide elimination after initiation of both devices. Advantages of ILA are the avoidance of all pump-related complications, reduced blood contacting surfaces , and simplified clinical management. Disadvantages are the indirect control of blood flow, which is the result of the arterio-venous pressure gradient, the low oxygen transfer capacity since already oxygenated blood is flowing into the device, the risk of limb ischemia because of arterial cannulation, and the arterio-venous shunt perfusion up to 25 % of cardiac output. These limitations and characteristics lead to specific contraindications, such as heart failure, septic shock with low mean arterial pressure, and severe peripheral arterial occlusive disease.

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VI Fig. 4. Picture and schematic drawing of arteria-venous pumpless interventional lung assist (ILAl.

The indications for ILA have not been formally established by well-controlled clinical trials but patients with severe hypercapnia and acute respiratory failure seem to benefit [17). Extracorporeal carbon dioxide elimination allows a more protective ventilation strategy with reduced airway pressure and tidal volume using a pressure controlled or pressure support ventilation mode not only in ARDS but also in other severe ventilation disorders such as bronchopleural fistula. In severe hypoxemia, limited extra corporeal oxygen transfer rate is often not sufficient and veno-venous ECMO is necessary. For patients with severe head injury and concomitant chest trauma, the dilemma arises between lung protective ventilation with permissive hypercapnia and increased intracranial pressure requiring normo- or hypocapnia. Application of ILA with low dose heparinization allows lung protective ventilation without increasing arterial CO2 and, thereby, controlling intracranial pressure [18). In a case study, 12 patients waiting for lung transplantation were treated with ILA as a bridge to transplant because of severe ventilation-refractory hypercapnia and respiratory acidosis [19). The results were promising with 10 patients successfully transplanted and 8 patients surviving after 1 year. Although the technique is fascinating, clearly more clinical studies and experience are necessary to evaluate the advantages, complications, and indications, as well as the contraindications of arterio-venous ILA. Larger scale clinical studies must define the role of ILA in context with lung protective ventilation strategies.

Future Development of ECLA A miniaturization of ECMO could offer the possibility to reduce filling volume, to shift the device closer to the patient, and to simplify clinical management. The complexity and hazards of inter- and intrahospital transfer could be reduced with this

Extracorporeal lung Assist for Acute Respiratory Distress Syndrome

smaller ECMO circuit. Initial attempts have been made to miniaturize ECMO with commercially available oxygenators and rotating blood pumps [20]. New concepts for highly integrated veno-venous ECMO couple the oxygenator and blood pump to reduce foreign surface area and priming volume even more and to use the waste heat of the pump motor hous ing instead of a heat exchanger to keep blood temperature constant [21]. The compact design should further simplify clinical management. Using oxygenators with further decreased flow resistance opens the possibility of using the right ventricle as the driving force for blood flow after implantation of the artificial lung in-series or parallel to the biological lungs. A paracorporeal oxygenator with a low pressure gradient of 7.5 mmHg was successfully implanted in adult sheep for 5 days after induction of ARDS with lethal smoke inhalation and burn trauma [22]. Clinical studies are necessary to confirm these concepts for acute and chronic respiratory failure.

Conclusion For 35 years, veno-venous ECMO has been an important therapy for the management of patients with ARDS. Because no clinical data support the use of ECMO as a standard treatment in ARDS, its application is limited to the most severe cases of ARDS with life threatening hypoxemia. Today it is a highly demanding intervention in terms of technical and personnel requirements requiring specialized centers. These centers offer the possibility to start ECMO in the referring hospital and to transfer the patient with ECMO running. New application areas now seem possible as technological progress continues , such as optimized membranes, miniaturized highly integrated systems, or alternative perfu sion routes. Indications and contraindications of these technique s will depend on the route of perfusion as well as the site of cannulation and must be weighed against the harm of conventional therapy. Well designed clinical studies are, therefore, necessary to implement these different devices for extracorporeal support into clinical practice. References

JJ (1972) Prolonged extracorporeal oxygenation for acute posttraumatic respiratory failure (shock-lung syndrome). N Engl J Med 286:629-634 Zapol WM, Snider MT, Hill JD, et al (1979) Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 242:2193-2196 Gatt inoni L, Pesenti A, Mascheron i D, et al (1986) Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respirator y failure. JAMA 256:881- 886 Morr is AH, Wallace CJ, Menlove RL, et al (1994) Randomized clinical tr ial of pressure -controlled inverse ratio ventilation and extracorporeal C02 removal for adult respiratory distre ss syndrome. Am J Respir Crit Care Med 149:295-305 CESAR Trial Group (2007) Conventional Ventilation or ECMO for Severe Adult Respiratory Failure - CESAR Trial. Available at: http://www.cesar-trial.org. Accessed Dec 2007 Meyns B, Vercaemst L, Vandezande E, Bollen H, Vlasselaers D (2005) Plasma leakage of oxygenators in ECMO depends on the type of oxygenator and on patient variables. Int J Artif Organs 28:30- 34 Eash HI, Jones HM, Hattler BG, Federspiel WJ (2004) Evaluation of plasma resistant hollow fiber membranes for artificial lungs. ASAIO J 50:491-497

1. Hill JD, O'Brien TG, Murray

2. 3. 4. 5. 6. 7.

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R. Kopp, U. Steinseifer, and R. Rossaint 8. Peek GJ, Killer HM, Reeves R, Sosnowski AW, Firmin RK (2002) Early experience with a polymethyl pentene oxygenator for adult extracorporeallife support. ASAIO J 48:480-482 9. Wendel HP, Ziemer G (1999) Coating-techniques to improve the hemocompatibility of artificial devices used for extracorporeal circulation. Eur J Cardiothorac Surg 16:342-350 10. Bindslev L, Eklund J, Norlander 0 , et al (1987) Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung. Anesthesiology 67:117-120 11. Conrad SA, Brown EG, Grier LR, et al (1998) Arteriovenous extracorporeal carbon dioxide removal: a mathematical model and experimental evaluation. ASAIO J 44:267-277 12. Hemmila MR, Rowe SA, Boules TN, et al (2004) Extracorporeallife support for severe acute respiratory distress syndrome in adults. Ann Surg 240:595-605 13. Rossaint R, Pappert D, Gerlach H, Lewandowski K, Keh D, Falke K (1997) Extracorporeal membrane oxygenation for transport of hypoxaemic patients with severe ARDS. Br J Anaesth 78:241-246 14. Kopp R, Dembinski R, Kuhlen R (2006) Role of extracorporeallung assist in the treatment of acute respiratory failure. Minerva Anestesiol 72:587- 595 15. Conrad SA, Zwischenberger JB, Grier LR, Alpard SK, Bidani A (2001) Total extracorporeal arteriovenous carbon dioxide removal in acute respiratory failure: a phase I clinical study. Intensive Care Med 27:1340-1351 16. Reng M, Philipp A, Kaiser M, Pfeifer M, Gruene S, Schoelmerich J (2000) Pumpless extracorporeallung assist and adult respiratory distress syndrome. Lancet 356:219-220 17. Bein T, Weber F, Philipp A, et al (2006) A new pumpless extracorporeal interventionallung assist in critical hypoxemia/hypercapnia. Crit Care Med 34:1372 -1377 18. Bein T, Scherer MN, Philipp A, Weber F, Woertgen C (2005) Pumpless extracorporeal lung assist (pECLA) in patients with acute respiratory distress syndrome and severe brain injury. J Trauma 58:1294-1297 19. Fischer S, Simon AR, Welte T, et al (2006) Bridge to lung transplantation with the novel pumpless intervent ionallung assist device NovaLung. J Thorac Cardiovasc Surg 131:719-723 20. Dembinski R, Kopp R, Henzler D, et al (2003) Extracorporeal gas exchange with the Deltastream rotary blood pump in experimental lung injury. Artif Organs 27:530-536 21. Cattaneo G, Strauss A, Reul H (2004) Compact intra- and extracorporeal oxygenator developments. Perfusion 19:251 - 255 22. Zwischenberger JB, Wang D, Lick SD, Deyo DJ, Alpard SK, Chambers SD (2002) The paracorporeal artificial lung improves 5-day outcomes from lethal smoke/burn-induced acute respiratory distress syndrome in sheep. Ann Thorac Surg 74:1011- 1016 23. Henzler D, Dembinski R, Kopp R, Hawickhorst R, Rossaint R, Kuhlen R (2004) Therapie des akuten Lungenversagens in einem Behandlungszentrum - Der Erfolg ist abhangig von der Indikationsstellung. Anaesthesist 53:235- 243 24. Mols G, Loop T, Hermie G, et al (2001) 10 Jahre Erfahrung mit extrakorporaler Membranoxygenierung. Anasthesiol Intensivmed Notfallmed Schmerzther 36:4- 14 25. Linden V, Palmer K, Reinhard J, et al (2000) High survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation . Intensive Care Med 26:1630-1637 26. Ullrich R, Lorber C, Roder G, et al (1999) Controlled airway pressure therapy, nitric oxide inhalation, prone position , and extracorporeal membrane oxygenation (ECMO) as components of an integrated approach to ARDS. Anesthesiology 91:1577-1586 27. Peek GJ, Moore HM, Moore N, Sosnowski AW, Firmin RK (1997) Extracorporeal membrane oxygenation for adult respiratory failure. Chest 112:759-764 28. Lewandowski K, Rossaint R, Pappert D, et al (1997) High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med 23:819-835

Section VII

VII Ventilatory Support

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Protective Mechanical Ventilation: Lessons Learned From Alveolar Mechanics S.

ALBERT,

B.

KUBIAK,

and G.

NIEMAN

Introduction Acute respiratory distress syndrome (ARDS) is a serious pulmonary disease characterized by respiratory failure with marked hypoxemia secondary to diffuse bilateral non-hydrostatic pulmonary edema and atelectasis. A formal definition of ARDS and acute lung injury (ALI) was introduced by an American-European Consensus Conference [1]. ALI has a devastating clinical impact, and current data estimates 190,600 new cases of ALI per year with 74,500 annual deaths in the United States alone [2]. The majority of patients with ALI, and in particular ARDS, require supportive therapy with mechanical ventilation. It has been shown, both clinically and experimentally, that improper mechanical ventilation causes ventilator-induced lung injury (VILI), which exacerbates the underlying ALI, leading to an increase in mortality [3]. If VILI could be eliminated by use of protective mechanical ventilation, an estimated 3,800 to 35,000 deaths associated with ALI could be prevented annually [3]. Multiple protective modes of ventilation are currently being used including low tidal volumes strategies and open lung strategies. However, it is necessary to understand the pathophysiology of VILI at the alveolar level in order to make informed decisions regarding the appropriate protective mode of ventilation.

Chapter Overview The goal of th is chapter is two fold: 1) To give the reader an understanding of the mechanism ofVILI at the alveolar level; and 2) to demonstrate how mechanical ventilation can be used to prevent VILI by normalizing alveolar mechanics. We will first give a brief review of ARDS pathophysiology, since ARDS is the disease primarily associated with VILI. This will be followed by an overview of both normal and abnormal (i.e., during ARDS) alveolar mechanics that leads into the mechanism of VILI. The chapter will conclude by describing current strategies of protective mechanical ventilation and discussing possible mechanisms of lung protection at the alveolar level. With a thorough understanding of both normal and abnormal alveolar mechanics, the concepts can be applied to the understanding and development of novel modes of mechanical ventilation. Ultimately, we hope to better define proper mechanical ventilation, eliminate VILI, and, thereby, reduce the morbidity and mortality associated with ARDS.

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Acute Respiratory Distress Syndrome ARDS can be caused by either direct lung injury (pneumonia or aspiration) or indirectly from a systemic process such as sepsis. ARDS is characterized by an increased permeability of the alveolar-capillary membrane leading to the leakage of edema fluid and plasma proteins from the vasculature into the alveolar spaces [4]. Alveolar flooding during ARDS is a heterogeneous process, largely in dependent lung regions, with injured lung regions lying directly adjacent to relatively spared lung parenchyma [5]. One of the primary pathologies associated with ARDS is surfactant deactivation . The edema fluid flooding the alveolus directly inhibits surfactant through plasma proteins, proteases, phosholipases, and reactive oxygen species (ROS) [6]. When the injury is severe enough, direct damage to the surfactant-producing type II epithelial cells can result [7]. These mechanisms combined result in an increase in alveolar surface tension , which causes alveolar instability and ultimately leads to a heterogeneous reduction in lung compliance and development of significant atelectasis. ARDS is a neutrophil-mediated disease that causes an increase in pulmonary vascular permeability. Neutrophils adhere to the capillary endothelium and diapedese from the capillary into the air space causing an increase in capillary permeability, which leads to alveolar flooding with a protein-rich edema fluid. These neutrophils become activated and release ROS, proteases, leukotrienes, and other pro-inflammatory molecules exacerbating the initial lung injury. Multiple pro- and anti-inflammatory cytokines are secreted which have been found to help initiate, amplify, and perpetuate the inflammation that occurs with ARDS [4] (Fig. 1 ).

Alveolar Mechanics There is no consensus on the exact behavior of alveoli during normal respiration although it is generally accepted that normal alveoli do not expand and contract with each breath like 300 million balloons [8]. There are currently two main schools of thought: One attributes increased lung volume to normal (non-pathologic) alveolar recruitment!derecruitment [9] by a folding and unfolding of alveoli [10] and the other attributes it to changes in the size of the alveolar duct and mouth with little change in the size of the alveolus [11]. Recently these concepts were challenged by Perlman and Bhattacharya who visualized expansion of alveoli during normal ventilation of rat lungs while utilizing realtime confocal microscopy [12]. These researchers found a non-uniform expansion of the alveolar wall by measuring differences in the length of multiple segments on the alveolar perimeter. They concluded that this non-uniform alveolar expansion is a primary mechanism of whole lung expansion, not alveolar recruitment/derecruitment. Work at our laboratory, using in vivo microscopy, has demonstrated minimal changes in the size of alveoli during tidal ventilation, even at tidal volumes as high as 30 mllkg and peak airway pressures exceeding 50 cmH20 [13]. In vivo microscopy suggests that the normal lung volume change is due to normal alveolar recruitment! derecruitment and not to balloon-like change in alveolar size [9]. Kitaoka et al. recently constructed a 4-dimentional model of dynamic alveolar and alveolar duct mechanics, which suggests that opening and closing of the alveolar mouth causes the alveolar ducts to change size with each breath and is a mechanism of normal lung volume change [11].

Protective Medlanical Ventilation: Lessons Learned From Alveolar Medlanics

Injured alveolus during the acute phase

Norma l alveolus

.

Sloughing of bronchial epithelium

~ -~~.-~u Necroticor apoptotic type I cell

TypeI cell

Epithelial basement membrane Intact type II cell

Epithelial basement membrane Swollen, injured endothelial cells Fibroblast

Fibroblast

Neutrophil

Fig. 1. The normal alveolus (left-hand side) and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome (right-hand side). In the acute phase of the syndrome (right-hand side), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting cytokines, interleukin (IL)-l, 6, 8, and 10, and tumor necrosis factor (TNF)-a, which act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other rytokines, including IL-1, 6, and 10. IL-l can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other pro-inflammatory molecules, such as platelet-activating factor (PAF). Anumber of anti-inflammatory mediators are also present inthe alveolar milieu, including IL-l receptor antagonist, soluble TNF receptor, autoantibodies against IL-8, and cytokines such as IL-l0 and 11 (not shown). The influx of protein rich edema fluid into the alveolus has led to the inactivation of surfactant. MIF: macrophage inhibitory factor. From [4] with permission.

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While the exact mechanism of normal dynamic alveolar function is not known, our current work suggests that the alveolar size remains stable during tidal ventilation in the normal lung. Using in vivo microscopy, we are able to visualize the dynamic changes in alveolar mechanics that occur in ALI and ARDS ( Fig. 2) [13]. Using a porcine surfactant deactivation model, we measured a dramatic change in dynamic alveolar mechanics, from stable in the normal lung to repetitive alveolar collapse and expansion with each breath (Fig. 2). In this ARDS lung model, unstable alveoli demonstrate a significant change in alveolar volume ( Fig. 2) [13]. Further studies have shown that these altered alveolar mechanics cause VILI [14, 15]. Thus, protective mechanical ventilation must change these repetitive alveolar collapse and expansion alveoli into normal stable alveoli in order to prevent VILI.

Fig. 2. Subpleural alveoli in the normal lung during inspiration (a) and expiration (b) and the injured lung (Tween instillation) during inspiration (9 and expiration (d). The microscopic field isthe same during inspiration and expiration such that the same alveoli are visualized throughout the ventilatory cycle. In the normal lung the same alveoli at peak inspiration (a) and end expiration (b) are circled with dotted lines. Note how little the alveoli change size during ventilation in the two dimensions that we can visualize with this technique. Contrast the dramatic change in alveolar mechanics Ii.e., the dynamic change in alveolar size and shape with ventilation) in the injured lung (c, d). At peak inspiration all alveoli inflate (c) and look very similar to normal alveoli (a). However, at end expiration many alveoli collapse or dramatically decrease in size (d). Four alveoli that appear fully inflated at peak inspiration (c, dotted circle) collapse totally at end expiration ( d, arrows, One alveolus is inflated fully at peak inspiration (c, solid circle ) and collapses greatly but not totally at end expiration (d, solid circl ~.

Protective Mechanical Ventilation: Lessons Learned From Alveolar Mechanics

Mechanisms of VILI at the Alveolar Level VILI is believed to be caused by three basic mechanisms: 1) Volutrauma; 2) atelectrauma; and 3) biotrauma. The first two mechanisms are mechanical injuries (physical bending or stretching of pulmonary tissues) and the third is a secondary inflammatory injury (tissue damage by endogenous inflammatory mediators such as neutrophils) . Volutrauma

The concept of volutrauma was first described by Dreyfuss et al. when they discovered that the high permeability edema resulting from mechanical ventilation was a direct result of high volumes and not high airway pressures [16]. Their studies also demonstrated that the ARDS lung is more susceptible to the harmful effects of high pressure-induced overinflation than normal healthy lungs. The injury caused by high-pressure mechanical ventilation is, therefore, synergistic rather than additive on the already injured lungs. These investigators concluded that flooding of alveoli with edema reduced the number of alveoli that were ventilated, exposing the alveoli with a normal compliance that remained open, to over inflate causing a severe injury [17]. Thus, in a lung with a heterogeneous compliance (i.e., ARDS lungs) the normal alveoli (mostly non-dependent lung areas) will be more susceptible to volutrauma unless the injured lung can be fully recruited (open lung strategies) early in the course of ARDS. Atelectrauma

The mechanism of atelectrauma is a shear stress-induced injury during repetit ive alveolar collapse and expansion . Multiple studies have demonstrated that repetitive alveolar collapse and expansion or alveolar recruitment/derecruitment is one of the primary mechanisms of VILI [18]. Mead et al. [19] developed an anatomical model of dynamic alveolar inflation, which described alveoli as interconnected units in a cluster around the bronchiole, similar to a honeycomb ( Fig. 3). Normal alveoli do

Fig. 3. Model of alveolar interdependence. a Adjoining alveoli equally inflated; b Alveolus in center collapses and distorts adjacent alveoli; c Alveolus in center expands and distorts adjacent alveoli; d Alveolus in center dramatically expands and greatly distorts adjacent alveoli. From [19] with permission.

a

c

b

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Direction of bubble progression ~

Collapsed airway

Fig. 4. Hypothetical stresses imparted on the epithelial cells of an airway during reopening. Acollapsed compliant airway is forced open by a finger of air moving from left to right. Adynamic wave of stresses is imparted on the airway tissues asthe bubble progresses. Circles show the cycle of stresses that an airway epithelial cell might experience during reopening. The cell far downstream is nominally stressed. As the bubble approaches the cell is pulled up and toward the bubble. After the bubble has passed, thecell is pushed outward. From [20] with permission.

not function independently but have shared walls that collectivelyprovide structural support. This has been termed 'alveolar interdependence' and is vital to stabilizing alveoli and preventing collapse at low lung volumes. Interdependence prevents alveolar collapse and over-distension due to stenting and cushioning, respectively ( Fig. 3) [19]. In ARDS, the loss of alveolar interdependence, along with surfactant dysfunction, leads to alveolar instability and repetitive alveolar collapse and expansion [13]. When an alveolus collapses, shear stress is placed on the walls of the collapsing alveoli and on the walls of all adjacent alveoli. Shear stress is again inflected on alveolar epithelial cells when the alveolus reopens. Bilek et al. demonstrated that reopening of collapsed airways caused a significant distortion of epithelial cells as the collapsed airway is forced open by the column of air ( Fig. 4l [20]. Regardless of the exact mechanism, these shear stresses have been shown to lead to gross disruptions of the alveolar wall, reversible and irreversible injury to the cell membrane of pulmonary cells, and ultrastructural disruption of the pulmonary epithelium and endothelium [16, 21, 22].

Biotrauma Volutrauma and atelectrauma are mechanical injuries resulting from injurious mechanical ventilation. Temblay and Slutsky used the term biotrauma to describe how these two mechanical injuries could cause an inflammatory response leading to biochemical injury [23]. Using a rat model, they were able to confirm the release of both inflammatory and anti-inflammatory cytokines by the normal lung subjected to injurious ventilation [24]. Chiumello et al. demonstrated that lung cytokines were also increased in the systemic circulation during ventilation due to leakage into the vascular space and loss of cytokine compartmentalization [25]. The cytokines and inflammatory mediators further recruit neutrophils into the lung, propagating the lung injury caused by mechanical damage (volu- and atelectrauma) and exacerbating VILI. The inflammatory process created is not confined to the lungs, but enters the systemic circulation and can have detrimental effects on end-organs. This can lead to multiple organ dysfunction syndrome, which is responsible for a large number of deaths in patients with ARDS.

Protective Mechanical Ventilation: Lessons Learned From Alveolar Mechanics

Protective Mechanical Ventilation and Alveolar Mechanics The goal of protective ventilation in patients with ALI and ARDS is to avoid the previously discussed mechanisms of VILI: Volutrauma, atelectrauma, and biotrauma. Thus, mechanical ventilation has two majors goal: 1) Support life-sustaining measures of oxygenation and ventilation; 2) avoid injurious ventilation patterns, which exacerbate the underlying disease condition. The lungs of ARDS patients have a heterogeneous injury, with areas of collapse and atelectasis and areas of relatively normal lung parenchyma intertwined. Modes of ventilation can either: 1) Ventilate only the normal areas of parenchyma while allowing the injured to 'rest' (low tidal volume strategy) or 2) recruit and keep the injured areas open with high pressure (open lung strategy). The low tidal volume strategy will reduce alveolar over distension , recruitment/derecruitment, and has been shown to reduce ARDS mortality [26]. However, some patients have a limited amount of healthy lung and, therefore, a low tidal volume strategy may not adequately oxygenate these patients. In addition, the low tidal volume strategy will result in a significant amount of atelectasis, which can exacerbate pneumonia development and prevent the reestablishment of alveolar interdependence. Open lung strategies use high constant airway pressure and/or positive end-expiratory pressure (PEEP) to recruit and stent open injured and non-injured lung regions, thereby reducing atelectasis and alveolar recruitment/dereeruitment, providing a more homogenous ventilation. Currently, there are multiple modalities of protective mechanical ventilation as it relates to VILI, and clinical trials will be necessary to determine the ideal mode for a heterogeneous population of ARDS patients. An understanding of alveolar mechanics and how they relate to VILI is important to understanding the mechanism for the potential benefits offered by lung protective mechanical ventilation strategies. We will discuss the impact on alveolar mechanics of low tidal volume strategies, the use of PEEP, open lung ventilation, high frequency oscillatory ventilation (HFOV), and airway pressure release ventilation (APRV).

PEEp, Low Tidal Volumes, and Alveolar Mechanics PEEP

The role of PEEP in lung protective ventilation is to stabilize alveoli while preventing alveolar overdistention in a low tidal volume ventilation strategy. Halter et al. [15], showed that low tidal volumes (6 mllkg) and high PEEP (20 cmHzO), stabilized alveoli, which was directly confirmed using in vivo microscopy [15]. Using computed tomography (CT) scanning Gattinoni et al. [27] showed that injured lungs have less lung participating in ventilation, and applying PEEP to these lungs can open collapsed alveoli and prevent the shear stresses caused by alveolar recruitment/derecruitment. Both Gattinoni and Halter have shown that PEEP has protective effects, by avoiding shear stress injury in ARDS damaged lungs. Low Tidal Volume

Low tidal volumes and PEEP levels high enough to open recruitable lung may allow the most injured portions of lung to 'rest' until the resolution of the underlying lung injury [27]. Chu et al., using an ex vivo normal rat lung showed that inflammatory cytokines (tumor necrosis factor [TNF]-a, interleukin [1L] -6, macrophage inflarn-

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s. Albert, B. Kubiak, and G. Nieman matory protein [MIP]-2) were greater in the lung exposed to cyclic opening and closing compared to the atelectatic lung [28]. Similarly, Caruso et al. showed results suggestive of less injury in atelectatic lungs [29]. IL-IP and alpha-l procollagen (PCIII) mRNA expression were reduced in the spontaneous breathing group compared to the low tidal volume and high tidal volume group. Low tidal volume did not prevent expression of these mediators; however the transcription of mRNA was significantly greater in the nondependent regions of the low tidal volume group. This would suggest that the dependent lung region (more collapsed region) is less affected by ventilation. In other words, atelectasis and lung collapse does not have deleterious alveolar effects on the lung parenchyma in ALI models. In terms of alveolar mechanics, low tidal volume ventilation prevents volutrauma to alveoli, and lung inflation is limited to areas that are the least injured. Non-ventilated lung regions are allowed to recover, preventing the volutrauma and shear stress injury incurred with larger tidal volumes (l0-15 mllkg).

Open Lung Approach and Alveolar Mechanics

VII

In the open lung approach, alveoli and small airways are stented open with a constant airway pressure. Multiple modes of ventilation will allow for open lung ventilation: HFOV, APRV, and recruitment maneuvers followed by the application of PEEP. In an editorial , Dr. Lachmann advocates to "Open the lung and keep the lung open:' in order to recruit collapsed alveoli, prevent shear stress injury, reduce surfactant depletion, and reduce pulmonary edema by keeping the pressure amplitude at a minimum [30]. The understanding gained through the study of alveolar mechanics would suggest that an open lung approach may minimize shear stress, and improve oxygenation. There are multiple experimental modalities for achieving open lung or in alveolar mechanical terms , maximal alveolar recruitment. Compliance measurements, CT scanning, electrical impedance tomography (EIT), and oxygenation ratios have all been used to determine if a lung has been fully recruited [27, 31, 32]. £IT is based on changes in lung aeration, which result in different electrical properties of lung tissue and is a dynamic tool that can be used at the bedside by clinicians. A saline lavage animal study used EIT and HFOV to show that HFOV has the ability to evenly distribute lung volume [33]. The study suggests that HFOV may reduce shear stress injury to alveoli, a prominent mechanism in VILI. Thus, EIT could be used as a bedside tool for determining lung recruitment in ARDS patients.

HFOV, APRV, and Alveolar Mechanics HFOV has been used for some time in the neonatal population. Recently this mode of ventilation has received much more attention in the adult population. There are multiple mechanisms associated with HFOV gas exchange, using very small tidal volumes, and include convection, pendulluft (regional gas mixing), and diffusion of gases along their gradients [34]. Given that large tidal volumes in ARDS cause alveolar stress, in theory, very small tidal volumes used in HFOV should be protective. When a patient is on HFOV, alveoli will be continuously recruited over time because of the higher constant airway pressure, and repetit ive opening and closing of alveoli is prevented by the very small tidal volumes.

Protective Mechanical Ventilation: Lessons Learned From Alveolar Mechanics

Multiple animal studies have concluded that HFOV is an effective mode of ventilation in ALI models when compared to conventional treatments . Imai et al., nicely showed in a saline lavage rabbit model that HFOV attenuated a reduction in oxygenation and pulmonary compliance compared to a low tidal volume strategy and various PEEP levels [35]. Additionally, in the same study, TNF-a levels and leukocyte alveolar infiltration were also reduced suggestive of reduced biotrauma in the HFOV group [35]. Other studies have shown improved oxygenation, lung recruitment, normal CO2 elimination and improved lung histology injur y scores using HFOV animal models [36,37]. APRV uses a constant positive airway pressure (CPAP) and intermittent pressure releases are utilized to allow for removal of CO2 [38]. A benefit to APRV is allowance of spontaneous ventilation during CPAP. Conventional mechanical ventilation preferent ially ventilates non-dependent lung regions [29], whereas spontaneous breathing would preferentially ventilate dependent lung regions rather than non -dependent lung regions [39]. Habashi describe s APRV as a type of constant recruitment maneuver with only very brief drops in pressure to allow for CO2 removal. The benefit to this mode is that alveoli are opened over time, like HFOV, but spontaneous breathing is allowed during the ventilatory cycle [38].

Conclusion The understanding of alveolar mechanics is vital to implementing appropriate ventilation strategies in ARDS patients in order to prevent VILI. VILI has three major alveolar mechanisms, which are volutrauma, atelectrauma, and biotrauma. Volutrauma and atelectrauma are mechanical injuries and biotrauma is a secondary inflammatory injury. Low tidal volume and PEEP have been shown to reduce shortterm mortality in large clinical trials and therefore is considered standard of care. Open lung modes of ventilation (APRV, HFOV) are being studied in the laboratory and clinical environments, and ultimately large patient trials will be needed to further advance mechanical ventilation in ARDS patients. References 1. Bernard GR, Artigas A, Brigham KL, et al (1994) Report of the American -European Consensus

2. 3. 4. 5. 6. 7. 8.

conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordinat ion. Consensus Committee. j Crit Care 9:72-81 Rubenfeld GD, Caldwell E, Peabody E, et al (2005) Incidence and outcomes of acute lung injury. N Engl j Med 353:1685- 1693 Rubenfeld GD (2003) Epidemiology of acute lung injury. Crit Care Med 31 (suppI4): 5276-284 Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl j Med 342: 1334-1349 Maunder R], Shuman WP, McHugh JW, Marglin 51, Butler J (1986) Preservation of normal lung regions in the adult respiratory distress syndrome. Analysis by computed tomography. JAMA 255:2463 - 2465 Schmidt R, Markart P, Ruppert C, et al (2007) Time-dependent changes in pulmonary surfactant function and composition in acute respiratory distress syndrome due to pneumonia or aspiration. Respir Res 8:55 Putman E, van Golde LM, Haagsman HP (1997) Toxic oxidant species and their impact on the pulmonary surfactant system. Lung 175:75-103 DiRocco j, Carney D, Nieman G (2005) The mechan ism of ventilator- induced lung injury: role of dynamic alveolar mechanic s. In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine, Springer, Heidelberg , pp 80- 92

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s. Albert, B. Kubiak, and G. Nieman 9. Carney DE, Bredenberg CE, Schiller HJ, et al (1999) The mechanism of lung volume change during mechanical ventilation . Am J Respir Crit Care Med 160:1697- 1702 10. Tschumperlin DJ, Margulies SS (1999) Alveolar epithelial surface area-volume relationship in isolated rat lungs. J Appl Physiol 86:2026- 2033 11. Kitaoka H, Nieman GF, Fujino Y, Carney D, DiRocco J, Kawase 1 (2007) A 4-dimensional model of the alveolar structure. J Physiol Sci 57:175-185 12. Perlman CE, Bhattacharya J (2007) Alveolar expansion imaged by optical sectioning microscopy. J Appl Physiol 103:1037 -1044 13. Schiller HJ, McCann UG 2nd, Carney DE, Gatto LA, Steinberg JM, Nieman GF (2001) Altered alveolar mechanics in the acutely injured lung. Crit Care Med 29:1049-1055 14. Steinberg JM, Schiller HJ, Halter JM, et al (2004) Alveolar instability causes early ventilatorinduced lung injury independent of neutrophils. Am J Respir Crit Care Med 169:57 -63 15. Halter JM, Steinberg JM, Gattro LA, et al (2007) Effect of positive end-expiratory pressure and tidal volume on lung injury induced by alveolar instability. Crit Care 11:R20 16. Dreyfuss D, Soler P, Basset G, Saumon G (1988) High inflation pressure pulmonary edema. Respective effects of high airway pressure , high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis 137:1159-1164 17. Dreyfuss D, Soler P, Saumon G (1995) Mechanical ventilation -induced pulmonary edema. Interaction with previous lung alterations. Am J Respir Crit Care Med 151:1568-1575 18. Taskar V, John J, Evander E, Robertson B, Jonson B (1997) Surfactant dysfunction makes lungs vulnerable to repetitive collapse and reexpansion. Am J Respir Crit Care Med 155: 313-320 19. Mead J, Takishima T, Leith D (1970) Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 28:596- 608 20. Bilek AM, Dee KC, Gaver DP 3rd (2003) Mechanisms of surface-tension-induced epithelial cell damage in a model of pulmonary airway reopening. J Appl Physiol 94:770 - 783 21. Hotchkiss JR, Simonson DA, Marek DJ, Marini JJ, Dries DJ (2002) Pulmonary microvascular fracture in a patient with acute respiratory distress syndrome. Crit Care Med 30:2368-2370 22. Gajic 0, Lee J, Doerr CH, Berrios JC, Myers JL, Hubmayr RD (2003) Ventilator-induced cell wounding and repair in the intact lung. Am J Respir Crit Care Med 167:1057 -1063 23. Tremblay LN, Slutsky AS (1998) Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians 110:482-488 24. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 99:944-952 25. Chiumello D, Pristine G, Slutsky AS (1999) Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome . Am J Respir Crit Care Med 160:109 -116 26. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301- 1308 27. Gattinoni L, Caironi P, Carlesso E (2005) How to ventilate patients with acute lung injury and acute respiratory distress syndrome. Curr Opin Crit Care 11:69 -76 28. Chu EK, Whitehead T, Slutsky AS (2004) Effects of cyclic opening and closing at low- and high-volume ventilation on bronchoalveolar lavage cytokines. Crit Care Med 32:168-174 29. Caruso P, Meireles SI, Reis LF, Mauad T, Martins MA, Deheinzelin D (2003) Low tidal volume ventilation induces proinflammatory and profibrogenic response in lungs of rats ." Intensive Care Med 29:1808-1811 30. Lachmann B (1992) Open up the lung and keep the lung open. Intensive Care Med 18:319321 31. Borges JB, Okamoto VN, Matos GF, et al (2006) Reversibility oflung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med 174:268-278 32. Suarez-Sipmann F, Bohm SH, Thsman G, et al (2007) Use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study. Crit Care Med 35: 214-221 33. van Genderingen HR, van Vught AJ, Jansen JR (2004) Regional lung volume during high-frequency oscillatory ventilation by electrical impedance tomography. Crit Care Med 32:787-794

Protective Mechanical Ventilation: lessons learned From Alveolar Mechanics 34. Imai Y, Slutsky AS (2005) High-frequency oscillatory ventilation and ventilator-induced lung injury. Crit Care Med 33 (suppl 3):SI29-134 35. Imai Y, Nakagawa S, Ito Y, Kwano T, Slutsky AS, Miyasaka K (2001) Comparison of lung protection strategies using conventional and high-frequency oscillatory ventilation. J Appl Physiol 91:1836-1844 36. Wang SG, Guo GH, Fu ZH, Zhou SF (2006) Comparison of conventional mandatory ventilation and high frequency oscillatory ventilation for treatment of acute lung injury induced by steam inhalation injury. Burns 32:951- 956 37. Muellenbach RM, Kredel M, Zollhoefer B, Wunder C, Roewer N, Brederlau J (2006) Sustained inflation and incremental mean airway pressure trial during conventional and high-frequency oscillatory ventilation in a large porcine model of acute respiratory distress syndrome . BMC Anesthesiol 6:8 38. Habashi NM (2005) Other approaches to open-lung ventilation: airway pressure release ventilation. Crit Care Med 33 (suppl 3):S228-240 39. Neumann P, Wrigge H, Zinserling J, et al (2005) Spontaneous breathing affects the spatial ventilation and perfusion distribution during mechanical ventilatory support. Crit Care Med 33:1090-1095

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Mechanical Ventilation for Acute Asthma Exacerbations D. DE MENDOZA, M. LUJAN,

and J.

RELLO

Introduction The prevalence and incidence of asthma are high in the Western world, and increasing in developing countries [1]. The risk of an acute attack increases with poor control of the disease, being greater in patients with low socioeconomic stratus and in patients with poor compliance of treatment. Among those patients suffering an acute exacerbation, the risk of needing intensive care unit (lCU) management ranges from 4 to 7 % of all asthma admissions. Mechanical ventilation is required in about 30 % of patients admitted to an ICU [2], and it has been estimated that 6,000-10,000 patients require mechanical ventilation for acute asthma in the United States each year [3]. Mortality is low for acute exacerbations, but increases up to 8 % when mechanical ventilation is required [4], and as the patients at risk are usually young, the social impact is not depreciable. The risk of death depends on the severity of the attack, with the rapidity of onset of the crisis and the response to treatment being crucial. Most deaths are related to the occurrence of cardiac arrest before reaching medical assistance, caused either by cardiac arrhythmias or by severe airflow limitation and hypoxemia leading to muscle exhaustion and respiratory arrest [5]. Another subset of deaths can be related to inappropriate recognition of the severity of the attack and , thus, to inappropriate management, particularly of the mechanical ventilation. Therefore, early identification of the severity and rapid transfer to an emergency department for early initiation of therapy can prevent morbidity and mortality [5]. Moreover, death must be considered an avoidable event among those patients who reach emergency care. Fast and accurate institution of pharmacologic therapy and especially of endotracheal intubation and mechanical ventilation where necessary is crucial in order to avoid a fatal outcome.

Pathophysiology of Acute Severe Asthma Lung Mechanics

Airway obstruction is the main process in acute exacerbations of asthma, and it is typically episodic, as opposed to chronic obstructive pulmonary disease (COPD). Obstruction occurs mainly in middle and small size airways, and is caused by inflammatory edema and muscle constriction. Mucus plugging is less frequent, but it is difficult to resolve when it appears . Expiratory airflow obstruction produces lung hyperinflation, by the trapping of air beyond functional residual capacity (FRC). The trapped air increases the total lung volume making tidal ventilation occur near or above total lung capacity (TLC).

Mechanical Ventilation for Acute Asthma Exacerbations

The increase in total lung volume improves the expiratory flow velocity as it increases the elastic recoil pressure of the lung and the diameter of the airways, facilitating the exhalation of tid al volume. Airway obstruction increases inspirator y pressure, and air trapping increases end expirator y pressure and therefore alveolar pressure. Work of breathing The elevated pressure at end expiration caused by air trapping, is known as intrinsic positive end-expiratory pressure (PEEPi) or auto PEEP, and it is the pressure level from which the pat ient's inspiratory effort has to start until it reaches zero atmo spheric pressure, when inspiratory flow begins. This high transpulmonary pressure increases the work of breathing (WOB), leading to further muscle fatigue, exhaustion and ultimately to respiratory arrest. Expiratory pressure and air trapping Different mechanisms contribute to total lung hyperinflation (Fig. 1). Static hyperinflation refers to the fixed amount of air that is trapped behind the occluded airways, regardless of the expiratory time, and it changes only in response to medical treatment. On the other hand, dynamic hyperinflation occurs when expiration is interrupted by the next inspir ator y effort, before the patient has reached the static equilibrium volume [6). Therefore, the amount of air trapped and the degree of autoPEEP will not only depend on the degree of obstruction , but will also be influenced by the respon se of the patient to the respiratory overload, and can be further increased by the inappropriate setting of mechanical ventilation. Dyspnea resulting from the increased WOB and the mild to moderate hypoxemia that can exist leads to an increase in respiratory rate, resulting in shortening of the expiratory time that fur ther reduces the amount of tidal volume exhaled, increasing air trapping and auto PEEP. Moreover, if the pat ient makes vigorous expiratory efforts in order to overcome the airflow limitation, collapse of medium and small airways may occur, as a result of the increase in pleural pressure. In addition, trapped air can produce segmental hyperinflation of lung units , which can collapse adjacent airways imped-

a

Fig. 1. Mechanisms of auto PEEP. a Rigid obstruction to expiratory airflow causes slow expiration and air trapping in the alveolus at end expiration. b Increase in respiratory rate shortens expiratory time, preventing complete expiration. c Forced expiratory efforts raise pleural pressure and compress small airways.

b

c

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ing inspiratory and especially expiratory airflow. This phenomenon is more likely to occur in patients with loss of elastic recoil due to structural bronchial disease, like cigarette smokers and patients with some degree of COPD. However, most asthmatic patients have rigid and inflamed airways that do not collapse easily because of hyperinflation, the static component being the main contributor to total hyperinflation, as was suggested by the comparison of a prolonged apnea and postapnea radiographic estimation of hyperinflation [7]. High inspiratory pressure Airway obstruction generates high resistance to airflow during inspiration, causing very high inspiratory pressures, which can lead to the development of barotrauma, either pneumothorax, pneumomediastinum, or subcutaneous emphysema. Pneumothorax has been reported to complicate status asthmaticus in 14 to 27 % of patients [8]. Airway pressure is progressively released along the bronchial tree, being much lower in the distal small size airways and alveoli, which have thin walls that can support less pressure. Because the medium and large size bronchial airways have thicker muscular and cartilaginous walls, they can tolerate higher levels of pressure with less risk of rupture. Therefore, because peak inspiratory pressure is dissipated in the medium and large airways, high levels are usually well tolerated, with alveolar pressure being the most important determinant for the occurrence of barotrauma. High airway pressure also has a great impact on cardiovascular performance, especially in patients receiving mechanical ventilation.

Gas Exchange The impact on gas exchange depends on the severity of the exacerbation. Some degree of hypoxemia is common, although it is not usually the main problem. Hypoxemia is usually mild to moderate, and mostly due to ventilation/perfusion (V/Q) mismatch, given that the hypoventilated areas are otherwise well perfused [9]. Moreover, hypoxic pulmonary vasoconstriction minimizes the extent of V/Q mismatch and, therefore, the degree of hypoxemia. If severe hypoxemia exists, efforts need to be made to search for pneumonia as a triggering cause of the exacerbation, or to exclude complications like pneumothorax. In the early stages, patients can be hypocapnic, due to overdrive of the respiratory response to dyspnea that, together with the adrenergic stimulation, leads to excessive minute ventilation. In the presence of severe hyperinflation, the increase in dead space leads to higher ventilatory demands, resulting in normocapnia with a presumed higher minute ventilation. As airway obstruction does not improve, muscle tiredness makes it impossible to overcome ventilatory demands and finally fatigue develops, leading to hypercapnia and respiratory acidosis, and eventual respiratory arrest. Lactic acidosis is also commonly seen in advanced stages, due to the excessive respiratory muscle effort.

Cardiovascular Dynamics Hyperinflation has a crucial role in the cardiovascular performance of asthmantic patients, as it greatly influences cardiac preload and afterload. Air trapping and autoPEEP increase intrathoracic pressure reducing right ventricular (RV) preload,

Mechanical Ventilation for Acute Asthma Exacerbations

and impairing RV afterload by increasing the length of pulmonary arteries, resulting overall in a decreased cardiac output. Pulsus paradoxus is a characteristic feature of status asthmaticus, and it is due to the great inspiratory and expiratory efforts that produce big swings in pleural pressure. During inspiration, a highly negative pleural pressure increases RV filling, distends the right ventricle, decreasing left ventricular (LV) compliance and preload, and increases LV transmural pressure thus increasing afterload, resulting overall in a fall in systolic blood pressure. On the other hand, in expiration, a highly positive pleural pressure due to the effort made to overcome airway obstruction impairs RV filling reducing cardiac output. However, high intrathoracic pressure also reduces LV transmural pressure, reducing LV afterload and improving LV ejection. These cyclical heart -lung interact ions lead to great swings in the blood pressure between inspiration and expiration, the difference (the pulsus paradoxus) being greater when the exacerbation is more severe. Attention must be paid to improvement or resolution of the pulsus paradoxus, as it can either be a sign of improvement of the airway obstruction, or of worsening respiratory muscle fatigue and impending respiratory arrest. High airway pressure and hyper inflation can also produce mechanical compression of the heart leading to obstructive shock and cardiovascular collapse, pulseless electrical activity, and death [10). This airway pressure-related cardiovascular collapse can be further facilitated by manual bag ventilation following endotracheal intubation and by mechanical ventilation, especially if improperly performed. High tidal insufflations after an artificial airway is instituted increase airway pressures considrably, often being the precipitating factor that leads to tension pneumothorax and cardiovascular collapse [11). Hypotension following endotracheal intubation has been reported to range between 20 and 41 % [8).

Mechanical Ventilation Indications It is difficult to establish a particular time at which the patient needs to be intubated.

Clinical parameters, such as respiratory fatigue or altered mental status, are better indicators of the need for mechanical ventilation than gasometric variables, like hypoxemia, hypercapnia, or acidosis. Agitation, confusion, and depressed consciousness precede muscle exhaustion and respiratory arrest, being absolute criteria for immediate intubation. Gas exchange impairment is probably less valuable to establish the need for ventilatory support, given that hypoxemia is easier to correct and hypercapnia is usually well tolerated. Dynamic parameters, like poor response to medical treatment or worsening hypercapnia, are better predictors of the need for mechanical ventilation.

Endotracheal Intubation Oral intubation is preferred over the nasal route, because larger size tubes can be inserted, offering less airway resistance and facilitating the suction of secretions. Furthermore, asthmatic patients are prone to have sinusitis and nasal polyps. Intubation must be performed by an expert operator, since repeated stimulation of the glottis can lead to edema and trigger laryngeal reflexes, ultimately making it impossible to achieve a secure airway.

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Once we decide to ventilate a patient, extreme care needs to be taken when using sedatives for induction and when performing manual bag ventilation prior to the connection of the ventilator. Sedatives for Induction Asthmatic pati ents in acute exacerbation are usually hypertensive and tachycardic, due to the adrenergic state and to the release of catecholamines, unless extreme hyperinflation puts them close to cardiovascular collapse . It may be thought then, that sedatives will be hemodynamicaly well tolerated. Nevertheless, tachypnea and high minute ventilation, sweating, and sometimes fever (if an infection is the trigger of the attack), make such patients relatively dehydrated and thus hypovolemic. Therefore, once the sedatives reverse the catecholamine release, their vasodilator effect can produce dramatic hypotension [12]. Consequently, the sedative dose needs to be cautiously titrated, whichever drug is used, and hypotension must be anticipated and prevented by rapid fluid administration. Propofol has a rapid onset of action and decreases airway resistance after intubation when compared to etomidate or barbiturates [13], but it has a strong vasodilator effect, so caution is required in normotensive and dehydrated patients. Benzodiazepines are somewhat better tolerated hemodynamically, but their clearance is slower. Etomidate would be the preferred agent in hypotensive patients, but it carries the risk of adrenergic insufficiency even if administered in a single dose, and has been associated with increased mortality [14]. The concomitant administration of hydrocortisone has , therefore, been recommended when etomidate is used for induction. Ketamine does not have vasodilator effects and it also has the advantage of bronchodilator properties, being a good choice for this situation [12, IS]. The potential of ketamine to induce delirium has to be taken into account, although this can be prevented by the concomitant administration of low doses of benzodiazepines. Opioids can also be used as analgesics and to avoid laryngeal reflexes, but are histamine releasers and can worsen bronchospasm and induce hypotension. Fentanyl causes less histamine release than morphine but high doses or rapid boluses can produce chest wall rigidity, making further ventilation even more difficult . Manual Bag Ventilation Manual ventilation is one of the most critical moments, when the two main complications of asthma (pneumothorax and hemodynamic collapse) often occur. Up to 75 % of pneumothoraces have been reported to occur during bag ventilation following endotracheal intubation [4]. In the aim of maintaining good oxygenation, and finding high resistance to the insufflation of air through the airway, it is common that operators try to push the air into the lungs, without any control over the pressure that is being applied. At this moment, the aim should be to avoid excessive pressure and to allow sufficient expiration while maintaining oxygenation, rather than trying to normoventilate or to defeat the resistance of the airway. Tidal insufflations must be small (about one third of the volume of the ventilation bag equals a tidal volume around 450 ml), and insufflation rate slow. Rates can be as low as 6 - 10 per minute, with the sound of the exhaled air through the ventilation bag being a good indicator when deciding to initiate the next insufflation. Manual compression of the chest wall as an active mechanical way of expiration has been pro-

Mechanical Ventilation for Acute Asthma Exacerbations

posed, but it has not been evaluated in clinical trials [15). If hypotension appears after starting the positive pressure ventilation, very slow rate ventilation (as low as 2-3 insufflations per minute) or an apnea test of about 60 seconds must be performed to allow complete exhalation. If hypotens ion persists, a tension pneumothorax must be suspected [5).

Ventilator Settings The main goal when setting the ventilator must be to facilitate expiratory airflow and to diminish the amount of trapped air, rather than to achieve normoventilation and normocapnia. The correction of hypoxemia should not be difficult if pneumo nia or other complications are not present. In order to achieve these goals we must first know how much air is trapped and to what extent it can be reduced. Measurement of air trapping In spontaneously breathing patients the measurement of the amount of air trapped and the degree of autoPEEP is quite difficult. Peak expiratory flow is a useful tool to asses the severity of the attack, although it measures the degree of obstruction and not of hyperinflation. The response of peak expiratory flow to treatment over time has a better predictive value than a single measure, with a variation over baseline greater than 40 % after 30 minutes of treatment a predictor of good outcome [5). However, patients in severe respiratory distress may not be able to cooperate so its value has to be interpreted cautiously. The magnitude of PEEPi can be estimated measuring pleural pressure (actually measuring esophageal pressure) and observing the change in pressure between the onset of inspiratory effort and the onset of inspiratory flow, which should not exist in the absence of air trapping [12). This measure is, however, difficult to perform in clinical practice in spontaneously breathing patients, either in the emergency department or in the ICU. In mechanically ventilated patients the measurement of air trapped can be performed either by analyzing airway pressures during volume cycled ventilation or by measuring the exhaled volume during a prolonged apnea . The measurement of total exhaled volume during a prolonged apnea allows calculation of the amount of volume trapped at end-expiration, by subtracting the tidal volume [16). Volume at endinspiration has been proposed to be a better predictor of the development of hypotension and barotrauma than airway pressures [8). This measurement requires paralysis of the patient. The analysis of airway pressure is more commonly used to assess the degree of hyperinflation. Both, inspiratory and expiratory pressures must be considered. Although peak inspiratory pressure can be extremely elevated in acute asthma, it is not useful for the assessment of hyperinflation, because it is influenced by the inspiratory flow velocity and the resistance of the airways, which are usually high. Moreover, peak inspiratory pressure does not change as hyperinflation is reduced when expiratory time is increased [17). Plateau pressure, however, is not influenced by airway resistance or inspiratory flow, and, as a reflection of alveolar pressure, increases when hyperinflation occurs, being a good indicator of air trapping [18). Alveolar pressure should not be high in the absence of decreased compliance, as occurs in asthmatic patients, except when air tr apping and hyperinflation exist. Therefore, changes in plateau pressure follow-

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Ppk

I

6" 60 I

5

~

!C ~

u:

1 t

I

30

Ppt

0 -----------------------------------------------------------

0

-- -

---

Air trapping

Expiratory occlusion

Fig. 2. Characteristic pressure and flow tracings ofa mechanically ventilated asthmatic patient. The great difference between peak pressure (Ppk) and plateau pressure (Ppt) identify inspiratory airway resistance. Slow expiratory flow interrupted by the following inspiration produces air trapping at end expiration. Expiratory pressure above atmospheric reflects dynamic intrinsic positive end-expiratory pressure (PEEPi). After an expiratory occlusion, flow stops and end expiratory pressure increases, reflecting static PEEPi.

ing variations in expiratory time are the result of variations in the degree of hyperinflation, when tidal volume is maintained constant [17]. Measurement of end-expiratory pressure is the easiest method to assess the degree of hyperinflation, having a good correlation with plateau pressure in the absence of decreased compliance. The observation of the pressure and flow tracings in the ventilator allows the recognition and measure of air trapping and autoPEEP ( Fig. 2.). In the absence of air trapping the expiratory flow must reach the zero level before the next inspiration begins. If airway obstruction exists, the passive expiration will need a longer time to be complete, and, if it is finally incomplete the flow tracing of the ventilator shows that expiratory flow does not reach the zero level before the next inspiration starts ..As air will remain inside the lung above the FRC at end-expiration, alveolar pressure at this moment will be higher than atmospheric (or than external PEEP if used), and will correspond to dynamic autoPEEP, its value reflecting the amount of air trapped and, thus, the severity of the airway obstruction. In order to accurately measure autoPEEP, an expiratory pause in the ventilator will have to be made, while the patient is paralyzed. At that moment distribution of the trapped gas occurs across the different alveolar units, and pressure at end-expiration reaches a plateau, corresponding to static autoPEEP. The length of the expiratory pause can influence the measured value of PEEPi. If the pause is too short and does not give enough time for the airway pressure to be stabilized, air trapping will be overestimated and autoPEEP underestimated. An expiratory pause of 3 seconds seems to be enough to avoid errors. AutoPEEP can also be underestimated if airway closure occurs because of severe airway obstruction or mucus plugging [19]. On the other hand, PEEPi can be overestimated if the patient makes expiratory efforts. Therefore, in order to accurately measure the value of PEEPi the pat ient must be sedated to the point of not making respiratory efforts, or paralyzed if necessary. Minute Ventilation, respiratory rate, and tidal volume Minute ventilation is the main determinant of hyperinflation, as was shown when compar ing different ventilator settings in severe asthma. End-expiratory volume was the same for a given minute volume, regardless of the different combinat ions of respiratory rate and tidal volume used [16]. Great reductions in minute ventilation have been proposed [12], but the extent of these reductions is controversial. In the majority of patients , an initial minute ventilation of 6-8 lImin will not cause dangerous hyper inflation [7].

Mechanical Ventilation for Acute Asthma Exacerbations

Respiratory rate must be low enough to allow complete expiration. It has been proposed that the respiratory rate must be around 12- 14/min [20]. This could be enough in some patients, particularly when the airflow obstruction is less severe and the dynamic contribution to hyperinflation plays a dominant role. However, sometimes the rate that allows sufficient expiratory time will need to be even lower. When baseline respiratory rate is already low, fur ther reductions will probably have less impact on the improvement of air trapping, because expiratory flow is slower at end-expiration and the prolongation of expiratory time will not significantly improve alveolar emptying [20]. In addition, the air trapped behind the occluded airways will not be exhaled by increasing expiratory time, so time will be needed for airflow obstruction mechanisms to resolve. Therefore, it is not possible to recommend a preset respiratory rate for ventilated asthmatic patients, and the only way to set the appropriate rate for a given patient is to look at the expiratory flow tracing of the ventilator and make sure that expiration is complete, and that by further increasing expiratory time there will not be further improvement in air trapping. Increases in expiratory time can be achieved, for a given respiratory rate, by increasing the inspiratory flow (up to 70-100 l/rnin), using a square inspiratory flow waveform, and eliminating inspiratory pause. However, the benefit of this approach is marginal when minute ventilation has already been reduced [20]. If respiratory rate is low but tidal volume is increased in order to achieve normoventilation, air will be trapped further despite a very high expiratory time . Increasing tidal volume in a hypercapnic patient may actually worsen hyper capnia by increasing the amount of trapped air that needs to be exhaled in the same expiratory time. Instead, reductions in tidal volume and minute ventilation will improve ventilation and hypercapnia as long as they reduce air trapping. In addition, higher tidal volumes will increase airway pressure and will increase the risk of barotrauma and hemodynamic collapse. Reducing the inspiratory flow for a given tidal volume will allow airway pressure to be decreased, allowing further increases in tidal volume titrated to safe levels of airway pressure. A compromise will often have to be made between the lower respiratory rate/longer expiratory time that allows a higher inspiratory time and a minimum tidal volume with a safe level of airway pressure. Expiratory flow and PEEP In the absence of spontaneous ventilation, and once minute ventilation has been reduced and expiratory time optimized, remaining hyperinflation is caused by rigid airway obstruction due to bronchial edema and muscle constriction. In this setting, the addition of external PEEP will raise total airway pressure, increasing the risk of barotrauma and hemodynamic compromise. Indeed, the addition of low levels of PEEP to paralyzed asthmatic patients did not show benefit, higher levels of PEEP that raised FRC being detrimental [16]. Conversely, in the non-paralyzed, spontaneously breathing, ventilated patient, extrinsic PEEP can be of help by reducing the superimposed WOB caused by PEEPi, and by keeping the airway open against the dynamic collapse caused by forced expiratory efforts. Only when some degree of COPD coexists, as in older asthmatics and cigarette smokers, does the use of PEEP contribute to compensate for the loss of elastic recoil, keeping small airways open against adjacent hyperinflated lung units. The reaction of airway pressure and expiratory flow to a PEEP trial will help to decide if it has a role in reducing hyperinflation or if its use will be detrimental. If airway pressure rises proportionally to the

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amount of PEEP added and expiratory flow does not approach zero at end-expiration, PEEP should be removed. Conversely, if total pressure does not increase and expiratory flow improves, the level of PEEP that reverses autoPEEP should be maintained. External PEEP should not exceed autoPEEP when applied. Hypercapnia Reductions in minute ventilation will lead to hypercapnia, which is usually well tolerated, even when acutely instituted. Moreover, in a retrospective analysis, hypoventilation was associated with better outcomes in asthmatic patients than conventional ventilation [21]. The only exceptions to allow permissive hypercapnia are intracranial hypertension and pregnancy. Hypercapnia produces cerebral arterial vasodilatation increasing cerebral blood flow and intracranial pressure. Intracranial hypertension is uncommon in acute asthmatic patients, unless hypoxic brain damage secondary to cardiorespiratory arrest coexists. Conversely, peripheral vasoconstriction induced by hypercapnia reduces placental blood flow producing fetal distress. Respiratory acidosis can be partially buffered by the administration of bicarbonate, but this approach is not recommended unless the pH falls below 7.15-7.10 [22). The effectiveness of this strategy is uncertain and it carries the risk of causing metabolic alkalosis once the airflow obstruction and the hypercapnia have been resolved, which will usually take less than 24 h in an asthmatic crisis [23). Muscle relaxation The presence of spontaneous ventilation can limit control over respiratory rate and minute ventilation, necessitating the use of deep sedation and even of muscle relaxation. Therefore, neuromuscular blocking agents can play a role reversing the dynamic component of hyperinflation, allowing long expiratory times to be set and abolishing forced expiratory efforts, further reducing autoPEEP. In addition, neuromuscular blocking agents have a direct bronchodilator effect on the airway smooth muscle, helping to reduce airflow obstruction. However, neuromyopathy has been attributed to the use of neuromuscular blocking agents, based on data from observational studies [24,25), especially when associated with concurrent use of steroids [26). Nevertheless, recent evidence does not support this association , pointing to hyperglycemia as the stronger predictor of neuromuscular dysfunction in critical illness [27). There is no evidence regarding the best way to use neuromuscular blocking agents, and, although they are commonly given in a continuous infusion, bolus administration is probably equally effective and allows more frequent assessment of ongoing requirements.

Delivery of Inhaled Drugs in the Ventilated Patient Mechanical ventilation just gives time for medical therapy to reverse airway obstruction, and therefore anti-inflamatory and bronchodilating drugs must be maintained while the patient remains on the ventilator. Inhaled drugs can be administered through the ventilator circuit, either nebulized or by metered dose inhalers. The amount of drug delivered that reaches the airway in the ventilated patient is usually low, ranging from 0 to 40 % [28), depending on many variables, such as the size of the endotracheal tube, the ventilator circuit, the driving gas flow, and the humidification system [29). The use of humidification can reduce drug deposition up to 40 %, but the addition of a spacer device can diminish this effect [30). Recommen-

Mechanical Ventilation for Acute Asthma Exacerbations

dations to improve aerosol delivery include the use of spacer chambers, the use of large internal diameter endotracheal tubes, the administration of the drug in the inspiratory limb dur ing inspiration and with a prolonged inspiratory time, the use of high flow and high volume fill when nebulizing, and discontinuation of humidifi cation (12).

Non-invasive Ventilation Non-invasive pressure support ventilation has been shown to reduce respiratory workload and to improve alveolar ventilation in hypercapnic respiratory failure [31]. However, in asthmatic exacerbations the lack of control over the respiratory rate and the expiratory time would not allow the controlled reduction of minute ventilation. Nevertheless, as alveolar ventilation improves by the increase in tidal volume, respiratory rate can decrease and expiratory airflow can be facilitated. On the other hand, static autoPEEP due to rigid airway obstruction cannot be offset by the use of external PEEP, as occurs in COPD patients. However, the use of PEEP can reduce the WOB, as it lessens the high transpulmonary pressure gradient generated by autoPEEP, and low levels of PEEP can also help to maintain the small airways open at end expiration, against the positive pleural pressure caused by forced expiration . There is no strong evidence supporting the use of non-invasive pressure support ventilation for severe asthmatic exacerbations. Non-randomized, observational studies have shown improvement in clinical parameters (heart and respiratory rate), and gasexchange (PCO z) using non-invasive pressure support ventilation with low levels of PEEP (3 -5 cmH zO) and moderate levels of pressure support (8 -12 cmll-O) [32,33]. The only randomized controlled trial comparing non-invasive pressure support ventilation with standard medical therapy showed that the use of nasal non-invasive pressure support ventilation in the emergency department reduced the need for hospitalization and improved lung function tests (forced expiratory volume in 1 sec [FEV tl, FVC, and peak expiratory flow) and respiratory rate, without a reduction in the need for endotracheal intubation or in mortality [34]. However, patients in both groups had a mean PCO z of 34 mmHg and a mean pH of 7.40, and there was no need for intubation or mortality in either group, pointing to the low severity of the patients. Therefore, before intubation is finally requ ired, it seems reasonable to perform a trial of non-invasive pressure support ventilation in selected patients. As when using non -invasive pressure support ventilation for other indications, the time of initiation and the comfort of the patient with the mask are key elements for the success of the technique. Using non-invasive pressure support ventilation in an extenuated or obtunded patient will necessarily lead to failure and the need for intubation in a worse clinical condition, the delay in invasive ventilation being a possible explanation for the high mortality observed when non-invasive pressure support ventilation was attempted and failed [4]. Likewise, if the patient is uncomfortable with the mask or there are significant leaks, superimposed WOB can exist, precipitating failure.

Alternative Therapies Despite optimal medical therapy and ventilatory management some patients will have refractory airflow obstruction. The absence of a response may be due to refractory bronchospasm, extreme hyperinflation, or mucus plugging. In such cases, alternative therapies may be attempted.

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Inhaled anesthetics have bronchodilator properties and have been advocated as a treatment for severe status asthmaticus. Their use has been associated with reductions in airway resistance and autoPEEP [35,36], as well as reductions in peak inspiratory pressure, PC0 2 , and air trapping [37]. However, they require specific equipment that is not usually available in the majority of ICU ventilators. Adverse effects include hypotension and myocardial irritability, but are less common with the use of sevoflurane, which has become the preferred agent over halothane and isoflurane. Heliox (the helium-oxygen mixture) is a low density gas that reduces frictional resistance and favors laminar flow [38]. The passage of a low density gas through a narrow airway reduces turbulence, diminishing resistance, and avoiding deposition of gas particles in the walls of the airways, therefore improving the delivery of aerosolized drugs [5]. The use of heliox in ventilated asthmatic patients has been shown to reduce peak inspiratory presure and PC0 2 [39], but this effect has not been confirmed when tidal volume and respiratory rate are kept constant [40]. Although there is not enough evidence to recommend the use of heliox in non-ventilated patients in the emergency department as a first line therapy, it has been recommended as an alternative for the most severe cases [41]. Technical issues make the use of heliox even more difficult to support. Since heliox is a low density gas, most ventilators are not prepared to operate accurately, and adjustments in volume and flow may be required [42]. Mixtures with less than 70 % of helium do not offer any benefit, therefore it cannot be used in severely hypoxemic patients. Bronchoscopy has been proposed in asthmatic exacerbations to remove the extensive mucus plugs that can be present, as well as to locally apply mucolytics [43]. However, this technique has a potential to worsen bronchospasm, and must be considered only for patients who fail to resolve the airway obstruction after several days of ventilation [20]. Extracorporeal gas exchange could have a role in patients with severe refractory hypercapnia [44], but experience with its use is scarce.

Conclusion Accurate management of mechanical ventilation in acute asthma is extremely important, since the occurrence of life-threatening complications is frequently associated with its use, and has a great influence on outcome. Extreme caution is required during endotracheal intubation and manual bag ventilation, particularly avoiding high insufflation volumes and allowing sufficient time for expiration. Identification and accurate measurement of air trapping allows correct setting of the ventilator, the analysis of the expiratory flow trace and the identification of alveolar and end expiratory pressures being essential. Minute ventilation must be low, as well as respiratory rate, in order to reduce hyperinflation. Acknowledgement: Supported in part by CIBER Enfermedades Respiratorias (CB061 06/0036), AGAUR (2005/SGR/920) and Marato TV3.

Mechanical Ventilation for Acute Asthma Exacerbations References 1. Eder W, Ege MJ, Von Mutius E (2006) The asthma epidemic . N Engl J Med 355:2226-2235 2. McFadden ER [r (2003) Acute severe asthma. Am J Respir Crit Care Med 168:740 -759 3. Pendergraft TB, Stanford RH, Beasley R, Stempel DA, Roberts C, McLaughlin T (2004) Rates and characteristics of intensive care unit admissions and intubations among asthma-related hospitalizations. Ann Allergy Asthma Inmunol 93:29 - 35 4. Afessa B, Morales I, Cury JD (2001) Clinical course and outcome of patients admitted to an ICU for status asthmaticus. Chest 120;1616- 1621 5. Rodrigo GJ, Rodrigo C, Hall JB (2004) Acute asthma in adults: A review. Chest 125:1081-1102 6. Blanch L, Bernabe F, Lucangelo U (2005) Measurement of air trapping, intrinsic positive end expiratory pressure , and dynamic hyper inflation in mechanically ventilated patients. Respir Care 50:110-123 7. Tuxen DV, Williams TJ, Scheinkestel CD, Czarny D, Bowes G (1992) Use of a measurement of pulmonary hyperinflation to control the level of mechanical ventilation in patients with acute severe asthma. Am Rev Respir Dis 146:1136-1142 8. Williams DJ, Tuxen DV, Scheinkestel CD, Czarny D, Bowes G (1992) Risk factors for morbidity in mechanically ventilated patients with acute severe asthma. Am Rev Respir Dis 146: 607 -615 9. Rodriguez-Roisin R (1997) Acute severe asthma : pathophysiology and pathobiology of gas exchange abnormalities. Eur Respir J 10:1359-1371 10. Rosengarten PL, Tuxen DV, Dziukas L, Scheinkestel C, Merrett K, Bowes G (1991) Circulatory arre st induced by intermittent positive-pressure ventilation in a patient with severe asthma. Anaesth Intensive Care 19:118-1 21 11. Lisboa T, de Mendoza D, Rello J (2007) A woman with asthma and cardiorespiratory arre st. N Engl J Med 357:420 12. Phipps P, Garrard CS (2003) The pulmonary physician in critical care: 12. Acute severe asthma in the intensive care unit. Thorax 58:81- 88 13. Eames WO, Rooke GA, Wu RS, Bishop MJ (1996) Comparison of the effects of etomidate, propofol and thiopental on respiratory resistance after tracheal intubation. Anesthesiology 84:1307 -1311 14. Malerba G, Romano -Girard F, Cravoisy A, et al (2005) Risk factors of relative adrenocortical deficiency in intensive care patients need ing mechanical ventilation. Intensive Care Med 31:388-392 15. Eason J, Tayler D, Cottam S, et al (1991) Manual chest compression for total bronchospasm. Lancet 337:366 16. Tuxen DV, Lane S (1987) The effects of ventilatory pattern on hyperinflation, airway pressures, and circulation in mechan ical ventilat ion of patients with severe airflow obstruction. Am Rev Respir Dis 136:872- 879 17. Leatherman JW, McArthur C, Shapiro RS (2004) Effect of prolongation of expiratory time on dynamic hyperinflation in mechanically ventilated pat ients with severe asthma . Crit Care Med 32:1542-1545 18. Oddo M, Feihl F, Schaller M-D, Perret C (2006) Management of mechanical ventilation in acute severe asthma: Practical aspects. Intensive Care Med 32:501-510 19. Leatherman JW, Ravenscraft SA (1996) Low measured auto-positive end-expiratory pressure dur ing mechanical ventilation of patients with severe asthma: Hidden auto-positive endexpiratory pressure. Crit Care Med 24:541-546 20. Leatherman JW (2006) Mechanical ventilation for severe asthma. In: Tobin MJ (ed) Principles and Practice of Mechanical Ventilation. Second edition. McGraw-Hill, New York,pp 649-662 21. Feihl F, Perret C (1994) Permissive hypercapnia: How permissive should we be? Am J Respir Crit Care Med 150:1722-1 737 22. Cardenas VJ [r, Zwischenb erger JB, Tao W, et al (1996) Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia. Crit Care Med 24:827 -834 23. Bellomo R, McLaughlin P, Tai E, Parkin G (1994) Asthma requiring mechanical ventilation : a low-morbidity approach. Chest 105:891-896 24. Griffin D, Fairman N, Coursin D, Rawsthorne L, Grossman JE (1992) Acute myopathy during

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25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.

treatment of status asthmaticus with corticosteroids and steroidal muscle relaxants Chest 102:510-514 Leatherman JW, Fluegel WL, David WS, Davies SF, Iber C (1996) Muscle weakness in mechanically ventilated patients with severe asthma. Am J Respir Crit Care Med 153:16861690 Behbehani NA, AI-Mane F, D'yachkova Y, Pare P, FitzGerald JM (1999) Myopathy following mechanical ventilation for acute severe asthma : The role of muscle relaxants and corticoste roids. Chest 115:1627-1631 Stevens RD, Dowdy DW, Michaels RK, Mendez-Tellez PA, Pronovost PJ, Needham DM (2007) Neuromuscular dysfunction acquired in critical illness: a systematic review. Intensive Care Med 33:1876-1891 Dhand R, Tobin MJ (1997) Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 156:3- 10 Thomas SH, O'Doherty MJ, Fidler HM, Page CJ, Treacher DF, Nunan TO (1993) Pulmonary deposition of a nebulised aerosol during mechanical ventilation . Thorax 48:154-159 Lange CF, Finaly WH (2000) Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers dur ing mechanical ventilation. Am J Respir Crit Care Med 161:1614-1618 Antonelli M, Conti G, Rocco M, et al (1998) A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 339:429-435 Meduri GU, Cook TR, Turner RE, Cohen M, Leeper KV (1996) Noninvasive positive pressure ventilation in status asthmaticus. Chest 1l0:767 - 774 Fernandez MM, Villagra A, Blanch L, Fernandez R. (2001) Non-invasive mechanical ventilation in status asthmaticus. Intensive Care Med 27:486-492 Soroksky A, Stav D, Shpirer I (2003) A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest 123:1018-1025 Maltais F, Sovilj M, Goldberg P, Gottfried SB (1994) Respiratory mechanics in status asthmaticus: Effects of inhalational anesthesia . Chest 106:140I - 1406 Rooke GA, Choi JH, Bishop MJ (1997) The effect of isoflurane, halothane , sevoflurane, and thiopental/nitrous oxide on respiratory system resistance after tracheal intubation. Anesthesiology 86:1294-1299 Maltais F, Reissmann H, Navalesi P, et al (1994) Comparison of static and dynamic measurements of intrinsic PEEP in mechanically ventilated patients. Am J Respir Crit Care Med 150:1318-1324 Reuben AD, Harris AR (2004) Heliox for asthma in the emergency department: A review of the literature. Emerg Med J 21:131-135 Gluck EH, Onorato DJ, Castriotta R (1990) Helium-oxygen mistures in intubated pat ients with status asthmatic us and respiratory acidosis. Chest 98:693-698 Schaeffer EM, Pohlman A, Morgan S, Hall JB (1999) Oxygenation in status asthmaticus improves during ventilation with helium-oxygen. Crit Care Med 27:2666-2670 Rodrigo GJ, Rodrigo C, Pollack CV, Rowe B (2003) Use of helium-oxygen mixtures in the treatment of acute asthma: A systematic review. Chest 123:891-896 Tassaux D, [olliet P, Thouret JM, Roeseler J, Dorne R, Chevrolet JC (1999) Calibration of seven ICU ventilators for mechanical ventilation with helium-oxygen mixtures . Am J Respir Crit Care Med 160:22- 32 Lang DM, Simon RA, Mathison DA, Timms RM, Stevenson DD (1991) Safety and possible efficacy of fiberoptic bronchoscopy with lavage in the management of refractory asthma with mucous impactation. Ann Allergy 67:324-330 Shapiro MB, Kleaveland AC, Bartlett RH (1993) Extracorporeallife support for status asthmaticus. Chest 103:1651- 1654

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Hypercapnia: Permissive, Therapeutic, or Not at All? P. HASSETT, M.

CONTRERAS,

and J.G.

LAFFEY

Introduction In the past, hypercapnia and its concomitant hypercapnic acidosis, have been considered to be adverse, and were strictly avoided in the critically ill. Support for this approach derived from concerns regarding the link between hypercapnia and/or acidosis and adverse outcome in diverse clinical contexts, including cardiac arrest , sepsis, and neonatal asphyxia [1]. However, accumulating evidence from experimental and clinical studies demonstrates the potential for mechanical ventilation to directly injure the lungs - a phenomenon termed 'ventilator-induced lung injury (VILI)' and has mandated a rethink of our approaches to hypercapnia. Permissive hypercapnia is a ventilatory strategy in which relatively high levels of PaC0 2 are tolerated in an effort to avoid high tidal volumes and pulmonary over distension, thus potentially reducing lung injury, and enhancing survival [2,3]. Permissive hypercapnia has been progressively accepted in critical care for patients requiring mechanical ventilation. Conventionally, the protective effect of ventilatory strategies incorporating permissive hypercapnia is considered to be solely due to reductions in lung stretch, with hypercapnia 'per mitted' in order to achieve this goal. Hypercapnia is a potent biologic agent, with the potential to exert both beneficial and harmful effects. If the overall effect of hypercapnia is beneficial, then deliberately elevating PaCOz - termed 'therapeutic hypercapnia' [1] - could provide an additional advantage to low tidal volume strategies alone. Conversely, in patients managed with conventional permissive hypercapnia, adverse effects of elevated PaC0 2 might be concealed by the benefits of lower lung stretch. Because intensive care unit (lCU) outcome might be related to the development of multiple organ failure (MOF) - as opposed to simply lung injury - it is also necessary to determine the effects of hypercapnia on systemic organs. It is therefore important to determine whether hypercapnia might exert overall beneficial or deleteri ous effects in the critically ill. To do this, we will examine the physiologic effects of hypercapnia in the lung and systemic organs. We will also consider evidence from laboratory models of lung and systemic organ injur y. The role of hypercapnia in a variety of clinical settings of relevance to the critically ill will then be considered. Finally the risks and benefits of hypercapnia will be considered in specific clinical situations.

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P. Hassett, M. Contreras, and J.G. Laffey

Physiological Effects of Hypercapnia The physiologic effects of hypercapnia are diverse and incompletely understood, with direct effects often counterbalanced by indirect effects. In addition, the net effect of hypercapnic acidosis may occur as a function of the acidosis or the CO2 per

se.

Pulmonary System Alterations in carbon dioxide tension can modulate regional ventilation in response to a primary change in perfusion, or alternatively alter regional perfusion to match primary changes in ventilation. A good example is hypocapnic bronchoconstriction secondary to acute regional pulmonary artery occlusion, e.g., pulmonary embolism [4]. Lung compliance is increased in response to hypercapnic acidosis, possibly due to increased surfactant secretion or more effective surface tension-lowering properties under acidic conditions [5]. CO2 administration increases arterial oxygenation via improved matching of ventilation and perfusion [4]. A dose-response relationship exists wherein increased FiC0 2 results in progressive augmentation of Pa02 [6,7]. Of concern, hypercapnia can increase pulmonary vascular resistance (PVR), and may worsen pulmonary hypertension. Reassuringly, however, data from an animal model of chronic hypoxia-induced pulmonary hypertension suggests that the effect of hypercapnia on PVR does not appear to be exacerbated in the setting of pre-existing pulmonary hypertension [8]. In acute respiratory distress syndrome (ARDS), the potential for permissive hypercapnia to increase shunt appears to be due to a reduction in tidal volume and airway closure rather than due to hypercapnia per se. Hypercapnia has been variably reported to both increase and decrease airway resistance. These effects may be explained by a direct dilation of small airways, and a vagally mediated large airway constriction, which may result in little net alteration in airway resistance. Prolonged exposure to high CO2 has been shown to have potentially damaging neuromuscular effects on the diaphragm [9], although the clinical significance of this finding is unclear.

Central Nervous System Hypercapnic acidosis increases cerebral tissue oxygenation, via augmented arterial Pa0 2, and increased cerebral blood flow [6] (Fig. 1). However, the potential for hypercapnia to increase cerebral blood flow is a clear concern in the setting of reduced intracranial compliance where increased global cerebral blood flow may critically elevate intracranial pressure.

Cardiovascular System Direct inhibitory cardiovascular effects of hypercapnic acidosis on cardiovascular contractility are counterbalanced by sympathetic stimulatory effects, which increase preload, heart rate, and myocardial contractility, and decrease afterload, resulting in a net increase in cardiac output [10]. Hypercapnia results in a complex interaction of altered cardiac output, hypoxic pulmonary vasoconstriction, and intrapulmonary shunt to produce a net increase in Pa0 2. Consequently, hypercapnia increases global oxygen delivery. Regional - including mesenteric - blood flow, is also increased [11].

Hypercapnia: Permissive, Therapeutic, or Not at All?

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Hypercapnia and acidosis shifts the hemoglobin-oxygen dissociation curve rightward, further increasing tissue oxygen delivery. Acidosis may reduce cellular respiration and oxygen consumption [12], which may further benefit a supply/demand imbalance .

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P. Hassett, M. Contreras, and J.G. Laffey

Insights from laboratory Studies Several research groups have examined the direct effects of hypercapnic acidosis in laboratory models of lung and systemic organ disease. Insights from this work have increased our understanding of the effects of hypercapnic acidosis on various organ systems and on cell and molecular signalling. Pulmonary System

Hypercapnic acidosis attenuates the increased lung permeability seen following free radical mediated (13), and ischemia-reperfusion induced lung injury (13, 14). In whole animal pre-clinical models, hypercapnic acidosis reduced lung injury following in vivo pulmonary (15) and systemic (7] ischemia-reperfusion. Hypercapnic acidosis attenuated the development of pulmonary hypertension and vascular remodeling induced by chronic hypoxia in newborn rats (16). The effect of hypercapnia in VILI is more complex. Hypercapnic acidosis attenuated VILI in the isolated rabbit lung (17), and in an in vivo whole animal model [18). However, not all the data are quite so positive. Hypercapnia exhibits more modest protective effects in the context of more clinically relevant tidal stretch. Strand et al. demonstrated that significant hypercapnic acidosis (mean PaCOz levels 95 mmHg) was well tolerated in preterm lambs, but only modestly reduced lung injury [19). In the context of a clinically relevant high tidal volume strategy (tidal volume, 12 ml/kg, positive end-expiratory pressure [PEEP) 0 cmHzO; rate 42/min), hypocapnia was deleterious, and hypercapnic acidosis modestly protective [7). However, inspired COz did not significantly attenuate lung injury induced in an atelectasis-prone model of lung injury, mimicking neonatal respiratory distress syndrome [20). In a subsequent study, hypercapnia did minimize the adverse effects of highvolume ventilation on vascular barrier function, but it impaired the ability of lung cells to repair the stretch induced injury [21). Taken together, these findings suggest that while hypercapnic acidosis attenuates injury due to excessive stretch, its effects in the context of more clinically relevant lung stretch or extensive atelectasis are modest, and concerns exist regarding the effects of hypercapnia on cellular repair following injury. Cardiovascular System

Hypercapnic acidosis protects the heart from ischemic-reperfusion injury [22). Acidosis (both hypercapnic and metabolic) reduced infarct size in an in vivo canine model of coronary artery ischemia-reperfusion [23]. Possible mechanisms for the protective effects of acidosis include reduction of calcium loading to the myocardium through H+ inhibition of calcium uptake, and, in the case of hypercapnic acidosis, the induction of coronary vasodilatation [22]. In contrast, severe hypercapnic acidosis - at levels well above that seen in clinical practice - reduced the success of resuscitation following ventricular fibrillation arrest in a rodent model [24]. Neurologic System

Hypercapnic acidosis protects the newborn porcine brain from hypoxia-reoxygenation induced injury [25). Hypercapnia also attenuates hypoxic-ischemic brain injury in the immature rat, while hypocapnia is deleterious [26). However, an important

Hypercapnia: Permissive, Therapeutic, or Not at All?

dose-response phenomenon exists, with mild to moderate hypercapnia (PaC0 2 4055 mmHg) significantly more neuroprotective than higher levels of PaC0 2 (> 70 mmHg). Potential mechanisms underlying these protective effects include a reduction in the cerebrospinal fluid glutamate [26], free radical inhibition [25], and attenuation of neuronal apoptosis. Of concern, hypercapnia may contribute to the pathogenesis of retinopathy of prematurity, an important issue in the setting of neonatal respiratory failure [27].

Cellular and Molecular Effects of Hypercapnia A clear understanding of the cellular and biochemical mechanisms underlying the effects of hypercapnia is a prerequisite to successfully translating laboratory findings to the bedside. It allows prediction of potential side effects, permitting identification of those in whom hypercapnia should be avoided. Acidosis versus Hypercapnia

The protective effects of hypercapnic acidosis in experimental lung and systemic organ injury appear to be primarily a function of acidosis per se. In the isolated lung, the protective effect of hypercapnic acidosis in ischemia-reperfusion was greatly attenuated if the pH was buffered towards normal [14]. The myocardial protective effects of hypercapnic acidosis are also seen with metabolic acidosis [23]. Metabolic acidosis exerts protective effects in other models of organ injury. In the liver, metabolic acidosis delays the onset of cell death in isolated hepatocytes exposed to anoxia [28]. Furthermore, isolated renal cortical tubules exposed to anoxia have improved ATP levels on reoxygenation at acidotic - compared with alkalotic - environmental pH levels [28]. Anti-inflammatory Effects

Both hypercapnia and acidosis impair neutrophil intracellular pH regulation, potentially overwhelming the capacity of neutrophils - especially when activated - to regulate cytosolic pH. This failure impairs important neutrophil functions such as chemotaxis and release of interleukin (lL)-8 following lipopolysaccharide (LPS) stimulation (29). Hypercapnic acidosis reduces bronchoalveolar lavage (BAL) levels of tumor necrosis factor (TNF)-a following in vivo pulmonary ischemia-reperfusion [15]. Hypercapnic acidosis also inhibit s lung neutrophil recruitment during ventilator-induced (18) and endotoxin -induced (30) lung injury. Free Radical Generation and Activity

Hypercapnic acidosis attenuates several key harmful oxidative processes. Oxidant generation by both basal and stimulated neutrophils appears to be regulated by ambient CO2 levels, with oxidant generation reduced by hypercapnia and increased by hypocapnia (29). The production of superoxide by stimulated neutrophils in vitro is decreased at acidic pH. Brain glutathione depletion and lipid peroxidation (representing free radical activity and tissue damage respectively) are reduced by hypercapnic acidosis (25). In the lung, hypercapnic acidosis reduces free radical tissue injury following ischemia-reperfusion [15], and attenuates the production of the

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P. Hassett, M. Contreras, and J.G. Laffey a IKB-a

b

_.- -- --- NC

CTL 0.5 h 1 h

HA

2h

3h

0.5 h 1 h

2h

I KB - ~

LPS (+)

c IKB-a

NC NC HA

IA

LPS (+) BH

-. - - - LPS (+)

3h

Fig. 2 Hypercapnia suppresses the degradation of hcB-a (Panel A) but not hcB-~ (Panel B) following exposure to lipopolysaccharide (LPS), thereby inhibiting the nuclear translocation of nuclear factor-kappa B (NF-lCB) and downstream cytokine production. The effects of isocapnic acidosis (IA) and buffered hypercapnia (Panel C) on IlCB-a degradation were intermediate between normocapnic control and hypercapnic acidosis (HA) conditions. BH: buffered hypercapnia; NC: normocapnia. From (32) with permission

higher oxides of nitric oxide (NO), such as N0 2 and N0 3, following both ventilatorinduced [17] and endotoxin-induced [30] injury. Hypercapnic acidosis inhibits injury mediated by xanthine oxidase, and directly inhibits the enzyme [13]. However, concerns exist regarding the potential for hypercapnia to potentiate tis sue nitration by peroxynitrite, a potent free radical. Buffered hypercapnia promotes the formation of nitration products from peroxynitrite in vitro [31]. The potential for hypercapnic acidosis to promote nitration of lung tissue in vivo appears to depend on the injury process. Hypercapnic acidosis decreased tissue nitration following pulmonary ischemia-reperfusion [15], but increased nitration following endotoxin exposure [30, 31].

Regulation of Gene Expression Hypercapnic acidosis regulates the expression of genes central to the inflammatory response. Nuclear factor-kappa B (NF-lCB) is a key regulator of the expression of multiple genes involved in the inflammatory response, and its activation represents a pivotal early step in the activation of the inflammatory response. Hypercapnic acidosis inhibits endotoxin-induced NF-lCB activation and DNA binding in pulmonary endothelial cells by decreasing IlCB-a degradation ( Fig. 2) [32]. Hypercapnic acidosis also suppressed endothelial production of intercellular adhesion molecule (ICAM)-1 and of IL-B, which are regulated by the NF-lCB pathway [32].

Current Clinical Role of Permissive Hypercapnia Acute Respiratory Distress Syndrome The potential for protective lung ventilation strategies incorporating permissive hypercapnia to improve survival in patients with ARDS was suggested initially by Hickling et al. [3]. Of the five prospective randomized controlled trials of protective ventilatory strategies [2,33-36] carried out in the last decade, two demonstrated an impact of ventilator strategy on mortality [2, 33], although three did not [34-36]. While to some extent permissive hypercapnia developed in all of the trials, there was considerable variability (Table 1). Therefore, the relationship between CO2 tension and outcome in these studies remains unclear.

Hypercapnia: Permissive, Therapeutic, or Not at All? Table 1. Ventilatory strategies and management of CO 2 in clinical trials. Trial

Mortality benefit

Control PaC02 (mmHg, Mean+SD)

'Protective' PaC0 2 (mmHg, Mean+SD)

Buffering permitted

ARDSnet Trial [33) Amato et al. [2) Stewart et al. [34) Brochard et al. [35) Brower et al. [36)

Yes Yes No No No

35.8 ± 36.0 ± 46.0 ± 41 .0 ± 40.1 ±

40.0 ± 58.0 ± 54.5 ± 59.5 ± 50.3 ±

Yes No No No Yes

8.0 1.5 10.0 7.5 1.6

10.0 3.0 15.0 19.0 3.5

The database of the largest of these studies [33) has been subsequently analyzed to determine whether in addition to the effect of tidal volume, there might also be an independent effect of hypercapnic acidosi s [37). Mortality was examined as a function of permissive hypercapnia on the day of enrolment, and, using multivariate analysis , controlling for other co-morbidities and severity of lung injur y. It was found that permissive hypercapnia redu ced mortality in pat ients randomized to the higher tidal volume, but not in those receiving lower tidal volumes [37). These are the first clinical data which suppor t a direct therapeutic role for hypercapnia in ARDS. Acute Severe Asthnna

The use of permissive hypercapnia was first described in patients with status asthmaticus [38). Permissive hypercapnia has been demonstrated to reduce dynami c hyperinflation and auto-PEEP during mechanical ventilation in acute severe asthma [39), by allowing an increase in the expiratory time, a reduction in inspiratory flow rates, and a reduction in tidal volume. Consequently, permissive hypercapnia (mean highest levels 62 mmHg ) is rout inely employed for patients with acute severe asthma admitted to ICUs across Europe. Chronic Obstructive Pulmonary Disease

Permissive hypercapnia is widely used in patients with severe chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation [40]. The rationale for the use of permissive hypercapnia in COPD is similar to that for acute severe asthma, i.e., it is permitted in order to minimize the potential for dynamic hyperinflation during mechani cal ventilation [40). Neonatal Respiratory Distress Syndronne

Acute respiratory failure in the preterm newborn results from parenchymal stiffness due to immaturity and surfactant deficiency, and may be complicated by adverse events, such as sepsis and meconium aspiration. Lung injury remains a leading cause of neonatal morbidity in neonates who receive ventilatory support [41). The duration and intensity of mechanical ventilation may be important determinants in the development of bronchopulmonary dysplasia/chronic lung disease. Mariani et al. reported beneficial effects of permissive hypercapnia in infants with neonatal respiratory distress syndrome [41). Preterm infants were randomly allocated to a target PaC0 2 between 35 and 45 mmHg or between 45 and 55 mmHg for the first 96 hours

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P. Hassett, M. Contreras, and J.G. Laffey

~ c

o .;::;

100

- - - - Normocapnia - - Permissive hypercapnia

80

p < 0.005

~

.;::;

c

~

60

"'0

~

.~

no

40

c

o

~

c

~

c

------ --------

I

20

o+--.-----r-, --,-------,-r=:::;:::::::::;.o 12 24 36 48 60 72 84 96 Duration of assisted ventilation (h)

Fig. 3. Duration of mechanical ventilation in neonates with respiratory failure randomized to conventional therapy or permissive hypercapnia. From [41] with permission

of life. Infants randomized to the higher PaC0 2 levels required less intensive ventilation and weaned significantly faster from mechanical ventilation (Fig. 3). A larger, multicenter trial of permissive hypercapnia randomized extremely lowbirth weight infants (501 g to 1000 g) mechanically ventilated before 12 hours of life to a PaC0 2 goal of normocapnia (C0 2 < 48 mmHg) or permissive hypercapnia (C0 2 > 52 mmHg) and to receive either dexamethasone or placebo, in a factorial design, for the first 10 post-natal days [42]. Unfortunately, the trial was stopped early because of adverse events related to dexamethasone therapy. Nevertheless, permissive hypercapnia demonstrated benefit, with only 1 % of the permissive hypercapnia group pat ients requiring mechanical ventilation at 36 weeks gestational age, compared to 16 % in the routine group (p < 0,01) .

Persistent Pulmonary Hypertension of the Newborn Traditional management of persistent pulmonary hypertension of the newborn (PPHN), a condition complicating neonatal sepsis, meconium aspiration, severe neonatal respiratory failure, or occurring in an idiopathic form in term and nearterm neonates, has emphasized the use of hyperventilation to decrease pulmonary arterial pressure . However, hypocapnia is associated with adverse neurologic outcome in PPHN survivors . In contrast, Wung et al. demonstrated lower than previous mortality, and reduced incidence of chronic lung disease, in 15 neonates suffering from persistent fetal circulation in severe respiratory failure [43]. More recently, all 34 infants with severe PPHN and severe respiratory failure at birth managed with permissive hypercapnia survived with a good neurological outcome [44]. Only two infants developed bronchopulmonary dysplasia, although neither required supplemental oxygen at follow up [44].

Congenital Diaphragmatic Hernia Permissive hypercapnia plays an increasing role in the ventilatory management of infants with congenital diaphragmatic hernia. This contrasts sharply with traditional management strategies, which involve aggressive hyperventilation with the aim of producing systemic alkalinization. However, the recognition that it is the hypoplastic lung that is the major pathophysiological defect has led to the use of

Hypercapnia: Permissive, Therapeutic, or Not at All?

permissive hypercapnia to minimize barotrauma. A retrospective analysis of the effect of three treatment protocols on the outcome of high risk infants with congenital diaphragmatic hernia demonstrated that permissive hypercapnia was associated with a substantial increase in survival, decreased barotrauma, and decreased morbidityat six months [45]. Congenital Heart Disease

Control of CO2 has traditionally played an integral role in the management of patients with complex congenital heart defects. In the context of single ventricle physiology, PVR can be controlled by inducing alveolar hypoxia and/or hypercapnia. The potential of hypercapnia to improve brain and other systemic organ oxygenation is increasingly recognized. In neonates with severe congenital heart defects, low cerebral blood flows have been associated with periventricular leukomalacia and adverse neurological outcome [46]. These deficits in cerebral blood flow were reversible when CO2 was administered [46]. A recent study demonstrated that, without altering tidal volume or mean airway pressure , addition of CO2 to the inspired gas improved cerebral blood flow and systemic oxygenation following cavopulmonary connection [47]. Taken together, these studies raise the potential that inhaled CO2 might have a future therapeutic role in this context.

Hypercapnia: Balancing Risk and Benefit Although hypercapnia and acidosis exert a myriad of biologically important effects, in practice there are few complications. Nevertheless, in certain clinical contexts, the potential for hypercapnia to exert deleterious effects needs to be carefully considered. Permissive Hypercapnia and Intracranial Pressure Regulation

The potential for hypercapnia-induced increases in cerebral blood flow to critically elevate intracranial pressure in situations where intracranial compliance is dimin ished is clear [48]. Nevertheless, clinical conditions predisposing to intracranial hypertension constitute a relative, rather than an absolute, contraindication to permissive hypercapnia. Consideration should be given to the insertion of an intracranial pressure monitor or a jugular venous oximetry catheter, which can then facilitate the gradual titration of permissive hypercapnia in a patient with a brain injury. The successful use of this approach has been described in the management of a child suffering from meningococcal septicemia complicated by both significantly elevated intracranial pressure and severe acute lung injury [48]. Permissive Hypercapnia and Pulmonary Vascular Resistance

Clinical conditions predisposing to pulmonary hypertension should be considered a relative rather than an absolute contraindication to permissive hypercapnia strategies. As discussed, permissive hypercapnia is increasingly utilized in the setting of severe neonatal respiratory failure resulting in persistent fetal circulation and pulmonary hypertension [43]. In addition, laboratory studies demonstrate that hypercapnic acidosis may retard the development of hypoxia-induced pulmonary hyper-

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tension in newborn rodents [16]. Concerns about significant pulmonary hypertension can be most rationally dealt with by measuring the degree of pulmonary hypertension or its sequelae (e.g., right ventricular failure, tricuspid regurgitation, or increased right to left shunting) , the effect of hypercapnia on pulmonary vascular resistance, and titrating the degree of hypercapnia accordingly. In this context, monitoring with transthoracic echocardiography or placement of a pulmonary artery catheter may be indicated.

Buffering Hypercapnic Acidosis: Rational or Not Buffering of the acidosis induced by hypercapnia remains a common, albeit controversial clinical practice. Buffering with sodium bicarbonate was permitted in the ARDS Network study [33]. The need to consider the effects of buffering hypercapnic acidosis is emphasized by the fact that both hypercapnia and acidosis per se may exert distinct biologic effects. However, as already discussed, there is evidence that the protective effects of hypercapnic acidosis in ARDS are a function of the acidosis, rather than elevated CO2 per se [14,31] . Buffering may simply ablate any protective effects, while not addressing the primary problem. Specific concerns exist regarding sodium bicarbonate, the buffer used most frequently in the clinical setting. The effectiveness of bicarbonate infusion as a buffer is dependent on the ability to excrete CO2 , rendering it less effective in buffering hypercapnic acidosis. In fact, bicarbonate may further raise PaC0 2 where alveolar ventilation is limited, such as in ARDS. While bicarbonate may correct arterial pH, it may worsen an intracellular acidosis because the CO2 produced when bicarbonate reacts with metabolic acids diffuses readily across cell membranes, whereas bicarbonate cannot.

Conclusion There is increasing evidence to support the use of permissive hypercapnia in multiple clinical settings, including ARDS, acute severe asthma, neonatal respiratory failure, and congenital heart disease. Furthermore, the potential for hypercapnia to directly contribute to the beneficial effects of protective lung ventilatory strategies is clear from experimental studies. These findings raise the possibility that hypercapnia might be induced for therapeutic effect in certain clinical contexts. However, concerns do persist regarding the potential for hypercapnia and/or acidosis to exert deleterious effects, particularly where intracranial compliance is reduced, or where increases in pulmonary vascular resistance may be deleterious. However, these should not be considered to be absolute contraindications to the careful use of permissive hypercapnia in these patients. The optimal ventilatory strategies for patients with severe respiratory failure, and the precise contribution of hypercapnia to these strategies, remain unclear. For the present , the clinician must continue to decide for each specific patient what the appropriate trade -off is between the benefits of avoiding high tidal volumes and the cost - and benefits - of the associated hypercapnia. A clearer understanding of the effects and mechanisms of action of hypercapnia is central to determining its safety and therapeutic utility.

Hypercapnia: Permissive, Therapeutic, or Not at All? References 1. Laffey JG, Kavanagh BP (1999) Carbon dioxide and the critically ill - too little of a good thing? Lancet 354:1283-1286 2. Amato MB, Barbas, CS, Medeiros DM, et al (1998) Effect of a protective-ventilat ion strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347-354 3. Hickling KG, Hende rson SJ, Jackson R (1990) Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 16:372-377 4. Swenson ER, Robertson HT, Hlastala MP (1994) Effects of insp ired carbon dioxide on venti lation -perfusion match ing in norrnox ia, hypoxia, and hyperoxia. Am J Respir Crit Care Med 149:1563-1569 5. Wildeboer-Venema F (1980) The influences of temperature and humidity upon the isolated surfactant film of the dog. Respir Physiol 39:63- 71 6. Hare GM, Kavanagh BP, Mazer CD, et al (2003) Hypercapnia increases cerebral tissue oxygen ten sion in anesthetized rats. Can J Anaesth 50:1061- 1068 7. Laffey JG, Iankov RP, Engelberts D, et al (2003) Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injur y. Am J Respir Crit Care Med 168:1383 -1390 8. Lee KJ, Hernandez G, Gordon JB (2003) Hypercapnic acidos is and compensated hypercapnia in control and pulmonary hypertensive piglets. Pediatr Pulmonol 36:94-101 9. Shiota S, Okada T, Naitoh H, Ochi R, Fukuchi Y (2004) Hypoxia and hypercapnia affect contractile and histological properties of rat diaphragm and hind limb muscles. Pathophysiology 11:23-30 10. Cullen DJ, Eger EI 2nd (1974) Cardiovascular effects of carbon dioxide in man. Anesthes iology 41:345-349 11. Cardenas VJ, Zwischenberger JB, Tao W, et al (1996) Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia. Crit Care Med 24:827- 834 12. Hillered L, Ernster L, Siesjo BK (1984) Influence of in vitro lactic acidosis and hypercapnia on respiratory activity of isolated rat brain mitochondria. J Cereb Blood Flow Metab 4:430-437 13. Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh BP (1998) Hypercapnic acidosi s may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. Am J Respir Crit Care Med 158:1578-1584 14. Laffey JG, Engelberts D, Kavanagh BP (2000) Buffering hypercapnic acidos is worsens acute lung injury. Am J Respir Crit Care Med 161:141-146 15. Laffey JG, Tanaka M, Engelberts D, et al (2000) Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med 162: 2287-2294 16. Kantores C, McNamara PJ, Teixeira L, et al (2006) Therapeutic hypercapnia prevents chron ic hypoxia-induced pulmonary hypertension in the newborn rat. Am J Physiol Lung Cell Mol PhysioI291 :L912-922 17. Broccard AF, Hotchkiss JR, Vannay C, et al (2001) Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med 164:802-806 18. Sinclair SE, Kregenow DA, Lamm WI, Starr IR, Chi EY, Hlastala MP (2002) Hypercapnic acidosis is protective in an in vivo model of vent ilator-induced lung injury. Am J Respir Crit Care Med 166:403-408 19. Strand M, Ikegami M, lobe AH (2003) Effects of high pcm on ventilated preterm lamb lungs. Pediatr Res 53:468-472 20. Rai S, Engelberts D, Laffey JG, et al (2004) Therapeutic hypercapnia is not protective in the in vivo surfactant-depleted rabbit lung. Pediatr Res 55:42-99 21. Doerr CH, Gajic 0, Berrios JC, et al (2005) Hypercapnic acidosis impairs plasma membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care Med 171:1371-1377 22. Nomura F, Aoki M, Forbess JM, Mayer JE [r (1994) Effects of hypercarbic acidotic reperfusion on recovery of myocardi al funct ion after cardioplegic ischemia in neonatal lambs . Circulation 90:11321-327 23. Kitakaze M, Takashima S, Funaya H, et al (1997) Temporary acidosis during reperfusion limits myocardial infarct size in dogs. Am J Physiol 272:H2071-2078

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P. Hassett, M. Contreras, and J.G. Laffey 24. von Planta I, Weil MH, von Planta M, Gazmuri RJ, Duggal C (1991) Hypercarbic acidosis reduces cardiac resuscitability. Crit Care Med 19:1177- 1182 25. Barth A, Bauer R, Gedrange T, Walter B, Klinger W, Zwiener U (1998) Influence of hypoxia and hypoxia/hypercapnia upon brain and blood peroxidative and glutathione status in normal weight and growth-restricted newborn piglets. Exp Toxicol Pathol 50:402- 410 26. Vannucci RC, Brucklacher RM, Vannucci SJ (1997) Effect of carbon dioxide on cerebral metabolism dur ing hypoxia-ischemia in the immature rat. Pediatr Res 42:24-29 27. Holmes JM, Zhang S, Leske DA, Lanier WL (1998) Carbon dioxide-induced retinopathy in the neonatal rat. Curr Eye Res 17:608-616 28. Bonventre JV, Cheung JY (1985) Effects of metabolic acidosis on viability of cells exposed to anoxia. Am J Physiol 249:CI49-159 29. Coakley RJ, Taggart C, Greene C, McElvaney NG, O'Neill SJ (2002) Ambient pC02 modulates intracellul ar pH, intracellular oxidant generat ion, and interleukin-8 secretion in human neutrophils. J Leukoc Bioi 71:603-610 30. Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P (2004) Hypercapnic acidosis attenu ates endotoxin-induced acute lung injury. Am J Respir Crit Care Med 169: 46-56 31. Lang JD Ir, Chumley P, Eiserich JP, et al (2000) Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway. Am J Physiol Lung Cell Mol Physiol 279: L994-1002 32. Takeshita K, Suzuki Y, Nishio K, et aI (2003) Hypercapnic acidosis attenuates endotoxin induced nuclear factor-[kappa)B activation. Am J Respir Cell Mol Bioi 29:124 - 132 33. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with trad itional tidal volumes for acute lung injur y and the acute respiratory distre ss syndrome. N Engl J Med 342:1301- 1308 34. Stewart TE, Meade MO, Cook DJ, et al (1998) Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 338:355- 361 35. Brochard L, Roudot-Thoraval F, Roupie E, et al (1998) Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 158:1831 -1838 36. Brower RG, Shanholtz CB, Fessler HE, et al (1999) Prospective, randomized, controlled clinical tr ial comparing traditional versus reduced tidal volume ventilation in acute respiratory dist ress synd rome patients. Crit Care Med 27:1492-1498 37. Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER (2006) Hypercapn ic acidosis and mortality in acute lung injury. Crit Care Med 34:1-7 38. Darioli R, Perret C (1984) Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 129:385-387 39. Tuxen DV, Williams TJ, Scheinkestel CD, Czarny D, Bowes G (1992) Use of a measurement of pulmonary hyperinflation to control the level of mechanical ventilation in patients with acute severe asthma. Am Rev Respir Dis 146:1136-1142 40. Caramez MP, Borges JB, Tucci MR, et al (2005) Paradoxical responses to positive end-expiratory pressure in patients with airway obstruction during controlled ventilation. Crit Care Med 33:1519-1528 41. Mariani G, Cifuentes J, Carlo WA (1999) Randomized trial of permi ssive hypercapnia in preterm infants. Pediatrics 104:1082-1088 42. Carlo WA, Stark AR, Wright LL, et al (2002) Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-Iow-birth-weight infants. J Pediatr 141:370-374 43. Wung JT,James LS, Kilchevsky E, James E (1985) Management of infants with severe respirator y failure and persistence of the fetal circulation , without hyperventilation. Pediatrics 76:488 -494 44. Marron MJ, Crisafi MA, Driscoll JM [r, et al (1992) Hearing and neurodevelopmental outcome in surv ivors of persistent pulmonary hypertension of the newborn. Pediatrics 90: 392- 396 45. Bagolan P, Casaccia G, Crescenzi F, Nahom A, Trucchi A, Giorlandino C (2004) Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hern ia. J Pediatr Surg 39:313-318

Hypercapnia: Permissive, Therapeutic, or Not at All? 46. Licht DJ, Wang J, Silvestre DW,et al (2004) Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc Surg 128:841-849 47. Hoskote A, Li J, Hickey C, et al (2004) The effects of carbon dioxide on oxygenation and systemic, cerebral, and pulmonary vascular hemodynamics after the bidirectional superior cavopulmonary anastomosis. J Am Coll Cardiol 44:1501-1509 48. Tasker RC, Peters MJ (1998) Combined lung injury, meningitis and cerebral edema: how permissive can hypercapnia be? Intensive Care Med 24:616-619

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The Cardiopulmonary Effects of Hypercapnia T.

MANCA,

L.c.

WELCH,

and

J.I.

SZNAJDER

Introduction cO 2 Physiology Carbon dioxide (C0 2) is a product of oxidative metabolism in humans. The arterial CO2 partial pressure (P0 2) can be represented by equation (1): P0 2 = K . (VCO/VA) + PiC0 2

(1)

where K is a proportion constant, VC0 2 the CO2 production, VA the alveolar ventilation , and PC0 2 is the inhaled CO2 • Aveolar ventilation (VA) is a component of the total ventilation (VT ) minus the dead space ventilation (Vo ), which is VA = VT - Vo or: VA = V r (l - Vr/Vr)

(2)

therefore , by combining equations 1 and 2, the following equation results: PC0 2 = K· VC0 2

/

V r (l - Vr/Vr) + PiC0 2

(3)

Consistent with this equation, we can identify four causes for hypercapnia: A) increased CO2 production (VC0 2 ) ; B) hypoventilation (increased value of IIVT ) ; C) increased dead space ventilation (Vo); and D) increased inhaled CO2 (PiC0 2 ) [1]. CO2 is a product of oxidative metabolism, and its formation is related to oxygen consumption (V0 2) according to equation (4), where RQ is the respiratory quotient, which varies from 0.7 (for lipids) to 0.85 (for proteins) and 1 (for carbohydrates): VC0 2 = RQ . V0 2

(4)

Non-metabolic generation of CO2 can also occur during tissue hypoxia, when the CO2 is not derived from the Krebs cycle, but from the hydrolysis of ATP and ADP. The high CO2 levels can be due to the increase of acids from anaerobic metabolism, which releases hydrogen ions, buffered by HC0 3- thus increasing PC0 2 (HC0 3- + H+ f-? CO2 + H 20) and can be a marker of low tissue oxygenation [2]. These conditions, of increased CO2 production, do not lead to hypercapnia if the lungs are functioning normally and CO2 is eliminated. However, in patients with lung diseases, hypoventilation, increased dead space ventilation, and/or an excessive dietary intake of carbohydrates can lead to hypercapnia [3]. In the blood, CO2 is transported dissolved in plasma, by the red blood cells (RBCs) or bound to hemoglobin (Hb). The reaction CO2+ H20 f-? HC0 3 - + W in RBCs is catalyzed by a carbonic anhydrase which increases its hydration by -5000 fold than without the action of the carbonic anhydrase. CO2 is also bound to Hb and it reacts with the amine radicals of Hb to form carboaminoHb. The deoxyHb has

The Cardiopulmonary Effects of Hypercapnia

higher affinity to form carboaminoHb and to bind H+ [4]. When the concentration of CO2 is higher, it is easier for O2 to be released from Hb (Bohr Effect). When O2 concentrations increase, Hb tends to release CO2 and H+ ions because the oxyHb becomes a stronger acid (Haldane Effect), and the released H+ ions are buffered by HC0 3- resulting in CO2 accumulation which is removed by alveolar ventilation [1]. Effects of Hypercapnia

CO2 has been long considered an 'inert' gas without specific effects on cells or tissues. However, recent reports have suggested that high PC0 2 may act as a molecular mediator either by itself or by decreasing pH [5-7]. More recently, there are also reports suggesting that high PC0 2 affects cellular/tissue function independently of pH. CO2 competes with O2 to bind with Hb (Haldane and Bohr Effect) or reacts with the amino radicals of Hb forming carboaminoHb, where CO2 binds amino groups producing carbamate residues leading to secondary and tertiary structural alterations of the protein. Furthermore, high CO2 leads to increased levels of H+, which also interacts with proteins and enzymes within the cell membranes and cellular aqueous environments [6, 7]. Some examples of the effects of high PC0 2 include alterations in microtubule assembly [8], changes in intracellular calcium concentration [6], modifications in the endothelial cell protein secretion [7], modulation of mediator activity and synthesis [5], modulation of cellular [9] and mitochondrial activity [10].

Hypercapnia and Lung Injury In patients with acute respiratory distress syndrome (ARDS), low tidal ventilation improves survival probably by decreasing the 'volutrauma' of overstretching the lung parenchyma [11]. As such, low tidal ventilation has become the standard of care in patients with ARDS in order to decrease the stretch stress. A possible consequence of low tidal ventilation is an increase in PC0 2, which has been branded as 'permissive hypercapnia' [12]. Some investigators have proposed a beneficial effect from the hypercapnia and termed it protective or 'therapeutic hypercapnia'. Laffey et al. reported that high PC0 2 had beneficial effects on lung permeability, oxygenation, and lung mechanics in the rat mesenteric ischemia-reperfusion and lipopolysaccharide (LPS)-induced acute lung injury (ALI) models [13]. These investigators found that hypercapnic rats had decreased levels of nitrate, nitrite, and nitrosothiols, but increased nitrotyrosine proteins; leading to the conclusion that high PC0 2 is protective for lung injury [13]. Also, in ventilator induced lung injury (VILI) models, some reports suggest that high PC0 2 decreased high stretch injury and did not show an increase in the release of cytokines [14]. However, other reports suggested that high PC0 2 had deleterious effects on the lungs. These studies suggest that high PC0 2 can cause oxidative stress in the lung by enhancing nitric oxide (NO) production and that CO2 can also react with peroxynitrite (ONOO-), derived from superoxide (02-) and NO, forming nitrosoperoxocarbonate (ONOOC0 2- ) , which can cause cell injury [7, 13, 15-17]. In these models, the effects of hypercapnia have been related to the loss of epithelial barrier integrity, increased apoptosis due to increased nitrosylation products, reduction of thiol antioxidant species, and decreased function of the surfactant protein A [7, 17]. CO2 reacts with ONOO- to form ONOOC0 2- , which causes

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a rapid decay of ONOO-. ONOOC0 2- is a more potent nitrating agent but has a shorter half life [18]. Thus, depending on which cells sense the high PC0 2, hypercapnia could have different effects and contribute to nitrosative cell injury [IS, 19]. Hypercapnia has been shown to decrease bronchial tone [20] and to cause pulmonary vasoconstriction similar to hypoxia-mediated pulmonary vasoconstriction [21]. In the healthy lung, the hypercapnic vasoconstrictive reflex plays an important role, and its sensitivity is greater than the pulmonary vessel sensitivity in response to hypoxia, with a fast and slow component [22].

Hypercapnia and Lung Clearance Alveolar fluid clearance is important to maintain the lungs free of edema and available for normal gas exchange [23, 24]. Alveolar fluid reabsorption from the alveolar space into the interstitium and the pulmonary circulation is regulated by active Na" transport where sodium enters via the apical surface by arniloride-sensitive and -insensitive Na" channels and is subsequently 'pumped' out of the cell by the Na,K-adenosine triphosphatase (Na+/K+-ATPase) . This process generates an osmotic gradient driving the movement of water out from the alveolar spaces through aquaporin water channels. Both alveolar epithelial type I and type II participate in this process [25, 26]. The Na+/K+-ATPase pump consists of a catalytic a-subunit and a regulatory ~-subunit to exchange Na" and K+ across the plasma membrane, consuming -40 % of the energy of the cell in this process [27]. Some stimuli, such as hypoxia [28] and hyperoxia [29], impair Na+/K+-ATPase activity and decrease the protein abundance of Na+/K+-ATPase at the plasma membrane and, thus, fluid clearance [28]. The alveolar epithelium is the primary site of CO2 elimination in mammals; therefore, it is reasonable to evaluate whether alveolar epithelial cells are affected by high levels of CO2 , Our laboratory has investigated the effects of high PC0 2 on alveolar epithelial function, focusing on alveolar fluid clearance. We have observed that in rat lungs, high PC0 2 independently of pH decreased alveolar fluid clearance [5]. Hypercapnia also inhibited alveolar epithelial Na+/K+-ATPase function by activating a signaling pathway, which led to the endocytosis of Na+/K+-ATPase from the plasma membrane into intracellular pools. This CO2-mediated effect was not mediated by reactive oxygen species (ROS), unlike what was observed in conditions of hypoxia and hyperoxia [28]. Thus, we reason that the alveolar cells sense and respond to different CO2 concentrations, independently of pH via a yet to be described mechanism.

Hypercapnia and the Heart It has been reported that acute hypercapnia may result in decreased contractility of the myocardium [30]. This effect appears to be due to a decrease in Ca2+ myofila-

ment responsiveness. In conditions of prolonged hypercapnia, after the initial decrease in contractility there is a recovery phase, where the adrenergic system plays an essential role, and which appears to be stimulated by high PC0 2 [31]. Similar to hypercapnia, the resultant acidosis signals lead to increased intracellular calcium by stimulating the Na+/H+ pump while inhibiting the Na+/K+-ATPase with the resulting increase in intracellular Na", which in turn activates the Na+/Ca2+ pump [32]. In

The Cardiopulmonary Effects of Hypercapnia

the toad heart, Salas et al. reported that by increasing the calcium intake , recovery from hypercapnic acidosis continued even after the correction of pH and the inhibition of the Na+/H+ pump; however, the recovery decreased when the Na+/Ca2+ pump and L-Ca2+ channel were inhibited suggesting a very important role for calcium in this process [33]. In models of ischemia-reperfusion cond itions, a rap id return to physiological intracellular pH (pHJ is detrimental and worsens tissue injur y [34, 35]. This phenomenon, during reperfusion, kno wn as the 'pH paradox', occurs with the activation of the sodium-hydrogen exchanger and the sodium-bicarbonate symporter. The activation of these pumps contributes to cellular and mitochondrial Ca2+ overload which leads to changes in heart contractility and mit ochondrial permeability transition pore (PTP) opening [35]. During ischernia-reperfusion, respiratory acidosis , by decreasing the calcium overload, has been reported to reduce the size of myocardial ischemia, and to facilitate the recovery from cardioplegic ischemia [36], thu s improving oxygen delivery in the ischemic phase [37,38]. Recently, it has been proposed that ROS, rather than a calcium overload, were responsible for the increase of cell death in myocardium after ischernia-reperfusion and that during ischemiareperfusion, hypercapnia inhibited the mitochondria oxidant injury by activating the NO synthase (NOS) pathway resulting in decreased myocardiocyte death [10]. In patients with lung diseases and hypercapnia, such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apn ea syndrome, there is increased cardiovascular risk [39,40]. In particular, an increased incidence of arrhythmias and sudden death can occur [39,40]. Also, systemic hypertension and hypertensive cardiomyopathy, diastolic dysfunction, and myocardial hypertrophy are common in patients with COPD and obstructive sleep apnea syndrome [41]. The association of hypercapnia to arrhythmias and sudden death is related to hypercapnia-mediated alterations in the myocardial conduction system, specifically the electrocardiographic (EKG) QT phase resulting in an increase in QTc and QT dispersion [42]. The systemic hypertension and hypertens ive cardiomyopathy in hypercapnic diseases can be due to the chronic stimulation of the adrenergic pathway [43], while in skeletal muscle , it has been reported that hypercapnia affects contractile and structural properties [44]. However, there have not been studies reporting a direct contribution of hypercapnia to the pathological myocardial remodeling.

Hemodynamic Effects of Hypercapnia Hypercapnia decreases vascular resistance by inducing relaxation of precapillary arterioles in the majority of vascular beds [31, 42]. Most reports show that hype rcapnia leads to an incre ase in total peripheral resistance, mean systemic arterial pressure, cardiac output and heart rate; however, other investigations have reported opposite findings. To understand these conflicting results, consideration should be given to hypercapnia's effects on different tissues and also the indirect effects of hypercapnia via the associated acidos is, such as the effects exerted on the sympathetic and parasympathetic systems [31,42]. For example, the vasodilatory effects of high PC0 2 on the cerebral, coronary, splanchnic, and skeletal muscle vasculature appear to be different to the effects on the pulmonary circulation [37, 38]. Recently, Komori et al., utilizing intravital microscopy, observed that a PC0 2 of -80 mmHg increased peripheral microvessel diameter, blood-flow velocity, blood-flow rate , and cardiac output, whereas a PC0 2 of - 20 mmHg exerted opposite effects [45].

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In the brain, it has been reported that metabolic and respiratory acidosis result in vasodilation via a decrease in extracellular pH [46]. Several mechanisms contributing to the hypercapnia-mediated vasodilation of cerebral arterioles have been proposed. Among them, the neuronal NOS (nNOS) pathway [47], Ca2+-sensitive potassium channels, ATP-sensitive potassium channels [48] and in newborns, endothelial cyclooxygenase [49]. It has been proposed that hypercapnia via nNOS increases NO production, with the subsequent activation of guanylate cyclase and increase in cGMP in the vascular smooth muscle cells. Also, NO and cGMP can activate potassium channels leading to cell hyperpolarization which, in turn, inhibits voltagegated Ca2+ channels leading to vasculature relaxation. Acidosis can also directly activate K+ channels [48]. Hypercapnia, by increasing vasodilation, can contribute to intracranial hypertension and intracranial bleeding which has led investigators to recommend hyperventilation to reduce blood mass without causing excessive vasoconstriction [50]. In addition to its hemodynamic effects, high PC0 2 leads to improved oxygen supply by increasing tissue perfusion and glucose aerobic metabolism, thus improving oxygen supply/demand balance during ischemia and hypoxia [10, 31,44].

Conclusion High peo 2 is observed in patients with lung disease, such as COPD, obstructive sleep apnea syndrome, and hypoventilation and also in critically ill patients ventilated with 'permissive' hypercapnia. Whether hypercapnia has negative effects on cardiovascular pathophysiology is an issue of debate. As depicted schematically in Figure 1, CO2, far from being a metabolically 'inert' gas, is 'sensed' in different tis sues by cells leading to the activation of a signal transduction cascade with specific effects. Although some of the physiological effects of PC0 2 are well known, the cellular mechanisms by which these effects are regulated, have yet to be elucidated. Hypercapnia has been proposed to contribute to cardiovascular dysfunction and reduced muscular mass in COPD, and to increased risk of intracranial bleed and sudden death in obstructive sleep apnea syndrome and COPD. There is still controversy as to whether or not hypercapnia contributes to increasing lung injury. More recent data suggest that hypercapnia, independently of pH, has deleterious effects on

Are the effects of high PC02 Deleterious or Protective?

~ ~

Fig. 1. Hypercapnia has been shown to be deleterious (blue) to the alveolar epithelium by activating signal transduction pathways leading to impairment of alveolar fluid clearance. Hypercapnia has also been reported to be protective (gray) by decreasing the inflammatory response. It also aids in decreasing lung injury due to stretch during mechanical ventilation.

The Cardiopulmonary Effects of Hypercapnia

alveolar epithelial function by inhibiting Na+/K+-ATPase function and thus active transport of sodium across the lungs. Further research is warranted to elucidate the sensors and signal transduction pathways regulating the effects of hypercapnia in different tissues. Acknowledgement: Supported in part by HL-85534 References 1. Dantzker DR (1991) Pulmonary gas exchange. In: Dantzker DR (ed) Cardiopulmonary Gas

Exchange, 2nd edn. WB Saunders , Philadelphia, pp 25- 43 2. Gutierrez G (2004) A mathematical model of tissue-blood carbon dioxide exchange during hypoxia. Am J Respir Crit Care Med 169:525-533 3. Talpers SS, Romberger DJ, Bunce SB, Pingleton SK (1992) Nutritionally associated increased carbon dioxide production. Excess total calories vs high proportion of carbohydrate calories. Chest 102:551- 555 4. Christiansen J, Douglas CG, Haldane JS (1914) The absorption and dissociation of carbon dioxide by human blood. J Physiol 48:244-271 5. Chen J, Lecuona E, Briva A, Welch LC, Sznajder JI (2008) Carbonic anhydrase II and alveolar Fluid Reabsorption During Hypercapnia. Am J Respir Cell Mol BioI 38:32-37 6. Nishio K, Suzuki Y, Takeshita K, et al (2001) Effects of hypercapnia and hypocapnia on [Ca2+1i mobilization in human pulmonary artery endothelial cells. J Appl Physiol 90:20942100 7. Zhu S, Basiouny KF, Crow JP, Matalon S (2000) Carbon dioxide enhances nitration of surfac tant protein A by activated alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 278:L1025 -1031 8. Eiserich JP, Estevez AG, Bamberg TV, et al (1999) Microtubule dysfunction by posttranslational nitrotyrosination of alpha-tubulin: a nitric oxide-dependent mechanism of cellular injury. Proc Nat! Acad Sci USA 96:6365-6370 9. Zhou Y, Zhao J, Bouyer P, Boron WF (2005) Evidence from renal proximal tubules that HC03- and solute reabsorption are acutely regulated not by pH but by basolateral HCOr and CO2, Proc Nat! Acad Sci USA 102:3875-3880 10. Lavani R, Chang WT, Anderson T, et al (2007) Altering CO2 during reperfusion of ischemic cardiomyoc ytes modifies mitochondrial oxidant injury. Crit Care Med 35:1709-1716 II. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respira tory distress syndrome. N Engl J Med 342:1301 -1308 12. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 99:944-952 13. Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P (2004) Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med 169: 46-56 14. Sinclair SE, Kregenow DA, Lamm WI. Starr IR, Chi EY, Hlastala MP (2002) Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 166:403-408 15. Berlett BS, Levine RL, Stadt man ER (1998) Carbon dioxide stimulates peroxynitrite-mediated nitration of tyrosine residues and inhibits oxidation of methionine residues of glutamine synthetase: both modifications mimic effects of adenylylation. Proc Nat! Acad Sci USA 95:2784- 2789 16. Gow A, Duran D, Thorn SR, Ischiropoulos H (1996) Carbon dioxide enhancement of peroxynitrite-mediated protein tyrosine nitration. Arch Biochem Biophys 333:42-48 17. Radi R, Denicola A, Freeman BA (1999) Peroxynitrite reactions with carbon dioxide-bicarbonate . Methods Enzymol 301:353-367 18. Schopfer FJ, Baker PR, Freeman BA (2003) NO-dependent protein nitration: a cell signaling event or an oxidative inflammatory response? Trends Biochem Sci 28:646-654

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19. Doerr CH, Gajic 0, Berrios JC, et al (2005) Hypercapnic acidosis impairs plasma membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care Med 171:1371-1377 20. van den Elshout FJ, van Herwaarden CL, Folgering HT (1991) Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects. Thorax 46:28-32 21. Ooi H, Cadogan E, Sweeney M, Howell K, O'Regan RG, McLoughlin P (2000) Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling. Am J Physiol Heart Circ Physiol 278:H331-338 22. Balanos GM, Talbot NP, Dorrington KL, Robbins PA (2003) Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography. J Appl Physiol 94:1543-1551 23. Matthay MA, Folkesson HG, Clerici C (2002) Lung epithelial fluid transport and the resolution of pulmonary edema . Physiol Rev 82:569- 600 24. Mut!u GM, Sznajder JI (2005) Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol 289:L685- 695 25. Johnson MD, Widdicombe JH, Allen L, Barbry P, Dobbs LG (2002) Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis. Proc Nat! Acad Sci USA 99:1966-1971 26. Ridge KM, Olivera WG, Saldias F, et al (2003) Alveolar type 1 cells express the alpha2 Na,KATPase, which contributes to lung liquid clearance. Circ Res 92:453 - 460 27. Skou JC (1998) Nobel Lecture. The identification of the sodium pump. Biosci Rep 18:155-169 28. Dada LA, Sznajder JI (2003) Mechanisms of pulmonary edema clearance during acute hypoxemic respiratory failure: role of the Na,K-ATPase. Crit Care Med 31:S248-252 29. Olivera WG, Ridge KM, Sznajder JI (1995) Lung liquid clearance and Na,K-ATPase during acute hyperoxia and recovery in rats. Am J Respir Crit Care Med 152:1229-1234 30. Orchard CH, Hamilton DL, Ast!es P, McCall E, Jewell BR (1991) The effect of acidosis on the relationship between Ca2+ and force in isolated ferret cardiac muscle. J PhysioI436 :559-578 31. Urboniene D, Dias FA, Pena JR, Walker LA, Solaro RJ, Wolska BM (2005) Expression of slow skeletal troponin I in adult mouse heart helps to maintain the left ventricular systolic function during respiratory hypercapnia. Circ Res 97:70-77 32. Hulme JT, Orchard CH (1998) Effect of acidosis on Ca2+ uptake and release by sarcoplasmic reticulum of intact rat ventricular myocytes. Am J Physiol 275:H977- 987 33. Salas MA, Vila-Petroff MG, Venosa RA, Mattiazzi A (2006) Contractile recovery from acidosis in toad ventricle is independent of intracellular pH and relies upon Ca2+ influx. J Exp Bioi 209:916-926 34. Bond JM, Chacon E, Herman B, Lemasters 11 (1993) Intracellular pH and Ca2+ homeostasis in the pH paradox of reperfusion injury to neonatal rat cardiac myocytes. Am J Physiol 265:CI29-137 35. Sakuma T, Takahashi K, Ohya N, et al (1999) Ischemia-reperfusion lung injury in rabbits: mechanisms of injury and protection. Am J Physiol 276:L137 -145 36. Hurtado C, Pierce GN (2000) Inhibition of Na(+)/H(+) exchange at the beginning ofreperfusion is cardioprotective in isolated, beating adult cardiomyocytes. J Mol Cell Cardiol 32: 1897-1907 37. Ishizaka H, Gudi SR, Frangos JA, Kuo L (1999) Coronary arteriolar dilation to acidosis: role of ATP-sensitive potassium channels and pertussis toxin-sensitive G proteins. Circulation 99:558-563 38. Tzou WS, Korcarz CE, Aeschlimann SE, Morgan BJ, Skatrud JB, Stein JH (2007) Coronary flow velocity changes in response to hypercapnia: assessment by transthoracic Doppler echocardiography. J Am Soc Echocardiogr 20:421-426 39. McNicholas WT, Bonsigore MR (2007) Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 29:156-178 40. Sin DO, Man SF (2005) Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2:8-11 41. Boussuges A, Pinet C, Molenat F, et al (2000) Left atrial and ventricular filling in chronic obstructive pulmonary disease. An echocardiographic and Doppler study. Am J Respir Crit Care Med 162:670-675 42. Kiely DG, Cargill RI, Lipworth BJ (1996) Effects of hypercapnia on hemodynamic, inotropic, lusitropic, and electrophysiologic indices in humans. Chest 109:1215- 1221

The Cardiopulmonary Effects of Hypercapnia 43. Cooper VL, Pearson 5B, Bowker CM, Elliott MW, Hainsworth R (2005) Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia - a mechanism for promoting hypertension in obstructive sleep apnoea. J Physiol 568:677- 687 44. Shiota 5, Okada T, Naitoh H, Ochi R, Fukuchi Y (2004) Hypoxia and hypercapnia affect contractile and histological properties of rat diaphragm and hind limb muscles. Pathophysiology 11:23- 30 45. Komori M, Takada K, Tomizawa Y, Nishiyama K, Kawamata M, Ozaki M (2007) Permissive range of hypercapnia for improved peripheral microcirculation and cardiac output in rabbits. Crit Care Med 35:2171-2175 46. Fortune JB, Feustel PI, deLuna C, Graca L, Hasselbarth J, Kupinski AM (1995) Cerebral blood flow and blood volume in response to O2 and CO2 changes in normal humans. J Trauma 39: 463-471 47. Iadecola C, Zhang F (1996) Permissive and obligatory roles of NO in cerebrovascular responses to hypercapnia and acetylcholine. Am J Physiol 271:R990-1001 48. Wang Q, Bryan RM [r, Pelligrino DA (1998) Calcium-dependent and ATP-sensitive potassium channels and the 'permissive' function of cyclic GMP in hypercapnia-induced pial arteriolar relaxation . Brain Res 793:187-196 49. Wagerle LC, Mishra OP (1988) Mechanism of CO2 response in cerebral arteries of the newborn pig: role of phospholipase, cyclooxygenase, and lipoxygenase pathways. Circ Res 62: 1019-1026 SO. Helmy A, Vizcaychipi M, Gupta AK (2007) Traumatic brain injury: intensive care management. Br J Anaesth 99:32- 42

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High Frequency Oscillation for Acute Respiratory Failure in Adults S.D. MENTZELOPOULOS, C. Roussos, and S.G. ZAKYNTHINOS

Introduction In the acute respiratory distress Syndrome (ARDS), major mechanisms of ventilatorinduced lung injury (VILI) include barotrauma, volutrauma, atelectrauma, and biotrauma [1, 2]. In an excellent review, Gattinon i et al. [2], argue that during conventional mechanical ventilation , lung stress and strain are the major determinants of VILI. Alveolar stress (i.e., transmural pressure) is the ratio of alveolar wall tension to thickness [3]. Overall lung parenchymal stress is reflected by plateau and peak transpulmonary pressures [1, 2]. Lung strain refers to the deformation of the lung parenchyma induced by the distending force applied by the ventilator. Strain is reflected by the tidal volume to end-expiratory lung volume ratio [3]. Early and severe ARDS is characterized by non-homogeneously distributed and frequently diffuse lung damage [4], with intra-alveolar and interstitial edema and hyaline membrane formation. The absolute reduction in ventilatable lung parenchyma supports the "baby lung" concept [5]. According to this simplified and theoretical description, the ARDS lung is "small but not stiff" [2, 5]. Consequently, the use of a high tidal volume should cause mechanical harm, ultimately resulting in increased mortality [2, 5-8]. High frequency oscillatory ventilation (HFOV) aims to maintain an open lung volume by applying a constant mean airway pressure [9]. Oxygenation is primarily achieved by increasing the mean airway pressure, which resembles increasing continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP) [10]. Also, ventilat ion is normally achieved by delivering very low tidal volumes of less than 4 mllkg ideal body weight [11] at frequencies of 3- 7 cycles/sec (Hz) [12]. This technique suggests a redu ction in lung strain, in conjunction with a reduced probability of cyclic alveolar collapse and reopening. Consequently, even relative to lung-protective conventional mechanical ventilation with tidal volumes of 6 mllkg ideal body weight [7, 8], HFOV can be regarded as an optimal application of the open lung-low tidal volume concept [12].

Mechanisms of Gas Transport and Exchange During HFOV, ventilation is achieved by an electromagnetically driven piston, which superimposes an oscillatory pressure amplitude (tiP) on the mean airway pressure. This results in peak-to-trough pressure excursions above and below mean airway pressure within the proximal HFOV circuit ( Fig. 1), thereby creating an inspiratory and an expiratory phase, respectively. An adjustable power control determines the amplitude of piston displacement and resultant peak-to-trough pressure difference

High Frequency Oscillation for Acute Respiratory Failure in Adults

Hz

A o :£

+3Scm H20

E v

mPaw = 30 em H

20 R - 1--1----1-- 1-- 1--1--- - 1 - - + - - - ----''---- --

II

a.

+30 em H20 ('active exhalation')

1-5em H 0 ('subambient pressure') 2

0/0 IT

Time

Fig. 1. High-frequency pressure wave in proximal circuit. Note active exhalation phase and that the proximal circuit pressure may drop below the ambient pressure if the oscillatory pressure amplitude (AP) is more than twice the mean airway pressure (mPaw) setting. IT: inspiratory time. From [9] with permission (~P). The time period of each oscillation of the piston is determined by the frequency setting (Hz) . Administered tidal volume is increased by lowering the frequency or increasing ~P. According to the results from theoretical models, animals, and humans [13 - 16], during HFOV, tidal volume has a greater effect on gas exchange than frequency. Ventilation efficiency (Q) is expressed as:

Q= ,-vl

(1)

where f = frequency, V T = tidal volume, and a and b are parameters dependent on the shape and complexity of the oscillatory pressure waveform. In equation (1), the a and b values approach 1 and 2, respectively [17]. During conventional mechanical ventilation, the main mechanisms of gasexchange are bulk convection and diffusion. By contrast, during HFOV, there are five additional mechanisms of gas-exchange, namely, asymmetric velocity profiles, Taylor dispersion and turbulence, cardiogenic mixing, pendelluft effect, and collateral ventilation [12, 17] (Fig. 2). During HFOV, bulk convection contributes to gas exchange in the most proximal alveoli. If delivered tidal volume falls below the HFOV circuit-related rebreathing volume, a sudden rise in PaC0 2 is observed [18]. Thus, bulk convection contributes significantly to CO2 elimination, whereas the associated turbulence in the large airways may augment gas mixing [19]. An asymmetric velocity profile means unequal velocity of the inspired gas particles. This inequality is accentuated at the airway bifurcations, where there is an increased probability of collisions and turbulence. Asymmetric velocity profiles, in conjunction with the airway bifurcation phenomenon, enhance longitudinal convective gas transport (20). The non -colliding, 'central' particles of the inspired gas are propelled down the length of the inner airway wall at maximum velocity, while alveolar gas is streamed away along the outer airway wall. Concurrently, the peripheral particles of the inspired gas are diffused radially, promoting axial gas exchange with the expired gas [21] (Fig. 2). This radial mixing may increase gas density and pressure and promote turbulence in the proximal airways. This causes an increase in pressure gradient(s) among proximal and distal airways, which further facilitates longitudinal convective gas transport (Taylor dispersion) [22].

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Convection Direct vent ilat ion of close alveoli

Turbulance ----ri'~"\~ J!II

Asymetri c velocit y profi les Velocity profi le on inspirat ion ~"'---

Convection and diffusion

Velocity profil e on expansion

Diffusion

Collateral vent ilation

Fig. 2. Gas transport mechanisms during high-frequency oscillation. The major gas transport mechanisms that are operative under physiologic conditions within each region are shown (convection, convection and diffusion, diffusion alone). There are seven potential mechanisms of gas transport during high-frequency oscillation: Turbulence in the large airways, causing enhanced mixing; direct ventilation of close alveoli; turbulent flow with lateral convective mixing; pendelluft (asynchronous flow among alveoli due to asymmetries in airflow impedance); gas mixing due to velocity profiles that are axially asymmetric (leading to streaming of gas toward the alveoli along the inner wall ofthe airway and the streaming of alveolar gas away from the alveoli along the outer wall); laminar flow with lateral transport by diffusion (Taylor dispersion); and collateral ventilation through nonairway connections between neighboring alveoli. From [19] with permission

Fredberg [13] postulated that the combination of Taylor dispersion and molecular diffusion accounts for almost all gas transport during HFOV. Spontaneous gas particle mixing arising from Brownian motion contributes to gas diffusion in the respiratory tract. In the alveolar region, gas velocities approximate zero as a result of the very high total cross-sectional area. In this zone, gas mixing occurs by molecular diffusion, with net gas transport best described by Fick's law [13, 17]. In addition, time-constant inequalities may generate bulk convective currents recirculating gas between peripheral lung units (pendelluft) [19, 23]. Pendelluft is mainly determined by asymmetries in inertia and compliance of peripheral airways and lung units [24]. Lastly, the transmission of the cardiac oscillations to the peripheral lung units may further promote peripheral gas mixing by generating gas flow among neighboring units [25].

High Frequency Oscillation for Acute Respiratory Failure in Adults

Mechanics of Ventilation and HFOV settings Apart from molecular diffusion, all HFOV gas transport mechanism s are dependent on convective fluid motion [26). Thus, the efficiency of HFOV is also dependent on the impedance of the combined ventilator circuit, endotracheal or tracheostomy tube, and respiratory system. Impedance encompasses elastance, resistance, and inertia. As impedance increases, higher peak-to-trough pressure excursions above and below mean airway pressure are required to generate flow and volume delivery to the lung parenchyma. As driving pressure differences also generate lung parenchymal stress [1,2], the major goal of a lung-protective HFOV strategy would be adequate gas transport with low tidal volumes while avoiding pressures that either overdistend (risk of barotrauma) or cause airway closure and alveolar collapse (risk of atelectrauma) (17). Decrease in Mean Airway Pressure Along Artificial Airways.

Simulations using a previously published theoretical model (27) showed that for any given tidal volume, the decrease in mean airway pressure between airway opening and alveoli increases with increasing frequency and with decreasing tracheal tube diameter (17) . Clinical measurements in anesthetized patients with acute lung injury (ALI) showed decreases in mean airway pressure of 3- 4 cmf-l.O along tracheostomy tubes of 9.0 mm internal diameter (28). Additional measurements performed in a recently completed clinical trial (CliniclTrials.gov identifier : NCT00416260) revealed decreases in mean airway pressure of 6- 7 cmH20 along endotracheal tubes of 8.0 mm internal diameter (Mentzelopoulos et al, unpublished observations). HFOV Settings

Setting the inspiratory time to 33 %, results in a decrease in mean airway pressure as a result of the flow-dependent tracheal tube resistance. This decrease in mean airway pressure can be significantly reduced by using an inspiratory time of 50 % (29). Frequency settings are a major determinant of tidal volume, with higher frequencies resulting in decreased volumes, ventilation efficiency, and magnitude of alveolar pressure swings [15, 17). In adults, employed frequencies usually range within 3-7 Hz [28, 30-32). Recently, titration of initial frequency settings to arterial pH has been recommended (33). Frequency selection should minimize lung parenchymal stress, without compromising ventilation efficiency. The latter is likely to occur slightly below the resonant frequency near the corner frequency of the lung [26]. LlP settings should also be targeted to achieve adequate ventilation , without causing transm ission of excessive oscillatory pressure swings to distal alveoli (9). This may be achieved by placing an endotracheal tube cuff leak. The cuff leak facilitates COz washout around the cuff, increases tidal volume delivery through the endotracheal tube, and reduces distal pressure and volume swings, even when mean airway pressure is restored to its baseline preleak setting [9]. Bias flow settings may range within 30-40 l/min [28,33). Lastly, and most importantly, the mean airway pressure setting should also be targeted to the best possible oxygenation index (calculated as 100 x mean airway pressure x [inspired Oz fraction (FiOz») / PaOz). A recent roundtable recommendation [33], comprises the use of specific combinations of FiOz (range, 0.4-1.0) and mean airway pressure (range, 22-45 cmHzO); however, the

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1600

1400

1400

~ 1200

~1 200

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OJ

E 1000

E 1000

:::J

(3

> c

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E

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400 200

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00

800 600 400 200

·~ I

I

Iii

I

I

5 10 15 20 25 30 35 40 45 50 55 Airway pressure (em H20 )

b

o -~"r=-r-r-r-.--.--.---.---.--..,--, 0

5 10 15 20 25 30 35 40 45 50 55 Airway pressure (emH20)

Fig. 3. Average inspiratory and expiratory pressure volume curves obtained before the initiation of highfrequency oscillation. a: First study period; b: Second study period. Bars represent standard error. PMC: point of maximal curvature of the expiratory pressure volume curve (mean ± standard error) used for the setting of mean airway pressure during high-frequency oscillation. From [28] with permission

usefulness of this ARDSnet-like protocol remains to be validated. A previously reported, arbitrary mean airway pressure setting was 5 cmH20 above the mean airway pressure of the pre-HFOV conventional mechanical ventilation [32]. In a recent study, on HFOV initiation, we set mean airway pressure at 1 cmH2 0 above the point of maximal curvature of the expiratory pressu re-volume curve ( Fig. 3) after performing a recruitment maneuver [28]; the point of maximal curvature is considered a reliable marker of the onset of expirator y derecruitment and aeration loss [34]. This combination resulted in rapid and augmented oxygenation improvement relative to the study of Derdak et al [32]. The protocolized use of recruitment maneuvers to maximize the HFOV-related oxygenation benefit has recently been advocated by others as well [31,33]. Lastly, we wish to note that another physiologically sound initial mean airway pressure setting would be to target mean airway pressure to a mean tracheal pressure (which is usually 3- 7 cmH20 lower than the actually set mean airway pressure) equal to or slightly higher than the point of maximal curvature change of the expiratory pressure volume-curve .

Respiratory Mechanics ARDS is characterized by a poorly compliant lung and respiratory system (usual respiratory compliance range, 20-40 mllcmH 20) [8,28]. The ARDS lung is inhomogeneously inflamed and damaged. During conventional mechanical ventilation , ventilation distribution is determined by the accentuated inequality in regional lung compliance, inevitably resulting in heterogeneous regional expansion and ventilation [17]. As ventilation frequency approaches the resonance frequency of the lung parenchyma, gas transport becomes less dependent on regional lung compliance [35], and increasingly dependent on the resistive, inert, and branching angle properties of the central airways [17,26,36-38]. During HFOV, compliant alveoli may be spared from excessive oscillatory pressures , with the larger pressure swings being directed to less compliant lung units [27]. ARDS lungs are overdarnped, partly due to the increase in extravascular lung water. In overdamped lungs, minimal addi-

High Frequency Oscillation for Acute Respiratory Failure in Adults

tional damping of oscillatory pressure swings can be achieved above the corner frequency [17, 26]. The corner frequency (fc) is given by the following formula:

fe =

1 / 2rr . RL

•

CL

(2)

where RL = total lung resistance [3], and CL = lung compliance. According to equation (2), as compliance decreases, fc increases. For an ARDS lung with compliance decreased to 1/10th of normal, fc is approximately 3.2 Hz. Consequently, at HFOV frequencies of approximately 3.2 Hz, ventilation homogeneity tends to be maximized [17]. This is in concordance with the current concepts of protective ventilation [3]. Monitoring of Respiratory Mechanical Variables during HFOV

Under certain clinically relevant conditions (e.g., HFOV frequency = 3 Hz, L\P = 90 cmf-l.O), HFOV tidal volume may even reach 6 mllkg ideal body weight [39]. Tidal volumes of this magnitude may limit the lung-protective advantages of HFOV [11]. Thus, volume measurement during HFOV may be useful. Techniques of volume measurement as well as other investigational monitoring modalities are described in detail elsewhere [17, 40].

Evidence Supporting the Clinical Use of HFOV Animal Data

Several animal studies have demonstrated reduced VIU with HFOV. Hamilton et al. [41] assessed oxygenation and lung pathology in rabbits with saline lavage-induced lung injury. HFOV-treated animals had attenuated lung injury as assessed by hyaline membranes. McCulloch et al. [42] ventilated rabbits with HFOV at high and low lung volume and conventional mechanical ventilation at low lung volume. Their results demonstrated that maintenance of an adequately high mean lung volume is critical to minimize VILI, and also emphasized the importance of appropriate lung recruitment during HFOV. Meredith et al. [43] used a premature baboon model and reported that application of HFOV for 24 hours protected animals from VIU as assessed by gas exchange, lung mechanics, morphologic findings, and measurements of platelet-activating factor (PAF) compared with conventional mechanical ventilation . In saline-lavaged adult rabbits, Matsuoka et al. [44] showed a decreased respiratory burst of neutrophil activation, and Imai et al. [45] showed decreased production of PAF and thromboxane A2 with HFOV versus conventional mechanical ventilation . Takata et al. [46] confirmed that just 60 min of HFOV resulted in less tumor necrosis factor (TNF)-a messenger RNA in intra-alveolar cells compared with conventional mechanical ventilation. Finally, von der Hardt et al. [47] used surfactantdepleted piglets and demonstrated that messenger RNA expression of cytokines (interleukin [IL]-I~, IL-6, lL-8, and lL-IO), transforming growth factor (TGF)-I~, endothelin-I, and adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule [ICAM] -I) in lung tissue and IL-8 expression in micro dissected alveolar macrophages were reduced with HFOV versus conventional mechanical ventilation. Notably, these favorable results were not reproduced by Papazian et al. [48] in their recent comparison of prone positioning and HFOV in adult patients with ARDS. Consequently, the important issue of lung inflammation during HFOV versus lungprotective conventional mechanical ventilation warrants further investigation .

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S.D. Mentzelopoulos, C. Roussos, and S.G. Zakynthinos Human Data

A multicenter trial of HFOV versus conventional mechanical ventilation with tradi tional tidal volumes in adult ARDS patients reported a trend toward reduced 3D-day mortality in the HFOV arm (37 % versus 52 % in the conventional mechanical ventilation arm ; p = 0.10). HFOV also resulted in improved oxygenation, whereas the incidence of complications such as barotrauma was similar in the HFOV and conventional mechanical ventilation arms [32]. However, to-date, HFOV has not been compared to lung-protective conventional mechanical ventilation [7,8], with respect to survival. Other studies [28, 30, 31] have also demonstrated both the feasibility and the oxygenation/oxygenation index benefits of HFOV versus conventional mechanical ventilation . Nevertheless, there are still insufficient data for the establishment of guidelines for the use of HFOV in adult patients with ARDS.

Complications during HFOV Pneumothorax

Mehta et al. [30] reported a 21.8 % incidence of pneumothorax in their observational report on 150 HFOV-treated patients. However, Derdak et al. [32] noted only a 9 % incidence of new or worsened air leak in their HFOV arm, which was similar to the air leak incidence (12 %) observed in the conventional mechanical ventilation arm. A similar incidence of gross barotrauma (8 %) was also reported by Ferguson et al. [31]. Notably, during HFOV, development of tension pneumothorax may not cause changes in the displayed mean airway pressure or ~P, with the first indication being hypotension or hypoxemia [9]. Air leaks during HFOV may be minimized by using a lower mean airway pressure and ~P, and higher frequencies and shorter inspiratory times [49]. Obstruction of the Artificial Airway

The incidence of tracheal tube obstruction is similar during HFOV and conventional mechanical ventilation [32]. Tube obstruction may be heralded by an abrupt rise in PaCO z in an otherwise stable patient [9]. Severe hypercapnia can also develop in the presence of supraglottic edema (as occurs in inhalation injuries), despite the placement of a cuff leak [9]. Other Complications

A sudden increase in ~P without change in mean airway pressure may signify endobronchial intubation or increase in airway resistance [9]. A decrease in mean airway pressure without change in ~P may indicate new or worsening air leak [9]. Additional reported complications include increases in central venous and pulmonary artery pressures, combined with decreases in cardiac output [30]. However, the potential hemodynamic perturbations of HFOV have not been consistently confirmed by others [28, 31, 32].

High Frequency Oscillation for Acute Respiratory Failure in Adults

Adjuncts to HFOV Both prone positioning and inhaled mtnc oxide (NO) have been reported to improve oxygenation during HFOV [50). For prone positioning, high vigilance is required for mucous plugs and tracheal tube obstruction. Finally, we have recently shown substantial improvements in oxygenation by superimposing tracheal gas insufflation (TGI) to HFOV (28) (Fig. 4). HFOV-TGI was compared with standard HFOV and lung-protective conventional mechanical ventilation. Besides oxygenation, HFOV-TGI versus standard HFOV improved oxygenation index, and HFOVTGI versus conventional mechanical ventilation improved shunt fraction, and mixed-venous oxygen saturation.

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First study period ~-Second study period-: I Standard HFO preceded HFO-TGI 1 HFO-TGI preceded standard HFO I : in patients nos. 1, 2, 6,8, 9, and 14 : in patients nos. 1,2, 6, 8,9, and 14 :

Fig. 4. Individual values of Pa0 2 inspired oxygen fraction (Fi02) during the two study periods shown in Figure 3. CMV1 : measurement during baseline conventional mechanical ventilation (CMV) obtained within 24 - 30 min before high frequency oscillatory ventilation (HFO)/HFO-tracheal gas insufflation (TGI) initiation. HFO/HFO-TGI measurements were obtained within 54-60 min after HFO/HFO-TGI initiation; CMV-2A and CMV-2B, second and third measurement during CMV obtained within 30-36 min and 150-156 min after HFO discontinuation, respectively. The order of HFO/HFO-TGI is presented for each study period. From [28] with permission.

Conclusion HFOV is a new and promising ventilatory strategy for adult patients with ARDS and severe oxygenation failure. Animal data suggest that HFOV may reduce VILI; however, this issue warrants further elucidation. New randomized controlled trials comparing HFOV with lung-protective conventional mechanical ventilation are needed to determine whether HFOV can offer a survival benefit. Finally, the potential benefits of HFOV adjuncts also deserve further validation.

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S.D. Mentzelopoulos, C. Roussos, and S.G. Zakynthinos References 1. Slutsky AS (1999) Lung injury caused by mechanical ventilation. Chest 116:9S-15S 2. Gattinoni L, Carlesso E, Cadringher P, Valenza F, Vaginelli F, Chiumello D (2003) Physical and biological tr iggers of ventilator-induced lung injury and its prevention. Eur Respir J 22 (suppl 47]:S15-S25 3. Mentzelopoulos SD, Roussos C, Zakynthinos SG (2005) Prone position reduces lung stress and strain in severe acute respiratory distress syndrome Eur Respir J 25:534-544 4. Rouby JJ, Puybasset L, Cluzel P, Richecoeur J, Lu Q, Grenier P, and the CT Scan ARDS Study Group (2000) Regional distribution of gas and tissue in acute respiratory distress syndrome II. Physiological correlations and definition of an ARDS Severity Score. Intensive Care Med 26:1046-1056 5. Gattinoni L, Pesenti A, Avalli L, Rossi F, Bombino M (1987) Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study. Am Rev Respir Dis 136:730-736 6. Hickling KG, Henderson SJ, Jackson R (1990) Low mortality associated with low volume pressure limited ventilation with perm issive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 16: 372-377 7. Amato MB, Barbas CS, Medeiros DM, et al (1998) Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347 - 354 8. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301-1308 9. Derdak S (2003) High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults. Crit Care Med 31 (suppl):S317-S323 10. Brazelton TV, Watson WF, Murphy M, Al-Khandra E, Thompson JE, Arnold JH (2001) Identification of optimal lung volume during high-frequency oscillatory ventilation using respirator y inductive plethysmography. Crit Care Med 29:2349 - 2359 11. Hager DN, Fessler HE, Kaczka DW, et al (2007) Tidal volume delivery during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med 35:1522-1529 12. Imai Y, Slutsky AS (2004) High-frequency oscillatory ventilation and ventilator-induced lung injury. Crit Care Med 33 (suppl):S129-S124 13. Fredberg JJ (1980) Augmented diffusion in the airways can support pulmonary gas exchange. J Appl Physiol 49:446- 448 14. Slutsky AS (1981) Gas mixing by cardiogenic oscillations: a theoret ical quantitative analysis. J Appl PhysioI51:1287-1293 15. Rossing TH, Slutsky AS, Lehr JL, Drinker PA, Kamm R, Drazen JM (1981) Tidal volume and frequency dependence of carbon dioxide elimination by high-frequency ventilation. N Engl J Med 305:1375-1379 16. larger MJ, Kurzweg UH, Banner MJ (1984) Transport of gases in high-frequency ventilation. Crit Care Med 12:708-710 17. Pillow JJ (2005) High frequency oscillatory ventilation: Mechanisms of gas exchange and lung mechanics. Crit Care Med 33 (suppl):S135-S141 18. Spahn DR, Leuthold R, Schmid ER, Niederer PF (1991) Significance of bulk convection during high frequency oscillation. Respir Physiol 84:1- 11 19. Slutsky AS, Drazen JM (2002) Ventilation with small tidal volumes. N Engl J Med 347:630631 20. Scherer PW, Haselton PR (1982) Convective exchange in oscillatory flow through bronchial tree models. J Appl Physiol 53:1023-1033 21. Taylor GI (1954) Diffusion and mass transport in tubes. Proc Phys Soc B 67:857-869 22. Taylor GI (1954) The dispers ion of matter in turbulent flow through a pipe. Proc R Soc Lond A 223:446- 448 23. Lehr JL, Butler JP, Westerman PA, Zats SL, Drazen JM (1985) Photographic measurement of pleural surface motion during lung oscillation. J Appl Physiol 59:623-633 24. High KC, Ultman JS, Karl SR (1991) Mechanically induced pendelluft flow in a model airway bifurcation dur ing high frequency oscillation. J Biomech Eng 113:342-347

High Frequency Oscillation for Acute Respiratory Failure in Adults 25. Slutsky AS (1981) Gas mixing by cardiogenic oscillations: a theoretical quantitative analysis. J Appl Physiol 51:1287- 1293 26. Venegas JG, Fredberg J) (1994) Understanding the pressure cost of ventilation: why does high frequency ventilation work? Crit Care Med 22 (suppl):S49-S57 27. Pillow J), Sly PD, Hantos Z, Bates JH (2002) Dependence of intrapulmonary pressure ampli tudes on respiratory mechanics during high-frequency oscillatory ventilation in preterm lambs. Pediatr Res 52:538- 544 28. Mentzelopoulos SD, Roussos C, Koutsoukou A, et al (2007) Acute effects of combined highfrequency oscillation and tracheal gas insufflation in severe acute respiratory distress syndrome. Crit Care Med 35:1500-1508 29. Thome U, Pohlandt F (1998) Effect of the TI/TE ratio on mean intratracheal pressure in high frequency oscillatory ventilation. J Appl Physiol 84:1520-1527 30. Mehta S, Granton J, MacDonald RJ, et al (2004) High -frequency oscillatory ventilation in adults. The Toronto experience. Chest 126:518-527 31. Ferguson N, Chiche JD, Kacmarek RM, et al (2005) Combining high -frequency oscillatory ventilation and recruitment in adults with early acute respiratory distress syndrome: The Treatment with Oscillation and an Open Lung Strategy (TOOLS) Trial pilot study. Crit Care Med 33:479-486 32. Derdak S, Mehta S, Stewart TE, et al (2002) High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults. A randomized controlled trial. Am J Respir Crit Care Med 166:801-808 33. Fessler HE, Derdak S, Ferguson ND, et al (2007) A protocol for high-frequency oscillatory ventilation in adults: Results from a roundable discussion. Crit Care Med 35:1649-1654 34. Albaiceta GM, Taboada F, Parra D, et al (2004) Tomographic study of the inflection points of the pressure-volume curve in acute lung injury. Am J Respir Crit Care Med 170:1066-1072 35. Tsuzaki K, Hales CA, Strieder DJ, Venegas JG (1993) Regional lung mechanics and gas transport in lung s with inhomogenous compliance. J Appl Physiol 75:206-216 36. Allen JL, Frantz ID III, Fredberg J) (1985) Regional alveolar pre ssure during periodic flow. Dual manifestations of gas inertia. J Clin Invest 76:620-629 37. Tsuda A, Kamm R, Fredberg J) (1990) Periodic flow at airway bifurcations. II. Flow partitioning. J Appl Physiol 69:553-561 38. Tsuda A, Fredberg J) (1990) Periodic flow at airway bifurcations. I. Development of steady pressure differences. J Appl Physiol 69:553-561 39. Sedeek KA, Takeuchi M, Suchodolski K, et al (2003) Determinants of tidal volume during high-frequency oscillation. Crit Care Med 31:227-231 40. Hager DN, Fuld M, Kaczka DW, Fessler HE, Brower RG, Simon BA (2006) Four methods of measuring tidal volume during high-frequency oscillatory ventilation. Crit Care Med 2006 34:751-757 41. Hamilton PP, Onayemi A, Smyth JA, et al (1983) Comparison of conventional and high frequency ventilation. J Appl Physiol 55:131-138 42. McCulloch PR, Forkert PG, Froese AB (1988) Lung volume maintenance prevents lung injury during high-frequency ventilation in surfactant-depleted rabbits. Am Rev RespirDis 137:1185-1192 43. Meredith KS, Delemos RA, Coalson J), et al (1989) Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons. J Appl Physiol 66:2150-2158 44. Matsuoka T, Kawano T, Miyasaka K (1994) Role of high-frequency ventilation in surfactantdepleted lung injury as measured by granulocytes. J Appl Physiol 76:539-544 45. Imai Y, Kawano T, Miyasaka K, Takata M, Imai T, Okuyama K (1994) Inflammatory chemical mediators during conventional ventilation and high frequency oscillatory ventilation. Am J Respir Crit Care Med 150:1550-1554 46. Takata M, Abe J, Tanaka H, et al (1997) lntraalveolar expression of tumor necrosis factor alpha gene during conventional and high frequency ventilation. Am J Respir Crit Care Med 156:272- 279 47. von der Hardt K, Kandle r MA, Fink L, et al (2004) High frequency ventilation suppresses inflammatory response in lung tissue and microdissected alveolar macrophages in surfactant depleted piglets . Pediatr Res 55:339-346 48. Papazian L, Gainnier M, Marin V, et al (2005) Comparison of prone positioning and high-Ire-

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S.D. Mentzelopoulos, C. Roussos, and S.G. Zakynthinos quency oscillatory ventilation in patients with acute respiratory distress syndrome. Crit Care Med 33:2162-2171 49. Ellsbury DL, Klein JM, Segar JL (2002) Optimalization of high-frequency oscillatory ventilation for the treatment of experimental pneumothorax. Crit Care Med 30:1131-1135 50. Varkul MD, Stewart TE, Lapinsky SE, Ferguson ND, Mehta S (2001) Successful use of combined high-frequency oscillatory ventilation, inhaled nitric oxide, and prone positioning in the acute respiratory distress syndrome. Anesthesiology 95:797 - 799

301

Airway Pressure Release Ventilation: Promises and Potentials for Concern J.

GUTIERREZ MEJfA,

E.

FAN,

and N.D.

FERGUSON

Introduction Mechanical ventilation is one of the most common interventions used in the intensive care unit (leU); it is a life-saving procedure and a cornerstone in supporting a wide variety of patients from those going through elective surgery procedures to patients with life-threatening processes such as severe sepsis or acute respiratory distress syndrome (ARDS) [1]. Initially conceived as supportive treatment for patients with complications of poliomyelitis but without parenchymal lung disease, positive-pressure mechanical ventilation has evolved over the years due to our expanding knowledge of respiratory physiology, and to advances in ventilator design which allow faster responses to the requirements of each patient. There is no one universal mode of ventilation that can be considered to be the best option for all patients. Generally speaking, how a ventilator mode is employed has been more important than which mode has been selected. This is in keeping with data from the last decade, which convincingly show that mechanical ventilation itself can induce or worsen lung damage [2-4] . Thus, our goals for mechanical ventilation have changed significantly over this time period - from (normalizing' arterial blood gas values, to strategies aimed at minimizing ventilator-associated lung injury (VALl) while maintaining adequate gas exchange. In this chapter, we will discuss airway pressure release ventilation (APRV), a mode of ventilation that has received increasing interest in recent years for the management of ARDS. In order to understand the context in which APRV might be beneficial for the ventilatory management of patients with ARDS, we must first discuss the principles of VALl and its prevention, and then judge how well APRV addresses these principles.

Ventilator-Associated Lung Injury (VAll) Ventilator-induced lung injury (VILI) was originally defined as lung injury that was

directly induced by mechanical ventilation in animal models. VILI was first appreciated when large tidal volumes gave rise to pulmonary lesions that were histologically identical to those seen in patients with ARDS [5-7] , namely diffuse alveolar damage [8]. This injury is heterogeneously distributed throughout the lung, resulting in pulmonary edema and amplification of local inflammatory cells and mediators, with eventual decompartmentalization and release into the systemic circulation [9]. In ventilated patients, it is impossible to distinguish between ARDS and VILI, which is why another term was proposed to denote this association. Thus, ventilator-associated lung injury (VALl) is considered lung injury that resembles ARDS, occurring in

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J. Gutierrez Mejia, E. Fan, and N.D. Ferguson

mechanical ventilated patients and which is indistinguishable from the pre-existing lung injury [3). One of the first recognized injurious lesions related to mechanical ventilation was high airway pressures producing gross barotrauma, characterized by leakage of air from the alveoli to the interstitium producing different clinical scenarios such as pneumothorax, pneumomediastinum, pneumoperitoneum, and subcutaneous emphysema [10). However, in terms of producing or worsening lung injury, VAll is now recognized to occur through several mechanisms, including tidal overdistention (volutrauma) [7) and cyclic alveolar collapse-reopening (atelectrauma) [11, 12), both of which can lead to biotrauma [4, 13), the induction of local and systemic inflammatory responses. Volutrauma arises when high tidal volume ventilation induces release of proinflammatory cytokines [6, 14) due to mechanotransduction - the conversion of cell deformation to inflammatory cell signaling. The exact mechanisms of this relationship are complex and are still the subject of ongoing study, but the process of injury may be related to the increasing phosphorylation of l-kappa B (lKB) and translocation of nuclear factor-kappa B (NF-KB) to the nucleus independently of the Toll-like (TLR)-4 receptor [15). The latter observation suggests that the mechanism of the inflammatory response is different from that used for innate immunity, and may provide an opportunity for new therapeutic targets to minimize VAll [16). Atelectrauma is a complex phenomenon thought to be a consequence of shear stress induced injury in relation to unstable alveoli being recruited and derecruited with each tidal breath [12, 17). Vascular perfusion pressure may also be an important factor in VAll, where increased microvascular pressures may produce capillary stress and facilitate bacterial translocation with a subsequent systemic response [18). These inflammatory components released locally in the lung as a result of volutrauma and atelectrauma have relevant systemic effects that are described as biotrauma [4). In both animal models and human studies, the specific ventilation strategy employed has been shown to affect systemic inflammation and even cell turnover in distant organs [9, 19). In ARDS patients, the heterogeneity of the existing lung injury predisposes the lung to further injury through exposure to mechanical forces not typically encountered in the normal lung. These forces include tensile strain (stretch) from overdistention and interdependence, and shear stress due to the movement of air and fluid during tidal ventilation [15). A reduced functional residual volume for the lung as a consequence of this inhomogeneous distribution of damage is expressed in the 'baby lung' lung concept [20). These patients are predisposed to overdistention injury because the small, more compliant, aerated portion of the lung receives the bulk of the tidal volume. In addition, atelectrauma is more likely to occur because some alveoli are collapsed or fluid-filled at the end of the exhalation, but are re-expanded at the end of inhalation, only to collapse again on the subsequent exhalation. Furthermore, volutrauma and atelectrauma can interact [5). Indeed, it is possible that treatments to limit atelectrauma such as increases in positive end-expiratory pressure (PEEP) also function to reduce volutrauma through lung volume recruitment and increases in the size of the 'baby lung'. Given this knowledge on the mechanisms of VAll, we can now better appreciate that any mode of ventilation that we are using to treat patients with ARDS (and potentially those at risk for ARDS) should be employed in such a way as to minimize these factors. Specifically, key attributes of a lung protective ventilation strategy would include: (1) the ability to limit tidal overdistention (e.g., low tidal volume ven-

Airway Pressure Release Ventilation: Promises and Potentials for Concern

tilation [21]); (2) lung recruitment to maximize the size of the 'baby lung' (e.g., with sustained inflations and recru itment maneuvers [22]); and (3) minimizing cyclic collapse and reopening (e.g., by employing adequate levels of PEEP [23]).

ARDS: Clinical Experience The incidence of ARDS has been estimated to be as high as 70 cases per 100,000 population per year [24]. This syndrome is characterized by the formation of protein rich pulmonary edema , hyaline membranes, and the influx of neutrophils into the air space [25]. Though it results in a clinical process dom inated by the appearance of hypoxemia, mortality is strongly associated with the presence of the multiorgan dysfunction syndrome [26]. ARDS has been defined by convention as the acute onset of bilateral infiltrates on a frontal chest radiograph, the absence of left atria hypertension (pulmonary-capillary wedge pressure :s 18 mmHg or less, if measured), and a decrease in the Pa0 2/Fi02 ratio :s 200 mmHg [27]. Since the original case series in which ARDS was first described in 1967, the only intervention that has been shown to produce a survival advantage in these patients is lung-protective ventilation strategies [21, 23, 28]. In the largest of these studies, the ARDS Network ventilation protocol, using 6 mllkg predicted body weight (PBW) and a plateau airway pressure limit :s 30 cmH 20 , led to a 9 % absolute mortality reduction [21]. The benefits of higher PEEP are not so clear; different results have been observed in diverse trials, and further research is needed in this area [28, 29]. What is clear, however, is that we have not yet determined the optimal mode or ventilation strategy for treating patients with ARDS. In addition to the conventional ventilation strategies discussed above, novel modes of ventilation, such as high-frequency oscillation (HFO) and APRV, have received greater scrutiny as alternative lung protective strategie s for treating ARDS and minimizing VALL

Airway Pressure Release Ventilation: The Basics APRV was originally proposed in 1987 as a strategy to treat lung injured patients who required continuous positive airway pressure (CPAP) and mechanical ventilatory support, with the purported benefits of not depressing cardiac output or increasing airway pressure (Paw) excessively [30]. APRV is a time-triggered, pressure-limited, and time-cycled mode of ventilation , in which spontaneous breathing is allowed at any point during the ventilatory cycle [31]. Conceptually it can be considered as two levels of CPAP - the majority of time is spent at high CPAP, with intermittent releases to the low CPAP being used to facilitate ventilation . The following terminology is typically employed to discuss and describe APRV: • Pressure High (Phigh, PI) : Baseline airway pressure level, which is the higher of the 2 pressures . This parameter is set with the goal of improving oxygenation. • Pressure Low (Plow> P2): The pressure set to deliver the release volume; can be set at O. The setting of this parameter has the goal of facilitating ventilation or CO2 clearance. • Time High (Thigh): Length of time for which Phigh is maintained. • Time Low (T1ow) : Length of time for which Plow is maintained.

303

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J. Gutierrez Mejia, E. Fan, and N.D. Ferguson

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Typically, Thigh is considerably longer than T1ow ; usually the former is set between 4- 6 seconds, with T10w being less than 1 second. This provides for 10- 12 release breaths per minute to aid in ventilation, but maintains a relatively high mean airway pressure throughout the respiratory cycle (Fig. 1). In this fashion, in the apneic patient (e.g., with neuromuscular blockade), APRV is indistinguishable from pressure-controlled inverse ratio ventilation. Indeed, it is this inverse inspiratory:expiratory (I:E) ratio that distinguishes APRV from bi-level positive airway pressure (BiPAP), which similarly uses 2 levels of CPAP and allows spontaneous breathing throughout this cycle, but typically employs a 1:1 I:E ratio [32].

Indications and Settings of APRV for Practical Use Because the vast majority of patients receiving mechanical ventilatory support can be adequately oxygenated and ventilated with conventional modes of ventilation, we typically reserve APRV for use in patients with significant hypoxemic respiratory

Airway Pressure Release Ventilation: Promises and Potentials for Concern

failure (e.g., severe ARDS). Our usu al indications include the ne ed for a FiO z of at least 0.6, along with a PEEP of 15 or a peak inspiratory pressure above 30 cmH zO. In addition, because of potential con cerns regarding gas trapping during the short relea ses we are somewha t ret icent about using thi s mode in patients with severe asthma or chronic obstructive pulmonary disease (COPD). Following transit ion to APRV, we attempt to allow spontaneous breathing within 24 hours of initiation, titrating seda tion to th e 'awake, calm, cooper ative' patient (i.e., Seda tion Agitation Scale [SAS] 3 - 4). We have develop ed a protocol for APRV use at our institution adapted from recommendations from recent review articles [31, 33]. Our initial settings on tr an sition from conventional sett ings typically include: • Phigh = plateau pressure on conventional ventilator or 30 cmrl-O, whi chever is lower • Plow = 10 cmll-O • T high = 4- 6 seconds • T low = 1 second • EiO, = 1.0 or 0.2 greater than on con ventional ventilation (for safet y during initial transition and adjustments)

In order to optimize oxygenation following initiation, we adjust mean airway pressure by increasing Phigh (usually to a maximum of 35 cmH zO) or Thigh (to a m aximum of 10 seconds) . Increasing Phigh recruits lung units with higher critical opening pressures [22], wh ile increasing T high enhances gas mixing and recruits lung un its with high resistance time constants. In addition, we attempt to optimize end-expiratory lung volume by in cre asing Plow in order to prevent de-recruitment with each relea se. As the lung is progressively recruited, release volumes typically increase. We therefore also make adjustments to Plowto achieve relea se volum es of approximately 6 - 8 mllkg PBW. After making these pressure adjustments as required, we wean FiOz as tolerated. In cases where th er e is inadequate ventilation and subsequent respiratory acido sis, we first assess for over -sedation and again attempt to titrate to a sedation level to th e 'awake, calm, co oper ative' patient in order to allow spontaneous breathing. We subsequently adjust T10w to allow for complete expiration (i.e., end-expiratory flow decays to 0) and examine the patient for evidence of decreased compliance (abdomen, chest wall, and pleural space) and con sider maneuvers to treat the se if present. If the patient continues to have hyp erc apnia in spite of these maneuvers, depending on the clinical situation, we would either accept permissive hypercapnia or increase Phigh and/or decrease Thigh to increase alveolar ventilation. While cons istent with so me protocols [34,35] , our approach to APRV is contrary to advi ce fro m other experts who suggest routinely sett ing Plow = 0 and adjusting Tlow su ch that end-expiratory flow d oes not reach 0, thereby using autoPEEP to prevent de-re cruitment with relea se breath s [31]. While thi s latter approach would ma ximize expiratory flow rates during releases, we have concerns that this may inappropriately prioritize COz clearance over the principles of lung protection. First, titrating Tlow to maintain autoPEEP would require frequent adjustments to ensure that changes in resist anc e and compliance over time had not inadvertently led to a loss of autoPEEP. Furthermore, in contrast to extrinsic PEEP (or Plow), autoPEEP is not uniformly distributed. Due to the heterogeneity of lung injury in ARDS patients, lung un its th at are particularly prone to collapse will do so, even while others are still open and providing ongoing expiratory flow. Finally, the use of a Plow of 0 may

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J. Gutierrez Mejia, E. Fan, and N.D. Ferguson

result in release volumes that are large (> 11 in some cases), and significantly greater than usually recommended tidal volumes of around 6 mllkg PBW. It has been argued that because these result from a release of pressure, rather than delivery of positive inspiratory pressure, that they may be safer in terms of the risk for volutrauma (31). However, we remain concerned about these large tidal changes in alveolar distention, especially since immediately following a release volume, the lung is re-inflated to Phigh, which is presumably the result of the immediate return of the majority of the release volume to the patient. Consistent with the philosophy of attempting to regulate release volumes, we wean APRV by simultaneously reducing both Phigh and Plow to maintain a release volume of 6- 8 mllkg PBW. At the same time, we gradually decrease Thigh in order to gradually reduce mean airway pressure and increase the contribution of spontaneous breathing to total minute ventilation. We typically transition to pressure support ventilation when Fi0 2 < 0.4 with Phigh = 10-15 and Plow = 5 cmH 20.

Airway Pressure Release Ventilation: Clinical Data, Advantages, Disadvantages Despite the availability of this mode on many modern critical care ventilators, data on the clinical outcome of patients receiving APRV are limited. To our knowledge there are no large randomized controlled trials that have examined the effect of APRV on mortality in patients with ARDS, and a search of www.clinicaltrials.gov at the time of writing does not return any such studies as ongoing or planned. Numerous small studies have been conducted (summarized in (31)) that demonstrate that APRV is effective in improving or maintaining gas exchange in a variety of populations . In terms of randomized trials, one small study (n = 30) is frequently cited as showing a reduction in duration of ventilat ion with APRV versus pressure-controlled ventilation (PCV) in trauma patients with ARDS. However, this comparison is significantly confounded by the fact that the control group received paralysis for their 3 days of PCV, then by design crossed over to APRV (34). Another recent trial (n = 58) compared APRV with synchronized intermittent mandatory ventilation plus pressure support, but failed to demonstrate differences in either mortality or ventilator-free days (36). The main putative advantages of APRV are its ability to safely deliver a high mean airway pressure, thereby recruiting the lung and improving oxygenation, and above all its ability to allow for the maintenance of spontaneous breathing. Spontaneous breathing during mechanical ventilation may have several theoretical advantages. First, because there is no issue of synchrony with the ventilator (since patients can initiate spontaneous breaths at any time during the ventilatory cycle), patients may require less sedation-analgesia and/or neuromuscular blockade, which may lead to a reduction in duration in ventilation. However, while some studies have shown a reduction in sedation requirements, this has not been a universal finding [37, 38). In addition to effects on sedation-analgesia, reductions in pleural pressure generated by diaphragmatic movement may also be useful in improving hemodynamics, with increased venous return and subsequent improvements in splanchnic and renal blood flow during APRV with spontaneous breathing [35, 39). The ongoing diaphragmatic contraction may also serve as a more efficient way of acquiring tidal volume, with the pattern of diaphragm displacement favoring dependent regions and improving ventilation-perfusion matching (40). This may facilitate improved oxy-

Airway Pressure Release Ventilation: Promises and Potentials for Concern

genation with lower applied airway pressures as compared with conventional vent ilation. On the other hand, this may paradoxically play an adverse role in the pat ient with severe ARDS. If high Phigh levels are required for oxygenation, significant spontaneous effort s could lower pleural pressures and , therefore, raise transpulmonary pressure s to potentially dangerous levels. This could contribute to further volutraum a in an occult fashion , since transpulmonary pressures are not measured routinely. This consideration, along with the potentials for large release volumes and for cyclic derecru itment with releases, makes us concerne d that the lung-protective potential of APRV is questionable, part icularly in the sickest patients , who are in most need of lung-protective ventilati on.

Conclusion At the present time , there are few clinical data to support the routine use of APRV in the management of patients with ARDS. While it has many potential benefits, including improved hemodynamics and reduced sedation-analgesia requirements, recent studies have report ed conflicting results which require confirmation in futur e studies. In addition, the relative ben efits of spontaneous breathing versus the lungprote ctive effects of APRV (or lack thereof) are unknown. Large clinical trial s are needed to explore the potentially salutary effects of APRV on important clinical and patient-centered outcom es in patients with ARDS. References 1. Esteban A, Anzueto A, Frutos F, et al (2002) Characteristics and outcomes in adult patients receiving mechan ical ventilation. A 28-day international study. JAMA 287:345- 355 2. Haitsma 11 (2007) Physiology of mechani cal ventilation. Crit Care Clin 23:117- 134 3. Pinhu L, Whitehead T, Evans T, Griffiths M (2003) Vent ilator-associated lung injury. Lancet 361:332-340 4. Tremblay LN, Slutsky AS (2006) Ventilator-induced lung injury : from the bench to the bedside. Intensive Care Med 32:24 - 33 5. Webb HH, Tiern ey DF (1974) Exper imental pulm onar y edema due to intermittent positive pressure ventilation with high inflation pressure s. Protection by positive end -expirat or y pressure. Am Rev Respir Dis 110:556- 565 6. Dreyfuss D, Soler P, Basset G, Saumon G (1988) High inflation pressure pulmonary edem a. Respective effects of high airway pressure, high tid al volume, and positive end-expirator y pressure. Am Rev Respir Dis 137:1159-11 64 7. Dreyfuss D, Saumon G (1998) Ventilator -induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med 157:294 - 323 8. Katzenstein AL, Bloor CM, Leibow AA (1976) Diffuse alveolar dama ge - the role of oxygen, shock, and related factor s. A review. Am J Pathol 85:209- 228 9. Ranieri VM, Suter PM, Tortor ella C, et al (1999) Effect of mechan ical ventilation on inflammator y mediators in patients with acute respiratory distress syndrome: a randomized controlled tr ial. JAMA 282:54-6 1 10. Weg JG, Anzueto A, Balk RA, et al (1998) The relation of pneumothorax and other air leaks to mortality in the acute respiratory distr ess syndrome. N Engl J Med 338:34I - 346 11. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 99:944-952 12. Slutsky AS (1999) Lung injury caused by mechanical ventilation. Chest 116:9S-15S 13. Tremblay LN, Slutsky AS (1998) Ventilation-induced lung injury: from barotrauma to biotraum a. Proc Assoc Am Phys 110:482-488

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J. Gutierrez Mejia, E. Fan, and N.D. Ferguson 14. Schultz MJ, Haitsma JJ, Slutsky AS, Gajic 0 (2007) What tidal volumes should be used in patients without acute lung injury? Anesthesiology 106:1226-1231 15. Frank J, Matthay M (2003) Science review: Mechanisms of ventilator-induced injury. Crit Care 7:233-241 16. Held HD, Boettcher S, Hamann L, Uhlig S (2001) Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. Am J Respir Crit Care Med 163:711 -716 17. Nieman G (2006) Can ventilator mode reduce ventilator-induced lung injury? Crit Care Med 34:565-566 18. Marini J, Hotchkiss J, Broccard A (2003) Bench-to-bedside review: Microvascular and airspace linkage in ventilator-induced lung injury. Crit Care 7:435-444 19. Imai Y, Parodo J, Kajikawa 0 , et al (2003) Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289:2104-2112 20. Gattinoni L, Pesenti A (2005) The concept of "baby lung". Intensive Care Med 31:776-784 21. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301-1308 22. Borges JB, Okamoto VN, Matos GFJ,et al (2006) Reversibility oflung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med 174:268-278 23. Amato MB, Barbas CS, Medeiros DM, et al (1998) Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347 - 354 24. Rubenfeld GD, Caldwell E, Peabody E, et al (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353:1685-1693 25. Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342: 1334-1349 26. Vincent JL, Zambon M (2006) Why do patients who have acute lung injury/acute respiratory distress syndrome die from multiple organ dysfunction syndrome? Implications for management. Clin Chest Med 27:725 -731 27. Bernard GR, Artigas A, Brigham KL, et al (1994) The American-European Consensus Conference on ARDS. Definitions, mechan isms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818 -824 28. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A (2006) A high positive end-expiratory pressure , low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 34:1311-1318 29. The National Heart Lung and Blood Institute ARDS Clinical Trials Network (2004) Mechanical ventilation with higher versus lower positive end-expiratory pressures in patients with acute lung injury and the acute respiratory distress syndrome. N Engl J Med 351:327-336 30. Stock MC, Downs JB, Frolicher DA, Stock MC, Downs JB, Frolicher DA (1987) Airway pressure release ventilation . Crit Care Med 15:462 -466 31. Habashi NMM (2005) Other approaches to open-lung ventilation : Airway pressure release ventilation. Crit Care Med 33 (suppl 3):S228-240 32. Rose L (2006) Advanced modes of mechanical ventilation : Implications for practice . AACN Adv Crit Care 17:145-158 33. Putensen C, Muders T, Varelmann D, Wrigge H (2006) The impact of spontaneous breathing during mechanical ventilation . Curr Opin Crit Care 12:13-18 34. Putensen C, Zech S, Wrigge H, et al (2001) Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med 164:43-49 35. Putensen C, Wrigge H (2004) Clinical review: biphasic positive airway pressure and airway pressure release ventilation. Crit Care 8:492- 497 36. Varpula T (2004) Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesthesiol Scand 48:722-731 37. Varpula T, Iousela I, Niemi R, Takkunen 0, Pettila V (2003) Combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury. Acta Anaesthesiol Scand 47:516-524 38. Fan E, Mullaly A, Ko M, et al (2007) Airway pressure release ventilation in acute lung injury/ acute respiratory distress syndrome patients . Crit Care 11:180

Airway Pressure Release Ventilation: Promises and Potentials for Concern 39. Kaplan LT, Bailey H, Formosa V (2001) Airway pressure release ventilation increases cardiac performance in patients with acute lung injury/adult respiratory distress syndrome. Crit Care 5:221-226 40. Neumann P, Hedenstierna G (2001) Ventilatory support by continuous positive airway pressure breathing improves gas exchange as compared with partial ventilatory support with airway pressure release ventilation. Anesth Analg 92:950-958 41. Frawley PM (2001) Airway pressure release ventilation: theory and practice. AACN Clin Issues 12:234- 246

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Postoperative Non-invasive Ventilation S. JABER, G.

CHANQUES,

and B. JUNG

Introduction The efficacy of non-invasive ventilation (NIV) was first demonstrated for the treatment of patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) [1,2], followed by a broader use for other kinds of acute respiratory failure of various etiologies including acute cardiogenic pulmonary edema [3], after solid organ transplant [4], and in immunosuppressed hematology patients [5]. NIV therapy is increasingly popular for the treatment of acute respiratory failure as well as for new indications such as postoperative acute respiratory failure [6-8]. This widening of indications has been accompanied by improvement in and development of ventilation techniques by physicians and manufacturers. The place of NIV in postoperative acute respiratory failure is not yet well established. Nevertheless, use of NIV to avoid reintubation or to treat postoperative acute respiratory failure has often been described in observational and/or randomized studies ( Table 1). Major changes in respiratory function occur in all patients after anesthesia and surgical incisions, especially on the thorax and upper abdomen (more so as the site of the surgery approaches the diaphragm), because of a decrease in the functional residual capacity (FRC) with minimal change in the closing volume leading to airway closure during tidal breathing. Indeed, postoperative acute respiratory failure is generally observed after abdominal and/or thoracic surgery. Anesthesia, surgery, and postoperative pain [9] lead to modifications in respiratory function including hypoxemia, reduced lung volumes [10, 11] with a restrictive syndrome combining reduced vital capacity and FRC, as well as diaphragmatic dysfunction [10, 11]. These early and transitory modifications of respiratory function may lead to respiratory failure affecting the 'pump' function (respiratory muscles) as well as the 'exchange' function (lungs) [10-12]. Initially, clinical experience reported in post-surgical patients was limited to the use of positive end-expiratory pressure (PEEP) alone without positive inspiratory pressure support ventilation (PSV), called continuous positive airway pressure (CPAP) [13-16]. Moreover, in these studies [13-16], CPAP was used to prevent acute respiratory failure after surgery (prophylactic use i.e., immediately following extubation) but not to treat acute respiratory failure once it developed (curative use). However, studies of acute respiratory failure in the postoperative setting have shown favorable results for both NIV (i.e., PSV+PEEP) and CPAP ( Table 1). In fact, postoperative NIV can be used in two ways (Fig. 1). The first is a preventive or 'prophylactic' application in order to prevent postoperative acute respiratory failure from developing in patients at risk (elderly, obese, COPD) and the second consists of a 'curative' application, once acute respiratory failure occurs, in order to

Year 1996

2000

2004 1997 2001

2001 1985 1997

2000 2000

Authors

Gust [23]

Matte [26]

Pasquina [27]

Aguilo [29]

Rocco [31]

Auriant [6]

Stock [15]

Joris [32]

Kindgen-Miles [16]

Antonelli [4]

Physiological

Prospective, randomized

Retrospective, Observational

Physiological

Physiological

Physiological

Physiological

Study design

Thoraco-abdominal (liver transplant, renal, lung)

Thoraco-abdominal Prospective, randomized

Prospective, observational

Abdominal Physiological (obese-gastroplasty)

Abdominal (cholecystectomy)

Pulmonary

Pulmonary (transplant)

Pulmonary

Cardiac

Cardiac

Cardiac

Type of surgery

Curative

Curative

Preventive

Preventive

Curative

Curative

Preventive

Preventive

Preventive

Preventive

Indication

1. Main studies using postoperative non-invasive ventilation

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n= 20

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n = 65 2 groups

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n = 21

n = 20 2 groups

n = 150 2 groups

n = 96 3 groups

n = 75 3 groups

Patients

-

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CPAP+10

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1) S6; 2) PSV+8-PEEP+5

1) S6; 2) CPAP+8

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PSV+14-PEEP+5

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1) S6; 2) CPAP; 3) PSV+PEEP

NIV mode

Facial

Nasal

Nasal

Facial

Nasal

Facial

Nasal

Facial

Facial

Facial CPAP Nasal PSV + PEEP

Interface

Intubation and mortality decrease

Oxygenation improvement,

Oxygenation and lung volumes improvement

Atelectasis decrease, FRC improvement

Intubation and mortality decrease

Feasibility, safety. Oxygenation improvement

Oxygenation improvement

Atelectasis decrease

Oxygenation and lung volume improvement

Extravascular lung water decrease

Results

II

IV

IV

IV

IV

IV

IV

IV

IV

Level of evidence

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2005

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n = 209 1) 5B 2 groups 2) CPAP +7.5

n= 72 P5V+14-PEEP+6

1) 5B 2) CPAP+10

Preventive n = 50 2 groups

NIV mode

Indication Patients

Facial and helmet

Facial

Nasal

Interface

level of evidence

Intubation and sepsis decrease

III Feasibility, safety. Oxygenation improvement

Oxygenation improve- III ment, Hospital stay decrease

Results

CPAP: continuous positive airway pressure; P5V: pressure support ventilation; PEEP: positive end-expiratory pressure; SB: spontaneous breathing; FRC: functional residual capacity

Prospective, randomized

Prospective, observational

Abdominal

2005

Jaber [8]

Abdominal

Prospective, randomized

Thoraco-abdominal

2005

Kindgen-Miles [33]

Study design

Type of surgery

Year

Authors

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Postoperative Non-invasive Ventilation

alleviate respiratory failure while avoiding endotracheal intubation, a cause of increased morbidity. This chapter's objectives are to recap on the main respiratory modifications induced by surgery, to justify the use of postoperative NIV, and to present the results obtained with preventive and curative NIV in a surgical context.

Epidemiology NIV was mainly developed in medical intensive care units (ICUs) to treat acute decompensation of COPD [1, 2], and was later used in acute respiratory failure of various medical causes [1, 17]. The main epidemiological data on NIV concern essentially medical patients in validated clinical situations (e.g., COPD) [1, 17]. In 2007, use of NIV in the postoperative period is difficult to estimate. Nevertheless, in a 2003 telephone survey of 60 ICUs in the south of France, 69 % of intensivists declared they used NIV for the first line treatment of postoperative respiratory distress [18]. Moreover, 54 % stated that they used NIV to treat postoperative atelectasis whether associated with acute respiratory failure or not [18]. NIV is usually applied in the ICU area and more recently some authors have reported the feasibility and safety of NIV use in the recovery room after various types of surgery [19-21].

Surgery-induced Respiratory Modifications and Rationale for Postoperative NIV Use Clinical arguments in favor of postoperative NIV are the same as those for using NIV in the post-extubation period as well as for the respiratory modifications caused by surgery. Indeed, anesthesia, surgery (more so as the site of surgery approaches the diaphragm) and postoperative pain lead to modifications of respiratory function. The main modifications observed are reduced lung volumes with a restrictive syndrome. These modifications are maximum in the first hours following surgery and generally regress after one to two weeks [10, 11]. There is also a mod ification in the breathing pattern, with tidal volumes reduced by 20 to 30 % and respiratory rates increased by 20 % in order to maintain adequate alveolar ventilation [10, 11]. These lung volume modifications are often associated with diaphragmatic dysfunction [10, 11,22]. Reduced lung volumes, modified breathing pattern, diaphragm dysfunction, and postoperative pain favor low tidal volume ventilation leading to alveolar hypoventilation and development of increased atelectasis [10, 11, 22]. These modifications favor the development of pneumonia and hypoxemia which seem to be well correlated to a reduction in FRC and explained by an altered ventilation/perfusion ratio. Moreover, hypoxemia frequently observed in the early postoperative period may be aggravated by excessive preoperative vascular loading [23]. As mentioned above, NIV may be considered in order to prevent the risk of respiratory complications by avoiding the development of acute respiratory failure (preventive) or to treat acute respiratory failure to avoid endotracheal intubation (curative) (Fig. 1). The expected benefit of NIV would be to partially compensate for the affected respiratory function by reducing the work of breathing, by improving alveolar ventilation associated with increased gas exchange, and by reducing atelectasis [24] .

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S. Jaber, G. Chanques, and B. Jung Post-operative Noninvasive ventilation (NIV) Curative

/

ARF: yes(present) Objective: to avoid intubation!

/\

CPAP

NIPSV

~

Prophylactic (preventive)

~

ARF: no (not present .. . at risk!) Objective: to avoid the development of ARF

/\

CPAP

NIPSV

Fig. 1.The two strategies for applying non-invasive ventilation in the postoperative period. ARF: acute respiratory failure; (PAP: continuous positive airway pressure; NIPSV: noninvasive pressure support ventilation (PSV+PEEP)

Results Cardiac Surgery Preventive NIV The restrictive syndrome consecutive to cardiac surgery is generally less severe than that observed after thoracic or abdominal surgery [25-27] . However, the incidence of diaphragm dysfunction is higher [28]. Early studies mainly compared CPAP to standard treatment (oxygen + physiotherapy); most reported improved oxygenation and ventilation parameters. None of these studies reported any reduction in the incidence of atelectasis in the groups treated by NIV, mostly CPAP, except for Iousela and colleagues [25]. Gust et al. [23] obtained a reduction in extravascular lung water when NIV was applied with CPAP alone or with bi-level pressure ventilation (PSV+PEEP). Matte et al. [26], in a study including 96 patients, evaluated 'preventive' NIV in the first 2 days following surgery. Various strategies were compared in three randomized groups. The first group received one hour of NIV with two pressure levels every three hours with an average assistance level of 12 cmHzO of PSV and 5 cmHzO of PEEP. The second group received a 1 h session of CPAP at 5 cmHzO every 3 hours and a third group had 20 min of incentive spirometry every 2 hours. Using NIV whether at one or 2 pressure levels permitted improved oxygenation and a lower reduction of lung volumes. However, the incidence of atelectasis was similar (12-15 %) in all three groups [26]. Pasquina et al. [27] compared the effect of systematic application of a 30-min trial of 5 cmHzO CPAP with NIV (PSV 10 cmHzO and PEEP 5 cmfl .O) in two groups of 75 patients. The NIV group had improved radiological scores (meaning less marked atelectasis) on standard chest X-ray. There was no significant difference in oxygenation parameters [27]. Positive effects of preventive NIV on ventilation parameters and gas exchange after cardiac surgery are now well documented. Curative NIV To our knowledge, at the time of writing, no study has been published concerning the effect of curative NIV in patients who have developed acute respiratory failure after cardiac surgery.

Postoperative Non-invasive Ventilation

Thoracic Surgery Preventive NIV In a physiological study, Aguilo et al. [29] studied the effects of a one-hour trial of NIV after pulmonary resection in 10 patients. NIV was applied without any complications due to the technique and allowed improved oxygenation without increasing leaks around thoracic drains in the study group compared to a control group who did not receive NIV [29]. Recently, Perrin et al. [30] reported, in a prospective randomized clinical trial, the benefits of NIV administered pre- and postoperatively. Patients were required to follow standard treatment without (control group, n = 18) or with NIV (study group, n = 14) for 7 days at home before surgery, and for 3 days postoperatively. In this study, two hours after surgery, oxygenation and lung volumes values were significantly better in the NIV group. On days 1, 2 and 3, oxygenation was significantly improved in the NIV group. The hospital stay was significantly longer in the control group than in the NIV group. The incidence of major atelectasis was 14 % in the NIV group and 39 % in the control group. This first prospective randomized study [30] showed that prophylactic use of NIV in a pre- and postoperative manner significantly reduced pulmonary dysfunction after lung resection. Curative NIV In an observational study Rocco et al. [31] described their experience of NIV after lung transplant in 21 patients who developed acute respiratory failure. Tolerance of NIV was good for all patients. Eighteen of the 21 pat ients treated were able to avoid re-intubation [31]. In a prospective randomized study including 24 patients in each group, Auriant et al. [6] showed the efficiency of NIV in acute respiratory failure after lung resection. In this trial [6], NIV was delivered by a nasal mask using a single circuit ventilator and, compared to standard treatment (oxygen + physiotherapy + bronchodilators), reduced the need for invasive mechanical ventilation (21 % vs 50 %) and mortality (13 % vs 38 %).

Abdominal Surgery Preventive NIV Stock et al. [15] showed that applying CPAP to patients having cholecystectomy by laparotomy permitted a significant improvement in the number of cases of atelecta sis compared to treatment by incentive spirometry. After bariatric sugery (gastroplasty) for morbid obesity, loris and colleagues [32] demonstrated a significant reduction in restrictive syndrome and significant improvement in oxygenation evaluated by oximetry (SpOz) with NIV applied for two-thirds of the first postoperative 24 hours. Compared with the control group, forced vital capacity was improved significantly only with a moderately high PSV level of 12 cmll-O, as another group treated with a PSV level of 8 cml-lyO did not have a significant improvement in FRC. This finding remains important today given the sharp increase in the rate of obesity surgery worldwide [32]. Kindgen -Milles et al. [33] studied the effect of systematic CPAP of 10 cmHzO for 12 to 24 hours a day after thoraco-abdominal surgery (aneurysm of thoraco-abdominal aorta). The group of patients (n = 25) receiving CPAP had significantly improved oxygenation and a shorter ICU and hospital stay than the control group (n = 25).

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Curative NIV Patients suffering from postoperative acute respiratory failure have been included among other types of patients in studies evaluating NIV to treat acute respiratory failure of multiple causes [34, 35]. In these studies, no comparison has been made between patients presenting with acute respiratory failure of medical causes and those with postoperative acute respiratory failure, probably because of the heterogeneity and small numbers of patients included. Varon et al. [36] reported the feasibility of NIV in postoperative acute respiratory failure in cancer patients (25 digestive, 15 urogenital, 6 lung). Intubation was avoided in 70 % of the included patients in this study [36]. Kindgen-Milles et al. [16], in a non-controlled prospective study, showed that CPAP rapidly improved oxygenation and avoided intubation in 18 of 20 patients treated after abdominal and/or thoracic surgery. In an observational study, Jaber and colleagues [8] reported their experience over a 2-year period using NIV in 72 patients with severe acute respiratory failure after digestive surgery. The patients who benefited from NIV by avoiding intubation were compared with those who needed intubation (failure group). In this prospective trial [8], intubation was avoided in 66 % of patients. The patients in the failure group were more hypoxemic than those in the success group. This study [8] demonstrated the feasibility, good tolerance, and safety of NIV for the treatment of acute respiratory failure after digestive surgery. More severe initial hypoxemia and less improvement in Pa0 2 after NIV were predictive of NIV failure [8]. More recently, in a match-controlled study, Conti et al. [37] compared the efficacy of NIV delivered by a helmet interface (n = 25) and a facial mask (n = 25) in patients with acute respiratory failure after abdominal surgery. These authors reported an NIV success rate of 80 % in the helmet group and of 52 % in the facial mask group [37]. Antonelli et al. [4] showed in a controlled randomized trial that in organ transplant recipients with hypoxemic acute respiratory failure, NIV reduced the rate of intubation, the incidence of fatal complications, and ICU mortality compared with the provision of supplemental oxygenation alone. Among the 40 included patients, 22 patients had a liver transplantation, 10 among the NIV group and 12 among the standard group, with no significant differences in terms of intubation rate or clinical outcomes between the two sub-groups [4]. A recent large Italian study [7] was stopped early due to improvements in intubation related to CPAP therapy in hypoxemic patients after abdominal surgery. This randomized study [7] included 209 patients in two groups: One group received CPAP of 7.5 cmH20 and a control group receiving oxygen via a facial mask. The patients receiving CPAP had significantly lower intubation, pneumonia, and sepsis rates than the control group [7].

Setting, Specificities, and Limits of Postoperative NIV Patient cooperation is crucial to the success of NIV. Patient comfort and interface acceptance may be gained by starting with PEEP alone and then slowly increasing the PSV level once the mask is applied. We recommend starting with a PSV of 3 to 5 cmH20 and increasing in increments of 2 cmH 20 to achieve a 6-8 mllkg expiratory tidal volume, a decrease in the patient's respiratory rate, and a comfort improvement [8, 24, 38, 39]. PEEP is started at 3 to 5 cmH20 and increased as needed to improve oxygenation without adverse hemodynamic effects up to 10 cmH 20 [8, 24, 38, 39]. The insufflation pressure (PSV+PEEP) applied should be

Postoperative Non-invasive Ventilation less than 25 cmfl-O, These setting recommendations are based solely on clinical experience without any form al data to support the superiority of one technique over another [8, 24, 38, 39]. A surgical complication arises in nearly half the cases of acute respiratory failure. Treatment in this case is generally a second intervention and the management of the acute respiratory failure is only a symptomatic treatment. In this case there is no reason to use NIV to avoid intubation as the patient will be intubated in the operating room for general anesthesia. Upper digestive stitching requires great prudence with early postoperative NIV. Historically, NIV was contraindicated for upper digestive anastomoses. In fact, there is a risk of intradigestive air insufflation when high insufflation pressures are applied (PSV+PEEP > 25 cmfl.O) . However, the risk of stitch leakage due to non -optimal NIV settings may be avoided by preferring CPAP over PSV, but the PSV level must be maintained below 6-8 cmrl .O, The presence of a nasogastric tube after digestive surgery may increase leaks around the facial mask during NIV. Some manufacturers have proposed specific devices to limit leaks around the mask with a nasogastric tube . These systems should be evaluated in clinical practice. It is recommended that the gastric tube be kept on a bag rather than in aspiration in order to detect deleterious gastric insufflation. With intragastric air insufflation, the bag will rapidly inflate, indicating that the NIV settings, and eventually the use of NIV itself, need to be re-evaluated. The choice of interface is very important when applying NIV and even more so in the presence of a gastric tube . Indeed, if the patient's morphology and the gastric tube lead to increased leaks, the medical team applying NIV must dispose of several interfaces to trial for each patient in order to choose the one with minimal leakage.

Conclusion Regardless of the presence of complications, thoracic and/or abdominal surgery necessarily and profoundly alters the respiratory system for long periods. Mechanical ventilation through an endotracheal tube may be responsible for extra morbidity (barotraumatic complications, nosocomial pneumonia...). Dur ing the last decade, NIV has proven to be an effective strategy to reduce intubation rates, nosocomial infections, ICU and hospital lengths of stay, morbidity, and mortality in patients with either hypercapnic or non-hypercapnic acute respiratory failure. While benefits of pathophysiological effects of NIV have also been documented in postoperative patients, further trials should now be performed to explore whether each technique (NIV or CPAP alone) can have a favorable impact on the outcome of postoperative patients when applied in a prophylactic or curative indication.

References 1. International Consensus Conferences in Intensive Care Medicine (2001) Noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med 163:283-291 2. Brochard L, Mancebo J, Wysocki M, et al (1995) Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 333:817 - 822 3. Nava S, Carbone G, DiBattista N, et al (2003) Noninvasive ventilation in cardiogenic pulmonary edema. A multicenter randomized trial. Am J Respir Crit Care Med 168:1432-1437 4. Antonelli M, Conti G, Bufi M, et al (2000) Noninvasive ventilation for treatment of acute respi-

ratory failure in patients undergoing solid organ transpantation-a randomized trial. JAMA

283:235 - 241

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S. Jaber, G. Chanques, and B. Jung 5. Hilbert G, Gruson D, Vargas F, (2001) Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 344:481 -487 6. Auriant I, [allot A, Herve P, Cerr ina J, et al (2001) Noninvasive ventilation reduces mortality in acute respiratory failure following lung resection. Am J Respir Crit Care Med 164:12311235 7. Squadrone V, Coha M, Cerutti E, et al (2005) Continuous positive airway pressure for treatment of postoperative hypoxemia : a randomized controlled trial. JAMA 293:589- 595 8. Jaber S, Delay J, Sebbane M, et al (2005) Outcomes of patients with acute respiratory failure after abdominal surgery treated with noninvasive positive-pressure ventilation. Chest 128: 2688-2695 9. Vassilakopoulos T, Mastora Z, Katsaounou P, et al (2000) Contribution of pain to inspiratory muscle dysfunction after upper abdominal surgery: A randomized controlled trial. Am J Respir Crit Care Med 161:1372-1375 10. Dureuil B, Cantineau JP, Desmonts JM (1987) Effects of upper or lower abdominal surgery on diaphragmatic function. Br J Anaesth 59:1230-1235 11. Simonneau G, Vivien A, Sartene R, et al (1983) Diaphragm dysfunct ion induced by upper abdominal surge ry. Role of postoperative pain. Am Rev Respir Dis 128:899- 903 12. Warner M (2000) Preventing postoperative pulmonary complications. The role of the anesthes iologist. Anesthesiology 92:1467-1472 13. Covelli HD, Weled BJ, Beekman JF (1982) Efficacy of continuous positive airway pressure administered by face mask. Chest 81:147-150 14. Duncan SR, Negrin RS, Mihm FG, Guilleminault C, Raffin TA (1987) Nasal cont inuous pos itive airway pressure in atelectasis . Chest 92:621- 624 15. Stock M, Downs J, Gauer P, Alster J, Imrey P (1985) Prevention of postoperative pulmonary complications with CPAP, incentive spirometry, and conservative therapy. Chest 87:151-157 16. Kindgen-Mille s D, Buhl R, Gabriel A, Bohner H, Muller E (2000) Nasal continuous positive airway pressure. A method to avoid endotracheal reintubation in postoperative high-risk patients with severe nonhypercapnic oxygenation failure. Chest 117:1106-1111 17. Carlucci A, Richard J, Wysocki M, Lepage E, Brochard L (2001) Noninvasive versus conventional mechanical ventilation. An epidemiologic survey. Am J Respir Crit Care Med 163: 874-880 18. Chanques G, Jaber S, Delay J, Lefrant J, Perrigault P, Eledjam J (2003) Enquete telephonique sur la pratique postoperatoire de la ventilation non invasive et ses modalites d'application. Ann F Anest Rea 22:879-885 19. Albala M, Ferrigno M (2005) Short-term noninvasive ventilation in the postanesthesia care unit: a case series . J Clin Anesth 17:636- 639 20. Battisti A, Michotte J, Tassaux D, van Gessel E, Iolliet P (2005) Non-invasive ventilation in the recovery room for postoperative respiratory failure: a feasibility study. Swiss Med Wkly 135:339-343 21. Tobias J (2000) Noninvasive ventilation using bilevel positive airway pressure to treat impending respiratory failure in the postanesthesia care unit. J Clin Anesth 12:409-412 22. Ford G, Whitelaw W, Rosenal T, Cruse P, Guenter C (1983) Diaphragm function after upper abdominal surgery in humans. Am Rev Respir Dis 127:431-436 23. Gust R, Gottschalk A, Schmidt H, Bottiger B, Bohrer H, Martin E (1996) Effects of continuous (CPAP) and bi-level positive airway pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting. Intensive Care Med 22:1345- 1350 24. Jaber S, Gallix B, Sebbane M, et al (2005) Noninvasive ventilation improves alveolar recruitment in postoperative patients with acute respiratory failure: a CT-scan study. Intensive Care Med 31:S148 (abst) 25. Iousela I, Rasanen J, Verkkala K, Lamminen A, Makelainen A, Nikki P (1994) Continuous positive airway pressure by mask in patients after coro-nary surgery. Acta Anaesthesiol Scand 38:311-316 26. Matte P, Jacquet M, Vandyck M, Goenen M (2000) Effects of conventional physiotherapy, continuous positive airway pressure and non-invasive ventilatory support with bilevel positive airway pressure after coronary artery bypass grafting. Acta Anaesthesiol Scand 44:75-81 27. Pasquina P, Merlani P, Granier J, Ricou B (2004) Continuous positive airway pressure versus

Postoperative Non-invasive Ventilation

28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.

noninvasive pressure support ventilation to treat atelectasis after cardiac surgery. Anesth Analg 99:1001-1008 Rezaigua S, Iayr C (1996) Prevention des complications respirato ires apres chirurgie abdominale. Ann Fr Anesth Reanim 15:623-646 Aguilo R, Togores B. Pons S. Mateu R, Barbe F, Agusti A (1997) Noninvasive ventilatory support after lung resectional surger y. Chest 112:117 - 121 Perrin C, [ullien V, Venissac N, et al (2007) Prophylactic use of noninvasive ventilation in pat ients undergoing lung resectional surgery. Respir Med 101:1572-1578 Rocco M. Conti G. Antonelli M. et al (2001) Non-invasive pressure suppot ventilation in patients with acute respiratory failure after bilateral lung transplantation. Intensive Care Medicine 27:1622 - 1626 [oris J, Sottiaux T, Chiche J. Desaive C, Lamy M (1997) Effect of bi-level posit ive airway pressure (BiPAP) on the postoperative pulmonary restrictive syndrome in obese patients undergoing gastropl asty. Chest 111:665-670 Kindgen-Milles D. Muller E. Buhl R. et al (2005) Nasal-continuous positive airway pressure reduces pulmonary morbidity and length of hospital stay following thoracoabdominal aortic surgery. Chest 128:821 - 828 Esteban A, Frutos-Vivar F, Ferguson N, et al (2004) Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 350:2452 - 2460 Antonelli M, Conti G, Esquinas A, et al (2007) A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med 35:18-25 Varon J, Walsh G, Fromm RJ (1998) Feasibility of non invasive mechanical ventilation in the treatment of acute respiratory failure in postoperative cancer patients. J Crit Care 13:55- 57 Conti G, Cavaliere F, Costa R, et al (2007) Noninvasive positive pressure ventilation with different interfaces in patients with respiratory failure after abdominal surgery: a match-control study. Respir Care 52:1463 -1471 Jaber S. Chanques G, Matecki S, et al (2002) Comparison of the effects of heat and moisture exchangers and heated humidifiers on ventilation and gas exchange during non invasive ventilation . Intensive Care Med 28:1590- 1594 Jaber S, Chanques G. Sebbane M, et al (2005) Noninvasive positive pressure ventilation in patients with respirato ry failure due to severe acute pancreatitis. Respiration 73:166- 172

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Section VIII

VIII Tracheostomy

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Choice of Tracheostomy Tube: Does One Size Fit All? J.

ORAM

and A.

BODENHAM

Introduction Tracheostomy is performed on intensive care unit (leU) patients to facilitate weaning and pulmonary toilet and to provide airway protection. The introduction of percutaneous techniques has led to the procedure being performed with increasing frequency. Much has been made of methods to improve safety during the procedure yet little attention is paid to the ongoing complications of the presence of tracheostomy tubes in the airway. Inappropriate tube choice can lead to short term complications such as local erosion and cutaneous infection and long term complications such as tracheal stenosis, tracheomalacia, and vascular and esophageal fistulation, and can also contribute to problems such as tube displacement.

Historical Perspective Much is made of the history of tracheostomy as a surgical procedure but less is known of the tubes used . Early descriptions of tracheostomy describe the use of a reed inserted through the stoma, via which the operator could then blow air. Sanctorius (1561-1636) is widely credited with the first trocar and cannula technique. He recommended leaving the cannula in place for a period of two to three days. These early devices consisted of curved silver tubes with multiple fenestrations. Martine (1702- 1743) introduced double lumen tubes, recognizing the need to clean the inner cannula without removing the tube in its entirety. The combination of these two designs was not dissimilar to Jackson's silver tubes from the twentieth century. Cuffs were first applied by Trendelenburg (1802-1872), and these were refined into high volume-low pressure cuffs by Grillo in 1967. Evolution of the tracheostomy tube from these early cannulae has been guided by intended use. For much of its history, tracheostomy has been performed for the relief of airway obstruction. It was not until the poliomyelitis epidemics of the 1950s that tracheostomy was performed to allow mechanical ventilation for prolonged periods. These facts may seem interesting, but essentially irrelevant to modern practice, yet it is history and intended use that has guided the evolution of the tracheostomy tube . The devices we use today have changed little from early designs that were intended for different purposes when prolonged ventilation was not a consideration. It is only recently that designs have developed to reflect current practice.

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Relevant Anatomy and Pathophysiology The trachea consists of a membranous tube supported by a series of cartilaginous rings. These rings are incomplete posteriorly; the posterior membranous portion is suspended between the tips of the c-shaped cartilages. The adult trachea is 12 em in length , with an external diameter of 2.3 em in the coronal plane [1). Each tracheal ring is approximately 4 mm wide, with a 2 mm membranous segment between each ring (2). These measurements are particularly pertinent when considering the external diameter of commonly used tubes (11-13 mm). The female trachea is smaller in both length and diameter. The cross-sectional shape of the trachea varies but is classically ovoid with posterior flattening. With age, the lower trachea becomes flattened laterally and lengthened antero-posteriorly (the 'sabre sheath' trachea). The angle of the trachea to the skin of the anterior neck is variable and changes with age. Similarly the depth of the trachea from the surface varies considerably between individuals. Our own research on an unselected group of adult leu patients undergoing percutaneous tracheostomy demonstrated that the depth of the trachea from the skin was between 18 and 32 mm. The posterior wall of the trachea was between 40 and 56 mm from the skin. The angle of the trachea to the fixation point on the anterior neck was also found to vary between individuals and was found in our study to be between 104-122° (unpublished data). Lesions of the skin, soft tissues, and trachea can be related either to tracheostomy insertion, or the ongoing presence of the tube . Formation of a stoma necessarily causes some degree of tissue disruption. Multiple studies have failed to show a persistent, significant difference in complication rates between surgical and percutaneous techniques , or between the many types of percutaneous technique available. The exception to this is infectious problems, which are generally higher in surgical tracheostomy, thought to be due to the larger skin defect generated in this procedure. Post-insertion problems are more influenced by the ongoing presence of the tra cheostomy than the method of insertion. Two mechanisms of pathogenesis of tracheal lesions have been proposed. 1. Pressure exerted by the tube or cuff on the tissues causes ischemia and tissue

destruction. Application of this theory led to the introduction of high volume-low pressure cuffs [3, 4). 2. Movement of the tube against the tissues will produce erosion of the tissues. This movement may be obvious (e.g., coughing or other patient movement) or it may be microscopic (e.g., movement from the ventilator transmitted through the circuit). Flexible catheter mounts are an important measure in the prevention of erosive lesions (5). After the initial defect has formed bacterial colonization occurs. This may not result in clinically evident infection, but will further limit tissue healing, and in the trachea can lead to softening of the cartilaginous rings (6). Stenosis is due to healing with fibrosis and collagen formation ; contraction of fibrotic tissue then leads to stenosis. This contraction is restricted by the rigid cartilages of the trachea. However if the cartilage has been damaged or softened this effect is limited and significant stenosis can occur (7). Although these effects were originally described for tracheal lesions, it would seem reasonable to assume that similar mechanisms are responsible for any problems occurring in the skin and soft tissues of the neck.

Choice of Tracheostomy Tube: Does One Size Fit All?

Tube Design Considerations Tracheostomy tubes are available in a number of sizes and designs for different intended uses. Figure 1 shows a number of commonly available tubes used in our hospital. Size and shape vary significantly. Materials used in tube construction also vary with some tubes being essentially rigid and others being fully flexible. Tubes are chosen based upon internal diameter in most cases. Less attention is paid to external diameter, length, and angulation, yet all these factors are important in ensuring the correct fit of tube to the patient. Sizing and choice of tracheostomy tubes has been recognized as an issue in pediatric practice for many years. This is due to the more obvious variation in size within the patient population, yet adult patients can also vary significantly; is a size 8.0 mm internal diameter tube suitable for both a 40 kg 80-year old and an obese 40-year old. Tracheal diameter may not change significantly, but the surrounding soft tissues will be significantly different. Ultrasound and other techniques to assess both depth and internal diameter of the trachea have been recommended in children in order to guide choice of tube [8]. Tube Construction

Most modern tubes are plastic and mass produced. Materials used in construction range from polyvinyl chloride (PVC) to the more expensive silicone rubber. These different materials display differing levels of rigidity, from entirely flexible to essentially rigid. Many manufacturers now label their tubes as (thermoplastic' indicating a tendency of the material used to soften at physiological temperatures. This leads

Fig. 1. Seven commonly available tracheostomy tubes. 1. Bivona armored, 2. Portex adjustable flange, 3. Shiley, 4. Tracoetwist, 5. Mallinckrodt Perc, 6. Portex blue-line, 7. Portex Blue-line Ultra. All the tubes in the image are size 8.0 internal diameter (Shiley is Jackson Size 8), yet there are large differences in length and external diameter. Angulation varies between 90 - 115°, and there are also differences in the length of the tube over which the angulation occurs.

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to the tube being more flexible when inserted than when it is outside the body. Whilst this characteristic is appealing it may lead to tube kinking or render the device more liable to external compression. Tubes made of rigid material (usually polyurethane) are still common. These devices can lead to pressure sores around the insertion site and will also transmit more movement from the ventilator circuit to the trachea than a fully flexible device, potentially leading to more erosion than softer tubes which may influence long term complication rates.

Sizing Tube choice has traditionally been made based upon the internal diameter of the tube. This is a reflection of the standards set out in International Standards Organization EN ISO 5366-1:2004. This recommends that tubes are sized according to their functional internal diameter, which may disregard the internal diameter of an inner cannula unless it is required for connection to the ventilator or breathing circuit. In addition to this, some tubes are still sized by the (Chevalier) Jackson system. This focus on internal diameter is convenient but over simplistic, as it neglects dimensions such as length and external diameter, which are both important in ensuring the correct fit. When considering length, tubes should be viewed as having two segments: Intrastomal and intratracheal, these being connected by the angle or curve of the tube (Fig. 2.). These components vary between different tube types and are common sources of poor fit. In the obese, the intrastomal segment can be too short , similarly in any patient not of 'average' height the intratracheal segment can be either too short or too long. Use of a tube with an inadequate intrastomal segment can also lead to the angle of the tube being pulled into the stoma and the lumen opening against the posterior wall of the trachea. Erosion of the stoma by the angle of the tube is a major risk factor for tracheo-innominate fistula formation [9]. The tip of the tube can impinge

Fig. 2. Representation of intrastomal and intratracheal segments of the tube. Intrastomal length can vary significantly with body habitus and neck anatomy. Insertion of a tube with too short an intrastomal segment will result in limited length of the tube within the trachea and compression of the anterior tracheal wall and tissues of the anterior neck between the cuff and the flange.

Choice of Tracheostomy Tube: Does One Size Fit All?

upon the posterior tracheal wall and cause erosions and pressure necrosis which may lead to fistulation into the esophagus [10]. Use of a 'standard' tube in these scenarios can also produce excessive pressure at the skin and can lead to pressure sores at the stoma site or under the flange. This is of particular concern if the flange is relatively rigid. An inadequate intratracheal segment can lead to there being too little of the tube inside the trachea , predisposing to tube dislodgement . Too long an intratracheal segment may lead to endobronchial intubat ion. Some tubes have no straight segment, consisting of a tube which is curved throughout its length. Tubes of this nature may be very difficult to fit accurately. External diameter is necessarily larger than the internal diameter and varies depending on manufacturer and type of tube . The external diameter defines the size of defect made in the anterior tracheal wall which in turn relates directly to the degree of long-term stenosis encountered [11, 12]. External diameter should, there fore, be kept to a minimum resulting in a compromise between adequate internal diameter, and excessive external diameter. Cuff function is also important (see below). The angulation of tracheo stomy tubes is often fixed between 90- 110°. Insertion of a tube with poorly fitting angulation may lead to the tip of the tube opening onto the anterior or posterior tracheal wall, causing obstruction of the tube and potentially leading to erosion of the trachea . It is also worth noting that continuously curved tubes (as opposed to those with a short angulated segment and two straight segments) may enter the trachea tangentially, potentially producing a larger defect in the anterior tracheal wall than tubes which enter the trachea perpendicularly.

Tube Design Features The basic design of a tracheostomy tube is relatively simple, consisting of little more than a plastic tube and flange, a IS mm connector and an inflatable cuff. There are however a number of additional features which are available which may be of value in the intensive care setting. Adjustable flange Adjustable flanged tubes allow tailoring of the length of the intrastornal, and in the case of fully flexible tubes without a fixed angle, the intratracheal, segments of the tube. These are particularly helpful in the obese when a longer intrastomal segment is of use. Double cannula Inner cannulae allow cleaning of the tube lumen without removing the whole tracheostomy tube . In this respect they are very valuable, in particular when dealing with acute obstructions due to secretions in the tube. However, these cannulae all decrease the internal diameter of any given tube. Most of these cannulae reduce the internal diameter by 1- 2 mm, which can have significant effects on work of breathing [13] and which may be relevant in those who are difficult to wean. Flexible/armored Fully flexible tubes are usually armo red to provide circumferential stability. Most currently available devices have no fixed angle, though some have a pre-molded angle of 110°. In conjunction with an adjustable flange these devices allow individu-

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alization of all tube dimensions related to length. Their use has so far been limited by lack of inner cannulae, but newer devices are becoming available with this feature. Double lumen Double lumen tubes designed for single lung ventilation are available, though rarely needed on the lCU. They are particularly useful for very low tracheostomies (transmanubrial) where the bronchial limb provides a degree of stability whilst allowing bilateral ventilation (the intratracheal component of normal tubes would tend to endobronchial positioning in these situations). Oval tubes Cicatricial tracheal stenosis following tracheostomy is more likely when a greater number of tracheal rings are disrupted as fibrotic shrinkage goes unopposed [11, 12]. Recognition of this fact has led to the development of tubes that have an oval cross section, being reduced in diameter in the vertical plane. Theoretically these devices will produce less tracheal ring disruption during insertion and ongoing residence in the airway. A preliminary study shows promising results [14]. Subglottic suction ports The addition of subglottic suction ports to the tube allows aspiration of secretions from above the cuff, and has been associated with reduced incidence of ventilatorassociated pneumonia (VAP) [15, 16]. Unfortunately the use of these devices was shown to produce excessive subglottic stenosis in an animal study [17] and their use cannot be recommended at present. Adaptations to percutaneous insertions Percutaneous tracheostomy requires a close fit between the leading edge of the tube and the dilator upon which it is introduced. This has led to the development of a number of modifications of both the tube and the dilator in order to streamline the tube during insertion. These modifications have little impact on the characteristics of the tubes as discussed above, but has led to tubes being packaged with the introducers. This could lead to operators picking a tube based on internal diameter rather than evaluating the requirements of individual patients.

Cuff Design Through the years there have been a number of attempts to redesign the cuff in an attempt to reduce the incidence of tracheal stenosis. The most successful of these is the high volume-low pressure cuff introduced by Cooper and Grillo [18]. These devices allow the cuff to fill the trachea and produce a seal, without exerting excessive pressure on the tracheal wall. The performance of these tubes may be compromised by over inflation, which will convert them to a traditional high pressure cuff. The most common reason for a tube to be overinflated is use of a device with too small a diameter. High pressure ventilation compresses the cuff from below, and can cause it to distort . The distortion reduces the area of contact between the cuff and the trachea and increases the pressure within the cuff leading to a potentially hazardous situation . Other cuff designs have been proposed including foam filled and 'gilled' cuffs, but none have become popular. 'Tight to shaft' cuffs have a cuff which is flush with the

Choice of Tracheostomy Tube: Does One Size Fit All?

tube when deflated. These tubes are useful when deflation tests are required (such as in laryngeal obstruction) and may have similar characteristics to distensible cuffed tubes. Distensible cuffs have been suggested in order to lim it micro-aspiration [19]. These cuffs exert minimal pressure on the tracheal wall and have recently been packaged with a fully flexible tube with a number of other desirable design features. Clinical trials are awaited.

Assessment of Tube Size and Position It is clearly desirable to insert only one tube, and to have that tube fit perfectly. Unfortunately assessment may be difficult pre-insertion and a number of tubes may need to be tried before the best fitting device is found. It is, however, possible to make some assessment pre -insertion. Physical assessment may, for example, reveal the trachea to be significantly deeper than anticipated (through obesity or other causes). Ultrasound can be used to assess tracheal depth from the skin and can also give an estimate of tracheal diameter. Angle from the skin may also be assessed. Post-insertion assessment of fit is done via bronchoscopy to assess the position of the luminal opening in relation to the center of the trachea, and also via observation of the inserted tracheostomy from above. The tube should lie centrally within the trachea and the cuff should be visible as an annulus around the tube. If the cuff is seen to lie above the tube then the intrastomal portion is too short. The cuff will abut the stoma and a different tube may be needed. Fully flexible tubes with an adjustable flange are ideal in that they can be made to fit most pat ients .

Conclusion The presence of a tracheostomy tube in the airway is associated with significant long-term complications. Some of these complications could potentially be reduced by better selection of tracheostomy tubes and individualization of choices according to factors related to patient size. Much research has gone into defining the ideal method of tracheostomy insertion with no clear answers found. Perhaps it is time to look at the tubes, which may spend weeks in the airway, rather than further dissect the surgical procedure which is over in a matter of minutes? References 1.

Grillo HC, Dignan EF, Miura T (1964) Extensive resection and reconstruction of mediastinal trachea without prosthesis or graft: an anatomical study in man. J Thorac Cardiovasc Surg

48:741- 749 2. Randestad A, Lindholm CE, Fabian P (2000) Dimensions of the cricoid cartilage and the trachea. Laryngoscope 110:1957 - 1961 3. Grillo HC, Cooper JD, Geffin B, Pontoppidan H (1971) A low-pressure cuff for tracheostomy

tubes to minimize tracheal injury A comparative clinical trial. J Thorac Cardiovasc Surg

62:898-907

4. Cooper JD, Grillo HC (1969) The evolution of tracheal injury due to ventilatory assistance through cuffed tubes: a pathologic study. Ann Surg 169:334-348 5. Andrews M, Pearson F (1971) Incidence and pathogenesis of tracheal injury following cuffed

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6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

tracheostomy with assisted ventilation. Analysis of a two year prospective study. Ann Surg 173:249-263 Weymuller EA Ir (1988) Laryngeal injury from prolonged endotracheal intubation. Laryngoscope 98:1-15 Grillo H (2004) Post intubation stenosis. In: Grillo H (ed) Surgery of the Trachea and Bronchi. BC Decker, Hamilton, pp 291- 339 Hardee PSGF, Ng SY, Cashman M (2003) Ultrasound imaging in the preoperative estimation of the size of tracheostomy tube required in specialised operations in children. Br J Oral Maxillofac Surg 41:312-316 Jones JW, Reynolds M, Hewitt RL, Drapanas T (1976) Tracheo-innominate artery erosion: Successful surgical management of a devastating complication. Ann Surg 184:194- 204 Couraud L, Bercovici D, Zanotti L, Clerc P, VellyJF, Dubrez J (1989) Treatment of esophagotracheal fistula following intensive care An experience of 17 cases. Ann Chir 43:677-681 Lindholm C, Grenvik A (1985) Intubation and tracheostomy In: Sprung C, Grenvik A (eds) Invasive Procedures in Critical Care. Churchill Livingstone, New York, pp 94 - 96 Arola MK, Puhakka H, Makela P (1980) Healing of lesions caused by cuffed tracheostomy tubes and their late sequelae; a follow-up study. Acta Anaesthesiol Scand 24:169-177 Cowan T, Op't Holt TB, Gegenheimer C, Izenberg S, Kulkarni P (2001) Effect of inner cannula removal on the work of breathing imposed by tracheostomy tubes: a bench study. Respir Care 46:460- 465 Lindholm CE, Randestad A, Gertzen H (2003) New design of a tracheostomy-cricothyroidostomy tube. Eur Arch Otorhinolaryngol 260:421-424 Gujadhur R, Helme BW, Sanni A, Dunning J (2005) Continuous subglottic suction is effective for prevention of ventilator associated pneumonia. Interact Cardiovasc Thorac Surg 4: 110-115 Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S (2005) Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med 118:11-18 Berra L, De Marchi ML, Panigada M, Yu ZX, Baccarelli A, Kolobow T (2004) Evaluation of continuous aspiration of subglottic secretion in an in vivo study. Crit Care Med 32: 2071-2078 Cooper JD, Grillo HC (1969) Experimental production and prevention of injury due to cuffed tracheal tubes. Surg Gynecol Obst 129:1235-1241 Young PJ, Pakeerathan S, Blunt Me, Subramanya S (2006) A low-volume, low-pressure tra cheal tube cuff reduces pulmonary aspiration. Crit Care Med 34:632- 639

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What's new in Percutaneous Dilational Tracheostomy? T.A. TRESCHAN,

B. PANNEN, and M.

BEIDERLINDEN

Introduction In critically ill patients percutaneous dilational tracheostomy has become the alternative to conventional open surgical tracheostomy. Several competing techniques exist to facilitate percutaneous dilational tracheostomy. Here we summarize current findings on the feasibility and constraints of percutaneous dilational tracheostomy in critically ill patients, regardless of the technique employed.

Percutaneous Dilational Tracheostomy: A Risky Procedure? Some of the general advantages of tracheostomy over translaryngeal intubation are easier airway care, reduced sedative needs, and better weaning [1]. However, percutaneous dilational tracheostomy itself is an elective operation with certain risks. It has been shown that the rate of severe complications of percutaneous dilational tracheostomy is significantly higher during early individual or institutional experiences [2]. Therefore, experience with percutaneous dilational tracheostomy should be gained under the supervision of very experienced staff and at least 20 percutaneous dilational tracheostomies are necessary to obtain relevant familiarity with the procedure [2,3] . Of note, recent reports show that for the very experienced, percutaneous dilational tracheostomy may even offer an option for airway control in emergency situations when orotracheal intubation is impossible [4, 5].

percutaneous Dilational Tracheostomy or Conventional Trachecstomn A systematic review of all randomized clinical trials in critically ill adults compared any method of elective percutaneous dilational tracheostomy to conventional tracheostomy [6]. Outcomes were incidence of wound infections, bleeding, overall mortality, and major peri-operative complications. Wound infections were significantly less frequent after percutaneous dilational tracheostomy with a pooled odds ratio of 0.28 (95 % confidence interval, 0.16 to 0.49, P < 0.0005). Overall, percutaneous dilational tracheostomy was equivalent to conventional tracheostomy for bleeding, major periprocedural and long-term complications. Heikkinen et al. [7] compared the costs and time consumption of percutaneous dilational tracheostomy with that of conventional tracheostomy when both procedures were performed in the intensive care unit (leU). While both techniques did not differ in duration, the mean costs (in US dollars) of percutaneous dilational tracheostomy were significantly lower ($161 (SD,

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T.A. Treschan, B. Pannen, and M. Beiderlinden

10.4; range, $159-$219 versus $357 (SD, $74; range, $239-$599). Thus, percutaneous dilational tracheostomy is a cost effective and safe procedure for critically ill pat ients.

When to Perform Percutaneous Dilational Tracheostomy? In 2001, the American College of Chest Physicians (ACCP) summarized studies on timing of tracheostomy, conventional tracheostomy or percutaneous dilational tracheostomy, as follows: "Because there is such a surprisingly small amount of quality data...recommendations for timing the procedure have been based on expert consensus;' The ACCP recommendation states that "Tracheostomy should be considered after an initial period of stabilization on the ventilator, when it becomes apparent that the patient will require prolonged ventilator assistance" [1]. Since 2001, only one prospective study has specifically addressed the question of early versus late percutaneous dilational tracheostomy [8]. Rumbak et al. found significantly less mortality, pneumonia, accidental extubations, and days on mechanical ventilation and on the ICU in medical patients who underwent percutaneous dilational tracheostomy within 48 hours after the start of mechanical ventilation as compared to percutaneous dilational tracheostomy after 14-16 days. Griffiths et al. [9] reviewed all randomized trials in which patients were prospectively assigned to early versus late tracheostomy (percutaneous dilational tracheostomy and conventional tracheostomy). Early tracheostomy was defined as conducted up to seven days after start of mechanical ventilation. Duration of mechanical ventilation and length of stay in the ICU were significantly lower in the early tracheostomy group. There were no significant differences for mortality or risk of hospital acquired pneumonia between early or late tracheostomies.

Patient Selection for Percutaneous Dilational Tracheostomy To date, percutaneous dilational tracheostomy is recommended as the procedure of choice for critically ill adult patients [10]. However, proper patient selection is mandatory to minimize the risks of the procedure. Recent studies help to specify risk factors and contraindications.

Coagulation Status Coagulation disturbances and anticoagulation requirements are very common in critically ill patients. Therefore, it is important to know the coagulation values for exclusion of patients from percutaneous dilational tracheostomy and for management of patients requiring systemic anticoagulation. Bleeding associated with percutaneous dilational tracheostomy can be divided into acute bleeding during the procedure as opposed to chronic bleeding persisting for more than 24 h after tube placement [2, 11]. This differentiation is of importance because acute bleeding does not relate to coagulation abnormalities and is not a risk factor for chronic bleeding. In contrast, the risk for chronic bleeding after percutaneous dilational tracheostomy is significantly influenced by coagulation variables (Fig. 1). Platelet transfusion is recommended prior to percutaneous dilational tracheostomy in patients with a platelet count of less than 50 x 109 1-1• Fresh frozen plasma

What's new in Percutaneous Dilational Tracheostomy?

Heparin administration

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Cannula size ID 9 mm PT < 50 % of normal value

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----1

•

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4.3; p = 0.03

H41~------t

aPTT > 50s

•3.7; P = 0.04

~t-----.......,

1-1

Platelet count < 50,000 nl'

:1-1 -

• - - - - ----i

.....

5.0; P =0.01

•9.5; P = 0.002

2 or more abnormal coagulation values

+-'-----.----,-:~---.--__._-____r--__._-____r-_____,

o

5

10

15

20

25

30

35

40

Fig. 1. Risk factors for chronic bleeding after percutaneous dilational tracheostomy. X-axis: 95 % confidence intervals, numbers are odds ratio and p-values. PT: prothrombin time; aPIT: activated partial thromboplastin time. Data from [11) with permission

or coagulation factor substitution is suggested in patients with activated partial thromboplastin time (aPTT) > 1.5 times and/or prothrombin time (PT) prolongation > 50 % of the normal value. Critically ill patients often require continuous low-dose heparin administration. Beiderlinden et al. [11] showed that heparin administration without changes in coagulation variables does not increase the risk of bleeding and percutaneous dilational tra cheostomy can be safely performed in such patients. Of note, use of bigger tubes increases the risk of bleeding. Thus, in patients with an increased risk of bleeding due to coagulation disturbances the use of big tubes (> 8 mm) should be avoided [2].

Obesity Byhahn et al. compared the risks for serious complications during percutaneous dilational tracheostomy in obese patients (body mass index > 27.5 kg/m') to control patient s of normal weight. These authors found a significantly higher incidence of peri -operative complications , especially of serious adverse events, in patients with obesity [12]. In patients with morbid obesity (body mass index > 40 kg/rn-) tracheostomy in general is associated with an increased complication frequency and more life-threatening complications [13]. A comparison of percutaneous dilational tracheostomy with conventional tracheostomy in morbidly obese patients revealed similar rates of adverse events for both techniques [14]. Worth mentioning, Watters and Waterhouse [15] performed percutaneous dilational tracheostomy in a 200 kg male patient, requiring an extra long tracheostomy tube. In this case the loading dilator was critically short to be withdrawn after tube placement. Thus, for percutaneous dilational tracheostomy in morbidly obese patients adequacy of equipment is of great importance.

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I.A. lreschan, B. Pannen, and M. Beiderlinden Ventilation with High PEEP Most studies on percutaneous dilational tracheostomy exclude patients ventilated with high positive end-expiratory pressure (PEEP). Some authors even regard severe respiratory failure as a contraindication for percutaneous dilational tracheostomy, because loss of high PEEP during percutaneous dilational tra cheostomy could jeopardize oxygenation, result in alveolar collapse, and worsen the respiratory situation. On the other hand, patients with severe respiratory failure are likely to benefit from all advantages of early tracheostomy, as they are usually mechanically ventilated for long per iods. Beiderlinden et al. [16) studied the consequences of percutaneous dilational tracheostomy on respiratory function in patients with severe respiratory failure. The influence of percutaneous dilational tracheostomy on arterial blood gas tensions in patients ventilated with PEEP> 10 mbar was compared to values from patients with PEEP :s 10 mbar. Percutaneous dilational tracheostomy did not significantly decrease oxygenation in either group. Of even greater interest , the sickest patients had the most benefit from percutaneous dilational tracheostomy. Regardless of the PEEP level, the oxygenation index improved most in those patients with the worst initial respiratory situation (Fig. 2). Therefore, high PEEP should not be considered a general contra indication for percutaneous dilational tracheostomy in experienced hands [16).

Which Neck is Suitable for Percutaneous Dilational Tracheostomy? Anatomical variances of the neck present a major hazard for serious complications during percutaneous dilational tracheostomy, such as hemorrhage or impossible tube placement. To avoid such complications, it is mandatory to carefully asses the patient's neck pr ior to the procedure. Patients with a very short neck, e.g., a markedly reduced cricoid to sternum difference, or a deeply lying, difficult to palpate trachea should be considered inappropriate for percutaneous dilational tra cheostomy. Cases with significantly altered anatomy due to previous surgery or disease, e.g., very large goiter, are also not suitable for percutaneous dilational tracheostomy [17). Patients, who otherwise seem suitable for percutaneous dilational tracheostomy may, however, have anatomical variances of neck vasculature [18). Therefore, it is

300

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100 50 -'---

--r-

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Fig. 2. PaO/Fi02-ratio in 25 % of patients with the lowest initial oxygenation index (lowest quartile) in patients ventilated with high (n = 22, squares) or low positive end-expiratory pressure (PEEP) (n =29, circles) at baseline (open symbols) and 1 and 24 hours after percutaneous dilational tracheostomy (PDT, closed symbols). Means ± standard deviation. *p < 0.05 vs. baseline. From [16] with permission

What's new in Percutaneous Dilational Tracheostomy?

strongly recommended that an ultrasound of the neck be performed in all cases prior to percutaneous dilational tracheostomy to avoid accidental puncture of aberrant veins or arteries [19). Spine fixation A few reports have demonstrated single cases of uneventful percutaneous dilational tracheostomy in pat ients after anterior cervical spine fixation [20,21) . Recently, Ben Nun et a1. published a series of percutaneous dilational tracheostomies in 38 patients with documented spine fracture, regardless of the fixation employed (Hallow apparatus, internal fixation or cranial traction) and found no procedure related morbidity or mortality [22). They conclude that percutaneous dilational tracheostomy is suitable and safe even for such patients, if it is performed by very experienced staff. Repeated percutaneous dilational tracheostomy Some patients may need repeated tracheostomy because of difficult weaning or recurring respiratory failure. However, scarring from a previous tracheostomy is usually considered as altered neck anatomy and thus a relative contraindication for percutaneous dilational tracheostomy. Furthermore, manufacturers of percutaneous dilational tracheostomy kits even list previous tracheostomy as a contraindication. On the other hand , percutaneous dilational tracheostomy has been proven to be a very safe procedure, if performed cautiously. Therefore, Meyer et a1. [23) studied the feasibility and safety of percutaneous dilational tracheostomy in patients with a history of previous percutaneous dilational tracheostomy. Time from first percutaneous dilational tracheostomy ranged between 10 days and 8 years and all tracheal stomas were completely closed. Present intubation time varied between 4 and 30 days. The authors used the existing scar for reincision of the skin, and, if palpable, the existing tracheal defect. With the Seldinger technique, 7- or 8-mm tracheostomy tubes were placed without complications in all 14 patients. Of note, flexible bronchoscopy was available but not employed in this study. Yilmaz et a1. [24) also found repeated percutaneous dilational tracheostomy to be safe and easy in 12 neuro-critically ill patients. Children and Teenagers

Most reports on percutaneous dilational tracheostomy are limited to adult patients and very few cases of children and teenagers have been published in adult case series [25, 26). To date, only one publication by Toursarkissian et a1. (27) reports experience with percutaneous dilational tracheostomy in 11 pediatric patients, 10- 20 years of age. Using the Seldinger technique and stepwise progressive dilation, percutaneous dilational tracheostomy was uneventful in 10 cases. In one case, the Seldinger wire was removed accidentally, but could be easily repositioned. The same patient suffered from a mild stomal infection. Otherwise no postprocedural complications were observed. Nine children were successfully decannulated and during follow-up (duration ranged from 4 to 73 weeks) no signs of tracheal stenosis occurred. The authors consider percutaneous dilational tracheostomy to be a safe alternative in children. However, they did not attempt to expand the use of percutaneous dilational tracheostomy to patients younger than 10 years of age. Major concerns about percutaneous dilational tracheostomy in children regard the small and soft anatomical landmarks and trachea, as well as the lack of data about long-term consequences such as tracheal stenosis [28).

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Ventilation during Percutaneous Dilational Tracheostomy Proper ventilation throughout the whole percutaneous dilational tracheostomy procedure is mandatory. Potential hazards are accidental extubation or damage to the tracheal tube or cuff by the introducer needle of the percutaneous dilational tracheostomy set. Recently, studies have reported the uneventful use of pediatric uncuffed tubes [29] or laryngeal mask airways (LMA) [30, 31] to prevent this problem. Ambesh et a1. [32] compared the use of LMA with endotracheal tube in 60 pat ients and found a very high rate of tube impalement (6.6 %), cuff puncture (6.6 %) and accidental extubations (3.3 %). These numbers stress the importance of maximum caution during airway management for percutaneous dilational tracheostomy. However, during LMA use the same authors report potentially catastrophic complications, such as loss of airway, inadequate ventilation of lungs leading to significant hypoxia, gastric distension and regurgitation in 33 % of patients. Even though these numbers are certainly not representative, they illustrate that there is no rationale to remove a secure airway and replace it by an LMA, as the requirement to re-intubate the trachea with a cuffed tube may occur at any stage during percutaneous dilational tracheostomy [33]. Bronchoscopic control of the procedure is common and strongly recommended. However, prolonged bronchoscopy along with the intraluminal dilators of the percu taneous dilational tracheostomy set may cause occult hypoventilation and hypercarbia which in turn might increase intracranial pressure (ICP) in selected patients [34]. Therefore, percutaneous dilational tracheostomy should not be performed in patients with critically high ICPs, but can otherwise be safely performed in neurosurgical critically ill patients [35].

Are Chest X-rays Necessary Afterwards? After percutaneous dilational tracheostomy, chest radiographs are common to ensure proper tracheostomy tube placement and to rule out pneumothorax or other significant changes. This approach is reasonable; however, it is costly and time consuming . Studies on the necessity of chest radiographs after percutaneous dilational tracheostomy report no significant findings in cases of uneventful percutaneous dilational tracheostomy [36, 37]. Haddad et a1. found atelectasis to be the only significant change, which led to modification of treatment in 4 % of patients [38]. All authors conclude that after an apparently uncomplicated percutaneous dilational tracheostomy, chest radiographs are not mandatory unless complications are anticipated from problems during the procedure [39].

Posterior Tracheal Wall Injury Although percutaneous dilational tracheostomy is generally a safe procedure, posterior tracheal wall injuries are a typical complication with an incidence varying from o [2] to 12.5 % [40]. In an animal model of percutaneous dilational tracheostomy, tracheal injuries were caused by improper stabilization of guiding catheter and guidewire or when the guiding catheter was withdrawn into the dilating catheter [40]. Therefore, it is recommended to check the tracheal wall after percutaneous dilational tracheostomy by bronchoscopy once the tracheostomy is in place. For this

What's new in Percutaneous Dilational Tracheostomy?

purpose the bronchoscope should be advanced translaryngeally to the carina next to the deflated cuff of the tracheostomy tube and then retracted to the vocal cords while the mucosa is inspected for potential injuries [41]. With tracheal perforation, persistent air leakage from the trachea can cause pneumothorax, pneumomediastinum, and pneumopericardium, and hence the leakage must be stopped immediately. After percutaneous dilational tracheostomy, injuries of the trachea are usually localized in the upper and middle third. Recent results show that such injuries can be treated conservatively, if they are bridged by an artificial airway [41, 42]. Fixed length tracheostomy tubes are not suitable for bridging as they may be too short. Therefore, tracheostomy tubes with adjustable flanges should be used. Persistent air leak despite positioning of the artificial airway just above the tracheal carina indicates a defect too close to the bifurcation. For such lesions and those below or close to the tracheal carina and with hemodynamic instability, emergency thoracotomy with surgical repair may be the treatment of choice. Every tracheal perforation requires an esophagoscopy to exclude perforation and , in doubtful situations , a chest computed tomography (CT) scan. Perforations of the esophagus or other mediastinal organs should not be treated conservatively. In case of successful bridging, regular inspection of the tracheal defect is necessary, to identify the need for surgical repair in cases of improper healing [41]. Figure 3 shows an algorithm for treatment of tracheal injuries.

Perform bronchoscopy A

+

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Placeairwaydistal to defect

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Fig. 3. Treatment algorithm for tracheal injuries. A: Consider chest computed tomography in case of hemodynamic instability to exclude tension pneumothorax, pneumomediastinum, and pneumopericardium; B: Consider antibiotic coverage. From [41] with permission

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long-term Outcome after Percutaneous Dilational Tracheostomy Long-term complications after percutaneous dilational tracheostomy include voice changes, severe hoarseness, and vocal cord abnormalities [43] . However, the most common long-term complication after percutaneous dilational tracheostomy is stenosis of different degrees. Subclinical narrowing of the trachea (at least 10 % of crosssectioned area) seems to be very frequent with an incidence up to 40 % [44]. Norwood et al. found moderate stenosis (25- 50 % of cross sectioned area) in 8.3 % of their patients [43]. Several cases of severe stenosis (> 50 % of cross sectioned area) including even complete obliteration of the tracheal lumen have been reported [43,45]. Most of these stenoses are not located at the level of the cuff, which is well below the inferior rim of the tracheostoma. Such stenoses would be due to chronic mucosal irritation of the trachea by the cuff. In contrast, most stenoses after percutaneous dilational tracheostomy occur at the level of the stoma or above. Koitschev et al. found severe (> 50 % cross sectioned area) stenosis in 23.8 % of patients after percutaneous dilational tracheostomy as compared to 7.3 % of patients after conventional tracheostomy [46]. Raghuraman et al. [47] studied 29 patients with severe symptomatic tracheal stenosis requiring tracheal reconstruction. Of these patients 15 had had percutaneous dilational tracheostomy, 14 had had conventional tracheostomy. After percutaneous dilational tracheostomy, the mean onset of stenosis was significantly earlier (5 weeks versus 28.5 weeks), significantly closer to the vocal cords (1.6 ern versus 3.4 em), and suprastomal cartilage damage (fracture or devoid) resulting in tracheal wall 'caving-in' was the typical surgical finding as opposed to marked infra- or suprastomal granul ations after conventional tracheostomy. Therefore, after percutaneous dilational tracheostomy, more complicated surgical techniques (partial cricoid resection with mucosal flap) were necessary to reconstruct the trachea. The length and diameter of the stenosis did not differ between patients after percutaneous dilational tracheostomy or conventional tracheostomy [47]. Even though this study is limited because of its retrospective design, it strengthens the need for bronchoscopy during percutaneous dilational tracheostomy in order to avoid punctures in the subglottic space [48].

Conclusion Percutaneous dilational tracheostomy is a safe and cost-effective technique for critically ill patients. With growing experience, the technique has overcome some of the limitations previously regarded as contraindications. References 1. MacIntyre NR, Cook OJ, Ely EW, [r., et al (2001) Evidence-based guidelines for weaning and

discont inuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Associat ion for Respiratory Care; and the American College of Critical Care Medicine. Chest 120:375S-395S 2. Beiderlinden M, Karl Walz M, Sander A, Groeben H and Peters J (2002) Complications of bron choscopically guided percutaneous dilational tracheostomy: beyond the learning curve. Inten sive Care Med 28:59- 62 3. Massick 00, Yao S, Powell OM, et al (2001) Bedside tra cheostomy in the intensive care unit: a prosp ective randomized trial compa ring open surgical tracheo stomy with endoscopically guided percutaneou s dilational tr acheotom y. Lar yngoscope 111 :494- 500

What's new in Percutaneous Dilational Tracheostomy? 4. Ben-Nun A, Altman E, Best LA (2004) Emergency percutaneous tracheostomy in trauma patients: an early experience. Ann Thorac Surg 77:1045-1047 5. Klein M, Weksler N, Kaplan DM, Weksler D, Chorny I, Gurman GM (2004) Emergency percutaneous tracheostomy is feasable in experienced hands . Eur J Emerg Med 11:108-112 6. Delaney A, BagshawSM, Nalos M (2006) Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systematic review and meta-analysis. Crit Care 10:R55 7. Heikkinen M, Aarnio P, Hannukainen J (2000) Percutaneous dilational tracheostomy or conventional surgical tracheostomy? Crit Care Med 28:1399-1402 8. Rumbak MJ, Newton M, Truncale T, Schwartz SW, Adams JW, Hazard PB (2004) A prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. Crit Care Med 32:1689-1694 9. Griffiths J, Barber VS, Morgan L, Young JD (2005) Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergo ing artificial ventilation. BMJ 330:1243 10. Pothmann W, Tonner PH, Schulte am Esch J (1997) Percutaneous dilatat ional tracheostomy: risks and benefits. Intensive Care Med 23:610-612 11. Beiderlinden M, Eikermann M, Lehmann N, Adamzik M, Peters J (2007) Risk factors associated with bleeding during and after percutaneous dilational tracheostomy. Anaesthesia 62:342-346 12. Byhahn C, Lischke V,Meininger D, Halbig S, Westphal K (2005) Peri-operative complications during percutaneous tracheo stomy in obese pat ients. Anaesthesia 60:12-15 13. El Solh AA, Iaafar W (2007) A comparative study of the complications of surgical tracheostomy in morb idly obese crit ically ill patients. Crit Care I1:R3 14. Heyrosa MG, Melniczek DM, Rovito P, Nicholas GG (2006) Percutaneous tracheostomy: a safe procedure in the morb idly obese. J Am Coli Surg 202:618-622 15. Watters M, Waterhou se P (2002) Percutaneous tracheostomy in morbidly obese patients. Anaesthesia 57:614- 615 16. Beiderlinden M, Groeben H, Peters J (2003) Safety of percutaneous dilational tracheostomy in patients ventilated with high positive end-expiratory pressure (PEEP). Intensive Care Med 29:944-948 17. Muhammad JK, Major E, Patton DW (2000) Evaluating the neck for percutaneous dilatational tracheostomy. J Craniomaxillofac Surg 28:336- 342 18. Muhammad JK, Major E, Wood A, Patton DW (2000) Percutaneous dilatat ional tracheostomy: haemorrhagic complications and the vascular anatomy of the anterior neck. A review based on 497 cases. Int J Oral Maxillofac Surg 29:217- 222 19. Bertram S, Emshoff R, Norer B (1995) Ultrasonographic anatomy of the anterior neck: implications for tracheostomy. J Oral Maxillofac Surg 53:1420-1424 20. Sustic A, Krstulovic B, Eskinja N, Zelie M, Ledic D, Turina D (2002) Surgical tracheostomy versus percutaneous dilational tracheostomy in pat ients with anterior cervical spine fixation: preliminary report. Spine 27:1942- 1945 21. Mazzon D, Di Stefano E, Dametto G, et al (1996) Percutaneous dilat ional tracheo stomy after anterior cervical spine fixation. J Neurosurg Anesthesiol 8:293-295 22. Ben Nun A, Orlovsky M, Best LA (2006) Percutaneous tracheostomy in patients with cervical spine fractures-feasible and safe. Intera ct Cardiovasc Thorac Surg 5:427-429 23. Meyer M, Critchlow J, Manshar aman i N, Angel LF, Garland R, Ernst A (2002) Repeat bedside percutaneous dilat ional tracheostomy is a safe procedure. Crit Care Med 30:986-988 24. Yilmaz M, Dosemeci L, Cengiz M, Sanli S, Gajic 0, Ramazanoglu A (2006) Repeat percutaneous tracheo stomy in the neurocritically ill patient. Neurocrit Care 5:120-123 25. Toye FJ, Weinstein JD (1986) Clinical experience with percutaneous tracheostomy and cricothyroidotomy in 100 patients. J Trauma 26:1034- 1040 26. Hazard PB, Garrett HE, [r., Adams JW, Robbins ET, Aguillard RN (1988) Bedside percutaneous tracheostomy: exper ience with 55 elective procedures. Ann Thorac Surg 46:63- 67 27. Toursarkissian B, Fowler CL, Zweng TN, Kearney PA (1994) Percutaneous dilational tracheo stomy in children and teenagers. J Pediatr Surg 29:1421-1424 28. Scott C], Darowski M, Crabbe DC (1998) Complications of percutaneous dilatational tracheostomy in children . Anaesthesia 53:477- 480

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T.A. Treschan, B. Pannen, and M. Beiderlinden 29. Ferraro F, Capasso A, Troise E, et al (2004) Assessment of ventilation dur ing the performance of elective endoscopic-guided percutaneous tracheostomy: clinical evaluation of a new method. Chest 126:159-164 30. Cattano D, Abramson S, Buzzigoli S, et al (2006) The use of the laryngeal mask airway during guidewire dilating forceps tracheostomy. Anesth Analg 103:453-457 31. Craven RM, Laver SR, Cook TM, Nolan JP (2003) Use of the Pro-Seal LMAfacilitates percuta neous dilatational tracheostomy. Can J Anaesth 50:718- 720 32. Ambesh SP, Sinha PK, Tripathi M, Matreja P (2002) Laryngeal mask airway vs endotracheal tube to facilitate bedside percutaneous tracheostomy in critically ill patients : a prospective comparative study. J Postgrad Med 48:11-15 33. Beiderlinden M, Eikermann M (2007) The laryngeal mask airway for airway management during percutaneous tracheostomy: everything should be made as simple as possible but not simpler. Anesth Analg 104:743-744 34. Reilly PM, Anderson HL, 3rd, Sing RF, Schwab CW, Bartlett RH (1995) Occult hypercarbia. An unrecognized phenomenon during percutaneous endoscopic tracheostomy. Chest 107: 1760-1763 35. Borm W, Gleixner M (2003) Experience with two different techniques of percutaneous dilational tracheostomy in 54 neurosurgical patients. Neurosurg Rev 26:188-191 36. Hoehne F, Ozaeta M, Chung R (2005) Routine chest X-ray after percutaneous tracheostomy is unnecessary. Am Surg 71:51-53 37. Das S, Jennings M (2007) Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Routine chest x rays following bronchoscopy guided percutaneous dilational tracheostomy. Emerg Med J 24:493- 494 38. Haddad SH, Aldawood AS, Arabi YM (2007) The diagnostic yield and clinical impact of a chest X-ray after percutaneous dilatational tracheostomy: a prospective cohort study. Anaesth Intensive Care 35:393-397 39. Datta D, Onyirimba F, McNamee MJ (2003) The utility of chest radiographs following percutaneous dilatational tracheostomy. Chest 123:1603-1606 40. Trottier SJ, Hazard PB, Sakabu SA, et al (1999) Posterior tracheal wall perforation during percutaneous dilational tracheostomy: an investigation into its mechanism and prevention. Chest 115:1383-1389 41. Beiderlinden M, Adamzik M, Peters J (2005) Conservative treatment of tracheal injur ies. Anesth Analg 100:210-214 42. Kuhne CA, Kaiser GM, Flohe S, et al (2005) Nonoperative management of tracheobronchial injuries in severely injured patients. Surg Today 35:518-523 43. Norwood S, Vallina VL, Short K, Saigusa M, Fernandez LG, McLarty JW (2000) Incidence of tracheal stenosis and other late complications after percutaneous tracheostomy. Ann Surg 232:233- 241 44. Walz MK, Peitgen K, Thurauf N, et al (1998) Percutaneous dilatational tracheostomy - early results and long-term outcome of 326 critically ill patients . Intensive Care Med 24:685-690 45. Koitschev A, Graumueller S, Zenner HP, Dommerich S, Simon C (2003) Tracheal stenosis and obliteration above the tracheostoma after percutaneous dilational tracheostomy. Crit Care Med 31:1574-1576 46. Koitschev A, Simon C, Blumenstock G, Mach H, Graumuller S (2006) Suprastomal tracheal stenosis after dilational and surgical tracheostomy in critically ill patients . Anaesthesia 61:832-837 47. Raghuraman G, Rajan S, Marzouk JK, Mullhi D, Smith FG (2005) Is tracheal stenosis caused by percutaneous tracheostomy different from that by surgical tracheostomy? Chest 127: 879-885 48. Marelli D, Paul A, Manolidis S, et al (1990) Endoscopic guided percutaneous tracheostomy: early results of a consecutive trial. J Trauma 30:433-435

Section IX

IX Infections

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Novel Therapies in the Prevention of Ventilator-associated Pneumonia P.].

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Introduction The pathogenesis of ventilator-associated pneumonia (VAP) is iatrogenic and multifactorial [1). Many of the known risk factors relate to the presence of an endotracheal or tracheostomy tube which bypass many of the patient's protective mechanisms and increase the chances of upper and lower airway colonization, aspiration, and infection [2]. The sequence of colonization of the aero digestive tract, followed by the tracheal tube and then ventilator circuit has been elegantly described by Feldman [3]. This sequence begins with oropharyngeal colonization after 1-2 days, followed by colonization of the stomach, then the lower respiratory tract (2-4 days), and thereafter the endotracheal tube. A reflection of the importance of the artificial airway has led some authorities to refer to the condition as "tracheal tube-associated pneumonia" [4]. Many techniques have been recommended to try to reduce YAP. These include: semi-recumbent rather than supine positioning; using subglottic secretion drainage endotracheal tubes; maintaining endotracheal tube cuff pressures to reduce aspiration of pooled secretions above them; managing gastric residual volumes that can lead to aspiration; small bowel feeding whenever possible; careful handling of vent ilator tubing to avoid condensate washing back to patients; and the use of non -invasive ventil ation (NIV) whenever possible. Antibiotic interventions may be useful in specific circumstances, such as giving 24 hours of therapy to patients following a witnessed aspiration, rotation of empiric regimens, and using selective digestive decontamination (SDD) in carefully selected populations [5). Each of these strategies carries its own level of evidence for efficacy and some are more practical in their applic ation than others. Many of thes e interventions have been thoroughly evaluated both clinically and by expert international consensus and recommendations for the management of ventilated pat ients have been made [6). The interventions broadly fall into two groups depending upon which part of the major YAP pathogenesis pathway they affect (Table 1): Upper aerodigestive tract colonization or pulmonary aspiration [2]. First, there are inte rventions that broadly reduce upper aero digestive tract coloni zation. Colonization of the stomach, dentition, sinuses, oropharynx, larynx, and subglottis normally occurs in the critically ill within hours of intubation and ventilation due to the presence of a foreign body (the endotracheal tube), the bacterial flora and antimicrobial pressures present, and the impedance of normal bacterial and secret ion clearance mechanisms [1]. Secondly, there are intervention s that reduce the pulmonary aspiration of these contaminated secretions that occurs around the endotracheal tube cuff. Leakage occurs past correctly inflated conventional cuffs. This observation has been easily and unequivocally demonstrated in a benchtop model and in the pig trachea [7- 9];

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Table 1. The relationship between the pathogenesis and prevention of ventilator associated pneumonia (VAP). Preventive Strategies for YAP

Pathogenesis of YAP

Avoid unnecessary antibiotics Shorten antibiotic courses Avoid ulcer prophylaxis Use sucralfate if required Oral rather than nasal intubation Consider chlorhexidine oral rinse Consider selective digestive decontamination Hand hygiene Consider non-invasive ventilation Shorten duration of mechanical ventilation Semirecumbent position Avoid gastric decompression Subglottic suctioning Avoid circuit changes/manipulation Drain circuit condensate Avoid patient transport Reduce accidental extubations

Bacterial colonization (oropharynx, stomach, sinuses)

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Aspiration of contaminated secretions (and ventilator circuit condensate, aerosol)

1

YAP

it has also been confirmed in anesthetized patients using direct bronchoscopic visualization of the folds [10] and in the critically ill [9]. This ubiquitous aspiration is reflected by the 89 % incidence of gastric to pulmonary transfer of material in critically ill patients with high-volume low-pressure (HVLP) cuffed tubes [11]. A third cause of YAP is due to inoculation of the tracheobronchial tree down the lumen of the artificial airway. There are interventions that reduce soiling of the tracheobronchial tree by contaminated material from the tracheal tube or ventilator circuit. Inoculation through the tracheal tube lumen may occur if there is a breakdown of infection control (with humidification, circuit manipulation, or poor tracheal suetioning techniques). More commonly, secondary colonization of the tracheal tube lumen will normally occur over time (following tracheobronchial colonization) due to adherence of mucus on the luminal surface of the tracheal tube. This may lead to repeated inoculation of the lung by secretions adherent to the tube lumen. This may perpetuate pneumonia because material is propelled back into the lung by the shear forces of gas flow and by the passing of tracheal suction catheters [12].

Is it Worth Investment in Novel Strategies?' There is an urgent need for investment in the prevention of YAP. We know that current tracheal tubes allow ongoing pulmonary aspiration [10, 11], aspiration causes YAP [I, 11] and YAP is the leading cause of nosocomial mortality in the leu [13]. The current HVLP cuffed tube is a cheap tool for short durat ion anesthesia that has essentially remained unchanged for 40 years. What is required is an engineered solution to the problem of pulmonary aspiration and upper airway colonization during longer term intubation and mechanical ventilation. Before considering potentially expensive improved technologies to reduce YAP

Novel Therapies in the Prevention of Ventilator-associated Pneumonia

one needs to consider if they make both clinical and financial sensei there is no use in developing exciting and expensive technologies that are not affordable. YAP is multifactorial and integrally associated with the tracheal tube. The development of a tracheal tube that assists the clinician to control some of the known , evidence based risk factors for YAP makes sense. Current tracheal tubes can cost less than 1 euro to purchase , yet are responsible for critical care's most prevalent and devastating nosocomial infective complication - each episode adding at least $10,000 to costs [14J. Investing in more advanced technologies makes sense. Dr Shorr and Wunderink declared in their editorial in Critical Care Medicine [15J that "....to make headway against YAP we need to focus our efforts on prevention .... Each case of YAP is associated with a direct cost of $50,000 .... Therefore, when we approach administrators who are skeptical of spending limited time and resources on prevention, we can argue strongly that with evidence-based prevention we are likely not only to limit mortality but also to save money....one can hypothesize that even marginally beneficial preventative interventions are likely to yield significant net savings".

Novel Strategies Upper Airway Decontamination 1. Oral hygiene: This is a mainstay of good nursing care. Cleaning the teeth is

important as bacterial colonization of the dentition has been linked to the pathogenesis of YAP [16]; however, antiseptic gels applied to the gums and teeth have not been shown to prevent YAP [17]. Unfortunately even the most diligent nurse cannot hope to effectively decontam inate the posterior pharynx, larynx, or subglottis. 2. Chlorhexidine: Using 0.12 % oral chlorhexidine solution in patients undergoing cardiac surgery can reduce the incidence of postoperative pneumonias [18]. It is not clear, however, whether this should generally be recommended [19J . 3. Selective oral decontamination: Three clinical trials have shown a survival benefit for critically ill patients treated with SDD [20- 22J . Selective oral decontamination alone may be effective in reducing YAP in intensive care unit (ICU) patients [23]. Fears of increased selection pressure have hampered widespread use of SDD in critically ill patients except in countries with a limited incidence of resistant organisms. 4. Peptides: A recent multicenter trial investigating iseganan, an antimicrobial peptide applied to the oral cavity, unfortunately failed to demonstrate efficacy in reducing YAP [24]. Subglottic Drainage Tubes

The Mallinckrodt HiLo EVAC endotrachel tube (Mallinckrodt, St Louis, USA) has a large bore dorsal channel on the tube which allows for the removal of secretions from the subglottic space. This can be performed continuously, semi-continuously, or intermittently. A meta-analysis of five studies has shown good evidence of a 50 % reduction in early YAP [25J, a reduction in mechanical ventilation by 2 days, and of length of ICU stay by 3 days. Not only was patient outcome improved, but because of the high costs of critical care there were also large cost savings [15J. In 2004, the Center of Disease Control (CDC) suggested the implementation of the use of subglottic secretion drainage tubes in the ICU [6].

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PJ. Young and M.C. Blunt These tubes are, however, infrequently used [26]. The reason is probably because of the disadvantages associated with this tube. 1. The Hilo EVAC tube is bulky and stiff compared to standard PVC tubes (because

of the dorsal port). This can cause serious tracheal and laryngeal pathology and has resulted in tracheal wall perforation and innominate artery fistulation [27]. Tube displacement during ventilation has also been attributed to this stiffness [28]. 2. The port of the Hilo EVAC tube is prone to blockage . During suctioning the mucosa is pulled into the single subglottic port causing blockage and failure of subglottic suctioning [29]. 3. Most importantly, shortly after the CDC issued the guidance, two papers were published examining the Hilo EVAC tube in mechanical ventilation in sheep [30, 31]. With continuous suctioning, severe suction injuries of the tracheal mucosa adjacent to the port opening were noted even at lower negative pressures. An accompanying editorial suggested that not only were these tubes "ineffective" because they did not completely prevent leakage, but they were also "unsafe" [32]. A subsequent small clinical study suggested a high incidence (40 %) of post-extubation laryngeal edema requiring reintubation in the Hilo EVAC group [33]. This means that only intermittent gentle suctioning and not continuous suct ioning can be recommended. This may reduce pulmonary aspiration but will not eliminate it. The Hilo EVAC tube has now been modified to bring the dorsal opening closer to the cuff and to increase the luminal cross-section [34]. This is to attempt to address the common problem of the subglottic port becoming blocked by indrawing of the tracheal mucosa. The potential danger of this approach is the possibility of increasing the area of contact of the tracheal mucosa area exposed to a potential suction injury as described above. Tracheostomy tubes are now also available with subglottic ports, allowing intermittent suctioning. Logically subglottic aspiration should be provided prior to times when aspiration past the cuff is most likely such as before tracheal suctioning, circuit disconnections, deflations of the cuff, or the loss of positive end-expiratory pressure (PEEP) [8].

Thin Walled Cuffs The large diameter HVLP cuff has been the standard in intensive care for nearly 40 years, as it ensures that tracheal mucosal pressure can be directly measured by measuring the pressure within the pilot balloon of the cuff. Unfortunately, even when correctly inflated within the trachea, these cuffs exhibit folds within their walls that allow passage of liquid between the cuff and the tracheal wall [10]. Cuffs made of thicker material have larger channels within the folds in the cuff wall, and, therefore, the rate of leakage past the cuff is greater [7]. Many manufacturers of conventional HVLP cuffed tubes have reduced the thickness of the cuff material to reduce the caliber of the folds within the wall following inflation within the trachea (for example, Kimberley Clark Microcuff''", Mallinckrodt Sealguardl'", and Portex Soft SeaFM). This reduction is potentially advantageous as thinner cuff materials produce narrower channels and reduce transcuff fluid leakage (Fig. 1). Studies suggest however that this is unlikely to eliminate leakage [8] and even a much reduced leakage rate can result in high volume aspiration given the extended time of use of tubes in the ICU.

Novel Therapies in the Prevention of Ventilator-associated Pneumonia

Fig. 1. Demonstration of three different endotracheal tubes showing liquid passing down the folds within cuffs inflated to their normal working pressure. (a) standard HVLP - Mallinckrodt HiLo EVAC; (b) ultra thin polyurethane HLVP; (c) LVLP LoTrach™

Combining Thin Walled Cuffs with Subglottic Drainage A recent study compared an endotracheal tube with a thin walled cuff and with a subglottic lumen (Mallinckrodt SealGuard™) to a conventional cuffed tube in 280 patients. Intermittent (hourly) suctioning was used. Tracheal aspirate samples were obtained at intubation, twice a week and on extubation. The occurrence of YAP was reduced from 22.1 % in the conventional cuffed group to 7.9 % with the new tube (p = 0.00l) . Importantly this held true for early-onset and late-onset YAP [35].

Securing the Tube A multicenter Spanish Study showed an 8 % incidence of unplanned extubation and accidental extubation carried a relative risk of 5.3 for the development of YAP [36]. Although endotracheal tubes are commonly secured using adhesive tape or cloth ties, commercial devices are available and provide more effective tube fixation [37, 38].

Antimicrobial Coating of Tracheal Tubes Both antiseptic- [39] and silver- [40] coated endotracheal tubes have been evaluated in animal studies with regard to biofilm and pneumonia prevention. Berra et al. [39] examined silver-sulfadiazine- and chlorhexidine-coated endotracheal tubes. These tubes acquired less biofilm and the ventilator circuits were protected from coloniza-

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PJ. Young and M.e. Blunt

tion but no difference in tracheal colonization was demonstrated. This finding is perhaps expected as coating of the tube lumen may reduce biofilm progression and re-inoculation of the tracheobronchial tree but will not prevent upper airway colonization and aspiration. Olson and colleagues reported the effect of using silver hydrogel coated endotracheal tubes on the lung bacterial burden of mechanically ventilated dogs challenged with a buccal administration of Pseudomonas aeruginosa [40]. The appearance of bacteria on the inner surface of the endotracheal tube was delayed and the bacterial burden and inflammation in the lung was reduced. A subsequent prospective, randomized, single-blind, multi-center study showed a reduced colonization rate and decreased bacterial burden but failed to demonstrate a reduction in the incidence of YAP [41]. These tubes can only impact on the incidence of YAP by reduction in bacterial burden but will not impact upon the major pathogenic pathway for YAP, namely aspiration of upper airway material past the cuff. LoTrach™ System

The Lo'Irach?' endotracheal tube, tracheostomy tube, and cuff pressure controller (Fig. 2) have been designed to reduce a number of risk factors of YAP while minimizing the mechanical forces on the airway and providing an effective airway seal at a low mucosal pressure [9]. The Lo'Irach'" system encompasses the following features: Low-volume low-pressure (LVLP) cuff: The cuff is calibrated during the manufacturing process such that at a single working intracuff pressure (80 cmH20 ) the tracheal wall pressure is kept at a desirable level of 22 mmHg (27 cmH20 ). The constant elasticity within the cuff wall effectively protects the tracheal wall from the totality of the intracuff pressure. There are no folds within the cuff wall to allow fluid to pass. Leakage is prevented in a model trachea (Fig. 1), in anesthetized patients, and in the critically ill mechanically ventilated patient [9, 42]. At equivalent tracheal wall pressures, a standard HVLP cuff will hold no fluid above it in the steady state, but the Lo'Irach'?' LVLP cuff will hold a column of 30 cm above it. This is well in excess of any column of fluid that could form in the human pharynx. Cuff pressure controller: To maintain inflation, the LoTrachTM is normally used with a constant pressure inflation device. If the tube is correctly placed and the cuff pressure maintained then the Lo'Irach?' offers not only complete protection against pulmonary aspiration but also continuous protection of the tracheal wall because overpressure is prevented. Surveys continue to show that current cuff pressure management practices are often suboptimal and both under- and over-pressure of the cuff is common [43-45]. The Lo'Irach'" cuff pressure controller also contains algorithms and alarms to assist the clinician in the detection and correction of hidden extubation should the tube be unintentionally pulled back into the laryngeal inlet. Triple subglottic ports: The Lo'Irach?" tube has three integral fine bore subglottic ports which open distally in a position on 3 quadrants of the circumference of the tube immediately above the cuff. The three suction channels join to one at the proximal end of the tracheal tube allowing intermittent gentle suctioning with a standard syringe. Intermittent suctioning is safer for the tracheal mucosa than continuous suctioning. The LVLP cuff on the Lo'Irach?' tube allows for efficacious intermittent suctioning because, unlike HVLP cuffs, it affords total protection against aspiration between episodes of suctioning. The presence of the three ports provides a maximal

Novel Therapies in the Prevention of Ventilator·assodated Pneumonia clearance of subglottic secretions independent of the geometry of the tube within the trachea and this also minimizes the possibility of the channels blocking with mucosa (thereby preventing suction injury). If one port is adjacent to mucosa, there is always a contra-lateral channel for fluid flow to occur. Upper airway cleansing: Despite best nursing care it is impossible to provide adequate oral, pharyngeal, and laryngeal hygiene due to difficulty with access. Because the LVLP cuff completely prevents leakage, the subglottic ports can be used to irrigate the upper airway. Normal saline can be injected into the subglottis (taking care not to increase the subglottic pressure to over 30 cmH20 ). The fluid refluxes through the laryngeal inlet and into the oral and/or nasal cavity carrying secretions with it. A suction catheter at the anterior oral cavity and/or nares is used to remove the effluent. Between 50 ml and 250 ml is typically required to remove all the offensive material and irrigations are normally performed 1- 3 times daily. Preventing unplanned extubation: The Lo'Irach" endotracheal tube has a securing system designed to reduce the incidence of unplanned extubation with its associated increased risk of YAP. Non-stick inner lumen: The inner lumen of the Lo'Irach" tube has a non-stick coating to inhibit the adhesion of biological materials. This has been designed to reduce secretion accumulation, facilitate the passage of suction catheters and broncho scopes, and delay tube blockage. These potential advantages await formal evaluation. Gentle to the airway: A tube designed for critical care use should minimize the mechanical forces known to cause injury to the airway. With long term placement of rigid, fixed curved PVC tubes, arytenoid, cuff, and tracheal tube tip injury is common. The Lo'Irach" has been designed to be flexible to allow the tube to conform to the airway rather than forcing the airway to conform to the tube. It has an atraumatic "boat tip" that minimizes forces exerted during intubation over a bougie or fibroscope [46], and also lies straight in the trachea so as to avoid the tip injuring the trachea. In summary, the Lo'Irach" tube has been designed to address six important risk factors. These are cuff leakage; cuff pressure maintenance (relative risk of YAP if failure to maintain > 20 cmH 20 = 4) (29); convenient suctioning of the subglottic space (approx. 50 % reduction in YAP) (25) ; allowance of irrigation of the upper airway; prevention of tube movement and unplanned extubation (relative risk of YAP = 5) (36); minimizing biofilm formation and tube occlusion (absolute risk unidentified).

Conclusion Colonization and aspiration are the key steps in the development of YAP, the most common cause of nosocomial mortality in the ICU. Conventional, low cost, HVLP cuffed tubes promote oral colonization and do not stop the universal problem of aspiration in the critically ill. New technologies need to be developed to address colonization, aspiration, and the multiple other factors implicated in the pathogenesis of YAP. Clinicians and hospital administrators need to understand the impact of YAP in terms of mortality (doubled), length of stay (increased by 6 days), and cost.

349

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=

M.e. Blunt

J-l

..,.BlJ

Fig. 2. a LoTrach™ endotracheal tube; b LoTrach™ tracheostomy tube; cLotrach™ cuff pressure controller.

Note the default setting is shown with the tracheal wall pressure set at 20 mmHg (= 30 cmH 20)

The Lo'Irach?" system can markedly reduce aspiration and allows for a thorough antibiotic/antiseptic-free irrigation and cleansing of the totality of airway and oral cavity above the tracheal tube cuff. With the development of systems, such as the Lo'Irach?", which have a major impact on the pathogenesis pathway, the efficacy of many conventional preventative strategies that influence upper airway colonization and pulmonary aspiration may become less relevant. References 1. Estes RJ, Meduri GU (1995) The pathog enesis of ventilator-associated pneumonia: I. Mecha-

nisms of bacterial transcolonization and airway inoculation. Intensive Care Med 21:365- 383 2. Kollef MH (2004) Prevention of hospital-associated pneumonia and ventilator-associated pneumonia. Crit Care Med 32:1396-1405 3. Feldman C, Kassel M, Cantrell J, et al (1999) The presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation. Eur Respir J 13:546-551 4. Kollef MH (2003) Infection: pneumonia. Cutting edge strategies for the prevention of ventilator-associated pneumonia. Program and abstracts of the 32nd Critical Care Congress; San Antonio, Texas. 5. Niederman MS (2001) Cost effectiveness in treating ventilator-associated pneumonia.Crit Care 5:243-244 6. Tablan ac, Anderson LJ, Besser R, Bridges C, Hajjeh R (2004) CDC Healthcare Infection Control Practices Advisory Committee. Guidelines for preventing health-care-asso ciated pneumo-

Novel Therapies in the Prevention of Ventilator-associated Pneumonia nia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep 53:1-36 7. Pavlin EG, VanNimwegan D, Hornbein TF (1975) Failure of a high-compliance low-pressure cuff to prevent aspiration. Anesthesiology 42:216-219 8. Young PJ, Rollinson M, Downward G, Henderson S (1997) Leakage of fluid past the tracheal tube cuff in a benchtop model. Br J Anaesth 78:557- 562 9. Young PJ, Pakeerathan S, Blunt MC, Subramanya S (2006) A low-volume, low-pressure tra cheal tube cuff reduces pulmonary aspiration. Crit Care Med 34:632 - 639 10. Seegobin RD, van Hasselt GL (1986) Aspirat ion beyond endotracheal cuffs. Can Anaesth Soc J 33:273 - 279 II. Metheny NA, Clouse RE, Chang YH, Stewart BJ, Oliver DA, Kollef MH (2006) Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients: frequency, outcom es, and risk factors. Crit Care Med 34:1007 -1015 12. Koerner RJ ( 1997) Contribution of endotracheal tubes to the path ogenesis of ventilator-associated pneumonia. J Hosp Infect 35:83- 89 13. Vincent JL, Bihari DJ, Suter PM, et al (1995) The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274:639-644 14. Safdar N, Dezfulian C, Collard HR, Saint S (2005) Clinical and economic consequences of ventilator-associated pneumonia: a systematic review. Crit Care Med 33:2184-2193 15. Shorr AF, Wunderink RG (2003) Dollars and sense in the intensive care unit: the costs ofventilator-associated pneumonia. Crit Care Med 31:1582- 1583 16. El-Solh AA, Pietrantoni C, Bhat A, et al (2004) Colonization of dental plaques. A reservo ir of respiratory pathogens for hospital -acquired pneumonia in institutionalised elders. Chest 126:1575-1582 17. Fourrier F, Dubois D, Pronn ier P, et al (2005) Effect of gingival and denta l plaque antiseptic decontamination on nosocomial infections acquired in the intens ive care unit: a double-blind placebo-controlled multi centre study. Crit Care Med 33:1728-1735 18. DeRiso AJ, Ladowski JS, Dillon TA, Justice JW, Peterson AC (1996) Chlorhexidine gluconate 0.12 % oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in pat ients undergoing heart surgery. Chest 109:1556-1561 19. Pineda LA, Saliba RG, El Solh AA (2006) Effect of oral decontamination with chlorhexidine on the incidence of nosocomial pneumonia: a meta-analysis. Crit Care 10:35 20. de Ionge E, Schultz MJ, Spanjaard L, et al (2003) Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomized controlled trial. Lancet 362:1011-1016 21. de la Cal MA, Cerda E, Garcia-Hierro P, van Saene HK, Gomez-Santos D, Negro E (2005) Survival benefit in critically ill burned patients receiving selective decont amination of the digestive tract: a randomized, placebo-controlled, double -blind trial. Ann Surg 241:424-430 22. Krueger WA, Lenhart F-P, Neeser G, et al (2002) Influence of combined intravenous and topical antibiotic prophylax is on the inciden ce of infections, organ dysfunctions, and mortality in critically ill surgical patients. A prospect ive, stratified, randomized, doubleblind, placebocontrolled clinical trial. Am J Respir Crit Care Med 166:1029-1037 23. Bergmans DCn, Bonten MJM, Gaillard CA, et al (2001) Prevention of ventilator-associated pneumonia by oral decontamination. Am J Respir Crit Care Med 164:382-388 24. Kollef M, Pittet D, Sanchez Garcia M, et al (2006) A randomized double-blind trial of iseganan in prevention of ventilator-associated pneumonia. Am J Respir Crit Care Med 173: 91-97 25. Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S (2005) Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta -analysis. Am J Med 118:11-18 26. Sierra R, Benitez E, Leon C, Rello J (2006) Prevention and diagnos is of ventilator-associated pneumonia: a survey on current practices in Southern Spanish ICUs. Chest 128:1667 - 1673 27. Siobal M, Kallet RH, Kraemer R, et al (2001) Tracheal-innominate artery fistula caused by the endotracheal tube tip: case report and investigation of a fatal complication of prolonged intubation . Respir Care 46:1012-1018 28. Takara I, Fukuda A, Koja H, Tomiyama H, Tokumine J, Sugahara K (2004) Unanticipated

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29. 30. 31. 32. 33. 34. 35.

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endotracheal tube displacement in a short-neck patient with a history of chronic rheumatoid arthritis: a comparison of three kinds of endotracheal tubes. Masui 53:1180-1184 Rello J, Sonora R, Iubert P, Artigas A, Rue M, Valles J (1996) Pneumonia in intubated patients : role of respiratory airway care. Am J Respir Crit Care Med 154:111-115 Berra L, De Marchi L, Panigada M, Yu ZX, Baccarelli A, Kolobow T (2004) Evaluation of continuous aspiration of subglottic secretion in an in vivo study. Crit Care Med 32:2071- 2078 Berra L, Panigada M, De Marchi L, et al (2003) New approaches for the prevention of airway infection in ventilated patients . Lessons learned from laboratory animal studies at the National Institutes of Health. Minerva Anestesiol 69:342-347 van Saene HK, Ashworth M, Petros AJ, Sanchez M, de la Cal MA (2004) Do not suction above the cuff. Crit Care Med 32:2160-2162 Girou E, Buu-Hoi A, Stephan F, et al (2004) Airway colonisation in long-term mechanically ventilated patients. Effect of semi-recumbent position and continuous subglottic suctioning. Intensive Care Med 30:225 - 233 Diaz E, Rodriguez AH, Rello J (2005) Ventilator-associated pneumonia: issues related to the art ificial airway. Respir Care 50:900 - 906 Lorente L, Lecuona M, Alejandro J, Maria M, Antonio S (2007) Influence of an endotracheal tube with polyurethane cuff and subglottic drainage . Am J Respir Crit Care Med 176:1079-

1083 36. de Lassence A, Alberti C, Azoulay E, et al (2002) OUTCOMEREA Study Group. Impact of 37. 38. 39. 40. 41. 42.

unplanned extubation and reintubation after weaning on nosocomial pneumonia risk in the intensive care unit: a prospective multicenter study. Anesthesiology 97:148-156 Patel N, Smith CE, Pinchak AC, Hancock DE (1997) Taping methods and tape types for securing oral endotracheal tubes. Can J Anaesth 44:330-336 Lovett PB, Flaxman A, Sturmann KM, Bijur P (2006) The insecure airway: a comparison of knots and commercial devices for securing endotracheal tubes. BMC Emerg Med 6:7 Berra L, De Marchi L, Yu ZX, Laquerriere P, Baccarelli A, Kolobow T (2004) Endotracheal tubes coated with antiseptics decrease bacterial colonization of the ventilator circuits, lungs, and endotracheal tube. Anesthesiology 100:1446-1456 Olson ME, Harmon BG, Kollef MH (2002) Silver-coated endotracheal tubes associated with reduced bacterial burden in the lungs of mechanically ventilated dogs. Chest 121:863 - 870 Rello J, Kollef M, Diaz E, et al (2006) Reduced burden of bacterial airway colonization with a novel silver-coated endotracheal tube in a randomized multiple-center feasibility study. Crit Care Med 34:2766-2772 Young PJ, Burchett K, Harvey I, Blunt MC (2000) The prevention of pulmonary aspirat ion with control of tracheal wall pressure using a silicone cuff. Anaesth Intensive Care 28:660-

665 43. Sathishkumar S, Young P (2002) Tracheal cuff pressure - a survey of clinical practice . Br J Anaesth 88:456 44. Mol DA, De Villiers Gdu T, Claassen AJ, Joubert G (2004) Use and care of an endotracheal! tracheostomy tube cuff - are intensive care unit staff adequately informed? S Afr J Surg 42: 14-16 45. Sierra R, Benitez E, Leon C, Rello J (2005) Prevention and diagnosis of ventilator -associated pneumonia: a survey on current practices in Southern Spanish ICUs. Chest 128:1667-1673 46. Greer JR, Smith SP, Strang T (2001) A comparison of tracheal tube tip designs on the passage of an endotracheal tube during oral fiberoptic intubation. Anesthesiology 94:729 -731

353

Management of Ventilator-associated Pneumonia M.

FERRER,

M.

VALENCIA,

and A.

TORRES

Introduction Pneumonia is the most important respiratory infection in mechanically ventilated patients. It is defined as the presence of microorganisms in the pulmonary parenchyma leading to the development of an inflammatory response by the host, which may be localized in the lung or may extend systemically. Nosocomial pneumonia is an infectious process which develops within 48 hours after admission to the hospital and that was not incubating at the time of hospitalization. Ventilator-associated pneumonia (VAP) is considered as a subgroup of nosocomial pneumonia and is an infectious pulmonary process which develops 48 hours after the presence of an artificial airway and mechanical ventilation. Since a large proportion of the patients who develop nosocomial pneumonia are intubated and receive mechanical ventilation, most epidemiological and clinical studies on nosocomial pneumonia have been focused on critically ill patients and those receiving mechanical ventilation. From a clinical point of view, nosocomial pneumonia is of great importance not only because of the consequences of the important morbidity and mortality but also due to the high costs associated with development of this disease.

Epidemiology Despite the large amount of data available on the epidemiology of YAP, the results provided by the different studies vary widely. This may be due to the lack of a standardized diagnostic approach and the different populations studied. Moreover, although YAP has been well defined, disagreement as to the final diagnosis may be attributed to: 1) focal areas of the lobe which may be missed; 2) negative microbiological studies despite the presence of inflammation in the lung; and 3) pathologists may disagree in their conclusions. The point of time at which YAP develops has important implications in the etiology, treatment and diagnosis of this disease. VAP has classically been determined as early-onset pneumonia, which occurs within the first four days after hospital admission, and late-onset pneumonia, which develops five or more days after admission [1]. Nosocomial pneumonia is the second most common hospital -acquired infection and is the leading cause of death among this type of infection. The incidence of nosocomial pneumonia ranges from 4 to 50 cases per 1000 admissions in community hospitals and general medical wards to up to 120 to 220 cases per 1000 admissions in some intensive care units (ICUs) or among patients requiring mechanical ventila-

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tion. The European Prevalence of Infection in Intensive Care (EPIC) study [2], a large I-day point prevalence study of infections, was carried out in 1417 ICUs and included 10,038 patients. The prevalence of ICU-acquired infections was of 21 %; 47 % of these patients had pneumonia, of nosocomial origin in 10 %. In a large, prospective cohort study including 1014 patients receiving mechanical ventilation , 177 (18 %) developed YAP [3]. The incidence of this disease was 24 % (78/322) in a Spanish study on risk factors for YAP [4]. In a recently published study, the mean incidence of hospital-acquired pneumonia in non-ICU patients was 3 ± 1.4 cases/ 1000 hospital admissions [5]. Most patients were in medical wards (64 %), had severe underlying diseases, and the hospital stay was greater than 5 days. The overall incidence of YAP varies from 8 - 28 %. A prospective Italian study on YAP including 724 critically ill patients who had received prolonged ventilatory support after admission reported an incidence of 23 % [6]. This rate rose from 5 % in patients receiving mechanical ventilation for 1 day to 69 % in those receiving mechanical ventilation for more than 30 days. In a study including 567 patients receiving mechanical ventilation, evaluated with invasive procedures, the rate of YAP was 9 % [7]. In this latter study the cumulative risk of pneumonia was estimated to be 7 % at 10 days and 19 % at 20 days after initiation of mechanical ventilation, thereby showing the classical incremental risk of pneumonia of 1 % per day [7]. However, in a large series of 1014 patients receiving mechanical ventilation, Cook et al. [8] described a rate of YAP of 18 %, and although the cumulat ive risk for developing YAP increased over time, the daily hazard rate decreased after day 5. The risk per day was determined to be 3 % on day 5, 2 % on day 10, and 1 % on day 15. Several studies have reported the rate of mortality in YAP to range from 24 -76 % [4, 7, 9]. Patients with YAP in the ICU receiving mechanical ventilation may have a 2 to lO-fold greater risk of death compared to patients without this complication. In a study of 78 episodes of nosocomial pneumonia detected in 322 consecutive patients receiving mechanical ventilation , the overall mortality rate was 23 % [4]. Similarly, the Neunos 2000 study group reported a mortality of 26 % (pneumoniaattributed 13.9 %) in 186 non-ICU patients with hospital-acquired pneumonia [5]. The mortality of patients with nosocomial pneumonia was higher (33 %) when compared with rates of patients without nosocomial pneumonia (19 %, P < 0.01). On step-forward logistic regression analysis the identification of 'high-risk' microorganisms (Pseudomonas aeruginosa, Enterobacteriaceae, and other Gram-negative bacilli, Enterococcus faecalis, Staphylococcus aureus, Candida spp. Aspergillus spp, and episodes of polymicrobial pneumonia), bilateral involvement on chest X-ray, the presence of respiratory failure, inappropriate antibiotic therapy, age over 60 years, or an ultimately or rapidly fatal underlying condition were independently associated with worse prognosis. The increased risk ratios of mortality in patients with YAP vary from 1.7 to 4.4 [10]. Although several studies have shown that YAP is a severe disease, the controversy as to attributing mortality to noso comial pneumonia continues . However, several studies have shown nosocomial pneumonia to be an independent prognostic factor. Patients in whom the attributable mortality is increased include patients undergoing cardiac surgery, patients with acute lung injury, and immunosuppressed patients [11]. In contrast, in patients with life-threatening medical conditions such as cardiac arrest in young patients with no underlying disease and those admitted due to trauma, nosocomial pneumonia does not seem to significantly increase mortality [12] .

Management of Ventilator-associated Pneumonia

Pathogenesis In developing pneumonia, virulent microorganisms must invade the lung parenchyma. This may occur either as the result of a defect in defense mechanisms of the host or by an overwhelming inoculum . The normal human respiratory tract has a variety of defense mechanisms such as anatomic barriers, cough reflex, cell and humoral-mediated immunity and a dual phagocytic system involving both alveolar macrophages and neutrophils. Virulent microorganisms can reach the alveolar space in several ways, such as colonization of the upper airway by potentially pathogenic microorganisms and posterior microaspiration, macroaspiration of gastric contents, contaminated respiratory care equipment such as condensates in ventilator tubing, fiberoptic bronchoscopes, tracheal suctioning material , or nebulizers, the hematogenous route and direct dissemination from contiguous sites such as the pleura, the pericardium or the abdomen. Oropharyngeal and tracheal colonization play a central role in the pathogenesis of VAP. Early colonization (within the first 24 hours of mechanical ventilation) has been described in patients who are intubated and in those receiving mechanical ventilation, varying from 80 % to 89 % [13). One study [14) demonstrated that 45 % of 213 patients admitted to a medical leu became colonized with aerobic Gram-negative bacilli by the end of one week in the hospital. Among the 95 colonized patients, 23 % developed nosocomial pneumonia while only four out of the 118 non-colonized patients developed pneumonia. Among the microorganisms colonizing the trachea, Pseudomonas spp. has an increased affinity to ciliated tracheal epithelial cells and these microorganisms are not usually present in the oropharynx. Adherence of Pseudomonas increases in desquamated epithelium following influenza virus infection, tracheostomy, or repeated tracheal suctions in intubated patients [15). In a study including 86 patients receiving mechanical ventilation, oropharyngeal colonization, which was detected either on admission or from subsequent samples, was a predominant factor of nosocomial pneumonia compared with gastric colonization [16). Oropharyngeal colonization with Acinetobactor baumanii yielded an estimated 7.45-fold increased risk of pneumonia compared with patients who had not yet or who were not identically colonized (p = 0.0004). DNA genomic analysis demonstrated that an identical strain was isolated from oropharyngeal or gastric samples and bronchial samples in all but three cases of pneumonia due to S. aureus [16).

Risk Factors There are considerable amounts of data concerning risk factors for VAP. These factors are important since they may contribute to the development of effective prevention programs by indicating which patients may be most likely to benefit from prophylaxis against pneumonia. We herewith discuss the most relevant risk factors for

Table 1. Risk factors for nosocomial pneumonia. Reintubation Decrease in pressure of the tracheal tube cuff Stress-ulcer prophylaxis (anti-H 2) Tracheostomy

Supine position Coma and head trauma Nasogastric tube and gastric distension Patient transport

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endogenous infection in YAP, although data on many of these factors continue to be controversial. These risk factors are listed in Table 1.

Antimicrobial Agents The distribution of microorganisms, especially potentially-resistant bacteria, differs in patients who have or have not received prior antibiotic therapy. Likewise, previous antibiotic administration may influence the development of YAP in two different ways: Its use may be associated with a protective effect against early-onset pneumonia, while, on the other hand, it may be associated with an increased risk of lateonset pneumonia. To determine the baseline and time -dependent risk factors for YAP, Cook et al. [8] evaluated 1014 patients. On multivariate analysis, independent predictors of YAP were a primary diagnosis on admission of burns (risk ratio 5.09), trauma (risk ratio 5.00), central nervous system disease (risk ratio 3.40), respiratory disease, cardiac disease (risk ratio 2.72), mechanical ventilation within the previous 24 hours (risk ratio 2.28), witnessed aspiration (risk ratio 3.25) and paralytic agents. Exposure to antibiotics conferred protection (risk ratio 0.37), but this effect attenuated over time. Rello et al. [17] evaluated the risk factors for YAP within the first 8 days of mechanical ventilation in 83 consecutive intubated patients undergoing continuous aspiration of subglottic secretions. Multivariate analysis showed the protective effect of antibiotic use (relative risk 0.10) whereas failure of continuous aspiration of subglottic secretions (relative risk 5.29) was associated with a greater risk of pneumonia. In addition, Sirvent et al. [18] evaluated the use of systemic prophylaxis with cefuroxime before intubation on the incidence of YAP in 100 patients with coma, 50 of whom received one dose of 1.5 g of cefuroxime intravenously at the time of intubation and a second dose 12 h later. The global incidence of early-onset YAP was 37 % (n = 37): 12 (24 %) in the cefuroxime group and 25 (50 %) in the control group (p = 0.007). All these studies demonstrate the protective effect of antibiotic therapy in early YAP caused by endogenous flora. In a prospective study in 277 patients receiving mechanical ventilation, Kollef [10] determined that the following four factors were associated with YAP: Index of systemic organ failure ~ 3 (odds ratio [OR]=10.2), age ~ 60 years (OR = 5.1), previous antibiotics (OR = 3.1), and supine head position within the first 24 hours of mechanical ventilation (OR = 2.9). In addition to the importance of antibiotic therapy as a risk factor for YAP, the influence of antibiotics on the etiology of this disease is also relevant. In a prospective study, Rello et al. [19] studied 129 consecutive episodes ofVAP to evaluate the influence of prior antibiotic administration on the etiology and mortality of YAP. The rate of YAP caused by Gram-positive cocci or Haemophilus injluenzae was statistically lower (p < 0.05) in patients who had received antibiotics previously while the rate of YAP caused by P. aeruginosa was statistically higher (p< 0.01). Step-forward logistic regression analysis only determined previous antibiotic use (OR 9.2) as significantly influencing the risk of death in YAP. Likewise, Trouillet and coworkers [20] demonstrated that three variables remained significantly associated with potentially resistant microorganisms as a causative etiology in YAP: Duration of mechanical ventilation ~ 7 days (OR 6.0), prior antibiotic use (OR 13.5), and prior use of broad-spectrum drugs (third generation cephalosporin, fluoroquinolones, and/or imipenem) (OR 4.1). All of these studies have demonstrated that antimicrobial therapy has a bimodal effect on the development of YAP. Antibiotics protect against early-onset pneumonia, especially pneumonia caused by endogenous flora, but they are also responsible for the selection of resistant microorganisms causing

Management of Ventilator-associated Pneumonia late-onset pneumonia such as P. aeruginosa and methicillin-resistant S. aureus (MRSA).

Body Position It has been demonstrated that up to 50 % of healthy adults aspirate at night. How-

ever, in these subjects it is not clinically significant since lung defense mechanisms remain intact. Torres and coworkers [21, 22] demonstrated the importance of body position in gastroesophageal reflux and tracheal aspiration. These authors instilled a colloid with technetium via the nasogastric tube, and by placing patients in a semirecumbent position they found a significant reduction in the radioactivity of tracheal secretions compared with patients in the supine position. Moreover, in another randomized study [23], this group studied the impact of body position on the development of VAP. Patients were placed in a semirecumbent (45°) or supine (0°) body position. Microbiologically-confirmed pneumonia developed in 5 % of the patients in the semirecumbent position and in 23 % of those in the supine (p = 0.018).

Gastric Colonization and Stress Ulcer Prophylaxis Low gastric pH prevents against bacterial growth in the gastric chamber and bacterial migration from the small bowel. The relationship between gastric pH and gastric colonization has been well established in several studies. The use of prophylactic agents for stress ulcers, which alter the gastric pH, may increase gastric colonization and the rates of VAP, although this remains to be demonstrated. In a 1991 metaanalysis , Tryba [24] found that antacids and Hy-antagonists were significantly more effective in preventing stress bleeding in treated versus untreated patients. Sucralfate was superior to Hz-antagonists. Patients treated with antacids or Hy-antagonists showed a significantly higher risk for the development of nosocomial pneumonia. In a later study, Cook et al. [25] demonstrated a trend toward less clinically important bleeding with Hj-antagonists and antacids than with sucralfate. They found a trend toward an increased risk of pneumonia associated with Hy-antagonists compared with no prophylaxis and a sign ificantly higher risk compared to sucralfate. Finally, another meta-analysis [26] concluded that ranitidine is not effective in the prevention of gastrointestinal bleeding and may increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. Currently, there are not enough data to give a conclusive recommendation.

Diagnosis The first problem in the diagnosis of nosocomial pneumonia and VAP is the lack of a gold-standard for comparing the different techniques used to confirm suspicion of an infectious process. Despite the use of histology in pulmonary biopsy and cultures of pulmonary tissue in the immediate post-mortem period, the value of these techniques in parenchymal infections has not been unequivocally demonstrated. Suspicion of nosocomial pneumonia depends on the finding of new and persistent infiltrates on chest X-ray in association with some clinical signs and symptoms (fever or hypothermia, purulent respiratory secretions and leukocytosis or leukopenia). Based on histology and microbiological cultures of post-mortem pulmonary biopsies, one

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M. Ferrer, M. Valencia, and A. Torres Table 2.The Clinical Pulmonary Infection Score (28) Criterion Tracheal secretions Pulmonary Radiology Temperature, ·C Blood leukocytes PaO/Fi0 2 Microbiology*

0 Absent No ;::: 36.5 and s 38.4 ;::: 4000 and s 11 000 > 240 or ARDS Negative

2

Non-purulent Diffuse ;::: 38.5 and :s 38.9 < 4000 or > 11 000

Purulent Localized ;::: 39 or s 36 = + bands > 50 % s 240 without ARDS Positive

* Culture evaluation delay at least 24 h; ARDS: acute respiratory distress syndrome

study demonstrated that the presence of radiological findings plus two or more clinical criteria showed a sensitivity and specificity of 69 % and 75 %, respectively [27]. In recent years the Clinical Pulmonary Infection Score (CPIS), validated by Pugin and coworkers [28], has been widely used. This score combines different clinical, radiological, physiological, laboratory and microbiological parameters (Table 2) in order to increase the specificity of the clinical diagnostic approach. A score greater than 6 demonstrates a good correlation with the presence of pneumonia. The results of different studies on the diagnostic performance of this score are contradictory with values of sensitivity and specificity of around 77 % and 42 %, respectively [27]. Some studies have been aimed at increasing the diagnostic yield of this score with the addition of Gram staining of secretions of the lower respiratory tract [29]. The diagnostic tests performed on suspicion of YAP have two objectives: The first is to determine whether the patient really has an infectious pulmonary process as indicated by the signs and symptoms leading to the use of these tests; the second is the isolation of the causative microorganisms of the disease. For many years, the diagnostic performance of the different techniques used to confirm suspicion of YAP has been under debate. At present, the value of non-invasive tests, such as tracheobronchial aspirate, and invasive bronchoscopic tests, such as bronchoalveolar lavage (BAL) and the protected specimen brush (PSB), as well as the advantages and disadvantages of each technique have been well established [30]. As a general rule, tracheobronchial aspirate has very good sensitivity with a specificity a little lower than the invasive tests when using a quantitative culture of the respiratory secretions obtained by this method [31]. In different studies, the sensitivity of this test varies from 38-100 % with a specificity of 14-100 % [32]. A negative tracheobronchial aspirate culture in a patient who has not received antibiotic treatment has a high negative predictive value for the presence of YAP. In one study on the diagnostic value of this technique, the negative predictive value was 72 % in 102 patients evaluated with this technique and with invasive methods. The sensitivity of PSB and BAL are 33 - 100 % and 42 - 93 %, respectively and the specificities are 50-100 % and 45-100 % [7]. On the other hand, the current controversy lays in the role invasive and non-invasive methods have in the prognosis and use of antibiotics in these patients. On analyzing only the randomized studies, we found that in a pilot study with 51 patients Sanchez-Nieto and coworkers [33] observed that bronchoscopic methods led to a greater change in initial antibiotic treatment (42 % versus 16 %, P < 0.05) with no significant differences as regards to either global or attributable mortality or morbidity. This study was limited by its small sample size and the lack of a standard treatment protocol in the invasive group. The study by Sole-VioIan and coworkers [34] demonstrated a greater number of antibiotic changes with invasive techniques with no clear influence on mortality, length of ICU stay, and

Management of Ventilator-associated Pneumonia

days on mechanical ventilation. Ruiz and coworkers [35] compared 765 patients with suspicion of YAP (39 non- invasive and 37 invasive) and concluded that the diagnostic performance of both techniques in YAP was similar, as was mortality at 3D days, number of days on mechanical ventilation, and length of leu stay. The costs of invasive studies were clearly greater. One study by Fagon and coworkers [36] reported positive results with respect to a decrease in mortality on day 14 and

Newand persistent infiltrate on CXR, plustwo of the following:feveror hypothermia, leukocytosis or leukopenia and purulent secretionsOR CPls > 6

~

Obtain lower respiratorytract sample (TBAs, BALor PsB*) for quantitative cultureand microscopy

~

Begin empiric antimicrobial therapy based on local microbiologic dataand the presence of the following criteria

~

Late-onsetpneumonia or riskfactors for multi-drug resistant microorganisms

I

I

~

~

Ceftriaxone or Levofloxacin, moxifloxacin or ciprofloxacin or Ampicillin/sulbactam or Ertapenem

Antipseudomona l cephalosporin or Antipseudomona l carbapenem or ~-lactamll3- lactama se inhibitor plus antipseudomonal fluoroquinoloneor aminoglycoside plus Linezolid or Vancomycin

I

I

No

Yes

I

I

Day 3: Check cultures andassess clinical response with clinical parameters, laboratory resu lts, CXRor CPls Criteria of Non-response: • Failure to improvethe Pa02/ Fi02or needfor intubation and mechanical ventilation • Persistence of feveror hypothermia •Worsen ing of the pulmonary infiltrates by >50% • Development of septic shockor MODS

Fig. 1. Algorithm for the management of patients with nosocomial pneumonia. CXR: Chest X Ray; CPIS: Clinical Pulmonary Infection Score; TBAS: Tracheobronchial aspirate; BAL: Bronchoalveolar lavage; PSB: Protected specimen brush; PaD): Oxygen arterial pressure; FiO): Inspired fraction of oxygen; MODS; Multiple organ dysfunction syndrome

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M. Ferrer, M. Valencia, and A. Torres

Sequential Organ Failure Assessment (SOFA) scores on days 3 and 7, a reduction in the use of antibiotics, and the number of antibiotic -free days with the invasive technique. Nonetheless, the study was limited by the use of qualitative cultures of the tracheal aspirates which thereby limited comparison with the other studies. In summary, we suggest the following diagnostic and management approach to nosocomial pneumonia (Fig. 1). First, clinical suspicion of pneumonia should be based on classical clinical criteria or a CPIS > 6. Respiratory secretions should be collected at this time by tracheobronchial aspirate or bronchoscopy for obtaining quantitative cultures. Reevaluation should be made at 48 to 72 h and the decision as to whether to continue antimicrobial treatment should be based on the probability of pneumonia, the results of the cultures, and the presence of an alternative diagnosis [37).

Treatment When deciding to treat a suspected episode of ICU-acquired pneumonia, several aspects should be taken into account. The importance of early initiation of adequate antimicrobial therapy for the treatment of YAP has been emphasized in recent years in several studies. Alvarez-Lerma [38) evaluated 430 patients with YAP and found a higher attributable mortality (24.7 % vs. 16.3 %, P =0.039) and a higher incidence of septic shock and gastrointestinal bleeding among patients receiving inadequate initial treatment. Similar results were also reported by Luna and coworkers [39) and Rello and Diaz [40). With mini-BAL fluid cultures, Kollefand Ward [41) reported that inappropriate antibiotic therapy was associated with an OR for death of 3.28. Empiric antimicrobial therapy may be inadequate as a consequence of the presence of unexpected pathogens not covered by the initial antibiotic schedule but this may be mainly due to unanticipated resistance. In most of the previously mentioned studies, a large proportion of the episodes of inadequate antimicrobial treatment were attributed to potentially resistant Gram-negative bacteria (especially P. aeruginosa, Acinetobacter spp. and Enterobacter spp.) or MRSA. Another important aspect to take into account is whether modification of the initial inadequate therapy according to microbiological results improves the outcome of the patient. Studies addressing this issue did not find any improvement in mortality with this strategy. Luna and coworkers [39) showed that therapeutic changes made after bronchoscopy led to more patients (n = 42) receiving adequate therapy. Nonetheless, the mortality in this group was comparable to the mortality reported among patients who continued to receive inadequate therapy (n = 23). In a study by Rello and coworkers [42), bronchoscopic results led to a change in antibiotic treatment in 27 cases (24 %) considered to have received inadequate initial treatment. Despite clinical resolution in 17 of these cases (63 %), the mortality was higher compared to patients with initial adequate therapy. Kollef and Ward [41) found a high prevalence (73 %) of inadequate initial antibiotic therapy in a study of 130 patients with YAP. In this study, the mortality of patients in whom the antibiotic therapy had been started or changed based on the results of mini-BAL culture was significantly higher compared to patients with unchanged or discontinued treatment (60.8 % vs. 33.3 % and 14.3 %, respectively). The results of these studies demonstrate the need for early initiation of broad-spectrum empirical antimicrobial therapy on suspicion of YAP. The American Thoracic Society (ATS) published its first guidelines for the management of hospital-acquired pneumonia in 1995 [43). In 1998, Trouillet et al. [20) suggested a different classifica-

Management of Ventilator-associated Pneumonia

tion for the prediction of pathogens and the selection of ant ibiotic treatment based on previous antibiotic use and the duration of mechanical ventilation. These classifications provide a different rationale for the prediction of microbial etiology with the aim of aiding clinicians to prescr ibe appropriate initial empiric therapy. In a prospective study, we evaluated the level of bacterial coverage and validated the adequacy of the antibiotic strategy proposed by the 1996 ATS guidelines and the Trouillet framework [44]. Both classifications were found to be effective in predicting the pathogen involved (91 % and 83 %, respectively). However, taking the in vitro sensitivity of the pathogens isolated into account, the adequacy of the antibiotic treatment proposed by these classifications was found to be rather lower (79 % for ATS and 80 % for Trouillet). The microorganisms involved in treatment inadequacy were multiresistant P. aeruginosa, A. baumanii, S. maltoph ilia, and MRSA. These findings underline the importance of considering additional parameters such as local microbial epidemiology and more accurate models of prediction of resistance to improve the level of coverage and the appropriateness of antibiotic treatment. The ATS recently publish ed new guidelines for the management of adults with hospital-acquired pneumonia [45] and, contrary to the previous guidelines, the severity of pneumonia does not play an important role in decisions regarding the initial empiric treatment to be implemented (Table 3). Regardless of the severity of pneumonia, patients with risk factors for infection with multi-drug resistant microorganisms or with hospital admission greater than 5 days should receive empiric broad-spectrum antibiotic therapy that adequately covers infection by P. aeruginosa. The different schedules recommended for this group include: a cephalosporin with anti-pseudomonal activity, a carbapenem or piperacillin/tazobactam, associated with an aminoglycoside or a tluoroquinolone with antipseudomonal activity. Linezolide or vancomycin should be included in cases with suspicion of MRSA infection or hospitals with a high incidence of this microorganism. Patients who do not fulfil the previously mentioned characteristics should receive empiric treatment with schedules which cover the 'core' microorganisms such as S. pneumoniae, H. influenzae , methicillin-sensitive S. aureus, and antibiotic-sensitive aerobic Gram-negative bacilli. The drugs of choice include ceftriaxone, a tluoroquinolone, a beta-lactaml beta -lactamase inhibitor, or ertapenem [45]. To date, the use of combined antibiotic therapy is still recommended in the treatment of YAP with suspicion of P. aeruginosa or other potentially resistant pathogens. Previous studies on bacteremic infections caused by P. aeruginosa [46] and KlebsiTable 3. Likely etiologic pathogens causing nosocomial pneumonia. Patients with no risk factors for MDR pathogens, early onset, and any severity.

Patients with late-onset pneumonia or risk factors for MDR pathogens and any severity

Streptococcus pneumoniae Haemophilus influenzae Methicillin-sensitive Staphylococcus aureus (MSSA) Enteric gram-negative bacilli Escherichia coli Klebsiella pneumoniae Enterabaeter spp Proteus spp Serratia marcescens

The same as the previous group Plus Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL) Acinetobacter spp Methicillin-resistant Staphylococcus aureus (MRSA) Legionella pneumophila

MDR: Multi-drug resistant; ESBL: Extended spectrum ~-Iactamases.

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ella spp. [47] demonstrated a higher mortality associated with the use of initial empiric monotherapy compared to combined therapy. However, these studies are limited in that they were performed when less active beta-lactams were used. Further trials are needed to clarify this issue. For now, the use of monotherapy should be limited to the treatment of severe nosocomial pneumonia in patients without risk factors for potentially resistant pathogens. The length of antimicrobial treatment is also under debate. In the ATS guidelines [45], the experts recommend that the length of treatment be shortened from the tra ditional 14- 21 days to shorter periods, to 7- 10 days. The latter shorter treatment is recommended in the treatment of S. aureus and H. influenzae pneumonia. However, in specific situations such as multilobar involvement, malnutrition, cavitation, Gram-negative necrotizing pneumonia, and/or isolation of P. aeruginosa or Acinetobacter spp., 14-21-day therapy should be initiated. Nonetheless, recent evidence has suggested that short treatment is as effective as longer treatment in YAP. Chastre and coworkers [48] evaluated 401 patients with YAP, 197 were randomized to receive short (8-day) treatment and 204 a long (IS-day) course of antibiotic treatment. No differences were observed in the mortality rate (I8 .8 % vs.17.2 %) or in the recurrence of pulmonary infection (28.9 % vs. 26 %) on comparing the two groups of pat ients. However, those treated with a short course of antibiotics had significantly more antibiotic-free days (I3 ± 7.4 vs. 8.7 ± 5.2 days, p < 0.00l). The possibility of providing adequate treatment with shorter courses of antibiotics will not only reduce health care costs but will also have favorable consequences on microbial ecology by reducing the selection pressure for resistance.

Conclusion Nosocomial pneumonia is the leading cause of death among the hospital-acquired infections. Its incidence ranges from 4 to 50 cases per 1000 admissions in community hospitals and general medical wards. Aspiration of colonized pharyngeal secretions is considered the most important pathogenic mechanism of nosocomial pneumonia. Risk factors for development of nosocomial pneumonia include previous use of antibiotics, supine body position, stress ulcer prophylaxis, and duration of hospital admission. The diagnostic approach to these patients should start with the criteria of clinical suspicion discussed above and be followed by quantitative cultures of respiratory secretions obtained through tracheobronchial aspirate or bronchoscopic samples. Initial empiric antimicrobial therapy is based on the previous duration of hospital admission and the presence of risks factor for multi-drug resistant microorganisms. References 1. Langer M, Cigada M, Mandelli M, Mosconi P, Tognoni G (1987) Early-onset pneum onia: a multicenter study in intensive care units. Intensive Care Med 13:342 - 346 2. Vincent JL, Bihari OJ, Suter PM, et al (1995) The prevalence of nosocomial infection in inten-

sive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA 274:639-644 3. Prod'hom G, Leuenberger P, Koerfer J, et al (1994) Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer. Ann Intern Med 120:653-662 4. Torres A, Aznar R, Gatell JM, et al (1990) Incidence, risk, and progno sis factors of nosocomial pneumonia in mechanically ventilated patients . Am Rev Respir Dis 142:523-528

Management of Ventilator-associated Pneumonia 5. Sopena N, Sabria M, and the Neunos Study group (2005) Multicenter study of hospitalacquired pneumonia in non -ICU pat ients. Chest 127:213-219 6. Langer M, Mosconi P, Cigada M, Mandelli M (1989) Long-term respiratory support and risk of pneumonia in critically ill patients . Intensive Care Unit Group of Infection Control. Am Rev Respir Dis 140:302-305 7. Fagon JY, Chastre J, Domart Y, et al (1989) Nosocomial pneumonia in pat ients receiving continuous mechanical ventilation. Prospect ive analysis of 52 episodes with use of a protected specimen bru sh and quantitative cultu re techniques . Am Rev Respir Dis 139:877- 884 8. Cook DJ, Walter SD, Cook RJ, et al (1998) Incidence of and risk factors for ventilator-assoc iated pneumonia in critically ill patients. Ann Intern Med 129:433-440 9. Craven DE, Kunches LM, Kilinsky V, Lichtenberg DA, Make BJ, McCabe WR (1986) Risk factors for pneumonia and fatality in pat ients receiving mechanical ventilation. Am Rev Respir Dis 133:792 -796 10. Kollef MH (1993) Ventilator-associated pneumonia: A mult ivariate analysis. JAMA 270:19651970 11. Lossos IS, Breuer R, Or R, et al (1995) Bacter ial pneumonia in recipients of bone marrow transplantation. A five-year prospective study. Transplantation 60:672 - 678 12. Antonelli M, Moro ML, Capelli 0, et al (1994) Risk factors for early-ons et pneumonia in trauma patients. Chest 105:224-228 13. Cardefiosa Cendrero JA, Sole-Violan J, Bordes Benitez A, et al (1999) Role of different routes of tracheal colonization in the development of pneumonia in patients receiving mechanical ventilation . Chest 116:462-470 14. Johanson WG, Pierce AK, Sanford JP, Thomas GD (1972) Nosocomial respiratory infection with Gram-negative bacilli: the significance of colonization of the respiratory tract. Ann Intern Med 77:701-706 15. Estes RJ, Meduri GU (1995) The pathogenesis of ventilator-associated pneumonia: I. Mechanisms of bacterial transcolonization and airway inoculation . Intensive Care Med 21:365-383 16. Garrouste -Orgeas M, Chevret S, Arlet G, et al (1997) Oropharyngeal or gastric colonization and nosocomial pneumonia in adult intensive care unit patients. A prospective study based on genomic DNA analysis. Am J Respir Crit Care Med 156:1647 - 1655 17. Rello J, Sonora R, Iubert P, Artigas A, Rue M, Valles J (1996) Pneumonia in intubated patients: Role of respiratory airway care. Am J Respir Crit Care Med 154:111-115 18. Sirvent JM, Torres A, El-Ebiary M, Castro P, de Batlle J, Bonet A (1997) Protective effect of intravenously admin istered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care Med 155:1729- 1734 19. Rello J, Ausina V, Ricart M, Castella J, Prats G (1993) Impact of previous antimicrobial ther apy on the etiology and outcome of ventilator-associated pneumonia. Chest 104:1230- 1235 20. Trouillet JL, Chastre J, Vuagnat A, et al (1998) Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am Rev Respir Dis 157:531-539 21. Torres A, Serra-Batlles J, Ros E, et al (1992) Pulmonary aspiration of gastric contents in pat ients receiving mechan ical ventilation : the effect of body posit ion. Ann Intern Med 116:540- 543 22. Orozco-Levi M, Torres A, Ferr er M, et al (1995) Semirecumbent position protect s from pulmonary aspiration but not completely from gastroesophageal reflux in mechanically ventilated patients. Am J Respir Crit Care Med 152:1387-1390 23. Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogue S, Ferrer M (1999) Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a rando mised trial. Lancet 354:1851-1858 24. Tryba M (1987) Risk of acute stress bleeding and nosocomial pneumonia in ventilated intensive care patients: Sucralfate versus antacids . Am J Med 83:117- 124 25. Cook D, Guyatt G, Marshall J, et al (1998) A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 338:791-797 26. Messori A, Tripoli S, Vaiani M, et al (2003) Bleeding and pneumonia in intensive care patients given ranit idine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled tr ials. BMJ 32:1103-1106 27. Fabregas N, Ewig S, Torres A, et al (1999) Clinical diagnosis of ventilator associated pneumo-

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28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.

44. 45. 46. 47. 48.

nia revisited: comparative validation using immediate post-mortem lung biopsies. Thorax 54: 867-873 Pugin J, Auckenthaler R, Mili N, Janssens JP, Lew PD, Suter P (1991) Diagnosis of ventilator associated pneumonia by bacteriologic analysis of bron choscopic and non-bronchoscopic "blind" bronchoalveolar lavage fluid. Am Rev Respir Dis 143:1121-1129 Fartoukh M, Maitre B, Honore S, et al (2003) Diagnosing pneumonia dur ing mechanical ventilation : The clinical pulmonary infection score revisited. Am J Respir Crit Care Med 168: 173-179 Ioanas M, Ferrer M, Angrill J, Ferrer M, Torres A (2001) Microbial investigation on vetilatorassociated pneumonia. Eur Respir J 17:791-801 Valencia M, Torres A, Insausti J, et al (2003) Valor diagnosti co del cultivo cuantitativo del aspirado endotraqueal en la neumonia adquirida durante la ventilacion mecanica. Estudio multicentrico. Arch Bronconeumol 39:394- 399 Torres A, Puig de la Bellacasa J, Xaubet A, et al (1989) Diagnostic value of quant itative cultures of bronchoalveolar lavage and telescoping plugged catheters in mechanically ventilated patients with bacterial pneumonia. Am Rev Respir Dis 140:306-310 Sanchez-Nieto JM, Torres A, Garcia-Cordoba F, et al (1998) Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: a pilot study. Am J Respir Crit Care Med 157:371-376 Sole-Violan J, Fernandez JA, Benitez AB, Cardenosa Cendrero JA, Rodriguez de Castro F (2000) Impact of quantitative invasive diagnostic techniques in the management of outcome of mechanically ventilated patients with suspected pneumonia. Crit Care Med 28:2737-2741 Ruiz M, Torres A, Ewig S, et al (2000) Noninvasive versus invasive microbial investigation in ventilator-asso ciated pneumonia. Am J Respir Crit Care Med 162:119-125 Fagon JY, Chastre J, WolffM, et al (2000) Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. Ann Intern Med 132:621-630 Torres A, Ewig S (2004) Diagnosing ventilator-associated pneumonia. N Engl J Med 350: 433-435 Alvarez-Lerma F (1996) Modification of empiric antibiot ic treatment in patients with pneumonia acquired in the intensive care unit. ICU-acquired Pneumonia Study Group. Intensive Care Med 22:387- 94 Luna CM, Vujacich P, Niederman MS, et al (1997) Impact of BAL data on therapy and outcome of ventilator-associated pneumonia. Chest 111:676-687 Rello J, Diaz E (2003) Pneumonia in the intensive care unit. Crit Care Med 31:2544-2551 Kollef MH, Ward S (1998) The influence of mini-BAL cultures on pat ient outcomes: implications for the antibiotic management of ventilator-associated pneumonia. Chest 113:412-420 Rello J, Gallego M, Mariscal D, Sonora R, Valles J (1997) The value of routine microbiologic investigation in the diagnosis of ventilator-associated pneumonia. Am J Respir Crit Care Med 156:196-200 American Thoracic Society (1996) Hospital-acquired pneumonia in adults: Diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. A consensus statement. Am J Respir Crit Care Med 153:1711-1725 Ioanas M, Cava1canti M, Ferrer M, et al (2003) Hospital-acquired pneumonia: coverage and treatment adequacy of current guidelines. Eur Respir J 22:876- 882 Niederman M, Craven D (2005) Guidelines for the management of adults with hospitalacquired pneumonia, ventilator-associated pneumonia, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388-416 Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR (1989) Antibiotic therapy for Pseudomonas aerugino sa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med 87:540-546 Korvick JA, Bryan CS, Farber B, et al (1992) Prospective observational study of Klebsiella bacteremia in 230 pat ients: outcome for antibiotic combinations versus monotherapy. Antimicrob Agents Chemother 36:2639- 2644 Chastre J, WolffM, Fagon JY, et al (2003) Comparison of 8 vs 15 days of antibiotic therapy for ventilator -associated pneumonia in adults: a randomized trial. JAMA 290:2588 - 2598

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Flucytosine Combined with Amphotericin B for Fungal Infections: A Postmarketing Surveillance and Future Perspectives P.H.J.

VAN DER VOORT

Introduction The incidence of fungal infections depends on the population studied. In immunodepressed patients and critically ill patients, fungal infections are emerging [1,2]. The clinical course is frequently complicated and prolonged, despite treatment. Treatment is unsuccessful in 30- 60 % of patients [1, 3]. A number of highly active new agents have recently become available [4]; as a consequence, amphotericin B is used less often [5,6]. However, until a few years ago, amphotericin B was the gold standard and the low costs of conventional amphotericin B deoxycholate still make this drug attractive for doctors in many countries. Most of the newer agents are used as monotherapy, while amphotericin Bcombined with flucytosine is usually seen as synergistic and as such is used for the treatment of severe infections [7,8]. The efficacy of this combination is high for treatment of cryptococcal meningitis [9, 10]. For other infections there are a limited number of reports [11]. The main reason for amphotericin B to be replaced by the newer, equally active agents is renal toxicity [5]. Monotherapy with flucytosine is not advocated because of resistance that can develop relatively easily for this drug . Though mostly used in combination with amphotericin B,flucytosine may be used in combination with the newer antifungal agents too. Flucytosine is a pyrimidine, activated by deamination within the fungal cells to 5-flurouracil. Flucytosine is an antimetabolite, which inhibits fungal protein synthesis by replacing uracil with 5-flurouracil in fungal RNA. In addition, it inhibits thymidylate synthetase resulting in decreased fungal DNAsynthesis [12]. Clinical trials involving the efficacy of flucytosine are scarce. The largest dataset on clinical efficacy and safety comes from a postmarketing surveillance .

Postmarketing Surveillance on Efficacy and Safety A post-marketing surveillance of flucytosine was recently performed in the UK and in the Netherlands. Individual doctors and hospital departments were invited based on the frequency of use of this agent. Other hospitals that were not explicitly invited to participate but who contacted the study coordinator were also invited to recruit patients for the study. The data were collected anonymously. A Case Record Form (CRF) was available to collect data in a uniform way. The data consisted of baseline information of the patient, the general condition and the current treatment (Table 1). Clinical and laboratory data (both microbiology and biochemical data) concerning the treatment period were recorded. Outcome data were recorded at the end of treatment and 3 months thereafter. The treating physician classified efficacy and safety in categories (good, moderate, not sufficient, not assessable).

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P.HJ. van der Voort Table 1. Main data items that were collected from study patients

Item Gender Age Height Weight Diagnosis

Properties Male/female Years Centimeters Kilograms Categories: possible/probable/proven

Intention of Categories: proven disease, empirical, pre-emptive, secondary prophylaxis, other treatment Site of infection Blood, abdominal, brain/meninges, trachea/lung, uri nary tract, other Comorbidity Surgery/AIDS/transplantation/neoplasm/neutropenia/intensive care/burn Previous treatment and current combination Combination treatment Biochemical and microbiology laboratory results Laboratory Treatment Efficacy Safety Adverse events Severity of infection Mortality

Time of collection Baseline Baseline Baseline Baseline Baseline, final diagnosis at end of treatment Baseline Baseline Baseline Baseline

Baselinel2 weeks/end of treatment Treatment dose and duration of f1ucytosine and co- End of treatment treatment Good, moderate, not sufficient, not assessable End of treatment Good, moderate, not sufficient, not assessable End of treatment Any adverse event End of treatment Categories: no more infection, slight, moderate, End of treatment severe End of treatment, 3 months Died or alive after start of treatment

AIDS: acquired immunodeficiency syndrome

Patients were included for 3 years and 5 months. Data were collected in 28 hospitals: 20 in the UK and 8 in the Netherlands. Two hundred and eighteen CRFs were collected from individual patients; 19 of these were children below 18 years and 2 patients were not treated with flucytosine. These 21 CRFs were excluded from analysis. From the remaining 197 CRFs, 48 were from The Netherlands and 149 were from the UK. The mean age was 54 years (standard deviation 17 years); male to female ratio was 66 % to 34 %. From these 197 patients, 102 were treated in the intensive care unit (ICU) (51.8 %). In 73 % of the patients, invasive mycotic infection was suspected on clinical grounds and confirmed by culture. In 10 % of the patients, the treatment was initiated based on a culture and in 17 % of the patients a clinical syndrome was the reason to initiate treatment but cultures could not confirm the suspected infection. In 32 % of the cases, flucytosine treatment was initiated because of failure of other antifungal treatment. In the pat ients with positive cultures, 59.9 % of the identified microorganisms were Candida (Table 2), 15.7 % were Cryptococcus, 6.6 % were Aspergillus, and 0.5 %

Flucytosine Combined with Amphotericin B for Fungal Infections Table 2. Frequency of Candida species in all patients

Candida species C. C. C. C. C. C. C.

albicans

glabrata tropicalis krusei parapsilasis stellatoidea glabrata & albicans Other Candida species

Frequency (%) 64 (32.5) 25 (12.7) 5 (2.5) 4 (2) 2 (1)

1 (0.5)

Unknown

9 (4.6) 10 (5.1) 77 (39.1)

Total

197 (100)

were a combination of Candida and Aspergillus. The infections were located in the abdomen (21.8 %). trachea/lung (16.2 %) , blood (13.7 %), meninges/brain (12.7 %). urinary tract (2.5 %), other sites or combined sites (10.2 %), not specified (5.6 %) . As stated before, the remaining 17.3 % of the patients had no pos itive culture confirmation of the clinical suspici on of Candida infection. The median du ration of treatment was 13 days (interquar tile range [IQR] 7 days). The median flucytosine dose was 5.5 g/d ay. One hundred and seventeen patients (59.4 %) were tre ated with continuous infusion , 65 patients (33.0 %) by bolus intra venous infusion , and in 15 pa tients (7.6 %) th e method of deliver y was no t reported. In 90.4 % of the patients, flucyto sine tr eatment was combined with amphotericin Bdeoxycholate intravenously. Nine patients (4.6 %) were treated with flucytosine monotherapy, two with liposomal ampho tericin B. The other eight pat ients were treated in combinat ion with flucon azole.

Efficacy of Flucytosine and Amphotericin B Treatment The treating physician evaluated the efficacy of treatment. In 74.7 % of cases , efficacy was described as sufficient (50.3 % clinically healed infection and 24.4 % clini cally improved) and in 7 % as treatment failure . In the remaining 36 patients (18.3 % ), efficacy was not assessable or unknown. Treatment failure occurred in 15.4 % of th e patients with aspergillosis, 7.7 % of the patients with Candida mycosi s, and 6.5 % of the patients with cr yptococcosis. All but one -treatment failure occurred in pati ent s receiving combination tr eatment with amphotericin B. The mortality was 29.4 % at the end of treatment; at that time, 13.2 % of patients had an ongoing fungal infection that was probably the rea son for dying. Most patients (67.9 %) died becau se of underlying disease without active fungal infection. Patients treated with a continuous infusion of flucytosine had a non-significant lower mortality compared to pat ient s given bolus infus ions (25.6 vs. 35.4 %). The treating physician evaluated the safety in the same way as the efficacy. It was described as good in 73.6 % of th e patients, moder ate in 11.7 %, not sufficient in 2 %, and not assessable in 12.7 %. Adverse event s were reported in 52 of the 197 pat ient s (26.4 %) . Diarrhea was reported 4 tim es, all other adverse events were reported once . A probable or possible relat ion of the adverse event with flucytosine, as judged by th e clini cian, was reported in 28.8 % of the events (15 cases, Table 3).

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Frequency (%)

Diarrhea Rigor Chest pain Erythema Liver failure Multiple organ failure Pancytopenia Pulmonary hemorrhage Rash Severe skin rash Thrombocytopenia Ventricular fibrillation/cardiac arrest

3 (20) 2 (13) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7)

Total

Adverse events

1S (100)

Side Effects of Flucytosine and Amphotericin on Renal and Hepatic Function Serum creatinine data were collected 3 weeks after start of therapy in 147 patients. Of this group, three patients showed an increase in serum creatinine of more than 150 umolll (Fig. 1). One of these patients was treated with flucytosine monotherapy, one patient was treated in combination with amphotericin B after a renal transplantation procedure, and one patient had received a relatively low dose of amphotericin B for a short period (0.5 mg/kg for 5 days). Bilirubin data were collected 3 weeks after start of therapy in 101 patients. The baseline bilirubin levels, prior to treatment, ranged from 3 to 375 umolll. The change in serum bilirubin ranged from a decrease of 128 umolll to an increase of 361 umol/l. From these 101 patients, five patients showed an increase in serum bilirubin concentration of more than 100 umolll, which is taken as an arbitrary level to define liver failure. Four of these five patients had elevated bilirubin levels at the

Fig. 1. Box-plot of the change in serum creatinine level (umol/l) over 3 weeks in 131 patients. * cases with a creatinine change outside the 95 % confidence limits.

Flucytosine Combined with Amphotericin B for Fungal Infections

time the treatment was started (94-375 umolll) . The reasons for an elevated baseline bilirubin for these four patients were liver transplantation (2) and multiple organ dysfunction syndrome during intensive care treatment (2). The 5th patient had a base line bilirubin level of 39 umolll. In contrast, 12 other patients had a bilirubin concentration above 50 umol/l prior to start of treatment but did not increase their bilirub in more than 100 umolll during treatment. Thus, the risk for progressive liver failure was 25 % (4/(12+4)) when the baseline bilirubin concentration was above 50 umolll and 1.2 % (1/(101-16)) when the baseline bilirubin was below 50 umolll (OR = 28).

Flucytosine and Amphotericin B in Candida Peritonitis Previously, it was shown that flucytosine levels in peritoneal fluid are more or less the same as serum levels (13). In contrast, amphotericin levels in peritoneal fluid in patients with candida peritonitis are substantially lower compared to serum levels. To obtain levels in peritoneal fluid which are above the minimal inhibitory concentration (MIC), the serum level of amphote ricin B should be higher than 0.5 mg/l (13). The largest subgroup in the postmarketing surveillance study was the patients with peritonitis (37 cases). Table 4 shows the Candida species that were found in 31 patients. From 6 patients, microbiological data from the abdominal fluid were unavailable. The duration of flucytosine treatment for this subgroup was 1 week in 19 % of the patients, 2 weeks in 51 %, 3 weeks in 16 %, and 4 weeks in 11 % of the patients. For 1 patient (3 %), this information was not available. Treatment was ended because patients were 'clinically healed' in 51 % of cases, improved in 22 % of the patients, and 3 % of the treatments were ended because of adverse events. Sixteen percent of the patients died during treatment; for one patient this information was not available and in two patients treatment was ended because of other, unspecified reasons. The efficacy of the treatment, as judged by the treating physician, was good in 84 %, moderate in 8 %, and not assessable in another 8 % of the patients . There was no significant relation between duration of treatment and efficacy. Safety, as judged by the treating physician, was not sufficient in one patient (2.7 %) and not assessable in 3 (8.1 %) . Safety was classified as good in 83.8 % of the patients and moderate in 5.4 % of the patients. The overall mortality at the end of treatment was 10 out of 37 patients (27 %) . Table 4. Frequency of

Candida species in patients with Candida peritonitis

Candida species

Frequency (%)

C. a/bieans C. g/abrata C. a/bieans and g/abrata C. stellatoidea C. tropicalis Other Candida species Unknown

13 (35.1) 6 (16.2) 4 (l O.8) 1 (2.7) 3 (8.1) 4 10.8) 6 (16.2)

Total

37 (100)

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Flucytosine and Amphotericin B in Meningeal Disease In 25 patients (12.7 %), the fungus or yeast was localized in the brain or meninges. One of these patients had aspergillosis and the other 24 patients had cryptococcal meningitis. These patients were younger than the complete population (42 vs. 54 years) and more often male (80 % vs. 66 %), with the majority of the patients having acquired immunodeficiency syndrome (AIDS, 80 % at the start of the medication). One of these 25 patients (4 %) was treated for one week, 12 for two weeks (48 %), 8 for 3 weeks (32 %), and 3 for 4 weeks (l2 %). For one patient these data were not available. At the end of treatment, the physician classified the infection as completely healed in 9 patients; 8 patients still had slight infection present. Overall, physicians classified the efficacy of treatment as good in 17 patients (68 %), moderate in 5 patients (20 %), and not sufficient in 3 (l2 %) patients; these 3 patients died.

Effectiveness of Flucytosine and Amphotericin B in Critically III Patients Studies concerning treatment of Candida infection with flucytosine and amphotericin B in the specific situation of critical illness have not been performed. In our postmarketing surveillance, there were 102 patients treated in the leu for severe mycotic infection. Of these patients, 72 % had Candida infection, 10 % Aspergillus, 3 % Cryptococcus, and the others did not have microbiological confirmation of the clinical diagnosis of mycotic disease; 32 % had Candida peritonitis, 20 % pulmonary infection, and 14 % blood stream infection. At the end of treatment, the infection was classified as clinically healed in 56 % and improved in 15 % of the patients. Treatment was unsuccessful in 6 % and treatment effect was not assessable in the other 23 %. The hospital mortality was 36 %. All patients were treated with amphotericin B in combination. Two patients showed an increase in creatinine of more than 150 umolll.

Future Perspectives on the Combination of Flucytosine and Amphotericin B A limited number of clinical studies have been published on flucytosine treatment of fungal infections . The treatment of cryptococcal meningitis has been studied most [10]. Limited cases of other diseases, such as esophagitis and fungemia, have been treated with flucytosine in small studies . One study addressed the treatment of pneumonia and peritonitis [11]. With such a limited number of studies, the present post-marketing surveillance of 197 adult patients treated with flucytosine adds significantly to the clinical knowledge of the efficacy and safety of this antifungal agent. However, postmarketing surveillance has limitations by design in that it is observational and non-randomized, includes a wide spectrum of patients in terms of diagnosis and severity of disease, covers non-standardized treatments, and, in this case, allows a relatively free interpretation by the clinicians of end-points such as efficacy and safety. In fact, the postmarketing surveillance describes the clinical practice of flucytosine treatment for suspected and proven mycotic disease. Given the results, it can be concluded that this drug is currently used in a non-standardized way. The method of administration (continuous or intermittent), the dose, and the duration

Flucytosine Combined with Amphotericin B for Fungal Infections

of treatment appear to be highly variable . Further research and guidelines may improve these aspects. This study shows that the efficacy of flucytosine , as classified by the physicians, is sufficient as in around half the patients the infection was healed and in an additional quarter of the patients the infection improved. Considering that one third of the patients had had a treatment failure on previous antifungal therapy, this overall efficacy rate is satisfactory. This clinical efficacy may be related to the high prevalence of susceptibility of Candida species [14]; however, MIC values were not determined. The registration of adverse events in this study is important as it shows that toxicity is infrequent but may be life-threatening. It must be stated , however, that other toxic medication (in particular amphotericin B) was combined with flucytosine in 96 % of the patients, and 52 % of the patients were critically ill and as such exposed to many other potentially harmful medications and events. These facts may have added to the incidence of the reported adverse events. A major finding is that the incidence of liver failure is high when flucytosine is started when serum liver enzymes are elevated. As a consequence, it is unwise to start flucytosine treatment in patients with elevated bilirubin concentrations (above 50 umolll). The adverse effects on renal function in several patients were more likely to be caused by amphotericin B as virtually all patients were also treated with amphotericin B and renal failure is not a known adverse effect of flucytosine. The clinicians participating in this postmarketing surveillance judged the efficacy and safety of the combination of flucytosine and amphotericin B as sufficient. However, currently available new antifungal drugs may have a better efficacy and safety profile. Controlled trials comparing the newer drugs with the flucytosine/amphotericin B combination are not available in general or in the intensive care setting in particular.

Conclusion Flucytosine and amphotericin B treatment were once the principle choice for the treatment of fungal infection . However, data on the clinical use of flucytosine combined with amphotericin B are scarce. Postmarketing surveillance of clinical practice in the Netherlands and the UK shows that clinicians find flucytosine an effective antifungal drug with infrequent adverse effects. Liver failure predominantly occurs when liver enzymes are elevated at the beginning of flucytosine therapy. However, significant variations in dosage and in method of delivery exist. Prospective studies are needed to determine the exact role of flucytosine in combination with amphotericin B for the treatment of invasive fungal infections in the era of new antifungal agents. Reviewing the current evidence, the newer antifungal drugs may well be in favor. References 1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analys is of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309 - 317 2. Vincent TL, Anaissie E, Bruining H, et al (1998) Epidemiolog y, diagnos is and treatment of systemic Candida infection in surgical patients under intensive care. Intens ive Care Med 24: 206-216

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P.HJ. van der Voort 3. McNeil MM, Nash SL, HllJJeh RA. er al (2001) Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis 33:317-323 4. Boucher HW, Groll AH, Chiou CC, Walsh TJ (2004) Newer systemic antifungal agents. Drugs 64:1997- 2020 5. Kleinberg M (2006) What is the current and future status of conventional amphotericin B? Int J Antimicrob Chemother 27(Suppl 1):12-16 6. Kauffman CA (2006) Fungal infections. Proc Am Thorac Soc 3:35-40 7. Lewis RE, Kontoyiannis DP (2001) Rationale for combination antifungal therapy. Pharrnacotherapy 21:149S·164S 8. Schwarz P, Dromer F, Lortholay, Dannaoui E (2003) In vitro interaction of flucytosine with convent ional and new antifungals against Cryptococcus neoformans clinical isolates. Antimicrob Agents Chemother 47:3361- 3364 9. Zhirong YAO, Wanqing LIAO, Hai WEN (2000) Antifungal therapy for treatment of cryptococcal meningitis. Chin Med J 113:178-180 10. Bennett JE, Dismukes WE, Duma RJ, et al (1979) A comparison of amphotericin B alone and combined with flucytosine in the treatment of Cryptococcal meningitis. N Engl J Med 301:126-131 11. Abele-Horn M, Kopp A, Sternberg U, et al (1996) A randomized study comparing fluconazole with amphotericin B/5·flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 24:426-432 12. Bennett JE (1977) Flucytosine. Ann Intern Med 86:319-322 13. van der Voort PH, Boerma EC, Yska JP (2007) Serum and intraperitoneal levels of amphotericin Band flucytosine during intravenous treatment of critically ill patients with Candida peritonitis. J Antimicrob Chemother 59:952- 956 14. Pfaller MA, Messer SA, Boyken L, Huynh H, Hollis RJ, Diekema OJ (2002) In vitro-activities of 5·fluorocytosine against 8,803 clinical isolates of Candida spp.: global assessment of primary resistance using national committee for clinical laboratory standards susceptibility testing methods. Antimicrob Agents Chemother 46:3518-3521

Section X

X Cellular Mechanisms in Sepsis

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Apoptosis in Critical Illness: A Primer for the Intensivist Z.

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and

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MARSHALL

Introduction The complexities of the cell cycle have occupied a prominent place in the history of cellular biology. Recognition of the process of mitosis dates back over a century, when Pol, Butschli, and Strasburger identified a network of intracellular points and lines, then called the karyokinetic figure, and today known as the mitotic apparatus. This discovery, dating to 1873, laid the foundation for the discovery of chromosomes and, later, the fundamental biologic processes of mitosis and meiosis [1]. But, while cellular growth and proliferation were understood to be essential to the emergence of multicellular organisms , the corollar y - that controlled cell death must be part of this calculus of cellular homeostasis - was not appreciated until quite recently. Although cell death was first described in 1859 by Virchow, it took more than a century to appreciate the importance of programmed cell death as a physiological process that eliminated unwanted cells [2]. The term 'apoptosis' was coined in 1972 by Kerr, Wyllie, and Currie to describe a distinct type of cell death characterized by the degradation of cellular constituents into membrane-bound apoptotic bodies [3]. Since then, recognition of the importance of apoptosis in health and disease, and an understanding of its cellular mechanisms, has increased exponentially.

Cellular Mechanisms of Apoptosis The word 'apoptosis' is of Greek origin, derived from 'apo' referring to separation, and 'ptosi s', translated as 'falling off, but more commonly used to describe the shedding of leaves from trees [2]. Apoptosis describes a discrete form of genetically programmed cell death that is central to development and homeostasis in metazoans [4], and that differs from cell death by necrosis which is precipitated by cellular damage, resulting in uncontrolled release of intracellular constituents [2]. The basic mechanisms of apoptosis are highly conserved (Fig. 1). Induction and Expression of Apoptosis

Apoptosis results in the efficient, and non-inflammatory removal of redundant, senescent, transformed, or infected cells [5]. Central to this process is the degradation of intracellular proteins by members of a family of intracellular cysteine proteases called caspases, so named because they cleave their target proteins through the recognition of tetrapeptide sequences adjacent to an aspartic acid residue. There are at least 14 caspases in mammals, eleven of which are found in humans;

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ExtrinsicPathway IntrinsicPathway

CD95/TN FR

Caspase-8 Inhibitorsof Apoptosis: Survivin

cIAP1) XIAP1, NAIP

Caspase-3

I DNA, Protein cleavage

Smac/ DIABLO

Fig. 1. Apoptosis is initiated in a receptor-mediated manner through the extrinsic pathway, or through altered mitochondrial permeability via the intrinsic pathway. Activation of either results in the assembly of macromolecular complexes that lead to initiator caspase activation, and, in turn, to the activation of effector caspases such as caspase-3. This process can be inhibited by intracellular inhibitor of apoptosis proteins, and the action of these, in turn, can be blocked by proteins such as SmaclDIABLO. See text for details.

seven of these have important established roles in apoptosis [6]. The caspase family can be further subdivided into initiator caspases that trigger the apoptotic cascade, and effector caspases responsible for enzymatic cleavage of a range of intracellular proteins, ultimately causing cell death [7]. The initiator caspases (primarily caspases-8 and -9, but also including caspases-2, and -10) are characterized by having at least one adaptor domain in their N-terminal region [7]. They are autoactivated and tightly regulated, through the assembly of multi-component complexes [8]. Effector caspases - predominantly caspases-3, -6, and -7 - contain prodomains that are activated by an initiator caspase through cleavage at specific aspartate residues. Two principal pathways of apoptosis exist in mammalian cells, intrinsic and extrinsic, determined by the origin of the death stimulus, The intrinsic pathway is initiated by stimuli that originate within the cell, such as DNA damage, or that directly induce cellular damage, such as ionizing radiation, and is triggered by changes in mitochondrial permeability [7]. Alterations in mitochondrial transmembrane potential trigger the release, from the mitochondrial intermembrane space into the cytoplasm, of proteins including cytochrome C, Smac/DIABLO, apoptosis-inducing factor (AIF), endonuclease G (EndoG), and Omi/HtrA2 [9]. The actions of the pro-apoptotic protein, cytochrome C, are best characterized, Cytochrome C binds to apoptotic protease activating factor (APAF)-l in the cytoplasm, inducing a conformational change that permits the binding of ATP/dATP to APAF-l, and recruiting pro-caspase-9 to create a multi-protein complex termed the apoptosome. Formation of the apoptosome results in the cleavage of pro-caspase-9, releasing activated caspase-9, and so triggering the apoptotic process, with activation of effector caspases, such as caspase-3 and caspase-7 [7, 10]. Other mitochondrial proteins such as Smac/DIABLO or Omi/HtrA2, released by changes in mitochondrial transmembrane potential, support the progression of apoptosis by blocking the activity of inhibitory proteins of the inhibitor of apoptosis protein (lAP) family. The extrinsic pathway is activated by the binding of an extracellular death ligand to its cell-surface death receptor. Death ligands, such as FasL and tumor necrosis factor (TNF)-a, interact with their receptors as homotrimers (complexes of three identical proteins), and so result in the clustering of three corresponding receptors, for example Fas (CD95) or the TNF-a receptor 1 (TNFRl), respectively. Each death

Apoptosis in Critical Illness: A Primer for the Intensivist

receptor is a transmembrane protein that contains a cytoplasmic death domain that connects the components of the apoptotic pathway intracellularly [11]. The association of receptor death domains induces recruitment of additional adaptor proteins that also contain death domains . Activated Fas receptor recruits Fas-associated death doma in (FADD), which, in addition to containing a death domain , also has a death effector domain (DED); the DED on FADD recruits and binds caspase-8. The resultant Fas/FADD/caspase-8 protein complex, termed the death -inducing signaling complex (DISC), leads to autocleavage and activation of caspase-8 [12], and, in turn, cleavage and activation of the effector caspase, caspase-3 [7]. TNF-a binding to TNFR1 also leads to receptor trimerization and the recruitment and binding of TNFR-associated DD-containing proteins (TRADDs) through their death domains. Like FADD, TRADD can recruit and activate caspase-8, activating caspase-3 and inducing apoptosis . However, TRADD can also associate with secondary adaptor molecules that include TNFR-associated factor-2 (TRAF2) and receptor -interacting protein (RIP): This interaction results in activation of the transcription factors nuclear factor-kappa B (NF-KB) and activator protein (AP)-l [13, 14], that promote the transcription ofIAP family members [15]. Thus, TNF-a can subserve the contradictory roles of inducing or inhibit ing apoptosis - the actual biologic activity resulting from TNFR engagement being dependent on poorly understood accessory signals accompanying receptor engagement (11). Caspase-3 activation, through either the intrinsic or extrinsic pathway, leads to cleavage of key cytostructural proteins, such as actin. Cleavage of another key protein target the inhibitor of caspase-activated DNase (ICAD) - results in the release of caspase activated DNase (CAD), an executioner of DNA fragmentation. Finally, the nuclear DNA repair enzyme, poly (ADP-ribose) polymerase (PARP), is inactivated through cleavage by caspase-3 (16). Together these processes result in chromatin condensation, and the creation of membrane-bound apoptotic bodies . The intrinsic and extrinsic pathways can interact at multiple levels. For example, activated caspase-8 can cleave Bid, a pro -apoptotic member of the Bcl-2 protein family. This truncated form of Bid (tBid) promotes the release of cytochrome C from mitochondria, thus activating the intrinsic pathway of apoptosis (17).

Regulation of Apoptosis Regulation of the intrinsic pathway occurs primarily through the Bcl-2 family of proteins. Bcl- 2 family members share at least one Bcl-2 homology (BH) domain , and are subdivided into proteins having pro-apoptotic or anti-apoptotic activity. Pro-apoptotic members of the Bcl-2 family, including Bax, Bad, Bak, Bid, and Bik, can be further subdivided on the basis of having only a BH3 domain, and so requiring assistance from pro-apoptotic members containing multiple BH domains in order to induce apoptosis. Pro-apoptotic Bcl-2 prote ins regulate the formation of large openings in the mitochondrial outer membrane, allowing for the release of intramembrane space proteins and the induction of apoptosis (18). Bcl-2, the initial member of this family to be identified, was isolated as a protein over-expressed in lymphocytes from a patient with a B cell lymphoma. Although the precise mechanism through which Bcl-2 inhibits apoptosis is unknown, it has been proposed that its activity arises through its capacity to block cytochrome C release, and to decrease Ca2+ sensitivity of the mitochondrial pore opening (19). Other anti-apoptotic Bcl-2 members, such as Bcl-2 and Bel-xi, may bind and sequester pro-apoptotic molecules, such as Bax, Bak, and Bid, through a hydrophobic cleft. Other anti-apo-

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ptotic proteins related to the Bcl-2 family, including Mel-I and AI, lack a protein domain necessary for interactions with pro-apoptotic Bcl-2 family members. Mel-I is found primarily in hematopoietic cells and exhibits rapid turnover; thus, protection from apoptosis is short-lived [20]. Little is known about the mechanism of action of Mel-I or AI, or about the specific protein targets with which they interact. The lAP family of proteins inhibits the progression of apoptosis within the cytoplasm. Originally identified as anti-apototic proteins encoded in the baculovirus genome, the lAP family is highly conserved and present in both mammals and Drosophila. There are eight mammalian lAPs: XIAP, clAP-I, clAP-2, ML-IAP/livin, ILP2, NAIP, Bruce/Apollon, and survivin; all but ML-IAP and ILP-2 are found in humans. Caspase-9 is inhibited primarily by XIAP, which also inhibits caspase-3 and -7; the latter caspases may also be inhibited by clAP-I, clAP-2, and NAIP. All lAPs contain at least one baculoviral repeat (BIR) domain, although each BIR domain may be responsible for distinct functions. XIAP inhibits activated caspase-9 through its third BIR domain, while caspase-3 and -7 are targeted by a region between its first two BIR domains [7]. The mechanism of caspase-9 inhibition appears to involve heterodimerization with monomeric caspase-9, preventing apoptosome formation and caspase-9 autoactivation [21]. Inhibition of the effector caspases-3 and -7 by XIAP occurs through a linker peptide preceding its second BIR domain. This peptide occupies the active site of caspase-3 or -7 and serves to block substrate contact [7]. A further level of complexity in the regulation of apoptosis occurs through proteins that can block lAPs. For example, Smac/DIABLO released from mitochondria during activation of the intrinsic pathway contributes towards apoptosome formation, leading to activation of caspase-9, a process inhibited by XIAP. Binding of XIAP to caspase-9 occurs through an lAP-binding tetrapeptide motif on caspase-9 that allows for recruitment of XIAP and inhibition of caspase-9 activity. SmaclDIABLO possesses a similar lAP-binding tetrapeptide motif that can bind to the BIR3 domain of XIAP, and so restore caspase-9 activation [7]. Dysregulated Apoptosis in the Pathogenesis of Critical Illness

The leading cause of death for critically ill patients in an intensive care unit (ICU) is the multiple organ dysfunction syndrome, a complex disorder that arises in association with an activated systemic inflammatory response and that has a mortality of 60 % or higher when three or more organs are affected for 7 or more days [22]. The evolution of multiple organ dysfunction syndrome is associated with profound alterations in metabolic, immunologic, and cardiovascular homeostasis, and even more fundamentally, with alterations in cell survival through either excessive activation, or abnormal inhibition, of the normal kinetics of programmed cell death. Excessive Apoptosis as a Mechanism of Multiple Organ Dysfunction Syndrome

Many of the classic cellular processes and biochemical mediators of systemic inflammatory response syndrome (SIRS)/mult iple organ dysfunction syndrome have the capacity to promote apoptosis in organ and endothelial cells. Apoptosis can be accelerated, for example, by increased release of some pro- and anti-inflammatory cytokines, increased oxidant production, increased release of heat shock proteins (HSPs) from the liver, elevated glucocorticoid levels, and the release of bacterial prod-

Apoptosis in Critical Illness: APrimer for the Intensivist

ucts into the circulation. Independently, these factors can alter apoptosis, however their aggregate effect in the setting of critical care may amplify this potential [23]. Vascular endothelial damage is a prominent feature of early organ dysfunction [24]. Recruitment of activated neutrophils may contribute to endothelial injury through the action of neutrophil-derived reactive oxygen species that have been implicated in altering apoptosis signaling pathways. An in vitro model of endothelial cell injury using porcine aortic endothelial cells showed that these cells underwent apoptosis when exposure to lipopolysaccharide (LPS) or cytokines was followed by heat shock; independently, these stimuli did not precipitate apoptosis. When antioxidants were administered prior to initial LPS stimulation, apoptosis was inhibited [23]. Apoptotic endothelial cell damage can potentially mediate organ injury by impeding normal tissue oxygen delivery. Other cell populations manifest increased rates of apoptosis in pre-clinical models of critical illness. Hotchkiss et al. showed increased rates of lymphocyte apoptosis in spleen, thymus, ileum, colon, lung, and skeletal muscle in a murine model of sepsis; parenchymal cells in ileum, colon, lung, kidney, and skeletal muscle were also shown to be apoptotic [25]. Differing cell populations show variable susceptibility to apoptotic stimuli. For example, aortic endothelial cells demonstrate greater susceptibility to endotoxin-induced apoptosis than pulmonary artery, and left and right ventricular endothelial cells [26]. The acute respiratory distress syndrome (ARDS) is a common complication of critical illness. Bronchoalveolar lavage (BAL) fluid from ARDS patients can induce both fibroblast and endothelial cell apoptosis, suggesting the presence of pro-apoptotic factors in the BAL fluid. Furthermore, histological analysis of lung tissue in ARDS revealed apoptotic cell death in airspace granulation tissue [27]. The liver is particularly susceptible to endotoxin-induced apoptotic injury, perhaps because it contains an increased number of TNF receptors and inflammatory cells capable of producing inflammatory mediators [26]. Increased levels of transarninases and hepatocyte apoptosis are observed following TNF or LPS administration in a murine model; anti- TNF therapy blocked both phenomena, suggesting that they are mediated by TNF [28]. In a porcine model, endotoxin administration increased plasma levels of TNF, upregulated inducible nitric oxide synthase (iNOS), and decreased anti-apoptotic Bcl-2 levels in liver and spleen [26]. On the other hand, liver apoptosis was not seen in the cecal ligation and puncture (CLP) model reported by Hotchkiss [25]. Apoptosis has also been observed in the kidney in models of acute illness. In vivo studies show apoptotic death of renal tubular cells during reperfusion, while in vitro studies demonstrate this effect during both hypoxia and reperfusion. Apoptosis of renal cortical cells was seen 12 hours following reperfusion in a rat model [26]. The number of apoptotic renal cells in mice correlates with prolonged renal ischemia and the time following reperfusion [23]. In vitro, apoptosis of renal tubular cells can also occur following exposure to Escherichia coli-derived toxins and verotoxins. Nephrotoxic acute renal failure can result from increased apoptosis in response to therapies administered to critically ill patients. Rats given gentamicin exhibited increased apoptosis in proximal and distal tubules, while patients who received an overdose of ciprofloxacin developed distal tubular apoptosis [26]. Work by Imai and colleagues showed that injurious mechanical ventilation strategies in rabbits evoked Fas ligand-dependent epithelial cell apoptosis in the kidney [29]. Although myocyte loss in critical illness has been attributed to necrosis, apoptotic cell death has also been implicated as a mechanism of injury. Following myocar-

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dial infarction, reduced perfusion and greater myocardial stretch can serve as triggers for apoptosis [26] . Myocardial infarction leads to myocyte apoptosis in rats, and reperfusion injury to cardiomyocyte apoptosis in rabbits [23] . Patients with end-stage congestive heart failure undergoing heart transplantation also exhibited cardiomyocyte apoptosis, and showed alterations in the expression of apoptotic mediators. Pro-apoptotic members of the Bcl-2 family remained unchanged, however anti-apoptotic members showed a 1.8 fold increase in expression when compared with levels in normal hearts; rates of apoptosis in failing hearts were 232 times greater than in normal hearts [30]. Lymphoid tissues also show evidence of aberrant apoptosis in critical illness. T-cell suppression, and a reduction in numbers of circulating T-lymphocytes are common characteristics of SIRS and multiple organ dysfunction syndrome [23]. Increased thymocyte apoptosis appears to contribute to thymic involution and T-cell suppression in a mouse model of gram-negative or-positive sepsis [31], and thymocyte apoptosis was reported in a rat CLP model. Thymocyte deprivation of interleukin (1L)-2 triggers thymocyte apoptosis, suggesting that low IL-2 levels may contribute to sepsis-associated T-cell depletion [23, 32]. Extensive lymphocyte and gastrointestinal epithelial cell apoptosis have been observed in sepsis in both animal models and human patients [25, 33, 34]. Postmortem examination of patients with sepsis revealed widespread apoptosis of lymphocytes in the spleen, intestinal lamina propria, and lymphoid aggregates. Further phenotypic studies comparing spleens from septic patients with those from critically ill patients who did not have sepsis showed that the particular lymphocytes affected include B cells, CD4+ T cells, and dendritic cells, but not macrophages [33,34]. Loss of muscle mass is believed to contribute to neuromuscular weakness both during and following critical illness. Such weakness manifests clinically as hypoventilation, prolonged dependence on mechanical ventilation, delayed mobilization, and muscle contractures . Although loss of muscle mass has been ascribed to accelerated protein breakdown due to systemic catabolism, myocyte apoptosis also appears to be a contributing factor. Following burn injury, apoptosis is accelerated in muscles located both adjacent to, and distant from, the burn site [26]. Accelerated apoptosis in multiple tissue beds, therefore, appears to contribute to organ dysfunction by depleting functional cells. However, apoptotic failure has also been implicated in the pathogenesis of acute organ failure.

Inadequate Apoptosis as a Mechanism of MODS Neutrophils are key effectors of the innate immune response to infection. Their migration to sites of infection occurs early in order to eliminate pathogens through phagocytosis and the production of toxic mediators. In the absence of pro-surv ival stimuli from the inflammatory microenvironment, neutrophils are constitutively apoptotic, with a circulating lifespan of 8- 20 hours. However multiple stimuli - of both microbial and host origin - can subvert this process, and prolong the functional survival of the neutrophil (Table 1). The normal expression of apoptosis and clearance of neutrophils from sites of inflammation is important in minimizing inadvertent bystander injury secondary to the release of neutrophil cytotoxic intracellular contents, as occurs during death by necrosis. Neutrophil longevity thus reflects a crucial balance between survival to fight infection and timely death to prevent collateral tissue damage. Additionally, neutrophil apoptosis must be regulated

Apoptosis in Critical Illness: A Primer for the Intensivist Table 1. Factors implicated in the inhibition of neutrophil apoptosis Microbial Products Endotoxin Lipoteichoic acid Mannan Modulins fro m coagulase-negative Staphylococci E. coli verotoxin H. pylori surface proteins Butyric acid Propionic acid Respiratory syncytial virus Physiologic Processes Transendothelial migration Hypoxia Acidosis

Host-derived Mediators Interleukin (IL}-l ~ IL-2 IL-3 IL-4 IL-6 IL-8 IL-1S Tumor necrosis factor Interferons G-CSF, GM-CSF Leptin Pre-B cell colony enhancing factor CSa Cathelicidins Leukotriene B4 70

60 ~ 50

Fig. 2. Whereas neutrophils harvested from healthy volunteers undergo spontaneous apoptosis following 24 hours of in vitro culture, this process is inhibited following culture with bacterial LPS, and further suppressed in circulating neutrophils from critically ill septic patients. Adapted from [38]

.~

o

40

15.. 30 o

~ 20

10

o

Control

LPs

Sepsis

carefully in order to maintain appropriate numbers within the body, since approximately 10" neutrophils are produced daily by healthy adults [11, 35). Suppressed neutrophil apoptosis has been described during a number of acute and chronic inflammatory diseases, including burn injury (36), multiple trauma (37), sepsis [38), and acute pancreatitis [39) (Fig. 2). Neutrophils harvested from BAL fluid from patients with ARDS show marked delays in apoptosis [40), and BAL fluid from patients with ARDS imparts anti-apoptotic effects on neutrophils, dependent on concentrations of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). Conversely, the phagocytosis of bacteria and fungi accelerates neutrophil apoptosis . In a rat model of intestinal ischemial reperfusion injury associated with marked pulmonary neutrophilia, intratracheal administration of killed E. coli attenuated lung injury, and improved survival [41).

Therapeutic Implications An enhanced understanding of the mechanisms of apoptosis, and of its role in the pathogenesis of disease, has begun to define potential options for therapeutic intervention to modulate apoptosis, and to point to new mechanisms of action for established therapies.

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The anti-inflammatory activity of corticosteroids arises, in part, from their capacity to increase apoptosis in eosinophils, T-cells, and monocytes. Glucocorticoids can suppress the cell survival transcription factor, AP-1, in lymphocytes, and so inhibit the transcription of survival factors. Studies in knockout mice indicate that both APAF-1 and caspase-9 are essential for corticosteroid-induced apoptosis of thymocytes. Conversely, caspase-1 and -3 deficiencies do not prevent corticosteroidinduced apoptosis [42]. The intracellular activities of steroids are complex, and glucocorticoids can affect the expression of the same genes in opposite ways, depending on the tissue and biologic context [43]. Glucocorticoids can also support the resolution of inflammation by enhancing the uptake of apoptotic neutrophils by phagocytic cells [44]. Significant decreases in plasma glutamine levels have been observed in critical illness, and glutamine deficiency has been associated with increased mortality in criti cally ill patients. Clinical trials studying glutamine administration in critically ill patients have suggested improvements in mortality, length of stay, and infectious morbidity [45]. Modulation of apoptosis is a potential mechanism for these effects. In a rat intestinal epithelial cell line, glutamine starvation for 24 hours caused a 60 % reduction in cell numbers as a consequence of increased apoptosis and caspase-3 activation . Glutamine is also required to protect human T cells from apoptosis. Glutamine downregulated Fas and FasL but upregulated Bcl-2 in stimulated T cells, raising the apoptotic threshold of these cells. Furthermore, glutamine inhibited the activation of caspase-3 and -8 in stimulated [urkat T cells [16]. Specific caspase inhibitors have been developed and evaluated in experimental models. Mice administered a broad-spectrum caspase inhibitor, zVAD-fmk, were protected from LPS-induced acute lung injury (ALI) and its attendant lethality [46]. The use of a selective caspase-3 inhibitor or a polycaspase inhib itor to prevent lymphocyte apoptosis in mice subjected to CLP resulted in improved survival [47]. Pretreatment with a caspase-3 inhibitor protected against TNF-mediated hepatocyte apoptosis. Additionally, caspase inhibition decreased apoptosis in models of renal, cardiac, cerebral, and hepatic ischemia/reperfusion injury, decreased infarct size in cardiac and cerebral ischemia, and improved survival in hepatic ischemia [26]. However caspase inhibition is not universally beneficial, for at least one group has shown that zVAD-fmk intensified TNF-induced toxicity by augmenting oxidative stress and mitochondrial damage, leading to increased mortality [48].

Conclusion Apoptosis is a highly conserved physiologic process that is fundamental to the survival of multicellular organisms. Alterations in its expression leading to either excessive or deficient apoptosis are emerging as important mechanisms of disease; an evolving body of literature implicates both excessive and inadequate apoptosis in the pathogenesis of critical illness. That apoptosis is also a highly regulated process suggests the potential for interventions to taget dysregulated apoptosis, and so to restore normal kinetics of cell death, and, hopefully, attenuate acute organ injury. However the translation of this complex biology into efficacious new therapies for the critically ill remains elusive.

Apoptosis in Critical I\Iness: APrimer for the Intensivist References 1. Gourret JP (1995) Modelling the mitotic apparatus. From the discovery of the bipolar spindle to modern concepts. Acta Biotheor 43:127-142 2. Duque-Parra JE (2005) Note on the origin and history of the term "apoptosis", Anat RecB New Anat 283:2-4 3. Kerr JF (2002) History of the events leading to the formulation of the apoptosis concept. Toxicology 181-182:471-474 4. Jacobson MD, Weil M, Raff MC (1997) Programmed cell death in animal development. Cell 88:347 -354 5. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer 26:239- 257 6. Shi Y (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 9:459-470 7. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Bioi 5:897- 907 8. Adams JM, Cory S (2002) Apoptosomes: engines for caspase act ivation. Curr Opin Cell Bioi 14:715-720 9. Wang X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15:2922-2933 10. Yuan J, Yankner BA (2000) Apoptosis in the nervous system . Nature 407:802-809 11. Akgul C, Edwards SW (2003) Regulation of neutrophil apoptosis via death receptors. Cell Mol Life Sci 60:2402- 2408 12. Medema JP, Scaffidi C, Kischkel FC, et al (1997) FLlCE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16:2794-2804 13. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281: 1305-1308 14. Nagata S (1997) Apoptosis by death factor. Cell 88:355- 365 15. Ward C, Chilvers ER, Lawson MF, et al (1999) NF-kappaB activation is a critical regulator of human granulocyte apoptosis in vitro. J Bioi Chem 274:4309-4318 16. Fuchs BC, Bode BP (2006) Stressing out over survival: glutamine as an apoptotic modulator. J Surg Res 131:26-40 17. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481-490 18. Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Bioi 15:691-699 19. Murphy E, Imahashi K, Steenbergen C (2005) Bcl-2 regulation of mitochondrial energetics. Trends Cardiovasc Med 15:283- 290 20. Edwards SW, Derouet M, Howse M, Moots RJ (2004) Regulation of neutrophil apoptosis by Mel-I, Biochem Soc Trans 32:489-492 21. Shiozaki EN, Chai J, Rigotti DJ, et al (2003) Mechanism of XIAP-mediated inhibition ofcaspase-9. Mol Cell 11:519 - 527 22. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ (1995) Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 23:1638-1652 23. Papathanassoglou ED, Moynihan JA, Ackerman MH (2000) Does programmed cell death (apoptosis) playa role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework. Crit Care Med 28:537- 549 24. McMillen MA, Huribal M, Sumpio B (1993) Common pathway of endothelial-leukocyte interaction in shock, ischemia, and reperfusion. Am J Surg 166:557- 562 25. Hotchkiss RS, Swanson PE, Cobb JP, Jacobson A, Buchman TG, Karl IE (1997) Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T-and B-cell-deficient mice. Crit Care Med 25:1298-1307 26. Lydon A, Martyn JA (2003) Apoptosis in critical illness. Int Anesthesiol Clin 41:65-77 27. Polunovsky VA, Chen B, Henke C, et al (1993) Role of mesenchymal cell death in lung remodeling after injury. J Clin Invest 92:388- 397 28. Leist M, Gantner F, Bohlinger I, Tiegs G, Germann PG, Wendel A (1995) Tumor necrosis fac-

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J.e. Marshall

tor-indu ced hepatocyte apoptosi s precedes liver failure in experimental mur ine shock models. Am J Pathol 146:1220-1234 Imai Y, Parodo J, Kajikawa 0 , et al (2003) Injuriou s mechanic al ventilation and end -organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respirator y distress syndrome. JAMA 289:2104 - 2112 Olivetti G, Abbi R, Quaini F, et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131 - 1141 Wang SD, Huang KJ, Lin YS, Lei HY (1994) Sepsis-induced apoptosis of the thymocytes in mice. J Immunol 152:5014-5021 Barke RA, Roy S, Chapin RB, Charboneau R (1994) The role of programmed cell death (apoptosis) in thymic involution following sepsis. Arch Surg 129:1256-1261 Hotchkiss RS, Tinsley KW, Swanson PE, et al (2001) Sepsis-induced apopto sis causes progre ssive profound depletion ofB and CD4+ T lymphocytes in humans . J ImmunoI166:6952-6963 Hotchkiss RS, Tinsley KW, Swanson PE, et al (2002) Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 168:2493-2500 Simon HU (2003) Neutrophil apopto sis pathways and their modifications in inflammation. Immunol Rev 193:101- 110 Chitnis D, Dickerson C, Munster AM, Winchurch RA (1996) Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients. J Leukoc Bioi 59:835- 839 Ertel W, Keel M, Infanger M, Ungethum U, Steckholzer U, Trentz 0 (1998) Circulating mediators in serum of injured patients with septic complications inhibit neutrophil apoptosis through up-regulation of protein-tyrosine phosphorylation. J Trauma 44:767- 775 Taneja R, Parodo J, Iia SH, Kapus A, Rotstein OD, Marshall JC (2004) Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit Care Med 32:1604-1469 O'Neill S, O'Neill AJ,Conroy E, Brady HR, Fitzpatrick JM, Watson RW (2000) Altered caspase expression results in delayed neutrophil apoptosis in acute pancreatitis. J Leukoc Bioi 68:15- 20 Matute-Bello G, Liles WC, Radella F 2nd (1997) Neutrophil apoptos is in the acute respiratory distres s syndrome. Am J Respir Crit Care Med 156:1969-1977 Sookhai S, Wang n, McCourt M, Kirwan W, Bouchier-Hayes D, Redmond P (2002) A novel therapeutic strategy for attenu ating neutrophil-mediated lung injur y in vivo. Ann Surg 235:285- 291 Distelhor st CW (2002) Recent insights into the mechanism of glucocorticosteroid- induced apoptosis. Cell Death Differ 9:6-19 Amsterd am A, Sasson R (2002) The anti -inflammatory action of glucocorticoids is mediated by cell type specific regulation of apopto sis. Mol Cell Endocrinol 189:1- 9 Liu Y, Cousin JM, Hughes J, et al (1999) Glucocorticoids promote nonph logistic phagocytosis of apoptotic leukocytes. J Immunol 162:3639-3646 Kelly D, Wischmeyer PE (2003) Role of L-glutamine in critical illness: new insights . Curr Opin Clin Nutr Metab Care 6:217-222 Mignon A, Rouquet N, Fabre M, et al (1999) LPS challenge in D-galactosamine- sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. Am J Respir Crit Care Med 159:1308-1315 Hotchkiss RS, Chang KC, Swanson PE, et al (2000) Caspase inhibitors improve survival in sepsis: a criti cal role of the lymphocyte. Nat Immunol 1:496- 501 Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P (2003) Caspase inhibition causes hypera cute tumor necrosis factor-induced shock via oxidative stress and phospholipa se A2. Nat Immunol 4:387- 393

385

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis: A Putative Role for Hypoxia Inducible Factor T.

REGUEIRA ,

S.M.

JAKOB,

and S.

DJAFARZADEH

Introduction Sepsis-related organ failure is the leading cause of mortality in European intensive care units (lCU). Although the inflammatory cascade of mediators in response to infection is well known, the relationships between regional inflammation, microvascular heterogeneity, hypoxia and hypoxia-inducible gene expression, and finally, organ dysfunction, are unknown. Growing evidence suggests that not only low oxygen supply to the tissues secondary to macrovascular and microvascular alterations, but also altered cellular oxygen utilization is involved in the development of multiorgan dysfunction [1- 3]. Microbial products and innate and adaptive dysregulated immune response to infection directly affect parenchymal cells of organs and may contribute to multiorgan dysfunction. Cellular energy production - biochemically referred to as adenosine triphosphate (ATP) gener ation - depends on three interconnected processes: Glycolysis within the cytoplasm , the Krebs cycle, and the electron transport chain within the mitochondria. Glycolysis is an oxygen-independent pathway, but is much less efficient than oxidative phosphorylation inside the mitochondria. Although some cells, such as T-cells, may survive and proliferate using mainly glycolysis as the pathway for energy produ ction, the common parenchymal cells are dependent on oxidative phosphorylation to maintain their metabolism. This chapter will briefly give an overview of mitochondrial function and will offer some theories as to how hypoxia inducible factor (HIF)-la, a key transcriptional factor in the eukaryotic response to hypoxia, may integrate the cellular response to inflammation by regulating mitochondrial function.

The Mitochondrion: The Powerhouse of the Cell Mitochondria produce the energy needed for normal cellular function and metabolic homeostasis. They are surrounded by a double layer of membranes, which separate an inter-membrane space. The outer mitochondrial membrane is different from the inner membrane: It comprises 50 % protein and 50 % lipids. It also contains channel-forming proteins, called porins, which allow the passage of low molecular weight molecules (less than 10 kDa). The inner membrane, in contrast, is highly impermeable and comprise s 80 % prote ins and 20 % lipids. The inner membrane is folded inwards to form cristae, which project into the matrix (Fig. 1).

386

T. Regueira, S.M. Jakob, and S. Djafarzadeh

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Fig. 1. Cell and mitochondria diagram. Energy is produced in the cell by two mechanisms: (1) glycolysis (which is oxygen independent) and (2) oxidative phosphorylation. Energy rich compounds NADH and FADH z are products of the tricarboxylic cycle (TCA) and enter the respiratory chain. Electrons move from complex I to IV coupled with proton flow from the mitochondrial matrix to the inter-membrane space. Afterwards, protons return to the matrix through theadenosine triphosphate (AlP) synthase that uses the energy available from proton flow to produce ATP from adenosine diphosphate (ADP) and inorganic phosphate (Pi).

The mitochondrial matrix contains ribosomes for protein synthesis and some genomic DNA. Mitochondria also reproduce by binary fission, making them largely autonomous. It is probable that mitochondria were originally bacterial cells that evolved in a symbiotic relationship within larger cells. The matrix of the mitochondria also contains the enzymes of the B-oxidation pathway, the pathway for catabolism of fatty acids, and almost all the enzymes needed for the tricarboxylic acid (TCA) cycle. The TCA cycle is part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats and proteins into energy rich compounds, such as NADH (nicotinamide adenine dinucleotide) phosphate and FADH z (flavin adenine dinucleotide). The TCA cycle is always followed by oxidative phosphorylation, which takes place in the inner mitochondrial membrane. This process extracts the energy (as electrons) from NADH and FADH z via an electron transport chain, recreating NAD+ and FAD, so that the cycle can continue . Oxidative phosphorylation traps this energy as the high-energy phosphate of ATP. The TCA cycle itself does not use oxygen, but oxidative phosphorylation does. ATP is the main energy molecule for living cells. It is used in innumerable vital metabolic reactions. The primary objective of the intermediary metabolism is to maintain ATP levels in a normal range so that living cells can grow, reproduce, and

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis

respond to stress arising from an insult. ATP is synthesized from ADP by two mechanisms: (1) substrate level phosphorylation (glycolysis), which is oxygen independent ; and (2) oxidative pho sphorylation , which takes place in the mitochondria and is by far the most important mechanism for synthesizing ATP (Fig. 1).

Electron Transport Chain Electron s of the energy rich products from the TCA cycle, six molecules of NADH and two molecule of FADH 2 originated from one glucose molecule , are transferred to the electron tr ansport chain located in the inner mitochondrial membrane (Fig. 2). The electron transport chain refers to the enzymes attached to the inner mitochondrial membrane forming complexes (I to IV) that receive and carry electrons from NADH and FADH 2 to oxygen to form water. While electrons are being carried from one complex to the other, released energy in the process is used to pump positively charged protons out of the mitochondrial matrix to the mitochondrial inter-membrane space. The electro-chemical gradient of protons, concentrated in the intermembrane space, is used by ATP synthase, also located in the inner mitochondrial

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Fig. 2. Respiratory chain diagram. Electron transport and proton flow during oxidative phosphorylation.

Note that reactive oxygen species (ROS) are constantly generated, but under stress stimulation (hypoxia or inflammation) an excess of ROS may be generated mainly from complex III. Excess of ROS may lead to cell damage and death. AlP: adenosine triphosphate; ADP: adenosine diphosphate; COX: cytochrome c oxidase; Cyt: cytochrome; FADH 2: flavin adenine dinucleotide; FMN: flavin mononucleotide; NADH 2: nicotinamide adenine dinucleotide; Q: ubiquinone; QH 2: ubiquinol; TCA: tricarboxylic acid

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T. Regueira, S.M. Jakob, and S. Djafarzadeh

membrane, to produce ATP coupled with the energy release by the flux of protons coming back to the mitochondrial matrix (Fig. 1). The mitochondrial respiratory chain comprises a series of reduction/oxidation reactions within complexes I to IV. First, NADH and FADH 2 , derived from the TCA cycle are oxidized. NADH gives its hydrogen molecules and electrons to complex I, also known as NADH:CoQ oxidoreductase, and FADH 2 gives its hydrogen molecules and electrons to complex II. Electrons coming from both complexes are then donated to ubiquinone (Q), which is then reduced to ubiquinol (QH2) as it accepts electrons and protons from complexes I and II. QH2 diffuses in the lipid phase of the inner mitochondrial membrane donating its electrons to complex III, whose principal components are the heme proteins, known as cytochromes band cl , and a nonheme-iron protein known as the Rieske iron sulfur protein. Similarly, cytochrome c, which is loosely associated with the outer face of the inner membrane, shuttles electrons from complex III to complex IV (also known as cytochrome c oxidase, or COX). COX contains the heme proteins known as cytochrome a and cytochrome a3, as well as copper-containing proteins in which the copper undergoes a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. Oxygen is the final electron acceptor, with water being the final product of oxygen reduction [4]. The energy available from electron transport - 57 kcallmol from NADH and 36 kcal/mol from FADH 2 - is used to pump positively charged protons out of the mitochondrial matrix into the mitochondrial inter-membrane space through the enzymatic complexes. To create this proton gradient, the inner mitochondrial membrane must be physically intact so that mitochondria can control the re-entry of protons into the mitochondrial matrix. The total electrochemical potential across the membrane is about 150 to 250 mV. In non-damaged mitochondria, protons return to the mitochondrial matrix from the mitochondrial inter-membrane space through ATP synthase (also called complex V or FIFO ATPase). ATP synthase drives the synthesis of ATP from adenosine diphosphate (ADP) and inorganic phosphate coupled with the energy available from the passage of protons back to the matrix. ATP synthase is composed mainly by two fractions: FO (0 stands for the oligomycin binding fraction), the portion that is within the membrane, and FI, the portion of the ATP synthase that is above the membrane (Figs. 1 and 2). In damaged mitochondria which are permeable to protons, ATP synthesis is not only reduced because of the proton gradient reduction, it is also affected by the reverse action of ATP synthase that take ATP from the matrix and works reversely as an ATP hydrolase, reducing ATP levels.

Measurement of Mitochondrial Oxygen Consumption Currently there are several methods to assess mitochondrial functions in-vivo and in-vitro. The most classical technique is to measure oxygen consumption polarographically directly from isolated mitochondria or permeabilized cells using a clark type electrode. For this technique, isolated mitochondria or cells from patients, animals, or cultures exposed to different insults are immersed into a medium with a previously known oxygen concentration. Total oxygen consumption can be estimated by measuring the decrease in P0 2 in a sealed container over a certain time. This method allows measurement of the basal mitochondrial respiration (state 1), respiration after the addition of specific substrates of the respiratory chain complexes I - IV (state 2), maximal respiratory (oxidative) capacities after the addition

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis

of saturating concentrations of ADP (state 3, active respiration), and resting respiration after ADP depletion (state 4). The respiratory control ratio (RCR) is calculated by dividing the state 3 respiration rate by the state 4 respiration rate. Since state 3 represents maximal respiratory capacity and state 4 the use of oxygen not coupled with ATP production, RCR is a strong index of the intactness of the complexes and the membrane (proton gradient) and the tightness of the coupling between respiration and phosphorylation. The progressive decrease in oxygen concentration during mitochondrial respiration can be used to calculate the oxygen use or flux (negative time derivative of oxygen concentration). Simple representative diagrams of mitochondrial respiratory studies from liver isolated mitochondria and from cultured hepatocytes performed in our laboratory using a high-resolution oxygen electrode are shown in Figure 3. Panels A and B are the profiles of respiration of isolated pig skeletal muscle mitochondria. Glutamate/malate are used to measure complex-Idependent respiration and succinate for cornplex-Il-dependent respiration after inhibition of complex I by rotenone .

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Fig. 3. Representative diagrams ofmeasurement of respiration rates in isolated mitochondria from pig liver tissue (panels Aand B) and permeabilized human cultured hepatocytes (panel C) using high resolution respirometry (Oxygraph-2k®, Oroboros Instruments, Innsbruck, Austria), and DatLab 4.2® software (Oroboros Instruments, Innsbruck, Austria) for data acquisition and analysis. Oxygen consumption is expressed as pmol oxygen/s/mg mitochondrial protein or number of cells. Substrates: complex I dependent respiration (glutamate and malate), complex II dependent respiration (succinate after inhibition of complex I with rotenone). State 2: respiration with substrates alone; state 3: active respiration after addition of ADP; state 4: resting respiration. Oxygen concentration decreases in time as mitochondria or cells use the available oxygen. The oxygen flux represents the directly calculated oxygen use (negative time derivative ofoxygen concentration).

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Hypoxia Inducible Factor-1 a HIF-la is a transcription factor that acts as a key regulatory factor in the evolution of oxygen homeostasis. Hundreds of genes are regulated by HIF-l a , which activates the transcription of target genes by binding to DNA at sequence 5'-RCGTG-3' [5]. HIF-l is a heterodimer consisting of the hypoxia-regulated subunit, HIF-la, and the constitutively expressed subunit HIF-l~. To be functional, the two subunits of HIF-l have to translocate inside the nucleus, dimerize, and bind to DNA sequences called hypoxia response elements (HREs), located within promoter or enhancer regions of target genes. Under normoxic conditions, HIF-la is continuously synthesized and degraded by hydroxylation of two proline residues by dioxygenases (prolyl hydroxylases, PDHl- 3) that utilize oxygen, Fe, and a-ketoglutarate (from the TCA cycle) as substrates. After hydroxylation, HIF-la is recognized by von Hippel Lindau (VHL) protein and targeted for degradation [6]. HIF-la can also be degraded by the action of FIH (factor inhibiting HIF). This factor hydroxylates an asparagine residue in a reaction using oxygen as a substrate. This hydroxylation functionally blocks the binding of HIF-l a to DNA transcription co-activators p300 and CBP (CREB [cAMPresponsive-element-binding protein)]-binding protein) [7]. During hypoxia, the low availability of oxygen limits the reaction; HIF-la is no longer degraded and rapidly accumulates. Also physiological levels of reactive oxygen species (ROS) - free radicals in the cell generated especially during hypoxia and mainly in complex III - can oxidize the prolyl hydroxylases and favor the accumulation of HIF-la (Fig. 4) [8].

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Fig. 4. Schema of some of the multiple proposed key regulatory mechanisms of hypoxia-inducible factor (HIF)-l a after hypoxia or inflammation. HIF-l a upregulates genes from glucose transporters, almost all the enzymes from the glycolytic pathway, lactate dehydrogenase and switches cytochrome c oxidase (complex IV) to isoforms associated with less reactive oxygen species (ROS) production. HIF-l a is also associated with inhibition of pyruvate dehydrogenase, decreasing mitochondrial respiration by decreasing substrate availability. FADH 2: flavin adenine dinucleotide; NAOH 2: nicotinamide adenine dinucleotide; EPO: erythropoietin; LPS: lipopolysaccharide; NF-KB: nuclear factor-kappa B; TeA: tricarboxylic acid; TLR4: Toll-like receptor 4; VEGF: vascular endothelial growth factor.

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis

HIF-Ia triggers the transcription of genes involved in oxygen homeostasis. Some genes regulated by HIF-I a help to augment tissue oxygen supply, such as vascular endothelial growth factor (VEGF) and erythropoietin, while others confer increased tolerance to severe oxygen deprivation (Fig. 4). HIF-Ia also participates in the regulation of glucose-energy metabolism [9]. It activates the transcription of genes encoding glucose transporters, and of virtually all the glycolytic enzymes in order to compensate for the reduced efficiency of ATP production. Macrophages, which must function in a hypoxic microenvironment associated with tissue inflammation, mainly depend on glycolysis for ATP production. In the absence of HIF-Ia, macrophages become non-functional [10].

HIF and Mitochondrial Respiration during Hypoxia Under hypoxic conditions, HIF mediates an increase in mRNA levels encoding for glycolytic enzymes, but also coordinates a decrease in mRNA levels of the respiratory chain proteins, preparing the cell to produce ATP mainly from glycolysis and not from oxidative phosphorylation. Normally, pyruvate is produced as an end product of the glycolytic pathway. Pyruvate can either be transformed to lactate by lactate dehydrogenase or to acetyl-CoA, by the mitochondrial enzyme pyruvate dehydrogenase (PDH), which enters the TCA cycle During hypoxia, HIF-Ia induces the expression of PDKI (PDH kinase I), which in turn negatively regulates the catalytic subunit of PDH by phosphorylation. By this way, pyruvate is shunted away from the mitochondria by the inhibition of PDH, reducing mitochondrial respiration, while lactate dehydrogenase is upregulated and lactate production is enhanced.

Endotoxin and Mitochondrial Function Low tissue oxygenation during sepsis, explained by mechanisms such as lung injury, low cardiac output, and microvascular and erythrocyte dysfunction, can only partially explain mitochondrial dysfunction as a result of reduced oxygen availability. Several studies in cells, animals, and patients have shown that endotoxin or sepsis is directly related to a deterioration in mitochondrial function and oxygen consumption , and ATP depletion [11-13] . A number of different mechanisms may participate in the development of mitochondrial dysfunction during sepsis. First, a decrease in PDH activity, with a concomitant decrease in pyruvate delivered to the mitochondria has been reported, This is similar to the HIF-Ia-mediated decrease in PDH during hypoxia, and is mainly due to an increase in PDH kinase activity [14, 15]. Second, increased nitric oxide (NO) concentrations in sepsis result in peroxynitrite production, a potent oxidant compound able to irreversibly inhibit mitochondrial respiration, at least at complexes I [16], II and V [17]. Third, the enzyme poly(ADP-ribose) polymerase (PARP1), a nuclear enzyme for single-strand break repair, has also been implicated in the development of mitochondrial dysfunction during sepsis. ROS, and particularly peroxynitrite, can lead to activation of PARP-l. Activation of PARP may dramatically lower the intracellular concentration of its substrate NAD, thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process may result in cell dysfunction and cell death [18]. In addition, PARP enhances the expres-

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sion of various pro-inflammatory mediators, via activation of transcription factor, nuclear factor-kappa B (NF-lCB), mitogen activated protein kinase (MAPK), and API and other signal transduction pathways [18, 19]. Increasing intracellular levels of NAD+/NADH have been related to improvements in mitochondrial respiration [20] and inhibition of PARP-1 was related to a decrease in transcriptional expression of HIF-1 [21]. Finally, mitochondrial content has been shown to be reduced during sepsis, seemingly related to lysosome clearance [22].

HIF and Inflammation Recently published reports have linked inflammation and endotoxin stimulation to HIF-1a activation . HIF-la has been shown to be upregulated and stabilized in lipopolysaccharide (LPS)-treated macrophages and monocytes under normoxic conditions [23,24] . It also has been shown that HIF complex stabilized by this pathway is functionally relevant since it binds to DNA hypoxia-responding elements [23]. LPS is a microbial activator of Toll-like receptor 4 (TLR4), a pattern recognition molecule critical for initiating innate immune response, signaling cascades, and proinflammatory responses. HIF-1a levels were shown to be decreased in macrophages deficient in TLR4 after LPS stimulation, suggesting that LPS stimulation of HIF-1a is mediated by TLR4 [24]. It has been shown that HIF-la expression in response to LPS mediates tumor necrosis factor (TNF)-a production [25]. Even more, HIF-1a seems to be critical in the determination of the sepsis phenotype, and, besides TNF-a, also promotes the production of other inflammatory cytokines, including interleukin (IL)-l, IL-6, and IL-12, to similar levels as are found in early sepsis [26]. In detail, this study shows that HIF-1a stabilization under normoxic conditions during LPS stimulation may be related to downregulation of prolyl hydroxylases 2 and 3, which limits the rate of hydroxylation and subsequent degradation of HIF-1a. Mice with macrophages deficient in HIF-la exhibited less hypothermia, hypotension and mortality after LPS challenge [26]. HIF-la also negatively regulates functions of CD4+ and CD8+ T lymphocytes [27]. Similarly, T cells can be recruited to strongly contribute to the anti-bacterial response if they are relieved from inhibition by HIF-la in areas with inflammat ion and hypoxia [28]. This may represent a way to increase the 'reserve' of anti-bacterial capacity of T cells. On the other hand, HIF-la induction may reduce microvascular heterogeneity and decreased contractility in the heart during the onset of septic injury [29]. In summary, HIF-1 complex is involved in gene activation in cells involved in inflammation following LPS exposure [23] and may contribute to upregulation of the inflammatory response and to a decrease in antimicrobial activity of T cells. Accordingly, inhibition or regulation of HIF-1a activity may represent a novel thera peutic target for LPS-induced sepsis.

Conclusion HIF-1a is a transcription factor that acts as a master regulator of gene expression induced by hypoxia. At low oxygen tension, HIF-1a upregulates specific genes involved in angiogenesis, erythropoiesis, glucose transport, and glycolysis. HIF-la

Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis

also decreases mitochondrial respiration during hypoxia by shunting pyruvate to lactate. Besides the established role of HIF-I a in cellular adaptation to hypoxia, accumulating data show that the inflammatory factor, LPS, can also upregulate HIFla protein expression, even in the absence of tissue hypoxia. This increase in HIFI a levels during inflammation seems to be associated with increasing levels of inflammatory cytokines, hypo-responsiveness of T cells, and the clinical phenotype of sepsis. References 1. Kreymann G, Grosser S, Buggisch P, Gottschall C, Matthae i S, Greten H (1993) Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit Care Med 21:1012-1019 2. Boekstegers P, Weidenhofer S, Kapsner T, Werdan K (1994) Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 22:640- 650 3. Hotchk iss RS, Swanson PE, Freeman BD, et al (1999) Apoptotic cell death in patients with sepsis, shock, and mult iple organ dysfunct ion. Crit Care Med 27:1230-1251 4. Schatz G (1995) Mitochondria: beyond oxidative phosphorylation. Biochim Biophys Acta 1271:123-126 5. Semenza GL (2007) Oxygen-dependent regulation of mitochondrial respirat ion by hypoxiainducible factor I. Biochem J 405:1- 9 6. Ivan M, Kondo K, Yang H, et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implicat ions for 02 sensing. Science 292:464-468 7. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation doma in a hypoxic switch. Science 295:858-861 8. Mansfield KD, Guzy RD, Pan Y, et al (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impair s cellular oxygen sensing and hypoxic HIF-alpha activation . Cell Metab 1:393- 399 9. Schumacker PT (2005) Hypoxia-inducible factor-I (HIF-I). Crit Care Med 33:S423-425 10. Cramer T, Yamanishi Y, Clausen BE, et al (2003) HIF-lalpha is essential for myeloid cellmediated inflammation. Cell 112:645-657 11. Kantrow SP, Taylor DE, Carraway MS, Piantadosi CA (1997) Oxidative metabolism in rat hepatoc ytes and mitochondria during sepsis. Arch Biochem Biophys 345:278- 288 12. Unno N, Wang H, Menconi MJ, et al (1997) Inhib ition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats. Gastroenterology 113:1246-1257 13. Zingarelli B, Day BJ, Crapo JD, Salzman AL, Szabo C (1997) The potential role of peroxynitrite in the vascular contractile and cellular energetic failure in endotoxic shock. Br J Pharmacol 120:259- 267 14. Vary TC, Siegel JH, Nakatani T, Sato T, Aoyama H (1986) Effect of sepsis on activity of pyruvate dehydrogenase complex in skeletal muscle and liver. Am J Physiol 250:E634-640 15. Vary TC (1991) Increased pyruvate dehydrogenase kina se activity in response to sepsis. Am J Physiol 260:E669-674 16. Brealey D, Karyampudi S, Jacques TS, et al (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286:R491-497 17. Radi R, Rodriguez M, Castro L, Telleri R (1994) Inh ibition of mitochondrial electron transport by peroxyn itr ite. Arch Biochem Biophys 308:89- 95 18. Szabo C (2007) Poly (ADP-ribose) polymerase activation and circulatory shock. Novartis Found Symp 280:92-103 19. Goldfarb RD, Marton A, Szabo E, et al (2002) Protective effect of a novel, potent inhibitor of poly(adenosine 5'-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. Crit Care Med 30:974-980 20. Khan AU, Delude RL, Han YY, et al (2002) Liposomal NAD(+) prevent s dim inished 0(2) consumption by immunostimulated Caco-2 cells. Am J Physiol Lung Cell Mol Physiol 282:Ll082- 1091

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T. Regueira, S.M. Jakob, and S. Djafarzadeh 21. Martin-Oliva D, Aguilar-Quesada R, O'Valle F, et al (2006) Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-l activation, during skin carcinogenesis. Cancer Res 66:5744-5756 22. Crouser ED, Julian MW,Huff JE, Struck J, Cook CH (2006) Carbamoyl phosphate synthase-I: a marker of mitochondrial damage and depletion in the liver during sepsis. Crit Care Med 34:2439- 2446 23. Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor lalpha. Blood 103:11241130 24. Frede S, Stockmann C, Freitag P, Fandrey J (2006) Bacterial lipopolysaccharide induces HIF-l activation in human monocytes via p44/42 MAPK and NF-kappaB. Biochem J 396:517-527 25. Kim HY, Kim YH, Nam BH, et al (2007) HIF-lalpha expression in response to lipopolysaccaride mediates induction of hepatic inflammatory cytokine TNFalpha. Exp Cell Res 313:1866-1876 26. Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007) Cutting edge: Essential role of hypoxia inducible factor-l alpha in development of lipopolysaccharide -induced sepsis. J ImmunoI178:7516-7519 27. Lukashev D, Klebanov B, Kojima H, et al (2006) Cutting edge: hypoxia-inducible factor lalpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes . J Immunoll77:4962-4965 28. Thiel M, Caldwell CC, Kreth S, et al (2007) Targeted deletion of HIF-lalpha gene in T cells prevents their inhibition in hypoxic inflammed tissues and improves septic mice survival. PLoS ONE 2:e853 29. Bateman RM, Tokunaga C, Kareco T, Dorscheid DR, Walley KR (2007) Myocardial hypoxiainducible HIF-lalpha, VEGF, and GLUTl gene expression is associated with microvascular and ICAM-l heterogeneity during endotoxemia. Am J Physiol Heart Circ Physiol 293:H448456

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Gram-positive and Gram-negative Sepsis: Two Disease Entities? S.

LEAVER,

A.

BURKE GAFFNEY,

and T.W. EVANS

Introduction Sepsis and its sequelae are the leading causes of death among critically ill patients in non-coronary intensive care units (ICUs). Paradoxically, despite a fall in the mortality rate, the incidence of sepsis has increased, with about 750,000 cases annually resulting in about 215,000 deaths a year [1, 2]. This is, in part, a consequence of increased provision of intensive care facilities in the UK and elsewhere [3]. Many factors contribute to the increasing incidence of sepsis and its sequelae including improved chemotherapy for malignancies leading to greater numbers of immunosuppressed patients; more organ transplantations and cardiac surgery; and also the increased use of internal devices such as prostheses, chest drains and endotracheal tubes [3]. Moreover, 40- 60 % of patients with severe sepsis develop acute lung injury (ALI) or its extreme manifestation, acute respiratory distress syndrome (ARDS), which is associated with a particularly high mortality [4, 5]. In addition, there has been a change in the etiology of sepsis in recent years. Thus, although bacteria still cause the majority of cases of sepsis an increasing proportion is due to Gram-positive rather than Gram-negative sepsis [6]. Indeed, a study from the USA performed in the year 2000 showed that Gram-positive bacteria accounted for 52.1 % of hospital admissions with sepsis, compared to 37.6 % for Gram-negative organisms [1]. Moreover, whereas mortality related to Gram-negative organisms has decreased that due to Gram-positive infections remains the same and the overall mortality resulting from Gram-positive septicemia is higher than that from Gram-negative bacteria [7]. Of particular concern is the increasing emergence of multi-resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), which may have contributed to this [8] with around 50 % of nosocomial S. Aureus isolates being methicillin-resistant strains. Infection with MRSA is associated with increases in ICU length of stay, post operative complications, treatment costs, and mortality [8]. Despite these emerging differences between Gram-negative and Gram-positive sepsis, current clinical dogma dictates that both should be managed with similar therapeutic protocols . However, evidence suggests that the mechanisms contributing to the clinical manifestations of Gram-positive and Gram-negative sepsis differ and that they, therefore, might represent distinct disease entities . We suggest that a better understanding of these differences could provide a new target to develop more specific therapeutic strategies for sepsis. In this chapter we discuss differences reported between Gram-positive and Gram-negative disease in stimuli, signaling pathways, cytokine release, clinical trial outcomes, clinical presentation, genetic predisposition, and therapeutic implications.

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Bacterial Components and the Origins of Sepsis Lipopolysaccharide (LPS) or bacterial endotoxin is exclusive to the outer part of the cell wall of Gram-negative bacteria. It has extensive biological activity, activates a wide range of effector cells, and represents a key component of Gram-negative bacteria that triggers the host response to infection [9]. Indeed, LPS is the main initiator of the cascade of cellular reactions that lead to circulatory failure and organ injury and is probably the best studied bacterial trigger of the innate immune system. Injection of LPS into humans and animals results in many of the characteristic features seen in sepsis [10, 11]. Although LPS has been well characterized as the component in Gram-negative bacteria that initiates cytokine production, the identity of the corresponding component in Gram-positive bacteria is unclear. Lipoteichoic acid (LTA) is a cell wall component of Gram-positive bacteria [12]. In common with LPS, it is exposed to the external environment and shed during bacterial replication and antibiotic therapy [13]. By contrast, the host response to LTA is less well defined, largely because of problems with the preparation of LTA for experimental use. However, highly purified LTA is now available.

Toll-like Receptors and Cell Signaling in Systemic Inflammation The Toll-like receptor (TLR) system has evolved to allow the immune system to respond to a vast array of infectious agents through a relatively small number of receptors. TLR were initially discovered in the fruit fly Drosophila melanogaster, in which they are essential receptors for defense against fungal infection [14]. It is now established that TLRs also represent a primary line of defense against invading pathogens in mammals. They are a type 1 transmembrane glycoprotein characterized by an extracellular leucine rich repeat domain and an intracytoplasmic region of about 200 amino acids. The cytoplasmic region shares considerable homology with the interleukin-l (IL-l) receptor cytoplasmic domain. Based on this it has been designated the TolllIL-l receptor homologous region (TIR). To date, only 10 TLR have been identified in humans. TLR recognize molecular structures common to infectious organisms (pathogen associated molecular patterns, PAMPs) that are very infrequently found in the host. In the last ten years, the 'quest' to find a receptor for LPS led to the discovery of TLR4. Other TLR, specifically TLRl, 2, and 5, are also known to playa key role in bacterial recognition. For a while, methodological difficulties in preparing pure ligands distorted the picture, but now it is generally considered that pure LTA and pure LPS ligate TLR2 and TLR4, respectively. Whilst it is unlikely that whole bacteria ligate these receptors so deanly, on balance it seems that Gram-positive sepsis has a TLR2-dominant signal and Gram-negative sepsis a TLR4-dominant signal. Mechanisms involved in the activation of the TLR pathways have been the focus of intensive investigation. Current evidence suggests that at least three different transcription factors pathways are activated by TLR: nuclear factor kappa B (NF-KB), activator protein-l (AP-l), and interferon response factor-3 (IRF-3).DifferentTLRare able to activate different transcription factor cascades by first binding to adaptor proteins, of which fivehave been described [15, 16]. It is thought that activation of divergent signaling programs occurs as a result of differential recruitment of adaptor proteins to TLRs [17]. However, ultimately,activation ofTLR results in an inflammatory response that attempts to clear the pathogen and activation of a more specific adaptive immune response.

Gram-positive and Gram-negative Sepsis: Two Disease Entities? Gram-positive and Gram-negative bacteria signal via different TLR. The concept that LPS is recognized by TLR4was initially identified in C3HIHeJ mice with a point mutation in the gene encoding TLR4, rendering them hypo responsive to LPS challenge [18]. LPS binds to LPS binding protein (LBP) and CD14 and MD2 are required as coreceptors that physically bind to the extracellular domain of TLR4 [19]. Following exposure of cells to LPS, TLR4 homodimerizes and recru its the adaptor molecules, myeloid differentiation factor 88 (MyD88) and MyD88 adaptor-like (Mal) (also known as TIRAP). These proteins function together to initiate a signaling cascade which leads to activation of NF-KB and AP-l and ultimately results in the transcription of numerous pro-inflammatory cytokines. This is known as the MyD88-dependent pathway. TLR4 is also able to signal via the MyD88-independent pathway using the adapter molecules, Toll receptor associated activator of interferon (TRIF) and Toll-receptor associated molecule (TRAM), which results in the activation oflate phase NF-KB, less optimally than with the MyD88-dependent pathway, and IRF-3 [20,21] (Fig. 1). TLR3

TLR4

MyD88 Dependent pat hway

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MyD88 Independent pathway

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NFKB Late phase C()

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Fig. 1. Toll like receptor 4 (TLR4) signaling pathway. TLR4 forms homodimers and requires either the adaptor molecules, myeloid differentiation factor 88 (MyD88) and MyD88 adaptor-like (Mal) for signaling via the MyD88-dependent pathway or the adaptor molecules, TLR-associated molecule (TRAM) and TLR-associated activator of interferon (TRIF) for signaling via the MyD88-independent pathway. The transcription factors, nuclear factor-kappa B (NF-1I:B), activator protein (AP)-' and interferon-beta (IFN~) are activated. IRAK: interleukin- l receptor-associated kinase; TRAF: tumor necrosis factor receptor-associated factor; IKK: IKB kinase; MAPK: mitogen-activated protein kinase; IRF3: interferon response factor 3; TBK1 : TANK binding kinase 1; RIP1 : receptor interacting protein 1.

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TLR lor 6

MyD88 Dependen t pathway

TLR2

1

;:~s p65

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Fig. 2. Toll-like receptor 2 (TLR2) signaling pathway. TLR 2 forms heterodimers with either TLRl or 6 and requires the adaptor molecules, myeloid differentiation factor 88 (MyD88) and MyD88 adaptor-like (Mal). Signaling is via the MyD88dependent pathway and results in the activation of the transcription factors, nuclear factor-kappa B (NF-KB) and activator protein (AP)-l . IRAK: Interleukin-l receptor-associated kinase; TRAF: tumor necrosis factor receptor-associated factor; IKK: IKB kinase; MAPK: mitogenactivated protein kinase.

is the only other TLR to use this pathway, but requires only the adapter molecule TRIF [20]. Gram-positive bacteria are recognized by TLR2. This was confirmed by demonstrating that TLR2 deficient (TLR2+) mice were susceptible to infection with S. aureus and S. pneumoniae [22, 23]. Other microbial components such as lipoproteins/lipopeptides from other bacterial species are also recognized by TLR2 [24]. The ability of TLR2 to recognize such a wide variety of compounds has been attributed to its ability to form heterodimers with other TLRs such as TLRI and TLR6, both of which are structurally related to TLR2. The association of TLR2 and TLRI facilitates the recognition of triacyl lipopeptides whereas TLR2/TLR6 heterodimers recognize diacyllipopeptides [25]. TLR2 signals via the MyD88 dependent pathway resulting in the activation of NF-KB and AP-l ( Fig. 2).

Cytokines and Systemic Inflammation Cytokines are a group of endogenous inflammatory mediators and immunomodulatory proteins that are key mediators in sepsis. Many cells, but predominantly macrophages and helper T (Th) cells, release cytokines in response to inflammatory stimuli and orchestrate the inflammatory response. Cytokines are divided broadly into pro- and anti -inflammatory. Pro-inflammatory cytokines such as IL-l~, tumor

Gram-positive and Gram-negative Sepsis: Two Disease Entities?

necrosis factor (TNF)-a, and IL-8 are required to initiate an effective inflammatory response to infection . However, when circulating in excess they are associated with multi-organ failure and increased mortality [26]. By contrast, anti -inflammatory cytokines such as IL-lO are essential in controlling and downregulating the inflammatory response ; however, they can lead to a depression of the immune system [27]. Observational studies show that cytokine profiles differ according to the infecting organism . Thus, Gram-negative disease is associated with greater plasma levels of TNF-a and IL-6 than Gram-positive infection [28]. Another study showed that Gram-negative meningo coccal sepsis was associated with greater plasma IL-lO and lower interferon (IFN)-y than Gram-positive sepsis [29]. Differences have also been demonstrated in the production of IFN-inducible protein 10 (IPI0) and the p70 subunit of IL-12 following infection with Gram-positive and Gram-negative bacteria. These mediators were elevated in human peripheral blood mononuclear cells following stimulation with a TLR4 agonist, but not a TLR2 agonist despite similar activation of mitogen-activated protein kinase (MAPK) and NF-KB [30].

Differences between Gram-positive and Gram-negative Sepsis Identified in Clinical Trials The CB0006 sepsis syndrome study group compared cytokine levels in patients with sepsis of differing origins and showed that levels of TNF and IL-6 were considerably greater in patients with Gram-negative bacteremia [28]. Mortality differences have also been shown based on blood bacteriology. Thus, in a randomized double blind, placebo-controlled trial to evaluate the safety and efficacy of a soluble fusion protein of TNF-receptor and the Fc portion of IgGl, no adverse events were seen in Gramnegative sepsis but there was a dose-dependent trend towards increased mortality in those with Gram-positive sepsis. [31]. These findings were mirrored in a trial of a monoclonal antibody to TNF [32], a trial of a platelet activating factor (PAF) receptor antagonist [33, 34], a phase 3 study of a human IL-l receptor antagonist [34], and a trial of anti-LPS (HA-IA) [35], all showing no benefit and possible harm to patients with Gram-positive sepsis. In contrast, a reduction in mortality was noted in two of the trials (the PAF receptor antagonist, BN52021, and the bradykinin antagonist, CP-0127, trials) in the subset of patients with Gram-negative sepsis [33,36]. The only therapeutic intervention that has so far been shown to be efficacious in sepsis, in a large, randomized, double blind , placebo controlled trial , is drotrecogin alfa (activated). However, it appears that this therapy is equally effective in both Gram-positive and Gram-negative sepsis [37,38] . It is likely that one of the reasons for the failure of therapeutic interventions in the treatment of sepsis is the heterogeneity of the disease and the high rates of culture-negative sepsis. This underlines our proposal that Gram-negative and Grampositive sepsis should be considered as two and not one disease entity.

Clinical Differences in Gram-positive and Gram-negative Sepsis The American College of Chest Physicians/Society of Critical Care definitions of the systemic inflammatory response syndrome (SIRS), sepsis and their sequelae (severe sepsis and septic shock) were published in 1992 [39]. By defining SIRS and its sequelae more precisely, it was hoped to enable clinicians and researchers to be

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s. leaver, A. Burke Gaffney, and T.W. Evans more consistent with diagnoses, monitoring, and treatment of patients with sepsis. These definitions have been widely used in practice and in numerous clinical trials for therapeutic intervention. Despite being criticized for being insufficiently specific to be of clinical value [40], an International Sepsis Definitions conference in 2001 concluded that these definitions were still useful to researchers and clinicians [41]. Thus, the syndromes are widely regarded as a spectrum of a single entity with little or no reference to the causative agent. Clinically it is difficult to distinguish between Gram-positive and Gram-negative sepsis and specific biochemical makers have proved difficult to identify. Clinical signs such as fever, hypotension, and tachycardia, and biochemical markers, such as raised C-reactive protein (CRP) and leukocytosis are non-specific. Occasionally the site of infection or a pathognomic rash aid antibiotic choice. In addition, certain patient groups are susceptible to sepsis caused by particular bacteria. For example, asplenic patients are prone to pneumococcal infection, whereas those with urological pathologies are more likely to develop sepsis as result of Gram-negative bacteria. As there are no consistent and reliable differences enabling the physician to distinguish between Gram-positive and Gram-negative bacteria, patients are customarily given broad spectrum antibiotics on an empirical basis until a specific pathogen is isolated. Traditionally, blood culture results have taken days to incubate although new molecular techniques, such as fluorescent in situ hypbridization (FISH), which allow faster identification of the insulting organism should soon enable clinicians to implement more tailored therapies at a much earlier stage of disease [42].

Genetic Predisposition Genetic predisposition to sepsis is now recognized. Thus, a number of polymorphisms have been discovered in the TLR signaling pathway [43]. A TLR4 polymorphism in humans, Asp299Gly, is associated with hyporesponsiveness to LPS with lower levels of pro-inflammatory cytokines released compared to wild type [44]; these individuals were, surprisingly, not more susceptible to bacterial sepsis although, conversely, they had a lower risk of atherosclerosis [45]. Likewise, of 91 patients screened for a polymorphism in the TLR2 gene, Arg753G, the two individuals with the mutation also had staphylococcal infections [46]. This suggests that mutations in the TLR2 gene may result in a predisposition to Gram-positive sepsis. A polymorphism in the downstream adaptor protein, Mal SIS0L,has also been identified [47]. Heterozygous carriage protects against general and severe malaria and also afforded a degree of protection against invasive pneumococcal disease, bacteremia, and tuberculosis. Interestingly, mutant homozygotes were absent in Africa where there is a higher prevalence of infectious disease. The advantage seen with heterozygosity suggests a beneficial effect of attenuated signaling with lower NF-KB production. By contrast, wild type homozygotes mount an excessive inflammatory response and the mutant homozygotes no response; thus, both cases are likely to result in increased adverse effects [47]. An ongoing trial is recruiting patients with sepsis secondary to pneumonia or peritonitis with the aim of identifying candidate genes involved in the development, progress, and outcome of sepsis (clinicaltrials.gov identifier NCT00131196). A greater understanding of the effects of polymorphisms in TLR2 and 4 and their downstream signaling molecules on outcome as the result of infection will help understand more about the innate immune responses to Gram-positive and Gram-

Gram-positive and Gram-negative Sepsis: Two Disease Entities?

negative sepsis, Moreover, it could provide a powerful tool for risk stratification as well as a more focused therapeutic approach .

Therapeutic Implications of TlRs Since TLRs are the most proximal part of the signaling pathway, they represent an excellent potential therapeutic target . Thus, successful inhibition of an over-exuberant inflammatory response might be clinically desirable . However, easier identification of an invading organism would be required to facilitate the use of therapeutic strategies targeting specific TLR. Putative agents could target any part of the signaling cascade including the receptor, the adaptor molecules, and the co-receptors . Tak 242, an inhibitor of TLR4, has been shown to reduce inflammatory mediator release and mortality in mice [48). Consequently, a randomized, double blind, placebo controlled trial is enrolling adult patients with severe sepsis to evaluate the safety and efficacy of Tak 242 (clinicaltr ials.gov identifier NCTOOI43611). GR270773, a protein free, phospholipid rich emulsion that neutralizes LPS in vitro is now being tested in a phase II trial for treatment of Gram-negative sepsis (clinicaltrials.gov identifier NCT00089986). The recombinant form of an anti-CDl4 monoclonal antibody that inhibits CDI4-LPS binding, which confers therapeutic benefit after endotoxin exposure when administered in vivo [49), is in a phase I trial at present and seems generally to be well-tolerated [50). This drug is also being investigated in a phase II trial in patients with acute lung injury (clinicaltrials.gov identifier NCT00233207).

Conclusion The current consensus definition of sepsis makes no reference to the infecting organism. However, numerous differences between Gram-positive and Gram-negative sepsis have now been documented in terms of genetic predisposition, disease presentation, signaling pathways activated and cytokines released, and clinical outcomes. Together this evidence suggests that Gram-positive and Gram-negative sepsis should be considered as two disease entities that may need to be treated differently. References 1. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United

States from 1979 th rough 2000. N Engl I Med 348:1546-1554 2. Angus DC, Linde-Zwirble WT, Lidicker I, Clermont G, Carcillo I, Pinsky MR (2001) Epidemi ology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303-1309 3. Friedman G, Silva E, Vincent IL (1998) Has the mortality of sept ic shock changed with time . Crit Care Med 26:2078 - 2086 4. Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC (2005) Clinical pre dictors of and mortality in acute respirato ry distress syndrome: potential role of red cell tr ansfusion. Crit Care Med 33:1191 -1198 5. MacCallum NS, Evans TW (2005) Epidemiology of acute lung injury. Curr Opin Crit Care 11:43-49 6. Brun -Buisson C, Doyon F, Carlet I (1996) Bacteremia and severe sepsis in adults: a multicenter prospective survey in ICUs and wards of 24 hospitals. French Bacteremia-Sepsis Study Group. Am I Respir Crit Care Med 154:617-624 7. Geerdes HF, Ziegler D, Lode H, et al (1992) Septicemia in 980 pati ents at a university hospital

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8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

in Berlin: prospective studies during 4 selected years between 1979 and 1989. Clin Infect Dis 15:991 - 1002 Wang JE, Dahle MK, McDonald M, Foster SJ, Aasen AO, Thiemermann C (2003) Peptidoglycan and lipoteichoic acid in gram-positive bacterial sepsis: receptors, signal transduction, biological effects, and synergism. Shock 20:402- 414 Detmer K, Wang Z, Warejcka D, Leeper-Woodford SK, Newman WH (2001) Endotoxin stimu lated cytokine production in rat vascular smooth muscle cells. Am J Physiol Heart Circ PhysioI281 :H661-H668 Martich GD, Boujoukos AJ, Suffredini AF (1993) Response of man to endotoxin. Imrnunobiology 187:403-416 Parker SJ, Watkins PE (2001) Experimental models of gram -negat ive sepsis. Br J Surg 88: 22-30 Fischer W, Mannsfeld T, Hagen G (1990) On the basic structure of poly(glycerophosphate) lipoteichoic acids. Biochem Cell Bioi 68:33-43 Ginsburg I (2002) The role of bacteriolysis in the pathophysiology of inflammation, infection and post -infectious sequelae. APMIS 110:753-770 Lemaitre B, Reichhart JM, Hoffmann JA (1997) Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc Nat! Acad Sci USA 94:14614-14619 O'Neill LA (2003) Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr Opin Pharmacol 3:396-403 O'Neill LA, Fitzgerald KA, Bowie AG (2003) The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 24:286- 290 O'Neill LA (2006) How Toll-like receptors signal: what we know and what we don't know. Curr Opin ImmunoI18:3-9 Poltorak A, He X, Smirnova I, et al (1998) Defective LPS signaling in C3HIHeJ and C57BL/ lOScCr mice: mutations in Tlr4 gene. Science 282:2085- 2088 Akira S, Takeda K, Kaisho T (2001) Toll-like receptors : critical proteins linking innate and acquired immunity. Nat Immunol 2:675-680 Yamamoto M, Sato S, Mori K et al (2002) Cutting edge: a novel Toll/IL-1 receptor domaincontaining adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 169:6668-6672 Yamamoto M, Sato S, Hemmi H, et al (2003) TRAM is specifically involved in the Toll-like receptor 4-mediated MyDSS-independent signaling pathway. Nat Immunol 4:1144-1150 Takeuchi 0, Hoshino K, Akira S (2000) Cutting edge: TLR2-deficient and MyDS8-deficient mice are highly susceptible to Staphylococcus aureus infection . J ImmunoI165:5392-5396 Echchannaoui H, Frei K, Schnell C, Leib SL, Zimmerli W, Landmann R (2002) Toll-like receptor 2-deficient mice are highly susceptible to Streptococcus pneumoniae meningitis because of reduced bacterial clearing and enhanced inflammation. J Infect Dis 186:79S-S06 Lien E, Sellati TJ, Yoshimura A, et al (1999) Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J Bioi Chern 274:33419-33425 Takeuchi 0, Kawai T, Muhlradt PF, et al (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933-940 Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E (1993) Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest lO3:565- 575 Gogos CA, Drosou E, Bassaris HP, Skoutelis A (2000) Pro- versus anti -inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 181:176-180 Fisher CJ, [r., Opal SM, Dhainaut JF, et al (1993) Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Crit Care Med 21:318-327 Bjerre A, Brusletto B, Hoiby EA, Kierulf P, Brandtzaeg P (2004) Plasma interferon-gamma and interieukin-lO concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock. Crit Care Med 32:433-438 Re F, Strominger JL (2001) Toll-like receptor 2 (TLR2) and TLR4differentially activate human dendritic cells. J Bioi Chern 276:37692-37699

Gram-positive and Gram-negative Sepsis: Two Disease Entities? 31. Fisher CJ [r., Agosti JM, Opal SM, et al (1996) Treatment of septic shock with the tumor necrosis factor receptor :Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 334:1697 - 1702 32. Cohen J, Carlet J (1996) INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 24:1431-1440 33. Dhainaut JF, Tenaillon A, Le Tulzo Y, et al (1994) Platelet-activating factor recepto r antagon ist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group. Crit Care Med 22:1720-1728 34. Fisher CJ Ir, Dhainaut JF, Opal SM, et al (1994) Recombinant hum an interleukin I receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double -blind, placebo-controlled trial. Phase III rhIL-lra Sepsis Syndrome Study Group. JAMA 271:1836-1843 35. The French National Registr y of HA-IA (Centoxin) in septic shock (1994) A cohort study of 600 patients. The National Committee for the Evaluation of Centoxin. Arch Intern Med 154: 2484-2491 36. Fein AM, Bernard GR, Criner GJ, et al (1997) Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group. JAMA 277:482- 487 37. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699- 709 38. Opal SM, Garber GE, LaRosa SP, et al (2003) Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated) . Clin Infect Dis 37:50- 58 39. American College of Chest Physicians/Society of Critical Care Medicine (1992) Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864-874 40. Vincent JL (1997) Dear SIRS, I'm sorry to say that I don't like you. Crit Care Med 25:372-374 41. Levy MM, Fink MP, Marsh all JC, et al (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530-538 42. Peters RP, van Agtmael MA, Simoons-Smit AM, Danner SA, Vandenbroucke-Grauls CM, Savelkoul PH (2006) Rapid identification of pathogens in blood cultures with a modified fluorescence in situ hybridization assay. J Clin Microbiol 44:4186-4188 43. Clark MF, Baudouin SV (2006) A systematic review of the quality of genetic association stud ies in human sepsis. Intensive Care Med 32:1706-1712 44. Arbour NC, Lorenz E, Schutte BC, et al (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187-191 45. Kiechl S, Lorenz E, Reindl M, et al (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347:185-192 46. Lorenz E, Mira JP, Corn ish KL, Arbour NC, Schwartz DA (2000) A novel polymorphism in the toll-like receptor 2 gene and its potential associat ion with staphylococcal infection . Infect Immun 68:6398- 6401 47. Khor CC, Chapman SJ, Vannb erg FO, et al (2007) A Mal funct ional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39:523- 528 48. Meng G, Rutz M, Schiemann M, et al (2004) Antagonistic antibody prevents toll-like recepto r 2-driven lethal shock-like syndromes. J Clin Invest 113:1473-1481 49. Schimke J, Mathison J, Morgiewicz J, Ulevitch RJ (1998) Anti-CD14 mAb treatment provides therapeutic benefit after in vivo exposure to endotox in. Proc Nat! Acad Sci USA 95:13875-13880 50. Reinhart K, Gluck T, Ligtenberg J, et al (2004) CDI4 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CDI4 monoclonal antibody (ICI4). Crit Care Med 32:1100-1108

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Methicillin-resistant Staphylococcus aureus-induced Sepsis: Role of Nitric Oxide ~ ENKHBAATAR,L. TRABER,

andD. TRABER

Introduction Sepsis is the 10th leading cause of death with an incidence of 750,000 cases per year in the United States and mortality rates up to 70 %, depending on severity [1- 3). Despite the outstanding achievements in treating sepsis in the past two decades, the morbidity and mortality still remain high. Fluid resuscitation, antibiotic therapy, and vasopressor agents are the basic treatment approach for sepsis. However, the increasing resistance of microorganisms to antibiotics and severe hypotension refractory even to aggressive fluid replacement and vasopressors complicates the course of therapy. Underestimation of the heterogeneity of the clinical symptoms! syndromes underlying the variations in the pathology, particularly the nature of the infectious agents and the diverse host responses to the different stimuli, may also diminish, at least in part, the effectiveness of the therapeutic interventions. Until 1980, Gram-negative microorganisms predominantly caused sepsis and accordingly extensive research has been dedicated to exploring the pathophysiology of and therapeutic approaches to Gram-negative sepsis-related multiple organ dysfunction, specifically Pseudomonas aeruginosa-induced septic changes. However, bacterial epidemiology evolves constantly and since 1990 sepsis due to Gram-positive cocci has increased in frequency and in antimicrobial resistance becoming a large causative factor for sepsis [3). Staphylococcus aureus bacteremia, especially those species resistant to methicillin (MRSA), has become a major source of morbidity and mortality [4-6). Despite the alarming trend of increased incidence of MRSA-related sepsis, the pathophysiological aspects of MRSA-induced sepsis or septic shock are neither well-described nor widely discussed. There is also a lack of clinically relevant large animal models describing the pathophysiological alterations due to Gram-positive organisms, particularly MRSA. In the present chapter, we will discuss the pathophysiology of MRSA-induced sepsis using a newly developed ovine model.

Epidemiology of MRSA Infections During the past 2- 3 decades, there has been a widespread shift from Gram-negative bacteria to Gram-positive bacteria among the bacteria causing sepsis. The occurrence of Gram-negative sepsis has diminished over the years to 25-30 % of total cases in 2000, while Gram-positive infections account for 30-50 % of all cases [3, 7, 8). The first penicillin-resistant strains of S. aureus appeared in the 1940s shortly after penicillin was introduced. With the introduction of methicillin in 1961, came the development of methicillin resistance. By the 1970s, penicillin-resistant isolates

Methicillin-resistant Staphylococcus aureus-induced Sepsis: Role of Nitric Oxide constituted the majority of S. aureus strains recovered from infections found in hospitals and the community. By the mid-1980s, 5-10 % of hospital-associated S. aureus isolates were MRSA [9, 10]. By 1998, 50 % of S. aureus isolates found in intensive care units (ICUs) were methicillin resistant [9]. It was also reported that the incidence of MRSA increased 29 % between the years of 1995- 2000 in the USA [11]. Pneumonia is one of the leading causes of sepsis. Gram-positive cocci, in particular S. aureus, account for 20- 30 % of all cases of hospital-acquired pneumonia [12]. Moreover, S. aureus has been shown to be a dominant pathogen in communityacquired pneumonia [13]. Rello et al. documented that MRSA pneumonia produced a significantly greater frequency of bacteremia (36.4 % vs. 10.5 %; MRSA vs, methicillin-susceptible S. aureus [MSSA], respectively) and septic shock (27.3 % vs. 7.9 %; MRSA vs. MSSA, respectively) when compared to MSSA pneumonia. Further, the infection-associated mortality was greater among patients with MRSA pneumonia (54.5 % vs. 2.6 %) [14]. In addition, about 35 % of -1 million burn victims in the USA every year have concomitant smoke inhalation injury and 38 % develop a subsequent pneumonia. Presence of smoke inhalation and pneumonia enhances the risk of sepsis and increases mortality of burn victims by 60 %. Because MRSA accounts for -51 % of burn isolates [15], the incidence of MRSA-related septic complications becomes a major complication in these patients.

Pathophysiology of MRSA-induced Pneumonia/sepsis Despite a progressively increasing incidence of both hospital and communityacquired MRSA-related pneumonia/sepsis, which is often associated with poor outcome, the pathophysiological aspects remain incompletely understood. Consequently, effective pathogenic treatment against this serious menace has not yet been well-described. Currently, a few small animal models of MRSA infection exist; how ever, no clinically relevant model of MRSA pneumonia/sepsis using large animals is available. There is also a lack of clinical studies comparing the differential pathophysiological responses and clinical symptoms in patients with Gram-negative and Gram-positive sepsis. To fill the existing gap, we have recently developed a clinically relevant ovine MRSA sepsis model and described its pathophysiological responses. In the present chapter, we will also discuss these pathological responses to MRSA compared with those seen in septic pneumonia induced by P. aeruginosa. Pneumonia/sepsis was induced by instillation of live P. aeruginosa or MRSA into the lungs of anesthetized sheep by bronchoscope following cotton smoke insufflation [16, 17]. Approximately 57 % of sheep (4 out of 7) exposed to MRSA displayed a positive blood culture analysis whereas positive blood cultures were found in 40 % of the sheep exposed to P. aeruginosa infection. Both groups of animals with Gram-negative (P. aeruginosa) or Gram-positive (MRSA) sepsis displayed similar signs of hyperdynamic sepsis evidenced by increased body temperature, tachycardia, severe hypotension, fall in systemic vascular resistance, and increased cardiac index. The blood pressure progressively decreased in both groups despite aggressive fluid resuscitation indicating that the animals eventually developed septic shock. Pulmonary morbidity in these stud ies was evidenced by deterioration in pulmonary gas exchange (decreased Pa02/Fi02' and increased pulmonary shunt fraction), increased lung water content, and ventilatory pressures. Interestingly, it appears that the degree of acute lung injury (ALI) is more pronounced in septic sheep following

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smoke inhalation and airway instillation of P. aeruginosa. The augmented lung tissue injury in these animals with Gram-negative sepsis was associated with significantly higher expression of inflammatory indices, such as interleukin (IL)-6 mRNA and increased myeloperoxidase activity (a marker of polymorphonuclear neutrophils) in lung tissue [18]. In contrast, vascular leakage syndrome was much more severe in MRSA animals compared to those that received P. aeruginosa, despite the similar hemodynamic responses [18]. The MRSA sepsis was associated with significantly higher body fluid accumulation (Fig. 1) and lower plasma oncotic pressure and plasma total protein compared to those seen in P. aeruginosa sepsis. The exact mechanism of these discrepancies in pathophysiological responses in the two models (Gram-positive and negative) of sepsis is not completely clear yet. It is worth noting that the more excessive vascular leakage syndrome seen in MRSA sepsis was associated with a 7 to 8-fold increase in plasma nitrite/nitrate (NOx) compared to baseline values, while the latter was increased in P. aeruginosa sepsis only by 2 to 2.s-fold (Fig. 2). It is well documented that production of excessive nitric oxide (NO) in the systemic circulation causes a profound vasodilatation, manifest as systemic hypotension [19-21], and microvascular hyperpermeability [22-24]. Previously, we reported an important role of excessive NO in cardiopulmonary morbidity in sheep exposed to smoke inhalation and P. aeruginosa pneumonia [19, 2S] using non-specific or specific inducible NO synthase (iNOS) or neuronal NOS (nNOS) inhibitors and documented the dominant role of nNOS-derived NO in the pathophysiology of cardiovascular collapse. We have also reported an important role of iNOS-derived NO in the pathophysiology of cardiopulmonary morbidity in sheep exposed to combined burn and smoke inhalation injury using the highly selective iNOS dimerization

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Methicillin-resistant Staphylococcus aureus-induced Sepsis: Role of Nitric Oxide inhib itor, BBS-2 [26, 27]. Taking together the results of previous and present studies , it is apparent that excessive NO production is mostly responsible for the severity of vascular hyperpermeability with subsequent accumulation of fluid in tissues or third spaces at least in septic conditions related to MRSA. Another interesting finding was that vascular endothelial growth factor (VEGF), a potent permeability factor measured by western blotting analysis in lung tissue, was much greater in MRSA sepsis [18]. Brkovic and Sirois documented that VEGF analogs increased vascular permeability through VEGF receptor (VEGFR)-2 activation; maximal protein leakage was induced under VEGF-A165 stimulation, and involved neuropilin (NRP)-1IVEGFR-2 complex formation . The authors further documented that the blockade of the platelet activating factor (PAF) and NO/cGMP pathway abolished VEGFA165-mediated permeability. Thus, it is possible that excessive NO may increase vascular permeability by a direct action or through interacting with VEGF. This possibility should be investigated in the near future. In our recent studies, we have reported that the non-specific NOS inhibitor, N(omega)-nitro -L-arginine methyl ester (L-NAME), reversed the excessive production of NO by MRSA and completely restored the fall in arterial blood pressure. Treatment of these animals with L-NAME also resulted in significantly less body fluid accumulation, suggesting a major role of excessive NO in augmented vascular leakage [29]. Interestingly, inhibition of iNOS using a potent iNOS dimerization inh ibitor did not affect the above changed variables [29], suggesting that constitutive NOS (cNOS) predominantly plays a role in the pathophysiology of cardiovascular collapse in MRSA sepsis. Although iNOS is generally accepted as harmful and eNOS as protective in sepsis, the results of recent stud ies indicate that cNOS, especially nNOS, may mediate pathophysiological responses [30-32] . In recent studies we have also reported an important role of nNOS-derived excessive NO in cardiopulmonary morbidity in septic sheep exposed to smoke inhalation and P. aeruginosa. Although, the role of nNOS-derived NO in MRSA-induced sepsis is unknown, we do not exclude its possible involvement in MRSA-related pathological alterations. This possibility should be tested in future studies using selective nNOS inhibitors. Since non -specific NOS inhibition is associated with unwanted side effects and could be even detrimental in septic patients [33], the priority to use selective nNOS inh ibitors is colossal. Recently, Traber et al. documented that initial activation of nNOS may further stimulate iNOS expression in certain pathological conditions [34]. Iijima et al. reported that nNOS is required for allergen-induced expression of iNOS in mice [35]. In support, Connelly et al. noted that the pathogenesis of sepsis is characterized by initial endothelial NOS (eNOS) activation, with the resultant NO acting as a costimulus for the expression of iNOS [36]. The above findings strongly highlight a novel pro-inflammatory role for eNOS, namely nNOS and eNOS, in pathological conditions. There are also recent studies [37-39] pointing to the possible involvement of eNOS in pathological responses to various stimuli. If cNOS, including both nNOS and eNOS, may be harmful in certain conditions, they should be pharmacologically suppressed to the same extent as iNOS. There are a few selective nNOS inhibitors available; however, no selective eNOS inhibitor exists. The results of recent stud ies indicate an urgent need for the development of selective eNOS inhibitors to elucidate a possible role of this enzyme in septic alterations. Excessive NO reacts with superoxide (0 2- ) to form a toxic product, peroxynitrite, which damages a DNA single-strand [40]. This results in the activation of poly(adenosine 5'-diphosphate[ADP]-ribose) polymerase (PARP), an energy-consuming enzyme that transfers ADP ribo se units to nuclear proteins [40]. When PARP is activated, the intracellular nicotinamide dinucleotide (oxidized) (NAD+) and ATP levels

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markedly decrease, resulting in cell dysfunction and cell death [41, 42]. The endothelial cell dysfunction occurring as a result of excessive formation of peroxynitrite and PARP activation may also be the reason for augmented vascular hyperpermeability. Activation of PARP in turn can also initiate the activation of nuclear factorkappa B (NF-KB), which stimulates iNOS expression, thus causing a vicious circle. We have previously reported that activation of PARP plays an important role in cardiopulmonary dysfunction in sheep models of smoke inhalation/pneumonia (P. aeruginosa) [43] and cutaneous burn/smoke inhalation [44]. Thus, excessive NO may cause cardiovascular dysfunction by: 1) a direct action; 2) interaction with VEGF; 3) through the peroxynitrite-PARP activation pathway (Fig. 3).

Conclusion In the present chapter we have described the pathophysiology of MRSA-induced sepsis and documented potential differences in host responses to different stimuli such as MRSA and P. aeruginosa. The differential responses to different pathogenic agents require a more focused treatment approach considering the nature of the infectious agents and the specific host responses to different agents. One dark side of excessive NO in septic conditions is to cause vascular hyporesponsiveness to both norepinephrine and vasopressin [45, 46]. Peroxynitrite has also been reported to contribute to the loss of vascular contractility and cellular energetics in a rodent model of endotoxin shock [47] as well as fatal cardiovascular depression . Takakura et al. reported a possible deactivation of vasopressors by peroxynitr ite in septic shock [48]. It is also well known that the use of high doses of vasopressors is associated with unwanted side effects such as mesenteric ischemia, coronary artery vasoconstriction, and myocardial dysfunction . Therefore, the combined use of low doses of specific NOS inhibitors and vasopressor agents should be considered for the management of cardiovascular collapse in septic patients, especially those who suffer from MRSA infection.

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27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

inhibitor BBS-2 prevents acute lung injury in sheep after burn and smoke inhalation injury. Am J Respir Crit Care Med 167:1021-1026 Enkhbaatar P, Murakami K, Shimoda K, et al (2003). Inducible nitric oxide synthase dimerization inhibitor prevents cardiovascular and renal morbidity in sheep with combined burn and smoke inhalation injury. Am J Physiol Heart Circ Physiol 285:H2430-H2436 Brkovic A, Sirois MG (2007) Vascular permeability induced by VEGF family members in vivo: role of endogenous PAF and NO synthesis . J Cell Biochem 100:727-737 [oncarn C, Enkhbaatar P, Esechie A, et al (2007) Nitric oxide synthase inhibition in an ovine model of methicillin resistant staphylococcus aureus (MRSA) sepsis. Surgical Infection 8:282 (abst) Xu L, Carter EP, Ohara M, et al (2000) Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis. Am J Physiol Renal PhysioI279:FlllO-FllI5 Gocan NC, Scott JA, Tyml K (2000) Nitric oxide produced via neuronal NOS may impair vasodilatation in septic rat skeletal muscle. Am J Physiol Heart Circ PhysioI278 :H1480-HI489 Mashimo H, Goyal RK (1999) Lessons from genetically engineered animal models . IV. Nitric oxide synthase gene knockout mice. Am J Physiol 277:G745-G750 Lopez A, Lorente JA, Steingrub J, et al (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32:21-30 Traber DL, Hawkins HK, Enkhbaatar P, et al (2007) The role of bronchial circulation in the acute lung injury resulting from burn and smoke inhalation. Pulm Pharmacol Ther 20: 163-166 Iijima H, Tulic MK, Duguet A, et al (2005) NOS 1 is required for allergen-induced expression of NOS 2 in mice. Int Arch Allergy Immunol 138:40-50 Connelly L, Madhani M, Hobbs AJ (2005) Resistance to endotoxic shock in endothelial nitricoxide synthase (eNOS) knock-out mice J Bioi Chern 280:10040-10046 Peng T, Lu X, Lei M, Feng Q (2003) Endothelial nitric-oxide synthase enhances lipopolysaccharide-stimulated tumor necrosis factor-alpha expression via cAMP-mediated p38 MAPK pathway in cardiomyocytes. J Bioi Chern 278:8099-8105 Barsacchi R, Perrotta C, Bulotta S, Moncada S, Borgese N, Clementi E (2003) Activation of endothelial nitric-oxide synthase by tumor necrosis factor-alpha: a novel pathway involving sequential activation of neutral sphingornyelinase, phosphatidylinositol-3' kinase, and Akt , Mol Pharmacol 63:886-895 Kawanaka H, Jones MK, Szabo IL, et al (2002) Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-alpha via the PI 3-kinase-Akt signaling pathway. Hepatology 35:393- 402 Szabo C (2006) Poly(ADP-ribose) polymerase activation by reactive nitrogen species-relevance for the pathogenesis of inflammation. Nitric Oxide 14:169-179 Szabo C, Dawson VI (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287- 298 Hauser B, Groger M, Ehrmann U, et al (2006). The parp-1 inhibitor ino-1001 facilitates hemodynamic stabilization without affecting DNA repair in porcine thoracic aortic crossclamping -induced ischemia/reperfusion. Shock 25:633- 640 Murakami K, Enkhbaatar P, Shimoda K (2004) Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis. Shock 21:126-33 Shimoda K, Murakami K, Enkhbaatar P, et al (2003) Effect of poly(ADP ribose) synthetase inhibition on burn and smoke inhalation injury in sheep. Am J Physiol Lung Cell Mol Physiol 285:L240-L249 Landry DW, Oliver JA (2001) The pathogenesis of vasodilatory shock. N Engl J Med 345: 588-595 Kirkeboen KA, Strand OA (1999) The role of nitric oxide in sepsis-an overview. Acta Anaesthesiol Scand 43:275- 288 Zingarelli B, Brian JD, James DC, et al (1997) The potential role of peroxynitrite in the vascular contractile and cellular energetic failure in endotoxic shock. Br J Pharmacol 120:259- 267 Takakura K, Xiaohong W, Takeuchi K, et al (2003) Deactivation of norepinephrine by peroxynitrite as a new pathogenesis in the hypotension of septic shock. Anesthesiology 98:928- 934

Section XI

XI Sepsis Therapies

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The Cardiovascular Management of Sepsis B.C. CREAGH-BROWN,

J. BALL,

and M.

HAMILTON

Introduction Sepsis is defined as suspected or proven infection plus a systemic inflammatory response syndrome. Severe sepsis is sepsis with organ dysfunction. Septic shock is severe sepsis with hypotension, despite adequate fluid resuscitation [1) and often requires treatment with vasoactive agents. The Sepsis Occurrence in Acutely III Patients (SOAP) study [2] confirmed the high prevalence of sepsis in European intensive care units (ICUs), with> 35 % of patients having sepsis at some point during their ICU stay. Patients with sepsis had an ICU mortality of 27 %, which rose to > 50 % in patients with septic shock. The International Surviving Sepsis Campaign guidelines [3] advise early goaldirected therapy on the basis of the landmark paper by Rivers et al. [4]. In that study, 263 patients with sepsis in the emergency department were randomized to early goal-directed therapy or "standard" therapy. The goal-directed therapy group of patients had improved outcomes; two more recent studies [5, 6) have added supportive data to these results. However, all of the studies involved small numbers, had limitations and questionable generalizability [7). To this end the NIH have funded a proto colized multicenter trial for the management of early septic shock (ProCESS) that aims to recruit 2000 patients. There is evidence to support the early and aggressive cardiovascular management of septic shock but the relative importance of the different interventions requires further clarification.

Cardiovascular Changes due to Sepsis In sepsis, cardiovascular dysfunction is characterized by circulatory shock with redistribution of blood flow, decreased vascular resistance, catecholamine hyporeactivity, and high cardiac output despite decreased myocardial contractility. These changes are combined with relative and absolute hypovolemia such that, even after the restoration of circulating volume, there remains maldistribution of cardiac output [8]. Figure 1 demonstrates the cardiovascular changes in septic shock. Myocardial depression (as defined by a depressed ejection fraction with ventricular dilatation on echocardiography) occurs in up to 50 % of patients with septic shock. It has been suggested that this may represent a protective energy-preserving response [9]. In survivors, these changes reverse over a period of some 7 -10 days. By contrast, non-survivors develop diastolic dysfunction with a reduced left and right ventricular end diastolic volume despite evidence of increased left atrial pressure. The etiology of myocardial depression in sepsis is unclear with both beneficial

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Immunedysregulation Hormonalalterations Metabolic changes Epithelial dysfunction Coagulation activation Mitochondrial failure

Fig. 1. The cardiovascular changes in sepsis.

and deleterious effects attributed to, amongst other mediators, nitric oxide (NO) [10]. There is some evidence that despite the absence of many typical features of myocardial ischemia and with normal or increased coronary blood flow, there are areas of focal myocardial ischemia [11]. This postulate is supported by the common finding of elevated concentrations of cardiac troponin in patients with sepsis [12]. The physiological response to shock includes activation of the sympathetic and renin-angiotensin systems with consequent peripheral vasoconstriction. However, in septic shock, vascular smooth muscle shows a decreased ability to contract, and the concomitant hypotension may be refractory to standard catecholamine vasopressors therapy. Vascular hyporeactivity may in part be due to endogenous overproduction of NO [13]. There is also adrenoceptor desensitization and downregulation and this is hypothesized to be due to high circulating levels of catecholamines.

The Management of Septic Shock The cardiovascular management of septic shock comprises fluid therapy, monitoring and vasoactive drugs. These components are employed in concert but will be first considered in isolation.

Optimization of Fluid Status Optimization of intravascular volume is traditionally considered the first therapeutic priority in the management of severe sepsis/septic shock. The choice of fluid to use has been the subject of much research. However, there is little evidence to support one type of fluid over another. Colloids continue to fail to fulfil their theoretical

The Cardiovascular Management of Sepsis advantage over crystalloids and desp ite the well-publicized shortcomings of 0.9 % saline [14] it remains the choice of many physicians. Vital signs There is no consensus on the optimal method of assessing the adequacy of fluid resuscitation [15]. Traditionally, repeated fluid challenges are given and improvements in clinical end points such as heart rate , urine output, and blood pressure are assessed. These are, however, unreliable endpoints of adequate resuscitation. Cardiac pressures If invasive pressure monitoring is available then aiming for either a pulmonary artery occlusion pressure (PAOP) of 12-15 mmHg or a central venous pressure (CVP) of 8-12 mmHg is often recommended [8]. The Surviving Sepsis Campaign guidelines [3] suggest using the combined targets of a CVP of 8-12 mmHg (or 12-15 mmHg if invasively ventilated) and central venous oxygen saturation (ScvOz) of > 70 % on the basis of what they consider to be Grade B evidence. With less confidence (Grade E) the campaign recommends repeated fluid challenges titrated against the response in blood pressure and urine output. There is controversy over the consideration of cardiac filling pressures as the 'gold standard' for guiding the adequacy of fluid resuscitation. The literature strongly suggests that neither static PAOP nor CVP are valuable for the guidance of fluid resuscitation in patients with circulatory failure including septic shock [16,17] . Targeting specific cardiac filling pressures, incorrectly assumes that a satisfactory pressure (within the specified targets) implies that further fluid boluses will not be beneficial. There is good evidence that static cardiac filling pressures are, in fact, poor predictors of fluid responsiveness in septic patients [18]. The expected response to a fluid bolus is an increase in right ventricular end-diastolic volume , left ventricular end -diastolic volume, stroke volume, cardiac output and, thus, end-organ perfusion. However, in studies of critically ill patients receiving fluid boluses, only 40 - 72 % of them show a significant increase in stroke volume or cardiac output [16]. This is for two reasons: First, the increase in end-diastolic volume as a result of fluid therapy depends on the partitioning of the fluid into the different cardiovascular compliances organized in series. Second, the increase in stroke volume consequent to increased end-diastolic volume depends on ventricular func tion. The Frank-Starling curve relates stroke volume and end-diastolic volume and where the ventricle finds itself on thi s curve determines to what extent an increase in end-diastolic volume will equate to an increase in cardiac output. There is also the effect of heart rate whereby at rate s > 90 bpm the stroke volume remains fixed and/or starts to decrease. Dynamic assessment of fluid status Serial fluid challenges titrated against a measure of cardiac output allows assessment of fluid responsiveness but risk excessive fluid administration and the associated adver se consequences [7]. Dynamic indices of heart-lung interaction such as pulse pressure variation (PPV), stroke volume variation (SVV), and systolic pressure variation (SPV) have limitations [19] but can provide useful information to guide fluid administration in select pat ients. In those who are spontaneously ventilating and/or are not in sinus rhythm the use of passive leg rais ing (a 'reversible self-volume challenge') can provide similarly useful information concerning volume responsiveness [20].

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B.C. Creagh-Brown, J. Ball, and M. Hamilton Cardiac output monitoring Proponents of the pulmonary artery catheter (PAC) argue that it possesses the unique ability to accurately measure cardiac output and other hemodynamic variables and thereby enables improved diagnosis and management of circulatory instability [21]. However, no published study to date, has convincingly supported this assertion [22]. Less invasive methods of assessing cardiac output are now commonplace. The safety and efficacy of any hemodynamic monitoring tool is determined by operator interpretation of the results and subsequent therapeutic interventions based on this interpretation. There is a strong theoretical argument that the measurement of flow in addition to static pressures is desirable. Many of the less invasive systems, whether based on pulse contour analysis or measurement of aortic blood flow using Doppler, allow dynamic assessment of flow and the impact that therapy has on that flow. Ultimately measurement of flow at a microvascular level may prove to be our best target , but to date, such systems remain research tools.

End-points of resuscitation The physiological end-points that determine the adequacy of resuscitation are related to improvements in oxygen delivery (DOz) to tissues. Due to microvascular perturbation the establishment of 'normal' hemodynamic variables does not guarantee adequate tissue DOz. Indeed, in the Rivers study [4], 40 % of the control group, who had achieved their goals (mean arterial pressure [MAP] > 65 mm Hg; CVP > 8 mm Hg, urine output > 0.5 mllkg/h) still had evidence of global tissue hypoxia, which was associated with a worse outcome. However, there are also good data suggesting that achievement of supranormal global DOz is detrimental to outcome in critically ill patients [23]. Thus, global DOz alone should not be used as the measure of adequate resuscitation.

Global oxygen balance Central venous oxygen saturation (ScvOz) or mixed venous oxygen saturation (SvOz) give an indicat ion of global oxygen supply-demand balance. These variables depend upon cardiac output, oxygen demand, hemoglobin concentration, and arterial oxygen saturation. ScvOz is now more commonly used given the decrease in use of the PAC and the realization that although not numerically equivalent (ScvO z values are, on average, approximately 5 % higher than SvO z values) they have a robust linear relationship and can be considered equivalent. DOz IS the product of cardiac output and arterial oxygen content. Oxygen uptake (VOz) usually takes a quarter of the arterial oxygen content and leaves the mixed venous saturations between 70 and 75 %. At times of diminished cardiac output, supply dependency may occur and ScvO z will fall, this has adverse prognostic significance [24] and can guide therapy. There are significant limitations to the use of ScvOz, in particular, it may be elevated in sepsis, despite corroborative evidence of tissue hypoxia, due to a combination of failure of cellular utilization of oxygen [25] and microvascular shunting [26]. Changes are inherently non-specific: A fall in ScvOz may equally imply a fall in DOz (whether it be arterial desaturation, acute hemorrhage or a fall in cardiac output), or an increase in VOz'

The Cardiovascular Management of Sepsis

Lactate and metabolic disturbance Increased blood lactate concentration (hyperlactatemia) results from lactic acid overproduction or underutilization, and in sepsis was traditionally ascribed to anaerobic glycolysis related to inadequate tissue perfusion causing tissue hypoxia. However, this is now recognized to be over-simplistic [27] and metabolic effects of both endogenous and exogenous catecholamines are implicated. The presence of hyperlactatemia in resuscitated septic patients should not be taken as proof of oxygen debt. Indeed, hyperlactatemia may represent a key protective metabolic event, favoring lactate rather than glucose oxidation in tissues in which oxygen is available, and preserving glucose for glycolysis in tissues in which oxidative metabolism is scarce [28]. Hyperlactatemia and lactic acidosis are not synonymous: Lactic acidosis is hyperlactatemia in the context of acidosis. Additional causes of hyperlactatemia include diminished hepatic clearance of lactate, cyanide poisoning, certain malignancies, production by the lung in acute lung injury (ALI), and the use of lactatebuffered solutions for renal replacement therapy. Base excess (or deficit) is a single variable used to quantify the metabolic component of acid-base status . Lactic acidosis is a common cause of a base deficit in sepsis but other causes include hepatic and renal dysfunction , drug toxicity, bicarbonate losses (usually from the intestine) , and iatrogenic hyperchloremia. Base deficit is a useful guide to the severity of illness and predicts outcome. Alternative methods of assessing acid-base, such as those described by Stewart, do not appear to offer any advantage in this regard [29]. Given the multiple and varied causes of a base deficit it is limited as an end-point in resuscitation. In summary, the pragmatic solution to the assessment of the adequacy of resuscitation is to use all of the above measures, together with as complete a clinical assessment of individual organs/tissues as is possible.

Vasoactive Agents By definition, fluid resuscitation alone is inadequate for patients with septic shock. There continues to be controversy regarding which vasoactive agent/s to use and more importantly which physiological end-points to target. The pharmacological properties of the agents and the relative risks and benefits have been covered exhaustively elsewhere [8]. Until recently there has been so little evidence that a Cochrane review [30] had to conclude that they were unable to determine whether any particular vasopressor is superior to any other in the treatment of shock. Current practice mirrors guidelines, in that norepinephrine and dopamine are the most commonly used vasoactive drugs in septic shock. A multicenter RCT comparing norepinephrine with dopamine as first-line vasopressors in septic shock is currently underway in Europe [31]. Guideline recommendations The Surviving Sepsis Campaign guidelines [3] formalize current practice with the recommendation: "When an appropriate fluid challenge fails to restore adequate blood pressure and organ perfusion, therapy with vasopressor agents should be started." They were only able to grade the evidence for this at level E, i.e., there is a lack of evidence to support what is common practice . What is an adequate blood pressure? Data from animal studies suggest that below an MAP of 60 mmHg, autoregulation is lost in the coronary, renal, and central ner-

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vous system vascular beds. This results in organ flow becoming linearly dependent on pressure and thus potentially inadequate [8]. In practice, therapy tends to be individualized rather than targeted against a set MAP, although this often remains arbitrary. The Surviving Sepsis Campaign guidelines go on to say, "In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output." Grade E. But what level of cardiac output needs treatment? There is no good evidence demonstrating the beneficial effects of increasing cardiac output in this context. Despite this, targeting a cardiac index of > 3 l/rnin/m- has been proposed [32]. The decline of dopamine? Dopamine has dose-dependent vasoconstricting and inotropic effects but, in practice, can be difficult to titrate effectively. Dopamine stimulates D1 (dopaminergic) receptors in the renal circulation, producing vasodilatation and increased blood flow. However, these theoretical benefits have failed to translate into clinical advantage [33] and the use of 'renal-dose' dopamine should have been totally abandoned. Fears about norepinephrine having adverse effects on the renal circulation should also be relegated to history [34]. In the SOAP study there was an increased mortality (49.9 % vs. 41.7 %, P = .01) in patients with septic shock who were treated with dopamine [35]. However, this retrospective subgroup analysis used non-standard definitions and should be interpreted with great caution [36]. A renaissance for epinephrine? When compared with norepinephrine in small randomized trials, epinephrine has shown deleterious effects on splanchnic blood flow and on acid-base balance [37]. On grade D evidence, the Surviving Sepsis Campaign guidelines recommend dopamine or norepinephrine as first-line drugs for the management of septic shock, with epinephrine reserved for patients who respond inadequately. Similarly, a systematic review concluded that epinephrine's use should be limited, due to its potentially deleterious effects on gastric blood flow and blood lactate concentrations [8]. To further investigate whether there is an advantage of norepinephrine plus dobutamine (whenever needed) over epinephrine alone, a prospective, multicenter, randomized, double-blind study has just been completed. It enrolled 330 patients with septic shock admitted to one of 19 participating ICUs in France [37]. There was no difference in all-cause mortality, in either the short-term or the long-term , between the two groups . Although epinephrine was associated with some delays in the normalization of arterial pH and lactate concentrations these had no clinical sequelae. Indeed, there was no evidence for any difference in the frequency of arrhythmias, ischemic damage to the brain or the heart, or any other serious adverse event between the two groups. Thus, in the best prospective study conducted to date, no superiority to either choice was evident. Whether that represents a failure of the study design will no doubt be the subject of much ongoing debate. An indication for vasopressin? Vasopressin is a peptide hormone released from the posterior pituitary gland in response to increased plasma osmolarity, hypovolemia, and hypotension. Under normal conditions, circulating levels are maintained at around 2 pg/ml. In prolonged vasodilatory shock, such as is seen in severe sepsis, there is a relative defi-

The Cardiovascular Management of Sepsis

ciency of vasopressin. In this circumstance, exogenous vasopressin has marked vasopressor effects [38]. The use of vasopressin is not analogous to the use of steroids in relative adrenal insufficiency, as vasopressin is not given as replacement but as a drug at supra-physiological levels. The doses used in clinical trials (0.04 units/ min), in the context of septic shock, typically result in plasma levels > 250 pg/ml [39]. There are three types of vasopressin receptor (VIR, V2R, V3R) and vasopressin also ligates with the oxytocin receptor and may exert some of its actions via th is route. Vasopressin is best known as (antidiuretic hormone' and has a maximal antidiuretic action achieved in the 5-10 pg/ml range . However, levels> 100 pg/ml, as produced by vasopressin infusions, have a well-documented natriuretic action. The use of the longer-acting vasopressin analogue , terlipressin, for indications other than septic shock (such as variceal bleeding or diabetes insipidus) does not cause hypertension and has been effectively used as a rescue therapy for catecholamine resistant shock [40]. A multicenter, triple-blind, randomized controlled trial (VASST) has been conducted to determine the effect of vasopressin compared to norepinephrine on survival. Although details of the trial design [41] and preliminary results have been presented at recent international meetings, complete details are yet to be published. In this multicenter trial, 779 septic shock patients who were already receiving norepinephrine were randomized to receive open-label norepinephrine in addition to blinded administration of either vasopressin (0.03 U/minute) or further norepinephrine (15 ug/min). There was no difference in the primary outcome, 28-day survival, between the groups (35.4 % vs. 39.3 %, P = 0.27). However, prior to randomization the investigators pre-defined a specified subgroup of patients receiving lower dose norepinephrine « 15 Ilg/min, 0.21 ug/kg/min). In this subgroup, there was a benefit in 28-day mortality (26.5 % vs. 35.7 %, P = 0.05) that was sustained until the 90-day mortality analysis (35.8 % vs. 46.1 %, P = 0.04). This may prove to be a very effective intervention in the treatment of septic shock, with a number needed to save one life of 10 [42]. In a small single center study of patients with advanced vasodilatory shock (mean norepinephrine dose prior to institution of vasopressin was 1.07 Ilg/kg/min) a higher dose of vasopressin (0.067 U/min) proved more efficacious than the doses used in the VASST trial [43] and this was not associated with any increase in adverse events. On current evidence, vasopressin (or terlipressin) should be reserved for rescue therapy, but this may change once the full results of the VASST study are published. Levosimendan in septic shock Levosimendan is a novel calcium sensitizer that shows potent dose-dependent positive inotropic and vasodilatory activity. Unlike conventional inotropes, levosimen dan is not associated with significant increases in myocardial oxygen consumption, pro arrhythmia, or neurohormonal activation. The most common adverse effect is vasodilatation. In a trial of levosimendan versus further dobutamine in septic patients with myocardial depression who were already receiving 5 ug/kg/min of dobutamine, it was shown that levosimendan improved systemic hemodynamics and regional perfusion [44]. Levosimendan significantly decreased mean pulmonary arterial pressure, right atrial pressure, and PAOP, and increased stroke index, cardiac index, DOz index, VOz index, and left ventricular stroke work index. Data from animal models of septic

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myocardial depression reveal that the lusitropic actions of levosimendan provide the unique advantage of improved diastolic function that is not a feature of treatment with either dobutamine or the phosphodiesterase inhibitor, milrinone [45]. There is some evidence supporting the safety and efficacy of using levosimendan in patients with catecholamine-refractory septic shock even without evidence of failure to respond to dobutamine [46]. Effects oflevosimendan on global and splanchnic circulation in septic shock are encouraging and it may become established as an excellent alternative to dobutamine in patients with sepsis-induced myocardial depression [47]. In Summary

Optimization of fluid status is desirable prior to initiation of vasopressors or inotro pes. There are no perfect measures to guide the adequacy of fluid resuscitation. In hemodynamic compromise, fluid loading against a dynamic assessment of fluid responsiveness is essential. In the face of a persistently low MAP with features of inadequate end-organ perfusion then vasoactive agents should be commenced, although which agent should be used remains unclear. Arguably assessment of end organ perfusion rather than an arbitrary MAP should be targeted. Fluid responsiveness should be re-checked repeatedly as vasoconstrictors will not only improve the MAP through increased arterial tone but will also venoconstrict, which will decrease venous capacitance and the response to fluid therapy.

Conclusion Despite advances in our understanding of the underlying pathophysiological processes and the refinement of our supportive therapies, septic shock remains both common and devastating . There can be no doubt that the Surviving Sepsis Campaign guidelines have been beneficial in influencing practice and disseminating the concept of 'early goal-directed therapy'. However, many of the cornerstones of the recommendations have come under renewed scrutiny since their initial publication and they are currently being revised. There is increasing recognition that sepsis is less chaotic than previously assumed and incorporates many protective as well as damaging pathways. Multiple organ failure may represent an adaptive response to a prolonged and severe inflammatory insult that enables the organs to recover adequate function to enable long-term recovery. Therefore, many of our current therapies may be interfering with the adaptive response and may in time, be shown to be deleterious [48]. References 1. Bone RC, Balk RA, Cerra FB, et al (1992) Definitions for sepsis and organ failure and guide-

lines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644-1655 2. Vincent JL, Sakr Y, Sprung C, et al (2006) Sepsis in European intensive care units: results of the SOAP stud y. Crit Care Med 34:344-353 3. Dellinger RP, Carlet JM, Masur H, et al (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858-873 4. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368- 1377

The Cardiovascular Management of Sepsis 5. Jones AE, Focht A, Horton JM, et al (2007) Prospective external validation of the clinical effectiveness of an emergen cy department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest 132:425-432 6. Lin SM, Huang CD, Lin HC, Liu CY, Wang CH, Kuo HP (2006) A modified goal-directed protocol improves clinical outcomes in intensive care unit patients with septic shock: a randomized controlled trial. Shock 26:551- 557 7. Bagshaw SM, Bellomo R (2007) The influence of volume man agement on outcome . Curr Opin Crit Care 13:541-548 8. Hollenberg SM, Ahrens TS, Annane D, et al (2004) Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 32 (suppl):S455-465 9. Rudiger A, Singer M (2007) Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 35:1599-608 10. Belcher E, Mitchell J, Evans T (2002) Myocard ial dysfunct ion in sepsis: no role for NO? Heart 87:507-509 11. Sibelius U, Grandel U, Buerke M, et al (2003) Leukotriene-mediated coronary vasoconstriction and loss of myocardial contractility evoked by low doses of Escherichia coli hemolysin in perfused rat hearts. Crit Care Med 31:683-688 12. Ammann P, Fehr T, Minder EI, Gunter C (2001) Elevation of troponin I in sepsis and septic shock. Intensive Care Med 27:965-969 13. Kim HW, Greenburg AG (2002)Nitric oxide scavenging, alone or with nitric oxide synthesis inhibition, modulates vascular hyporeactivity in rats with intrap eritoneal sepsis. Shock 17:423 - 426 14. Stephens R, Mythen M (2003) Resuscitation fluids and hyperchloraemic metabolic acidosis. Trauma 5:141-147 IS. Vincent JL, Gerlach H (2004) Fluid resuscitation in severe sepsis and septic shock: an evidence-based review. Crit Care Med 32:S451-S454 16. Michard F, Teboul JL (2002) Predicting fluid responsivenes s in ICU patients: A critical analysis of the evidence. Chest 121 :2000- 2008 17. Bendjelid K, Romand JA (2003) Fluid responsivenes s in mechanically ventilated patients: A review of indices used in intensive care. Intensive Care Med 29:352- 360 18. Osman D, Ridel C, Ray P, et al (2007) Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med 35:64-68 19. Pinsky MR (2007) Heart -lung interactions. Curr Opin Crit Care 13:528-531 20. Monnet X, Rienzo M, Osman D, et al (2006) Passive leg raising predicts fluid respons iveness in the critically ill . Crit Care Med 34:1402- 1407 21. Vincent JL (2006) A reappra isal for the use of pulmonary artery catheters. Crit Care 10 (suppl 3): Sl 22. Harvey S, Harrison DA, Singer M, et al (2005) Assessment of the clinical effectiveness of the pulmonary artery catheter; a randomised controlled trial. Lancet 366:472- 477 23. Gattinon i L, Brazzi L, Pelosi P, et al (1995) A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 333:1025- 1032 24. Krafft P, Steltzer H, Hiesmayr M, Klimscha W, Hammerle AF (1993) Mixed venous oxygen saturation in critically ill septic shock patients. The role of defined events. Chest 103:900 - 906 25. Fink MP (2002) Bench-to-bedside review: Cytopathic hypoxia. Crit Care 6:491-499 26. Bateman RM, Sharpe MD, Ellis CG (2003) Bench-to-bedside review: microvascular dysfunction in sepsis - hemodynamics, oxygen transport, and nitric oxide. Crit Care 7:359-373 27. James JH, Luchette FA, McCarter FD, Fischer JE (1999) Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet 354:505-08 28. Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE (2005) Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet 365:871-875 29. Cusack RJ. Rhodes A, Lochhead P, et al (2002) The strong ion gap does not have prognostic value in critically ill patients in a mixed medical/ surgical adult ICU. Intensive Care Med 28:864-869 30. Mullner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G (2004) Vasopressors for shock. Cochrane Database Syst Rev: CD003709 31. Vincent JL (2006) Is the current management of severe sepsis and septic shock really evidence based? PLoS Med 3:e346

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B.C. Creagh-Brown, J. Ball, and M. Hamilton 32. Zanotti Cavazzoni SL, Dellinger RP (2006) Hemodynamic optimization of sepsis-induced tissue hypoperfusion. Crit Care 10 (suppl 3):S2 33. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J (2000) Low-dose dopamine in patients with early renal dysfunction: A placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356:2139-2143 34. Albanese J, Leone M, Garnier F,Bourgoin A, Antonin i F, Martin C (2004) Renal effects of norepinephrine in septic and nonseptic patients. Chest 126:534-539 35. Sakr Y, Reinhart K, Vincent JL et al (2006) Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely III Patients (SOAP) Study. Crit Care Med 34:589- 597 36. Bracco D (2006) Pharmacologic support of the failing circulation: practice, education, evidence, and future directions. Crit Care Med 34:890- 892 37. Annane D, Vignon P, Renault A, et al (2007) Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet 370:676-684 38. Barrett LK, Singer M, Clapp LH (2007) Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med 35:33- 40 39. Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA (2001) Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 29:487- 493 40. Leone M, Albanese J, Delmas A, Chaabane W, Garnier F, Mart in C (2004) Terlipressin in catecholamine-resistant septic shock patients. Shock 22:314- 319 41. Russell JA, Cooper DJ, Walley KR, et al (2007) Vasopressin and Septic Shock Trial (VASST): baseline characteristics and organ dysfunction in vasopressor dependent patients with septic shock. Am J Respir Crit Care Med 167:A548 (abst) 42. Martin GS (2007) An update on Sepsis. Available at: http ://www.medscape.com/viewarticle/ 558470. Accessed December 2007 43. Luckner G, Mayr V, lochberger S, et al (2007) Comparison of two doses of arginine vasopressin in advanced vasodilatory shock. Crit Care Med 35:2280-2285 44. Morelli A, De Castro S, Teboul JL, et al (2005) Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 31:638- 644 45. Barraud D, Faivre V, Damy T, et al (2007) Levosimendan restores both systolic and diastolic cardiac performance in lipopolysaccharide-treated rabbits: comparison with dobutamine and milrinone. Crit Care Med 35:1376-1382 46. Powell BP, De Keulenaer BL (2007) Levosimendan in septic shock: a case series. Br J Anaesth 99:447-448 47. De Backer D, Taccone FS, Radermacher P (2007) Levosimendan in septic shock: another piece in the puzzle, but many pieces are still lacking. Intensive Care Med 33:403-405 48. Singer M (2006) The key advance in the treatment of sepsis in the last 10 years...doing less. Crit Care 10:122

423

Terlipressin in Septic Shock: When and How Much? C.

ERTMER,

A.

MORELLI,

and

M. WESTPHAL

Introduction Septic shock is the prototype of distributive shock characterized by arteriolar and venous vasodilation and pronounced vascular leakage, resulting in tissue edema, low systemic vascular resistance (SVR) and a subsequent fall in mean arterial pressure (MAP) [1). Multiple mechanisms are involved in the pathogenesis of the vasodilatation noticed in septic shock. Excessive nitric oxide (NO) formation subsequent to upregulation of inducible NO synthase (iNOS) and increased activity of the neuronal NOS isoform (nNOS) represents a major contributor to vasodilation, basically mediated by interaction with the cyclic guanosine monophosphate (cGMP) pathway [1). In addition, there is increasing evidence that adenosine triphosphate (ATP)-sensitive potassium (K+ATP) channels are critically involved in the regulation of arterial vascular smooth muscle tone, as well as in the pathophysiology of catecholamine tachyphylaxis in the presence of systemic inflammation and shock states [1,2) . Further mechanisms include adrenoceptor desensitization and downregulation due to high circulating levels of catecholamines [3,4). Last but not least, vasopressin deficiency has been considered as a causative factor in the pathogenesis of vasodilation in septic shock [1, 5). The current treatment regimen of patients with septic shock includes a targeted antimicrobial/anti-inflammatory therapy and early goal-directed hemodynamic therapy including aggressive fluid challenge, infusion of blood components, inotropic and vasopressor agents [6, 7). Aiming to increase total peripheral resistance and to preserve organ perfusion, a continuous infusion of catecholamines with predominantly u- and ~-adrenergic properties is often needed . In this context, norepinephrine represents the catecholamine of choice to treat patients remaining hypotensive despite adequate fluid resuscitation. As a result of adrenergic receptor downregulation , G-protein uncoupling, and disturbances in intracellular calcium metabolism , the efficacy of adrenergic agents often gradually decreases over time, thereby complicating hemodynamic support [1). Therefore, increasing attention is currently paid to alternative treatment strategies using non-adrenergic vasopressor agents, such as agonists of the vasopressinergic system. Since a multitude of review articles has been published on recent studies investigating the use of arginine vasopressin in vasodilatory shock states [8-15), this chapter specifically focuses on the cutting edge knowledge about the pharmacology and efficacy of terlipress in, a synthetic long-acting vasopressin analog, relevant to the treatment of septic shock. In addition, this chapter critically discusses: 1) potential advantages of terlipressin over arginine vasopressin; 2) the putative optimal time point for the initiation of terlipressin therapy; and 3) the importance of choosing the appropriate mode of administration (bolus vs. continuous infusion) and the right dosage (high dose vs. [ultra) low dose).

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Pharmacokinetic Aspects of Terlipressin Terlipressin (N't-triglycyl-Bvlysine-vasopressin; Fig. 1) is a synthetic dodecapeptide (12 amino acids) containing the nonapeptide sequence that represents the natural hormone lysine-vasopressin. Lysine-vasopressin is the innate vasopressin analog in pigs, hippos, warthogs, and marsupials. Its structure is identical to human arginine vasopressin, except for the substitution of lysine for arginine at position 8. Terlipressin is a pro-drug exerting only moderate intrinsic vasopressin activity prior to the cleavage of its three glycyl residues by endogenous proteases. Once the glycyl residues are spliced, the main active metabolite, i.e., lysine-vasopressin, is released. Due to the transient release of mono- and diglycyl-lysine-vasopressin, entire liberation of the vasoactive lysine-vasopressin takes several hours [16-18]. In clinical practice, terlipressin is, therefore, 'classically' administered as intermittent bolus infusions in doses of 0.5 to 1 mg [19-22].

Fig. 1. Chemical structure of terlipressin (TP, Na-Triglycyl 8-lysine vasopressin). The ellipse labels the three glycyl residues.

Following intravenous bolus administration of 7.5 flglkg terlipressin in healthy humans, the elimination half-life of terlipressin is about 50 min, whereas its hemodynamic effects last up to 6 h. Plasma levels of lysine-vasopressin increase 40- 60 min after bolus injection of terlipressin, peaking at 60-120 min post administration; plasma clearance of terlipressin equals 9 mllkg/min [16, 18].

Pharmacodynamics of Terlipressin Relevant to the Treatment of Septic Shock Exogenous administration of terlipressin and subsequent release of lysine-vasopressin exerts intrinsic activity on vasopressinergic VI and V2 receptors. The signal transduction following stimulation of vascular VI and renal V2 receptors is schematically displayed in Fig. 2. As compared to arginine vasopressin (VI: V2 ratio = 1: l ), terlipressin is characterized by a more specific VI agonistic effect (VI :V2

Terlipressin in Septic Shock: When and How Much?

AVPfTP •

AVPfTP VSMC

•

-=:;;;_ _ PI P2

@

+-

::!"'''~

DAG

IPJ

(.'~ ""J

Kidney

GDP

AMP

cAMP

~~ll[lI I

Fig. 2. Signal transduction of terlipressin (TP). AMP: adenosine monophosphate; AQP2: aquaporin 2; AVP: arginine vasopressin; Ca 2+: calcium; cAMP: cyclic adenosine trisphosphate; DAG: diacyl glycerol; GDP: guanosyl diphosphate; GTP: guanosyl triphosphate; H20: water; IP3: inositole trisphosphate; MLCK: myosin light chain kinase; PIP 2: phosphatidyl inositole bisphosphate; PKA: proteinkinase A; PLC: phospholipase C; Vl : Vl vasopressin receptor; V2: V2 vasopressin receptor; VSMC: vascular smooth muscle cell.

ratio = 2.2: 1) [9]. Interestingly, the antidiuretic effects occur approximately 120 minutes after intravenous terlipressin injection in healthy volunteers, whereas the vasopressor effects become apparent after just 3 minutes [16, 18]. This, in turn, implies that the V2 receptor-mediated effects after terlipressin administration are mainly related to the release of lysine-vasopressin, whereas terlipressin itself exerts immediate intrinsic activity on VI receptors. As mentioned above, the effective halflife of terlipressin is longer when compared with arginine-vasopressin (4- 6 h vs. 6-20 min) [16, 18]. This may imply a potential advantage of terlipressin over arginine-vasopressin, since significant rebound hypotension has been reported following discontinuation of arginine-vasopressin infusion [5]. In this context it is noteworthy that, despite its pro-drug kinetics, no accumulation of terlipressin has yet been reported, even after a continuous infusion of 48 h [23].

Rationale for the Use of Terlipressin in Shock States Due to its vasoconstrictive activity on vascular smooth muscle cells and its pronounced vasoconstriction within the splanchnic circulation, terlipressin may (dosedependently) reduce regional intestinal blood flow, thereby lowering portal blood pressure [24]. The reduction of splanchnic blood flow provoked by terlipressin, however, represents the rationale for its therapeutic use in patients with bleeding esophageal varices and hepato -renal syndrome secondary to liver cirrhosis [25, 26]. In addition, terlipressin has been suggested as the ideal drug for patients chronically treated with long-term angiotensin-converting enzyme (ACE) inhibitors who

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develop refractory perioperative arterial hypotension [27]. During recent years, terlipressin has also been identified as a useful non-adrenergic vasopressor in the treatment of catecholamine-refractory septic shock [19-23], and is thus increasingly used in the treatment of sepsis-associated arterial hypotension.

Experimental Evidence for the Use of Terlipressin All experimental studies on the use of terl ipressin in septic or endotoxemic shock consistently demonstrate a significant increase in arterial blood pressure. In ovine endotoxemia, however, the beneficial effects of 15 ug/kg terlipressin bolus injection (equivalent to 1.05 mg in a 70 kg subject) on MAP were accompanied by significant increases in pulmonary vascular resistance index and decreases in oxygen delivery index (DOzI) [28]. These unwanted side effects probably occurred in response to high doses of terlipressin causing an excessive increase in left ventricular afterload. Aiming to prevent the adverse effects associated with terlipressin bolus infusion, our research group was the first to have demonstrated that, despite its pro-drug pharmacokinetics, terlipressin may also be administered as a titrated infusion, thereby exactly achieving pre-defined goal-MAP values in endotoxemic sheep [29]. However, continuous terlipressin infusion (l0 - 40 flg/kg/h equivalent to 0.7 - 2.8 mg/h in a 70 kg patient) was also associated with a dose-dependent drop in cardiac output and systemic DOz. Notably, Asfar et al. [30] reported that administration of repetitive low-dose boluses of 6 flg/kg terlipressin (equivalent to 0.42 mg in a 70 kg subject), in associa tion with adequate fluid challenge, stabilized systemic hemodynamics and even improved blood flow within the ileal microcirculation in endotoxemic rats . In the latter study, however, terlipressin administration without prior fluid resuscitation had deleterious effects on ileal blood flow and even increased mortality. This finding supports the importance of early and aggressive fluid resuscitation prior to the use of terlipressin in vasodilatory septic shock. Subsequently, the same authors confirmed that titrated continuous infusion of terlipressin (equivalent to 0.35-1.05 mg/h in a 70 kg subject) not only reversed the hypotensive-hyperdynamic circulation in porcine endotoxernia, but also slightly decreased global oxygen consumption (VOz) without compromising splanchnic metabolism and organ functions, as indicated by an unaffected ileal peo z gradient, liver and gut oxygen uptake, portal and hepatic venous pH, as well as bilirubin and liver enzymes [31]. Whereas terlipressin decreased portal venous blood flow in this setting, hepatic arterial blood flow was increased. It is, therefore, conceivable that the observed decrease in systemic VOz in the above referenced experimental studies was due to a pathological delivery and demand dependency. Alternatively, it is tempting to postulate a decrease in metabolic demand due to an intrinsic antipyretic/anti-inflammatory effect of terlipressin [32, 33]. Recently, the effects of conventional bolus injections (l mg) versus continuous low-dose infusion (equivalent to 0.14 mg/h in a 70 kg subject) of terlipressin have been directly compared in experimental ovine endotoxemia [34]. In this study, terli pressin bolus injections were linked to excessive increases in systemic and pulmonary vascular resistance that were followed by sudden and strong rebound effects (Fig. 3). In add ition, terlipressin bolus administrations were associated with significant reductions in heart rate and cardiac index immediately after each injection followed by overshooting increases in these variables 3-4 h thereafter. On the contrary,

Terlipressin in Septic Shock: When and How Much?

11 0 100 0> I 90 E

Ec, «

~

80 70 60

BL 0

6

12

18

24

Time (h)

Fig. 3. Terlipressin bolus vs. continuous infusion. Effects of terlipressin bolus infusion (1 mg at 0,6, 12, and 18 h, diamonds) vs. continuous infusion (0.5mg/6 h, triangles) on mean arterial pressure (MAP) in ovine endotoxemia (modified from (34)). Squares represent control animals receiving only the vehicle (normal saline).

continuous low dose infusion of terlipressin permanently restored systemic arterial pressure and improved left ventricular stroke work index, thereby preventing the side effects observed in sheep treated with intermittent terlipressin bolus injections (Fig. 3). The latter study suggests that continuous infusion of terlipressin is more effective than bolus infusion in maintaining a stable increase in MAP and allows an approximately 50 % reduction in cumulative terlipressin doses. Preliminary results from a comparative study of arginine -vasopressin versus terlipressin in fulminant ovine septic shock suggest that 1 flg/kg/h of terlipressin (equivalent to 0.07 mg/h in a 70 kg patient) may improve survival and increase mesenteric perfusion as compared to 30 mU/kg/h arginine-vasopressin (equivalent to 0.035 U/ min in a 70 kg patient) [35]. In addition, a highly selective VI agonist (FE 202158) has recently been demonstrated to markedly reduce vascular leakage and mortality in ovine experimental sepsis as compared to arginine -vasopressin [36] . In summary, experimental data on the use of terlipressin in septic or endotoxemic shock suggest that high doses may be associated with severe side effects related to excessive vasoconstriction, whereas lower doses appear to have a more favorable benefit/risk ratio. In addition, it has been reported that a continuous low-dose terlipressin infusion may be as efficacious as repeated bolus injections, thereby, avoiding excessive increases in vascular resistance and rebound hypotension [34]. Recent preliminary data even suggest that terlipressin may be advantageous over argininevasopressin, probably due to its higher VI selectivity [35, 36]. However, future stud ies are needed to investigate this interesting and clinically relevant issue in more detail. Table 1 gives an overview of previous experimental studies on the use of terlipressin in sepsis or endotoxemia .

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C. Ertmer, A. Morelli, and M. Westphal Table 1. Studies on bolus injection and continuous infusion of terlipressin in experimental sepsis. Publication Subjects

Interventions

Dose equiva- Main results lent for a 70 kg patient

0.6 mg terlipressin

1 mg

Bolus terlipressin Scharte et 6 sheep (39 kg) al. [28] with endotoxemia vs. healthy sheep

Asfar et al. 25 rats (200 - 350 g) 0.0012 - 0.0021 mg 0.42 mg [30] with endotoxemia terlipressin withl without fl uid diallenge

Increases in SAp, SVR, PVR; decrease in cardiac output Increases in SAp, mesenteric vein blood flow, ileal microcirculation (only in fluid-challenged rats)

Continuous terlipressin Westphal et al. [29]

6 sheep (35 kg)

with endotoxemia vs. healthy sheep

Asfar et al. 18 pigs (50 kg) [31 ] with endotoxemia Lange et al. [34]

24 sheep (40 kg) with with endotoxemia

1.05 mg/h terli-

2.1 mg/h

Increases in SAp, PVR; decreases in cardiac output, 002< V02

0.25- 0.75 mg/h

0.35 -1.05 mg/h

Increases in SAp, SVR, hepatic artery flow; decreases in cardiac output, V0 2; attenuation of hepatosplanchnic venous acidosis

0.08 mg/h terlipressin vs. 1 mg

0.1 4 mg/h

Continuous terlipressin increases SAp, SVR, and LVSWI without decreases in cardiac output, 002 and increases in PVR

pressin

terlipressin vs. no treatment

terlipressin bolus vs. no treatment

SAP: systemic arterial pressure, SVR: systemic vascular resistance, PVR: pulmonary vascular resistance, 002: global oxygen delivery, Sv0 2: mixed-venous oxygen saturation, V02: global oxygen consumption, LVSWI: left ventricular stroke work index

Clinical Evidence for the Use of Terlipressin Similar to arginine-vasopressin [37], terlipressin is characterized by an excellent dose/response relationship in septic shock patients [23]. In this context, O'Brien and colleagues were the first to report a marked pressor response following terlipressin bolus administration in the clinical setting of septic shock [19]. In eight patients with sepsis-induced arterial hypotension unresponsive to fluid resuscitation and high-dose norepinephrine infusion, bolus adm inistration of 1- 2 mg terlipressin increased MAP within minutes, from an average of 52 mmHg to 72 mmHg at 2 h post-injection. Infusion rates of norepinephrine remained unchanged in one patient, and were temporarily decreased in three patients, or even discontinued in four patients within 48 h. In this context, however, it is noteworthy that bolus infusion of 2 mg terlipressin even entailed glyceryl trinitrate infusion to lower peak MAP in one patient [19]. Increases in MAP and reductions in catecholamine requirements after terlipressin administration have subsequently been confirmed in several clinical reports. In these studies, terlipressin was either used as first-line [21] or rescue therapy [20, 22]. The positive effects of terlipressin infusion on arterial pressure and catecholamine

Terlipressin in Septic Shock: When and How Much?

requirements in adults have likewise been confirmed in children and infants with refractory septic shock [38 - 40]. Bolus infusion of terlipressin in adults with septic shock has been consistently followed by marked increases in MAP, urine output, and creatinine clearance that are accompanied by reductions in heart rate and cardiac output, mainly due to a marked increase in left ventricular afterload. However, in some patients, terlipressin bolus infusion was also associated with a reduction in global VOz, arousing discussions about a potential oxygen supply dependency [20-22, 41]. However, arterial lactate concentrations decreased following terlipressin injection in these patients [21, 22]. In view of the high catecholamine doses in some of the investigated patients (> 2 Ilg/kg/min), the decrease in arterial lactate and VOz may best be explained by a marked reduction in catecholamine infusion rates (norepinephrine from 3.8 ± 1.3 to 0.7 ± 0.5 Ilg/kg/min) [22]. However, in the same patients, bilirubin concentrations and aminotransferases activities markedly increased over time, suggesting some degree of liver hypoperfusion. Conversely, Morelli and coworkers even reported increased gastrointestinal perfusion following terlipressin bolus injection [20]. A recent randomized clinical trial (DOBUPRESS study) assessed whether dobutamine infusion was capable of reversing the decrease in systemic DO z following bolus terlipressin infusion [42]. Patients treated with a combination of terlipressin and dobutamine were characterized by higher systemic DO z and mixed venous oxygen saturation (SvOz) as compared to sole bolus terlipressin infusion. Interestingly, there was no difference in MAP or norepinephrine requirements between the two groups. However, since dobutamine infusion itself may be associated with severe complications (increase in myocardial VOz, ventricular arrhythmias) it remains inconclusive whether its combination with terlipressin offers a significant advantage over sole terlipressin administration in septic shock. Aiming to prevent the typical reduction in global DO z in response to bolus terlipressin infusion, Morelli et al. recently reported a case series of three patients with arterial hypotension related to septic shock treated with a continuous low-dose terlipressin infusion [23]. Two patients received terlipressin infusion at 2.6 Ilg/min (equivalent to 0.18 mg/h in a 70 kg subject) as an adjunct to a previously started norepineprhine infusion. Another patient was treated with terlipressin at a dose of 1.3 Ilg/min (equivalent to 0.09 mg/h in a 70 kg subject) as first line therapy, while norepinephrine infusion was additionally started if MAP was less than 65 -75 mmHg. Notably, none of these patients developed a decrease in cardiac index or increase in gastric mucosal PCOz gap. In the two patients receiving norepinephrine as first-line therapy in conjunction with the higher terlipressin dose, i.e., 2.6 ug/rnin, severe skin necrosis occurred. However, it remains unclear whether this complication was a side effect of terlipressin infusion and/or high-dose norepinephrine treatment, or septic shock per se. In this regard it may be important to notice that the incidence of skin necrosis appears to be independent of the use of vasopressin analogs [43]. Taken together, published clinical data on the use of terlipressin in septic shock clearly demonstrate that exogenous terlipressin increases MAP and allows a marked weaning from conventional adrenergic vasopressor agents. A potentially disadvantageous decrease in cardiac index and global DO z might be prevented by additional dobutamine infusion [42] and/or continuous instead of bolus infusion [23, 34]. When using bolus terlipressin infusion in patients with septic shock, the potential risk of liver hypoperfusion should be taken into account [21, 22]. Table 2 summarizes the published clinical studies on the use of terlipressin in patients with septic shock.

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C. Ertmer, A. Morelli, and M. Westphal

Table 2. Clinical studies on bolus injection and case reports on continuous infusion of terlipressin in patients with septic shock.

Publication Patients

Interventions

Main results

O'Brien 8 patients with et al. [19] septic shock

1-2 mg terlipressin

Increase in SAP; decrease in cardiac output

Leone 17 patients with et al. [22] septic shock

1-2 mg terlipressin

Increase in SAP; decrease in cardiac output and platelet count; increase in liver enzymes and bilirubin

Morelli 15 patients with et al. [20] septic shock

1 mg terlipressin

Bolus terlipressin

Albanese 20 patients with et al. [21] septic shock

Increase in SAP and gastric mucosal perfusion; decreases in cardiac output, DOl< VOl< Pc0 2 gradient 1- 2 mg terlipres- Decreases in cardiac output, DOl< V0 2 sin vs. titrated norepinephrine

Continuous terlipressin

Jolley 1 patient with et al. [44] septic shock

0.25- 0.5 mg/h

Zeballos 1 infant with et al. [40] septic shock

0.7 - 1.4 mg/ Increase in SAP 70 kg/h terlipressin

Morelli 3 patients with et al. [23] septic shock

0.09 and 0.18 mg/

terlipressin

Increase in SAP; decrease in cardiac output

Increase in SAP without decrease in cardiac out70 kg/h terlipressin put or increase in Pco2 gradient at both doses; increase in liver enzymes, increase in bilirubin, and skin necrosis only at the higher dose

SAP: systemic arterial pressure; 002: global oxygen delivery; V0 2: global oxygen consumption

Limiting Adverse Effects: Less May Be Best Terlipress in has the potential to excessively increase total peripheral resist ance and redu ce cardiac index as well as global oxygen supply in a dose-dependent manner [19, 29]. In one particular case, bolus doses as high as 2 mg necessitated a glyceryl trinitrate infusion to counteract overshooting vasoconstriction [19]. On the contrar y, doses of 0.5 mg or less appear to appropriately increase MAP and redu ce catecholamine requ irements, thereby pot entially limiting the incidence of unwanted side effects [30]. Aggressive fluid challenge (as a stand ard therapy of septic shock) is of paramount importance when using strong vasopresso r agents, such as terlipressin. Notably, experimental data clearly dem onstrated deleterious effects of terlipressin on the splan chnic microcirculation and mortality in the absence of adequate int ravascular volume replacement [30]. Since terlipressin has been reported to decrea se platelet count and increase bilirubin concent rations as well as aminotransferases activities [21, 22], these labor atory variables should be strictly monitored in addition to hemodynamic parameters.

Terlipressin in Septic Shock: When and How Much?

View into the Future The results of VASST (Vasopressin And Septic Shock Trial) have recently been presented at several major critical care meetings. In brief, this randomized controlled trial demonstrated that low-dose arginine-vasopressin infusion (up to 0.03 U/min) represents a safe adjunct in the treatment of vasopressor-dependent septic shock. However, survival was only improved in the subgroup of patients receiving arginine-vasopressin early in the course of the disease (i.e., norepinephrine doses < 5 ug/rnin). It appears, therefore, that early administration of vasopressin analogs is superior to a last resort treatment. On this background, a randomized controlled clinical study has recently been initiated to evaluate the efficacy and safety of a continuous low dose terlipressin infusion as first-line therapy in fluid resuscitated septic shock patients (TErlipressin in Septic Shock Trial, TESST-l). Patients are treated with either a continuous low dose terlipressin infusion (2 fJg/kg/h; equivalent to 0.14 mg/h in a 70 kg patient), ultra low dose terlipressin infusion (l Ilg/kg/h; equivalent to 0.07 mg/h in a 70 kg patient), or titrated norepinephrine (started at 0.1 fJg/kg/min). In both terlipressin groups, additional norepinephrine is administered to achieve an MAP of 65 ± 5 mmHg, if necessary. The study is designed to monitor pharmacokinetics of terlipressin, hemodynamic variables, and organ function over an intervention period of 48 h. Secondary endpoints include intensive care unit (leU) stay and survival. In addition, an ongoing trial (TERLIVAP) is directly comparing the efficacy and safety of continuous infusions of either arginine-vasopressin (0.03 U/min) or terlipressin (1.3 ug/kg/h) in patients with septic shock .

Summary and Conclusion Several clinical and experimental studies clearly demonstrated that intravenous terlipressin administration is feasible to increase MAP and reduce catecholamine requirements in septic shock. Whereas recent experimental data even suggest a superiority of terlipressin over arginine-vasopressin [35, 36], this notion remains to be confirmed in the clinical setting. Bolus injections of terlipressin are consistently associated with an excessive increase in total peripheral resistance and subsequent decreases in cardiac output and DOz. In this regard, the reduction in cardiac output was independent of whether terlipressin was administered as a first-line [21] or last resort treatment [19,20,22]. Although it has never been proved that this reduction in cardiac output is deleterious, it should be regarded as a potentially harmful side effect, since it may potentially increase the risk of organ hypoperfusion or oxygen supply dependency. Even though not yet supported by major clinical trials, experimental data [31,34] and clinical reports [23] suggest that a continuous infusion of relatively low terlipressin doses (1.3 - 2.6 Ilg/kg/h) may be suitable to prevent reduc tions in cardiac output, excessive vasoconstriction, and rebound arterial hypoten sion . The results of VASST as well as preliminary clinical data on the use of terlipressin [23] suggest that 'less may be best and the earlier the better'. The assumption that a continuous ultra low dose infusion of terlipressin (l ug/kg/h) represents a safe and efficacious first-line treatment of septic shock patients will be answered by a currently ongoing randomized controlled trial (TESST-l) in the near future. While awaiting these results, terlipressin should not (yet) routinely be used outside the scope of controlled clinical trials .

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C. Ertmer, A. Morelli, and M. Westphal References 1. Landry OW, Oliver JA (200I) The pathogenesis of vasodilatory shock. N Engl J Med 345: 588-595 2. Lange M, Morelli A, Ertmer C, et al (2007) Role of adenosine triphosphate-sensitive potassium channel inhibition in shock states: Physiology and clinical implications. Shock 28:394- 400 3. Saito T, Takanashi M, Gallagher E, et al (1995) Corticosteroid effect on early beta-adrenergic

down-regulation during circulatory shock: hemodynamic study and beta-adrenergic receptor assay. Intensive Care Med 21:204-210 4. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med

348:138- 150 5. Landry OW, Levin HR, Gallant EM, et al (1997) Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 95:1122-1125 6. Hollenberg SM, Ahrens TS, Annane 0, et al (2004) Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 32:1928-1948 7. Dellinger RP, Carlet JM, Masur H, et al (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858 - 873 8. Holmes CL, Patel BM, Russell JA, Walley KR (2001) Physiology of vasopressin relevant to management of septic shock. Chest 120:989-1002 9. Westphal M, van Aken H, Ertmer C (2004) Role of vasopressin and terlipressin in the setting 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

of systemic inflammation. In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Hedielber 9, pp 193-205 Holmes CL, Walley KR (2004) Vasopressin in the ICU. Curr Opin Crit Care 10:442-448 Cartotto R, McGibney K, Smith T, Abadir A (2007) Vasopressin for the septic burn patient. Burns 33:441-451 Barrett LK, Singer M, Clapp LH (2007) Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med 35:33- 40 Lee CS (2006) Role of exogenous arginine vasopressin in the management of catecholaminerefractory septic shock. Crit Care Nurse 26:17- 23 Ertmer C, Bone HG, Westphal M (2006) Arginine vasopressin versus norepinephrine: will the stronger one win the race? Crit Care 10:144 Vincent JL (2006) Vasopressin in hypotensive and shock states. Crit Care Clin 22:187 -197 Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E (1990) Pharmacokinetics of terlipress in after single i.v. doses to healthy volunteers . Drugs Exp Clin Res 16:307-314 Pesaturo AB, Jennings HR, Voils SA (2006) Terlipressin: vasopressin analog and novel drug for septic shock. Ann Pharmacother 40:2170-2177 Forsling ML, Aziz LA, Miller M, Davies R, Donovan B (1980) Conversion of triglycylvasopressin to lysine-vasopressin in man. J Endocrinol 85:237 - 244 O'Brien A, Clapp L, Singer M (2002) Terlipressin for norepinephrine-resistant septic shock. Lancet 359:1209-1210 Morelli A, Rocco M, Conti G, et al (2004) Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock. Intensive Care Med

30:597-604 21. Albanese J, Leone M, Delmas A, Martin C (2005) Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study. Crit Care Med 33:1897 -1902 22. Leone M, Albanese J, Delmas A, Chaabane W, Garnier F,Martin C (2004) Terlipressin in catecholamine-resistant septic shock patients. Shock 22:314- 319 23. Morelli A, Ertmer C, Lange M, Westphal M (2007) Continuous terlipressin infusion in

patients with septic shock: less may be best, and the earlier the better? Intensive Care Med

33:1699 - 1670 24. Aronsen KF, Bjorkman I, Lindstrom K, Nylander G, Mulder J (1979) The mechanism of lysine-vasopressin hemostasis in bleeding esophageal varices. Acta Chir Scand 145:231- 234 25. Ortega R, Gines P, Uriz J, et al (2002) Terlipressin therapy with and without albumin for

patients with hepatorenal syndrome: results of a prospective , nonrandomized study. Hepatology 36:941- 948 26. Ioannou GN, Doust J, Rockey DC (2003) Systematic review: terlipressin in acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther 17:53- 64

Terlipressin in Septic Shock: When and How Much? 27. Boccara G, Ouattara A, Godet G, et al (2003) Terlipressin versus norepinephrine to correct refractory arte rial hypoten sion after general anesthes ia in patients chronically treated with renin-angiotensin system inhibitors . Anesthesiology 98:1338-1344 28. Scharte M, Meyer J, Van Aken H, Bone HG (2001) Hemodynam ic effects of terlipressin (a synthet ic analog of vasopressin) in healthy and endotoxemic sheep. Crit Care Med 29: 1756-1 760 29. Westphal M, Stubbe H, Sielenkamper AW, et al (2003) Terlipressin dose response in healthy and endotoxemic sheep: impact on cardiopulmonary performance and global oxygen transport. Intensive Care Med 29:301 - 308 30. Asfar P, Pierrot M, Veal N, et al (2003) Low-dose terlipressin improves systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats. Crit Care Med 31:215-220 31. Asfar P, Hauser B, Ivanyi Z, et al (2005) Low-dose terlipressin during long-term hyperdynamic porcine endotoxemi a: effects on hepatosplanchnic perfusion , oxygen exchange, and metabolism . Crit Care Med 33:373- 380 32. Zhao L, Brinton RD (2004) Suppression of proinflammatory cytokines interleukin-Ibeta and tumor necrosis factor-alpha in astroc ytes by a VI vasopressin receptor agonist: a cAMP response element-binding protein-dependent mechanism . J Neurosci 24:2226-2235 33. Naylor AM, Cooper KE, Veale WL (l98 7) Vasopressin and fever: evidence supporting the existence of an endogenous antipyretic system in the brain. Can J Physiol Pharmacol 65:1333-1338 34. Lange M, Koehler G, Morelli A, et al (2007) Continuous versus bolus infusion of terlipressin in ovine endotoxemia . Shock 2007 28:623-629 35. Rehberg S, Ertmer C, Lange M, Morelli A, Van Aken H, Westphal M (2007) Effects of vasopressin and terlipress in in ovine septic shock on mesenteric blood flow and survival. Crit Care II :PI9 (abst) 36. Traber D (2007) Selective VIa receptor agonists in experimental septic shock. Crit Care 1l:P51 (abst) 37. Landry DW, Levin HR, Gallant EM, et al (1997) Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 25:1279-1282 38. Rodriguez-Nunez A, Fernandez-Sanmartin M, Martinon-Torres F, Gonzalez-Alonso N, Martinon-Sanchez JM (2004) Terlipressin for catecholamine-resistant septic shock in children. Intensive Care Med 30:477- 480 39. Rodriguez-Nunez A, Lopez-Herce J, Gil-Anton J, Hernandez A, Rey C (2006) Rescue treat ment with terlipress in in children with refractory septic shock: a clinical study. Crit Care 10:R20 40. Zeballos G, Lopez-Herce J, Fernandez C, Brandstrup KB, Rodriguez-Nunez A (2006) Rescue therapy with terlipressin by continuous infusion in a child with catecholamine -resistant septic shock. Resuscitation 68:151-153 41. Westphal M, Ertmer C, Van Aken H, Bone HG (2004) Terlipressin in patient s with septic shock: friend or foe? Intensive Care Med 30:992 42. Morelli A, Ertmer C, Lange M, Broking K, Orecchioni A, Rocco M, Van Aken H, Pietropaoli P, Westphal M (2007) Effects of simultaneously infused terlipressin and dobutamine in septic shock. Crit Care A794 43. Dunser MW, Mayr AJ, Tur A, et al (2003) Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 31:1394-1398 44. Jolley DH, De Keulenaer BL, Potter A, Stephens DP (2003) Terlipressin infusion in catecholamine-resistant shock. Anaesth Intensive Care 31:560-564

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Blood Purification Techniques in Sepsis and SIRS P.M.

HONORE,

O.

]OANNES-BoYAU,

and B.

GRESSENS

Introduction The rationale for blood purification in sepsis has been a matter of debate for 25 years. For more than a decade [1], it has been suggested that a reduction in cytokines and other mediators in the blood compartment could, in theory, lead to a reduction in mortality in patients with sepsis and the systemic inflammatory response syndrome (SIRS). However, as the pharmacodynamics and pharmacokinetics of cytokines are complex, it seems likely that this is an oversimplification. In recent years, three theories have been put forward as possible explanations for the clinical findings in septic patients undergoing various blood purification techniques. We will discuss these theories in this chapter and describe the high volume hemofiltration (HVHF) and hybrid techniques available to the clinician at the present time. As no consensus exists regarding the definition of 'high-volume', we will use those proposed during the 12th International Conference on Continuous Renal Replacement Therapy (CRRT) in San Diego (March 2007) [2], i.e., continuous HVHF consists of a continuous dose greater than 35 mllkg/h; pulse HVHF consists of a dose greater than 45 ml/kg/h carried out for 4, 6, or 8 hours and followed by continuous HVHF at 35 mllkg/h (a post-hoc analysis of a study by Ronco et al. [3] suggested that this dose [45 mllkg/h] may be beneficial for patients with septic acute renal failure). Finally, we will review possible effects in immunoparalysis and the concept of prophylactic hemofiltration, as well as the pleiotropic properties of HVHF before discussing the possible clinical implications of HVHF in the septic patient.

Three New Theories of Blood Purification Although our understanding of the complex pharmacodynamics and pharmacokinetics of cytokines throughout the body remains limited, a number of concepts have been put forward concerning mediator removal during continuous renal replacement therapy (CRRT). The Peak Concentration Hypothesis

In the peak concentration hypothesis [4-6], described by Ronco and Bellomo, efforts are concentrated on removing mediators and cytokines from the blood compartment in the pro-inflammatory phase of sepsis. It is hoped that by reducing the amount of free cytokines, remote organ (associated) damage can be limited, thereby

Blood Purification Techniques in Sepsis and SIRS

attenuating associated mortality. Changes in mediators and cytokines at the interstitial and tissue level are not taken into account in this theory, although they are of obvious clinical importance, and changes at this level can play an important role in organ damage. In this setting, techniques that allow rapid and substantial removal of cytokines or mediators from the blood compartment are favored. Among them, high volume (HVHF) and very high volume hemofiltration (VHVHF) feature prominently, as do a number of hybrid therapies encompassing high permeability hemofiltration (HPHF) [7-9], super high flux hemofiltration (SHFHF) [10], hemo-adsorption or coupled filtration and adsorption (CPFA) [11], and any adsorptive techniques using physical or chemical forces rather than the driving forces normally implemented in hemofiltration-derived techniques. The Threshold Immunomodulation Hypothesis

After an extensive literature review, a model was developed that coupled mediator removal from the blood compartment to changes in the interstitium and the blood compartment. This second concept, the threshold immunomodulation hypothesis, sometimes referred to as the Honore concept [12, 13], takes a far more dynamic view of the system. Pro-mediators as well as mediators are removed at the interstitial and tissue levels, following removal from the blood compartment, until a so-called threshold point is reached at which some pathways and cascades are brought to a complete standstill. At this level, the cascade is subsequently blocked and no further harm can be done to the tissues of the organism. However, when applying HVHF in clinical practice, determining this threshold point is fraught with difficulty as there may be significant changes at interstitial and tissue levels, while no changes in the blood compartment can be determined. A number of studies using HVHF, although only observational, have demonstrated improved hemodynamics and survival in some patients without a significant decrease in mediator levels inside the blood compartment [14-16]. This observation suggests an effect of HVHF outside the blood compartment. One could, therefore, conclude that the substantial biological effects of HVHF are obtained without any dramatic decrease in the plasma cytokine level because cytokine or mediator levels decrease at the tissue level where they actually do harm. Although a study performed by Klouche and colleagues [17] did not use HVHF (but lower volumes), nevertheless the results of this study do, in part, support this theory. In this model, it still remains unclear how HVHF promotes mediator and cytokine flow from tissue and interstitium to the blood compartment. The Mediator Delivery Hypothesis

In the mediator delivery hypothesis [18], otherwise known as the Alexander concept, the use of HVHF and especially high replacement volumes (3 to 5 liters/hour) enables a 20 to 40- fold increase in the lymphatic flow [19- 21] with associated drag and displacement of mediators and cytokines to the blood compartment, making them available for removal. Thus, the use of high volumes of replacement fluid might be of great importance, not only for extraction but also to propaga te lymphatic transport between the interstitium and tissue on the one hand, and the blood compartment on the other.

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Blood Purification Techniques Available in 2008 A number of blood purification techniques are currently available to the clinician treating sepsis in the intensive care unit (lCU). Within this myriad of different techniques, solute transport is effectuated either by diffusion or convection or ad/absorption or a combination of these modalities. In classic intermittent hemodialysis and derived techniques utilized in the ICU, diffusion (a concentration gradient across a semi-permeable membrane causes solute transport) is the driving force behind solute removal. In hemofiltration and derived techniques, solute removal is perpetuated by convection (a pressure gradient causes fluid movement across a semi-permeable membrane with so-called solute drag), favoring removal of middle molecules. There is no evidence favoring one form of solute clearance over the other in the septic patient, nor is there evidence favoring a continuous technique over intermittent hemodialysis. However, there is evidence to suggest that clinicians are more inclined to choose a continuous technique, if available, for the unstable patient [22]. It stands to reason that the delivered dose, as in conventional intermittent hemodialysis outside the ICU setting, could influence morbidity and , therefore, mortality. Indeed, positive effects on outcome have been described in a number of randomized controlled studies both for intermittent hemodialysis [23], for continuous venovenous hemofiltration (CVVH) [3], and for a combination of these techniques [24]. However, a smaller randomized controlled trial found no association between survival and ultrafiltration dose [25]. It should be noted that in this study [25], the 28day survival in all groups was relatively high compared to other studies, fuelling a suspicion that the population studied differed from those in other studies. Nevertheless, when looking at hospital survival (and not only at 28-day survival) , the casemix of the population appears to be more comparable. Indeed, hospital survival rates in the study by Bouman et al. [25] were 63, 49, and 61 %, in patients receiving early HVHF, early low-volume hemofiltration (LVHF), and late LVHF, respectively, while 90-day survival rates in the study by Saudan et al. [24] were 59 and 34 %, in patients receiving continuous veno-venous hemod iafiltration (CVVHDF), with an increased dialysis dose, and CVVH, respectively (and 64 and 38 %, respectively, if untreated and moribund patients were included). Hospital surv ival in the study by Bouman et al. [25] was, therefore, comparable to the 90-day survival in the higher volume group in the study by Saudan et al. [24]. As mentioned above, a number of observational studies [14-16, 26], with higher fluid replacement in CVVH seem to demonstrate an additional beneficial effect of this strategy on survival, although methodological restrictions must be taken into consideration. A position paper published by the ADQI (Acute Dialysis Quality Initiative) group has suggested that HVHF could be used by clinicians in catecholamine-resistant septic shock (level V evidence and grade E recommendation) [27]. This same position paper supports the extended use of fluid replacement at 35 ml/kg/h in CVVH (level II evidence and a grade C recommendation) [27]. A recent guideline, based on an updated literature review, elevates this to a Grade A recommendation [28]. Nevertheless, it is difficult to identify a recommended dose for septic versus nonseptic acute renal failure as, in nearly all reported randomized studies, the populations studied contained a mixture of both types of patient; therefore, we must await the results of ongoing trials in patients with septic acute renal failure before we can make definitive recommendations in this group of patients. The knowledge that many mediators have molecular weights exceeding the cutoff points of conventional hemofilters has led to the development of techniques

Blood Purification Techniques in Sepsis and SIRS whereby filter porosity is increased [29-31] , for example, HPHF [7,8,9,29-31] and SHFHF [10]. The use ofhemofilters with increased filter porosity is burdened by the potential risk of losing larger, beneficial molecules (drugs, hormones, nutrients, anti-inflammatory components). Because of this, a number of hybrid techniques have been developed, such as CPFA [11] and cascade hemofiltration (CCHF) [32], in which the type of substances removed can be targeted more precisely. In theory, removal of relatively large molecules within a narrow band of molecular weights is possible with these hybrid techniques. It should be noted, however, that , strictly speaking, in some of the techniques, adsorption is not the appropriate term as blood floods through a semi-permeable membrane. Therefore, it is not the net effect of convective plus oncotic forces that results in the passage of mediators through this kind of device, and the term, absorption, is more appropriate as chemical and physical forces come into play in this setting [27].

Which Technique is Best: Increasing Volume or Increasing Porosity? In the setting of the peak concentration hypothesis, techniques that remove cytokines or mediators from the blood compartment more rap idly and substantially are favored . Intrinsically, both convective and diffusive techniques are able to clear the blood compartment of mediators. However, in both the threshold immunomodulation hypothesis and the mediator delivery hypothesis, effects are brought to bear outside the blood compartment in the interstitium and at the tissue level, while in the mediator delivery hypothesis, high fluid replacement rate is obligatory. Prominence is then given to high -volume (and possibly very high -volume) hemofiltration techniques as well as to a number of hybrid techniques using high fluid replacement, though as yet these conclusions remain speculative [33, 34]. It is reasonable to assume that some form s of extracorporeal removal, such as high flow hemofiltration, could dramatically increase lymphatic transport of med iators and cytokines from the tissues and interstitial space to the blood compartment for potential removal. Other forms of extracorporeal removal, such as HPHF or CPFA, with the capacity to remove larger amounts of mediators and cytokines from the blood compartment, are, in their present form, unable to increase lymphatic flow and , as a consequence, are unable to mobiliz e crucial cytokines and mediators at the interstitial and tissue level (where they do harm) [34]. This fact can go some way to explaining why, despite high hopes, some recent studies with these tech niques have been shown to be ineffective in improving hemodynamics and survival in animal models for acute sepsis [35]. Despite the complexity of the rat ionale for mediator removal, it seems sensible that increasing filter porosity would have an overall beneficial effect [8]. More sophisticated techniques, such as HPHF, SHFHF, and hemo-adsorption, are favored in this context as many mediators have a high molecular weight. Although these techniques likely remove more substantial amounts of these larger mediators from the blood compartment, the repercussions of this at the tissue level remain unclear. Furthermore, many important nutrients, hormones, drugs, in particular antibiotics, and unknown metabolites may also be lost. For this reason investigators have chosen to use hybrid techniques, utilizing some of the advantages of the different techniques, whilst avoiding some of the more obvious drawbacks. Indeed, because a large portion of treated blood is returned to the patient, both CPFA and CCHF [11, 32] are able to retrieve large amounts and large molecules

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P.M. Honore, O. Joannes-Boyau, and B. Gressens

without risking the loss of important nutrients. In theory, further development of hybrid techniques, such as CCHF and CPFA, will one day offer the possibility of optimal and precise targeting of molecules, with negligible loss of beneficial molecules. We should also be aware of a completely neglected domain in the filter porosity 'spectru m'. At present, most activity is concentrated at either end of the molecular spectrum. At the lower end, HVHF and derived techniques seek to modify concentrations of molecules below 45 kDa, whereas at the higher end, in plasma filtration, molecules of around 900 kDa are targeted . The domain in between begs attention both from clinicians and investigators and remains largely neglected at present. Studies utilizing high cut-off hemofiltration (filter cut-off at 60 kDa), demonstrating better filter clearance of some mediators, is a first small step in the right direct ion [8,31] . As a consequence of this new knowledge, clinicians should be aware of these new insights regarding the rationale for extra-corporeal removal in severe septic shock, thereby enabling them to make well informed choices regarding adjunctive treatment for severe septic shock at the bedside.

Which Mode of Renal Replacement Therapy and which Dose is Superior? In clinical practice, it is safe to say that dose most definitely plays an important role, despite the fact that no mode of renal replacement therapy is superior [36]. Both in the paper published by the ADQI group and in the more recent guideline [27, 28], an effluent rate of at least 35 mllkg/h is recommended in CRRT. In intermittent hemodialysis, a similar dose corresponds to a single pool KtlV of 1.4 per day, implying the need for daily intermittent hemodialysis if this mode is chosen [37]. Currently, the dose recommendations apply to all critically ill patients with acute renal failure whether it is secondary to sepsis or not. In classic hyperdynamic septic shock, especially accompanied by acute septic renal injury or acute septic renal failure (based on the risk of renal failure, injury to the kidney, failure of kidney function , loss of kidney function, and end-stage renal failure [RIFLE] classification [38]), the results of a number of dose outcome studies (the ATN study in the US, the RENAL study in Australia and New Zealand, and the IVOIRE study in Europe) are awaited with interest [39]. Two of these dose outcome studies (the ATN and RENAL studies) are not restricted to acute septic injury, including also patients with nonseptic renal failure. The IVOIRE study has the potential to provide us with important insights for the future, hopefully giving us further tools to determine optimal dosing in subgroups of septic patients with acute renal injury. More than 480 ICU patients with septic shock plus acute renal injury as defined by the RIFLE classification will be included. After computer randomization into two groups, one group will receive standard volume hemofiltration (35 ml/kg/h) and the other early HVHF (70 mllkg/h) . In the light of the findings of the study by Ronco et al. [3], whereby septic patients in the 45 mllkg/h group tended to have better survival, this study has been designed to demonstrate an increase in overall survival in the higher dose group (70 nil/kg/h). This study is now fast approaching its first interim analysis [39]. Table 1 summarizes positive and negative stud ies looking at HVHF and dose [40-45].

Blood Purification Techniques in Sepsis and SIRS Table 1. Summary of the most important published and ongoing studies" on HVHF in sepsis and SIRS plus acute renal failure in the last decade.

Design

Hemofiltra- Effect on survival tion dose, ml/kg/h

Author, year of publication

Number Clinical setting of patients

p value

Oudemans van Straaten, 1999 [42]

306

SIRS, shock, acute renal failure

Prospective, uncontrolled, cohort

65

Observed mortality < 0.05 less than that predieted by severity scores

Honore, 2000 [26]

20

Refractory septic shock

Prospective, uncontrolled, cohort

115

Observed mortality < 0.05 less than expected

Ronco, 2000 [3]

425

Intensive care unit, acute renal failure

RCT, subgroup

45

No benefit in this subgroup

> 0.05

Bouman, 2002 [25]

106

SIRS, acute renal failure, MOF

RCT

48

None

0.8

Jiang, 2005 [40]

37

Severe acute pancreatitis, sepsis

RCT

54

Observed mortality < 0.05 less than expected

Laurent, 2005 [41]

61

Out-of-hospital car- RCT diac arrest, myocardial infarction, sepsis

200

Improved survival compared to no hemofiltration

0.026

Piccinni, 2006 [43]

80

Septic shock, acute Retrospective, renal failure, acute historical lung injury cohort

45

Improved survival compared to no hemofiltration

< 0.05

Honore, 2006 [44]

45

Refractory septic shock

Prospective, cohort, uncontrolled

100

Observed mortality < 0.05 less than expected

Cornejo, 2006 [45]

20

Refractory septic shock

Prospective, cohort, uncontrolled

100

Observed mortality 0.03 less than expected

IVOIRE, ongoing [39]

480

Septic shock and RCT acute kidney injury

70

Ongoing

* Studies selected by the authors for their scientific merit in terms of design and number of patients included. SIRS: systemic inflammatory response syndrome; MOF: multiple organ failure; RCT: randomized controlled trial

The Concept of 'Immunoparalysis' and 'Prophylactic' Hemofiltration Recent studies in an animal model [46, 47] have provided evidence for a role for extracorporeal removal (in this case HVHF) as a 'prophylactic' measure in the second phase of sepsis (the so-called immunoparalysis phase or the CARS [Compensator y Anti-inflamm atory Response Syndrome] phase as described by Roger Bone [48]).

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The groups of Yekebas [46] and Li Chi Lee [47] have both worked to develop an animal model for this phenomenon of post-SIRS immunoparalysis. Traumatic pancreatitis was induced in healthy pigs and hemofiltration was initiated 12 hours after trauma but before sepsis and shock occurred. After twelve hours, fulminant peritonitis and intravascular sepsis due to bacterial translocation occurred, inducing a shock state in these pigs. By comparing different settings of hemofiltration, especially low dose (20 mllkg/h) plus adsorption and HVHF at the rate of 100 ml/kg/h, the authors were able to demonstrate that the early, prophylactic use of HVHF resulted in a reduction in the severity of immunoparalysis and, therefore, the subsequent risk of secondary infection and, ultimately, the death rate. For the first time, albeit in an animal model, HVHF was shown to have a beneficial effect not only on the pro-inflammatory phase but also, as a prophylactic measure, on the secondary immunoparalysis phase. This finding seems to dispel the fear that removal of mediators in a phase other than the pro-inflammatory phase could have a negative effect because of removal of beneficial, anti-inflammatory mediators.

Mediator Removal is Obsolete as Many Pathways are Involved in a 'Pleiotropic' Approach Extracorporeal mediator removal can influence the pro-inflammatory phase and inhibit its expression by potentially reducing unbound cytokine levels and reducing the corresponding remote organ damage [14-16] . This simple mantra, however, does not explain the full effects of extracorporeal mediator removal. An alteration and reduction of cardiovascular compounds (in the blood compartment) responsible for the shock state in humans has been documented. Endothelin-l , responsible for early pulmonary hypertension in sepsis, endocannabinoids, responsible for vasoplegia, and myodepressant factor, responsible for the cardiodepression in sepsis [12, 34], can all be removed easily by HVHF. Coagulation too can be influenced by HVHF. A decrease in plasminogen activator inhibitor-l (PAl-I) levels, which are correlated with high APACHE II scores and higher mortality rates in sepsis [49], has been documented with a reduction in the occurrence of disseminated intravascular coagulopathy (DIe) as an eventual consequence. Furthermore, it has been shown in animals that HVHF can reduce the risk of immunoparalysis post-sepsis and the subsequent risk of nosocomial or secondary infection [46,47]. Finally, it has been demonstrated that HVHF can reduce the degree of inflammatory cell apoptosis occurring during sepsis. Extraction of caspase-3 products with a molecular weight of about 35,000 Da and other products of the caspase-8 pathway, seems to be the basis for this effect. These pathways playa major role in the setting of inflammatory cell apoptosis, in particular in macrophages and neutrophils [50]. In many experimental and clinical models, hemodynamics can be improved without a significant reduction in plasma mediators [14, 35]. As stated earlier, many other pathways can be involved in producing these beneficial effects. However, catecholamine-resistant septic shock is an exception as an improvement in hemodynamics has been proven to be associated with a significant decrease in plasma mediator concentration [37].

Blood Purification Techniques in Sepsis and SIRS

Clinical Implications and Conclusion In recent years, a number of techniques have been studied and developed in the field of renal replacement therapy in the patient with sepsis. Manipulation of ultrafiltrate dose, membrane porosity, mode of clearance, and combinations of techniques have given promising results. However, conclusive evidence from well-designed, randomized controlled trials rema ins scarce, limiting the practical implementation of many techniques in daily clinical practice. The three theories described above undoubtedly have a role to play in the further development and study of techniques and go some way to explain current findings. On the basis of the few well designed and documented studies we do have, it is safe to say that optimalization of the delivered renal replacement therapy dose has a proven positive effect. An ultrafiltration rate between 35 and 45 ml/kg/h, with adjustment for predilution and down-time, can be recommended with confidence in the septic patient, although, despite the evidence, recent unpublished surveys have shown that less than 40 % of ICUs (at least in continental Europe) apply this regimen. The results of further dose outcome studies with higher ultrafiltration rates will likely be the stepping stone to further improvements in daily clinical practice . Clinicians must be aware of new insights regarding the rationale for extra-corporeal therapy in severe septic shock. These insights will facilitate the choice of optimal adjunctive treatments in severe septic shock in the clinical setting. The exchange volume is not only important for removal of mediators but also for displacement of mediators throughout the body. Clinicians should use the technique that can achieve the best blood clearance rate but also the best tissue clearance rate. Membrane poros ity or system complexity alone can never replace systems that use high exchange rates of volume with simple membrane separation technology. Hybrid techniques will certainly have a role to play in the expanding field of renal replacement therapy in the septic patient and further research into combination techniques is warranted. The world of hemofiltration and associated hybrid therapies is still evolving rapidly. Both investigator and clinician should be aware of recent advances as the results from several ongoing dose-outcome studies may profoundly change our daily practice. At the same time, a critical evaluation and balanced view of the published studies in this area is needed . References 1. Casey LC, Balk RA, Bone RC (1993) Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771-778 2. Honore PM, loannes-Boyau 0 , Gressens B, Boer W (2007) Safe and rigorous implementation of pulse-high volume hemofiltration in ICU (100 mllkg/h): A combined medical and nursing approach. Blood Pur if 25:197 - 198 (abst) 3. Ronco C, Bellomo R, Homel P, et al (2000) Effects of different doses in continuous veno-

venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 356:26- 30 4. Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bellomo R (2003) Interpreting the mechan ism of continuous renal replacement therapy in sepsis. The peak concentration hypothes is. Artif Organs 27:792-801 5. Ronco C, Bellomo R (2002) Acute renal failure and multiple organ dysfunction in the ICU: From renal replacement therapy (RRT) to multiple organ support ther apy (MOST). Int J Artif Organs 25:733 -747

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P.M. Honore, O. Joannes-Boyau, and B. Gressens 6. Ronco C, Ricci Z, Bellomo R (2002) Importance of increased ultrafiltration volume and impact on mortality : sepsis and cytokine story and the role for CVVH. EDTRA ERCA J 2:13-18 7. Honore PM, Zydney AL, Matson JR (2003) High volume and high perme ability haemofiltration in sepsis. The evidences and the key issues. Care of the Critically III 3:69-76 8. Matson JR, Zydney RL, Honore PM (2004) Blood filtration (2004): New opportunities and the implication s on system biology. Crit Care Resusc 6:209- 218 9. Morgera S, Haase M, Kuss T, et al (2006) Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Crit Care Med 34:2099-2104 10. Uchino S, Bellomo R, Goldsmith D, et al (2002). Super high flux hemofiltration: a new technique for cytokine removal. Intensive Care Med 28:651-655 11. Bellomo R, Tetta C, Ronco C (2003) Coupled plasma filtration adsorption. Intensive Care Med 29:1222-1228 12. Honore PM, Ioannes-Boyau 0 (2004) High volume hemofiltrat ion (HVHF) in sepsis : a comprehens ive review of rationale, clinical applicability, potential indications and recommendations for future research. Int J Artif Organs 27:1077-1082 13. Honore PM, Matson JR (2004) Extracorporeal removal for sepsis : acting at the tissue level the beginning of a new era for this treatment modality in septic shock. Crit Care Med 32: 896-897 14. Honore PM, [amez J, Wauthier M, Dugernier T (1998) Prospective evaluation of short-time high volume isovolemic hemofiltration on the haemodynamic course and outcome of patients with refractory septic shock. Crit Care Nephrol 90:87- 99 15. Honore PM, [amez J, Wittebole X, Wauthier M (1997) Influence of high volume haemofiltration on the haemodynamic course and outcome of patients with refractory septic shock. Retrospective study of 15 consecutives cases. Blood Purif 15:135-136 16. Joannes-Boyau 0, Rapaport S, Bazin R, Fleareau C, Janvier G (2004) Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock. ASAIO J 50:102-109 17. Klouche K, Cavadore P, Portales P, Clot J, Canaud B, Beraud JJ (2002) Continuous venovenous hemofiltration improves hemodynamic in septic shock with acute renal failure without modifying TNF-a and IL-6 plasma concentrations. J Nephrol 15:150-157 18. Di Carlo JV, Alexander SR (2005) Hemofiltration for cytokine-driven illness: the mediator delivery hypothesis. Int J Artif Organs 28:777 - 786 19. Olszewski WL (2003) The lymphatic system in body homeostas is: physiological conditions . Lymphat Res Bioi 1:11- 21 20. Onarherim H, Missavage E, Gunther RA, Kramer GC, Reed RK, Laurent TC (1991) Marked increase of plasma hyaluronan after major thermal injury and infusion therapy. J Surg Res 50:259-265 21. Wasserman K, Mayerson HS (1952) Dynamics of lymph and plasma protein and exchange. Cardiologia 21:296-307 22. Cho KC, Himmelfarb J, Paganini E, et al (2006) Survival by dialysis modality in critically ill patients with acute kidney injury. J Am Soc NephroI 17:3132-3138 23. Schiffl H, Lang SM, Fisher R (2002) Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 346:305-310 24. Saudan P, Niederberger M, De Seigneux S, et al (2006) Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int 70:13121317 25. Bouman CS, Oudemans-Van-Straaten HM, Tijssen JG, Zandstra DF, Kosecioglu J (2002) Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial. Crit Care Med 30:2205- 2211 26. Honore PM, [amez J, Wauthier M, et al (2000) Prospective evaluation of short term high volume isovolemic haemofiltration on the haemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 28:3581- 3587 27. Bellomo R, Honore PM, Matson JR, Ronco C, Winchester J (2005) Extracorporeal blood treatment (EBT) methods in SIRS/Sepsis. Consensus statement.Position paper. ADQI III Conference. Int J Artif Organs 28:450- 458

Blood Purification Techniques in Sepsis and SIRS 28. Bouman CSC, Oudemans-van-Straaten HM (2006) Guidelines for timing, dose, and mode of continuous replacement therapy for acute renal failure in the critically ill. Neth J Crit Care 10:561- 568 29. Lee PA, Weger G, Pryor RW, Matson JR (1998) Effects of filter pore size on efficacy of continuous arterio-venous hemofiltration therapy for staphylococcus aureus-induced septicaemia in immature swine. Crit Care Med 26-730-737 30. Lee WC, Uchino S, Fealy N, et al (2004) Super high flux hemodialysis at high dialysate flows : an ex vivo assessment. lnt J Artif Organs 27:24-28 31. Honore PM, Matson JR (2002) Hemofiltration, adsorption, sieving and the challenge of sepsis therapy design. Crit Care 6:394 - 396 32. Valbonesi M, Carlier P, leone A, et al (2004) Cascade filtration: a new filter for secondary filtration - a multicentric study. Int J Artif Organs 27:513-515 33. Ioannes-Boyau 0, Honore PM, Boer W (2006) Hemofiltration: the case for removal of sepsis mediators from where they do harm. Crit Care Med 34:2244 - 2246 34. Honore PM, Ioannes-Boyau 0, Meurson L, et al (2006) The Big Bang of haemofiltration: the beginning of a new era in the third Millennium for extra-corporeal blood purification! Int J Artif Organs 29:649 - 659 35. Honore PM, Ioannes-Boyau 0, Gressens B (2007) Blood and plasma treatments: the rationale of high-volume hemofiltration. Contrib Nephrol 156:387- 395 36. Honore PM, [oannes-Boyau 0 (2006) "The French Hemodiafe Trial" : not either a decisive nor a definitive study regarding controversy for renal replacement therapy in the ICU field! Int J Artif Organs 29:1190- 1192 37. Honore PM, Ioannes-Boyau 0, Gressens B (2007) Blood and plasma treatments: high-volume hemofiltration-a global view. Contrib Nephrol 156:371-386 38. Bellomo R, Ronco C, Kellum J,Mehta R, Palevsky P, and the ADQI workgroup (2004). Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:204-212 39. Ioannes-Boyau 0, Honore PM (2004) The IVOIRE study. Available at: www.clinicaltrialsgow/ ct/show/NCT00241228 Accessed Dec 2007 40. Jiang HL, Xhue WJ, Li OK, et al (2005) Influence of continuous veno-venous hemofiltration on the course of acute pancreatitis. World J Gastroenterol 11:4815-4821 41. Laurent I, Adrie C, Vinsonneau C, et al (2005) High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study. J Am Coil Cardiol 46:432-437 42. Oudemans-van Straaten HM, Bosman RJ, van der Spoel JI, Zandstra DF (1999) Outcome of critically ill patients treated with intermittent high-volume haemofiltration: a prospective cohort analysis. Intensive Care Med 25:814-821 43. Piccinni P, Dan M, Barbacini S, et al (2006) Early isovolaemic haemofiltration in oliguric patients with septic shock. Intensive Care Med 32:80- 86 44. Honore PM, loannes-Boyau 0, Merson L, Fleureau C, Roze H, Janvier G (2006) Pulse high volume hemofiltration in septic shock plus acute renal failure (PULSHAR Study). Blood Purif 24:267- 268 (abst) 45. Cornejo R, Downey P, Castro R, et al (2006) High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock. Intensive Care Med 32:713 -722 46. Yekebas EF, Strate T, Zolmajd S, et al (2002) Impact of different modalities of continuous veno-venous hemofiltration on sepsis-induced alterations in experimental pancreatitis. Kidney Int 62:1806-1818 47. Wang H, Zhang ZH, Yan XW, et al (2005) Amelioration ofhaemodynamics an oxygen metabolism by continuous veno venous hemofiltration in experimental pancreatitis. World J Gastroenterol 11:127-131 48. Bone RC (1996) Sir Isaac Newton, Sepsis, SIRS and CARS. Crit Care Med 24:1125-1128 49. Garcia Fernandez N, Lavilla FJ, Rocha E, Purroy A (2000) Haemostatic changes in systemic inflammatory response syndrome during continuous renal replacement therapy. J Nephrol 13:282- 289 50. Bordoni V, Balgon I, Brendolan A, et al (2003) Caspase 3 and 8 activation and cytokine removal with a novel cellulose trace tate super-permeable membrane in vitro sepsis model. Int J Artif Organs 26:897 - 905

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Glutathione in Sepsis and Multiple Organ Failure U. FLARING and J.

WERNERMAN

Introduction Glutathione , a tripeptide (L-y-glutamyl-L-cysteinyl-glycine) with antioxidant properties, is present at high concentrations (mmol) in most tissues in man. Its major functions are to scavenge toxic reactive oxidant species (ROS), to detoxify exogenous toxic compounds, including drugs, and to regulate protein metabolism. The ubiquitous cytoprotective effects of glutathione are well established [1]. In skeletal muscle from intensive care unit (ICU) patients, low glutathione concentrations are seen, which correlates with glutamine depletion [2] and with mortality [3]. The consequences of glutathione depletion are not fully understood. In this chapter, new insights into the glutathione status of ICU patients are presented including the temporal pattern [4,5], the effect of exogenous glutamine supplementation [6], and the relation between glutathione status in different tissues [7].

Glutathione Metabolism Glutathione is mainly an intracellularly acting molecule, as reflected by the ratio between intracellular and plasma concentrations ranging from 500:1 to 1000:1. Glutathione is synthesized in all human cells from its constituent amino acids glutamate, cysteine, and glycine. An outline of glutathione metabolism is given in Figure 1. Plasma glutathione concentration is regulated by the efflux from the liver [8]. Gluta-

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Fig. 1. Schematic presentation of glutathione metabolism. Enzymes: 1. y-glutamyicysteine synthetase. 2.Glutathione synthetase. 3. y-glutamyl transpeptidase. 4. y-glutamylcyclotransferase. 5. 5-oxoprolinase. 6. Glutathione transferase.

Glutathione in Sepsis and Multiple Organ Failure

Lipid-OOH H20 2

Fig. 2. The enzymatic redox-reac-

tions of glutathione. GPX: glutathione peroxidase; GR: glutathione reductase; G6PDH: glucose-6-phosphate dehydrogenase.

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thione has many protective functions within the cell; among the most recognized is the protection against ROS, either by: (i) acting directly as a scavenger; (ii) being a cofactor for the enzyme glutathione peroxidase; and/or (iii) maintaining other antioxidants such as ascorbate (vitamin C) and a -tocopherol (vitamin E) in an active form [1]. Access to glutathione is also essential for mitochondrial function. Glutathione has a structural characteristic that facilitates its stability, namely the y-glutamyl bond. This makes glutathione resistant to all peptidases except y-glutamyl transpeptidase [1]. The degradation of glutathione, on the other hand, is not fully understood. Glutathione appears in a monomeric reduced form (GSH) and in a dimeric oxidized form (GSSG). GSSG is formed by the action of glutathione peroxidase. Adequate concentrations of both GSH and selenium are needed for optimal glutathione peroxidase function. Intracellularly, glutathione is predominantly maintained in the reduced form [1]. When glutathione has been oxidized it can be re-reduced, using NADPH as the reducing agent. The redox cycling of glutathione is shown in Figure 2.

Effects of Glutamine Supplementation on Glutathione in Muscle As glutamate is a precursor for glutathione synthesis, and glutamate can be formed from glutamine, there is an obvious relation between glutamine and glutathione synthesis. Glutamine is the most abundant free amino acid in the body and , besides being crucial for glutathione synthesis, it is an essential energy source for rapidly dividing cells, such as mucosa cells and lymphocytes. Moreover, glutamine is a precursor for the synthesis of purines and pyrimidines. Consequently, all rapidly dividing cells require a cont inuous supply of glutamine. During severe metabolic stress, such as in septic patients with multiple organ failure (MOF), plasma glutamine is frequently less than 50 % of normal values. In addition, the pool of free glutamine in skeletal muscle is generally depleted down to 25 % of normal within the initial 24 h after admission to the ICU [9]. This dramatic decrease in muscle glutamine concentrations correlates with the muscle glutathione depletion seen simultaneously [2]. The low muscle glutamine concentration remains low and unaltered during the ICU stay, despite unchanged glutamine production/release from skeletal muscle [10]. Glutamine depletion during critical illness is considered to reflect a demand for glutamine in excess of the endogenous production. Therefore, the term "conditionally essential" has been introduced to descr ibe the relative shortage of glutamine during severe metabolic stress [11]. This is supported by low plasma glutamine concentrations being related to a poor outcome in ICU patients [12]. In addition, intravenous

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glutamine supplementation has beneficial effects on morbidity and mortality in ICU patients [13- 17]. However, the mechanisms by which glutamine exerts its beneficial effects, and the possible relation to glutathione metabolism, need to be further explored. In particular, the possibility of influencing glutathione status by exogenous glutamine supplementation has not been evaluated in man. Data from animal studies demonstrate that glutamine supplementation preserves liver glutathione levels and improves survival after severe hepatic injury elicted by chemotherapy [18, 19]. Muscle glutathione depletion is attenuated by half in patients receiving glutamine supplementation after major surgery ( Fig. 3) [6]. This occurs in spite of similar decreases in muscle concentrations of both glutamine and glutamate in control and treatment groups. This is to a certain extent a surprising finding, since it might be expected that restored pool sizes of both glutamine and glutamate would be required to attenuate the decrease in glutathione concentration. The explanation for this observation might be an increased flux through both glutamine and glutamate pools, without affecting the pool sizes. Thereby, sufficient glutamate becomes available for glutathione synthesis. However, the change in glutathione concentration has been shown to correlate with the change in the concentrations of both glutamine and glutamate, but not with the other two constituent amino acids of glutathione, cysteine and glycine. This underscores that glutamate availability may be the limiting factor for maintaining glutathione status after major surgery. As both cysteine and glycine concentrations remained unchanged during the study period [6], it is unlikely that availability of these two precursors influenced glutathione concentration. This contrasts to what is seen in erythrocytes of weight-stable patients with human immunodeficiency virus (HIV) and in children with severe protein energy malnutrition. In these conditions the erythrocyte concentration of cysteine is low, and is related to glutathione depletion [20, 21]. The redox status of glutathione is unaltered after surgery, while an increased fraction of oxidized glutathione is seen in critically ill ICU patients [2, 22, 23]. This indicates ongoing oxidative stress in ICU patients. On the other hand, following elective surgery, ROS production can be handled by increasing the antioxidant capacity as indicated by the unaltered redox status of glutathione .

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Glutathione in Sepsis and Multiple Organ Failure

Temporal Pattern of Muscle Glutathione in ICU Patients Glutathione metabolism in human skeletal muscle has recently been characterized in various catabolic states as well as in healthy individuals of different age groups : (i) healthy volunteers studied in the basal state [24]; (ii) patients undergoing elective surgery [23]; and (iii) a group of ICU patients [2]. With respect to skeletal muscle, the total glutathione concentration is not affected by age, diurnal variation, or food intake. Moreover, during short-term starvation (72 h) the concentration of glutathione remains unaltered, in contrast to the decrease in concentration of muscle free glutamine [24]. At 48 h following moderate size surgery, both reduced and total glutathione in skeletal muscle decrease by 40 % as compared to preoperative levels. At 72 h postoperatively, there is a recovery in reduced and total glutathione. No change in the redox status of glutathione is seen following surgery [23]. ICU patients with MOF show a similar level of muscle glutathione depletion as postoperative patients . In contrast to postoperative patients, however, ICU patients show an increased fraction of oxidized glutathione, suggesting ongoing oxidative stress in relation to the scavenging capacity. Additionally, statistical correlations have been reported between the concentrations of total glutathione and free glutamine in muscle, and between the concentration of free muscle glutam ine and the redox status of muscle glutathione. This suggests that glutamine depletion may be a limiting factor for glutath ione synthesis and that there is a relation between glutamine depletion and glutathione redox status . When glutamine depletion is more pronounced, the fraction of oxidized glutathione is increased [2]. During severe cardiogenic shock, skeletal muscle glutathione is dramatically depleted [25]. In parallel to the glutathione depletion , a low level of mitochondrial oxidative capacity is seen. The bioenergetic failure seen in this patient group may be partly explained by glutath ione depletion. In septic patients, studied within 24 h after admission to the ICU, a more pronounced depletion of reduced glutathione in skeletal muscle is seen in non-survivors as compared to survivors [3]. The concentrations of both reduced and total muscle glutathione are restituted back to normal after 7 to 9 days in septic ICU pat ients with MOF, without any specific intervention [5]. At baseline, within 72 h after admission to the ICU, muscle glutathione concentrations are low, confirming earlier reports [2]. The concentrations stay at low levels also on stud y day 3; recovery starts between study day 3 and 6. Interestingly, the restitution of glutathione status in muscle occurs spontaneously, despite persistent very low concentrations of muscle glutamine. On the other hand, all the direct precursors of glutathione (glutamate, cysteine and glycine) increase between study day 3 and 6, which indicates that substrate availability is sufficient at that time point. After moderate surgery, muscle glutathione depletion occurs to the same extent initially as in ICU patients, but restitution starts earlier, between 48 to 72 h [23]. The longitudinal changes in muscle total glutathione concentration after surgery and in ICU patients are illustrated in Figure 4. The rapid restoration of muscle glutathione status suggests it is a prioritized biological process after surgery and in septic ICU patients. The assumption that glutathione restoration is of biological importance is supported by reports from patients suffering from cardiogenic as well as septic shock [3, 25]. In contrast to the restoration of muscle glutathione concentrations, the redox status of muscle glutathione remains in a more oxidized state throughout the whole study period in ICU patients [2, 5]. After surgery on the other hand, the redox status of glutathione in muscle is not significantly affected [6].

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Fig. 4. Asummary ofthe muscle total glutathione concentrations in surgical patients (squares) and ICU patients (circles). The average time of inclusion for the ICU patients was 2.4 days of ICU stay. Data from [5,6).

Temporal Pattern of Blood Glutathione in ICU Patients Like most other tissues, erythrocytes have the capacity to synthesize glutathione. The intracellular concentration in the erythrocyte is normally kept in the mmollevel. The plasma concentration of glutathione is far less, approximately 5 umol/l in healthy subjects. The plasma glutathione concentration is mainly regulated by efflux from the liver [8]. Until now glutathione metabolism in erythrocytes and plasma has not been well characterized during sepsis and MOP. As in other tissues, animal data show somewhat conflicting results related to the species and to the shock model used. In piglets subjected to subcutaneous turpentine, no change in erythrocyte glutathione concentration was seen in well nourished animals, compared to malnourished animals in which glutathione concentration decreased [26]. In a rat model of sepsis, whole blood glutathione concentration decreased by so %, 48 h after a live Escherichia coli challenge as compared to pair-fed controls [27]. In man, short-term food deprivation did not influence erythrocyte glutathione concentration [28, 29], similar to the findings in skeletal muscle. In pediatric patients with septic shock and in adult patients with severe burns, low levels of whole blood total glutathione have been reported [30,31]. Also in other, less catabolic states, such as weight-stable HlV-positive patients and children with edematous protein malnutrition, whole blood glutathione concentration is low [20, 21]. In these reports, patients were investigated only on one occasion, presumably in the early phase of the disease. The time dependence of glutathione metabolism during the course of disease was not characterized. In septic patients with MOF, glutathione remained depleted in erythrocytes during a period of 6 to IS days ofICU stay [4]. This demonstrates that whole blood concentrations are not representative of the changes in glutathione status occurring in skeletal muscle. The redox status of whole blood glutathione consistently shows an increased oxidized state during the ICU stay. On the other hand, plasma total glutathione concentration is high. Erythrocytes have a specific ability to transport and neutralize superoxide from plasma that is different from other tissues, including skeletal muscle [32]. Therefore, it is likely that erythrocytes possess a capacity to detoxify ROS on a whole body level, which might explain the consistent glutathione depletion seen in whole blood. An additional difference of erythrocytes as compared to muscle is the precursor availability. In muscle, all precursors increase, in contrast to plasma where a low concentration of glycine is typically seen [9].

Glutathione in Sepsis and Multiple Organ Failure

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Glutathione Status following Endotoxin Administration By using stable isotope tracers , turnover rates can be measured on a whole body level as well as on a tissue level. The fractional synthesis rate (FSR) of glutathione can be calculated and it becomes possible to determine whether a decrease in concentration is related to a change in synthesis rate or not. Glutathione kinetics have mainly been studied in erythrocytes/whole blood . The FSR in healthy individuals ranges from 57 to 89 % per 24 h in different studies [20, 21, 29, 30]. When healthy volunteers are given a sulfur amino acid-free diet, the FSR and the absolute synthesis rate (ASR) of whole blood glutathione decreases, although the concentration remains unaltered [29]. Protein-energy malnutrition, exemplified by infected patients with kwashiorkor and marasmus , is characterized by a low erythrocyte glutathione synthesis rate only in its most severe form, the marasmic-kwashiorkor syndrome [20]. In weight-stable HIV patients and in burned patients , there is a low ASR in erythrocytes, while FSR is unaltered [21 , 31]. On the other hand, in fully developed septic shock, both the FSR and ASR of whole blood glutathione are low as compared to matched controls [30]. In septic patients, a glutathione depletion of more than 40 % both in skeletal muscle and in whole blood is established 24 to 72 h after ICU admission. The initial effect of sepsis on glutathione status is not well characterized. Therefore, a model employing healthy volunteers given an endotoxin challenge was used. The concentrations of glutathione in muscle and whole blood remained unaltered at 4 hours [7]. The redox status and the concentration of the oxidized fraction of glutathione also remained unaltered in both skeletal muscle and whole blood at 4 hours after the endotoxin challenge. This suggests that glutathione depletion in erythrocytes is a slow phenomenon despite the pronounced metabolic changes that are elicted by endotoxin. In contrast to the unaltered glutathione status, plasma concentrations of glutamine and glutamate decrease by 25 % already 3 h after an endotoxin challenge in healthy volunteers [33]. This precursor depletion in plasma might be expected to result in glutathione depletion in whole blood and muscle, which, however, does not occur. The explanation might be that the intracellular concentrations of the glutathione precursors and glutathione production are maintained or adjusted. In parallel, the glutathione synthesis rate, as determined by measuring the incorporation rate of labeled glycine (13C glycine) into glutathione tends to increase. The

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mean values for FSR and ASR increased by 55 % (p = 0.088) and 45 % (p = 0.10), respectively. A possible rationale for this increase may be that the healthy subjects studied had the capacity to compensate for an increased demand in ROS scavenging, by increasing glutathione synthesis rate thus maintaining the whole blood concentration. The decrease in plasma glutathione concentration following endotoxin administration contrasts to what was seen in septic ICU patients [4]. In septic ICU patients, the plasma concentration of total glutathione is high compared to healthy volunteers and patients with end-stage chronic obstructive pulmonary disease (COPD). The decrea se in plasma glutathione following endotoxin administration may be a consequence of an increased demand for cysteine in the activated immune system. Lymphocytes are dependent on plasma glutathione for their uptake of cysteine [8]. In addition, the low plasma glutathione concentration may also reflect an uptake of glutathione, or the precursors of glutathione via y-glutamyl transpeptidase, to maintain the intracellular glutathione pool in various tissues.

Discussion Glutathione is important for maintaining cellular homeostasis in most cell types in man [34-36] . In other words, glutathione is crucial for the well-being of cells. During critical illness, the capacity of glutathione to scavenge free radicals, protect cell membranes, and maintain energy production may be crucial for a positive outcome [37). This is underscored by a correlation between the degree of glutathione depletion in muscle tissue and mortality in septic shock patients [3]. Healthy volunteers have the capacity to compensate for increased glutathione requirement in muscle and whole blood during the first 4 h following endotoxin challenge. As shown in both surgical patients and ICU patients, glutathione depletion is thereafter fully established in both tissues within an additional 20 h. The decrease in glutathione concentration is approximately 50 % in whole blood and 40 % in muscle as compared to preoperative values in surgical patients and to the reference groups for the ICU patients. From 24 h after the insult until day 3, whole blood and skeletal muscle glutathione concentrations remain depleted in ICU patients. Thereafter, glutathione status shows a completely different pattern in muscle and whole blood: Glutathione concentration normalizes in muscle, while it remaines depleted in whole blood ( Fig. 5). A spontaneously normalized muscle glutathione concentration is seen in patients with MOF despite constant muscle glutamine depletion . This indicates that muscle tissue is able to counteract the glutathione depletion after a major inflammatory insult. The changes in amino acid concentrations favor glutathione synthesis since all the constituent amino acids of glutathione in muscle increased to high physiological levels ensuring adequate substrate availability. In contrast, a decrease in total amino acids in muscle of 35 % is typically seen in this patient group [9). A normalization of muscle glutathione concentrations occurs 7 to 9 days after admission to the ICU. After surgery, a spontaneous restitution of muscle glutathione concentration starts already on day 3. In patients undergoing major surgery, muscle glutathione deplet ion can be attenu ated by glutamine supplementation. The restitution occurs spontaneously also in ICU patients, and exogenous glutamine supplementation does not increase the speed of recovery of muscle glutathione [38). The low plasma glutamine concentration seen in septic ICU patients indicates that glutamine consumption exceeds production and it is also associated with worse outcome

Glutathione in Sepsis and Multiple Organ Failure

[12]. The exact mechanism by which glutamine supplementation is beneficial for these patients is unknown, but the benefits of glutamine supplementation have been suggested to be related to its effects on mucosa and white blood cells [13, 16,39,40]. There is a large ongoing glutamine production in skeletal muscle, directed mainly to the splanchnic tissues and to the immune system. In these tissues, glutamine is used as an oxidative substrate and for nucleotide synthesis [39, 41]. As glutamine is an important precursor for glutathione synthesis, it is likely that part of the glutamine production goes into glutathione synthesis in the mucosa and immune cells as in skeletal muscle. Some of the beneficial effects of glutamine supplementation may be to maintain glutathione status in these tissues. Animal data support this hypothesis as glutamine supplementation increases glutathione production in the mucosa [42]. Some of the positive effects of glutamine on infectious complications and on tolerance to enteral nutrition in ICU patients may also be explained by the interrelation of glutamine with glutathione [43]. It can be hypothesized that one possible explanation is mitochondrial dysfunction, resulting in impaired capacity to use oxygen for energy production. This is supported by the decrease in oxygen consumption often seen during severe sepsis and septic shock, associated with mitochondrial dysfunction [44]. The mitochondrial enzymes involved in ATP production are inhibited by ROS. This enzyme inhibition is suggested to be facilitated by glutathione depletion [3]. ROS are produced in large amounts during sepsis, especially nitric oxide, superoxide anion, and peroxynitrite [37] and low tissue ATP concentrations are associated with increased mortality and correlated with a low mitochondrial complex I activity. Furthermore, complex I activity correlated with tissue glutathione concentration, suggesting a relation between capacity of energy production and glutathione status . In rats, the development of mitochondrial dysfunction in sepsis is a relatively slow phenomenon of > 12 h [44]. This is consistent with the results presented here, where glutathione concentrations remain unaltered in both erythrocytes and skeletal muscle during the initial 4 h after an endotoxin challenge. A longer study period after endotoxin administration may reveal the initial changes in glutathione concentration. The relation to mitochondrial enzyme activities in the initial phase of sepsis may then also be elucidated.

Conclusion Tissue glutathione depletion seen following sepsis has a different temporal pattern in different tissues. In skeletal muscle, a restoration of the concentration is seen despite persistent changes in the redox status. This is different from red blood cells, where the depletion , in terms of low concentration accompanied by a more oxidized redox status, is unaltered over time in patients with MOP. In the initial phase of sepsis, as reflected in human volunteers given an endotoxin challenge, concentration and redox status remain unaltered while the de novo synthesis of glutathione increases. Provision of exogenous glutamine attenuates the decrease in muscle glutathione concentration seen postoperatively, but does not influence the spontaneous restoration seen in ICU patients

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u. Flaring and J. Wernerman References 1. Meister A (1991) Glutathione deficiency produced by inhibition of its synthesis, and its reversal; Applications in research and therapy. Pharmacol Ther 51:155-194 2. Hammarqvist F, Luo JL, Andersson K, Wernerman J (1997) Skeletal muscle glutathione is depleted in critically ill patients . Crit Care Med 25:78- 84 3. Brealey D, Brand M, Hargreaves 1, et al (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219-223 4. Flaring UB, Rooyackers OE, Hebert C, Bratel T, Hammarqv ist F, Wernerman J (2005) Temporal changes in whole-blood and plasma glutathione in leu patients with multiple organ failure. Intensive Care Med 31:1072- 1078 5. Flaring UB, Rooyackers OB, Wernerman J, Hammarqvist F (2003) Temporal changes in muscle glutathione in leu patients . Intensive Care Med 29:2193-2198 6. Flaring UB, Rooyackers OE, Hammarqvist F, Wernerman J (2003) Glutamine attenuates posttraumatic glutathione depletion in human muscle. Clin Sci 104:275 - 282 7. Flaring UB, Rooyackers OE, Hammarqvist F, Wernerman J (2006) Glutathione metabolism in human endotoxemia. Intensive Care Med 32 (suppl 1):S284 (Abst) 8. Kaplowitz MON (1998) Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine. Semin Liver Dis 18:313-329 9. Gamrin L, Essen P, Hultman E, Wernerman J (1996) A descriptive study of skeletal muscle metabolism in critically ill patients : free amino acids, energy rich phosphates , protein , nucleic acids, fat, water and electrolytes. Crit Care Med 24:575- 583 10. Vesali RF, Klaude M, Rooyackers OE, Tjader I, Barle H, Wernerman J (2002) Longitudin al pattern of glutamine/glutamate balance across the leg in long-stay intensive care unit patients . Clin Nutr 21:505-514 11. Lacey JM, Wilmore DW (1990) Is glutamine a conditionally essential amino acid? Nutr Rew 48:297-309 12. Oudemans-van Straaten HM, Bosman RJ, Treskes M, van der Spoel HJ, Zandstra DF (2001) Plasma glutamine depletion and patient outcome in acute leU admissions. Intensive Care Med 27:84-90. 13. Novak F, Heyland DK, AvenellA, Drover JW, SU X (2002) Glutamine supplementation in serious illness: A systematic review of the evidence. Crit Care Med 30:2022- 2029 14. Huodijk A, Riijnsburger E, Jansen J, et al (1998) Randomised trial of glutamine enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 352:772- 776 15. Griffiths RD, Jones C, Palmer A (1997) Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 13:295 - 302 16. Ziegler TR, Young LS, Benfell K, et al (1992) Clinical and metabolic efficacy of glutaminesupplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med 116:821- 828 17. Wernerman J (1998) Glutamine-containing TPN: a question of life and death for intensive care un it-patients? Clin Nutr 17:3- 6 18. Hong RW, Helton WS, Rounds JD, Wilmore DW (1990) Glutamine-supplemented TPN preserves hepatic glutathione and improves survival following chemotherapy. Surg Forum 41:9-11 19. Hong RW, Rounds JD, Helton WS, Robinson MK, Wilmore DW (1992) Glutamine preserves liver glutathione after lethal hepatic injury. Ann Surg 215:114-119 20. Reid M, Badaloo A, Forrester T, et al (2000) In vivo rates of erythrocyte glutathione synthesis in children with severe protein-energy malnutrition. Am J Physiol 278:E405-E412 21. [ahoor F, Jackson A, Gazzard B, et al (1999) Erythrocyte glutathione deficiency in symptomfree HIV infection is associated with decreased synthesis rate. Am J Physiol 276:E205-211 22. Reeds P, [ahoor F (2000) Methods for measuring glutathione concentration and rate of synthesis. Curr Opin Clin Nutr Metab Care 3:385-390 23. Luo J-L, Hammarqvist F, Andersson K, Wernerman J (1996) Skeletal muscle glutathione after surgical trauma. Ann Surg 223:420-427 24. Hammarquist F, Andersson K, Lou J, Wernerman J (2005) Free amino acid and glutathione concentrations in muscle during short-term starvation and refeeding. Clin Nutr 24:236-243 25. Corbucci GG, Gasparetto A, Candiani A, et al (1985) Shock-induced damage to mitochon drial function and some cellular antioxidant mechanisms in humans. Circ Shock 15:15-26

Glutathione in Sepsis and Multiple Organ Failure 26. ]ahoor F, Wykes L], Reeds PI, Henry ]F, del Rosario MP, Frazer ME (1995) Protein-deficient pigs cannot maintain reduced glutathione homeostasis when subjected to the stress of inflammation. J Nutr 125:1462-1472 27. Malmezat T BD, Capitan P (2000) Glutathione turnover is increased during the acute phase of sepsis in rats. J Nutr 130:1239- 1246 28. Faber P, Johnstone AM, Gibney ER, et al (2002) The effect of rate of weight loss on erythrocyte glutathione concentration and synthesis in healthy obese men. Clin Sci (Lond) 102: 569-577 29. Lyons J, Rauh-Pfeiffer A, Yu YM, et al (2000) Blood glutath ione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci USA 97:5071-5076 30. Lyons J, Rauh-Pfeiffer A, Ming-Yu Y, et al (2001) Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Crit Care Med 29:870-877 31. Yu YM, Ryan CM, Fei ZW, et al (2002) Plasma L-5-oxoproline kinetics and whole blood glutathione synthesis rates in severely burned adult humans. Am J Physiol Endocrinol Metab 282:E247 - 258 32. Richards RS, Roberts TK, Dunstan RH, McGregor NR, Butt HL (1998) Erythrocyte antioxidant systems protect cultured endothelial cells against oxidant damage. Biochem Mol Biol1nt 46:857-865 33. Vesali RF, Klaude M, Rooyackers 0, Wernerman J (2005) Amino acid metabolism in leg muscle after an endotoxin injection in healthy volunteers . Am J Physiol Endocrinol Metab 288:E360 - 364 34. Beutler E (1989) Nutritional and metabolic aspects of glutathione. Annu Rev Nutr 9:287- 302 35. Reed D, Fariss M (1984) Glutathione depletion and susceptibility. Pharmacol Rev 36:25S-33S 36. White A, Thannickal V, Fanburg BL (1994) Glutathione deficiency in human disease. J Nutr Biochem 5:218-225 37. Salvemini D, Cuzzocrea S (2002) Oxidative stress in septic shock and disseminated intravascular coagulation. Free Radic Bioi Med 33:1173-1185 38. Tjader I, Rooyackers 0, Forsberg AM, Vesali RF, Garlick PJ, Wernerman J (2004) Effects on skeletal muscle of intravenous glutamine supplementation to ICU patients. Intensive Care Med 30:266-75 39. Wilmore DW, Shabert ]K (1998) Role of glutam ine in immunologic response . Nutrition 14: 618-626 40. Van der Hulst RVMM, Van Kreel B, Brummer R, Soeters P (1993) Glutamine and the preservation of gut integrety. Lancet 341:1363-1365 41. Tremel H, Kienle B, Weilemann LS, Stehle P, Furst P (1994) Glutamine dipeptide-supplemented parenteral nutrition maintains intestinal function in the critically ill. Gastroenterology 107:1595-1601 42. Ziegler TR, Evans M, Fernandez-Estivariz C, Jones D (2003) Trophic and cytoprotective nutrition for intestinal adapt ion, mucosal repair, and barrier function . Annu Rev Nutr 23:229-261 43. Dechelotte P, Hasselmann M, Cynober L, et al (2006) L-alanyl-L-glutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, double-blind, multicenter study. Crit Care Med 34:598- 604 44. Boveris A, Alvarez S, Navarro A (2002) The role of mitochondrial nitric oxide synthase in inflammation and septic shock. Free Radic Bioi Med 33:1186-1193

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Selenocompounds and Selenium: A Biochemical Approach to Sepsis X.

FORCEVILLE

and P. VAN

ANTWERPEN

Introduction Septic shock, an uncontrolled systemic host response to invasive infection leading to multiple organ failure (MOF), is a major public health issue due to its frequency, associated cost, and a 45 % mortality rate despite all the improvements made in intensive care over the past 20 years. However, the pathophysiology of sepsis is now better understood, with increasing data supporting the key role of oxidant free radicals, especially in endothelial damage [1- 4]. The link between endothelial damage or dysfunction and MOF and biochemistry (reactive oxygen species [ROS] toxicity, control of peroxide tone) is difficult to understand and requires comprehension of interatomic liaisons and not only of molecular biochemistry. ROS appear to play a key role in septic shock because of their actions as bactericidal compounds, toxic agents, and intracellular second messengers [3, 4]. Selenocompounds, especially sodium selenite, are oxidants in themselves [5, 6] and act secondly as antioxidants through the incorporation of the atom selenium into key selenoenzymes. They act on the redox potential of the ionic water in different compartments to control molecular adhesion, tridimensional conformation, and cellular function either in a pro-oxidant or an anti-oxidant way [7]. Thus, selenocompounds could completely modify cell metabolism in septic shock, opening new opportunities for treatments focused at the endothelium and at wider multiple targets . However, recent clinical results have yielded both positive and null results [8, 9]. Animal data are required to better understand the efficacy and toxicity of selenium and sodium selenite in septic shock.

Oxygen: Oxidation, Reactive Oxygen Species, and Redox-potential Oxygen appeared in the Earth's atmosphere 2.5 billion years ago. Most of the damaging effects of oxygen can be attributed to the formation of free oxygen radicals (see Table 1 for definitions) . There are anaerobic microorganisms that survive but are killed by exposure to oxygen. Other organisms develop antioxidant defense systems to protect against oxygen toxicity and to control oxygen levels (POz tension is only around 0.5 mmHg in mitochondria); this allows them to use oxygen for energy production (i.e., mitochondrial respiratory chain) and metabolic transformation (i.e., by cytochrome P450). For example, mitochondria produce over 80 % of the ATP required by mammal cells [7]. One should stress that all these reactions occur in aqueous solutions, highlighting the importance of water, which is the major constituent of the organism, represent-

Selenocompounds and Selenium: A Biochemical Approach to Sepsis Table 1. Definitions Free radical (R"): Species containing 1 or more unpaired electrons; can be highly reactive. Reactive oxygen species (ROS): Free radical and non-radical oxidant molecules. Oxidation: A gain in oxygen or a loss of electron by a molecule. It is often a chain reaction. Redox balance: Determines whether a compound can reduce (oxidize) or not another molecule. Peroxide tone: Concentration of peroxides (R-OOH), e.g., hydrogen peroxide (H 20 2); one of the determinants of the redox balance.

NB. All these molecules or reactions are in aqueous solution in cells [7)

ing around 50 % of the body weight. Water form s part of the liquid in the body (i.e., in blood) (5 %) but also the ionic hydric gel in the interstitium (20 %) and within the cells (25 %) [10]. The target of selenocompound-based treatment is the modification of the redox potential in the ionic body water: (i) in the sense of a diminution of selenoenzymes; and (ii) as a transient increase in oxidative selenocompounds, like selenite (in high concentration). Therefore, selenocompounds have a wide , multitarget action. Increased Reactive Oxygen Species in Sepsis There is significant evidence that ROS, including free radicals, increase dramatically during human sepsis, causing redox imbalance and oxidative stress [3, 4]. ROS are produced by three main mechanisms: 1. Activated neutrophils produce superoxide anion (0 2

) as a cytotoxic agent as part of the respiratory burst through the NADPH oxidase complex. With acti vated endothelial cells there is also a production of the free radical, nitric oxide (NO) that reacts with superoxide anion to form peroxynitrite, a powerful oxidant and bactericidal molecule ( Fig. 1); 2. Via the mitochondrial respiratory electron transport chain especially if it is dysfunctioning; 3. By enzymes like xanthine oxidase activated during ischemia/reperfusion processes [7, 11].

Bactericidal Effect of ROS and Bacterial Defenses The damaging effects of oxygen on strict an aerobes seem to be the result of oxida tion of essential cellular components. To protect themselves, aero-anaerobic bacteria have developed mechanisms mainly based on iron metabolism control and superoxide dismutase (SOD) [12]. The virulence of bacteria, but perhaps not their survival, may be dependent on the existence of these mechanisms; they do not seem to use selenoenzymes for antioxidant defense s, as do human cells. Damaging Effects of ROS on Human Cells especially Endothelium ROS can damage cells by lipid peroxidation (mainly on polyunsaturated lipids), by protein alterations (e.g., on tyrosine), and by DNA breaks or alterations (e.g., on guanine). At the mitochondrial level, ROS can damage the membrane and the cytochromes, which are iron proteins, especially cytochrome c, the release of which activates caspases and induces apoptosis [3, 4].

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detoxification

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Fig. 1. Detoxification of reactive oxygen species (ROS) in sepsis or systemic inflammatory response syndrome (SIRS) by selenoenzymes. ATP: Adenosine triphosphate, SOD: Superoxide dismutase, GPx: Glutathione peroxidase; PHGPx: Phosphohydroxyl GPx; The Fenton reaction can also occur with copper. There is also a complex regulation of Fe++ concentration involving ceruloplasmin. ** Mn-SOD in the mitochondria; (Adapted from [11] with permission)

Modulation of Cell Metabolism

ROS are also extremely important for cell functioning through the modulation of the redox potential. The control of peroxide tone is especially important. As an example, an increase in peroxide tone causes a reduction in redox potential and thus increases disulfur bridge formation. This modifies how proteins and enzymes function [7]. To summarize, even though oxidant molecules (i.e., ROS) can damage major cell constituents they can also playa major role in modulating cell metabolism. Their production and level are tightly controlled, notably by the presence of antioxidant defenses.

Biological Importance of Selenium Defense against oxygen free radicals involves complex non-enzymatic and enzymatic systems, that can be divided into 4 parts (adapted from [13]):

Selenocompounds and Selenium: A Biochemical Approach to Sepsis 1. passive - prevents radical chain propagation through scavenger small molecules (e.g., vitamin E and C).

2. enzymatic - together with scavengers, transforms ROS into water. 3. repairing - transforms oxidized molecules back to their native form (e.g., selenium phospholipid hydroperoxide glutathione peroxidase (Se-PHGPx) for lipids, or poly (ADP ribose) polymerase (PARP) for DNA). 4. genetic - through genes involved in a rapid adaptive defense.

In 1957, selenium was first recognized as an essential trace element in rats by Schwartz and Foltz (14). An essential trace element is a mineral found in small quantities in the body but crucial for life [13, 15). In the 1970s, selenium deficiency was associated with a severe lethal human cardiomyopathy, "Keshan disease", that can be prevented by or treated with oral selenium supplementation (16). Numerous studies suggest that selenium deficiency leads to immune dysfunction with impairment of both cell-mediated immunity and B cell function. Most probably, Keshan disease is linked to two factors both related to selenium deficiency: An immunodepression of the Keshan population leading to increased virulence of Coxsakie viruses, associated with impaired antioxidant defenses resulting in fatal myocarditis. Selenium is now recognized to be of fund amental importance to human health for its antioxidant functions (6). Selenoenzymes playa major role in these defense mechanisms and are, therefore, essential for human health . There is only 10 to 20 mg of selenium in the organism (0.2 mg/kg). Glutathione peroxidase (Se-GPx) was the first antioxidant selenoenzyme to be discovered [17, 18). This enzyme requires glutathione as a cofactor as shown in Fig. 2. In selenoenzymes , or selenoproteins, there is only one atom of selenium in the form of a 21st amino acid, selenocysteine, where selenium replaces sulfur in the cysteine [6], modifying our knowledge of the genetic code [19]; plasma selenoprotein P is the only known exception with up to 10 selenocysteines. Selenium, in the form of selenocysteine, is always found at the active site of selenoenzymes and is essential for their enzymatic activities. The deletion of the gene that encodes selenocysteine transfer ribonucleic acid (tRNA) is lethal in mice. Moreover, the increased concentration of selenium induces the synthesis of selenoenzymes. Since 1973, more than 30 selenoenzyme families have been identified [19], most of them are involved in antioxidant defenses, especially against peroxides ( Fig. 2). Selenoenzymes are ubiquitou s: They are localized in the plasma (GPx3), in the membrane as phospholipid hydroperoxide GPx (PHGPx) or GPx 3 and 4, in the cytosol (GPx-), in the mitochondria (specific PHGPx), and in the nucleus. Thioredoxine reductase (TRx) is one of these antioxidant enzymes ( Fig. 2). Selenoenzymes have been reported to be responsible for a reduct ion to water of 92 % of hydrogen peroxide (HzOz). They are, in particular, required in the thyroid, an organ producing extremely high levels of ROS. With selenoenzymes, mammal cells have a very efficient antioxidant mechanism especially for peroxide detoxification in which most of the selenoenzymes are involved. Their efficacy is better than iron or sulfur enzymes. Seleno and non-seleno (i.e. Cu,Zn-SOD) antioxidant enzymes have a cooperative action as schematically shown in Fig. 1 [11]. Apart from selenocysteine, selenium can be incorporated into selenomethionine instead of sulfur by a non-genetically controlled process. This selenium is considered to be in a non-biologically active form. It constitutes a reserve that may be mobilized through catabolism. Proteins containing selenomethionine are not considered as selenoproteins.

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Fig. 2.Detoxification oftheorganic peroxides, role ofGPx. GSH: reduced glutathione;GSSG:oxidized glutathione; Thio-S-S-Thio: oxidized thioredoxin; Thio-SH: reduced thioredoxin; ROOH: alkyl peroxide (oxidized); NADPH: nicotinamide-adenine-dinucleotide phosphate (reduced); G6PDH:glucose-6-phosphate dehydrogenase. The oxidation ofG6P permitted the regeneration ofNADPH through thepentose pathway. The ratio ofreduced tooxidized glutathione GSH/ GSSH in normal cells is high. The other non-seleno-dependent peroxidases have a secondary role. (adapted from [11] with permission)

Illustration of the Importance of Peroxide Tone Control by Selenoenzymes Selenoenzymes control the peroxide tone of the cellular compartments. This gives them the power to modulate cellular metabolism as illustrated below in four intracellular examples: (1) The arachidonic acid cascade: At the level of the arachidonic cascade, the peroxides modulate the activity of the key enzymes of the cascade [11]. For example, as thromboxane synthetase is less sensitive to peroxides than prostacyclin synthetase, high concentrations of intracellular peroxide induce the synthesis of thromboxane A2, a powerful vasoconstrictor and platelet-aggregating factor instead of prostacyclin PGI2, a vasodilator and inhibitor of platelet activation. (2) Nuclear factor-kappa B (NF-KB) activation : Most of the extra-cellular signals which activate NF-KB (like tumor necrosis factor [TNF]-u and interleukin [IL]-I) trigger an increase in the intracellular production of ROS and of lipid peroxides, which appear to be the second essential messengers of these extra-cellular signals [20]. Similarly, ROS appear to be the second essential messengers in signal transduction, gene expression, and the cell proliferation [4]. By controlling the activity of GPx, the intracellular selenium concentration is one of the major elements regulating the activation of NF-KB and controlling gene expression in the early immuno-inflammatory response [20]. (3) The prevention of apoptosis: Selenoenzymes may prevent apoptosis in at least two different ways: (i) through membrane protection by PHGPx, increasing intracellular anti-oxidant defenses and reducing DNA fragmentation mediated by hydrogen peroxide [21]; (ii) through overexpression of mitochondrial PHGPx preventing the release of cytochrome c, and caspase-3 activation [22]. (4) Other : On the cascades that can be modulated by selenoenzymes; for example, complement cascade activation and platelet aggregation.

Selenocompounds as Prooxidants Historically, selenium was known to cause animal poisoning from ingestion of selenium-rich plants . This was first reported by Marco Polo a long time before the discovery of selenium in 1817by JJ Berzelius [19]. Sodium selenite is listed in the mate-

Selenocompounds and Selenium: A Biochemical Approach to Sepsis

rial safety data sheets from the u.s. Office of Environmental Health and Safety as a dangerous poison in large amounts (carcinogenesis and teratogenesis). Selenium toxicity has been extensively studied in livestock and laboratory animals, in particular, in terms of different selenium compounds, modes of administration, and durations of intoxication. The mechanism of toxicity is thought to be related to the interaction between selenium and sulfur, especially the effects on thiol groups and disulfur bridges. Toxicity varies greatly among selenium compounds, selenite being a rather pro oxidative compound (23). In acute intoxication models, the minimum lethal dose for intravenous administration of sodium selenite is between 1.5 to 3.0 mg/kg in rabbits, rats, dogs, and cats (5). The minimum lethal dose has been reported to be 0.7 mg/kg in a sheep model of sodium selenite acute intoxication with a narrow margin : from 100 % survival at 0.6 mg/kg to 100 % mortality at 0.8 mg/kg (24), and the time to death being more rapid for the higher doses. In man, chronic industrial intoxication is recognized, but acute lethal poisoning is rare [5, 25, 26). The plasma selenium concentration in lethal human cases seems to be around 30 umol/l (26) but the toxic level most probably depends on the compound used. Animals and humans die from acute pulmonary edema and shock (that may be refractory) preceded by gastrointestinal (persistent vomiting and diarrhea) and neurological (severe weakness) symptoms. In less severe acute intoxication, reversible kidney and liver damage has been described. The observed clinical toxic effects of selenium in humans seem similar to those of arsenic (25). Treatment of acute intoxication other than supportive therapy is difficult. Use of a metal chelator may be useful, but can also be harmful. Hemodialysis has also been proposed (26). The pro oxidant effects of selenocompounds are currently being studied for use in cases of drug resistant cancers. At the early stage of severe inflammatory diseases such as septic shock, there could be - paradoxically - a great interest in a controlled use of the pro oxidative effect of selenium compounds on thiol groups. This could help to reduce overactivated phagocytic cells, assimilating septic shock to an acute transient hematological disease. Selenium compounds, and especially sodium selenite, could directly inhibit NF-KB binding to DNA through a reversible rupture of the disulfur bridge fixation at concentrations higher than 5 urnol/l [27, 28). After stimulation by TNF-a, there is activation of NF-KB leading to its translocation into the nucleus and NF-KB binding to the DNA binding domain through cysteine residues. This binding involves disulfur bridges. This leads to the expression of NF-KB target genes, including induction of inducible NO synthase (iNOS). Adjunction of sodium selenite for 3 hours to the media of nuclear extract inhibited NF-KB binding to DNA, most probably by the formation of RS-Se-SR adducts, and further incubation with a thiol reducing agent restored the binding activity (27). This was also shown for lipopolysaccharide (LPS)-activated [urkat T cells with a dose-dependent and proportional inhibition of iNOS activity from 5 umol/I to 100 pmol/l, and in a mouse model of allergen-induced asthma where the NF-KB inhibition effect of selenite likely underlies its anti-inflammatory action (28). At higher concentrations, selenite could inhibit cellular adhesion even inducing a reversible pro-apoptotic effect (29). At even higher concentrations, selenocompounds could be bactericidal, virucidal, and cytotoxic (23). The pro oxidant effect is likely transitory due to the rapid incorporation of selenium into the selenoenzymes, especially in the case of the small molecule, sodium selenite (NaZSe03 ) , causing, first, an antioxidant action with, second, an opposite action (antioxidant, anti-apoptotic actions) that reverses the previous effect.

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Selenium Content in Plasma

in Healthy Individuals

In healthy individuals, selenoprotein P (Sel-P) is the major selenoprotein in plasma [30], accounting for 52 % of the total plasma selenium. Glutathione peroxidase, GPx, accounts for another 39 %, albumin for 9 %, and free selenium forms less than 1 % [31] (see Table 2 for reference values). Selenium in albumin is in the form of nonactive selenomethionine. Selenoprotein P plays a major role in selenium transport and is known to have a short half-life (3 - 4 hours) under normal conditions [32]. In addition, selenoprotein P has a role in endothelial protection as observed in a rat model of herbicide diquat intoxication where selenoprotein P bound to the inflamed endothelium to protect it against oxidation [32]. In vitro, selenoprotein P reduces peroxynitrite [32]. Of note, there is no glutathione in the plasma, thus the functional activity of Se-GPx-3 in the plasma is debatable.

In Sepsis In leu patients with systemic inflammatory response syndrome (SIRS), especially in patients with septic shock, there is a 40 % decrease in plasma selenium concentration [33] ( Fig. 3). A selenium concentration < 0.7 umol/l in leU patients was associated with a 4-fold increase in mortality and a 3-fold increase in the rate of new organ failure and ventilator-associated pneumonia (VAP) [33]. Such a decrease in plasma selenium has also been observed after LPS injection in rat studies [34]. A progressive decrease in selenium preceding clinical events has also been observed in a fecal peritonitis model in ventilated sheep and enabled us to determine the best time for sodium selenite administration in this model [35]. In a recent article, Sakr Table 2. Reference values for plasma selenium and selenoprotein concentration Total selenium GPx-3 Sel-P There is almost

1 ± 0.15 umol/l (always incorporated into proteins) 260 to 340 nmolll corresponding to about 26 mg/I 40 to 80 nmolll corresponding to abo ut 5- 6 mg/I no free Se in plasma.

GPx: Glutathione peroxidase; Sel-P: Selenoprotein P (contains upto 10selenocysteine residues) (Correspondence for selenium: 1Ilmolll = 78.9Ilg/l; 1Ilg/1 = 0.013 umol/l [30, 32))

1.2

o

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0.8 0.6

0.4

0.2 n = 15 (0)

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n = 13 (3)

n = 12 (7)

Severe sepsis Septic shock

Fig. 3. Plasma selenium concentration related to severity of sepsis at ICU admission. Selenium plasma concentration in Ilmol/!. Dashed line, mean +/- SD normal plasma selenium concentration (1.00 +/- 0.15 Ilmolll); n, number of patients, including, in parentheses, number of non-surviving patients, for each sepsis severity grade. Values are expressed as median (middle line in the box) with the top and bottom of the box encompassing the 25th to the 75th percentiles; capped lines indicate the 10th to 90th percentiles of the data; circles, values above the 90th and below the 10th percentiles. p :5 0.05 for sepsis vs. severe sepsis; p :5 0.05 for sepsis vs. septic shock (analysis of variance). (From [33] with permission).

Selenocompounds and Selenium: ABiochemical Approach to Sepsis

et al. [36] have confirmed that lower plasma selenium concentrations, especially during infection, are associated with higher degrees of tissue damage, with the presence of infection or organ dysfunction/failure, and with increased ICU mortality. In a receiver operator characteristic (ROC) analysis, the Simplified Acute Physiology Score (SAPS) II score [area under the curve (AUC) = 0.903] and minimum selenium concentration (AUC = 0.867) were the strongest predictive factors for ICU mortality. Selenoprotein P

Plasma selenium concentration, however, is a global measure of the concentrations of different compounds, selenoprotein P, GPx, and albumin, as discussed above. However, the breakdown of these different compounds is not known in septic ICU patients. To test the hypothesis that selenoprotein P fixes to the surface of activated endothelium for protective purposes, we measured the plasma selenoprotein P concentration on admission in 21 ICU patients and 7 healthy volunteers [37, 38]. On admission to the ICU, we observed a selenoprotein P concentration rate 70 % lower in the 10 patients with severe systemic inflammation (7 suffering from septic shock and 3 from severe SIRS) than the value in healthy volunteers . There was no significant decrease in the other ICU patients. Contrary to the low selenoprotein P concentrations on admission, GPx concentrations were not significantly different in these 10 patients compared to the other subjects [37]. Before death, the three patients with septic shock had a significantly lower selenoprotein P plasma concentration compared to 3 non-SIRS patients whose selenoprotein P level did not decrease. This difference was significant despite the small number of patients [38, 39]. This drastic decrease in plasma selenoprotein P concentration was all the more surprising to the biochemists, since selenoprotein P concentration was thought to be stable except in severe selenium deficiency. Further studies are required to confirm the role of selenoprotein P in the decrease in selenium seen in patients with septic shock and severe SIRS, and the possibility of selenoprotein P being a marker of septic shock linked to an endothelial protection mechanism.

Selenium Administration in Nutrition and in ICU Patients To avoid harmful effects, the Recommended Dietary Allowance (RDA) for selenium has been established as 55 Ilg in both men and women. The tolerable upper intake level is set at a maximum of 400 Ilg [40] and the no adverse event level at 800 Ilg [1, 41, 42]. However, a single ingestion dose of 4 mg of selenium has been considered to be non-toxic in a healthy human [5]. In the case of oxidative stress related to septic shock, administration of more than 700 ug/day of selenium is currently not recommended taking into consideration the pro-oxidative effect of selenocompounds [1,41,42]. It is well known in nutrition that trace element supplementation, particularly for selenium, is characterized by a dose response curve that goes from an increasing beneficial effect to a plateau which is followed by toxicity if doses are increased [13,40,43]. The microcirculation is the main target of selenium-based treatments through induction of antioxidant selenoenzymes, selenoprotein P, or for the transient prooxidative effect on activated cells in the blood compartment. There are also biologicalor experimental data supporting actions on key functions: On cardiovascular function (myocardial protection, inhibition of iNOS in vitro); on pulmonary func-

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tion (effect on acute asthma by selenite in mice); on the brain (deleterious effect of selenoprotein-P knock-out model on brain); on the kidney (main concentration of GPx, protective effect shown in a study by Angstwurm et al. [44]), on the hematological system (platelet inhibition by long term selenium supplementation, inhibition of complement activation, and improvement in immune function); and on liver and metabolic function (deleterious effect of liver selenocysteine knock-out model, significant reduction in lactate concentration observed in rat and sheep model, inhibition of arachidonic acid cascade in pancreatitis). In his article, Olson reviews experiments on farm animals, reports on acute selenosis in man, and chronic selenosis in man and animals [5]. He concludes that, in man, the maximum suggested safe single dose (by ingestion) of selenite, DL-selenocysteine, or DL-selenomethionine is 0.05 mg selenium/kg body weight [5]. To our knowledge there is no published study on the toxicity of selenocompounds, especially sodium selenite, in a sepsis model. In our study performed on a LPS rat model there was a significant, dose-related increase in toxicity of sodium selenite. Mortality was significantly increased for doses up to 0.6 mg/kg, compared to 3 mg/kg in healthy rats [45]. Rats died from acute edema in accordance with the previously described selenite toxicity. The safety margin of selenite administration in septic shock animal models needs to be further studied, as well as ways of preventing or treating selenite intoxications. Therapeutic Approach

In our opinion, there are three main approaches to selenium (or selenocompound) administration in ICU patients with severe sepsis or SIRS: The first two approaches can be considered nutritional because they use selenium supplements to compensate for a relative selenium deficiency in these patients. These approaches use doses less than the no-observed-adverse-effect level for two objectives: (i) to restore antioxidant defenses in a situation of oxidative stress, and (ii) to augment immunity. The first approach is a multi-micronutrient approach (including trace elements: Zinc, copper, selenium and vitamins E and C) reported especially by M Berger et al. since 1986 [42] (Table 3). Supplements are based on redistribution data. The objective is to supplement the electron chain for ROS detoxification with all the micronutrients involved (see Fig. 1), progressively focusing on selenium (and zinc). Selenium is mainly administered intravenously through sodium selenite, and ideally combines intravenous and enteral administration. The second approach focused on selenium, as the essential constituent of GPx and PHGPx [46], and more recently on selenoprotein P for its endothelial functions [47]. These studies have mainly been conducted in Germany (Table 4) with use of intravenous selenium supplementation in the form of sodium selenite (NaZSe03 ) , most probably sodium selenite pentahydrate (NazSe0 35H zO). The third approach is therapeutic [48]. It consists of deliberate administration of prooxidative doses of selenocompounds, especially sodium selenite, intravenously. This allows high concentrations of selenite to be obtained in the blood leading to a transient direct inhibition of NF-KB to DNA binding, of cellular adhesion, and even apoptosis of over-activated cells especially at the microcirculation level leading to an anti-inflammatory effect. Due to the incorporation of selenium this prooxidative transient action is rapidly followed by an optimal induction of selenoprotein P and other anti-oxidant selenoenzymes reducing ROS damage, and implementing immunity.

Selenocompounds and Selenium: A Biochemical Approach to Sepsis Table 3. Early studies of selenium by Berger et al [Reference]

Year

Included patients

Treatment Se*

n

Se

Ctrl

[57]

1998

Burns > 30% BSA

160 j.Jg/day Se + (Cu, Zn)

20

10%

0%

3.9%

[58]

2001

ISS > 15, 2 body systems < 24 h of inj.

500 j.J g/day Se Slowi.v. infusion 5 days ± AT, Zn

31

22 %

8%

7.2%

[59]

2001

- - - - -

- -- - - -

32

0%

8%

3.8%

[60]

2002

Burns > 20 % BSA

370 j.Jg/day + (Cu, Zn)

17

11 % 13 %

5.4%

Mortality

Weight in meta-analysis by Heyland et al. [1]

* Doses expressed in selenium, as sodium selenite in accordance to the articles; Cu: copper; Zn: zinc; AT: alpha-tocopherol; n: number of patients; BSA: body surface area; ISS: injury severity score; l.v, intravenous; Se: selenium treated group; Ctrl: control group. The molecular weight of selenium (Se) is 78.9g/mol and that of sodium selenite (Na 2Se03) is 172.9g/mol. Given the respective molecular weights of selenium and sodium selenite, 1 mg of selenium corresponds to 2.2 mg of sodium selenite. Table 4. Early studies of selenium conducted in Germany [Reference]

Year

Included patients

Treatment NaSe*

n

Mortality

Se Kuklinski [51]

1991

Pancreatitis pts

Zimmerman [SOl

1997

SIRS + MOF pts APACHEII > 15

Angstwurm [44]

1999

Sepsis + APACHE II ::::15 24 h admission (mainly pneumonia ?)

Weight in metaanalysis by Heyland et al. [1]

Ctr

17

0 % 89 %

4.98 %

Bolus 1 mg, + 40 1 mg/day continuous infusion 15 days

15% 40%

51%

33% 52 %

24 %

Bolus > 500j.J g, 100 j.J g/day 5 days

535 j.J g 3 days, 285 j.Jg 3 days, 155 j.J g 3 days

42

* Doses expressed in sodium selenite in accordance to the articles; NaSe: sodium selenite; n: number of patients; Se: selenium treated group; Ctrl: control group; SIRS: systemic inflammatory response syndrome; MOF: multiple organ failure. Given the respective molecular weights of selenium and sodium selenite, 1 mg of sodium selenite (Na 2Se03) corresponds to 0.46 mg of selenium (Se).

Clinical Results and Analysis Recent meta-analyses The two most recently published meta-analyses on selenium supplementation in septic shock concluded that selenium administration in the form of sodium selenite

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could lead to a decrease in mortality in septic shock patients with a dose-dependent relation [1,41]. We will focus on the meta-analysis of Heyland et al. [1], splitting it according to the different approaches discussed above. • Multi-micronutrient approach: The weight of studies using this approach is only 20 % in the meta-analysis ( Table 3). Studies were conducted mainly in burned or trauma patients with a low mortality rate in the control group and, therefore, little impact on this parameter. Antioxidant supplements might have resulted in a reduction in organ failure and in infectious complications; this observation is further supported by the publication of the aggregation of two randomized trials showing a significant reduction in nosocomial pneumonia after major burns by trace element supplementation [49]. • Selenium alone supplementation approach: this accounts for nearly 80 % of the total weight of the Heyland meta-analysis [1] and the study by Zimmerman et al. [50] accounts for half of this weight (Table 4). Studies using this approach have been conducted in more severely ill patients with a mortality rate of 40 to 90 % in the control group, choice of mortality as an end-point, and slightly larger patient groups. They are also mono-centered. The first study by Kuklinski et al. [51] was very successful with no mortality in the treated group and a high mortality in the control group. In the study by Zimmerman et al. [50], it is difficult to precisely define which patients were included and the time of administration. The effect seemed to occur quickly with a significant decrease in APACHE III score and MOF on the second day in the treated group associated with a significant reduct ion in inflammatory mediators such as IL-6 and TNF-a [50]. It should be noted that Zimmerman et al, and most probably Kuklinski et al, administered the first dose of sodium selenite as a bolus, with, therefore, a transient peak in blood sodium selenite concentrations. All the studies cited in Table 4 most probably used the same sodium selenite pentahydrate. Other contradictory studies A randomized study by Lidner et al. on 70 patients with pancreatitis, who were given a dose of 2 mg sodium selenite followed by four days of 300 ~g/day did not report any benefit, especially on mortality [52]. The randomized study by Mishra et al. again showed no benefit with selenium administration [53]. It should be noted that two other mono-centered, double-blind, placebo-controlled negative studies on selenium administration in septic ICU patients have also been reported in abstract form [54, 55] with selenium given as sodium selenite at a dose of 500 ~g and 1 mg the first day. These studies seem not to have administered sodium selenite as a bolus. The two recent multicenter studies: Contradictory findings of SIC and Serenite? Two recent multicenter studies have explored the value of selenium administration in patients with sepsis. The Selenium in Intensive Care (SIC) study [8] was conducted in 11 ICUs in Germany and enrolled 249 patients with severe SIRS, sepsis, or septic shock and an APACHE II > 70. Patients were randomized to receive 1000 ~g of sodium selenite as a 30-min bolus injection, followed by 14 daily continuous intravenous infusions of 1000 ~g, or placebo. In the 238 patients included in the intention-to-treat analysis, 28-day mortality rates were lower in the selenium-treated patients. In the SERENITE study [9], 60 patients with septic shock were enrolled in 7 French ICUs and randomized to receive either 4000 ~g selenium, as sodium sele-

Selenocompounds and Selenium: A Biochemical Approach to Sepsis

nite, as a continuous infusion on the first day followed by 1000 ug/day as a continuous infusion for the nine subsequent days, or placebo. There were differences among groups in outcome measures including mortality. The patients included in the SIC and SERENITE studies were very similar at inclusion [8, 9). The main differences were diabetes present in 62 % vs 20 % in SIC and SERENITE, respectively, and chronic renal deficiency in 48 % vs 7 %. Mortality rate at 28 days was very similar in the placebo groups . There is some confusion regarding the dose administered in the SIC study, which may have been 1 mg sodium selenite as a bolus followed by 1 mg continuously for 14 days, or twice this dose as the total selenium dose is reported to be 15 mg in the methods section [8). The dose administered in the SERENITE study was 4 mg selenium as sodium selenite for the first day as continuous adm inistration followed by 1 mg daily for 9 days. Although a single ingestion of 4 mg selenium is considered to be non-toxic in healthy humans [5], we chose to administer the initial dose using a continuous administration, rather than a bolus, to limit the risk of toxicity. The lack of a beneficial effect in the SERENITE study may be related to the small size of the study. However, all secondary end points also suggested no efficacy or toxicity. Another possible explanation for the absence of a beneficial effect could be an incipient toxicity of selenite counterbalancing any moderate beneficial effect related to selenium infusion. Time to treatment may also be an explanation. However, inclusion to treatment was less than 24 hours for the majority of patients, included mainly for commun ity infection, in both studies. In vitro studies have shown that selenite concentrations greater than 5 umol/l induce a reduction in the binding of NF-KB to DNA [27]. In detached mice cells, higher sodium selenite concentrations inhibit cell attachment, and induce apoptosis and cyotoxicity [23]. However, in man, in continuous infusions, even with a dose of selenite corresponding to 4 mg selenium over the first day, the blood selenite concentration may have been lower than the concentration required to decrease NF-KB to DNA binding and even more for inducing activated polymorphonuclear apoptosis. We observed, in a recent experimental ventilated peritonitis sheep model, that this 5 umol/l selenium concentration was not obtained in the plasma by continuous administration but was obtained by bolus injection [56]. In a rat study [34], we observed a mortality of 50 % compared to 70 % for the control group, clinical improvement and a significant decrease in plasma lactate concentration in surviving rats with an optimal administration dose of selenium as sodium selenite of 0.25 mgt kg, corresponding to 20 mg in a human. This administration was performed intraperitoneally 1 h after LPS administration, therefore, similar to a bolus administration [34]. More recently, we [56] conducted a study on ventilated sheep to compare the effects of continuous and bolus administration. Hypotension developed 4 hours later in the bolus injection group than in the other s (p< 0.05). Lactic acidosis appeared 5 hours later in the bolus injection group than in the others (p< 0.05). Cardiac index and left ventricular stroke work were better maintained in the bolus injection group (p< 0.05). We concluded that the inject ion of a large bolus of sodium selenite (rather than a continuous administration) may improve hemodynam ics and lengthen survival in septic shock. Moreover, the effect seems to depend on the specific selenocompound injected .

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Conclusion In order to understand the mechanisms of oxidant-antioxidant (redox) potential we must study at a deeper level than molecules, to the electron level, which is responsible for the links between molecules and the three-dimensional conformation of these molecules. Currently, sodium selenite is used for parenteral selenium supplementation. There are biological and clinical data supporting that administration of sodium selenite below the tolerable-upper-intake-level, i.e., 400 flg selenium per day as a continuous perfusion, may be beneficial. However, it has not been firmly demonstrated that this administration improves outcomes. Until studies confirm its efficiency and safety, bolus injection should be avoided in routine practice. A putat ive teratogenic risk should also be taken into consideration. In rout ine practice, administration of selenium compounds above the no-observed-adverse-effect level (800 flglday) requires: (i) a process of drug development, (ii) to be confirmed by at least one phase III study, and (iii) must be approved to be on the market for the treatment of patients with severe sepsis or SIRS. The results of the SIC study are impressive but not conclusive. Further understanding of mechanisms of action, optimal time to administration, optimal dose, type of administration, and also potential toxicity, require rodent and non-rodent resuscitated animal models, and dose effect phase II studies, before a phase III trial can be conducted. For the future, we are convinced that selenium compound based treatment of severe sepsis and septic shock will play a crucial role. This therapy will probably involve the use of selenium compounds other than sodium selenite in order to act more specifically on different parts of the cells and tissues. Among these molecules, we believe that selenoprotein P has very interesting pathophysiologic, therapeutic, and diagnostic implications. Acknowledgement: We would like to thank Jeannette de Vigan for her help with language editing . References 1. Heyland DK, Dhaliwal R, Suchner U, Berger MM (2005) Antioxidant nutrients: a systematic

2. 3. 4. 5. 6. 7. 8.

9.

review of trace elements and vitamins in the critically ill patient. Intensive Care Med 31:327-337 Aird WC (2004) Endothelium as an organ system. Crit Care Med, 32 (suppl 5):S271- 279 Crimi E, Sica V, Williams-Ignarro S, et al (2006) The role of oxidative stress in adult critical care. Free Radic Bioi Med 40:398-406 Macdonald J, Galley HF, Webster NR (2003) Oxidative stress and gene expression in sepsis. Br J Anaesth 90:221- 232 Olson OE (1986) Selenium toxicity in animals with emphasis on man. J Am Coli Toxicol 5: 45-69 Rayman MP (2000) The importance of selenium to human health. Lancet 356:233- 241 Halliwell B, Gutteridge JMC (1999) Free Radicals in Biology and Medicine, Third edn. Oxford University Press, Oxford Angstwurm MW, Engelmann L, Zimmermann T, et al (2007) Selenium in Intensive Care (SIC): results of a prospect ive randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med, 35:118-126 Forceville X, Laviolle B, Annane D, et al (2007) Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase 11 study. Crit Care 11:R73

Selenocompounds and Selenium: ABiochemical Approach to Sepsis 10. Hays RM (1980) Dynamics of body water and electrolyt es. In: Maxwell MH, Kleeman CR (eds) Clinical Disorde rs of Fluid and Electrolyte Metabolism, Edn 3. McGraw-Hill, New York, pp 1-36 II. Forceville X, Vitoux D (1999) Selenium et sepsis. Nutrition Clinique et Metabolism 13:177186 12. Touati D, Jacques M, Tard at B, Bouchard L, Despied S (1995) Lethal oxidative damage and mutagenes is are generated by iron in delta fur mutants of Escher ichia coli: protective role of superoxide dismutase . I Bacteriol 177:2305- 2314 13. Favier A (1991) Les oligoelements en nutr ition humaine. In: Doc LT (ed) Les Oligoelements en Medecine et Biologie. Lavoisier, Paris pp 41-75 14. Schwartz K, Foltz CM (1957) Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration. I Am Chern Soc 79:3292- 3293 15. Mertz W (1981) The essential trace elements . Science 213:1332-1338 16. Chen XS, Yang GO, Chen IS, Chen XC, Wen ZM, Ge KY (1980) On the relations of selenium and Keshan Disease. Bioi Trace Elem Res 2:91-107 17. Rotruck )T, Pope AL, Ganther HE, et al (1973) Selenium: biochemical role as a component of glutathione peroxidase . Science 179:588 - 590. 18. Flohe L, Giinzler WA, Schock HH (1973) Glutathion e peroxidase : a selenoenzyme. FEBS Lett 32:132-1 34 19. Hatfield DL, Berry M), Gladyshev VN (2006) Selenium, second edn. Springer, New York 20. Brigelius-Flohe R, Friedrichs B, Maurer S, Schultz M, Streicher R (1997) Interleukin-l -induced nuclear factor kappa B activation is inhibited by overexpression of phospholipid hydroperoxide glutathione peroxidase in a human endothelial cell line. Biochem I 328(Pt 1):199-203 21. Kayanoki Y, Fujii I. Islam KN, et al (1996) The protect ive role of glutathione peroxidase in apoptosis induced by reactive oxygen species. I Biochem (Tokyo) 119:817-822 22. Nomura K, Imai H, Koumura T, Kobayashi T, Nakagawa Y (2000) Mitochondrial phospho lipid hydroperoxide glutathione peroxidase inhibit s the release of cytochrome c from mitochondria by suppres sing the peroxidat ion of cardiolipin in hypoglycaemia-induced apoptosis. Biochem I 351(Pt I):183 - 193 23. Stewart MS, Spallholz )E, Neldner KH, Pence BC (1999) Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis. Free Radic Bioi Med 26:42-48 24. Blodgett D), Bevill RF (1987) Acute selenium toxicosis in sheep. Vet Hum ToxicoI29:233-236 25. Carter RF (1966) Acute selenium poisoning. Med I Aust 1:525-528 26. Spiller HA, Pfiefer E (2007) Two fatal cases of selenium toxicity. Forensic Sci Int 171:67-7212 27. Kim IY, Stadtman TC (1997) Inhibition of NF-kappaB DNA binding and nit ric oxide induction in human T cells and lung adenocarcinoma cells by selenite treatment. Proc Natl Acad Sci USA 94:12904- 12907 28. Jeong DW, Yoo MH, Kim TS, Kim )H, Kim IY (2002) Protection of mice from allergeninduced asthma by selenite: prevention of eosinophil infiltration by inhibit ion of NF-kappa B activation . I Bioi Chern 277:17871-17876 29. Chung YW, Kim TS, Lee SY, et al (2006) Selenite-induced apoptosi s of osteoclasts mediated by the mitochondrial pathway. Toxicol Lett 160:143-150 30. Mostert V (2000) Selenoprotein P: Properties, functions, and regulation. Arch Biochem Biophys 376:433-438 31. Harri son I, Littlejohn D, Fell GS (1996) Distribution of selenium in human blood plasma and seru m. Analyst 121:189-194 32. Burk RF, Hill KE (2005) Selenoprotein P: An extracellular protein with unique physical characteristic s and a role in selenium homeostasis Annu Rev Nutr 25:215-235 33. Forceville X, Vitoux D, Gauzit R, Combes A, Lahilaire P, Chappuis P (1998) Selenium, systemic immune respons e syndrome, sepsis, and outcome in critically ill patients. Crit Care Med 26:1536-1544 34. Forceville X, Chancerelle Y, Agay D, Ducros V, Laporte F (2004) At moderately high level, sodium selenium seems to decrease mortality in lipopolysaccharide rat model. Intensive Care Med 30:S110 (abst) 35. Forceville X, Van Antwerpen P, Zhen W, et al (2008) Diminution precoce de la concentration en selenium plasmat ique lors d'un etat de choc sur per itonite (modele de brebis ventileie) XXXVle Congres de la Societe de Reanimation de Langue Francaise (abst, in press)

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X. Forceville and P. Van Antwerpen 36. Sakr Y, Reinhart K, Bloos F, et al (2007) Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure. Br J Anaesth 98:775 - 784 37. Forceville X, Moster V, Vitoux D, Plouvier E, Lahilaire P, Combes A (2001) Early marked selenoprotein p decrease in severe inflammatory and septic patients . In: 1st International FESTEM Congress on Trace Elements and Minerals in Medicine and Biology 0.26 (abst) 38. Forceville X, Moster V, Vitoux D, Plouvier E, Lahilaire P, Thuillier F (2001) Prolonged selenoprotein P decrease in severe inflammatory and septic patients. J Trace Elem Exp Med 14:3- 5 (abst) 39. Forceville X (2007) Effects of high doses of selenium. as sodium selenite, in septic shock patients a placebo-controlled, randomized, double blind , multi-center phase II study - Selenium and sepsis. J Trace Elem Med Bioi 21 (suppl 1):62-65 40. Institute of Medicine Panel on dietary antioxidants and related compounds , interpretation and uses of dietary reference intakes (2000) Selenium. In: Dietary reference intakes for vitamin C, vitamine E, selenium and carotenoids . National Academy of Sciences, Washington, pp 284-324 41. Avenell A, Noble DW, Barr J, Engelhardt T (2004) Selenium supplementation for critically ill adults. Cochrane Database Syst Rev CD003703 42. Berger MM (2005) Can oxidative damage be treated nutritionally? Clin Nutr 24:172-183 43. Forceville X (2006) Seleno-enzymes and seleno-compounds: the two faces of selenium. Crit Care 10:180 44. Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R (1999) Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 27:1807-1821 45. Forceville X, Chancerelle Y, Agay D, Ducros V, Laporte F (2004) At very high level, selenium toxicity increase in lipopolysaccharide rat model. Intensive Care Med 30 (suppl1):SllO (abst) 46. Gartner R, Albrich W. Angstwurm MW (2001) The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma. Biofactors 14:199-204 47. Angstwurm MW,Gaertner R (2006) Practicalities of selenium supplementation in critically ill patients . Curr Opin Clin Nutr Metab Care 9:233- 238 48. Forceville X (2001) Selenium and the "free" electron . Selenium - a trace to be followed in septic or inflammatory ICU patients? Intensive Care Med 27:16-18 49. Berger MM, Eggimann P, Heyland DK, et al (2006) Reduction of nosocomial pneumonia after major burns by trace element supplementation: aggregation of two randomised trials. Crit Care 1O:R153 50. Zimmermann T, Albrecht S, Kuhne H, Vogelsang U, Grutzmann R, Kopprasch S (1997) [Substitution of selenium in septic patients -A prospective randomized study]. Med Klin 92 (suppI3):3-4 51. Kuklinski B, Zimmerman T, Schweder R (1995) Decreasing mortality in acute pancreatitis with sodium selenite. Clinical results of 4 years antioxidant therapy. Med Klin 90 (suppl 1):36-41 52. Lindner D, Lindner J, Baumann G, Dawczynski H, Bauch K (2004) [Investigation of antioxidant therapy with sodium selenite in acute pancreatitis. A prospective randomized blind trial]. Med Klin 99:708-712 53. Mishra V, Baines M, Perry SE, et al (2007) Effect of selenium supplementation on biochemical markers and outcome in critically ill patients. Clin Nutr 26:41- 50 54. Kazda A, Brodska H, Valenta J. et al (2006) Selenium and its substitution in critically ill. Crit Care 1O:S79 55. Kiessling AH, Isgro F, Skuras JA. Kammerer I, Lehmann A, Saggau W (2006) Selenium application in intensive care medicine. Intensive Care Med 32:S89 (abst) 56. Wang Z, Forceville X, Pignarelli M, Van Antwerpen P, Neve J. Vincent JL (2008) High bolus dose of sodium selenite prolongs survival in an ovine model of septic shock. Crit Care Med (abst, in press) 57. Berger MM, Spertin i F, Shenkin A, et al (1998) Trace element supplementation modulates

Selenocompounds and Selenium: A Biochemical Approach to Sepsis pulmonary infection rates after major burns: a double-blind, placebo -controlled trial. Am J Clin Nutr 68:365-371 58. Berger MM, Reymond MJ, Shenkin A (2001) Influence of selenium supplements on the post tr aumat ic alterations of the thyro id axis: a placebo -controlled trial. Intensive Care Med 27:91-100 59. Berger MM, Baines M, Chiolero RL, et al (2001) Influence of early trace element and vitamin E supplement s on antioxidant status after major trauma: a controlled trial. Nutr Res 21:41-54 60. Berger MM, Baines M, Wardle CA, Cayeux MC, Chiolero R, Shenkin A (2002) Trace element supplements modulate tissue levels, antioxidant status and clinical cour se after major burns prelim inary results. Clin Nutr 21 (suppl 1):66 (abst)

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Section XII

XII Metabolic Alterations

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473

The Role of Hypoxia and Inflammation in the Expression and Regulation of Proteins Regulating Iron Metabolism S. BRANDT,

J. TAKALA,

and P.M. LEPPER

Introduction Sepsis is a leading cause of morbidity and mortality in western countries. Sepsisrelated inflammation causes microcirculatory dysfunction, inadequate tissue oxygen supply, and cellular and subcellular function disturbances including mitochondrial dysfunction and decreased availability of adenosine triphosphate (ATP). The provision of sufficient oxygen to tissues is a fundamental physiologic challenge. It is, therefore, not surprising that almost all life on earth - from microbes to mammals - has developed possibilities of generating responses to hypoxia, which help minimize the deleterious effects of oxygen shortage. Organisms adapt to hypoxia with well-known hemodynamic responses, e.g., by increasing cardiac output and oxygen-extraction. In addition, genes encoding transporters, enzymes, and growth factors are induced, which cause molecular and histological modifications that may reduce the cellular need for and dependence on oxygen. Most of these physiological processes including oxygen transport, adaptation to reduced oxygen supply, and mitochondrial respiration interact with the chemical element, iron. If energy availability becomes critical (e.g., due to inflammation or hypoxic hypoxia), the powerhouse (mitochondrion) and the oxygen transport must work more efficiently and for this iron is urgently needed . On the other hand, patho genic germs need the host organism's iron for their reproduction. So, iron restric tion can help to defend the host against microbial invaders (infection anemia). However - as we will see later - iron is also important in multiple different aspects of host defense during inflammation. Finally, ionized iron is highly involved in the production of potentialy harmful oxygen radicals, which can cause, for example, mitochondrial dysfunction, and are suspected of contributing to the high mortality in sepsis. Regulatory loops for oxygen and iron metabolism are closely connected and may overlap at certain points. In this chapter, we elucidate on these interactions between iron homeostasis, adaptation to hypoxia, and host defense.

Iron Homeostasis One milliliter of blood contains 0.5 mg of iron and, thus, a steady blood loss of as little as 3- 4 ml (1.5- 2 mg of iron/d) can result in a negative iron balance. The majority of iron being bound to hemoglobin in red blood cells (RBCs), prolonged iron deficiency leads to decreased production of hemoglobin resulting in anemia. Iron supply to RBC precursors in the bone marrow and to other tissues is largely

XII

474

S. Brandt, J. Takala, and P.M. Lepper maintained by daily recycling of 20 mg of iron from senescent RBCs. Additionally, a dietary intake of 1- 2 mg per day is sufficient to replace ordinary iron losses. In humans, iron uptake takes place mainly in the duodenum and both elementary iron and heme are taken up by duodenal enterocytes. Iron uptake is tightly regulated, as humans cannot excrete surplus iron other than by hemorrhaging. If regulatory mechanisms fail or are circumvented by parenteral administration of iron or blood, excessive iron is deposited in tissues and promotes the generation of oxygen radicals and reactive oxygen species (ROS), which, in turn, can lead to tissue injury and organ failure. The main cells involved in iron homeostasis generating relevant iron flows into the plasma are duodenal enterocytes, hepatocytes as the main site of iron storage, and macrophages that recycle iron from senescent RBCs [I]. Hence, macrophages are important for iron homeostasis and host defense. It is intriguing to speculate that in sepsis both roles cannot be fulfilled.

Hepcidin: The Main Iron-regulating Protein? Hepcidin (formerly liver expressed antimicrobial peptide 1 [LEAP-I]) was first described as an antimicrobial peptide (AMP) predominantly synthesized in the liver [2,3]. Later it was found that the iron-regulatory activity ofhepcidin is already demonstrated at IOO-fold lower concentrations than those required for antimicrob ial activity [4]. The modest in vitro antimicrobial activity is apparent only at very high (l0-30 flM) concentrations and its physiologic relevance remains to be established. Hepcidin deficiency leads to massive iron overload with iron deposition in the liver and the pancreas and iron deficiency anemia (a picture similar to hereditary hemochromatosis, where patients are more susceptible to certain infections) [5]. In contrast, mice that overexpress hepcidin develop severe iron deficiency anemia. The hepcidin receptor, ferroportin, is the sole significant exporter of iron in tissues involved in iron absorption, recycling, and storage - including macrophages [6]. Hepcidin regulates ferroportin by binding to this receptor, leading to internalization and degradation in lysosomes [7]. The hepcidin-ferroportin system ( Fig. 1) is the efferent arm of iron regulation as it can control iron uptake in the duodenum as well as the release of stored iron in hepatocytes and macrophages. When iron stores are normal or high, the liver produces hepcidin, traveling to the small intestine. Hepcidin blocks the release from dietary iron to the circulation by targeting ferroportin of the enterocytes. The short-lived enterocytes are shed from the intestine, removing the iron from the body. When iron stores are low, hepcidin production is suppressed, leading to upregulation of ferroportin of enterocytes and iron is exported to plasma transferrin. In macrophages, recycling senescent RBCs, hepcidin-induced degradation of ferroportin results in iron trapping in macrophages. High levels of hepcidin in inflammatory states would, therefore, account for the finding of iron-containing macrophages despite low plasma iron. The transport of the potentially toxic iron from the site of absorption in the jejunum to the place of utilization and storage is done by the glycoprotein, transferrin. Transferrin binds ferric iron (Fe3+) very tightly but reversibly. Hemoglobin synthesis is stringently dependent on transferrin as a source of iron. Iron recovery takes place in macrophages of the reticuloendothelial system, where the heme moiety is split from hemoglobin. The process is catalyzed by heme oxygenase-I (HO-I) . Interestingly, HO-I deficiency results in severe anemia and inflammation [8,9] . Ferritin is the intracellular storage molecule for iron. The characterization of cellular models in which ferritin expression is modulated has shown that the ferroxi-

Role of Hypoxia/Inflammation in the Expression/Regulation of Proteins Regulating Iron Metabolism

Interleukin-Receptor

TLR-4

~j TNFo

Oxygen-Sensor

Mitochondrial dysfunction?

/~-

1

Iron dependent HIF-stabilization (PHDs)

???

ROSt t

i

-~ Hepcidin

o~

Hepcidin

Fig. 1. Cellular mechanisms of iron regulation involving hepcidin and the response to hypoxia and inflammation. IL: interleukin; LPS: lipopolysaccharide; TLR: Toll-like receptor; ROS: reactive oxygen species; TNF: tumor necrosis factor; HIF: hypoxia-inducible factor

dase catalytic site on the H-chain has a central role in regulating iron availability. In turn, this has secondary effects on a number of cellular activities, which include proliferatio n and resistance to oxidative damage. Moreover, the response to apoptotic stimuli is affected by H-ferritin expression. The recent discovery of a new ferr itin, specific for the mitochondria, opens new perspectives in the study of the relationships between iron, oxidative damage, and free radicals [10]. Hepcidin regulation by hypoxia and inflammation If oxygen supply is low (e.g., anemia or hypoxic hypoxia), hepcidin production is suppressed. Anemia due to bleeding or phenyl hydrazine-induced hemolysis in mice caused a decrease in hepcidin mRNA levels [11]. Hepcidin mRNA was also suppressed in mice housed in hypobaric chambers and in rats exposed to 10 % oxygen [11, 12]. Blood loss and hypoxia stimulate erythropoietin release, which increases the (iron-dependent) production of erythrocytes. The simultaneous decrease in hepcidin levels is adapt ive because it allows increased iron absorption from the diet and iron mobilization from macrophages and hepatocytes, making more iron available

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for erythrocyte production. The exact molecular pathways that regulate hepcidin in response to hypoxia are not known ( Fig. 1). In contrast, infection and inflammation markedly induce hepcidin synthesis [13, 14]. These effects are mediated by inflammatory cytokines, predominantly interleukin (1L)-6. In human volunteers infused with IL-6, urinary hepcidin excretion increased an average of 7.5-fold within two hours after infusion, whereas IL-6 knockout mice (in contrast to control mice) failed to induce hepcidin in response to turpentine-induced peritonitis [15]. Treatment of primary hepatocytes with (a) IL-6 directly, (b) lipopolysaccharide (LPS) or peptidoglycan, or (c) supernatants of LPS- or peptidoglycan-stimulated macrophages, increased hepcidin mRNA expression [15], and this induction was blocked by treatment with anti-IL-6 antibodies. IL-l~ also increased hepcidin mRNA expression in vitro; in human primary hepatocytes , this was blocked by antiIL-6 antibodies, but in mouse hepatocytes, the IL-l~ effect was independent of IL-6 [16]. This finding suggests that there may be species-specific differences in cytokine involvement between mice and humans. Tumor necrosis factor (TNF)-a, on the other hand, was shown to suppress hepcidin mRNA expression in human hepatic cells in vitro [15]. It now appears that the question "Is hepcidin the main iron regulatory protein?" can be answered by "yes". Despite the fact that hepcidin first appeared in publications only 7 years ago, we have already learned that this particular protein not only regulates the organism's iron balance as 'stores regulator' and 'erythroid regulator' under normal conditions but also controls inflammation- and hypoxia-induced iron absorption and recycling.

Hypoxia-Inducible Factor (HIF-1a): A Link between Iron and Oxygen? As explained above, organisms have evolved strategies to adapt to anemia, hypoxia and inflammation, e.g., using the hepcidin -ferroportin system. The main effect can be fully described only in physiologic terms as adjusting the organism's iron supply to the needs of erythropoiesis and/or restricting iron availability to microbial invaders. One could easily hypothesize that a connection between the control of iron homeostasis and the physiology of cellular and subcellular hypoxic response would be meaningful. In fact, hypoxia-inducible factors (HIFs) were recently suggested as the potential link between iron metabolism, iron sensing, and oxygen adaptation [17). The transcriptional activity of HIFs is one mechanism cells use for adapting to a lack of oxygen. HIFs are stabilized when a lack of molecular oxygen inhibits their degradation by iron-dependent prolyl hydroxylases (PHDs). These hypoxia-stabilized HIFs enhance the transcription of genes that allow either increased oxygen delivery and/or improve cell survival in conditions of limited oxygen availability. Thus, HIF-regulated genes have important roles in angiogenesis (vascular endothelial growth factor [VEGF], platelet-derived growth factor [PDGF]), vasodilation (inducible nitric oxide synthase [iNOS]), erythropoiesis (erythropoietin [EPa]), and anaerobic glycolytic pathways [18]. HIFs are heterodimers containing one of three distinct a -subunits (Iu-, 2a-, or 3a-subunit) linked to HIF-l~, which is also known as aryl hydrocarbon receptor nuclear translator (ARNT). HIF-l~ mRNA and protein expression are not influenced by hypoxia (thus, this situation resembles a house-keeping gene situation), whereas hypoxia upregulates HIF-la expression mostly at a posttranslational

Role of Hypoxia/Inflammation in the Expression/Regulation of Proteins Regulating Iron Metabolism

level. HIF-l a is mainly expressed under hypoxic conditions , but there is also evidence for the accumulation of HIF-la under some normoxic conditions [19]. For example, in a case of upcoming inflammation it would make sense that the organism's cells prepare for a possible lack of oxygen in a later course of the disease. Indeed, Lukashev et al. provided insight into the immune response hypoxia-independent, normoxic upregulation of the HIF-l a subunit in antigen receptor-activated murine T lymphocytes [20]. These observat ions suggest that HIF-la is expressed as an immediate early gene, ensuring rapid adaptation of cells to changing demands in metabolism in activated or hypoxic conditions [20). This expression pattern of HIF1a points to a physiological role of HIF-l a in T-cell activation and is in agreement with the view that activated Tcells derive their ATP supply almost completely from glycolysis instead of oxidative phosphorylation in the resting state [21]. Recently, it has been shown that Toll-like receptors (TLRs) - the cell's sensors for microbial invaders - can signal via HIF-la [17,22), thus innate immunity is linked to iron regulation and might also be involved in the regulation of mitochondria.

Mitochondria Another important link between iron, oxygen, and inflammation might be the mitochondrion. Numerous mitochondrial proteins including the respiratory chain are dependent on iron-containing proteins . Mitochondria are particular sensitive to (e.g., ferrous ion-induced) oxidative stress and mitochondrial damage may be responsible for the high mortality in sepsis ( Fig. 1). Iron imbalance/accumulation - leading to iron-induced oxidative stress - has been implicated in oxidative injury associated with many degenerative diseases such as hereditary hemochromatosis, beta-thalassemia, and Friedreich's ataxia. High loads of iron cause extensive lipid peroxidation and membrane permeabilization in isolated mitochondria. Recently mitochondria were again in the spotlight as mitochondrial ferritin and mitochondrial iron transporters were discovered [23). ROS are generated as a toxic byproduct of mitochondrial respiration. Mitochondrial DNA (mtDNA) is directly susceptible to attack by ROS produced during oxidative phosphorylation, and mitochondrial DNA lacks histones and requisite repair enzymes that are protective of nuclear DNA. Moreover, expression of the entire mitochondrial genome is required to maintain the functional integrity of mitochondria. During systemic inflammation, mitochondrial dysfunction seems to be involved in the pathogenesis of multiple organ failure. As a consequence of the imbalance between ATP supply and demand cellular metabolism must decrease or the cell will die. In sepsis, NO overproduction, loss of antioxidants, mitochondrial dysfunction, and energy depletion has been associated with decreased survival [24]. Suliman et al. showed, that TLR4 activation by LPS not only triggered oxidative and nitrosative damage to liver mitochondria but coordinated mitochondrial transcription factor A (Tfam) induction and mitochondrial biogenic responses that stem from nuclear factor-kappa B (NF-KB) and perhaps Akt activation [25). TLR4 activation depletes mtDNA through the NF-KB-dependent synthesis of NO in concert with the elaboration of TNF-a but an intact TLR4 response is also required for apposite Tfam expression and maintenance of organ mitochondrial DNA content by replication and/or biogenesis. The implication is that the integration of mtDNA damage with Tfam expression through the iNOS response anticipates the need to protect mitochondria during infections by stimulating biogenesis before a critical degradation of mitochondrial function occurs [25].

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Further data on the interaction of TLRs and mitochondria are lacking at this point, however there is evidence that TLRs and mitochondrial dysfunction may playa critical role in ischemia/reperfusion injury [26, 27).

HIF-l a and Mitochondria The role of mitochondria in cellular oxygen sensing is the subject of a long-lasting debate. Experiments with cell lines lacking mitochondrial DNA (so-called pO cells) revealed deficient oxygen sensing (i.e., the stabilization of HIF-la) in some reports [28, 29), but not in others [3D, 31). In the 'mitochondrial oxygen-sensing' model, oxygen availability affects mitochondrial production of ROS which serve as second messengers, somehow signaling towards HIE Although the majority of studies published so far have reported an increase in ROS production, decreased ROS production has also been reported under hypoxic conditions [29). Neither a spatial nor a functional direct molecular link between ROS and HIF-la regulation has been established. Importantly, mitochondria- and ROS-dependent HIF-la induction can be seen only under hypoxic (1.5 % Oz) but not under anoxic (0 % Oz) conditions. Oxygen consumption of mitochondria is usually estimated by measuring the decrease in POz in a sealed vessel over a certain time using a Clark type electrode. Differences in subcellular oxygen distribution during the fall in POz and cell-to-cell variations are ignored by this method. Unfortunately, it is currently impossible to measure subcellular oxygen levels because the available electrodes are much too big and no fluorescent chemistry is yet available that would allow confocal video microscopy. The actual redirection of oxygen, hence, has never been demonstrated experimentally.

Clinical Potential At this point one can merely speculate about the potential impact of studies linking On iron-, and pathogen-sensing. From a clinical point of view it would be desirable to know exactly what patients die of when they acquire severe infections. Understanding the mechanisms of interaction between these three essential signal transduction pathways could lead to the development of new drugs regulating cellular function during inflammation. Chelation of iron has been shown to induce HIF-la via the inhibition of HIF-la proline hydroxylation by iron-containing prolyl-4-hydroxylases [32). Clement and coworkers found reduced blood vessel spreading from chick aorta and decreased vessel formation in Matrigel assays after treatment with ciclopirox in vitro. Of note, Clement et al. induced angiogenesis by supplementation of the cell culture media with exogenous VEGF. They concluded that, based on these in vitro assays, ciclopirox inhibits angiogenesis and could, therefore, be used as an antitumor drug targeting tumor angiogenesis [33).

Challenges/Perspectives/Summary Understanding diseases at a molecular level allows the search for new therapies and drugs . For example, in tumor therapy, important advances have been made with the

Role of Hypoxia/Inflammation in the Expression/Regulation of Proteins Regulating Iron Metabolism

advent of 'small-molecules' targeting receptors , which are involved in growth and metastasis (e.g., anti-epidermal growth factor [EGRF)-antibodies). In recent years, in spite of major progress in critical care and surgical techniques, the incidence of sepsis and the number of sepsis-related deaths has increased [34). Targeting the microbial invader early with powerful antibiotics, supporting failing organs, and hemodynamic optimization are obviously not enough, since the mortality in sepsis remains substantial. The next promising step - even if it seems remote at the moment - might be the introduction of novel, innovative drugs for the 'fine-tuning' of underlying molecular mechanisms. References 1. Andrews NC (2005) Molecular control of iron metabolism. Best Pract Res Clin Haematol 18:159-169 2. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG (2000) LEAP-I, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 480: 147-150 3. Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Bioi Chern 276:7806-7810 4. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090-2093 5. Fleming RE, Sly WS (2001) Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA 98:81608162 6. Donovan A, Brownlie A, Zhou Y, Shepard 1, Pratt SJ (2000) Positional cloning of zebrafish ferroportinl identifies a conserved vertebrate iron exporter. Nature 403:776-781 7. Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F (2005) The presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and downregulated by hepcidin. Blood 106:3979-3802 8. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol ToxicoI37:517-554 9. Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reut ilization. Proc Natl Acad Sci USA 94:10919-10924 10. Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B (2003) Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia . Blood 101:1996-2000 11. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia , hypoxia, and inflammation. J Clin Invest 110: 1037-1044 12. Leung PS, Srai SK, Mascarenhas M, Churchill LJ, Debnam ES (2005) Increased duodenal iron uptake and transfer in a rat model of chronic hypoxia is accompanied by reduced hepcidin expression . Gut 54:1391-1395 13. Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D (2005) Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106:1864-1866 14. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T (2003) Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101 : 2461-2463 15. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S (2004) lL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113:1271-1276 16. Lee P, Peng H, Gelbart T, Wang L, Beutler E (2005) Regulation of hepcidin transcription by interleukin-I and interleukin-6. Proc Natl Acad Sci USA 102:1906-1910 17. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al (2007) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117: 1926-1932 18. Semenza GL (1999) Regulation of mammalian 02 homoeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Bioi 15:551-578

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S. Brandt, J. Takala, and P.M. Lepper 19. lung YJ, Isaacs JS, Lee SM, Trepel J, Liu ZG, Neckers L (2003) Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappa B activation. Biochem J 370:1011- 1017 20. Lukashev D, Caldwell C, Ohta A, Chen P, Sitkovsky M (2001) Differential regulation of two alternatively spliced isoforms of hypoxia-inducible factor-I alpha in activated T lymphocytes. J BioI Chern 276:48754-48763 21. Brand KA, Hermfisse U (1997) Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J 11:388-395 22. Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007) Cutting edge: Essential role of hypoxia inducible factor-lalpha in development of lipopolysaccharide-induced sepsis. J ImmunoI178:7516-7519 23. Levi S, Corsi B, Bosisio M, et al (2001) A human mitochondrial ferritin encoded by an intronless gene. J BioI Chern 276:24437 - 24440 24. Brealey D, Brand M, Hargreaves I, et al (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219-223 25. Suliman HB, Welty-Wolf KE, Carraway MS, Schwartz DA, Hollingsworth JW, Piantadosi CA (2005) Toll-like receptor 4 mediates mitochondrial DNA damage and biogenic responses after heat-inactivated E. coli. FASEB J 16:1531-1533 26. Halestrap AP, Clarke SJ, Khaliulin I (2007) The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta 1767:1007 -1031 27. Shimamoto A, Chong AJ, Yada M, et al (2006) Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114:1270-1274 28. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Nat! Acad Sci USA 95:1171511720 29. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA (2000) Reactive oxygen species generated at mitochondrial complex III stabilize HIF-l during hypoxia: a mechanism of 02 sensing. J Bioi Chern 275:25130-25138 30. Srinivas V, Leshchinsky I, Sang N, King MP, Minchenko A, Caro J (2001) Oxygen sensing and HIF-l activation does not require an active mitochondrial respiratory chain electron-transfer pathway. J Bioi Chern 276:21995-21998 31. Vaux EC, Metzen E, Yeates KM, Ratcliffe PJ (2001) Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 98:296- 302 32. Epstein AC, Gleadle JM, McNeill LA, et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43 - 54 33. Clement PM, Hanauske-Abel HM, Wolff EC, Kleinman HK, Park MH (2002) The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Int J Cancer 100:491-498 34. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546-1554

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Hyperammonemia in the Adult Critical Care Setting K.

DAMS, W. MEERSSEMAN,

and A.

WILMER

Introduction Ammonia is produced from the breakdown of prote ins, aminoacids, purines, and pyrimidines. About half of the ammonia arising from the intestine is synthesized by bacteria, the remainder coming from dietary protein and glutamine. Ammonia is a highly toxic compound, particularly to the brain . When blood concentrations of ammonia are sufficiently elevated, respiratory alkalosis, cerebral edema, altered mental status, seizures, coma and death can ensue. The liver normally converts ammonia to urea in the Krebs-Henseleit cycle (urea cycle). Urea is a non-toxic compound excretable in the urine . Hyperammonemia is observed most often in patients with severe liver disease, although intensivists should be aware of other etiologies such as urea cycle disorders and valproate toxicity. It is crucial for clinicians to be aware of the clinical findings seen in hyperammonemia. Early recognition and appropriate treatment are critical to prevent devastating neurologic sequelae. This chapter outlines the causes, pathophysiology, diagnosis, symptoms, and management of hyperammonemia in adult patients.

Causes of Hyperammonemia Hyperammonemic encephalopathy can occur in various clinical settings, of which liver disease is, by far, the most studied [1- 2). In general, three mechanisms can be responsible for the accumulation of ammonia: A massive load of nitrogen can be presented to a normal functioning liver via the portal circulation (e.g., parenteral nutrition in a patient with a urea cycle defect); ammonia can bypass the liver (e.g., shunt in congenital vascular malformations of the liver, portal hypertension in cirrhotic patients); ammonia metabolism in the liver can be impaired (e.g., liver cirrhosis). In liver disease, hyperammonemic encephalopathy can occur in fulminant acute hepatic failure or can be part of chronic liver disease with underlying cirrhosis . In this latter form, various precipitating factors (e.g., hemorrhage, infections, constipation , electrolyte abnormalities, high-protein diet) playa role in the overload of nitrogen waste and triggering of hyperammonemic episodes. Non-hepatic causes of ammonia accumulation are much rarer and often pose a diagnostic challenge for clinicians [3]. Non-hepatic causes include congenital defects in metabolism (e.g., inborn errors in the urea cycle or disorders in fatty acid oxidation , occasionally presenting only in adulthood), drug-associated hyperammonemia

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K. Dams, W. Meersseman, and A. Wilmer Table 1. Classification of hyperammonemic encephalopathy Type A

Encephalopathy associated with acute liver failure

Type B

Encephalopathy associated with portal-systemic bypass and all other causes of encephalopathy without parenchymal liver disease: 1. portosystemic shunts' (e.g., Rendu-Osler-Weber disease, trauma, patent venous duct, iatrogenic complication of surgery) 2. urea cycle defects 3. other ra re metabolic diseases (organic acidurias, primary carnitine deficiency, fatty acid oxidation defects, distal renal tubular acidosis) 4. drug-induced hyperam monemia (valproate, asparaginase, 5-fluorouracil) 5. urease-producing bacteria present in an anatomically abnormal urinary system 6. iatrogenic overload of proteins (parenteral nutrition)

Type C

Encephalopathy associated with chronic liver disease (cirrhosis, portal hypertension)

* needs to be distinct from the more frequently encountered shunts in the context ofchronic liver disease (e.g., valproate, 5-fluorouracil, cyclophosphamide , and salicylates), porto-systemic shunts (e.g., vascular malformations in Weber-Rendu-Osler disease), and urinary tract infection with urease-producing bacteria (e.g., Proteus mirabilis). This latter condition is the consequence of a massive load of ammonia produced by urease-producing bacteria in an anatomically abnormal bladder. Table1 summarizes the hepatic and non -hepatic causes of hyperammonemia.

Pathophysiology of Hyperammonemia We will restrict our description of the pathophysiology of hyperammonemia to four conditions which are relevant to an adult critical care setting: Patients with liver disease, patients with subtle urea cycle disorders, patients on valproate therapy, and patients with a urinary tract infection. The small intestine is an important generator of ammonia via glutamine uptake. Colonic bacteria are also important ammon ia producers by splitting urea and amino acids. Hyperammonemia results from the release of a large amount of waste nitrogen that is insufficiently metabolized by the liver. The kidney and, to a lesser extent, the muscles can also help to metabolize excess ammonia. Ammonia is a toxic compound that mainly damages the brain . The effects of an acute increase in plasma ammonia should be distinguished from chronic moderate increases. In the classical model of hepatic encephalopathy (secondary to liver cirrhosis) , ammonia plays a pivotal role in the genesis of neurological symptoms. Factors in favor of the importance of ammonia include improvement of hepatic encephalopathy by lowering ammonia concentrations with antibiotics and lactulose; precipitation of encephalopathy in patients with cirrhosis by administration of a large amount of protein, and the existence of a similar syndrome of hyperammonemic encephalopathy, caused by urea cycle disorders in which liver disturbances are very mild. In patients with hyperammonemia, glutamine in the brain is synthesized from ammonia and glutamate and acts as a major detoxification pathway [4-5]. This process takes place in the astrocytes. Due to the osmotic effect of glutamine, these cells start to swell and give rise to cerebral edema, which causes the symptoms of hepatic encephalopathy. The paucity of symptoms, sometimes encountered in patients with

Hyperammonemia in the Adult Critical Care Setting

chronic liver disease is the consequence of osmotic adaptations that take place in the brain (e.g., decreased water in astrocytes due to an increase of myoinositol in the blood). The occurrence of hepatic encephalopathy despite normal ammonia concentrations in some patients proves that ammonia is not the sole factor in the development of encephalopathy. Inflammation and sepsis, which frequently occur in hepatic encephalopathy, may playa role in the severity of symptoms. Experimentally, at least 85 % of liver function must be impaired before ammonia starts to accumulate . Ammonia is mainly generate d via the metabolism of amino acids and is converted to urea in the liver (Krebs-Henseleit urea cycle) [6]. An alternative pathway to rid the body of ammonia was discovered by Brusilow and colleagues in 1979 [7]. Drugs, such as phenylacetate and benzoate, are important substrates of this alternative pathway (see treatment section). The generated urea is subsequently eliminated in the urine as nitrogenous waste. The six enzymes involved in the urea cycle are present only in normal liver cells. Ammonia is incorporated into an amino acid at each enzymatic step removing one ammonium ion at each step until urea is formed ( Fig. 1). Hyperammonemia is most severe when the enzyme defect occurs in the early steps of the urea cycle (e.g., ornithine transcarbamylase deficiency). The bulk of the literature concerning urea cycle defects involves patients with critically high blood levels of ammonia in the newborn period. However, there is a growing list of case reports from patients with urea cycle defects who manifested only in adulthood [8]. There are some clues suggestive of a possible urea cycle defect when confronted with an adult patient with appar-

Mitochondrion

NHJ+ HCOJ+2ATP E~==~_-+. Carbamyl phosphate

Cytoplas m

~

~ ornithine

Urea

orn ithi n )

Ornit hine t ranscarbamylase [ Arginase )

Citrulli ne \ Cit rulline

Arginine

r.-:-:--..,----,

Aspartate Argininosuccinate

Fig. 1. The urea cycle and its principal enzymes. Six enzymes are involved in the conversion of ammonia (NH 3) to urea: N-acetylglutamate synthetase, carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase. From [20] with permission

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ently unexplained hyperammonemic encephalopathy. First, a history of a prolonged clinical course with a seemingly routine illness (e.g., influenza) should prompt suspicion. Any disease that gives rise to a temporarily catabolic state and increased protein breakdown from muscle is sufficient to cause encephalopathy in a patient with a urea cycle defect. Second, since most of these disorders are inherited in an autosomal recessive manner, a family history (e.g., early infant mortality) should rout inely be taken. Finally, a dietary history of elective decreased protein intake «(auto-selective vegetarianism") is also suggestive. Valproic acid is a commonly used drug in neurology and psychiatry, effective in the treatment of seizure disorders, among other conditions. Valproic acid is a broadspectrum anti epileptic drug that is usually well tolerated, but serious complications may occur such as hyperammonemic encephalopathy. Valproic acid-induced hyperammonemic encephalopathy is a rare phenomenon in adults, especially with monotherapy, but it is a serious disease that can lead to death . In chronic valproic acid dosing, hyperammonemia occurs in nearly 50 % of patients, but this remains asymptomatic in almost 50 % [9 -10]. Valproic acid is extensively metabolized by the liver, mainly via glucuronic acid conjugation and mitochondrial B-oxidation (same pathway used by long-chain fatty acids). Carnitine appears essential to ensure proper metabolism via this latter pathway. Long-term valproic acid therapy leads to carnitine deficiency. It is well known that carnitine depletion impairs the urea cycle, which might explain the ammonia accumulation. Also, metabolites of valproic acid inhibit the mitochondrondial carbamoyl phosphate synthetase, which is the first enzyme necessary for ammonia elimination via the urea cycle. Ornithine transcarbamylase (the second enzyme in the urea cycle) deficiency is an X-linked disorder and is the most commonly inherited cause of hyperammonemia. Heterozygote females are frequently asymptomatic, but are prone to encephalopathy when they start treatment with valproic acid. There are currently no specific recommendations for screening people for asymptomatic hyperammonemia, nor are there any known consequences [10]. There does not seem to be any relationship between the development of valproic acid-induced hyperammonemic encephalopathy and serum valproic acid levels. Urea-splitting urinary tract infections that cause severe neurologic symptoms as a result of hyperammonemia are rare in the adult population. Because urea is present in the urine, urinary tract infections with urea-splitting bacteria such as P. mirabilis or Pseudomonas aeruginosa can cause urine ammonia concentrations to rise. A prerequisite for ammonia to enter the blood is an extended bladder, resulting in a large surface area for ammonia diffusion. Since ammonia is a weak base, diffusion is facilitated in urine with an alkaline pH. Urologists should include hyperammonemia in their differential diagnosis when examining a patient with bladder or pouch retention combined with unexplained neurological or neuropsychiatric symptoms [11 -12] .

Symptoms of Hyperammonemia A progressive increase in blood ammonia concentration, irrespective of cause, will result in onset of cerebral edema, coma and eventual death. Early symptoms are lethargy, vomiting and slurred speech. Clinical manifestations of the most frequent form of hyperammonemic encephalopathy, hepatic encephalopathy, may vary widely and are related to the mental status, from nearly normal to deep coma, neuromuscu-

Hyperammonemia in the Adult Critical Care Setting Table 2. West Haven criteria for semi-quantitative grading of mental state. From [14) with permission Grade 1

• • • •

Trivial lack of awareness Euphoria or anxiety Shortened attention span Impaired performance of addition

Grade 2

• • • • •

Lethargy or apathy Minimal disorientation for time or place Subtle personality change Inappropriate behavior Impaired performance of substraction

Grade 3

• Somnolence to semi-stupor, but responsive to verbal stimuli • Confusion • Gross disorientation

Grade 4

• Coma (unresponsive to verbal or noxious stimuli)

lar changes, flapping tremor, and modifications in mood and behavior. The extrapyramidal signs present in some patients with hepatic encephalopathy may be due to the accumulation of manganese in the brain [13). Due to differences in the brain uptake of ammonia, the correlation between the degree of hepatic encephalopathy and ammonia concentrations in the blood is poor. The consensus conference on the nomenclature of hepatic encephalopathy suggested that the classical West Haven classification be maintained as four degrees, especially useful in acute hepatic encephalopathy ( Table :1,) (14). The Glasgow Coma Scale is useful for patients in stages III and IV. Cirrhosis is the most frequent liver disease causing hepatic encephalopathy. Hepatic encephalopathy appears, on most occasions, due to a superimposed precipitating factor (gastrointestinal bleeding, infections/systemic inflammatory response syndrome [SIRS) , renal and electrolyte disturbances, psychotropic drugs, constipation, increase in protein intake, etc) (2). An adult suspected of having a urea cycle disorder should be studied immediately and thoroughly for this possibility, because without early diagnosis and aggressive intervention, these patients have a poor prognosis. In essence, symptoms are the same as in hepatic encephalopathy. The main challenge is recognition of the disease for which an immediate determination of an ammonia level is warranted. Clinicians should consider partial inborn errors of metabolism in those patients in the critical care setting whose degree of coma does not fit the apparent clinical causes. A hyperammonemic patient who denies alcohol abuse and who does not take valproate, warrants vigilance. Typical triggers that might lead to an otherwise unexpected diagnosis include catabolic stress with protein breakdown, such as in infections (e.g., during childhood), during surgery, fasting, or growth spurts. Increased protein exposure can also originate from parenteral nutrition, high doses of steroids, trauma with blood loss, and during the postpartum period (8). Urease producing urinary tract infections need to be considered in comatose patients with a histor y of an abnormally functioning bladder. Other clinical scenarios in which an ammonia level is warranted, are comatose patients on chronic valproate therapy and patients receiving chemotherapy.

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Diagnosis of Hyperammonemia A blood sample to measure the ammonia concentration should be taken, according to standardized methods, whenever hyperammonemia is suspected. Ideally, patients should have fasted for at least 6 hours and their arm should be as relaxed as possible, because muscle exertion may increase venous ammonia levels. Heparin is the preferred anticoagulant for collecting samples since it reduces red blood cell ammonia production. EDTA can also be used. Blood is drawn in a chilled tube that is immediately placed on ice and plasma is separated within 15 minutes because the ammonia concentration in standing blood and plasma increases spontaneously; this increase is attributed to the generation and release of ammonia from red blood cells and the deamination of amino acids, particularly glutamine [15-16] . Plasma ammonia levels of whole blood maintained at 4 °C stay stable for < 1 hour. Averagevalues for arterial blood and plasma are 18 and 23 umol/l, respectively, and for venous blood and plasma 28 and 32 umol/l, respectively. Arterial ammonia measurement is a more valid diagnostic procedure than venous measurement. Arterial ammonia is composed of the ammonia coming from the liver through the hepatic vein, which shunted around the liver through porto-systemic collaterals, and the ammonia that flows back to the right heart having escaped liver ammonia uptake. It provides a more accurate assessment of the amount of ammonia at the blood brain barrier [15, 16]. In addition to a raised ammonia level, the presence of respiratory alkalosis is an early biochemical abnormality in every patient with hyperammonemic encephalopathy. Once confirmed, additional laboratory tests are useful to determine the specific cause and a search for precipitating events should be undertaken simultaneously. Brain imaging is important to exclude other acute cerebral pathologies. Electroencephalography (EEG) shows continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. The diagnostic elaboration of a specific urea cycle defect is beyond the scope of this review. Clinical recognition, followed by an urgent determination of an ammonia level, is of vital importance in order to start treatment urgently. An increased glutamine concentration in plasma (normal < 700 umol/l) is the most sensitive indicator of insufficient urea synthesis. Routine urinalysis is important to rule out other metabolic diseases. Liver function tests, including partial thrombin time, partial tissue thromboplastin time, transaminases, bilirubin, and albumin are important to address the possibility of liver bypass or liver insufficiency as the cause of hyperammonemia. Routine testing is followed by specialized diagnostic testing . This includes plasma quantitative amino acid analysis, which will often be diagnostic [17]. Specific advice needs to be sought with a physician who has expertise in inborn errors of metabolism.

Treatment of Hyperammonemia Neurological abnormalities and impaired cognitive function correlate significantly with the duration of hyperammonemia and encephalopathy. Treatment, therefore , should be initiated as soon as hyperammonemia is suspected and should proceed concurrently with diagnostic evaluation. Respiratory status should be closely monitored as the clinical condition can deteriorate rapidly. When respiratory compromise presents , assisted ventilation should

Hyperammonemia in the Adult Critical Care Setting

be started because the increased work of breathing results in higher caloric demands, leading to increased catabolism and nitrogen accumulation. Hepatic Encephalopathy

The intestinal production of ammonia can be reduced by restricting the intake of dietary protein and inhibiting urease-producing colonic bacteria. However, patients with cirrhosis often require minimal daily protein intakes of 0.8 to 1.0 g/kg to maintain nitrogen balance. Long-term restriction to values below this range should be avoided if possible. However, in the acute setting, we would be reluctant to start parenteral nutrition with a high protein content . Oral administration of non-absorbable disaccharides (lactulose, lactitol, lactose in lactose-intolerant individuals) or admin istration by enema is considered the cornerstone of treatment for hepatic encephalopathy [18- 20]. As well as having an osmotic cathartic action, these agents lower the colonic pH as a result of the production of organic acid by bacterial fermentation . This decrease in pH changes the gut flora by creating an environment that is hostile to the survival of urease-producing intestinal bacteria and may promote the growth of non-urease-producing lactobacilli. However, a Cochrane review has questioned the benefit of non -absorbable dissacharides. This review identified no significant effect of non-absorbable dissacharides on the risk of no improvement of hepatic encephalopathy and non-absorbable disaccharides appeared to be inferior to antibiotics in reducing the risk of no improvement [21]. There is, in fact, insufficient high-quality evidence to support or refute this treatment [21]. As colonic bacteria are the primary source of ammonia, treatment initially consisted of poorly absorbed antibiotics, especially neomycin. Different antibiotics, such as neomycin and paromomycin, have been tested, both in open and controlled studies. The potential adverse effects preclude their first-line use for hepatic encephalopathy. Although neomycin and paromomycin are generally poorly absorbed, they may reach the systemic circulation in amounts sufficient to cause serious adverse effects, including nerve deafness, renal toxicity, malabsorption, and serious derangement of the intestinal flora. The limited data available suggest that in the majority of patients who have an inadequate response to lactulose alone, combined therapy with antibiotics and lactulose may have a superior effect accompanied by an enhanced clinical response . However, an increase in stool pH after the addition of an antibiotic suggests that disaccharide-metabolizing intestinal bacteria have been eradicated, and combination therapy should then be discontinued [18- 20]. Ornithine and aspartate are important substrates in the metabolic conversion of ammonia to urea and glutamine, respectively. Ornithine-aspartate thus provides substrate for both of these ammonia-detoxification pathways. The clinical efficacy of both oral and parenteral L-ornithine-L-aspartate (LOLA) has been confirmed in randomized, placebo-controlled, double-blind studies in patients with manifest hepatic encephalopathy and hyperammonemia [22]. LOLA decreased protein breakdown and stimulated protein synthesis in muscle. Side effects are limited to nausea and vomiting, increasing with higher intravenously administered dosages; therefore, the maximal infusion dosage should be fixed in the range of 5 g LOLA/h. The therapy is well tolerated after oral and parenteral administration. However, available studies have not compared LOLA to other interventions and theoretically the glutamine produced by the muscle may be rapidly recycled to glutamate, thereby recycling ammonia in the kidney and gut.

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Zinc deficiency is common in cirrhosis, particularly of alcoholic origin, and has been involved in altered nitrogen metabolism, since zinc is a cofactor for two of the six enzymes of the urea cycle. Several factors, such as poor dietary intake, impaired intestinal absorption, and excessive urinary losses may be responsible for reduced whole-body zinc content. Long-term oral zinc supplementation (600 mg daily) speeds up the kinetics of urea formation from amino acids and ammonia. No studies have been performed in critical care [23]. Artificial liver support aims to substitute liver function. These devices use extracorporeal blood purification to dialyze albumin-bound hydrophobic substances (e.g., ammonia, bilirubin, bile acids, aromatic amino acid metabolites, and mediumchain fatty acids). Currently, the clinical benefit of such devices is unclear, although they clearly can improve encephalopathy and may offer a bridge to transplantation [24]. Orthotopic liver transplantation is the most radical therapy for improving hepatic encephalopathy. The presence of hepatic encephalopathy in a cirrhotic patient, regardless of the degree of hepatic encephalopathy and the factors causing the episode, carries a very bad prognosis. Hepatic encephalopathy should be an indication for evaluation and eventual listing for liver transplantation in every cirrhotic patient. Urea Cycle Disorders Prompt recognition of a urea-cycle disorder is important. Treatment should aim to reduce the production of nitrogenous waste by the use of a low-protein diet and prevent endogenous catabolism through the provision of adequate calories (300 gram glucose intravenously per day). Adequate amounts of fluid need to be administered to stimulate ammonia excretion. Extracorporeal detoxification (hemodialysis) should be initiated with ammonia concentrations> 500 umol/l , Urea cycle intermediates can be replenished by administration of arginine (l00-500 mg/kg/day) and citrulline (100-170 mg/kg/day). Mitochondrial function needs to be supported with supplementation of carnitine. Emergency pharmacologic management with ammonia scavengers should be initiated as soon as possible. Drug therapy consists of a loading dose followed by a maintenance infusion of sodium phenylacetate and sodium benzoate (for drug regimens see [25]). In these special circumstances, advice from metabolic experts is required. Valproic Acid-induced Hyperammonemic Encephalopathy The primary treatment for valproic acid -induced hyperammonemic encephalopathy is the withdrawal of valproic acid. Complete recovery generally occurs over a period of one to a few days. Prolonged recovery times have been reported [10]. L-carnitine supplementation has been shown to improve the symptoms of valproic acid related toxicities. Carnitine plays an essential role in the metabolism of valproic acid by facilitating transport into mitochondria and maintaining the ratio of acyl-CoA to free CoA in the mitochondria. Patients might benefit from an oral supplement of Lcarnitine with 100 mg/kg/day at first, followed by 25 mg/kg/8 h. The optimal dose and whether administration should be oral or intravenous is not clear, because no published studies have demonstrated statistically significant changes in ammonium kinetics in patients treated with L-carnitine compared to controls [26].

Hyperammonemia in the Adult Critical Care Setting

Urea-splitting Urinary Tract Infection

In this rare condition, again, early recognition with determination of the ammonia level in every patient with bladder retention and unexplained neuropsychiatric symptoms, is of vital importance. Treatment with antibiotics and drainage of the distended bladder are mandatory [11].

Conclusion Hyperammonemia is frequently encountered in the ICU. In addition to patients with hepatic encephalopathy, adult patients who have urea cycle defects are being found with increasing frequency. Valproic acid therapy as a possible cause of hyperammonemic encephalopathy should also be recognized. Ammonia is a toxic compound, particularly to the brain; urgent recognition of hyperammonemia is of vital importance. The ammonia level should be determined in any patient who is lethargic, obtunded or comatose, and in whom the cause of the central nervous system depression is unknown. Early detection of at risk patients with early intensive therapy can avoid neurologic sequelae and death. References 1. Ialan R, Hayes PC (1997) Hepatic encephalopathy and ascites. Lancet 350:1309-1315 2. Showcross D, Ialan R (2005) Dispelling myths in the treatment of hepat ic encephalopathy. Lancet 365:431- 433 3. Hawkes N, Thomas G, Jurewicz A, et al (2001) Non-hepatic hyper ammonemia: an important, potentially reversible cause of encephalopathy. Postgrad Med J 77:717-722 4. Brusilow SW (2002) Hyperammonemic encephalopathy. Medicine 81:240-249 5. Brachmann C, Braissant 0 , Villard AM, Boulat 0, Henry H (2004) Ammonia toxicity to the brain and creatine. Mol Gen Metab 81:S52-S57 6. Wraith YE (1989) Diagnosis and management of inborn errors of metabolism . Arch Dis Child 64:1410-1415 7. Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn errors of urea synthes is. Lancet 1979 2:452- 454 8. Summar ML, Barr F, Dawling S, Smith W, et al (2005) Unmasked adult-onset urea cycle disorder s in the critical care sett ing. Crit Care Clin 21:S1 -S8 9. Wadzink i j, Franks R, Roane D, Bayard M (2007) Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med 20:499-502 10. Segura-Bruna N, Rodriguez -Campello A, Puente V, Roquer J (2006) Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scan 114:1- 7 11. Albersen M, joniau S, Van Poppel H, Cuyle Pl, Knockaert DC, Meersseman W (2007) Ureasplitting urinar y trac t infection contr ibut ing to hyperammonemic encephalopathy. Nat Clin Pract Urol 4:455-458 12. De Ionghe B, janier V, Abderrahim N, Hillion D, Lacherade jC, Outin H (2002) Urinary tract infection and coma. Lancet 360:996 13. Mas A (2006) Hepatic encephalopathy: from pathophys iology to treatment. Digestion 73 (suppl 1):86-93 14. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT and the Members of the Working Party (2002) Hepatic encephalopathy - Definition, nomenclature, diagnosis , and quantification: Final report of the working party at the 11th world congresses of gastroenterology, Vienna, 1998. Hepatology 35:716-721 15. Barsotti Rj (2001) Measurement of ammonia in blood . J Pediatr 138:S1I-520 16. da Fonseca-Wollheim F (1990) Preanalyt ical increase of ammonia in blood specimens from healthy subjects. Clin Chern 36:1483- 1487

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K. Dams, W. Meersseman, and A. Wilmer 17. Steiner RD, Cederbauw SD (2001) Laboratory evaluation of urea cycle disorders. J Pediatr 138:S21-S29 18. Mas A (2006) Hepatic encephalopathy : from pathophysiology to treatment. Digestion 73 (suppl1):86-93 19. Wright G, [alan R (2007) Management of hepatic encephalopathy in pat ients with cirrhosis. Best Pract Res Clin Gastroenterol 21:95- 110 20. Riordan SM, Williams R (1997) Treatment of hepatic encephalopathy. N Engl J Med 337: 473-479 21. Als-Nielsen B, Gluud LL, Gluud C (2004) Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev CD 003044 22. Kircheis G, Wettstein M, Dahl S, Haussinger D (2002) Clinical efficacy of L-Ornithine-LAspartate in the management of hepatic encephalop athy. Metab Brain Dis 17:453-462 23. Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M (1996) Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology 23:1084-1092 24. Laleman W, Wilmer A, Evenepoel P, Verslype C, Fevery J, Nevens F (2006) Review article: non-biological liver support in liver failure. Aliment Pharmacol Ther 23:351-363 25. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A (2007) Survival after treatment with phenylacetate and benzoate for urea-cycle disorders . N Engl J Med 356: 2282-2292 26. Lheureux PER, Penaloz A, Zahir S, Gris M (2005) Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care 9:431-440

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and L. TELCI

Introduction Magnesium is the fourth most abundant cation in the body and the second most abundant intracellular cation . It activates many of the enzyme systems mainly involved in energy metabolism and acts as a natural calcium antagonist by regulating calcium access into the cell. Although magnesium was considered as the
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Magnesium Physiology and Clinical Aspects A brief overview of magnesium's physiologic interactions is necessary since these may underlie the physiology and pharmacology of magnesium's therapeutic role either as supplementation in a deficiency state or as a medical therapy. Magnesium is a cofactor in hundreds of enzymatic reactions and it is important for those enzymes that use nucleotides as cofactors [12]. For enzymes like ATPase which is of central importance in energy metabolism, it is not the free nucleotide, but a magnesium complex that is the actual cofactor in its activation. Magnesium is also required for protein and nucleic acid synthesis, the cell cycle, cytoskeletal and mitochondrial integrity, and for the binding of substances to the plasma membranes [12]. Magnesium is, therefore, required not only for substrate formation as an activator of enzyme activity but also for membrane stability. Magnesium modulates ion transport by pumps, carriers, and channels [13]. It intervenes in the action of calcium and sodium-potassium ATPase (Na+/K+ATPase) activation. Serving as a cofactor in this enzyme system, it influences sodium and potassium flux across the cell membrane. Magnesium blocks outward movement of potassium through potassium channels in cardiac cells. Decreases in magnesium cause outward movement of potassium, inducing depolarization and, thereby, causing cardiac arrhythmias. Moreover, disorders of magnesium, by altering sodium/potassium gradients and transmembrane potentials, may result in neuromuscular excitability or irritability. Magnesium acts as a calcium antagonist at intracellular sites and in membrane channels. The interaction of magnesium with calcium channels creates a competitive antagonist action against calcium inflow. By inhibiting calcium activation at the sarcoplasmic channel, magnesium also limits the outflow of calcium from the sarcoplasmic reticulum , which is the main site of intracellular calcium storage [14]. With this mechanism, magnesium regulates intracellular calcium levels and, thereby, influences smooth muscle tone. By regulating smooth muscle tone, magnesium deficiency has been proposed to cause hypertension, neuromuscular hyperexcitability, bronchial airway constriction, coronary spasms, and seizures [4]

Metabolism of Magnesium The distribution of magnesium is regulated by metabolic and hormonal effects on gastrointestinal absorption and renal excretion [12]. Total body stores of magnesium average 2000 mEq and the normal serum range is considered as 1.4 to 2.1 mEq/1 [14]. Magnesium is distributed in the body in the following percentages: 53 % in bone, 27 % in muscle, 19 % in soft tissue, 0.5 % in erythrocytes, and 0.3 % in serum. Extracellular magnesium in serum is 33 % protein bound, 12 % complexed to anions, and 55 % in a free ionized form [14]. Unlike other cations, magnesium is absorbed equally well in the ileum and the jejunum by passive absorption. This absorption varies according to the amount of magnesium in the diet. The kidney serves as the other major site regulating magnesium balance. Studies have demonstrated that only 5 % of filtered magnesium is excreted where 70 % is reabsorbed in the loop of Henle [4]. The maximum renal tubular reabsorption for magnesium is at the normal plasma magnesium level, thus elevated concentrations will decrease reabsorption and increase excretion. It has been demonstrated that a magnesiumrestricted diet will result in significantly increased reabsorption without any changes

Magnesium in the ICU: Sine qua non

in serum concentrations [14]. During renal failure, the excretion of magnesium progressively increases to maintain normal serum magnesium levels until later stages when hypomagnesemia supervenes . These compensatory mechanisms to maintain magnesium homeostasis are not fully understood. Early studies proposed a specific hormonal control of magnesium homeostasis; however, knowledge about the endocrine factors that control circulating or urinary magnesium is incomplete. Neither vitamin D nor parathyroid hormone (PTH) has been shown to directly affect magnesium status [15]. A number offactors cause shifts in the usual intracellular: extracellular ratio of magnesium. Both acidosis and ischemia promote release of magnesium from intracellular binding sites and lead to an efflux of magnesium from the cell. A number of commonly encountered situations in critical care, such as refeeding syndromes, insulin use, admin istration of intravenous solutions containing glucose, and amino acid infusions may lead to an acute shift of magnesium into the cells [16].

Assessment of Magnesium Status As stated previously, the adult body contains 21- 28 g (about 1 mole) of magnesium, of which more than half is stored in bone and the rest in muscle and soft tissue [4]. About 1 % of the magnesium is present in the blood plasma and red cells. Serum magnesium concentration, which we measure to assess magnesium status, only represents 0.3 % of total body magnesium content [14]. Standard measurement of serum total magnesium concentrations, which range between 1.7- 2.3 mg/dl (1.4-2.1 mEq/l), includes ionized, protein bound, and complexed forms [12]. It is, therefore, obvious that measuring total serum magnesium does not provide much information about the body stores of magnesium or about the biologically active ionized form. An alternative to total serum magnesium, is the assessment of the ionized serum magnesium concentration as an active form. Recent technological advances in ion selective electrodes for magnesium have enabled rapid determination of ionized magnesium on an analyzer [17]. Discordance between total seru m and ionized magnesium has been reported in some but not all studies. In some clinical studies [18] a strong correlation was found between serum ionized and total magnesium, which led the investigators to suggest that ionized magnesium can be inferred from total magnesium. Similarly, a significant correlation between serum ionized and total magnesium was found in patients undergoing abdominal surgery [19]. In contrast, Huijgen et al. reported a low total serum magnesium in 51 % of critically ill patients, but 71 % of these had normal ionized magnesium levels [20]. A weak correlation of ionized and total magnesium has been demon strated not only in critically ill patients but also in patients in whom magnesium statu s is being investigated. These studies have conflicting results in terms of deciding whether measurement of serum ionized magnesium has a greater impact than total serum magnesium in patients for whom magnesium status is required . In situations of suspected hypomagnesemia, ionized magnesium is preferred above the routinely measured serum total magnesium. However, it has been suggested that problems with the ion selectivity and interference with calcium ions may reduce the relevance of the ionized magnesium assay [15]. As ionized magnesium determinations have not yet proven to be superior to the routinely used available measurement of total serum magnesium, further assessments are needed in critically ill populations .

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Erythrocyte, mononuclear cell, and muscle magnesium levels have been used to more accurately assess magnesium status; however, no advantage over measurement of serum levels has been demonstrated. In normal subjects, there is no correlation among magnesium levels in mononuclear cells compared with serum and erythrocytes [21]. Techniques have also recently been introduced to measure intracellular free magnesium using magnetic resonance imaging and magnesium sensitive dyes [12]; however, these methods are largely used as research tools and have little clinical application. A parenteral loading test with subsequent evaluation of the percentage retained has been used for many years as a reliable assessment of total body magnesium status in patients at risk of hypomagnesemia [1]. Retention of more than 50 % of the administered dose indicates magnesium deficiency. As renal dysfunction is common in critically ill patients, the magnesium loading test is infrequently performed in the ICU. Hebert et al. tested the feasibility of using a magnesium loading test in critically ill patients and validated serum assays. Using this test as a reference method, both serum total and ionized magnesium levels were found to be insensitive markers of magnesium deficiency in ICU patients without renal dysfunction [22]. However, to assess magnesium deficiency with a loading test may not be practical and reliable in critically ill patients as the necessary steady state conditions are infrequent. Most of the studies in the literature that evaluated hypomagnesemia in critically ill patients measured total serum concentration. Ionized magnesium levels were assessed in two studies [3, 20]. Soliman et al. [3] found a good correlation between ionized and serum magnesium levels for the total patient population; however, nearly half of the patients with ionized hypomagnesium had a normal total serum magnesium. These authors, therefore, suggested that total serum is a weak predictor of ionized hypomagnesemia. In the second study by Huijgen et al. [20], no association was found between extracellular and intracellular magnesium measurements. The laboratory tools available for the assessment of actual magnesium status in critical illness are, therefore, inadequate. The utility of serum ionized magnesium to reflect body magnesium status has not been clarified. If measurement of ionized magnesium concentration is to change the clinical approach to intensive care patients, more data are required to correlate levels with clinical situations.

Magnesium in Analgesia and Sedation The analgesic effect of magnesium has been demonstrated in several animal and human studies. The effect of magnesium on perioperative analgesic requirements was first evaluated by Koinig and colleagues in patients with identical levels of surgi cal stimulation [6]. The data gathered by these investigators demonstrated that magnesium can be an adjuvant to peroperative analgesic management by lowering fentanyl requirements. In another study, magnesium sulfate, given as a bolus after induction, produced a significant reduction in remifentanil consumption during general anesthesia [23]. Our group also demonstrated a significant reduction in remifentanil consumption during intravenous anesthesia with continuous infusion of magnesium in patients undergoing elective spinal surgery [24]. Recently, different dose regimens of magnesium were studied to compare the effects of magnesium on intraoperative propofol requirements, postoperative pain, and morphine consumption in gynecologic patients [25]. Both a single bolus and a bolus plus infusion regimen reduced

Magnesium in the leu: Sine qua non

intraoperative propofol requirements and had a nearly 40 % morphine-sparing effect during the postoperative phase. Contrary to these findings, there are data showing no change with addition of magnesium for analgesia [26). Different surgical stimulation, heterogeneous patient populations, and the use of varying doses and timing may account for this discrepancy. However, most important is that the doseresponse relationship of magnesium with respect to its potentiating effect is not easy to determine, since available measurements in clinical practice do not represent the actual magnesium state of the patients. This determination may be even more complicated in the critical care patient. In a study conduc ted in ICU patients, investigators assessed whether the addition of a magnesium sulfate infusion could decrease the sufentanil infusion required to maintain sedation [27). Magnesium was infused at 2 g/h to reach a magne sium level two times the upper limit in the studied, mechanically ventilated patients. Decreased consumption of sufentanil was reported at all times. In our recent study of a post -thoracotomy ICU patient population, the effect of addition of magnesium was assessed on morphine consumption adminis tered via patient control analgesia [28). Cumulative mean morphine consumption and valid analgesic demand were found to be lower in those patients receiving magnesium as an adjunct to pain the rapy. Magnesium's beneficial effect in reducing anesthetic and analgesic requirements during the perioperative period have been extensively studied; however, there is a lack of data on how addition of magnesium affects ICU sedation . Given the fact that magnesium is readily available, inexpensive and safe, even a small absolute benefit would lead to enormous cost savings in the ICU.

Neuroprotective Effects of Magnesium Magnesium has been used in a var iety of animal models of brain injury to limit secondary neuronal injury and to improve neurological outcome. Recent evidence suggests that magnesium plays a critical role in the injury process after traumatic brain injury, not only having direct effects on cellular metabolism but also regulat ing other proposed secondary injury factors [29). Brain edema formation is one of the pathophysiologic events occurring later as a secondary injury mechanism. Magnesium has been reported to decrea se edema formation measured by regional brain tissue water content after fluid percussion injury in rats [30). Attenuation of brain edema with magnesium measured by brain tissue specific gravity has also been shown to correlate with a better neurological outcome in a head trauma model in rats [31). Comparable results were evident in our previous experimental study of a closed injur y model in rats [32). Magnesium administration right after the trauma caused a significant reduction in brain edema formation and main tained blood brain barrier integrity. Possible beneficial effects of magne sium after diffuse traumatic brain injury have been attributed to its role in cellular metabolism and function . Magnesium is essential for normal cell functions, such as membrane integrity, cellular respiration, maintenance of normal sodium-potassium grad ient, and regulation of calcium transport and accumulation [29). Another important effect is through the unique relationship between magnesium and the N-methyl-d-aspartate (NMDA) receptor. It is suggested that magnesium, acting as an endogenous noncompetitive antagonist at the NMDA receptor, protects neurons from the deleterious effect of excitatory amino acids and thus reduces cytotoxic brain edema [33).

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Vasospasm remains a significant source of neurological morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH), despite advances in current medical, surgical, and endovascular therapies. Magnesium sulfate therapy has been demonstrated to be both safe and effective in preventing neurological complications in obstetric patients with eclampsia [34]. Evidence obtained using experimental models of brain injury, cerebral ischemia, and SAH indicate that magnesium may also have a role as a neuroprotective agent. Recent trials suggested that magnesium infusion in patients with SAH decreased the incidence of cerebral vasospasm and improved outcome [35, 36]. In an elegant experimental study using an in vitro porcine carotid artery model, magnesium caused a dose-dependent decrease in tension following contraction generated by cerebrospinal fluid (CSF) from patients with vasospasm [37]. In another experiment, rats were subjected to middle cerebral artery occlusion and reperfusion. Administration of magnesium at the beginning of reperfusion improved electrophysiological and neurobehavioral recovery and reduced brain infarction [38]. To test the hypothesis that magnesium plays a role in reducing the reperfusion injury that may happen in patients with cerebral vasospasm, a randomized, double blind, placebo-controlled multicenter trial has been conducted [35]. In this recently published trial, the investigators assessed whether magnesium sulfate therapy reduced the frequency of delayed cerebral ischemia in patients with aneurysmal SAH. Magnesium treatment reduced the risk of the primary measure of delayed cerebral ischemia by 34 %. Delayed cerebral ischemia occurred in 16 % of magnesium treated patients, and 24 % of placebo treated patients . By 3 months, 18 patients in the magnesium group had an excellent outcome compared with 6 patients in the placebo group. In another randomized clinical trial evaluating the effects of magnesium on cerebral vasospasm after SAH, the investigators reported a trend towards a reduced incidence of clinical vasospasm (24 % vs 54 %) and an improved outcome after 3 months [36]. Comparable effects of magnesium to nimodipine in preventing delayed ischemic neurological deficits after SAH have also been reported in a clinical study [38]. In another clinical study, magnesium did not seem to interfere with vasospasm frequency, however, administration of magnesium did decrease morbidity and length of hospital stay [39]. Although the results of these trials published in the literature all showed a trend toward an improved outcome with magnesium after aneurysmal SAH, a recently reported large clinical trial on magnesium sulfate in acute ischemic stroke (IMAGES) failed to demonstrate any beneficial effect [40]. In this study, patients were randomized to receive either magnesium or saline within 12 hours of ischemic stroke. The delayed therapy in this trial was suggested to be responsible for the lack of efficacy. These results suggest that to understand the neuroprotective effects of magnesium in different injury models we need a better comprehension of the time, dose, and the assessment parameters of magnesium therapy. How peripherally administered magnesium acts on the central nervous system and when it may offer neuroprotective effects are not very clear. A decline in brain intracellular free magnesium concentration following experimental traumatic brain injury has been widely reported in a number of studies [29, 41]. Some investigators reported a decline in serum ionized magnesium concentration after traumatic brain injury in experimental rat models. In these studies, magnesium depletion led to a significantly worse outcome in animals. Low concentrations of serum ionized magnesium have been reported in patients after traumatic brain injury [42]. The decline in serum ionized magnesium was shown to be correlated with the grade of brain injury.

Magnesium in the leu: Sine qua non

Recently, the brain bioavailability of peripherally administered magnesium sulfate was analyzed in patients with acute brain injury secondary to different insults [43]. eSF total and ionized magnesium concentrations were measured during sustained hypermagnesemia. Only small increases in eSF total and ionized magnesium was determined during two-fold increases in systemic magnesium. Similar maximal increases were found both with ionized and total eSF magnesium indicating that total eSF magnesium represented ionized eSF magnesium . The data available do not show which specific magnesium concentration is sufficient for any neuroprotective effects. The levels of hypermagnesemia needed to attain neuroprotective magnesium concentrations should be studied in future investigations.

Magnesium and Sepsis Hypomagnesemia is common in patients with sepsis and septic shock. Several experimental and clinical stud ies showed a strong association of ionized hypomagnesemia with sepsis and septic shock. Sepsis has been reported as one of the independent risk factors for developing hypomagnesemia during the leu stay. This magnesium deficiency in sepsis was reported to be associated with poor outcome. In a recent clinical study, patients with ionized hypomagnesemia at any time had more severe organ dysfunction and higher mortality rates [3]. The important role of magnesium in sepsis might be attributed to its effects on immunologic functions . Magnesium ions are essential for important immunologic functions . Experimental data suggest that magnesium deficiency has important immunomodulatory consequences in septic shock. Salem et al. showed that progressive magnesium deficiency was strongly associated with increased lethality and magnesium therapy provided significant protection from endotoxin challenge [44]. The authors suggested that improved survival in magnesium treated animals was related to the restoration of magnesium dependent immunologic functions . In vitro and in vivo experimental evidence suggests that magnesium ions are essential for macrophage activation, adherence, and bactericidal activity, granulocyte oxidative burst, lymphocyte proliferation, and endotoxin binding to monocytes [44]. In magnesium deficiency sepsis models, significant time-dependent increases in circulating cytokine concentrations were recorded [45]. Magnesium ions play an important role in regulating lethal cellular calcium ion entry in shock states. It has been suggested that cell membrane calcium ion channels are magnesium -dependent and that magnesium is important in regulating sepsisassociated calcium entry. White and Hartzell exposed isolated myocytes to different concentrations of magnesium and reported that lower magnesium concentrations were associated with an efflux of free calcium from the sarcoplasmic reticulum into the cytosol [46]. Supporting this, experimental data showed increased intracellular calcium in hypomagnesemia during endotoxin challenge [47]. Increased intracellular calcium may also cause activation of calcium sensitive nitric oxide (NO) synthase (NOS). Overproduction of NO in a magnesium deficient rat model has been reported [48]. Patients with severe sepsis often manifest symptoms of encephalopathy, a term which has been replaced by 'sepsis-associated delirium'. Acute alterations in mental status, which occur fairly frequently in septic patients, have been shown to be associated with poor prognosis. However, not much is known about the exact mechanism of brain injury in sepsis. Studies have suggested that septic encephalopathy

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0.008 0.007 Q)

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0.006

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0.005

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c

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Control (n = 8) • • •

Septic (n = 8) Control-Mg (n = 8) Septic-Mg (n = 8)

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Fig. 1. Assessment of blood-brain barrier permeability by Evans blue dye in brain tissue [51]. a: p < 0.01 septic versus sham control; b: p < 0.01 septic versus sham control magnesium sulfate-treated; c: p < 0,001 septic versus sham control; d: p < 0,001 septic versus sham control magnesium sulfatetreated

might involve a disturbance of plasma and brain neutral amino acid transport across the blood brain barrier (BBB), similar to those seen in porto-systemic encephalopathy. This process has been related to the breakdown of the BBB because patients with sepsis-associated delirium have high protein levels in the CSF [49). Manipulating the BBB has been suggested to be a therapeutic option for sepsis-associated delirium . Positive effects of magnesium sulfate against BBB breakdown after severe insulin-induced hypoglycemia have been reported in animals [50). Taking this into consideration, we hypothesized that magnesium might have an effect on brain dysfunction associated with sepsis. In our previous cecal ligation and perforation (CLP) model, treatment with magnesium reduced BBB permeability and brain edema formation [51). Sepsis caused a significant increase in BBB permeability to Evans blue dye; the dye content of each hemisphere was significantly lower in the magnesium treated septic rats (Fig. 1.). Although it is not easy to clarify the exact mechanism of magnesium's beneficial effect on the integrity of the BBB, magnesium may influence many aspects of the mediator cascade that can cause a permeability defect in the BBB. Magnesium can also act directly on the BBB via its cytoprotective effects demonstrated in the hypoglycemia model. It has been suggested that even before magnesium reaches the brain site, it interacts with the endothelial cells forming the BBB and inhibits their activation [50). Data on magnesium in sepsis are mostly experimental. Clinical data are needed to verify whether magnesium supplementation can alter outcomes from sepsis and septic shock. Results of present studies showing a relation between the physiological and immunological effects of magnesium during sepsis and septic shock suggest that magnesium supplementation, either to prevent or to correct hypomagnesemia, may alter outcome. The potential benefit of magnesium therapy to achieve higher serum levels in sepsis deserves further experimental and clinical studies.

Conclusion Magnesium is the main intracellular metal cation that plays an essential role in fundamental cellular reactions. Studies have reported that hypomagnesemia is frequent postoperatively and in the ICU, and this often unrecognized condition is responsible for increased morbidity and mortality. Hypomagnesemia should, therefore, be detected and corrected systematically. Although the assessment of actual magne-

Magnesium in the

leu: Sine qua non

sium status in critical illness is problematic, serum total magnesium level remains the only agreed laboratory method. Magnesium has been reported as an effective medical therapy in very many different medical conditions. Other than its known indications, recent studies have led to the establishment of new indicat ions for magnesium therapy. Results of magnesium therapy in neuro-lCU patients encourage serious consideration of its use in trauma, stroke, and SAH. Immunoregulatory effects of magnesium deficiency and supplementation create a new area of research to determine whether readily available and cheap magnesium therapy may have any effect in sepsis and septic shock. Given the wide clinical spectrum in which magnesium play a beneficial role, one might expect its use to be a panacea , especially in critical illness. References I. Ryzen E, Wagers PW, Singer FR, Rude RK (1985) Magnesium deficiency in a medicallCU

population. Crit Care Med 13:19-21 2. Rubeiz G], Thill-Baharozian M, hard ie D, Carlson RW (1993) Association of hypomagnesemia and mortality in acutely ill med ical patients. Crit Care Med 21:203- 209 3. Soliman HM, Mercan D, Lobo SS, Melot C, Vincent [L (2003) Development of ionized hypomagnesemia is associated with higher mort ality rates. Crit Care Med 31:1082-1087 4. Tong GM, Rude DK (2005) Magnesium deficiency in critical illness. I Intens ive Care Med 20:3-1 7 5. The Eclampsia Trial Collaborative Group (1995) Which anticonvulsant for women with eclampsia ? Evidence from the Collaborative Eclampsia Trial. Lancet 345:1455-1463 6. Koinig H, Wallner T, Marhofer P, Andel H, Horauf K, Mayer N (1998) Magnesium sulfate in postope rative analgesia. Anesthe siology 87:206 - 210 7. Kizilirmak S, Karakas SE, Akca 0 , et al (1997) Magnesium sulfate stops postanesthetic shivering. Ann N Y Acad Sci 813:799-806 8. Lipman j, james MFM, Erskine j, Plit ML, Eidelman j, Esser jD (1987) Autonomic dysfunction in severe tetanus: magne sium sulfate as an adjunct to deep sedat ion. Crit Care Med 15: 987-988 9. Galoe A, Gradual N (1994) Magnesium and myocardi al infarction . Lancet 343:1286-1287 10. England MR,Gordon G, Salem M, et al (1992) Magnesium administration and dysrhythm ias after cardiac surgery: A placebo controlled, double-blind, randomized trial. JAMA 268:2395-402 11. Silverman RA, Osborn H, Ruge j, et al (2002) Intravenous magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled tria l. Chest 122:489-497 12. Saris NEL, Mervaala E, Karppanen H, Kwawaja jA, Lewenstam A (2000) Magnesium : An update on physiolog ical, clinical and analytical aspects. Clin Chim Acta 294:1-26 13. Agus ZS, Morad M (1991) Modulation of cardi ac ion channel s by magne sium . Annu Rev Physiol 53:299 - 307 14. Mclean RM (1994) Magnesium and its therapeutic uses: a review. Am j Med 96:63-76 15. Dube L, Granry [C (2003) The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can j Anesth 50:732- 746 16. Dacey M] (2001) Hypomagnesemic disorders. Crit Care Clin 17:155- 73 17. Huijgen Hj, Sanders R, Cecco SA, Rehak NN, Sanders GT, Elin Rj (1999) Serum ionized magnesium: comparison of results obtained with three ion-selective analyzers. Clin Chem Lab Med 37:465 - 470 18. Koch SM, Warters RD, Mehlhorn U (2002) The simultaneous measurement of ionized and total calcium and ionized and total magnesium in inten sive care unit patients. I Crit Care 17:203-205 19. Lanzinger Mj, Morelti EW, Wilderman RF, El-Moalem HE, Tofaletti ic, Moon RE (2003) The relationship between ionized and total seru m magnesium concentrations during abdominal surgery j Clin Anesth 15:245-249 20. Huijgen Hl, Soesan M, Sanders R, Mairuhu WM, Kesecioglu J, Sanders GT (2000) Magnesium levels in critically ill pat ients . What should we measure? Am I Clin Pathol 114:688-695

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F. Esen and L. Teld 21. Altura BM, Altura BT (1996) Role of magnesium in patho-physiological processes and the clinical utility of magnesium ion selective electrodes. Scand J Clin Lab invest Suppl 224: 211-234 22. Hebert P, Mehta N, Wang J, Thomas H, Gwynne J, Pierre C (1997) Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med 25:749-755 23. Schulz-Stiibner S, Wettmann S, Reyle-Hahn SM, Rossaint R (2001) magnesium as a part of balanced general anesthesia with propofol, remifentanil and mivacurium: a double-blind, randomized prospective study in 50 patients . Eur J Anaesthesiol 18:723-729 24. Telci L, Esen F, Akcora D, Erden T, Canbolat AT, Akpir K (2002) Evaluation of effects of magnesium sulphate in reducing intraoperative anesthetic requirements. Br J Anaesth 89:594- 598 25. Seyhan TO, Tugrul M, Sungur MO, et al (2006) Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth 96:247 - 252 26. Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS (2001) Magnesium sulfate does not reduce postoperative analgesic requirements.95:640- 646 27. Memis D, Turan A, Karamanlioglu B, Oguzhan N, Pamukcu Z (2003) Comparison of sufentanil with sufentanil plus magnesium sulphate for sedation in the intensive care unit using bispectral index. Crit Care 7:R123 -128 28. Erginozcan P, Tugrul S, Senturk NM, et al (2008) Role of magnesium sulfate in postoperative pain management for patients undergoing thoracotomy. J Cardiothorac VascAnesth (in press) 29. Vink R (1991) Magnesium and brain trauma. Magnes Trace Elem 10:1-10 30. Okiyama K, Smith DH, Gannarelli TA, Simon RP, Leach M, McIntosh TK (1995) The sodium channel blocker and glutamate release inhibitor BW 1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem 64: 802-809 31. Feldman Z, Gurevitch B, Artru AA, et al (1996) Effects of magnesium given 1 hour after head trauma on brain edema and neurological outcome. J Neurosurg 85:131-137 32. Esen F, Erdem T, Aktan D, et al (2003) Effects of magnesium administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats. J Neurosurg Anesthesiol 15:119-125 33. Choi OW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369-379 34. Cotton OB, Janusz CA, Berman RF (1992) Anticonvulsant effects of magnesium sulfate on hippocampal seizures: therapeutic implications in preeclampsia-eclampsia. Am J Obstet Gynecol 166:1127 -1134 35. van den Bergh WM, Algra A, van Kooten F, et al (2005) Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke 36:1011-1015 36. Wong GK, Chan MT, Poon WS, Boet R, Gin T (2006) Magnesium therapy within 48 hours of an aneurysmal subarachnoid hemorrhage: neuro -panacea. Neurol Res 28:431-435 37. Pyne GJ, Cadoux-Hudson TA, Clark JF (2001) Magnesium protection against in vitro cerebral vasospasm after subarachnoid hemorrhage. Br J Neurosurg 15:409-415 38. Schmid-Elsaesser R, Kunz M, Zausinger S, Prueckner S, Briegel J, Steiger HJ (2006) Intravenous magnes ium versus nimodipine in the treatment of pat ients with aneurysmal subarachnoid hemorrhage: a randomized study. Neurosurgery 58:1054-1065 39. Prevedello OM, Cordeiro JG, de Morais AL, Saucedo NS [r, Chen lB, Araujo JC (2006) Magnesium sulfate: role as possible attenuating factor in vasospasm morbidity. Surg Neurol 65: S1 :14-21

40. Muir KW, Lees KR, Ford I, et al (2004) Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke Trial): Randomized controlled trial. Lancet 363:439-445 41. Heath OL, Vink R (2001) Subdural hematoma following traumatic brain injury causes a secondary decline in brain free magnesium concentration. J Neurotrauma 18:465-469 42. Polderman KH, Bloemers FW, Peerdeman SM, Girbes AR (2000) Hypomagnesemia and hypophosphatemia at admission in patients with severe head injury. Crit Care Med 28: 2022-2025 43. McKeeJA, Brewer RP, Macy GE, et al (2005) Analysis of the brain bioavailability of peripherally administered magnesium sulfate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med 33:661- 666

Magnesium in the ICU: Sine qua non 44. Salem M, Kasinski N, Munoz R, Chernow B (1995) Progressive magnesium deficiency increase s mortality from endotoxin challenge: protective effects of acute magnesium replacement. Crit Care Med 23:108-118 45. Weglicki WB, Philips TM, Freedman AM, Cassidy MM, Dickens BF (1992) Magnesium-deficiency elevates circulating levels of inflamm ator y cytokines and endothelin. Mol Cell Biochern 110:169-173 46. White RE, Hartzell HC (1988) Effects of intracellular free magnesium on calcium current in isolated cardiac myocytes. Science 239:778- 780 47. Sayeed MM, Zhu M, Maitra SR (1989) Alterations in cellular calcium and magnesium during circulatory/septic shock. Magnesium 8:179-189 48. Mak IT, Komarov AM, Wagner TL, Stafford RE, Dickens BF, Weglicki WB (1996) Enhanced NO production during Mg deficiency and its role in mediating red blood cell glutathione loss. Am J Physiol 271:C385-C390 49. Basler T, Meier-Helman A, Brele D, Reinhart K (2002) Aminoacid imbalance early in sepsis encephalopathy. Intens ive Care Med 28:293- 298 50. Kaya M, Kucuk M, Bulut KR, et al (2001) Magnesium sulfate attenuates increased blood brain permeability dur ing insulin-induced hypoglysemia in rats. Can J Physiol Pharmacol 79: 793-798 51. Esen F, Erdem T, Aktan D, et al (2005) Effect of magnesium sulfate administration on bloodbrain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. Crit Care 9:R18-23

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Strict Glycemic Control: Not If and When, but Who and How? M.J.

DE GRAAFF,

P.E. SPRONK, and M.J.

SCHULTZ

Introduction Nurse-driven strict glycemic control aimed at normoglycemia (i.e., blood glucose concentrations between 80-110 mg/dl) decreases mortality and morbidity of intensive care unit (lCU) patients [1, 2]. Of note, with more successful strict glycemic control (i.e., blood glucose concentrations closer to 80 mgldl) more benefit is achieved [3, 4]. Indeed, the lowered blood glucose concentration rather than the insulin dose is related to reduced mortality, critical illness polyneuropathy, bacteremia, and inflammation [3]. Blood glucose control with insulin comes with a risk of hypoglycemia. Clearly, with strict glycemic control the incidence of severe hypoglycemia (defined as blood glucose concentrations < 40 mg/dl) is five- to ten-fold higher as compared to a conventional blood glucose strategy [1, 2]. Until now, fear of severe hypoglycemia, at least in part, hampers broad implementation of strict glycemic control [5]. Although many ICUs have adopted some form of strict glycemic control, frequently the applied strict glycemic control-regimens have higher blood glucose concentrationtargets than those used in the original studies by Van den Berghe et al [1]. In addition, in many ICUs strict glycemic control is not (solely) a task of ICU nurses, which may be far from ideal and probably even incorrect. It is often suggested that ICU nurses lack sufficient background knowledge to safely apply strict glycemic control, in particular when strict glycemic control aims at the lower normal limits of blood glucose concentrations. Nevertheless, several arguments suggest that strict glycemic control should be applied independently by ICU nurses. To gain insight into the current status of strict glycemic control in daily ICU practice, we searched for opinions, surveys, and clinical studies on strict glycemic control in the medical literature. We were interested in recommended and used blood glucose concentration-thresholds. Furthermore we determined what kind of strict glycemic control-protocols are being applied and, if possible, who is responsible for the application of strict glycemic control in the ICU.

Search Criteria Editorials and commentaries dealing with strict glycemic control were searched for in four leading journals in the field of intensive care medicine (i.e., the American Journal of Respiratory and Critical Care Medicine, Critical Care Medicine, Critical Care, and Intensive Care Medicine) as well as two leading journals of general medicine (i.e., the New England Journal of Medicine, and the Journal of the American Medical Association).

Strict Glycemic Control: Not Ifand When, but Who and How?

To search for surveys and clinical stud ies on strict glycemic control, the Medlinedatabase was used to identify Medical Subjects Headings (MeSH) to select search terms . In addition to the MeSH terms we also used free text words. Search terms referred to aspects of the population ("critical care" [MeSH]; "intensive care" [MeSH]) and the condition ("insulin" [MeSH] OR "intensive insulin therapy" OR "intensive glucose control" OR "tight glycemic control" OR "strict blood glucose control" OR "strict glucose control" OR "strict glycemic control" OR "insulin ther apy"). These were combined with the terms "survey", "nurse-driven" and "physician-driven" and "clinical protocols" [MeSH] OR "guidelines"[MeSH] OR "nomograms" [MeSH] . The search for editorials and opinion manuscripts on strict glycemic control resulted in the identification of 14 manuscripts [6-19] . The combination of the searches in the Medline-database resulted in the identification of 60 manuscripts: From the search we identified four surveys on current practice of strict glycemic control [20- 23] and 31 relevant articles reporting on experiences with some sort of strict glycemic control. Manuscripts regarding intelligent technology protocols or decision support were excluded. Articles merely describing protocol development were excluded, as were the articles from the group of Greet Van den Berghe, who first published on strict glycemic control [1, 2]. One author described the same protocol in two separate publications [24, 25]. The remaining 25 studies are listed in Table 1.

What is Being Advised: Opinions and Recommendations Since publication of the first trial by Van den Berghe et al. [1], strict glycemic control has been recommended standard of care for the critically ill by several groups, including the Joint Commission on Accreditation of Healthcare Organization (www.jcaho.org), the Institute for Healthcare Improvement (www.ihi.org), the American Association of Clinical Endocrinology [26], and the Volunteer Hospital Organization (www.vha.com). In addition, strict glycemic control is promoted as a part of a care bundle for sepsis by the American Thoracic Society (www.thoracic.org) and experts in the field [27]. Strict glycemic control has also became, to some extent, a benchmark for the quality of rcu care [17]. In the meantime, numerous opinion papers related to this topic have been published in the medical literature. The majority of papers were published after the first presentation of data from the second trial on strict glycemic control by Van den Berghe et al., in which it was shown that medical rcu patients do benefit from strict glycemic control, but to a lesser extent than surgical rcu patients [2]. Most of the papers mention doubt about the generalizability of the findings by Van den Berghe et al. [6- 11, 14, 16, 17, 19]; it is uncertain whether results can be extrapolated to all rcu patients, but also whether results from a single center study can be extrapolated to other centers across the world. Indeed, unrecognized differences between the rcu in Leuven and other centers may be responsible for different results from strict glycemic control. Noteworthy, many opinion papers mention the risk of hypoglycemia [10, 11, 13, 16, 17, 19]. While some papers rationalize the risk of hypoglycemia [10, 11, 13], other papers strongly mention hypoglycemia as the (one) reason not to perform strict glycemic control (at all) [17]. Most papers do not challenge the thresholds for blood glucose concentrations with strict glycemic control; in two papers , however, other (higher) thresholds are explicitly mentioned to prevent hypoglycemia

503

year

2001 2004 2004

2004 2004 2004 2004 2004 2005 2005 2005 2005

ref

[30] [31] [29]

[50]

[41] [42] [33] [34] [51] [35]

Brown et al.

Krin sley et al.

Kanji et al

Grey et al.

Zimmerman et al. [32] [40]

Author

Laver et al.

Goldberg et al.

Goldberg et al.

Ku et al.

Chant et al

Bland et al.

Moeniralam et al.

BA

RCT

BA

BA

PC

PC

BA

BA

RCT

BA

BA

BA

9,219

8

86

156

52

11 8

27

342

61

100

1,600

167

study N design

sliding scales

text based

normogram

algorithm

tables

tables

not reported

tables

not reported

sliding scales

sliding scales

sliding scales

type of SGC-protocol

mean BGC 105 vs. 177 mg/dl

80-110 vs. 180 - 200 mg/dl 80- 140 mg/dl vs. no TGC

nurses nurses + physicians

mean BGC 137 vs. 164 mg/dl

52 % vs. 20 % of BGC within target

90-144 mg/dl vs. no SGC nurses

BGC < 40 mg/dl in 5 vs. 2% of patients

BGC < 40 mg/dl in 0.1 % of measurements

hypoglycemia in 0.4 vs. 0.2 % of measurements

BGC < 40mg/dl in 11 vs. 4 % of patients 15 % vs. 33 % of BGC > 180 mg/dl 80-180 mg/dl vs. no SGC

nurses

100- 139 mg/dl

BGC < 60mg/dl in OJ % of measurements

nurses

nurses

66% of BGC between 80-139 mg/dl

BGC < 40mg/dl in only 3 cases

100 - 139 mg/dl

mean BGC 112 vs. 166 mg/dl

BGC < 40mg/dl in 7 vs. 3 % of patients 61 % vs. 47% of BGC within target

BGC < 60mg/dl in 0.2% of measurements

72 -1 26mg/dl

80-150mg /dl vs. no SGC

80-120 vs. 180-220 mg/dl

BGC < 60mg/dl in 32 vs. 7 % of patients

BGC < 40 mg/dl in 16 vs. 4 % of patients

BGC in target in 11 .5 vs. 7.1 hours per day mean BGC 125 vs. 179 mg/dl

incidence of hypoglycemia did "not change" with SGC

mean BGC 131 vs. 152 mg/dl

< 140 mg/dl vs. no SGC 81- 11 0 mg/dl vs. no SGC

BGC < 63 mg/dl in 27 vs. 20% of measurements

mean time to target 2 vs. 4 hours

126-207 mg/dl vs. no SGC

-

incidence of hypoglycemia (vs. control, if applicable)

efficacy of the SGC protocol (vs. control, if applicable)

SGC thresholds (vs. control, if applicable)

73 % of BGC in target

nurses

nurses

not reported

nurses alone vs. physicians + nurses

not reported

unknown

who applied the SGCprotocol

1. Studies reporting on the efficacy and safety of a local strict glycemic control (SGC) protocol

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[36] [43] [44] [45] [46] [24] [37] [49] [38] [52] [48] [47] [39]

Taylor et al.

Dilkhush et al.

Carr et al.

Clayton et al.

Osburne et al.

Lonergan et al.

Toft et al.

Balkin et al.

Barth et al.

McMullin et al.

Lacherade et al.

Smith et al.

Reed et al.

BGC< 50mg/dl in 7.7 % of patients hypoglycemia reported to be "rare" BGC < 60mg/dl in 0.9% of measurements BGC < 80mg/dl in 1.4 % of measurements BGC < 40mg/dl in 14% of patients BGC < 40mg/dl in 0.1 % of measurements

50% of BGC < 130 mg/dl mean BGC 124 mg/dl mean time to target 13 hours mean BGC 104 mg/dl mean BGC 11 0 vs. 133 mg/dl

< 110 mg/dl 80-120 mg/dl 80-110 mg/dl 80-110 mg/dl 80-110 vs. < 216 mg/dl

nurses nurses

mean BGC 142 mg/dl mean BGC 130 vs. 169 mg/dl

100 -150 mg/dl 90-126 vs. 144 -180 mg/dl

nurses nurses

matrix

90

BGC < 40mg/dl in 2% of patients incidence of hypoglycemia reported to be "low"

79.9% of BGC < 150 mg/dl mean BGC 125 mg/dl

80-150 mg/dl 80-110 mg/dl

nurses nurses

algorithm not reported

BA

PC 3725

145

BGC < 40mg/dl in 19% of patients mean BGC 123 mg/dl

90-126 mg/dl

nurses

sliding scales

105

PC

nurses

sliding scales

20

RCT

BGC < 40mg/dl in 36% of patients

366

BA

PC normogram

mean BGC 133 mg/dl

80-120 mg/dl

nurses

algorithm

271

BA

sliding scales

11

nurses

nurses

BGC < 40 mg/dl in 4 % of patients

BGC < 60mg/dl in 23 % of patients

mean time to target 13 hours

80-130 mg/dl

nurses

PC

tables

normogram

sliding scales

tables

hypoglycemia range 1- 3.4 % all groups

incidence of hypoglycemia (vs. control, if applicable)

mean BGC 132 vs. 163 vs. 190 mg/dl

80-110 vs. 120 -150mg/dl

table vs. table physicians + vs. no protocol nurses

efficacy of the SGC protocol (vs. control, if applicable)

20

70

737

30

285

SGC thresholds (vs. control, if applicable)

who applied the SGCprotocol

type of SGC-protocol

PC

PC

PC

PC

BA

study N design

Data are reported for SGC-treated patients versus 'control' if applicable, or for SGC-treated patients alone. abbreviations: BA, before-after study; PC, prospective cohort study; ReT, randomized controlled trial; N, number of patients; BGC, blood glucose level.

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MJ. de Graaff, P.E. Spronk, and MJ. Schultz

with strict glycemic control [16, 17]. Interestingly, none of the opinion papers mention which personnel should be involved in strict glycemic control.

What is Said to be Performed: Surveys On Strict Glycemic Control McMullin et al. surveyed ICU nurses and physicians on actual blood glucose concentration-thresholds in five university-affiliated multidisciplinary ICUs in Canada [20]. The reported clinically important threshold for hyperglycemia was remarkably high. Indeed, the median threshold was 180mg/dl (interquartile range [IQR] 162-216 mg/dl). The reported median clinically important threshold for hypoglycemia was 72 mg/dl (IQR 54-72 mg/dl). ICU nurses acted on slightly,but significantly, higher blood glucose concentration thresholds than ICU physicians (mean difference of 9 mg/dl), Avoidance of hyperglycemia was judged most important for diabetic patients, patients with a recent seizure, patients with advanced liver disease, and for patients with acute myocardial infarction. Surprisingly, avoidance of hyperglycemia was judged not important for surgical patients, the patients who were targeted in the first study on strict glycemic control in ICU patients by Van den Bergh et al. [1]. In this survey report no information was given regarding presumed risks of strict glycemic control, in particular the risk of hypoglycemia, and the impact of this risk on the chosen blood glucose concentration thresholds. Mackenzie et al. reported on a survey in large English hospitals [21] . Only 25 % of ICUs reported blood glucose concentration targets similar to those used in the study by Van den Berghe et al. [1]. The majority of ICUs in which strict glycemic control was practiced reported higher normal blood glucose concentration limits. The majority of the ICU nurses (82 %) reported being afraid of hypoglycemia in the patients receiving strict glycemic control, although a clear reasoning for these feelings was lacking [28]. The findings of Mackenzie et al. are, in part, in line with a survey in the Netherlands in 2004 [22]. Over 100 participants at the annual meeting of the Dutch Society of Intensive Care were surveyed. The majority were ICU physicians. Of the survey respondents, 69 % stated that strict glycemic control was already being applied in their ICU, while 7 % mentioned that they would start with this intervention shortly. Of those that said they applied strict glycemic control, 62 % used some sort of strict glycemic control protocol with sliding scales. However, blood glucose concentration limits of 80-110 mg/dl were reported by only 26 % of respondents, 80-145 mg/dl by 73 %, and 80-180 mg/dl by 2 %. Strict glycemic control was applied solely by ICU nurses in only 18 % of centers; it was applied by ICU physicians alone or by ICU nurses and ICU physicians as a team in 16 % and 65 % of centers, respectively. In contrast to the survey in the Netherlands, a survey in 2003 by Mitchell et al. reported that few Australian and New Zealand ICUs have adopted strict glycemic control [23]. Only 10 % of the ICU directors reported using a strict glycemic control regimen in all patients in their ICUs. Another 30 % used strict glycemic control only in selected patient groups, predominantly those staying in the ICU unit > 3 days. Similar to other surveys, the reasons for not adopting strict glycemic control were concerns about the risk of hypoglycemia, but also doubts about the external validation of the original study by Van den Berghe et al. [1].

Strict Glycemic Control: Not If and When, but Who and How?

What Is Performed: Studies on Experiences with Strict Glycemic Control Twelve of the analyzed studies were combined retrospective-prospective cohort studies (i.e., with a historical control group, frequently referred to as before-after studies) [29-40] , 11 were prospective cohort studies simply evaluating the implementation of strict glycemic control (i.e., a control group was lacking) [24, 25, 41- 49], and th ree were randomized controlled trials [50 - 52]. Only one study directly compared a nurse-driven strict glycemic control-strategy with a physiciandriven strategy [36]. In only seven of the abovementioned studies [24,29,36,37,39,46,51] , were identical targets used as in the two successful studies by Van den Berghe et al. [1, 2]. All the other studies used different blood glucose concentration thresholds, most of them with a higher upper lim it (up to 150 mg/dl) . Of interest, in the majority of the papers it was stated that higher blood glucose concentration limits were deliberately chosen to facilitate acceptance of the protocol, because it was suspected that there would be an 'unacceptably' high incidence of hypoglycemia when applying the limits as used in the studies by Van den Berghe et al. [1,2]. The reported incidence of hypoglycemia varied from as low as 2.0 % of patients to as high as 19 %, when defin ing hypoglycemia as blood glucose concentration < 40 mg/dl; when using blood glucose concentration < 60 mg/dl as a definition for hypoglycemia, incidences were reported to be as high as 32 %. However, since the reliabil ity of capil lary blood glucose measurements (blood obtained from a finger stick) is not satisfac tory, with bad precision and a high percentage of discordance, in many of the reviewed studies the incidence of hypoglycemia may have been higher than reported. It is worth mentioning that in all the studies that described the con sequences of hypoglycemia in their pat ients, none reported serious or persisting complications. As a matter of fact, nearly all the authors explicitly declared their protocol to be safe. Although it was not always clearly stated in the papers, it seems that ICU nurses were the pr imary healthcare workers involved in the performance of strict glycemic control. Only one study compared a nurse-driven strict glycemic control protocol with a protocol applied by ICU physicians alone [36]. In this cohort study, three consecutive regimens wer e compared: Strict glycemic control applied by ICU physicians with no specific targets, strict glycem ic control applied by ICU nurses aimed at blood glucose concentrations between 120- 150 mg/dl, and strict glycemic control applied by ICU nurses aimed at blood glucose concentrations as in the study by Van den Berghe et al. [1, 2]. There was a significant decrease in average daily blood glucose concentrations, from 190 to 163 mg/dl, and further to 131 mg/dl in the three consecutive phases of the study. Of interest, the incidence of severe hypoglycemia (defined as blood glucose concentration < 40 mg/dl) was similar in the three groups, ranging between 1.1 % and 3.4 %. Remarkably, protocol compliance was reported to be low (only approximately 50 % of orders were followed), and blood for blood glucose concentration monitoring was sometimes obtained from a finge r stick, which may have led to underscoring of hypoglycemia.

Discussion Conventional wisdom was that hyperglycemia in ICU patients is favorable and that hypoglycemia is hazardous. Results from two randomized controlled trials and two before-after studies, however, showed that strict glycemic control aimed at normog-

507

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lycemia decreased mortality and morbidity of ICU patients [I, 2, 18, 31]. Although the evidence for strict glycemic control does not yet support the highest recommendation, it does appear stronger than the evidence to continue existing practice of tolerating hyperglycemia [10]. Nevertheless, the ICU community has been reluctant to implement this strategy (as a whole) in daily practice [5]. The reasons for this include the fear of hypoglycemia [20,23 ,28] . Also, the impact of strict glycemic control on costs and human resources has been questioned [11]. In addition, it has been suggested that very complex protocols are mandatory for proper performance of strict glycemic control [53]. Concern has arisen about validity of the studies by Van den Berghe et al. [1, 2]. One concern is the relatively high mortality in relation to severity of illness among patients in the control group in the first study [1]. Also, the frequent administration of parenteral calories led to some criticism in the literature. Of note, while the second study by Van den Berghe et al. [2] is often referred to as a negative trial (i.e., no benefit from strict glycemic control over conventional blood glucose control), in fact this study also showed beneficial effects of strict glycemic control. Indeed, although an intention-to-treat analysis showed no impact on mortality, morbidity was altered by strict glycemic control. Also, a per-protocol analysis (of pre-defined subgroups) showed mortality reduction with strict glycemic control. Although the discrepancies between the two studies are thought-provoking, the different results are certainly not a reason to use other thresholds than those in the original studies. Presently, the results of one much larger trial are eagerly awaited: the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) study, conducted jointly by the Australia and New Zealand Intensive Care Society and the Canadian Critical Care clinical trials groups, will randomize over 5,000 medical and surgical ICU-patients at multiple centers, to one of two different insulin regimens designed to achieve strict glycemic control or conventional blood glucose control, with target ranges similar to those of Van den Berghe et al [54]. The results of this trial are anticipated shortly. Unfortunately, the multicenter VISEP-trial on strict glycemic control in Germany by the SepNet-group was discontinued prematurely because of identical mortality rates in the treatment groups but a higher incidence of hypoglycemia in the strict glycemic control-group (12.1 % versus 2.1 %) [55]. The early termination of this study was rather inopportune. First, the increase in the incidence of hypoglycemia in the strict glycemic control group was not surprising. Indeed, similar findings were reported in the two randomized controlled trials by Van den Berghe et al. [1,2], as well as the numerous other studies reporting on some form of strict glycemic control (most before-after studies) [5]. The European GLUControl trial was also stopped before inclusion was completed. The primary reason was the relatively high incidence of hypoglycemia in the intensive insulin group. From the data this study has disclosed until now, it is clear that the glycemic control in the strict group was not sufficiently better than the regulation in the control group . More importantly, however, we are left with two underpowered studies which cannot be used as evidence in the discussion on a potential benefit of strict glycemic control. The observed incidence of hypoglycemia in the numerous studies varies considerably, and depends on the definition of hypoglycemia, the target range of blood glucose concentrations, and the way in which blood glucose concentrations were monitored. However, reporting the incidence of a blood glucose concentration below a particular value may be counterproductive [22, 28]. Adverse consequences of blood glucose concentrations either above or below the desirable range are likely to be due

Strict Glycemic Control: Not If and When, but Who and How?

to both the extent and duration of excursion. Information on the proportion of time spent in the target range, above the target range, and below the target range would be more useful when evaluating published reports on the efficacy and safety of strict glycemic control [56]. The most feared consequence of hypoglycemia is potential irreversible neurological damage. Sedated leu patients and patients with disturbances in the counter-regulatory responses to hypoglycemia are at risk for neuroglycopenia because of the absence of clinical symptoms of severe hypoglycemia. Neuroglycopenia may cause cerebral damage, epileptic insults, or even coma [57]. How low does the hypoglycemia need to be, and for how long, for this to occur [28]? In the early 20th century, repeated episodes of insulin-induced hypoglycemic coma for periods ranging from 45 minutes to 3 hours for the treatment of opiate addiction and schizophrenia, were found to have minimal long-term effects and a mortality of less than 1 % [58]. In addition, long-term follow-up of patients with diabetes mellitus randomized in large prospective trials of strict glycemic control failed to detect any association between the frequency of severe hypoglycemia and cognitive decline [59, 60]. Only subtle, reversible impairments in attention could be detected in non-diabetic patients undergoing dynamic pituitary function assessment using hypoglycemic stress with blood glucose concentrations of 29 mg/dl [61]. In two years of strict glycemic control, Mackenzie et al. recorded 128 instances of hypoglycemia (blood glucose concentration < 40 mg/dl) out of 29,733 measurements, with a median value of 33 mg/dl OQR 25-36 mg/dl) and a median duration of 18.2 minutes (8,4- 37.5 minutes) [28]. The incidence of hypoglycemia at this center decreased significantly with time. The risk of a patient suffering prolonged severe hypoglycemia was concluded to be small and the risk of this resulting in significant neurological damage even smaller. Even more so, recent experimental data on the effects of hypoglycemia on the brain have indicated an important different mechanism that may cause damage to the brain [62]. The study was conducted to evaluate the effects of the duration and severity of hypoglycemia in the rodent brain. These experiments showed that it was not the period of hypoglycemia itself, but the correction with intravenous dextrose that caused formation of radicals and subsequent damage in the brain. The damage was correlated to the concentration and amount of dextrose used. Bolus glucose reperfusion of the depleted brain may, therefore, be causing more damage than the period of hypoglycemia itself. A recent study by Krinsley and Grover was set up to determine the risk factors and consequences of hypoglycemia for leu patients [63]. Hypoglycemia was independently associated with an increased risk of mortality and the authors correctly concluded that in order to implement strict glycemic control in a safe way, frequent blood glucose concentration measurements are of great importance. It also became clear that the additional risk of hypoglycemia does not outweigh the benefits of strict glycemic control in this group of patients [63, 64]. The above mentioned findings are another reason to rethink our fear of hypoglycemia and our clinical response to this condition in the leu. Although in the two studies by Van den Berghe et al. the strict glycemic control in leU patients was a nurse -driven protocol [1, 2], it is questionable whether leU nurses really want to adopt strict glycemic control, especially when the targets are set at the lower normal limits of blood glucose concentrations. First, it should be mentioned that in the Leuven studies, leu nurses at first were dedicated research nurses, probably with a different attitude than routine leU nurses. From personal experience we know that nurses may violate the protocol now and then, in particular

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at the lower normal limits, to prevent hypoglycemia. It was even suggested that strict glycemic control might be better applied by ICU physicians in one survey [22]. However, in the one study that compared ICU physicians with leu nurses [36], no differences in respect to safety (incidence of hypoglycemia) or efficacy (average daily blood glucose concentration) were seen. In addition, the continuous presence of leu nurses at the bedside may prevent deterioration of glucose control. Indeed, many of the predisposing factors for hypoglycemia in leu patients are easily recogn izable by leu nurses , such as a decrease in nutrition without adjustment for insulin infusion [65]. After the first strict glycemic control study, the Leuven group incorporated strict glycemic control into the daily routine of the regular leu nurses without loss of strict regulation. Future studies could focus on how to implement strict glycemic control in daily practice , paying special emphasis to who should actually apply strict glycemic control guidelines - Special nurse teams, all leu nurses , leu nurses alone or with the help of leu physicians - and to what extent? One final point of discussion concerns the strict glycemic control protocols presently used across Europe and the Americas. It has been argued that complex protocols are required to safely and adequately perform strict glycemic control in clinical practice . Indeed, this is exactly how most intensivists feel about strict glycemic control - in a recently performed postal survey in the Netherlands we found as many as 46 different local protocols of 6 different types were in use, including flowcharts, sliding scales, calculators, conversion tables, text based protocols, and electronic decision support systems) [66]. All these protocols had only two things in common - first, they indeed all dealt with blood glucose. But more interestingly in this context, they were all exceptionally complex and large, and frequently very difficult to understand. Next to this, the measurements used for the 'success' of strict glycemic control are very heterogeneous and this makes it difficult to compare results. Because average glucose levels are not a very good reflection of overall regulation, other parameters should receive more attention in the future. In particular, the 'time to target', duration of hyper- and hypoglycemia and the fluctuation of glucose levels are of interest. Recently, we had the opportunity to visit the Leuven hospital to see how leu nurses apply strict glycemic control and were surprised to see the simplicity of their protocol. It is a remarkable concise protocol, far from complex and consequently very easy to follow - in fact their protocol is no more than a small set of guidelines which nurses hardly ever use after having gained experience with applying the protocol for some months, because (quoting the Leuven nurses) "tight glucose control is something you do by heart, not from a sheet of paper".

Conclusion Although the evidence for strict glycemic control does not yet support the highest recommendation, it does appear stronger than the evidence for continuing our existing practice of tolerating hyperglycemia. One reason for not implementing strict glycemic control is fear of hypoglycemia. However, it is questionable whether this fear is rational. Moreover, rapid correction of hypoglycemia may be more detrimental than a more gradual approach. In addit ion, many different strict glycemic controlprotocols are being used, protocols that at times are very different from the one (presently) used in Leuven. As compared to the regulation of inotropes, insulin infusion is a dynamic process that requires frequent measurement of glucose and flexible response to changes.

Strict Glycemic Control: Not If and When, but Who and How?

Research on strict glycemic control should focus on who is to be primarily involved in strict glycemic control, and also on which protocol is best usable for ICU nurses. In the meantime, let us start the easy way first: simply implement exactly what Van den Berghe et al. showed to be beneficial for ICU patients and effective in daily practice , i.e., a simple protocol, which forms a solid basis for ICU nurses to apply strict glycemic control. References 1. Van den Berghe G, Wouters P, Weekers F, et al (2001) Intensive insulin therapy in the crit ically ill patients. N Engl J Med 345:1359-1367 2. Van den Berghe G, Wilmer A, Hermans G, et al (2006) Intensive insulin therapy in the medical ICU. N Engl J Med 354:449-461 3. Van den Berghe G, Wouters PJ, Bouillon R, et al (2003) Outcome benefit of intensive insulin therapy in the crit ically ill: Insulin dose versus glycemic control. Crit Care Med 31:359-366 4. Finney SJ, Zekveld C, Elia A, Evans TW (2003) Glucose contro l and mortality in crit ically ill patients. JAMA 290:2041-2047 5. Schultz M1, Royakkers AA, Levi M, Moeniralam HS, Spronk PE (2006) Intensive insulin ther apy in intensive care: An example of the struggle to implement evidence-based medicine. PLoS Med 3:e456 6. Evans TW (2001) Hemodynamic and metabolic the rapy in crit ically ill patients. N Engl J Med 345:1417-1418 7. Cariou A, Vinsonneau C, Dhainaut JF (2004) Adjunctive therapies in sepsis: an evidencebased review. Crit Care Med 32 (II Suppl):S562-S570 8. Devos P, Preiser JC (2004) Tight blood glucose control : a recommendation applicable to any crit ically ill patient? Crit Care 8:427- 429 9. Finney SJ (2004) Insulin and metabolic substrates during human sepsis. Crit Care 8:227- 228 10. Angus DC, Abraham E (2005) Intensive insulin therapy in critical illness. Am J Respir Crit Care Med 172:1358-1359 11. Fowler RA, Annane D (2006) The highs and lows of intensive insulin therapy. Am J Respir Crit Care Med 173:367- 369 12. Beishuizen A, Groeneveld AB (2006) Implementing strict glucose control : it is not that simple.. Crit Care Med 34:3050-305 1 13. Van den Berghe G (2006) First do no harm ... hypoglycemia or hyperglycemia? Crit Care Med 34:2843 - 2844 14. Diringer MN (2006) Is aggressive treatment of hyperglycemia for everyone? Crit Care Med 34:930-931 15. Krinsley JS (2006) A simple intervention that saves lives and money. Crit Care Med 34:896897 16. Polderm an KH, Girbes AR (2006) Intensive insulin therapy: of harm and health , of hypes and hypoglycemia. Crit Care Med 34:246- 248 17. Malhotra A (2006) Inten sive insulin in inten sive care. N Engl J Med 354:516-518 18. Devos P, Preiser JC (2006) Is it time for implementation of tight glycaemia control by intensive insulin therapy in every ICU? Crit Care 10:130 19. Russell JA (2006) Management of sepsis. N Engl J Med 355:1699-1713 20. McMullin J, Brozek 1, Iaeschke R, et al (2004) Glycemic control in the ICU: a multicenter survey. Inten sive Care Med 30:798- 803 21. Mackenzie I, Ingle S, Zaidi S, Buczaski S (2005) Tight glycaemic control: a survey of intensive care practice in large English hospitals. Intensive Care Med 31:1136 22. Schultz MJ, Spronk PE, Moeniralam HS (2006) Tight glycaemic control : a survey of intensive care practic e in the Netherlands. Intensive Care Med 32:618-619 23. Mitchell I, Finfer S, Bellomo R, Higlett T (2006) Management of blood glucose in the critically ill in Australia and New Zealand: a practice survey and inception cohort study. Intensive Care Med 32:867- 874 24. Lonergan T, Compte AL, Willacy M, et al (2006) A pilot study of the SPRINT protocol for tight glycemic control in critically III patients. Diabetes Technol Ther 8:449- 462

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MJ. de Graaff, P.E. Spronk, and MJ. Schultz 25. Lonergan T, Le Compte A, Willacy M, et al (2006) A simple insulin-nutrition protocol for tight glycemic control in critical illness: development and protocol comparison. Diabetes Technol Ther 8:191-206 26. Garber AJ, Moghissi ES, Bransome ED Ir, et al (2004) American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract 10 SuppI2:4 -9 27. Dellinger RP, Carlet JM, Masur H, et al (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858- 873 28. Mackenzie I, Ingle S, Zaidi S, Buczaski S (2006) Hypoglycaemia? So what! Intensive Care Med 32:620-621 29. Kanji S, Singh A, Tierney M, Meggison H, McIntyre L, Hebert PC (2004) Standardization of intravenous insulin therapy improves the efficiency and safety of blood glucose control in critically ill adults. Intensive Care Med 30:804- 810 30. Brown G, Dodek P (2001) Intravenous insulin nomogram improves blood glucose control in the critically ill. Crit Care Med 29:1714- 1719 31. Krinsley JS (2004) Effect of an intensive glucose management protocol on the mortality of critically ill adult patients . Mayo Clin Proc 79:992 -1000 32. Zimmerman CR, Mlynarek ME, Jordan JA, Rajda CA, Horst HM (2004) An insulin infusion protocol in critically ill cardiothoracic surgery patients . Ann Pharmacother 38:1123-1129 33. Ku SY, Sayre CA, Hirsch lB, Kelly JL (2005) New insulin infusion protocol Improves blood glucose control in hospitalized patients without increasing hypoglycemia. It Comm J Qual Patient Saf 31:141-147 34. Chant C, Wilson G, Friedrich JO (2005) Validation of an insulin infusion nomogram for intensive glucose control in critically ill patients. Pharmacotherapy 25:352-359 35. Moeniralam HS, Spronk PE, Korevaar JC, et al (2005) Intensive insulin therapy in intensive care unit patients increases the frequency of hypoglycaemia. Crit Care 9:P388 (abst) 36. Taylor BE, Schallom ME, Sona CS, et al (2006) Efficacy and safety of an insulin infusion protocol in a surgical ICU. J Am ColI Surg 202:1-9 37. Toft P, Jorgensen HS, Toennesen E, Christiansen C (2006) Intensive insulin therapy to noncardiac ICU patients: a prospective study. Eur J Anaesthesiol 23:705 -709 38. Barth MM, Oyen LJ, Warfield KT, et al (2007) Comparison of a nurse initiated insulin infusion protocol for intensive insulin therapy between adult surgical trauma, medical and coronary care intensive care patients . BMC Emerg Med 7:14 39. Reed CC, Stewart RM, Sherman M, et al (2007) Intensive insulin protocol improves glucose control and is associated with a reduction in intensive care unit mortality. J Am ColI Surg 204:1048-1054 40. Laver S, Preston S, Turner D, McKinstry C, Padkin A (2004) Implementing intensive insulin therapy: development and audit of the Bath insulin protocol. Anaesth Intensive Care 32: 311-316 41. Goldberg PA, Sakharova OV, Barrett PW, et al (2004) Improving glycemic control in the cardiothoracic intensive care unit: clinical experience in two hospital settings. J Cardiothorac Vasc Anesth 18:690 -697 42. Goldberg PA, Siegel MD, Sherwin RS, et al (2004) Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit. Diabetes Care 27:461-467 43. Dilkhush D, Lannigan J, Pedroff T, Riddle A, Tittle M (2005) Insulin infusion protocol for critical care units. Am J Health Syst Pharm 62:2260-2264 44. Carr JM, Sellke FW, Fey M, et al (2005) Implementing tight glucose control after coronary artery bypass surgery. Ann Thorac Surg 80:902- 909 45. Clayton SB, Mazur JE, Condren S, Hermayer KL, Strange C (2006) Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit. Crit Care Med 34: 2974-2978 46. Osburne RC, Cook CB,Stockton L, et al (2006) Improving hyperglycemia management in the intensive care unit: preliminary report of a nurse-driven quality improvement project using a redesigned insulin infusion algorithm. Diabetes Educ 32:394-403 47. Smith AB, Udekwu PO, Biswas S, et al (2007) Implementation of a nurse -driven intensive insulin infusion protocol in a surgical intensive care unit. Am J Health Syst Pharm 64:1529-1540 48. Lacherade JC, Iabre P, Bastuji-Garin S, et al (2007) Failure to achieve glycemic control despite

Strict Glycemic Control: Not Ifand When, but Who and How?

49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66.

intensive insulin therapy in a medical ICU: incidence and influence on ICU mortality. Inten sive Care Med 33:814-821 Balkin M, Mascioli C, Smith V, et al (2007) Achieving durable glucose control in the intensive care unit without hypoglycaemia: a new practical IV insulin protocol. Diabetes Metab Res Rev 23:49- 55 Grey NJ, Perdrizet GA (2004) Reduction of nosocomial infections in the surg ical intensivecare unit by strict glycemic control. Endocr Pract 10 Suppl 2:46-52 Bland DK, Fankhanel Y, Langford E, et al (2005) Intensive versus modified conventional control of blood glucose level in medical intensive care patients: a pilot study. Am J Crit Care 14:370-376 McMullin J, Brozek J, McDonald E, et al (2007) Lowering of glucose in critical care: a randomized pilot trial. J Crit Care 22:112- 118 Shulman R, Finn ey SJ, O'sullivan C, Glynne PA, Greene R (2007) Tight glycaemic control: a prospective observat ional study of a computerised decision-supported intensive insulin therapy protocol. Crit Care 11:R75 Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation - NICE-SUGAR STUDY. Available at: http ://www.controlled-trials.com/ISRCTN04968275/ 04968275. Accessed Dec 2007 Brunkhorst FM, Kuhnt E, Engel C, et al (2005) Intensive insulin in patients with severe sepsis and septic shock is associated with an increased rate of hypoglycemia -results from a randomized multicenter study (VISEP). Infection 33:19-20 Mackenzie I, Ingle S, Underwood C, Blunt M (2005) Which measure of glycaemic control ? Proc Am Thorac Soc A37 (abst) Vriesendorp TM, DeVries JH, van Santen S, et al (2006) Evaluation of short-term consequences of hypoglycemia in an intensive care unit. Crit Care Med 34:2714-2718 Sargant W, Slater E (1944) Physical Methods of Treatment in Psychiatry. Livingstone, Edinburgh Austin EJ, Deary IJ (1999) Effects of repeated hypoglycemia on cognitive function: a psychometrically validated reanalysis of the Diabetes Control and Complications Trial data. Diabetes Care 22:1273-1277 Jacobson AM, Musen G, Ryan CM, et al (2007) Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 356:1842-1852 Osorio I, Arafah BM, Mayor C, Troster AI (1999) Plasma glucose alone does not predict neurologic dysfunction in hypoglycemic nondiabetic subjects. Ann Emerg Med 33:291- 298 Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA (2007) Hypoglycemic neuronal death is triggered by glucose reper fusion and activation of neuronal NADPH oxidase. J Clin Invest 117:910-918 Krinsley JS, Grover A (2007) Severe hypoglycemia in critically ill patients: Risk factors and outcomes . Crit Care Med 35:2262- 2267 Nasraway SA [r (2007) Sitting on the horns of a dilemma : Avoiding severe hypoglycemia while practicing tight glycemic control. Crit Care Med 35:2435- 2437 Vriesendorp TM, van Santen S, DeVries JH, et al (2006) Predisposing factors for hypoglycemia in the intensive care unit. Crit Care Med 34:96- 101 de Graaff MJ, Sponk PE, Schultz MJ (2007) Tight glycaemic control: intelligent technology or a nurse -wise strategy? Crit Care 11:421

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Cortisol Metabolism in Inflammation and Sepsis B. VENKATESH and

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COHEN

Introduction Steroid therapy has not been consistently shown to provide benefit in severe sepsis and may even be associated with adverse effects. The driver for steroid therapy is based on the controversial and unproven premise that there is relative adrenal insufficiency (based on a blunted cortisol response to corticotropin) in septic shock [1]. Recent research has identified an enzyme of steroid metabolism, ll~-hydroxyste roid dehydrogenase (l1~-HSD), which regulates intracellular concentrations of cortisone (inactive) and active cortisol [2]. Disturbances of this enzyme system have been implicated in the pathogenesis of hypertension, obesity, and vascular disease, highlighting the pivotal role of elevated tissue cortisol concentrations in the genesis of these diseases [3]. Preliminary data in inflammatory and septic states suggest that alterations of this enzyme system may lead to potentially elevated tissue cortisol concentrations, an argument against the adrenal insufficiency hypothesis. In this chapter, we review the physiology of the 11~-HSD system and discuss its potential role in inflammation and sepsis.

Brief Review of Physiology Cortisol, the major glucocorticoid synthesized by the adrenal cortex, plays a pivotal role in normal metabolism. It is necessary for the synthesis of adrenergic receptors, normal immune function, wound healing, and vascular tone. Under normal circumstances, cortisol is secreted in pulses, and in a diurnal pattern. The normal basal output of cortisol is estimated to be 15-30 mglday, producing a peak plasma cortisol concentration of 110-520 nmolll (4-19 Ilgldl) at 8-9 am, and a minimal cortisol level of < 140 nmol/l « 5 Ilg/dl) after midnight. Secretion is under the control of the hypothalamic pituitary axis. There are a variety of stimuli to secretion, including stress, tissue damage, cytokine release, hypoxia, hypotension, and hypoglycemia. The majority of circulating cortisol is bound to an alpha-globulin called trans cortin (corticosteroid-binding globulin, CBG). At normal levels of total plasma cortisol (e.g., 375 nmolll or 13.5 Ilg/dl) less than 5 % exists as free cortisol in the plasma; however it is this free fraction that is biologically active. Circulating CBG concentrations are approximately 700 nmolll. In normal subjects, CBG can bind approximately 700 nmolll (i.e., 25 ug/dl). At levels greater than this, the increase in plasma cortisol is largely in the unbound fraction. CBG levels have been documented to fall during critical illness [4], and these changes are postulated to increase the amount of circulating free cortisol [5].

Cortisol Metabolism in Inflammation and Sepsis

Cortisol has a half life of 70-120 min. It is eliminated primarily by hepatic metabolism and glomerular filtration . The excretion of free cortisol through the kidney represents 1 % of the total secretion rate. To date most of our knowledge and understanding of adrenal dysfunction has focused predominantly on plasma cortisol, either total or the free fraction .

Modulation of Tissue Cortisol Concentrations Research in the past 15 years has highlighted the importance of pre-receptor metabolism of glucocorticoids as a way of modulating their action within a given tissue, irrespective of the circulating concentrations of hormone. It has now emerged that an enzyme of steroid metabolism, 11B-HSD, regulates intracellular concentrations of cortisone (inactive) and active cortisol. These microsomal enzymes catalyze the conversion of l l -hydroxysteroids (e.g., cortisol) to l l-ketosterolds (e.g., cortisone) and vice versa. To date two 'isoenzymes' of lIB-HSD (l and 2) have been characterized and cloned in human tissues ( Table 1). lIB-HSDI is predominantly reductase, generating active cortisol from inactive cortisone. The directionality of lI-BHSDI is thought to be maintained by the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) by another microsomal enzyme, hexose-6-phosphate dehydrogenase (H6PDH). Conversely, IIB-HSD2 is exclusively dehydrogenase, producing inactive cortisone from cortisol. The action of the lIB-HSD enzyme system on glucocorticoid metabolism is profound . The activity of the hypothalamic-pituitary-adrenal (HPA) axis is influenced by the balance between the activity of lIB-HSDl in generating cortisol and of lIBHSD2 in inactivating it. Additionally, at a local tissue level the isoenzymes regulate the intracellular hormone levels available to bind to the glucocorticoid receptor. Endogenous inhibitors of both isoenzymes (glycyrrhetinic acid like factors [GALF]) at a tissue level have been reported and these provide further regulation of local tissue corti sol bioactivity in humans [6]. Thus intracellular glucocortico id concentrations are not uniform between tissues and are not solely dependent upon plasma free cortisol levels. The many roles of this enzyme system and its part in the pathophysiology of conditions such as the metabolic syndrome, essential hypertension, and polycystic ovarian syndrome amongst others have been the subject of intense interest in recent years. Recently, drugs that modulate the activity of this enzyme system have been developed. Non-steroidal agents that inhibit lIB-HSDl have been developed [7]. Carbenoxolone and glycyrrhetinic acid are inhibitors of lIB -HSD2. The cortisol/cortisone equilibrium measured by the ratio of total corti sol to corti sone (F:E ratio) is used as an index of the activity of the lIB-HSD system. In healthy volunteer s, plasma F:E ratio s have been shown to be stable and free of any circadian variation [8]. The normal reference range for the F:E ratio is 6 - 8. Similar results Table 1. Tissue distribution and function of the 11 ~-HSD system Structure Function Tissue location

1 1 ~-H SD1

1 1 ~- H SD2

Bidirectional, but mainly reductase, NADPH cofactor Converts cortisone to cortisol Liver, lung, gonads, pituitary, brain

Dehydrogenase. NAD cofactor Converts cortisol to cortisone Kidney, colon, salivary glands, placenta

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have been noted with salivary F:E ratios [9]. Evidence is now emerging that the 11~ HSD system may be upregulated in systemic inflammation, sepsis, and septic shock.

Regulation of 11 -JlHSD1 by Inflammatory Mediators There have been numerous studies demonstrating upregulation of 11~-HSD1 activity by inflammatory mediators . Escher et al. showed that tumor necrosis factor (TNF)-a and interleukin (IL)-l~ increase the expression of 11~-HSD1 protein in mesangial cell cultures [10]. Cooper et al. demonstrated stimulation of 11 ~-HSD1 and inhibition of 11 ~- HSD2 activity in human osteoblasts by TNF-a and IL-1~ [11]. Cai et al. described a similar effect in human aortic smooth muscle cells [12]. Studies have also described expression of l1~-HSD1 in rat spleen and lymph nodes [13]. Transcripts for 11~-HSD1 have now been described in the human lymphocyte and macrophage population suggesting a major role for the 11~-HSD1 system during inflammation. Evidence for l1~-HSD activation during inflammation also exists in humans . In a group of hospitalized patients, Vogeser et al. [14] demonstrated an increase in the plasma F:E ratio (an indicator of the set point of HSD1 and 2 activity) in association with the acute phase response. In this heterogeneous study population, increased C-reactive protein (CRP) concentrations correlated significantly with an increased F:E ratio (p < 0.001; r = 0.65). This correlation was independent of increased serum cortisol concentrations. The median ratio was 6.4 in patients with a CRP concentration :5 20 mg/l, and 11.2 in patients with CRP > 20 mg!l (p < O.O!). The same authors demonstrated significant elevations in the F:E ratio in a group of postoperative cardiac surgical patients [15]. The F:E increase in this group was of longer duration than the rise in postoperative plasma total cortisol. Thus, a consistent pattern can be seen in which pro-inflammatory mediators act to promote local glucocorticoid availability.

Evidence of 11 Jl-HSD System Activation in Sepsis Baker et al. examined the role of altered cortisol metabolism in patients with active and cured tuberculosis as compared to healthy controls [16]. In active pulmonary tuberculosis, the F:E ratio in 24-h urine and in the bronchoalveolar lavage (BAL) fluid, and the serum cortisol were significantly elevated demonstrating a shift towards active cortisol (Table 2). Central control of glucocorticoid production was normal but peripheral metabolism was deviated in favor of the active metabolite cortisol. The authors suggested that these data offered a possible mechanism to explain the immunoparesis observed in progressive pulmonary tuberculosis. Data from patients with listerios is also suggest that altered steroid metabolism plays an important role in susceptibility to listeriosis. Hennebold et al., in a murine Table 2.Serum and bronchoalveolar lavage (BAL) total cortisol tocortisone (F:E) ratios in tuberculosis (TB) [16] Serum cortisol (nmol/I) after a 25 mg oral dose of cortisone Urine F:E ratio BAL F:Eratio

Active TB

Cured TB

Volunteers

1157 ± 55

862 ± 50

882 ± 73

2.94 ± 0.4 7.7 ± 1.5

2.28 ± OJ

1.54 ± 0.2 4 ± OJ

Cortisol Metabolism in Inflammation and Sepsis

0 '."

- Sepsis e Trauma .. Burns

60

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Fig. 1. Cortisol/cortisone ratios in critically ill patients, From [18) with permission

0

0

2

3

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5 6 Time (days)

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model of listeriosis, demonstrated that inhibition of IIB-HSD2 enzyme with glycyrrhetinic acid was associated with an enhanced susceptibility to listeriosis (17). Glycyrrhetinic acid, by inhibiting llB-HSD2, will increase local concentrations of cortisol, thus, supporting the immunoparesis hypothesis.

Evidence of 1113-HSD System Activation in Septic Shock The two models of sepsis described above represent models of chronic inflammation. We investigated whether acute septic shock would have any different influence on cortisol metabolism (18). Three cohorts of critically ill patients (septic shock, trauma, and burns, n = 52) were studied serially over a 10-day period and their plasma F:E ratios measured. As compared to controls (normal value 5- 7), the plasma F:E ratio was significantly elevated in the sepsis and trauma cohorts on day 1(22 ± 9, P = 0.01, 23 ± 19, P = 0.0003, respectively) and remained elevated over the study period. Importantly, there also appeared to be a trend towards a biphasic response in the septic shock group around D5-D7 (Fig. 1). Interestingly, the observed changes were not due solely to an increase in total plasma cortisol levels; the corti sone levels were also significantly increased, suggesting a shift in total body II BHSD activity. The changes could be explained by differential increases in llB-HSDI and llB-HSD2 activity, with a proportionately greater increase in the former.

Mechanisms of HSD Activation in Inflammation and Sepsis Potential mechanisms for altered llB-HSDI activity include cytokine activation and changes in redox potential within the cell. The oxo-reductase activity seen in intact cells requires NADPH and leads to the activation of glucocorticoids. Thus, concentrations of NADPH (which in turn are determined by cytosolic redox) influence the activity of the enzyme (19). Critically ill septic patients frequently demonstrate alterations in cellular redox potential mediated largely by endotoxin (20).

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Implications and Conclusion In conclusion, several lines of evidence suggest that plasma F:E ratios may be increased in inflammation and sepsis reflecting altered enzymatic activity of the llB-HSD system. An elevated plasma ratio may signify increased tissue cortisol exposure. The beneficial consequence of this might be greater hemodynamic stability and a reduced need for inotropes or pressor use in shock states. Other benefits may include protection of the cell from the deleterious effects of excess pro -inflammatory cytokines. Conversely, the deleterious effects of this metabolic change may include insulin resistance , hyperglycemia, fluid retention, and some of the immunological alterations of septic shock. Furthermore, these data (which indicate potentially increased tissue availability of cortisol) call into question results from previous studies which have concluded a high incidence of relative adrenal insufficiency in septic shock. The suggestion that the global tissue availability of cortisol is increased in the critically ill reignites the debate about the need for steroid supplementation in this cohort. Further research examining the relationship between tissue cortisol and outcome may shed more light on the significance of alterations in the llB-HSD system and the potential for therapeutic modulation of this enzyme system. References 1. Venkatesh B, Prins J, Torpy D, et al (2006) Relative adrenal insufficiency in sepsis: match point or deuce? Crit Care Resusc 8:376-380 2. Seck! JR, Walker BR (2001) Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action . Endocrinology 142:1371-1376 3. Stewart PM, Krozowski ZS (1999) 11 beta-Hydroxysteroid dehydrogenase . Vitam Horm 57: 249-324 4. Beishuizen A, Thijs LG, Vermes I (2001) Patterns of corticosteroid-binding globulin and the free cortisol index dur ing septic shock and multitrauma. Intensive Care Med 27:1584 -1 591 5. Hamrahian AH, Oseni TS, Arafah BM (2004) Measurements of serum free cort isol in crit ically ill patients. N Engl J Med 350:1629-1638 6. Morris DJ, Latif SA, Hardy MP, Brem AS (2007) Endogenous inhibitors (GALFs) of l lbetahydroxysteroid dehydrogenase isoforms 1 and 2: derivatives of adrenally produced cortico sterone and cortisol. J Steroid Biochem Mol BioI 104:161- 168 7. Vicker N, Su X, Ganeshapillai D, et al (2007) Novel non-steroidal inhibitors of human 11betahydroxysteroid dehydrogenase type 1. J Steroid Biochem Mol BioI 104:123-129 8. Nomura S, Fujitaka M, Sakura N, Ueda K (1997) Circadian rhythms in plasma cort isone and cortisol and the cortisone/cortisol ratio. Clin Chim Acta 266:83 -91 9. Ierjes WK, Cleare AJ, WesselyS, Wood PJ, Taylor NF (2005) Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J Affect Disord 87:299-304 10. Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ (1997) Tumor necrosis factor alpha and interleukin lbeta enhance the cortisone/cortisol shuttle. J Exp Med 186:189-198 11. Cooper MS, Bujalska I, Rabbitt E, et al (2001) Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocr ine switch from glucocorticoid inactivation to activation . J Bone Miner Res 16:1037 -1044 12. Cai TQ, Wong B, Mundt SS, Thieringer R, Wright SD, Hermanowsk i-Vosatka A (2001) Induction of 11beta-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli. J Steroid Biochem Mol BioI 77:117-122 13. Whorwood CB, Franklyn JA, Sheppard MC, Stewart PM (1992) Tissue localization of 11 betahydroxysteroid dehydrogenase and its relationship to the glucocorticoid receptor. J Steroid Biochem Mol BioI 41:21-28 14. Vogeser M, Zachoval R, Felbinger TW, Jacob K (2002) Increased ratio of serum cortisol to cortisone in acute-phase response. Horm Res 58:172-175 15. Vogeser M, Felbinger TW, Roll W, Jacob K (1999) Cortisol metabolism in the postoperative period after cardiac surgery. Exp Clin Endocrinol Diabetes 107:539-546

Cortisol Metabolism in Inflammation and Sepsis 16. Baker RW, Walker BR, Shaw RJ, et al (2000) Increased cort isol: cortisone ratio in acute pulmonary tuberculosis. Am J Respir Crit Care Med 162:1641-1647 17. Hennebold JD, Ryu SY, Mu HH, Galbraith A, Daynes RA (1996) 11 beta-hydroxysteroid dehydrogenase modulation of glucocorticoid activities in lympho id organs. Am J Physiol 270: RI296-1306 18. Venkatesh B, Cohen J, Hickman 1,et al (2007) Evidence of altered corti sol metabolism in critically ill patients: a prospective study. Inten sive Care Med 33:1746-1753 19. Hewitt KN, Walker EA, Stewart PM (2005) Minireview: hexose-6-phosphate dehydrogenase and redox control of 11{beta}-hydroxysteroid dehydrogenase type 1 activity. Endocrinology 146:2539 - 2543 20. Victor VM, Rocha M, De la Fuente M (2004) Immune cells: free radicals and ant ioxidants in sepsis. Int Immunopharmacol 4:327- 347

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Section XIII

XIII Fluid Management

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Assessment of Perioperative Fluid Balance M.T.

GANTER

and C.K.

HOFER

Introduction Incorrect fluid therapy in the peri operative period is associated with considerable morbidity and mortality [1]. Multiple factors have to be considered when devising a rational approach to fluid management for patients in the peri operative period. All available information related to patient's pre-existing diseases, preoperative fluid status , surgical interventions, and intraoperative anesthetic management must be known. To complete the picture, in-depth clinical examination, hemodynamic moni toring and laboratory tests have to be performed ( Table 1). Different fluid compartments cannot be measured easily in the clinical setting, except for the intravascular fluid space. Therefore, a patient's volume statu s (normo-, hypo- and hyper volemia) is most frequently assessed according to cardiac filling, heart function and end-organ perfusion. Because every individual parameter per se is non -specific, these parameters may best complement each other and the clinical evaluation . For adequate assessment of a patient's fluid balance, all available data have to be taken into account like the pieces of a puzzle. Furthermore, to optimize fluid status and avoid fluid overload, frequent re-evaluations are required, especially during a 'fluid trial ', the intravenous administration of a specified amount of fluid over a short period of time. Table 1. Assessment of fluid balance in the perioperative period. Patient's history Preoperative history

• Medical history, preexisting diseases • Preoperative volume status

Surgery/intervention

• Type and duration of surgery/intervention • Blood loss • Third space loss

Anesthesia • • • •

Type and duration of anesthesia Fluid replacement including transfusion Type of monitoring Intraoperative course of physiologica l variables (trends)

Patient's current clinical condition

• Physical examination • Physiological variables from routine, advanced monitoring • Laboratory parameters, medical imaging

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Physical Examination and Routine Monitoring There is a sequence of compensatory mechanisms in the body after intravascular fluid loss (i.e., hypovolemia due to dehydration or bleeding) to maintain adequate tissue perfusion and end-organ oxygenation. In the acute phase, this is mediated predominantly by an increased sympathetic outflow. At fluid losses> 15 % of the blood volume, filling of the jugular veins, preload, and stroke volume decrease. To maintain optimal cardiac output , the heart rate increases to > 100beats/min . Simultaneously, afterload is increased by peripheral vasoconstriction. Therefore, blood pressure is sustained during ongoing volume losses and decreases only with a loss> 30- 40 % blood volume. The mucous membranes become increasingly dry and skin turgor decreases. As signs of reduced tissue perfusion and end-organ oxygenation, decreased urinary output « 0.5 mllkglh) and impaired mental status (confusion, somnolence or coma in severe fluid losses) are observed. Unfortunately, some of these typical pathophysiological signs of hypovolemia are not reliable indicators of a reduced intravascular fluid status in the perioperative period. Anesthetic drugs and stress reactions (due to pain, postoperative nausea and vomiting, body temperature derangements, or respiratory insufficiency) alter pulse rate, blood pressure, and cerebral function . Nevertheless, thirst in an awake patient, dry or parched mucus membranes, collapsed jugular veins, and reduced urinary output are still important sign of hypovolemia in the perioperative clinical setting. In contrast to the evaluation of fluid balance in adults, assessment in children requires additional understanding of age-specific physiology: Cardiac output is primarily regulated via heart rate and not stroke volume due to the relative myocardial stiffness. Furthermore, the elasticity of a child's vessels is higher when compared to that of an adult. Under normal circumstances, the heart rate of children is higher and the blood pressure is lower than that of adults limiting the validity of these parameters to assess hypovolemia in pediatric patients. Evaluation of the capillary refill (Le., the microcirculation of the skin) is an important test to assess the volume status in children. For its assessment, the skin is examined after pressure release performed by the index finger. Delayed normalization of the skin color (> 3 seconds after pressure release) indicates a prolongation of capillary refill and, therefore, reduced skin/end-organ perfusion. The formation of a skin fold on the back of the child's hand between the examinor's thumb and index finger and its persistence after pressure release indicates decreased skin turgor and is another sign of hypovolemia in the child. However, this is rarely seen in the perioperative period . Perioperative hypervolemia may become manifest as arterial hypertension, increased urinary output and pulmonary edema (especially in patients with cardiovascular compromise). Signs of pulmonary edema include crackles, wheezing, and frothy sputum. The diagnosis is confirmed by chest X-ray showing edema of the alveoli, increased vascular filling, and upper lobe diversion. Decreased pulmonary gas exchange may lead to hypoxemia with cyanosis. Ankle edema and anasarca (edema on the back of a bedridden patient) are chronic signs of hypervolemia and prompt a re-evaluation of the patient's history in the perioperative period .

Advanced Hemodynamic Monitoring Different devices are available for advanced hemodynamic monitoring . They can be clinically used in a stepwise escalating approach - from invasive blood pressure

Assessment of Perioperative Fluid Balance Table 2. Advanced hemodynamic monitoring to assess the fluid status. Monitoring device and parameter

Abbreviation

Standard values

CVP SCV02

> 70 %

Invasive blood pressure Visual evaluation of pressure variation Arterial blood gas analysis Central venous catheter Central venous pressure Central venous oxygenation

2-8 mmHg

Invasive, advanced hemodynamic monitoring ("gold standard")

Pulmonary artery catheter Pulmonary artery occlusion pressure Cardiac index Stroke volume index Continuous end-diastolic volume index Mixed venous oxygen saturation

PAOP

8- 18 mmHg

SVI CEDVI Sv02

35-50 ml/m' 100- 200 ml/m' > 75 %

Transpulmonary thermodilution Global end-diastolic volume index Intrathoracic blood volume index Extravascular lung water

GEDVI ITBVI EVLW

700- 800 ml/m' 875- 1000 rnl/rn' :::: 10 mllkg

Pulse contour/wave analysis Pulse pressure variation Stroke volume variation

PPV SVV

< 10 - 13 %

CI

2- 3.5 l/min/rn?

Less invasive, advanced hemodynamic monitoring

< 10 - 13 %

Transesophageal Doppler Aortic flow measurements Transesophageal, transthoracic echocardiography Visual evaluation End-diastolic area End-diastolic volume

EDA EDV

measurement, central venous cannulation, pulmonary artery catheterization, less invasive, advanced hemodynamic monitoring, to transesophageal echocardiography (TEE) ( Table 2). Indications are primarily based on the patient's physical status, related cardiovascular and pulmonary co-morbidities, and the scheduled intervention . For example, invasive blood and central venous pressure (CVP) monitoring are typically applied to a patient with the American Society of Anesthesiologists (ASA) classification I-III undergoing a surgical intervention with anticipated large fluid shifts and losses. Additional sophisticated monitoring, including assessment of cardiac output, is highly desirable for the same interventions in a patient with considerably limited cardiac function. The standard technique to measure cardiac output has been the pulmonary artery catheter (PAC) for the last 30 years. Its routine use, however, is being questioned based on studies demonstrating conflicting results for its impact on patient outcome [2, 3]. Today, several less invasive advanced hemodynamic monitoring techniques are commercially available. They can replace the PAC under different clinical circumstances and some of these techniques additionally allow a more refined fluid assessment [4]. In this section, traditional and newly available techniques of hemodynamic monitoring to evaluate a patient's fluid status are discussed.

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M.T. Ganter and C.K. Hofer Invasive Blood Pressure Monitoring

Invasive blood pressure measurement is important in the evaluation of a patient with ongoing intravascular volume losses and/or limited cardiac function. It allows continuous measurement and is more reliable in hypotonic states than intermittent non-invasive blood pressure measurement. Additionally, in the mechanically ventilated patient, the observation of increased respiratory variations in the arterial blood pressure waveform may help in the assessment of the fluid balance. During inspiration, increased intrathoracic pressure reduces venous return, i.e., preload, and, thus, diminishes stroke volume. As a result, systolic and diastolic pressures decrease and increase with a short delay after inspiration and expiration, respectively ( Figure 1a). The effect is more pronounced for systolic pressure and is typically amplified with progressive hypovolemia. Furthermore, arterial cannulation allows a convenient withdrawal of blood for repeated blood gas analysis and additionallaboratory parameters.

p

~=::::::;::::====;:::::=====::::;::==~I t Inspiration

Expiration

p

Inspiration

Fig. 1. Arterial waveform analysis. a Visual assessment of pulse pressure (PP) variation. Typical pulse pressure variation caused by hypovolemia as a result of intermittent positive pressure ventilation. Note the changes in both the systolic and the diastolic arterial pressure with a higher decrease in the systolic pressure than in the diastolic pressure as a result ofa reduced preload caused by inspiration, i.e., an increase in intrathoracic pressure. P: pressure; t: time. b Quantitative assessment of pulse pressure (PP) and stroke volume (SV) using less invasive hemodynamic monitoring device (pulse contour analysis). PPmax: maximal pulse pressure; PPmin: minimal pulse pressure. PP variation is assessed asthe % change during theventilatory cycle according to thefollowing equation: PPV (%) = (PPmax - PPmin)/PPmean. PPmax/PPmin = the mean values of the four extreme values of pulse pressure; PPmean = average value for this time period. SVmax: maximal stroke volume; SVmin: minimal stroke volume. SW asthe% change ofstroke volume (SV) can be determined during the same time interval accordingly: SW (%) = (SVmax - SVmin) I SVmean. SVmax/min = mean values ofthefour extreme values ofstroke volume during a period of30 sec; SVmean = average value for this time period. p: pressure; t: time.

Assessment of Perioperative Fluid Balance Cardiac Output Measurement

Continuous cardiac output measurement may help to evaluate volume status and to guide fluid resuscitation in patients with impaired cardiac function. As mentioned above, the standard device for assessment of cardiac output is the PAC. Alternatively, less invasive devices can be used considering their specific characteristics and limitations. The most frequently applied techniques are pulse contour/wave analysis and transesophageal Doppler flow measurements [4]. More important than a single value for cardiac output is the analysis of the time course of these values (trends), e.g., the response of cardiac output to fluid administration. Furthermore, cardiac output has to be evaluated in context with clinical examination and other hemodynamic parameters. For example, when cardiac output is low, fluid administration should only be performed when other signs of hypovolemia co-exist. However, if the patient is hypervolemic (cardiac failure), treatment with beta-sympathomimetic catecholamines is required to improve cardiac function. Cardiac Filling Pressures: Central Venous and Pulmonary Artery Occlusion Pressure

Traditionally, CVP and pulmonary artery occlusion pressure (PAOP) have been considered to indirectly reflect heart filling, i.e., right and left ventricular preload ( Fig. 2a). CVP is widely used to assess the fluid status in patients without significant right ventricular (RV) dysfunction and pulmonary alterations when large and rapid changes of the volume status occur. Recent studies however, revealed only a weak correlation between cardiac filling pressures and volumes [5]. These findings may be primarily explained by the fact that transduced intra-thoracic as well as intraabdominal pressures interfere with these pressure measurements. It has to be emphasized that preload according to Frank-Starling is defined as end-diastolic myocardial fiber tension [6]. Because this cannot be measured in a clinical setting, only surrogate markers of preload can be determined. Although pressure is a determinant of a compliant system like the heart, this refers to transmural but not intravascular pressure . Moreover, frequently observed alterations of the cardiac valves or obstruction of the heart cavities may introduce false measurements. Despite these limitations, CVP and PAOP are still used in clinical practice worldwide. It is important that these parameters are interpreted in a clinical context. Furthermore, trends towards low or high values are more predictive for hypo- or hypervolemia than absolute values and the dynamics of changes are essential: For example, a small increase in filling pressures during a fluid trial in a hypovolemic patient may indicate the need for additional fluid administration, whereas a dramatic increase in filling pressures may indicate imminent fluid overload and fluid administration needs to be restricted. Volumetric Preload Parameters

Because cardiac filling pressures do not necessarily reflect the patient's volume status, easy accessible parameters to determine end-diastolic volumes are highly desirable. Two thermodilution based techniques provide volumetric preload parameters, which are calculated from cardiac output using the modified Stewart-Hamilton equation and indicator passage times [7]. Continuous end-diastolic volume index (CEDVI) is assessed by a modified PAC (CCOmbo CCO/Sv02/CEDV catheter 774HF75 Edwards Lifescience LLC, Irvine, CA; USA). Based on the site of measure-

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M.T. Ganter and (.K. Hofer

a

Central venouspressure Pulmonary artery (CVP) occlusion pressure (PAOP)

- -

Global end-diastolic volume index (GEDVI)

c

b

Intrat horacic blood volume index (ITBVI)

d

Continuousend-diastolic volume index (CEDVI)

Extravascular lung water (EVLW)

Fig. 2. Basic and advanced hemodynamic monitoring. a Right and left heart filling pressures. Central venous pressure (CVP) is measured at the transition of the superior vena cava and the right atrium. For pulmonary artery occlusion pressure (PAOP) measurement, the balloon at the tip ofthe pulmonary artery catheter is inflated and floats to the wedge position. The blood flow ceases and a hydrostatic column is created between the tip of the catheter and the right atrium. bContinuous end-diastolic volume index (CEDVI). Continuous end-diastolic volume is determined from continuous cardiac output monitoring and the indicator travel time in the right heart (indicator: intermittent release ofsmall heat quantities from the thermal filament). C Global end-diastolic volume index (GEDVI) and intrathoracic blood volume index (ITBVI). GEDV and ITBV are calculated from cardiac output and different indicator passage time after injection through a central venous catheter and the detection by a thermistor tipped arterial catheter in the femoral artery(see Fig. 3). d Extravascular lung water (EVLW) is calculated from cardiac output and different indicator passage time after injection through a central venous catheter and the detection by a thermistor tipped arterial catheter in the femoral artery (see Fig. 3).

ment, CEDVI reflects right heart end-diastolic volume ( Fig. 2b). Global end-diastolic volume index (GEDVI) and the closely related intrathoracic blood volume index (ITBVI) are determined via transpulmonary thermodilution ( Fig. 2C) , which is used for the calibration of one of the less invasive cardiac output monitoring systems based on pulse contour analysis (PiCCOplus, Pulsion Medical Systems, Munich, Ger-

Assessment of Perioperative Fluid Balance

-oT ('C) Recirculatio n of th e indicat or

Inj ecti on of th ermal ind icator

In

-sr (' C)

-MTt

<, :

,: <;

Dst

Fig. 3. Transpulmonal thermodilution curve and typical indicator passage time required for the calculation of global end-diastolic volume index (GEDVI), intrathoracic blood volume index (lTBVI), and extravascular lung water (EVLW). MTt: mean transit time of the indicator; DSt: down slope time of the indicator; 61: temperature change as result of thermal indicator injection. GEDVI, ITBVI and EVLWI are calculated according to the following formulas: GEDVI = CO x (MTt - DSt) x BSA; ITBVI = 1.25 x GEDVI; EVLW = CO x (MTt - 1.25 x [MTt - DSt]). CO: cardiac output; BSA: body surface area

many). This concept assumes that the thermal indicator travels from the site of injection (central venous catheter) through different central compartments connected in series (i.e., right atrium and ventricle, pulmonary vessels and lungs, left atrium and ventricle) to the indicator detection site (a thermistor tipped arterial catheter typically inserted in the femoral artery). Based on different indicator passage times through these compartments, different volumes can be calculated ( Fig. 3). Thus, GEDVI includes the volume of all heart cavities and of the descending aorta. ITBVI additionally includes the volume of the pulmonary vessels. All volumetric preload parameters have shown to be superior preload indictors than cardiac filling pressures [8-10). Apart from the assessment of GEDVI and ITBVI, the PiCCO system further allows to calculate the extravascular lung water (EVLW, Fig. 2d). EVLW may be useful to better characterize pulmonary edema and acute respiratory distress syndrome (ARDS), to evaluate the success of different ventilatory strategies, and to predict outcome in ARDS. However, careful interpretation of EVLW data is required in the presence of large pulmonary vascular obstruction (e.g., pulmonary emboli), focal lung injury or lung resection [7, 11). Pulse Pressure and Stroke Volume Variation

Variations in pulse pressure (PPV) and stroke volume (SVV) occur due to cyclic changes in intrathoracic pressure induced by mechanical ventilation. The major determinant is a reduced venous return during inspiration of positive pressure ventilation. PPV and SVV were recognized as potential parameters for guiding fluid

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Fig. 4.The concept offluid responsiveness based on theassessment of stroke volume variation (SW). EDV: end-diastolic volume; oEDV: change SVVlarge of end-diastolic volume induced by fluid application; SV: stroke volume; oSV: change in stroke volume induced by fluid administration; SWlarge: stroke volume variation EDV typically higher than 15 %; SWsmall: 6EDV 6EDV stroke volume variation smaller than 12 %. Fluid administration in a patient with a large SW typically results in an increased EDV and an increased SV (so called 'fl uid responder'). During fluid administration, SW decreases and travels up along an imaginary individual Frank-Starling curve. IfSW becomes low, further fluid administration will only induce small changes in both EDV and SV (shallow part of the Frank-Starling curve, so called 'fluid non-responders'). SV svvsmall 6SV ::::::: :::: ::::::: ::: : :: :: : ::: : : : :: : :: : : :: : ::::: :: : : :: : - ~

osv··················· n

replacement therapy more than 20 years ago. However, only with the recent introduction of cardiac output monitoring devices based on pulse wave/contour analysis, is automated quant ification of this phenomenon now possible in clinical practice (Fig. 1b). The method appears to visualize the individual cardiac response (changes in stroke volume) related to myocardial contractility due to diastolic volume loading: In the presence of hypovolemia, high SVV can be observed and the preload dependence of left ventricular (LV) function is pronounced, i.e., the ventricle operates on the ascending limb of the Frank-Starling curve. During volume expansion, there is a right-ward shift of LV function on the Frank-Starling curve, which is thought to correspond to the observed decrease in SVV ( Fig. 41. PPV and SVV have been used to assess fluid responsiveness and have been shown to be sensitive in predicting the ventricular response to fluid administration (i.e., sensitive detection of fluid responders). However, alterations in vasomotor tone may influence PPV more than SVV. Moreover, it should be stressed that this dynamic preload assessment is only reliable in fully sedated, mechanically ventilated patients with a regular heart rhythm [12, 13].

Transesophageal Echocardiography Different echocardiographic approaches allow preload quantification by measuring and calculating either LV end-diastolic area (LVEDA) or volume (LVEDV). LVEDA is determined at mid-papillary level in a short axis view. However, different echocardiographic positions and measurements are required for the volumetric calculation of LVEDV. These calculations are typically based on the Simpson algorithm assuming that the ventricle consists of a sum of small cylinders and a truncated ellipse [14]. Conflicting results have been reported using the Simpson algorithm and, in daily practice, LVEDA is widely used as surrogate of LV preload [15]. However, as this technique is highly operator dependent, the real benefit of echocardiography is the visualization of ventricular function, wall motion abnormalities, and cardiac filling and the 'real-time' guiding of fluid therapy in acute, critical hemodynamic situations. The detection of 'kissing papillary muscles', i.e., the end-systolic contact of these structures, is highly pathognomonic for a hypovolemic state, whereas in hypervolemia a distended left ventricle with decreased function, and mitral insuffi-

Assessment of Perioperative Fluid Balance

ciency as an expression of an enlarged mitral annulus can be seen. Furthermore, echocardiography is of invaluable help as a diagnostic tool (e.g., detection of papillary muscle rupture, pericardial tamponade, acute valvular pathologies, and dissection of the ascending aorta) [16, 17]. Microcirculation/regional Blood Flow

The maintenance of microcirculatory perfusion aims to provide an adequate tissue oxygenation. Consequently, different methods have been developed in recent years to directly visualize the microcirculation. Nailfold microvideoscopy was the first technique available for bedside measurement. Unfortunately, local alterations of the vascular structure due to temperature changes and influences of vasoactive substances rendered readings unreliable. Furthermore, results may fail to represent the microcirculation of target organs like the intestines or the brain. The recently introduced orthogonal polarization spectral (OPS) imaging and sidestream dark-field (SDF) technique are applied to the sublingual mucosal surface. The significance of these techniques has also been questioned for the same reasons as nailfold microvideoscopy. However, use of these monitoring techniques has revealed interesting insights into the hemodynamic pathophysiology of the macro- and microcirculation, for example, in sepsis, where microcirculatory alterations are most likely to occur. The microcirculation improved as a result of a dobutamine infusion unrelated to cardiac output and mean arterial pressure in septic patients [18]. Furthermore, in a comparative model of septic and hemorrhagic shock, changes in the microcirculation were also observed in hemorrhagic shock, but were less pronounced than in septic shock. Resuscitation and restoration of the macro circulation resulted in an increased microcirculation in hemorrhagic shock, whereas treatment failed to improve capillary blood flow in septic shock [19]. It seems that these techniques of microcirculation monitoring provide additional and necessary information for the optimization of end-organ perfusion. However, because they are time consuming and because clearly defined end-point s are lacking, they should still be considered experimental [20].

Laboratory Evaluation Laboratory evaluation supports the assessment of a patient's fluid status primarily by providing information on the effects of an inadequate end-organ perfusion. Parameters assessed by blood gas analysis reflect global tissue hypoperfusion, but also allow the calculation of tissue oxygen extraction (in combination with cardiac output measurement). Furthermore, renal function and the electrolyte composition of the urine provide information on the global fluid status and end-organ perfusion of the kidney. Finally, hormones released from myocardial cells in response to volume expansion and possibly increased wall stress (e.g., B-type natriuretic peptide [BNPJ) may provide some information on the patient's volume status and help to differentiate non-cardiogenic and cardiogenic pulmonary edema ( Table 3).

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M.T. Ganter and (.K. Hofer Table 3. Laboratory parameters to assess fluid balance Standard values Arterial blood gas analysis Metabolic acidosis (pH) Lactate Base excess (BE)

< 7.36 - 7.44 < 2 mEq/1

- 2 - +2 mEq/1

Laboratory parameters of renal function Creatinine (Creat) Blood Urea Nitrogen (BUN) BUN:Creatinine ratio Fractional sodium excretion (FENa) = (Na u x Creats) : (Napx Creatul x 100 Urinary sodium (Na u) Urinary osmolality (Osmul

70-110 mmol/l (0.8-1.25 mg/dl) 2.1-8.9 mmolll (6-25 mg/dll

PRA 20:1 < 1%

ATN 10:1 - 20:1 > 2%

< 10-20 mEq/1 > 450 mOsm/kg

< 350 mOsm/kg

~

Laboratory parameter of cardiac failure Brain natriuretic peptide (BNP) PRA

> 20- 40 mEq/1

< 125 pg/ml

= pre-renal azotemia, ATN = acute tubular necrosis, u = urinary, p = plasma.

Arterial Blood Gas Analysis Inadequate tissue perfusion, i.e., impairment of oxygen delivery (D0 2) and regional hypoxia induces a change in the energy supply from aerobic to anaerobic metabo lism: Instead of 36 only 2 ATP molecules are produced per metabolized glucose molecule, while pyruvate is converted to lactate. Anaerobic metabolism results in the formation of a large amount of hydrogen ions, and metabolic lactic acidosis develops with decreased pH and increased lactate level (> 2 meq/l). Independent of global hypoperfusion and anaerobic metabolism, lactate levels may also be elevated dur ing admin istration of large amounts of lactated Ringer's solution and reduced hepatic clearance of lactate. On the other hand, pH is a function of the available amount of plasma bicarbonate and arterial CO2 , The interaction between pH, HC0 3 - , and PaC0 2 is explained by the Henderson -Hasselbalch equation: pH = pK

+ log HC03- /O .03(PaC02J

for clinical purposes a simplification may be sufficient: pH - HC03-

/

PaC02

Typically, levels of bicarbonate and base excess decrease during the development of tissue hypoperfusion and progressive metabolic lactic acidosis, because plasma bicarbonate acts as hydrogen ion buffer. Base excess is defined as the amount of base required to raise 1 I of blood to a pH predicted from actual PC0 2 and is a derived parameter from bicarbonate and pH:

Base excess = HC03

-

24.8 + (16.2 x [pH - 7.4])

Base excess has been shown to be a better indicator of global hypoperfus ion and the development of metabolic acidosis than pH, primarily because of the compensatory physiologic mechanisms to maintain the pH in a normal range [21, 22). However, base excess can also be altered by etiologies other than global hypoperfusion. For example, hypercholemic metabolic acidosis induced by infusion of normal saline,

Assessment of Perioperative Fluid Balance

diabetic ketoacidosis, and acidosis due to chronic renal failure may result in a decreased base excess (increased base deficit) [23]. Apart from these main parameters indicating global hypoperfusion, arterial blood gas analysis together with advanced hemodynamic monitoring may further allow calculation of how much oxygen is being delivered to the tissue of the body, expressed as the DOz index (DOzI): DOi (mltmin/m') = CI x 13.4 x Hb x Sa02 where CI = cardiac index, Hb = hemoglobin concentration, Sa02 = arterial oxygensaturation. DOzI may help to estimate a deficit in oxygen supply. Several studies have demonstrated an improved outcome when supranormal DOzI levels (> 600 ml/min/m') have been achieved during preoperative resuscitation [24]. However, conflicting results have been reported in studies applying this concept to trauma and septic patients [25,26]. Venous Blood Gas Analysis

The oxygen saturation of venous blood is either measured in the pulmonary vein (mixed venous oxygen saturation [SvO z]) or in the superior vena cava (central venous oxygenation saturation [ScvOz]) using co-oximetry in order to determine the balance between systemic oxygen delivery and consumption (i.e., tissue oxygen extraction). Hypoperfusion due to hypovolemia for example results in a decreased DOz. The determ ination of SvOz requires the placement of a PAC and , in order to avoid the inherent risk related to its use, assessment of ScvOz via a central venous catheter is advocated [27]. SvOz reflects the oxygen extraction of the total body, ScvOz only that of the brain and the upper part of the body. Under physiologic conditions ScvOz values are lower than SvOz values (higher oxygen extraction by the brain), whereas in a sedated patient after major abdom inal surgery, SvOz values may be significantly lower (higher oxygen extraction by the intestines). Thus, it has been argued that SvOz and ScvOz may not necessarily be used interchangeably [28]. However, since trends in these two parameters show a good correlation [29], SvOz and ScvOz are helpful tools for the fluid assessment and resuscitation in complex hemodynamic situations. Because frequent blood gas analyses are required, the use of a modified pulmonary artery or central venous catheter (with fiberoptic sensors to measure oxygen saturation) has to be considered. Parameters of Renal Function

In a patient without renal disease or diuretic therapy, hypovolemia and renal hypoperfusion lead to increased urea reabsorption and a proportionately greater elevation in blood urea nitrogen (BUN) than plasma creatinine. Therefore, the BUN:creatinine ratio can increase from 10: 1 to ~ 20: 1 and help to assess a patient's volume status. However, increased urea production (hyperalimentation, glucocorticoid therapy, gastrointestinal bleeding) may also increase this ratio. Because the appropriate response to fluid deficits is an enhanced renal Na+ and water reabsorption, the urine composition typically reflects the patient's fluid status. In a hypovolemic patient, urine osmolality and specific gravity are generally > 450 mOsm/kg and l.015 g/ml because of maximal concentration of the urine (enhanced arginine vasopressin secretion). Furthermore, the urine Na+ concentration is usually < 20 mEq/l in hypovolemia. For example, if the urine Na+ concentration remains < 20 mEq/l after fluid therapy, then the kidney is sensing persistent volume

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depletion and more fluids should be given. However, the use of urine Na+ concentration cannot be applied to an edematous patient with heart failure or cirrhosis. In these patients, the urine Na+ concentration is a marker of effective circulating volume depletion but not necessarily an indicator of the need of more fluid. Additionally, urine Na+ concentration does not reflect the volume status in conditions associated with impaired Na+ reabsorption, as in acute tubular necrosis. Another exception is hypovolemia due to vomiting, since the associated metabolic alkalosis and increased filtered HCOr impair proximal Na+ reabsorption. In this case, the urine Cl- is low « 20 mEq/l). Finally, in hypovolemia due to diabetes insipidus, urine osmolality and specific gravity are indicative of inappropriately dilute urine.

Conclusion Careful assessment of the fluid balance is required in the perioperative period since incorrect fluid therapy is associated with considerable morbidity and mortality [1]. Protocols with endpoints to achieve, like hemodynamic and metabolic parameters (Tables 2 and 3), should help the clinician to provide optimal fluid therapy: Immediate restoration and/or maintenance of an optimal effective circulating volume with sufficient oxygen carrying capacity and normal electrolyte composition is the primary goal (fluid and electrolyte balance). Currently there is no single endpoint that universally diagnoses hypovolemia and hypoperfusion or identifies when the goals of resuscitation have been met. Trends in resuscitation endpoints over time and their ability to normalize within 24 h following severe trauma has definitively been proven more useful than individual values. Only with frequent re-evaluation of endpoint parameters can resuscitation be tailored specifically to the individual patient and change a 'non-responder' into a 'responder'. Serum pH, bicarbonate, base deficit, and lactate have all been demonstrated to be metabolic indicators of the severity of hypovolemia, and to help determine the adequacy of resuscitation. They have also proved to be more useful than estimated blood loss, heart rate, and blood pressure [30]. Which endpoint is used to guide resuscitation is less important than how the results are interpreted and how the therapy is altered to return the patient to adequate global tissue oxygenation [23]. References 1. Lobo DN, Macafee DA, Allison SP (2006) How perioperative fluid balance influences postoper-

ative outcomes. Best Pract Res Clin Anaesthesiol 20:439- 455 2. Shah MR, Hasselblad V, Stevenson LW, et al (2005) Impact of the pulmonary artery catheter in critically ill patients : meta-analysis of randomized clinical trials. JAMA 294:1664-1670 3. Harvey S, Young D, Brampton W, et al (2006) Pulmonary artery catheters for adult patients in intensive care. Cochrane Database Syst Rev 3:CD003408 4. Hofer CK, Ganter MT,Zollinger A (2007) What technique should I use to measure cardiac output? Curr Opin Crit Care 13:308-317 5. Kumar A, Ane! R, Bunnell E, et al (2004) Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Crit Care Med 32:691-699 6. Starling EH (1920) On the circulatory changes associated with exercise. J R Army Med Corps 34:258-262 7. Isakow W, Schuster DP (2006) Extravascular lung water measurements and hemodynamic monitoring in the critically ill : bedside alternatives to the pulmonary artery catheter. Am J Physiol Lung Cell Mol Physiol 291:LI118-LIl31

Assessment of Perioperative Fluid Balance 8. Durham R, Neunaber K, Vogler G, Shapiro M, Mazuski J (1995) Right ventricular end-diastolic volume as a measure of preload. J Trauma 39:218-223 9. Della Rocca G, Costa GM, Coccia C, Pompei L, Di MP, Pietropaoli P (2002) Preload index: pulmonary artery occlusion pressure versus intrathoracic blood volume monitoring during lung transplantation. Anesth Analg 95:835- 843 10. Hofer CK, Furrer L, Matter-Ensner S, et al (2005) Volumetric preload measurement by ther modilution: a comparison with transoesophage al echocardiography. Br J Anaesth 94:748- 755 11. Michard F (2007) Bedside assessment of extravas cular lung water by dilution methods: temptations and pitfalls. Crit Care Med 35:1186- 1192 12. Hofer CK, Muller SM, Furrer L, Klaghofer R, Genoni M, Zollinger A (2005) Stroke volume and pulse pressure variation for prediction of fluid responsiveness in patients undergoing off-pump coronary artery bypass grafting. Chest 128:848-854 13. Michard F (2005) Changes in arterial pressure during mechanical ventilation. Anesthesiology 103:419-428 14. Schiller NB, Shah PM, Crawford M, et al (1989) Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 2:358- 367 15. Hofer CK, Ganter MT, Rist A, Klaghofer R, Matter-Ensner S, Zollinger A (2008) The accuracy of preload assessment by different transesophageal echo cardiographic techniques in patients undergoing cardia c surgery. J Cardiothorac Vase Anesth (in press) 16. Konstadt SN, Thys D, Mindich BP, Kaplan JA, Goldman M (1986) Validation of quantitative intraoperative transesophageal echocardiography. Anesthesiology 65:418-421 17. Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA (1994) Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventricular function. Anesthesiolog y 81:376-387 18. De Backer D, Creteur J, Dubois MJ, et al (2006) The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 34:403- 408 19. Fang X, Tang W, Sun S, et al (2006) Comparison of buccal microcirculation between septic and hemorrhagic shock . Crit Care Med 34:S447-S453 20. Buchele GL, Ospina -Tascon GA, De Backer D (2007) How microcirculation data have changed my clinical practice. Curr Opin Crit Care 13:324 - 331 21. Davis JW, Shackford SR, Mackersie RC, Hoyt DB (1988) Base deficit as a guide to volume resuscitation. J Trauma 28:1464-1467 22. Davis JW, Kaups KL, Parks SN (1998) Base deficit is superior to pH in evaluating clearance of acidosis after traumatic shock. J Trauma 44:114-118 23. Englehart MS, Schreiber MA (2006) Measurement of acid-base resuscitation endpoints: lactate, base deficit, bicarbonate or what? Curr Opin Crit Care 12:569-574 24. Velmahos GC, Demetriades D, Shoemaker WC, et al (2000) Endpo ints of resuscitation of critically injured patients: normal or supranormal? A prospective randomized trial. Ann Surg 232:409-418 25. Gattinoni L, Brazzi L, Pelosi P, et al (1995) A trial of goal-oriented hemodynamic therapy in critically ill patients. Sv02 Collaborative Group. N Engl J Med 333:1025-1032 26. McKinley BA, Kozar RA, Cocanour CS, et al (2002) Normal versus supranormal oxygen delivery goals in shock resuscitation: the response is the same. J Trauma 53:825-832 27. Marx G, Reinhart K (2006) Venous oximetry. Curr Opin Crit Care 12:263-268 28. Chawla LS, Zia H, Gutierrez G, Katz NM, Seneff MG, Shah M (2004) Lack of equivalence between central and mixed venous oxygen saturation. Chest 126:1891-1896 29. Dueck MH, Klimek M, Appenrodt S, Weigand C, Boerner U (2005) Trends but not individual values of central venous oxygen saturation agree with mixed venous oxygen saturation during varying hemodynamic conditions. Anesthesiology 103:249- 257 30. Rixen D, Siegel JH (2005) Bench-to-bedside review: oxygen debt and its metabolic correlates as quantifiers of the severit y of hemorrhagic and post-traumatic shock. Crit Care 9:441-453

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Fluid Resuscitation and Intra-abdominal Hypertension I.E. DE LAET,

J.J.

DE WAELE,

and M.L.N.G. MALBRAIN

Introduction Fluid resuscitation has been a cornerstone of critical care medicine for as long as critical care medicine has existed. Over the years, fluid management has not changed as much as the technology used to guide it. Although there are enough recent data to indicate that current fluid management strategies may increase morbidity and mortality [1, 2] as well as prevent it, these data have been slow to seep through into guidelines and protocols. This chapter will focus on recent scientific data regarding risks of current fluid management and offer some clues for future research.

Why do we like Fluids? The importance of increasing circulating blood volume in hypovolemic shock, such as in trauma patients, has been apparent for decades and, undoubtedly, the implementation of guidelines and protocols for fluid management in trauma (such as the Advanced Trauma Life Support [ATLS] protocol proposed by the American College of Surgeons) has saved countless lives [3,4]. After the success obtained in hypovolemic shock, aggressive fluid resuscitation has been studied in distributive shock as well. Burn resuscitation is a well known example, where mortality was significantly decreased using aggressive crystalloid resuscitation [5]. In fact, most burn resuscita tion guidelines in the 21st century are still based on the Parkland formula published in the 1960s [6]. In septic shock as well, fluid resuscitation is the first therapeutic action recommended in the Surviving Sepsis Campaign Guidelines [7]. Traditionally, fluid resuscitation protocols are aimed at restoration of 'basic' physiologic parameters, such as blood pressure, central venous pressure (CVP), and urine output. The advantages of this approach are multiple and easy to understand: These parameters are readily available at the bedside and do not require expensive or operator-dependent equipment , leading to broad applicability worldwide. Many aspects of intensive care medicine have undergone extensive changes in the last 20 years, and insights into disease pathophysiology have evolved dramatically, enabling the development of more sophisticated and reliable devices for monitoring and therapy; however, the concept of fluid resuscitation as a ubiquitous positive influence on patient outcome has scarcely been challenged. Over time, the only significant evolution regarding the use of fluid resuscitation has been a gradual increase in emphasis on the importance of time. Both in trauma and burns, delayed fluid resuscitation has been associated with increased mortality and ATLS guidelines as well as burn resuscitation guidelines have stressed the importance of prompt administration of fluids for a long time.

Fluid Resuscitation and Intra-abdominal Hypertension The importance of time in sepsis was highlighted more recently in the landmark paper by Rivers et al. [8) and current sepsis guidelines have embraced this concept (7).

Which Fluids do we Like? The ultimate goal of treatment in shock is to restore the balance between oxygen demand and oxygen delivery, Le., to optimize cardiac output and create an effective circulat ing volume. Therefore, the goal of fluid resuscitation is to restore circulating blood volume, which may mean substitution of external losses, supplying volume to a dilated vascular system, or supplementing internal losses due to third spacing or capillary leak. This goal has traditionally been accomplished using isotonic crystalloid solutions which contain mainly sodium chloride (NaCl). Since the Na+ ion is an extracellular ion, crystalloid solutions will be evenly distributed throughout the extracellular body water compartment after intravenous administration. This means that intravenous adm inistration of 1000 ml of a 0.9 % NaCI solution leads to approximately 200 to 300 ml of intravascular compartment expansion and, in order to achieve a 1000 ml increase in circulating volume, 3000 to 5000 ml of isotonic crystalloid solution would need be administered. In the search for fluids that would selectively expand the intravascular compartment, colloids, both synthetic and natural, were developed and evaluated . According to Starling's equation ( Fig. 1) such fluids Hydrostatic pressure

Arteriole

+8 mm Hg

Osmotic (oncotic) pressure Force Into interstitium Into capillaries

Pressure

r.

:rt; :rtc

Pj

Net pressure

Arteriole 30 mmHg 6 mmHg -28 mmHg - 0 mmHg +8 mmHg Into interstitium

Jv = K,([Pc - P;] - o[:rtc - :rtjJ) where J, is the net fl uid movement between compartments.

Other factors are: 1. Capillary hydrostatic pressure (Pc) 2. Interstitial hydrostatic pressure (P;) 3. Capillary oncotic pressure (:rtc)

Venule 15 mmHg 6 mmHg -28 mmHg - 0 mmHg -7 mmHg Into capillaries

4. Interstitial oncotic pressure (:rtj) 5. Filtration coefficient (K,) 6. Reflection coefficient (0)

Fig. 1 The Starling equation. Capillaries act rather like a leaky hosepipe; although the bulk ofthe fluid continues along the pipe, the pressure forces come out ofthe walls. Hydrostatic (blood) pressure is not the only force acting to cause fluid movement in and out ofthe capillaries. The plasma proteins that cannot cross the capillary walls exert an osmotic pressure to draw water back into the capillaries which outweighs the hydrostatic pressure at the venous end ofthe capillaries. The net pressure at the arteriolar site is +8 mmHg and forces fluids into the interstitium, the net pressure at the venular site is -7 mmHg and drives fluids back into the capillaries. Each day about 20 I are lost while 16 I are regained

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should tip the balance in favor of fluid movement from the interstitial to the intravascular compartment and thus plasma volume expansion. However, several studies were unable to demonstrate a surv ival benefit in favor of colloid resuscitation using either albumin or synthetic colloid solutions in various clinical situations [9 -11). Furthermore, colloids are expensive, albumin and gelatins are derived from human and animal tissue and, therefore, carry a small risk of disease transmission, and synthetic colloids are associated with adverse effects such as anaphylaxis, renal failure, and coagulation defects. These limitations of colloid solutions resulted in crystalloid solutions being incorporated into guidelines as the gold standard for fluid resuscitation, especially in North American literature and guidelines [7). The implementation of structured aggressive fluid resuscitation in a multitude of intensive care unit (leU) patient populations has undoubtedly decreased mortality rates, but it has also lead to administration of vast amounts of crystalloid solution in the first 24 h after major trauma, burns, or septic shock. In several studies, mean administration of more than 30 I of crystalloid over 24 h has been reported [12, B)! In situations associated with capillary leak this approach leads to development of massive tissue edema and the iatrogenic complications that ensue may lead to multiple organ failure (MOF) and death. Reports of mortality secondary to massive fluid resuscitation after trauma or shock are increasingly common [I, 14-16)

Do we like Fluids too Much? The dangers of under-resuscitation in terms of amount or timing of fluid administration are clear, but the adverse effects of over-resuscitation, especially using crystalloids, have only recently been recognized. There is increasing evidence that intraabdominal hypertension (lAH) may be the missing link between overresuscitation, MOF, and death [17). Risk factors for the development of IAH and definitions related to IAH and abdominal compartment syndrome (ACS) as published by the World Society for the Abdominal Compartment Syndrome are listed in Tables 1 and 2 [18). Intra-abdominal pressure (lAP) and ACS are concepts that have been well known to trauma surgeons for many years [19-21) and, as early as 1999, trauma surgeons reported these clinical findings in patients who received massive fluid resuscitation after extra-abdominal injury [22). The mechanism through which massive fluid resuscitation causes IAH is probably related to capillary leak and edema, both of the abdominal wall (leading to decreased abdominal wall compliance) and of the bowel wall (leading to increased abdominal volume). Both these mechanisms have been implicated in the development of IAH ( Fig. 2). In a retrospective series by Maxwell et al. [16), the incidence of abdominal decompression among non-abdominal trauma victims was reported to be 0.5 %. The mean amount of fluid administered was 19 ± 5 I of crystalloid and 29 ± 10 units of packed red blood cells (RBCs); the mortality rate was 67 % and non-survivors were decompressed approximately 20 h later than survivors . The authors suggested that the incidence of secondary ACS may be higher than previously thought in non-abdominal trauma victims and that early decompression may improve outcome since some improvement in organ function was seen after decompression. These authors [16) recommended lAP monitoring in patients receiving large amounts of fluid resuscitation . A landmark paper by Balogh et al. confirmed these findings [1). In this series, 11 (9 %) of 128 patients who underwent standard shock resuscitation developed secondary ACS. All presented in

Fluid Resuscitation and Intra-abdominal Hypertension Table 1. Risk factors for the development of IAH according to the World Society of the Abdominal Compartment Syndrome [18]. Related to diminished abdominal wall compliance

• • • • • • • • • • •

Mechanical ventilation, especially fighting with the ventilator and the use of accessory muscles Use of positive end expiratory pressure (PEEP) or the presence of auto-PEEP Basal pleuropneumonia High body mass index Pneumoperitoneum Abdominal (vascular) surgery, especially with tight abdominal closures Pneumatic anti-shock garments Prone and other body positioning Abdomin al wall bleeding or rectus sheath hematomas Correction of large hernias, gastroschisis or omphalocele Burns with abdominal eschars

Related to increased intra-abdominal contents

• • • •

Gastroparesis/gastric distention/ileus/colonic pseudo-obstruction Abdominal tumor Retroperitoneal/abdominal wall hematoma Enteral feeding

Related to abdominal collections of fluid, air or blood

• • • •

Liver dysfunction with ascites Abdominal infection (pancreatitis, peritonitis, abscess,..) Hemoperitoneum Pneumoperitoneum

Related to capillary leak and fluid resuscitation

• Acidosis (pH below 7.2) • Hypothermia (core temperature below 33 °C) • Coagulopathy (platelet count below 50000/mmJ OR an activated partial thromboplastin time (aPTT) more than 2 times normal OR a prothrombin time (PT) below 50 % OR an international standardized ratio (INR) more than 1.5) • Polytransfusion/trauma (» 10 units of packed red cells124 h) • Sepsis (as defined by the Consensus Conference definitions) • Severe sepsis or bacteremia • Septic shock • Massive fluid resuscitation (> 5 I of colloid or > 10 I of crystalloid/24 h with capillary leak and positive fluid balance) • Major burns

IAV Cab = 00

Fig. 2. Relationship between intra-abdominal volume (IAV), abdominal wall compliance (Cab), and intra-abdominal pressure (lAP). The direction of the movement associated with the sole action of the rib cage inspiratory muscles, abdominal expiratory muscles, and the diaphragm are shown. The direction of the latter depends on Cab but is constrained within the sector shown.

LR_ib_c_ac:... ge_a_c_ t io_ n

Diaphragm action

Abdominal contraction _ lAP

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I.E. de Laet, JJ. De Waele, and M.L.H.G. Malbrain Table 2. Definitions related to intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) as published by the World Society of the Abdominal Compartment Syndrome [18) Definition 1

lAP is the steady-state pressure concealed within the abdominal cavity.

Definition 2

APP = MAP - lAP

Definition 3

FG

Definition 4

lAP should be expressed in mmHg and measured at end-expiration in the complete supine position after ensuring that abdominal muscle contractions are absent and with the transducer zeroed at the level of the mid-axillary line.

Definition 5

The reference standard for intermittent lAP measurement is via the bladder with a maximal instillation volume of 25 ml of sterile saline.

= GFP -

PTP

= MAP -

2 * lAP

Definition 6

Normal lAP is approximately 5- 7 mmHg in critically ill adults.

Definition 7

IAH is defined by a sustained or repeated pathologic elevation of lAP > 12 mmHg.

Definition 8

IAH is graded as follows: • Grade I: lAP 12-15 mmHg • Grade II: lAP 16-20 mmHg • Grade III: lAP 21-25 mmHg • Grade IV: lAP > 25 mmHg

Definition 9

ACS is defined as a sustained lAP > 20 mmHg (with or without an APP < 60 mmHg) that is associated with new organ dysfunction/failure.

Definition 10

Primary ACS is a condition associated with injury or disease in the abdomino-pelvic region that frequently requires early surgical or interventional radiological intervention.

Definition 11

Secondary ACS refers to conditions that do not originate from the abdomino-pelvic region.

Definition 12 Recurrent ACS refers to the condition in which ACS redevelops following previous surgical or medical treatment of primary or secondary ACS. APP: abdominal perfusion pressure; FG: filtration gradient; GFP: glomerular filtration pressure; lAP: intraabdominal pressure; MAP: mean arterial pressure; PTP: proximal tubular pressure

severe shock (systolic blood pressure 85 ± 5 mmRg , base deficit 8.6 ± 1.6 mEq/l), with severe injuries (injury severity score 28 ± 3), and required aggressive shock resuscitation (26 ± 2 units of blood, 38 ± 3 I crystalloid within 24 hours). All cases of secondary ACS were recognized and decompressed within 24 h of hospital admission. After decompression , bladder pressure and systemic vascular resistance decreased, while the mean arterial pressure, cardiac index, and static lung compliance increased. The mortality rate was 54 %. Those who died failed to respond to decompression with increased cardiac index and a sustained decrease in lAP. In analogy to trauma, secondary ACS has also been described in patients with burns and sepsis [23]. Multicenter studies on the prevalence and incidence of IAR in mixed ICU patient populations also showed that a positive net fluid balance as well as a positive cumulative fluid balance were predictors for poor outcome; non-survivors had a positive cumulative fluid balance of about 6 I versus 1 I in survivors [24, 25]. Similar results have also been reported by Alsous and colleagues: At least 1 day of negative fluid balance « -500 ml) achieved by the third day of treatment was a good independent predictor of survival in patients with septic shock [26]. Very recently, Daugherty et al. conducted a prospective cohort study among 468 medical

Fluid Resuscitation and Intra-abdominal Hypertension

ICU patients [27]. Forty patients (8.5 % ) had a net positive fluid balance of more than 5 I after 24 h (after exclusion of patients with risk factors for primary ACS). The incidence of IAH in this group was a staggering 85 % and 25 % developed secondary ACS. The study was not powered to detect differences in mortality and outcome parameters were not statistically different between patients with or without IAH and ACS. Nevertheless, there was a trend towards higher mortality in the IAH group and mortality figures reached 80 % in the ACS group. Although epidemiologic research regarding this subject is virtually non-existent, the increase in reported series seems to indicate an increasing incidence of this highly lethal complication of massive fluid resuscitation. In light of this increasing body of evidence regarding the association between massive fluid resuscitation , IAH, organ dysfunction, and mortality, it seems wise to at least incorporate lAP as a parameter in future studies regarding fluid management, and to question current clinical practice guidelines, not in terms of whether to administer fluids at all, but in terms of the parameters we use to guide our fluid administration.

So, How Should We Use Fluids? The nature and the quantity of fluid resuscitation still need to be addressed . As a result of increasing problems with massive fluid resuscitation, many researchers have gone back to the concept of small volume resuscitation . This concept, to achieve the same physiologic goals as in 'classical' crystalloid resuscitation using smaller volumes, requires the use of hypertonic or hyperosmotic solutions. In the American literature there has been considerable attention paid to the use of hypertonic saline in several conditions [28,29]. The European literature focuses mainly on new synthetic colloids, such as 130 kDa hydroxyethyl starch (HES) [30]. Attempts to combine both strategies have lead to several studies using mixed hypertonic saline and colloid infusions, e.g., hyperHES, a solution consisting of NaCI 7.2 % in HES, with mixed results [31, 32]. Although good results have been obtained with small volume resuscitation in most of these studies , many of them unfortunately make no mention of lAP or the incidence of IAH and ACS. In the area of burn resuscitation there are some exceptions: Oda et al. [33) reported a reduced risk for ACS (as well as lower fluid requirements during the first 24 h and lower peak inspiratory pressures after 24 h) when using hypertonic lactated saline for burn resuscitation and O'Mara et al. reported lower fluid requirements and lower lAP using colloids compared to crystalloids [34). Another major issue in guiding fluid therapy is the lack of reliable resuscitation targets in patients with IAH or ACS. From a theoretical point of view, fluid administration is warranted as long as it promotes cardiac output and, thus, oxygen delivery (DO z). Therefore, the parameter we are most interested in is fluid responsiveness. Since this phenomenon is hard to measure or calculate, it is traditionally substituted by cardiac preload which is, essentially, a volumetric parameter (although many definitions are used). Since cardiac volumes are also hard to measure, preload is usually estimated using cardiac filling pressures (CVP and pulmonary artery occlusion pressure [PAOP]). However, in IAH, the increased lAP is partially transmitted to the thorax in a variable manner dependent mostly on compliance of the abdominal and thoracic wall. The tr ansmission index is estimated to be around 50 % [35, 36). This mechanism leads to an increase in all intrathoracically measured pressures including

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CVP and PAOP which in this situation, although measured correctly, are no longer a reliable measure for cardiac preload. In situations of IAH, 'volumetric indices' such as global end-diastolic volume (GEDV), right ventricular end-diastolic volume (RVEDV), or left ventricular end-diastolic area (LVEDA) have been shown to be more reliable estimates for cardiac preload, but even they do not necessarily represent fluid responsiveness. Several non-invasive cardiac output monitoring tools also provide measurements of systolic pressure variation (SPV), stroke volume variation (SVV), and pulse pressure variation (PPV) which have been shown to correlate well with fluid responsiveness [37]. However, Duperret et al showed that SPY, SVV, and PPV were increased in euvolemic pigs with IAH, which may compromise their use in clinical practice [38]. These authors reported that the Spy and PPV, and inferior vena caval flow fluctuations were dependent on lAP values which caused changes in pleural pressure swings, and this dependency was more marked during hypovolemia. A group of investigators from Brazil [39] found that SPY was modified by hemorrhage but it was also influenced by pneumoperitoneum, and, thus, by IAH. In contrast, PPV was modified by hemorrhage but not by pneumoperitoneum [39]. These findings would suggest that PPV should be used preferentially instead of Spy to detect hypovolemia and to guide fluid therapy during laparoscopic surgery. However, lAP was only increased to 10 mmHg, a very low value since most laparoscopic insufflators are limited to 14 mmHg and IAH has been defined as an lAP above 12 mmHg [18]. Both studies suggest that (some) dynamic indices are not exclusively related to volemia in the presence of increased lAP. The results of Duperret et al. [38] also suggest a dose-related effect since pressure variations were more pronounced during abdominal banding to gradually increase lAP in 5 mmHg steps up to 30 mmHg. Systolic pressure variations were 6.1 ± 3.1 %, 8.5 ± 3.6 %, and 16.0 ± 5.0 % at 0, 10, and 30 mmHg lAP, respectively, in normovolemic animals (mean ± SD; p < 0.01 for lAP effect); these values were 12.7 ± 4.6 %, 13.4 ± 6.7 %, and 23.4 ± 6.3 % in hypovolemic animals, respectively (p < 0.01 vs normovolemic group). However, the authors did not assess the isolated effect of hypovolemia (without the increased lAP) on Spy and PPV in their model which might have created some bias in interpreting the results, especially related to the time-course of their animal experiments. With regard to preload, Duperret looked at left ventricular enddiastolic pressure (LVEDP) and LVEDA and found that the increase in lAP induced a progressive increase in intrathoracic pressure, as indicated by the increased pleural pressure swings, and, therefore, a relative hypovolemia owing to a redistribution of blood volume [38]. Although this factor likely played a role at the highest values of lAP as a decrease in LVEDA was observed, a moderate value of lAP was, on the contrary, associated with an increase in thoracic blood volume as previously shown [40]. Duperret et al. [38] observed an increase in the LVEDA and in the transmural LVEDP. Since the authors did not subject the animals to a fluid challenge they were unable to ascertain whether SPY, SVV, or PPV still represented fluid responsiveness although the pigs were euvolemic prior to the IAH. Moreover, IAH may itself induce hypovolemia and lead to increased SVV and PPV. The studies by Bliacheriene [39] and Duperret [38] demonstrate the importance of the interactions between different compartments, namely the thoracic and abdominal compartment [41]. Recently, simultaneous changes in lAP and CVP tracings were studied in 24 patients during spontaneous breathing [42]; one group included 18 patients without active expiration and the second group included 6 patients with active expiration. The best CVP was defined as the end-expiratory CVP during relaxed breathing. To correct for the effect of expiratory muscle activity

Fluid Resuscitation and Intra-abdominal Hypertension

(uncorrected CVP), a corrected CVP was calculated by subtracting the changes in lAP (~ lAP) from the end-expiratory CVP during active expiration . The bias compared to the best CVP was lower for corrected CVP (2.3±2 mmHg) than for uncorrected CVP (l2.5±4.7 mmHg) [42]. The most important clinical findings from this study were that : first, in the presence of active expiration, a reasonable estimate of transmural CVP can be obtained by subtracting the expiratory increase in lAP from the end-expiratory CVP; and second, this approach may lessen the likelihood that fluid therapy would be withheld from hypovolemic patients . In a recent study by Valenza and colleagues, not only the transmural CVP, but also volumetric measurements of preload were unaffected by lAH or increased positive end-expiratory pressure (PEEP) [43]. This confirms the superiority of 'volumetric' indices of resuscitation adequacy, like GEDV over 'barometric' intracardiac filling pressure measurements, such as end-expiratory CVP or PAOP [35,44]. The clinical relevance of these recent observations is obvious. First, these studies stress the importance of linking the different compartments whilst interpreting compartmental (intravascular) pressures. Second, they advocate the routine use of lAP monitoring in daily clinical practice whilst observing the dynamic changes in lAP and intra cardiac filling pressures during respiration; as a rule of thumb, a rough estimate of transmural CVP can be obtained by subtracting half the lAP from the end-exp iratory CVP value since the average abdomino-thoracic transmission is around 50 % [41]. Third, the abdominal compliance can be estimated by looking at the changes in lAP during respiration. Fourth, the Surviving Sepsis Campaign Guidelines advocate the use of 'barometric' indices of preload, such as CVP and PAOP, but we know that these are erroneously increased in patients with lAH and ACS. Therefore, future resuscitation strategies should preferably be guided by 'volumetric ' preload indices and fluid responsiveness assessed using functional hemodynamics (SVV or PPV), or at least include lAP monitoring with adjustment of barometric target parameters according to lAP. These findings concern all critical care physicians who choose to use end-expiratory intracardiac filling pressures to guide the resuscitation of their patients. Using uncorrected barometric preload indices places the patient at risk of under- or overresuscitation with resultant organ dysfunction , organ failure, and increased mortality. Several authors suggest that, in analogy to cerebral perfusion pressure in the brain , abdominal perfusion pressure (APP: mean arterial pressure - lAP) may be a better resuscitation target than mean arterial pressure [45, 46].

If My Patient Develops Secondary ACS, How do I clear the Fluid excess? Decompressive laparotomy is still the only available definitive treatment for established ACS. In a systematic review, De Waele et al. [47] demonstrated that decompressive laparotomy has a proven beneficial effect on organ function, but mortality after decompressive laparotomy remains high (around 50 %). Delay in treatment has been proposed as a possible explanation for this high mortality. Therefore, any patient with full-blown (primary) ACS should be decompressed immediately, whatever the cause of the lAH. However, in the earlier stages of lAH without or with mild organ dysfunction, other strategies may be beneficial [48]. lAH in general is most frequently caused by either an increased intra-abdominal volume or decreased abdominal wall compliance (Fig. 2.) and both these mechanisms

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are implicated in secondary ACS. Massive fluid resuscitation can lead to large amounts of free fluid being accumulated in the abdominal cavity and development of edema, both in the bowel wall (leading to increased volume) and the abdominal wall (leading to decreased compliance). The increased intra-thoracic and intraabdominal pressures cause disturbances in the thoraco-abdominal lymphatic flow which further promotes the formation of edema and free intraperitoneal fluid, leading to a negative spiral. Therapeutic measures aim at decreasing abdominal volume or increasing abdominal wall compliance. Intra-abdominal volume can be reduced by actively searching for and draining free intraperitoneal fluid. In order to avoid further fluid overload, fluid administration should be restricted and small volume resuscitation should be used (with hypertonic and/or hyperoncotic solutions), as described above. Decreased abdominal wall compliance due to edema is another important target for treatment. The aim of treatment is to decrease the amount of extracellular, extravascular or interstitial water without compromising intravascular effective circulating volume. Theoretically this can be achieved by expanding the intravascular compartment using hyperoncotic solutions (such as albumin 5 % or 20 %) to increase fluid flow from the interstitial space to the intravascular compartment, followed by diuretics to clear the excess fluid from the intravascular space. Some positive results have been reported using the combination of albumin and furosemide [49). However, this approach can only be used when renal function is sufficient to respond to diuretic administration. Since the kidney is the organ most easily affected by IAH (probably due to its unique anatomical position and blood supply) even at levels far lower than the lAP of 20 mmHg that defines ACS, the combination of albumin and diuretics is often of little use. However, in patients with renal dysfunction, renal replacement therapy with aggressive ultrafiltration can provide even better control of excess fluid. Continuous renal replacement therapy (CRRT) enables a minute-to-minute control so that fluid extraction is only limited by the patient's hemodynamic tolerance. Kula et al. described excellent fluid control, as well as a beneficial effect on lAP and respiratory function using continuous veno-venous hemofiltration (CVVH) with ultrafiltration [50). An additional benefit of renal replacement therapy might lie in the removal of cytokines from the bloodstream, as was described by Jiang et al. in patients with acute pancreatitis, where CRRT lead to a decrease in both lAP and plasma interleukin (Il.j-e levels [51). In our institution, we have suggested PAL therapy, an acronym that stands for PEEP-albumin 20 %-lasix (furosemide). The philosophy behind this therapy is that high PEEP levels (equal to lAP) force the alveolar fluid into the interstitium, the albumin will then attract the interstitial fluid towards the intravascular space, while the furosemide will finally remove the excess fluid from the patient. In anuric patients, 'PAL' becomes 'PAU' where the U stands for aggressive ultrafiltration with CVVH. Other non-surgical options for treatment of IAH, unrelated to fluid management, such as the administration of neuromuscular blockers [52) or drainage of intraabdominal collections [53) are listed in Table 3. If all these non-surgical interventions fail and the patient progresses to overt ACS, decompressive laparotomy should be considered immediately, even when no intraabdominal pathology can be found. The invariably high mortality described in the literature for secondary ACS, may be partly due to a reluctance of surgeons and critical care physicians to resort to surgery in these patients. In the previously mentioned series by Daugherty et al. [27], 10 patients were described with secondary

Fluid Resuscitation and Intra-abdominal Hypertension Table 3. Non-surgical treatment strategies in intra-abdominal hypertension 1. Improvement of abdominal wall compliance • Sedation • Pain relief (not fentanyl!) • Neuromuscular blockade • Body positioning • Negative fluid balance • Skin pressure decreasing interfaces • Weight loss • Percutaneous abdominal wall component separation 2. Evacuation of intraluminal contents • Gastric tube and suctioning • Gastroprokinetics (erythromycin, cisapride, metoclopramide) • Rectal tube and enemas • Colonoprokinetics (neostigmine, prostigmine bolus or infusion) • Endoscopic decompression of large bowel • Colostomy • Ileostomy 3. Evacuation of peri-intestinal and abdominal fluids • Ascites evacuation in cirrhosis • CT- or US-guided aspiration of abscess • CT- or US-guided aspiration of hematoma • Percutaneous drainage of (blood) collections • Ascites evacuation in cirrhosis 4. Correction of capillary leak and positive fluid balance • Albumin in combination with diuretics (furosemide) • Correction of capillary leak (antibiotics, source control,...) • Colloids instead of crystalloids • Dobutamine (not dopamine!) • Dialysis or CWH with ultrafiltration • Ascorbic acid in burn patients 5. Specific therapeutic interventions • Continuous negative abdominal pressure (CNAP) • Negative external abdominal pressure (NEXAP) • Targeted abdominal perfusion pressure (APP) • (experimental: Octreotide and melatonin in ACS) CT: computed tomography; US: ultrasound; ACS: abdominal compartment syndrome

ACS after massive fluid resuscitation. None of the 10 patients with ACS (appropriately defined as lAP> 20 mmHg and new or progressive organ dysfunction) underwent surgical decompression. The authors state that these patients were not deemed to be surgical candidates due to their moribund state or to a downward trend in lAP following diuretic s, fluid restriction, or dialysis. One patient arrested immediately prior to planned decompression and could not be resuscitated. Although these patients were apparently adequately treated with non-surgical methods aimed at the cause of the ACS, i.e., the fluid overload, one is left to wonder whether promp t decompressive laparotom y could not have improved the outcome in those patients who did not improve with non -surgical measures.

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Conclusion Although fast and adequate fluid resu scitation rem ain s a cornerston e of eme rgency room and ICU treatm en t in many condi tions, thi s stra tegy carries the r isk of fluid overloa d. Fluid over-resu scitation has been shown to cause increased morbidity and mort ality and IAH may be the missing link bet ween fluid over load and un favorable outcome. Therefore , lAP should be moni tored in all patients receiving massive fluid resuscitation and hem ody namic targ ets should be ada pted accord ing to lAP values. In situat ions with massive fluid requ irements , sma ll volume resu scitation may be considered. In cas es of IAH, non-surgical strategies to decrease fluid overload and decrea se lAP have proved to be successful in some cases. If overt ACS develops, prompt decom pressive lap arot omy should be conside red, whatever th e cause of the ACS. References I. Balogh Z, McKinley BA, Cocano ur CS, et al (2002) Secondary abdom inal compartment syn-

drom e is an elusive early com plication of tr aum atic shock resuscitatio n. Am ] Surg 184: 538-543 2. Kirkpa tri ck AW, Balogh Z, Ball CG, et al (2006) The secondar y abdo minal compartment syndrom e: iatrogenic or unavoidable? ] Am Coil Surg 202:668-679 3. Styner ]K (2006) The birth of Advanced Trauma Life Support (ATLS). Surgeon 4:163-1 65 4. Driscoll P, Wardrope I (2005) ATLS: past, present, and future . Emerg Med I 22:2-3 5. Saffle ]R (1998) Predicting outcomes of burns. N Engl I Med 338:387- 388 6. Hettiaratchy S, Papini R (2004) Initial manag eme nt of a major burn: II - assessment and resusci tation. BMI 329:101- 103 7. Dellinger RP, Carlet ]M, Masur H. et al (2004) Sur viving Sepsis Campaign guidelines for managemen t of severe sepsis and septic shock . Intensive Care Med 30:536-555 8. Rivers E. Nguyen B. Havstad S. et al (2001) Early goa l-d irected therapy in the tr eat ment of severe sepsis and septic shock. N Engl I Med 345:1368- 1377 9. Schierhout G, Roberts I (1998) Fluid resuscitatio n with colloid or crys talloid solutions in crit ically ill patients: a systematic review of rando mised tr ials. BM] 316:961-964 10. Cochrane Injuries Group Albumin Reviewers (1998) Hum an albumin administration in cri tically ill patients: systematic review of rand omis ed contro lled tr ials. BM] 3I7:235- 240 11. The SAFE Study Investigators (2004) A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. N Engl I Med 350:2247- 2256 12. Asensio [A, Forno W, Castillo GA, Gambaro E, Pet rone P (2002) Posterior ische mic optic neu ropathy related to pro found shock after pene tra ting thoracoabd omi nal tra uma . South Med I 95:1053- 1057 13. Asensio lA, McDuffie L, Petro ne P, et al (2001) Reliable varia bles in the exsanguinated patient which indicate damage contro l and pred ict outcome . Am ] Surg 182:743 - 751 14. Balogh Z, McKinley BA, Holcomb IB, et al (2003) Both primary and secondary abdo minal compartment syndrome can be pred icted early and are harbingers of multiple organ failure . I Trauma 54:848- 859 15. Biffl WL, Moore EE, Burch ]M, Offner P], Fra nciose R], John son ]L (2001) Secondary abdo minal compar tmen t syndrome is a highly leth al event. Am I Surg 182:645- 648 16. Maxwell RA, Fabian TC, Croce MA, Davis KA (1999) Secondary abdominal compar tment syndro me: an underappr eciated mani festa tion of severe hemor rhagic shoc k. I Trauma 47:995-999 17. Kirkpatrick AW, De Waele J/, Ball CG, Ranson K, Widder S, Laupland KB (2007) The secondary and recur rent abdominal compartme nt syndro me. Acta Clin Belg:60- 65 18. Malbrai n ML, Cheatha m ML, Kirkpatr ick A, et al (2006) Results from the International Conference of Experts on Intra-abd ominal Hypert ension and Abdo minal Compa rtment Syndrom e. I. Definitions. Intensive Care Med 32:1722 - 1732 19. Kron IL, Harman PK, Nolan SP (1984) The mea surement of int ra -abdominal pr essu re as a criterion for abdominal re-exploration. Ann Surg 199:28 - 30

Fluid Resuscitation and Intra-abdominal Hypertension 20. Cullen DJ, Coyle JP, Teplick R, Long MC (1989) Cardiovascular, pulmonary, and renal effects of massively increased intra-abdominal pressure in critically ill patients. Crit Care Med 17:118-121 21. Schein M, Wittmann DH, Aprahamian CC, Condon RE (1995) The abdominal compartment syndrome: the physiological and clinical consequences of elevated intra-abdominal pressure. JAm Coll Surg 180:745-753 22. Maxwell RA, Fabian TC, Croce MA, Davis KA (1999) Secondary abdominal compartment syndrome: an underappreciated manifestation of severe hemorrhagic shock . J Trauma 47:995-999 23. Ivy ME (2006) Secondary abdominal compartment syndrome in burns. In: Ivatury R, Cheatham M, Malbrain M, Sugrue M (eds) Abdominal Compartment Syndrome. Landes Bioscience, Georgetown, pp 178-186 24. Malbrain ML, Chiumello D, Pelosi P, et al (2004) Prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study. Intensive Care Med 30:822-829 25. Malbrain ML, Chiumello D, Pelosi P, et al (2005) Incidence and prognosis of intraabdominal hypertension in a mixed population of critically ill patients: a multiple-center epidemiologi cal study. Crit Care Med 33:315-322 26. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA (2000) Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest 117:1749-1754 27. Daugherty EL, Hongyan L, Taichman D, Hansen-Flaschen J, Fuchs BD (2007) Abdominal compartment syndrome is common in medical intensive care unit patients receiving largevolume resuscitation. J Intensive Care Med 22:294- 299 28. Morishita Y, Harada T, Moriyama Y, et al (1988) Simultaneous retrieval ofthe heart and liver from a single donor: an evaluation through preservation and transplantation. J Heart Transplant 7:269- 273 29. Tyagi S, Kaul UA, Nair M, Sethi KK, Arora R, Khalilullah M (1992) Balloon angioplasty of the aorta in Takayasu's arteritis: initial and long-term results. Am Heart J 124:876-882 30. Palumbo D, Servillo G, D'Amato L, et al (2006) The effects of hydroxyethyl starch solution in critically ill patients. Minerva Anestesio1 72:655- 664 31. Feng X, Yan W, Liu X, Duan M, Zhang X, Xu J (2006) Effects of hydroxyethyl starch 130/0.4 on pulmonary capillary leakage and cytokines production and NF-kappa B activation in CLP-induced sepsis in rats. J Surg Res 135:129-136 32. Hoffmann IN, Vollmar B, Laschke MW, Inthorn D, Schildberg FW, Menger MD (2002) Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology 97:460-470 33. Oda J, Ueyama M, Yamashita K, et al (2006) Hypertonic lactated saline resuscitation reduces the risk of abdominal compartment syndrome in severely burned patients. J Trauma 60:64-71 34. O'Mara MS, Slater H, Goldfarb IW, Caushaj PF (2005) A prospective, randomized evaluation of intra -abdominal pressures with crystalloid and colloid resuscitation in burn patients. J Trauma 58:1011-1018 35. Cheatham ML, Malbrain ML (2007) Cardiovascular implications of abdominal compartment syndrome. Acta Clin Belg Suppl 62:98-112 36. Pelosi P, Quintel M, Malbrain ML (2007) Effect of intra-abdominal pressure on respiratory mechanics . Acta Clin Belg Suppl 62:78-88 37. Bouteau N, Tavernier B (2004) Stroke volume variation as an indicator of fluid responsive ness. Anesth Analg 98:278 38. Duperret S, Lhuillier F, Piriou V, et al (2007) Increased intra-abdominal pressure affects respiratory variations in arterial pressure in normovolaemic and hypovolaemic mechanically ventilated healthy pigs. Intensive Care Med 33:163-171 39. Bliacheriene F,Machado SB, Fonseca EB, Otsuke D, Auler JO Ir, Michard F (2007) Pulse pressure variation as a tool to detect hypovolaemia during pneumoperitoneum. Acta Anaesthesiol Scand 51:1268-1272 40. Vivier E, Metton 0, Piriou V, et al (2006) Effects of increased intra-abdominal pressure on central circulation. Br J Anaesth 96:701- 707 41. Malbrain ML, Wilmer A (2007) The polycompartment syndrome: towards an understanding of the interactions between different compartments! Intensive Care Med 33:1869-1872

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I.E. de Laet, JJ. De Waele, and M.l-N.G. Malbrain 42. Qureshi AS, Shapiro RS, Leatherman JW (2007) Use of bladder pressure to correct for the effect of expiratory muscle activity on central venous pressure. Intensive Care Med 33: 1907-1912 43. Valenza F, Chevallard G, Porro GA, Gattinoni L (2007) Static and dynam ic components of esophageal and central venous pressure during intra-abdominal hypertension. Crit Care Med 35:1575-1581 44. Cheatham ML, Safcsak K, Block EF, Nelson LD (1999) Preload assessment in patients with an open abdomen. J Trauma 46:16-22 45. Cheatham ML, White MW, Sagraves SG, Johnson JL, Block EF (2000) Abdominal perfusion pressure : a superior parameter in the assessment of intra -abdominal hypertension. J Trauma 49:621-626 46. Malbrain ML (2002) Abdominal perfusion pressure as a prognostic marker in intra-abdominal hypertension. In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg, pp 792-814 47. De Waele JJ, Hoste EA, Malbrain ML (2006) Decompressive laparotomy for abdominal compartment syndrome - a critical analysis. Crit Care 10:R51 48. De laet I, Malbrain ML (2007) ICU management of the patient with intra -abdominal hypertension : what to do, when and to whom? Acta Clin Belg Suppl 190-199 49. Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR (2005) A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med 33:1681-1687 50. Kula R, Szturz P, Sklienka P, Neiser J, lahoda J (2004) A role for negative fluid balance in septic patients with abdominal compartment syndrome? Intensive Care Med 30:2138-2139 51. Jiang HL, Xue WJ, Li DQ, et al (2005) Influence of continuous veno-venous hemofiltration on the course of acute pancreatitis. World J Gastroenterol 11:4815-4821 52. De Laet I, Hoste E, Verholen E, De Waele JJ (2007) The effect of neuromuscular blockers in patients with intra-abdominal hypertension. Intensive Care Med 33:1811-1814 53. Latenser BA, Kowal-Vern A, Kimball D, Chakrin A, Dujovny N (2002) A pilot study comparing percutaneous decompression with decompressive laparotomy for acute abdominal compartment syndrome in thermal injury. J Burn Care Rehabil23 190- 195

Section XIV

XIV Acute Kidney Injury

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Introduction Intensive care medicine has its roots in the care of patients with respiratory insufficiency, and hemodynamic impairment. Since the 1950s, the pioneer years of critical care medicine, intensivists filled the gap in knowledge and workforce that was left open by traditional medical specialties such as surgery and medicine . However,some aspects of the care of critically ill patients were still covered by non-intensivists, and sometimes they still are. Examples of this are infectiology, liver failure, and acute kidney injury (AKI). The most important reason for this is probably a pragmatic one. Specialists in infectiology, acute liver disease, and AKI had the knowledge to care for these diseases in critically ill patients, and were also willing to invest time in this. For the care of patients with AKI, there is another important economic reason, nephrologists already had the necessary infrastructure, dialysis machines, and nurses , to treat these patients. Consequently, the critical care medical literature focuses on 'traditional' topics, and less on these 'specialized' issues. Since the introduction of continuous renal replacement therapy (CRRT), at the end of the 1980s, intensivists also became more interested in AKI. This is maybe best illustrated by the foundation of the Acute Dialysis Quality Initiative (ADQI, www.ADQI.net) in August 2000 [1]. ADQI is an organization where nephrologists and intensivists specialized in the care for patients with AKI collaborate. This group set itself, as an important goal, to summarize the existing evidence on AKI treatment and on the basis of this summary to formulate recommendations for treatment and further research. One of the important accomplishments of the ADQI is the introduction of a consensus definition of AKI, the RIFLE classification [2]. The RIFLE classification defines three increasing levels of severity of AKI on the basis of an increase in serum creatinine concentration or decrease in urine output. An important aspect of the classification is the emphasis on less severe AKI: Patients already meet the RIFLE criteria for AKI when serum creatinine increases by 50 %. Recently, the RIFLE criteria were modified according to recent data from the literature to create the AKI staging system ( Table 1) [3]. Epidemiologic studies have demonstrated that a very large proportion of intensive care unit (leU) patients, between 10 and 67 %, meet the RIFLE criteria for AKI [4]. Although RIFLE is such a sensitive classification, AKI defined by the RIFLE classification is associated with increased mortality. In other words, less severe AKI also has an impact on outcome in severely ill critically ill patients . Despite this shift in focus of intensivists, the proportion of papers on AKI in the critical care literature is still disproportionately low. This chapter will provide an overview of some 'truths' regarding the epidemiology and treatment of AKI that should be brought to the attention of the 'general intensivist' as well as the critical care nephrologist. For several of these truths, there are insufficient data in the available literature to provide strong

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E.AJ. Hoste Table 1. The Acute Kidney Injury Staging System [3] Creatinine criteria

Urine output criteria

Stage 1

Increase in serum creatinine to 2: 150 % and < 200% from baseline OR Increase in serum creatinine 2: OJ mg/dl (26.4 prnol/l)

Urine output < 0.5 ml/kg/hr for 6 hrs

Stage 2

Increase in serum creatinine 2: 200% and < 300 % from baseline

Urine output < 0.5 ml/kg/hr for 12 hrs

Stage 3

Increase in serum creatinine 2: 300 % from baseline OR Serum creatinine of 2: 4 mg/dl (354 prnol/l) with acute increase of 2: 0.5 mg/dl (44 urnol/l) OR renal replacement therapy

Urine output < OJ mllkg/hr for 24 hrs OR anuria for 12 hrs

Creatinine criteria for diagnosis of AKI must be fulfilled within a 48 hour time period. When criteria for AKI are met, development of AKI through the stages is not restricted in time.

evidence-based support. In these cases, we will present the data and a personal interpretation.

Truth No.1: AKI Kills Patients This statement has already been introduced in the introduction to this chapter, and is probably the statement that is the least disputed . For a long time there was a strong belief that supportive measures and treatment with renal replacement therapy could 'bridge' the period to recuperation of kidney function. When a patient died during this process, this was attributed to the consequences of the underlying disease. Loss of kidney function had after all been replaced by the renal replacement therapy. The notion that severe AKI, defined by the need for renal replacement therapy, leads to extra mortality has been demonstrated in cardiac surgery patients [5], general ICU patients [6], sepsis patients [7], and many other cohorts. Since the mid1990s, there is also increasing evidence that less severe AKI also impacts on outcome. It was Levy et al. who demonstrated that contrast-induced nephropathy (CIN), defined by a 25 % increase in serum creatinine concentration, had an independent effect on outcome and led to increased mortality [8]. After that study, several others demonstrated that small changes in kidney function have an independent effect on hospital outcome [9-13].

Truth No.2: The Incidence of AKI is High and Increasing There is a wide variation in the incidence of AKI in ICU patients reported in the medical literature. Two important factors that contribute to this variation in incidence are the baseline characteristics of the patient cohort, and the definition for AKI that is used. The RIFLE classification has been used in a series of single center studies, and 2 multicenter studies on the epidemiology of AKI. In these studies, the incidence of AKI ranged from 10.8 % [14] to 67 % of ICU patients [10]. This wide

Six Truths about Acute Kidney Injury that the Intensivist Should Be Aware Of

range of proportions illustrates the importance of the baseline characteristics of the patient cohort under study. AKI defined by the need for renal replacement therapy, the most severe form of AKI, occurs in approximately 5 % of ICU patients [6, 15]. The incidence is typically very low in cardiac surgery patients, on average 1.4 % [16], but may be as high as 20 % in other ICU cohorts [15]. The population incidence of AKI, defined by the need for renal replacement therapy, ranges from 40 [17] to 1238 patients per million population [18]. This wide range may be explained by the fact that we are comparing different study periods (1988 vs. 2002), and different regions. Another interesting finding is the increasing incidence of AKI over the last 20 years. This was demonstrated in two studies from the USA using large administrative databases maintained by health insurance organizations [17, 19], and also recently in a study from Australia [20]. Waikar et al. demonstrated that the incidence of AKI with need for renal replacement therapy increased from 40 patients per million population in 1988 to 270 patients per million population in 2002 [17]. Whether these numbers are indeed the reflection of a true increase in the incidence, or whether they can be explained by a more liberal use of renal replacement therapy in certain indications is uncertain. What these figures undeniably illustrate is the growing impact of AKI on health care, and on the total health care budget. When we compare the incidence of AKI to that of two other common and important disease entities in ICU patients, sepsis and acute lung injurylacute respiratory distress syndrome (ALI/ARDS), we reach some astonishing facts. The incidence of AKI defined by the need for renal replacement therapy, is now comparable to that of ALII ARDS [17, 21] (ALII ARDS: 112- 320 patients per million population vs. AKI-renal replacement therapy : 110- 286 patients per million population). In addition, the incidence of AKI defined by International Classification of Diseases (ICD)-9 coding [17] is comparable to that of sepsis (sepsis: 3000 patients per million population vs. AKI: 2880patients per million population) .

Truth No.3: Diuretics Offer no Survival Benefit in the Treatment of AKI Loop diuretics have been proposed as a treatment for AKI on the theoretical grounds that they diminish oxygen consumption by blocking sodium and chloride adsorption in the thick ascending limb of the loop of Henle. The medulla is the region in the kidney that is constantly on the verge of oxygen debt [22]. Diminishing oxygen consumption, could, therefore theoretically prevent renal tubular ischemia and acute tubular necrosis. Another reason for use of these drugs could be that they correct volume overload in AKI patients with decreased diuresis by increasing urine output. Despite this theoretical background, and despite loop diuretics being cheap and widely used, there are still only five prospective randomized controlled studies and eight non -randomized stud ies, including, respect ively, 591 and 2520 patients, that have evaluated hospital mortality as the hard endpoint [23]. All but three of these trials are over lO-years old, and the median trial quality was only mediocre , 11 on a scale of 31. Loop diuretics seem beneficial in reducing the period of oliguria, and the number of dialysis treatments, both secondary end-points. However, when we consider mortality, an endpoint that is more relevant to patient care, none of the individual trials demonstrated a surv ival benefit. In addition, meta-analyses could not find benefit [23], and even more alarming, the most recent meta-analysis found that patients treated with diuretics had an 84 % probability of in-hospital mortality compared with control patients [23]. In summary, there is no proof in favor of the

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use of loop diuretics. Considering the ir potential harm, the current liberal use of these drugs in patients with AKI should be discouraged, and a well powered, prospective, randomized trial should be performed.

Truth No.4: Renal Dose Dopamine Should Not Be Used This is a fairly straightforward statement, supported by over 60 trials, some of which of high quality (24), and several meta-analyses [25-27). Let us first reiterate why renal dose dopamine, at a dose of 2 to 4 fig/kg/min, has been considered to be of benefit. Low-dose dopamine promotes diuresis and natriuresis by stimulation of the Dl, D2, and D4 receptors in the kidneys, and thus may be used to prevent or treat AKI. Several animal studies and small clinical studies confirmed this hypothesis. By far the most important, adequately powered, and prospective randomized controlled trial on this topic was performed by the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. In this trial, 324 patients were randomized to treatment with low dose dopamine or control. There was no effect on the primary endpoint, in-hospital mortality, nor on a series of secondary endpoints. These findings were confirmed in three meta-analyses [25-27). None of the trials of low-dose dopamine showed a benefit on mortality, development of AKI,or need for renal replacement therapy. Some trials reported that patients treated with dopamine had increased urine output during the first 24 hours of treatment. However, this finding was not confirmed in the ANZICS trial. In summary, there is considerable proof that renal dose dopamine has no effects on renal or patient outcomes. In addition, there is considerable evidence of several important side effects, including pituitary dysfunction (28) .

Truth No.5: Prevention of Contrast-induced Nephropathy: Volume Matters Intravenous contrast media are widely used in ICU patients for contrast-enhanced abdominal computed tomography (CT) scans and diagnostic and therapeutic angiography procedures. ICU patients are particularly at risk of developing CIN, because many have one or more risk factors for CIN [29, 30). ICU patients who undergo radio-contrast procedures may be hypovolemic, or have impaired kidney function, even when serum creatinine concentration is normal [10, 31). Many patients are treated with concomitant drugs that increase the risk for CIN, such as diuretics or nephrotoxic drugs (e.g., aminoglycosides), and, finally, many patients have comorbid conditions, such as diabetes . There is only one study that has evaluated the incidence of CIN in ICU patients. This single-center study was performed in a surgical ICU setting, where all patients who underwent contrast procedures were treated with intravenous fluids and N-acetylcysteine (NAC) (32). In a series of 486 contrast-enhanced abdominal CT scan procedures, 7 patients (1.4 %) developed CIN, defined as a 0.5 mg/dl increase in serum creatinine. In an additional 17 patients (3.5 %), renal replacement therapy was started after the procedure. CIN has an important impact on outcomes. It has been demonstrated that patients with CIN have increased mortality (8). Further, CIN will incur higher costs, by increased length of ICU and hospital stay, and use of renal replacement therapy. Several strategies have been evaluated for prevention of CIN. However, there are only two studies that have evaluated preventive measures specifically in the ICU set-

Six Truths about Acute Kidney Injury that the Intensivist Should Be Aware Of

ting [33, 34). We, therefore, have to extrapolate studies in non -ICU patients to the ICU setting. Some of the prevent ive measures for CIN, e.g., discontinuation of nephrotoxic drugs and diuretics are not always possible, or the urgency of the diagnostic procedure does not permit waiting for 24 hours or longer. Volume expansion is a well established strategy for prevention of CIN. Although, there are no prospective randomized studies that demonstrate the benefit of volume expansion over no-volume expansion, observational data suggest that volume expansion can reduce the incidence of CIN. In addition, in prospe ctive controlled trials that evaluated various volume expansion strategies , more aggressive volume expansion always reduced the incidence of CIN. Initial trials demonstrated a benefit of half-normal saline (NaCl 0.45 %), while a subsequent trial demonstrated that normal saline (NaCl 0.9 %) was superior compared to half-normal saline (35). Finally, a small, single-center, prospective, randomized trial demonstrated that sodium bicarbonate was superior to NaCI (36). It has been hypothesized that alkalinization of the urine may explain the superiority of sodium bicarbonate over NaCl; however, the exact mechanism for this finding is still uncertain. The general consensu s is that additional trials are needed before the superiority of sodium bicarbonate over saline can be established (30). None of the volume expansion trials was performed in an ICU population; however, there is no reason to belief that volume therapy with saline or sodium bicarbonate is less efficient in this cohort. While volume loading over 12 hours before the radio contrast procedure was more effective than a 300 ml saline bolus during contrast administration (37), this regimen is less practical in ICU patients where the decision for a contrast-enhanced CT scan is seldom made 12 hours beforehand. The sodium bicarbonate protocol is easily applicable in an ICU populat ion and, therefore, deserves extra attention: In this study [36], sodium bicarbonate (154 mEq/l) was admin istered at a rate of 3 ml/kg/h r for 1 hour before the contrast procedure, and at a rate of 1 ml/kg/hr for 6 hours after the procedure. Hemodialysis is effective in removing contrast medium; however, trials that have evaluated the use of hemodialysis did not demonstrate a benefit (30). One trial compared hemofiltration and volume loading in patients with serum creatinine levels > 2 mg/dl, and demonstrated a reduced incidence of CIN, defined as a 25 % increase in serum creatinine, and reduced in-hospital and l-year mortality (38). However, the flawed study design of this trial - serum creatinine was used as an endpoint while this molecule is very effectively removed by hemofiltration - does not allow firm conclusions to be drawn . Over 15 different pharmacological agents have been evaluated for prevention of CIN, in multiple trial s. However, firm evidence for benefit has not yet been demonstrated, and pharmacological agents cannot currently be recommended (30). Only theophylline and NAC have been evaluated in an ICU setting, and will be discussed below [33, 34]. NAC has been intensely studied in over 23 randomized controlled trials, and over 9 meta-analyses. The trials and meta-analyses were inconsistent regarding the benefit of NAC; however, most concluded that NAC was beneficial [29,30). An important limitation for correct interpretation of the trials and meta-analysis on NAC is the considerable heterogeneity of the individual trials (39). Furthermore, NAC may decrease serum creatinine concentration, the clinical endpoint in most trials , while glomerular filtration rate, the effect that is wanted, is not affected [40]. The evidence for a benefit of NAC for prevention of CIN is, therefore, still inconclusive. Several smaller trials demonstrated that theophylline was beneficial, including two performed in an ICU population; a meta-analysis also confirmed benefit [33,34 ,

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41]. Although larger confirmatory trials are needed, theophylline should be considered for prevention of CIN, especially in high risk patients.

Truth No.6: Continuous Renal Replacement Therapy Offers No Survival Benefit over Intermittent Renal Replacement Therapy (Yet!) The theoretical advantages of CRRT are many: CRRT is thought to be better hemodynamically tolerated, remove cytokines, and improve renal recovery and survival. To date, four prospective randomized trials have been published that compared CRRT to intermittent renal replacement therapy, and none of these trials demon strated a survival benefit [42-45]. However, all studies were underpowered, and had various limitations. In addition, two meta-analyses, which included observational trials and trials only published in abstract form, could not demonstrate a survival benefit [46, 47]. However, there was important heterogeneity between studies, and when this was corrected for, Kellum et al. reported in their meta-analysis a survival benefit for patients treated with CRRT [46]. In addition to these data on survival, two large observational trials found a reduced incidence of end-stage kidney disease in patients treated with CRRT [48,49] . In summary, after over 25 years of CRRT, the data are still inconclusive regarding its potential benefit. This year we are expecting the results of two large, well powered, multicenter studies, the Acute Renal Failure Trial Network CATN) Study and the ANZICS RENAL study. These studies will hopefully provide the answer regarding the optimal modality of renal replacement therapy for ICU patients with AKI.

Conclusion In the last decade, we have seen important changes in the epidemiology of AKI in ICU patients. There has been an important increase in the incidence of patients with AKI who are treated with renal replacement therapy, although the indications for initiation of renal replacement therapy have not changed drastically. Further, there is growing consensus on the definition of AKI, with the introduction of the RIFLE classification, which has been modified recently into the AKI staging system. An important aspect of this classification is the gradation of AKI severity in three stages of increasing severity, including even small decreases in kidney function. Importantly, despite including less severe AKI, AKI defined by the RIFLE classification is associated with increased mortality, even after correction for covariates. Although diuretic agents and dopamine are widely used in AKI, their use cannot be recommended. Volume expansion with saline or sodium bicarbonate is the recommended strategy for prevention of CIN. Pharmacologic treatment for prevention of CIN has not proven beneficial yet, although some drugs are promising. Finally, despite many theoretical advantages of CRRT, the optimal modality for renal replacement therapy in ICU patients with AKI is still not established. References 1. Kellum JA, Mehta RL, Angus DC, Palevsky P, Ronco C (2002) The first international consensus conference on continuous renal replacement therapy. Kidney Int 62:1855-1863 2. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, and the ADQI workgroup , (2004)

Acute renal failure - definition, outcome measures, animal models, fluid therapy and infor-

Six Truths about Acute Kidney Injury that the Intensivist Should Be Aware Of mation technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiat ive (ADQI) Group. Crit Care 8: R204-R212 3. Mehta RL, Kellum JA, Shah SV, et al (2007) Acute Kidney Injury Network (AKIN): report of an initi ative to improve outcomes in acute kidney injury. Crit Care (London, England) 11:R31 4. Hoste E, Kellum JA (2006) Acute kidney injury: Epidemiology and diagnostic criteria. Curr Opin Crit Care 12:531-537 5. Chertow GM, Levy EM, Hammermeister KM, Grover F, Daley J (1998) Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 104: 343-348 6. Metnitz PG, Krenn CG, Steltzer H, et al (2002) Effect of acute renal failure requiring renal replacement therapy on outcom e in critically ill patients. Crit Care Med 30:2051 - 2058 7. Hoste EA, Lameire NH, Vanholder RC, Benoit DD, Decruyenaere JM, Colardyn FA (2003) Acute renal failure in patients with sepsis in a surgical ICU: predictive factors, incidence , comorbidity, and outcome . J Am Soc NephroI14:1022-1030 8. Levy EM, Viscoli CM, Horwitz RI (1996) The effect of acute renal failure on mortality. A cohort analysis. JAMA 275:1489-1494 9. Lassnigg A, Schmidlin D, Mouhieddine M, et al (2004) Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 15:1597-1605 10. Hoste EA, Clermont G, Kersten A, et al (2006) RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 10: R73 11. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates OW (2005) Acute kidney injury, mortality, length of stay, and costs in hosp italized patients. J Am Soc NephroI16:3365-3370 12. Uchino S, Bellomo R, Goldsmith 0, Bates S, Ronco C (2006) An assessment of the RIFLE criteria for acute renal failure in hospitalized pat ients. Crit Care Med 34:1913-1917 13. Ostermann M, Chang RW (2007) Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 35:1837- 1843 14. Cruz D, Bolgan I, Perazella M, et al (2007) North East Italian prospective hospital renal outcome survey on acute kidney injury (NEiPHROS-AKI): Targetting the problem with the RIFLE criteria. Clin J Am Soc Nephrol 2:418-425 15. Uchino S, Kellum JA, Bellomo R, et al (2005) Acute renal failure in critically ill patients: a mult inational, multicenter study. JAMA 294:813-818 16. Mehta RH, Grab JO, O'Brien SM, et al (2006) Bedside tool for predicting the risk of postoperative dialysis in pat ients undergoing cardiac surgery. Circulation 114:2208- 2216 17. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM (2006) Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 17:1143-1150 18. Ali T, Khan I, Simpson W, et al (2007) Incidence and outcomes in acute kidney injury: A comprehensive population-based study. J Am Soc NephroI18:1292-1298 19. Xue JL, Daniels F, Star RA, et al (2006) Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 17:1135-1142 20. Bagshaw SM, George C, Bellomo R (2007) Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care 11:R68 21. Goss CH, Brower RG, Hudson LO, Rubenfeld GO (2003) Incidence of acute lung injury in the United States. Crit Care Med 31:1607-1611 22. Lameire N, Van Biesen W, Vanholder R (2005) Acute renal failure. Lancet 365:41 7-430 23. Sampath S, Moran JL, Graham PL, Rockliff S, Bersten AD, Abrams KR (2007) The efficacy of loop diuret ics in acute renal failure: Assessment using Bayesian evidence synthesis techniques. Crit Care Med 35:2516-2524 24. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J (2000) Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356:2139-2143 25. Friedrich JO, Adhikari N, Herridge MS, Beyene J (2005) Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death . Ann Intern Med 142: 510-524 26. Kellum JA, M Decker J (2001) Use of dopamine in acute renal failure: a meta-analysis . Crit Care Med 29:1526-1531 27. Marik PE (2002) Low-dose dopamine: a systemati c review. Intensive Care Med 28:877-883

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E.AJ. Haste 28. Van den Berghe G, de Zegher F (1996) Anterior pituitary function during critical illness and dopam ine treatment. Crit Care Med 24:1580-1590 29. Schultz MJ, Baas MC, van der Sluijs HP, Stamkot GA, Smit W (2006) N-acetylcysteine and other preventive measures for contrast-induced nephropathy in the intensive care unit. Curr Med Chern 13:2565-2570 30. Stacul F, Adam A, Becker CR, et al (2006) Strategies to Reduce the Risk of Contrast-Induced Nephropathy. Am J CardioI98:59-77 31. Hoste EA, Damen J, Vanholder RC, et al (2005) Assessment of renal function in recently admitted critically ill patients with normal serum creatinine. Nephrol Dial Transplant 20: 747-753 32. Haveman JW, Gansevoort RT, Bongaerts AH, Nijsten MW (2006) Low incidence of nephropathy in surgical ICU patients receiving intravenous contrast: a retrospective analysis. Intensive Care Med 32:1199-1205 33. Huber W, Jeschke B, Page M, et al (2001) Reduced incidence of radio contrast-induced nephropathy in ICU patients under theophylline prophylaxis: a prospective comparison to series of patients at similar risk. Intensive Care Med 27:1200-1209 34. Huber W, Eckel F,Hennig M, et al (2006) Prophylaxis of contrast material-induced nephropathy in patients in intensive care: Acetylcysteine, theophylline, or both? A randomized study. Radiology 239:793- 804 35. Mueller C, Buerkle G, Buettner HJ, et al (2002) Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 162:329-336 36. Merten GJ, Burgess WP, Gray LV, et al (2004) Prevention of contrast-induced nephropathy with sodium bicarbonate: A randomized controlled trial. JAMA 291:2328-2334 37. Bader BD, Berger ED, Heede MB, et al (2004) What is the best hydration regimen to prevent contrast media-induced nephrotoxicity? Clin Nephrol 62:1-7 38. Marenzi G, Marana I, Lauri G, et al (2003) The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med 349:1333-1340 39. Bagshaw SM, McAlister FA, Manns BJ, Ghali WA (2006) Acetylcysteine in the prevention of contrast-induced nephropathy: A case study of the pitfalls in the evolution of evidence. Arch Intern Med 166:161-166 40. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK (2004) The value of N-acetylcysteine in the prevention of rad iocontrast agent-induced nephropathy seems questionable. J Am Soc NephroI15:407-41O 41. Ix JH, McCulloch CE, Chertow GM (2004) Theophylline for the prevention of radio contrast nephropathy: a meta-analysis. Nephrol Dial Transplant 19:2747 - 2753 42. Mehta RL, McDonald B, Gabbai FB, et al (2001) A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 60:1154- 1163 43. Augustine JJ, Sandy D, Seifert TH, Paganini EP (2004) A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARE Am J Kidney Dis 44:10001007 44. Uehlinger DE, Jakob SM, Ferrari P, et al (2005) Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant 20:1630-1637 45. Vinsonneau C, Camus C, Combes A, et al (2006) Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial . Lancet 368:379 -385 46. Kellum JA, Angus DC, Johnson JP, et al (2002) Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med 28:29-37 47. Tonelli M, Manns B, Feller-Kopman D (2002) Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 40:875 - 885 48. Bell M, Granath F, Schon S, Ekbom A, Martling CR (2007) Continuous renal replacement therapy is associated with less chronic renal failure than intermittent haemodialysis after acute renal failure. Intensive Care Med 33:773- 780 49. Uchino S, Bellomo R, Kellum JA,et al (2007) Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury. Int J Artif Organs 30:281- 292

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Role of Poly{ADP-Ribose) Polymerase in Acute Kidney Injury R. VASCHETTO, EB. PLOTZ, and A.B.]. GROENEVELD

Introduction Acute renal failure or acute kidney injury (AKI) is common in critically ill patients and carries significant morbidity and mortality. AKI has been used to describe the fullblown clinical picture of, predominantly, acute tubular necrosis following ischemic or nephrotoxic injury. Once risk factors for impending renal failure have been recognized, current clinical management is hardly able to beneficially affect the natural course, so that renal replacement therapy has to be instituted when hyperkalemia, over hydration, or other detrimental sequelae of AKI occur [1 - 3]. A better understanding of early mechanisms could help to design trials in the future to attenuate the development of AKI in high-risk patients. These mechanisms are, however, still poorly understood. Ischemia-reperfusion and nephrotoxins are responsible for most episodes of AKI, leading to acute tubular necrosis [1 - 3]. Two components are important in the acute decrease in glomerular filtration: A vascular component, including pre-/intrarenal vasoconstriction with a fall in glomerular filtration pressure, vascular congestion in the outer medulla, and activation of tubuloglomerular feedback; and a tubular component, including tubular obstruction, transtubular backleak of the filtrate, and interstitial inflammation [3]. At the tubular level, ischem ic damage occurs predominantly in the early proximal tubule (53 segment) and the thick ascending limb of the loop of Henle [4, 5]. Hypoxia resulting from decreased blood flow leads to a variety of secondary factors that promote tubular injury including the generation of reactive oxygen species (R05), the intracellular accumulation of calcium and others, ultimately resulting in apoptosis and/or necrosis [2, 5, 6]. The massive DNA damage that follows from R05-induced DNA single strand breakage, leads to excessive activation of the DNA repair enzyme, poly(ADP-ribose} polymerase (PARP}-l.

PARP-l PARP-1 is a member of the PARP enzyme family consisting of 18 proteins with distinct properties and subcellular localization [7]. PARP-1, the 'founding member' of the PARP enzyme family and one of the most abundant nuclear enzymes, is responsible for more than 90 % of the cellular poly(ADP-ribosyl}ation capacity. PARP-1 is a 116-kDa protein that consists of three main domains: The N-terminal DNA-binding domain containing two zinc fingers, the automodification domain, and the Cterminal catalytic domain. The primary structure of the enzyme is highly conserved in eukaryotes with the catalytic domain showing the highest degree of homology

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1.DNA damage

JIIIIIII 2. PARP-l activation

ADP-Ribose

( +

3. ADP-ribosylation of histones

PARP-l activation

NAD+

Nicotinamide

Accumulation of negative charges

Fig. 1. The catalytic activity of poly(ADP-ribose) polymerase (PARP)-l . Upon DNA breakage, PARP-1 catalyzes the cleavage of nicotinamide adenine dinucleotide (NAD+) into nicotinamide and ADP-ribose and uses the latter to synthesize branched nucleic acid-like polymers of poly(ADP-ribose) covalently attached to nuclear acceptor proteins such as histones. Poly(ADP-ribos)ylation confers negative charge to histones, leading to electrostatic repulsion between DNA and histones.

between different species. PARP-l plays an important role in multiple physiological functions, as well as in pathophysiology of many diseases. PARP-l functions as a DNA damage sensor and signaling molecule binding to single and double-stranded DNA breaks. Upon binding to damaged DNA, PARP-l catalyzes the cleavage of nicotinamide adenine dinucleotide (NAD+) into nicotinamide and ADP-ribose and uses the latter to synthesize branched nucleic acid-like polymers of poly(ADP-ribose) covalently attached to nuclear acceptor proteins ( Fig. 1). Due to its highly negative charge, the covalently attached ADP-ribose polymer dramatically affects the function of target proteins. PARP-l itself is the first target of poly(ADP ribosy)lation, resulting in the downregulation of the enzyme activity. In addition to PARP-l, histones are also considered as the major acceptors of poly(ADP-ribose). Poly(ADPribos)ylation confers negative charge to histones, leading to electrostatic repulsion between DNA and histones. This process has been implicated in chromatin remodeling, DNA repair and transcriptional regulation. PARP-l regulates transcriptional activity by at least two non-exclusive mechanisms: Through the modulation of chromatin structure and through direct interaction with transcriptional factors. PARP-l acts as a co-activator of nuclear factor kappa-B (NF-KB), a key inflammatory transcription factor [8]. It directly binds to NF-KB subunits, resulting in enhanced transactivation. Contrasting ideas are reported as to whether PARP-l catalytic activity is needed for NF-KB activation [9, 10]. PARP-l has also been implicated in the regulation of activator protein (AP)-l. Andreone et al. [11] reported alterations in AP-l activation in oxidatively stressed or interIeukin (IL)-l-treated murine PARP-l knockout fibroblasts. In contrast to its role as a survival factor in the presence of low levels of DNA damage, PARP-l acts to promote cell death in the presence of extensive DNA damage. As such, chemical inhibition or genetic deletion of PARP-l can protect animals from several DNA damage-dependent pathophysiological conditions leading to aberrant cell death, including ischemia-reperfusion injury and toxic and inflammatory injury. Although a role for PARP-l in these conditions has been well established, the

Role of Poly(ADP-Ribose) Polymerase in Acute Kidney Injury

mechanisms by which PARP-l activation leads to cell death are still under active debate. Several mechanisms have been proposed, including energy failure-induced necrosis and apoptosis-inducing factor (AIF)-dependent apoptosis . Necrosis is a cell death process in which a cell swells and ruptures as it dies, releasing intracellular components into the surrounding tissue, which promotes an inflammatory response [12]. Hypersynthesis of poly(ADP)-ribose by PARP-l in response to extensive DNA damage can promote cell death through necrosis, which occurs as a result of the depletion of cellular NAD+ and ATP, and subsequent cellular energy failure [13]. In contrast, apoptosis is an ordered cell death process in which the cell is systematically dismantled within membrane-enclosed vesicles that are engulfed by phagocytes, preventing the release of intracellular components into the surrounding tissue [12]. Studies by Yu et al. [14] show that PARP-l can playa role in caspase-independent apoptotic cell death through AlE AIF is a pro-apoptotic flavoprotein that, upon PARP-l activation when extensive DNA damage occurs, is released from the mitocondria and triggers peripheral chromatin condensation and DNA fragmentation that is considered an irreversible step in cell death [15]. Exactly how PARP-l activation triggers the release of AIF from mitochondria is not clear, yet. The mechanisms underlying the choice of PARP-l-dependent cell death pathways (i.e., necrosis vs. apoptosis) in response to genotoxic stimuli have not been determined, but may be influenced by the type, strength, and duration of the stimuli, as well as the cell type and cellular metabolic status [16].

PARP-l in Acute Kidney Injury Different renal injuries have been associated with PARP-l activation [17]. Pharmacological inhibition and gene ablation of PARP-l attenuated oxidant injury in different models of AKI. Pharmacological inhibition of PARP-l might be a therapeutically viable strategy in preventing the progression of AKI in patients. We will summarize the recent findings on the role of PARP-l in AKI associated with ischernia-reperfusion, inflammation, and toxic injury, and will consider potential future clinical applications. PARP-1 in Renal Injury after Ischemia-reperfusion

Zheng et al. (18) demonstrated enhanced PARP activity in ischemic kidneys as early as 6 h and activation persisted at 12 h, 1, and 5 days post-injury. Chatterjee et al. [19, 20] also reported PARP-l activation in proximal tubules in ischemic rat kidneys at 2,4, and 6 h post-injury and PARP-l inhibitors markedly reduced PARP-l activity when compared to untreated controls. Martin et al. [21] showed the exact localization of PARP-l after ischernia-reperfusion renal injury. They observed increased PARP-l expression compared to controls at 12 h post-injury in S3 segments of the proximal tubule, in the cells sloughed into the tubule lumen and in papillary proliferations, and the expression persisted at day 5 (21). Interestingly, ROS measurements in mitochondria derived from ischemia-reperfusion injury-induced rat kidneys demonstrated that production was approximately 1.5- and 4-times increased in ischemic and reperfused kidneys, respectively (22). Moreover, ROS levels were still enhanced at 12 and 24 h post ischemia-reperfusion and contributed to DNA damage [18]. Thus, the continued presence of ROS in the ischemic kidney that may sustain DNA damage, may be responsible for prolonged PARP activation.

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Depending on the severity of DNA damage, genotoxic stimuli can trigger three different pathways. Under homeostatic conditions, following mild DNA damage, PARP facilitates DNA repair and thus survival. More severe DNA damage can induce apoptotic or necrotic cell death depending on the severity of the injury. PARP-l knock out mice had diminished necrosis compared to wild-type mice 24 h after bilateral clamping of the renal pedicle [18]. Interestingly, these authors also showed diminished apoptosis detected by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end-labeling) staining at 12 h post-clamping. However, the number of apoptotic cells in the wild-type and in PARP-deficient kidneys was comparable at 24 h [18]. In vitro data showed that kidney cells, pre-treated with a potent PARP-l inhibitor, 5aminoisoquinolinone (5-AIQ), displayed less cell death after hydrogen peroxide (HzOz) injury compared to untreated cells [20]. Unfortunately, the lactate dehydrogenase (LDH) measurement the authors used to detect cell death is unable to distinguish between necrosis and late stage apoptosis. Renal ischemia induces a large number of sublethally injured cells in the proximal tubules and their survival greatly depends on the cellular energy levels. The reduced number of necrotic cells and improved histology in the kidneys from PARP-l genedeficient mice kidneys and from PARP-l inhibited rat kidneys may partly be due to the absence of PARP-mediated ATP depletion in the sublethally injured cells [18-21] . The regenerative capacity of the renal proximal tubule immediately after ischemia-reperfusion injury is indeed dependent on the number of non-injured or sublethally injured tubular cells that survive and can initiate the reparative mechanisms that restore the structure and function of the renal tubular epithelium. A major requirement for initiation of the cellular repair process is repletion of intracellular ATP. ATP levels fall to undetectable levels after 60 min of renal ischemia [23]. During the first 2 h after the ischemic insult, ATP recovery occurs in two phases. There is a rapid initial increase in levels of ATP that occurs immediately on reflow, followed by a more gradual elevation to normal levels [24]. The restoration of ATP levels back to normal takes more than 48 h. Martin et al. [21] showed that PARP inhibition post-injury restored levels of ATP close to normal levels at 24 h while the vehicle-treated controls showed that ATP levels were reduced to 54 % of those in kidneys of sham operated rats. Preservation of ATP levels is thus one of the mechanisms by which PARP inhibition may ameliorate ischemia-reperfusion injury. Several PARP-l inhibitors have been tested in animal studies as novel therapeutic interventions against ischemia-reperfusion of the kidney and associated injury. Specifically, Chatterjee et al. [19] tested the efficacy of three chemically distinct PARP inhibitors on ischemic renal injury: 1,5 hydroxyisoquinolinone, (ISO), 3-aminobenzamide (3-AB), and nicotinamide. Male Wistar rats were subjected to 45 min of bilateral renal pedicle clamping followed by reperfusion for 2, 4, and 6 h. PARP inhibitors were administered as a bolus 1 min prior to initiation of reperfusion and an infusion was maintained throughout the reperfusion period. On histological examination, tissue morphology appeared improved in PARP inhibitor-treated rat kidneys. All three PARP inhibitors reduced creatinine concentration and plasma urea, increased glomerular filtration rate, and reduced fractional excretion of sodium when administered before and during reperfusion, suggesting improved renal function . The same group showed a similar effect with the administration of 5-AIQ [20]. More recently, Stone et al. [25] evaluated the effect of PJ-34 on renal injury following thoracic aortic ischemia-reperfusion in mice. PJ-34 was administered 1 hour before and after 11 min of aortic cross clamping. The authors showed that PJ-34 improved renal mitochondrial function and reduced the expression of

Role of Poly(ADP-Ribose) Polymerase in Acute Kidney Injury

neutrophil gelatinase-associated lipocalin (NGAL) mRNA, a specific biomarker of renal injury, at 48 h. Hauser et al. [26] tested the inhibition ofpARP-I by INO-IOOI in a pig model of thoracic aortic cross-clamping-induced ischemia-reperfusion. INO-IOOI was administered starting 90 min before the clamping, stopped during the clamping period and restarted again after declamping for the remaining 4 h. In this model, PARP inhibition failed to preserve renal function although INO-IOOI reduced the need for vasopressor support required to maintain hemodynamics during the early reperfusion period. The effect of PARP on kidney function has also been studied in wild-type and PARP-I deficient mice [18]. Absence of PARP activity following renal ischemia reperfusion injury accelerated recovery of renal functions as reflected by lower plasma concentrations of creatinine during days 1- 3 post-ischemia, and improved glomerular filtration rate at 24 h post-injury. The accelerated recovery in renal function was coupled with improved renal histology at 1 and 5 days following injury. PARP and Renal Injury by Hypothermia Preservation

Kidneys retrieved from cadaver donors for transplantation are preserved to attenu ate the ischemic injury during storage. Despite major advances in preservation solutions and techniques, prolonged cold storage of kidneys can still lead to ischemic injury. Tissue damage due to ischemic injury is a leading cause of delayed graft function after transplantation. Hypothermia is the primary strategy used to preserve cadaveric kidneys ex vivo, thereby reducing oxygen demand by about 97 %. This strategy, albeit effective, is not enough to fully prevent preservation injury of the tissues. Paradoxically, hypothermia also inhibits Na+/K+-ATPase activity and induces an electrolyte imbalance that leads to fluid influx and cell swelling. The cellular edema caused by the influx of water is the primary pathophysiologic event that affects ischemic organs . Furthermore, continued hydrolysis of phosphorylated adenine nucleotides without adequate simultaneous regeneration lowers cell ATP levels and results in loss of adenine nucleotide precursor molecules at reperfusion. Recently, several improvements have been made in the preservation of ischemic organs to reduce this injury by including adenos ine and impermeable saccharides in preservation solutions. Mangino et al. [27] reported that activation of PARP participates in the hypothermic ischernia-reperfusion injury that is associated with prolonged cold storage of kidneys . Adult canine kidneys with and without prior exposure to warm ischemia were harvested, flushed with preservation solutions and stored at 4 °C for 24-120 h. Tissue slices of the cortex were prepared at days 0, I, 3, and 5 and incubated under warm oxygenated conditions to simulate short-term reperfusion at transplantation. The expression of PARP protein increased with cold storage independent of reperfusion. PARP activity increased with prolonged cold storage and was dependent on both reperfusion and preservation medium. The increase in PARP activity was abrogated by prior exposure of the canine kidneys to warm ischemia. This finding is in contrast to previous observations that warm ischemia induced PARP activity in the kidney after reperfusion and that pharmacological inhibition improved kidney function [21]. Inhibition of ROS did not reduce PARP activity in the reperfused cold stored kidneys suggesting that oxidant stress is not a necessary or a likely condition for activating PARP in this sett ing [27]. The functional significance of PARP activity in cold preservation and reperfusion was also tested in isolated canine renal proximal tubule s [27]. Cold preservation of the cells for 48 h followed by 2 h of reperfu-

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sion resulted in 50 % cell death. Surprisingly, inhibit ion of PARP activity enhanced cell death suggesting a protective role for PARP activation in hypothermic cold storage of canine renal cells. However, in renal proximal tubular cells derived from PARP-l gene-deficient mice, hypothermic cold storage did not alter the cell viability and PARP deficiency did not potentiate preservation injury. The role of PARP in hypothermic cold storage and the potential for PARP inhibitors in renal preservation thus remain to be established. PARP-l in Renal Injury during Multiple Organ Failure and Inflammation

Multiple organ failure (MOF) remains a principal cause of death after severe shock or trauma, with or without evidence of sepsis. This syndrome is characterized by severe inflammation leading to the deterioration of several organ functions. AKI is associated with mechanical ventilation, MOF, and death. Several animals model have been described to understand the pathophysiologic mechanisms. Among these, hemorrhagic shock may be a contributory factor by generation of ROS. McDonald et al. [28] showed that hemorrhaging rats for 90 min followed by resuscitation with shed blood (for 4 h) resulted in a substantial increase in the plasma levels of urea and creatinine indicating the development of AKI. Hemorrhage and resuscitation also caused an increase in the plasma levels of the transaminases, indicating hepatocellular injury, and of lipase indicating pancreatic injury. The authors analyzed the effect of the administration, 5 min prior to resuscitation, of three, chemically distinct PARP inhibitors at different concentrations (i.e., 3-AB, nicotinamide and ISO). Treatment of rats subjected to hemorrhage and resuscitation with the PARP inhibitors 3-AB (10 mg/kg) and nicotinamide attenuated the renal dysfunction measured as an increase in plasma level of urea and creatinine. In contrast, the lower dose of 3-AB (3 mg/kg) had no effect. Although ISO also attenuated the rise in the serum levels of urea and creatinine, its vehicle had a similar effect. Similar results were obtained for liver and pancreatic dysfunction. Septic shock is frequently associated with AKI and frequently leads to MOE Septic shock is characterized by severe hypotension and decreased perfusion to critical organ systems despite increased circulating levels of endogenous catecholamines. In addition , sepsis, like other inflammatory conditions, results in a large increase in the production of ROS within the body. Various studies have demonstrated that in isolated cells and tissues, peroxynitrite is capable of mimicking many of the pathophysiological alterations associated with shock (endothelial and epithelial dysfunction, vascular hyporeactivity, and cellular dysfunction), and these alterations are, in part, mediated by PARP activation. In a rat model of septic shock, induced by injecting endotoxin 40 mg/kg intraperitoneally, PARP-l inhibition 1 h before the challenge reduced the increase in plasma creatinine and urea levels at 16 h, compared to untreated rats [29]. Furthermore, PJ-34 exerted a protective effect on liver, lung, and gut. PARP-l in Renal Toxic Injury

Cisplatin remains the drug of choice in many platinum based chemotherapy regimens. It acts by damaging DNA owing to platination to form covalent platinum DNA adducts. DNA damage elicits a series of signal transduction cascades involving chromatin remodeling, which eventually lead to DNA repair, cell cycle arrest , or cell death. The therapeutic effects of cisplatin are dose dependent but the major limit to

Role of Poly(ADP-Ribose) Polymerase in Acute Kidney Injury

its promising efficacy as an antineoplastic drug is its nephrotoxicity. Thus, the prevention of nephrotoxicity is clinically important in cisplatin chemotherapy; however, effective therapeutic or prophylactic agents for cisplatin -induced nephropathy have not been found, except for massive fluid infusions and diuretics. Cisplatin preferen tially accumulates in cells of the S3 segment of renal proximal tubules. Interaction of cisplatin with CYP2El results in the generation of ROS that causes renal injury and initiates cell death. It has been reported that various free radical scavengers or antioxidants showed protective effects on cisplatin nephrotoxicity both in vivo and in vitro. It has been shown that the PARP inhibitor, BGP-1S, ameliorates the renal dam age caused by injection of cisplatin in mice and rats, suggesting that activation of PARP-l is implicated in the etiology of cisplatin nephrotoxicity [30]. Burkle et al. [31] showed that cisplatin caused PARP-l activation in renal tubular cells. Different studies have shown cisplatin-induced apoptosis or necros is in renal tubular cells in vitro, depending on the time of exposure . Shino et al. [32] showed that 3-AB and benzamide can inhibit porcine tubular cell damage in a transient model of cisplatin toxicity. Moreover, ATP was depleted by transient exposure to cisplatin or hydroxyl radical, an effect which was reversed by PARP inhibitors, suggesting that radical generation followed by PARP activation contributes to the necrotic cell injur y caused by transient exposure to cisplatin.

Potential Future Clinical Applications Research on PARP has led to a better understanding of the roles of PARP-l in various normal cellular processes and the pathophysiology of various diseases. PARP activation is relevant for the ability of cells to repair injured DNA but, at the same time, also plays a role in the pathogenesis of various cardiovascular and inflammatory diseases. Thus, depending on the circumstances, pharmacological inhibitors of PARP may be able to attenuate ischemic and inflammatory cell and organ injury or may be able to enhance the cytotoxicity of antitumor agents. Both aspects of the 'double-edged sword' role of PARP can be exploited for the experimental therapy of disease. As several classes of PARP inhibitors move towards clinical development , or have already entered the stage of clinical tr ials, it is expected that in the upcoming few years, new knowledge on PARP inhibitors therapeutic effect will be obtained in human disease. In vivo and in vitro data show that PARP inhibitors exert protective effects in a variety of acute cardiovascular disorders [33]. These are predominantly associated with acute and severe bursts of ROS that can occur due to occlusion and sudden reopening of a blood vessel supplying an organ (such as in stroke or in myocardial infarction). Other diseases associated with ischemia-reperfusion where PARP activation plays a pathogenetic role include hemorrhagic shock (a whole-body ischemiareperfusion type event), major vascular surgery (which is associated with occlusion and release of the aorta), and kidney ischemia-reperfusion injury. In all these disorders, preclinical data demonstrate the ability of PARP inhibitors to improve the function of the affected organs. In vivo and in vitro data also show that PARP inhibitors might be effective also in a variety of chronic indications, such as chronic heart failure, diabetic complications, and Parkinson's disease. When considering all these potential clinical applications of PARP inhibitors, various of practical issues need to be considered, including long-term safety and interactions with other drugs.

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Conclusion Over the last decade, a variety of studies have demonstrated the role of PARP activation in a wide range of pathophysiological conditions. AKI is associated with excessive DNA damage leading to PARP overactivation. The consequences are energy depletion and necrosis in the S3 segments of the proximal tubule of the injured kidney. PARP-l activation also enhances the inflammatory cascade. PARP inhibition may represent an effective approach to treat AKI, and to improve renal function and histopathology in different animal models. The wide variety of disease models in which PARP inhibition has proved beneficial also indicates that PARP inhibitors block a common pathway of tissue injury such as NF-lCB activation or oxidative stress-induced cytotoxicity. The marked beneficial effect of PARP inhibitors in many animal models of various diseases suggests that PARP inhibitors can be exploited to treat human diseases, particularly in the critically ill with impending AKI at high risk for need of renal replacement therapy. However, before potent PARP inhibitors can be used in humans, crucial safety issues must be addressed. Because PARP has been implicated in DNA repair and maintenance of genomic integrity, one possible risk associated with long-term PARP inhibition might be an increased mutation rate and cancer formation. References 1. Kikeri D, Pennell JP, Hwang KH, Jacob AI, Richman AV, Bourgoignie JJ (1986) Endotoxemic acute renal failure in awake rats. Am J PhysioI250:FI098-FI106 2. Thadhani R, Pascual M, Bonventre JV (1996) Acute renal failure. N Engl J Med 334:14481460 3. Lameire N, Van Biesen W, Vanholder R (2005) Acute renal failure. Lancet 365:417-430 4. Venkatachalam MA, Bernard DB, Donohoe JF, Levinsky NG (1978) Ischemic damage and repair in the rat proximal tubule: differences among the SI, S2, and S3 segments. Kidney Int 14:31-49 5. Versteilen AM, Di Maggio F, Leemreis JR, Groeneveld AB, Musters RJ, Sipkema P (2004) Molecular mechanisms of acute renal failure following ischemia/reperfusion. Int J Artif Organs 27:1019-1029 6. Kaushal GP, Basnakian AG, Shah SV (2004) Apoptotic pathways in ischemic acute renal failure. Kidney Int 66:500- 506 7. Smith S (2001) The world according to PARP. Trends Biochem Sci 26:174-179 8. Oliver FJ, Menissier-de Murcia J, Nacci C, et al (1999) Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-l deficient mice. EMBO J 18:4446-4454 9. Chang WJ, Alvarez-Gonzalez R (2001) The sequence-specific DNA binding of NF-kappa B is reversibly regulated by the automodification reaction of poly (ADP-ribose) polymerase 1. J BioI Chem 276:47664-47670 10. Hassa PO, Covic M, Hasan S, Imhof R, Hottiger MO (2001) The enzymatic and DNA binding activity of PARP-l are not required for NF-kappa B coactivator function . J Bioi Chem 276:45588-45597 11. Andreone TL, O'Connor M, Denenberg A, Hake PW, Zingarelli B (2003) Poly(ADP-ribose) polymerase-l regulates activation of activator protein-l in murine fibroblasts. J Immunol 170:2113-2120 12. Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Bioi 16:663 -669 13. Bouchard VJ, Rouleau M, Poirier GG (2003) PARP-l, a determinant of cell survival in response to DNA damage. Exp Hematol 31:446-454 14. Yu SW, Wang H, Poitras MF, et al (2002) Mediation of poly(ADP-ribose) polymerase-l dependent cell death by apoptosis-inducing factor. Science 297:259-263

Role of Poly(ADP-Ribose) Polymerase in Acute Kidney Injury 15. Susin SA, Lorenzo HK, Zamzam i N, et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441-446 16. Virag L (2005) The expanding universe of poly(ADP-ribosyl)ation. Cell Mol Life Sci 62: 719-720 17. Devalaraja-Narashimha K, Singaravelu K, Padanilam BJ (2005) Poly(ADP-ribose) polymerase-mediated cell injur y in acute renal failure. Pharmacol Res 52:44-59 18. Zheng J, Devalaraja-Narashimha K, Singaravelu K, Padanilam BJ (2005) Poly(ADP-ribose) polymerase-I gene ablation protects mice from ischemic renal injury. Am J Physiol Renal Physiol 288:F387-F398 19. Chatterje e PK, Zacharowski K, Cuzzocrea S, Otto M, Thiemermann C (2000) Inhibitors of poly (ADP-ribose) synthetase reduce renal ischemia -reperfusion injury in the anesthetized rat in vivo. FASEB J 14:641- 651 20. Chatterjee PK, Chatterjee BE, Pedersen H, et al (2004) 5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion. Kidney Int 65:499- 509 21. Martin DR, Lewington AJ, Hammerman MR, Padanilam BJ (2000) Inhibit ion of poly(ADPribose) polymerase attenuates ischemic renal injury in rats. Am J Physiol Regul Integr Comp Physiol 279:RI834-RI840 22. Gonzalez-Flecha B, Boveris A (1995) Mitochondrial sites of hydrogen peroxide production in reperfused rat kidney cortex. Biochim Biophys Acta 1243:361-366 23. Karasawa A, Kubo K (1990) Protection by benidipine hydrochloride (KW-3049), a calcium antagonist, of ischemic kidney in rats via inhibitions of Ca-overload, ATP-decline and lipid peroxidat ion. lpn J Pharmacol 52:553- 562 24. Stromski ME, Cooper K, Thulin G, Gaudio KM, Siegel NJ, Shulman RG (1986) Chemical and functional correlates of post ischemic renal ATP levels. Proc Nat! Acad Sci USA 83:6142-6145 25. Stone DH, AI-Badawi H, Conrad MF, et al (2005) PJ34, a poly-ADP-ribose polymerase inhibitor, modulates renal injury after thoraci c aortic ischemia/reperfusion. Surgery 138:368-374 26. Hauser B, Groger M, Ehrmann U, et al (2006) The parp-I inhibitor ino-l00l facilitates hemo dynamic stabilization without affecting DNA repair in porcine thoracic aort ic cross-clamping-induced ischemia/reperfusion. Shock 25:633- 640 27. Mangino MJ, Ametani M, Szabo C, Southard JH (2004) Poly(ADP-ribose) polymerase and renal hypothermic preservation injury. Am J Physiol Renal Physiol 286:F838-F847 28. McDonald MC, Filipe HM, Thiemermann C (1999) Effects of inhibitors of the activity of poly (ADP-ribo se) synthetase on the organ injury and dysfunction caused by haemorrhagic shock. Br J Pharmacol 128:1339-1345 29. Iagtap P, Soriano FG, Virag L, et al (2002) Novel phenanthridinone inhibitors of poly (adenosine 5'-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents. Crit Care Med 30:1071-1082 30. Racz I, Tory K, Gallyas F Ir, et al (2002) BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity. Biochem Pharmacol 63:1099-1111 31. Burkle A, Chen G, Kupper JH, Grube K, Zeller WJ (1993) Increased poly(ADP-ribosyl)ation in intact cells by cisplatin treatment. Carcinogenesis 14:559-561 32. Shino Y, Itoh Y, Kubota T, Yano T, Sendo T, Oishi R (2003) Role of poly(ADP-ribose)polymerase in cisplatin-induced injury in LLC-PKI cells. Free Radic Bioi Med 35:966-977 33. Graziani G, Szabo C (2005) Clinical perspectives of PARP inhibitors. Pharmacol Res 52:109118

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From Hemodynamics To Proteomics: Unraveling the Complexity of Acute Kidney Injury in Sepsis M. MATEJOVIC,

P.

RADERMACHER,

and V. THONGBOONKERD

Introduction Sepsis is a complex syndrome characterized by an uncontrolled and deregulated systemic inflammatory response to infection. This is mediated by a broad spectrum of endogenous mediators whose actions result in multiple organ dysfunction distant from the original focus of infection. The kidney is a common 'victim organ' of various insults in critically ill patients. Sepsis and septic shock are the dominant causes of acute kidney injury (AKI), accounting for nearly 50 % of episodes of acute renal failure [1]. The incidence of AKI in sepsis increases proportionally with the severity of sepsis, with AKI developing in 19 % of patients with sepsis, 23 % of those with severe sepsis, and 51 % of patients with septic shock [2]. The mortality of sepsis patients with co-existing acute renal failure reaches 70 %, thereby outstripping that of patients with other causes of AKI [3]. Interestingly, even relatively minor increments in serum creatinine levels coincide with markedly increased morbidity and mortality [4], highlighting the potentially important role ofkidney dysfunction during the natural history of critical illness. However, the precise understanding of the multifactorial mechanisms of sepsis-induced AKI that would allow the development of new therapeutic strategies to prevent AKI or to hasten its recovery remains a mystery. Here, we review the most recent advances in the understanding of the molecular mechanisms and pathophysiology of sepsis-induced AKI, focusing on renal hemodynamic and microvascular changes and on the importance of a rapidly evolving proteomics approach to evaluating sepsis-induced kidney dysfunction.

Kidney Hemodynamics in Sepsis: A Challenging Concept Undoubtedly, sepsis-associated hypovolemia caused by increased venous capacitance and venous pooling, generalized increased vascular permeability with fluid leak into the tissue interstitium, increased insensible losses and, frequently, restricted fluid intake, is the dominant 'pre-renal' and, hence, potentially reversible cause of AKI in sepsis. Progression of sepsis into septic shock is associated with the development of hypotension and consequent further rapid fall in glomerular filtration rate due to reduced renal perfusion pressure , a principal driving force of glomerular filtration . Provided the precipitating cause is controlled and adequate renal perfusion restored in the initial stage of sepsis, the result may still be functional and reversible dysfunction not associated with impaired tubular cell integrity. However, persistent renal hypoperfusion unavoidably leads to ischemic acute tubular injury. It is important to stress that even modest, often clinically silent reductions in renal

From Hemodynamics To Proteomics: Unraveling the Complexity of Acute Kidney Injury in Sepsis

perfusion pressure might result in manifest AKI ifleft unrecognized [5]. Particularly susceptible to this so called normotensive ischemic AKI is the kidney with chronically impaired autoregulation of renal blood flow and glomerular filtration, occurring typically in elderly patients, in patients with advanced atherosclerosis, arterial hypertension, chronic nephropathy, or in patients with pharmacologically diminished autoregulatory capability (i.e., patients on non-steroidal anti-inflammatory drugs [NSAIDs], angiotensin-conve ring enzyme [ACE] inhibitors or angiotensinreceptor blockers) [5]. On the other hand, a number of septic patients do develop progressive reduction of renal function despite timely and adequate control of systemic hemodynamic alterations . Acute tubular necrosis (ATN) is generally regarded as the most frequent mechanism of acute renal failure in critically ill patients (approximately 75 % of all AKI cases) [6]. This type of cellular injury is traditionally ascribed to the effect of ischemia and/or toxins. The concept of renal vasoconstriction and kidney ischemia as a key pathogenic factor in acute renal failure is well embedded in the critical care and nephrology literatures. Although this is certainly valid for all low flow states, such as cardiogenic or hemorrhagic shock, during sepsis and other acute systemic inflammatory conditions the hemodynamic alterations within the kidney remain contro versial [7, 8]. This reasoning is supported by several findings: 1) The concept of an ischemic etiology of AKI in sepsis is derived from experimental models with limited clinical relevance [7]; 2) there is no published study in septic patients, which would provide conclusive histopathological evidence of the presence of ATN in the course of sepsis-induced AKI using a series of renal biopsies [8]; 3) no signs of morphological kidney injury have been found in over 90 % of histopathological findings made at autopsy in patients dying from AKI associated with severe sepsis [9]. The behavior of renal blood flow and renal vascular resistance in human sepsis is not clearly understood. Results of experimental studies are fairly inconsistent and the limited potential for accurate renal hemodynamic measurements in critically ill patients precludes exact research . Recent systematic review of the available experimental evidence showed that about 30 % of animal studies reported unchanged or even increased renal blood flow [7]. It should be emphasized that the majority of studies reporting a reduction in renal blood flow were derived from very heterogeneous, short-term, and mostly hypodynamic models characterized by a reduced cardiac output, which, therefore, have limited resemblance to human pathophysiology. Remarkably, cardiac output appears to be the dominant predictor of both renal blood flow and renal vascular resistance in sepsis [7, 10]. Hence, a fundamental step to understand the pathophysiology of septic AKI is the use of animal models designed to meet the criteria of human sepsis/septic shock [11]. Indeed, utilizing a clinically relevant model of sepsis-induced AKI, Bellomo and his group [12- 14] largely challenged our conventional presumption by suggesting that renal vasoconstriction may not necessarily be a prerequisite for AKI to develop during hyperdynamic sepsis. In their studies in a sheep model of sepsis, a hyperdynamic and normotensive circulation induced by injecting or continuously infusing Escherichia coli was accompanied by significant renal vasodilatation and increased renal artery blood flow [12- 14]. These findings are consistent with our observations obtained from a 24-h porcine model of fecal peritonitis-induced sepsis, in which renal blood flow remained well-preserved during progres sion of sepsis to septic shock provided that a hyperdynamic circulat ion was maintained (unpublished data) . Moreover, the study by Langenberg et al. [13] extended their research into the process of resolution of AKI and showed, for the first time, renal

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hemodynamic and functional patterns during the recovery from experimental AKI in sepsis. Strikingly, an association between relative renal vasoconstriction, reduction in renal blood flow, and functional improvement was found during recovery from AKL This finding suggests that the renal vascular bed participates in systemic hemodynamic alterations not only during the evolution of sepsis, but also during its resolution.

Renal Microcirculation: A Culprit in Acute Kidney Injury Widespread microvascular dysfunction is considered as a crucial element in the sepsis syndrome, and is likely involved also in its complications [13]. There is emerging evidence that renal microvascular dysfunction may be critically involved in the development of sepsis-induced renal injury. Renal Glomerular Hemodynamics in Sepsis: A Vasomotor Nephropathy?

There is a widely held assumption that increased afferent arteriolar resistance mediated by circulating vasoconstrictors represents a physiological substrate for decreased intraglomerular capillary pressure and, hence, reduced glomerular filtration rate [1,5,17]. However, the absolute lack of data from humans and experimental models of hyperdynamic, well-resuscitated sepsis questions the robustness of this paradigm. Although it seems reasonable to argue that changes in intraglomerular hemodynamics are likely involved in the deterioration of glomerular filtration, at least in the early stages, the exact response of both afferent and efferent arterioles in the course of sepsis is completely unknown. Interestingly, significant renal vasodilatation, increased renal artery blood flow, and reduced glomerular filtration with preserved tubular functions observed in the above mentioned large animal studies [12-14] offer a provocative hypothesis: Decreased rather than increased glomerular vascular resistance affecting both the afferent and efferent arterioles, with the effect predominating in the latter vessels, might explain the fall in glomerular filtration, and the opposite changes in the intraglomerular circulation might account for the restoration of glomerular filtration. The lack of effectiveness or even worse outcome in clinical trials investigating various vasodilators in septic acute renal failure [18, 19] and, conversely, increased urine output and creatinine clearance achieved by vasopressin-mediated action mostly on efferent arterioles [20] fits well with the above hypothesis. Collectively, an imbalance in intraglomerular vasomotor control and as yet undefined disharmony of glomerular vascular balancing mediators [21] may represent a form of vasomotor nephropathy as a primary cause of early, 'functional' AKI, preceding an intrinsic renal structural injury [22].

There are important regional differences in the circulation within the kidney, which may have considerable significance in critical illness. Under physiologic conditions, blood flow throughout the cortex (provided by afferent arterioles) is much higher than in the medulla (provided by efferent arterioles), rendering the medulla susceptible to hypoxic injury. Although intrarenal redistribution of blood flow towards the cortex at the expense of the medulla has been suggested [23], Di Giantomasso et al. [14] showed that cortico-medullary microvascular redistribution does not occur in

From Hemodynamics To Proteomics: Unraveling the Complexity of Acute Kidney Injury in Sepsis

hyperdynamic sepsis in sheep. Nevertheless, their observation does not completely dismiss the potential of renal microcirculation as the main 'culprit' in AKI. Although kidney microvascular endothelial injury has been acknowledged in ischemic acute renal failure [24), direct evidence for the role of peritubular capillary injury has only recently begun to emerge. Several recent long-term rodent models of sepsis-induced AKI demonstrated substantial renal microvascular disturbances [25-27). In the study by Wu et al. [27), an early and marked decline in cortical peritubular capillary perfusion was associated with tubular redox stress and preceded the development of renal failure. Interestingly, despite full recovery of renal function at 48 h, functional capillary density recovered only partially [27). These findings are corroborated by an even more recent study by Gupta et al. [28), in which quantitative two-photon intravital microscopy revealed markedly reduced peritubular capillary blood flow in an endotoxemia model in rats. Although the pathogenesis of renal microvascular injury is certainly multifactorial, there is emerging evidence supporting the role of oxidative stress in mediating these abnormalities. Wu et al. [29) demonstrated real-time generation of reactive nitrogen species by renal tubules and linked decreased peritubular capillary perfusion to overproduction of nitric oxide (NO) and reactive nitrogen species and tubular injury. Moreover, the potential of selective inducible NO synthase (iNOS) inhibition to markedly attenuate abnormalities in peritubular vasculature indicates the contribution of an iNOS-dependent pathway in the development of septic AKI [25,29). These data obtained from rodent models are indirectly supported by our series of experiments demonstrating that both selective iNOS inhibition (L-NIL) and a free radical scavenger (Tempol) maintained renal function in bacteremic swine as documented by the prevention of the otherwise progressive rise in serum creatinine concentration [30, 31). Finally, the association between iNOS-generated NO-dependent pathways and tubular injury has recently been confirmed in human endotoxemia and sepsis [32). In their study, Heemskerk et al. [32) documented increased iNOS mRNA expression in cells isolated from urine of both septic patients and healthy volunteers challenged with endotoxin and showed that renal iNOS-associated proximal tubule injury is preventable through selective iNOS inhibition. Note that acute renal microvascular injury may result in chronic microvascular alterations and rarefaction, thereby predisposing surv ivors of an episode of AKI to the development of chronic kidney disease [33]. Taken together, the maintenance of peritubular microcirculation seems to be an important therapeutic target to improve renal outcome in patients with AKI.

From Hemodynamics to Proteomics: Sepsis and Acute Kidney Injury from a Molecular Perspective Although the renal macro- and microcirculatory alterations play an important role in the pathogenesis of septic AKI, there is growing evidence that other mechanisms, including the interaction of the inflammatory response and coagulation , renal tubular apoptosis, and a variety of cellular events contribute significantly to the pathogenesis of AKI ( Fig. 1) [15). In support of this notion, we showed that early norrnobaric hyperoxia improved renal function without aggravating oxidative or nitrosative stress in hyperdynamic porcine septic shock. Reduced tissue apoptosi s and putative improved cellular energy metabolism due to enhanced energy substrate (glucose) oxidation might contribute to the observed improved renal function [34). Nevertheless, this picture does not completely represent the entire complexity of the

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Decreased

renal function

Fig. 1. Pathophysiology ofacute kidney injury depicting the complex of mutually interacting multiple factors and their consequences involved in tubular injury. From (5) with permission.

molecular mechanisms and pathophysiology of septic AKI, which is most likely achievable through a robust methodology. A Brief Overview of Proteomics

After completion of the Human Genome Project, several innovative technologies have been developed to utilize the genomic information to explain the complexity of cellular biology and physiology. Proteomics (defined as "the systematic analysis of proteins for their identity, quantity and function" [35]) is a powerful post-genomic biotechnology used for simultaneous examination of a large number of proteins or the proteome. Commonly used methods for current proteomics studies include twodimensional gel electrophoresis (2-DE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), liquid chromatography coupled to electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), surfaceenhanced laser desorption/ionization coupled to TOF MS (SELDI-TOF MS), capillary electrophoresis coupled to MS (CE-MS), and microarrays. Among these commonly used techniques, each has advantages and limitations. 2-DE is available in most proteomics laboratories and is simple to perform. However, it is time-consuming and not applicable for proteins or polypeptides smaller than 10 kDa. Its use is still limited for highly hydrophobic proteins [36,37] . LC-ESIMS/MS can be automated with a high sensit ivity. However, it is time-consuming and too sensitive for interfering compounds [36, 37]. Moreover, quantitative analysis

From Hemodynamics To Proteomics: Unraveling the Complexity of Acute Kidney Injury in Sepsis

using LC-ESI-MS/MS is rather complicated. SELDI-TOF MS is an easy-to-use system with an automation and high-throughput manner. Only a small volume (i.e., less than 10 ul.) of biological sample is required for SELDI-TOF MS. However, the information obtained from SELDI-TOF MS is restricted only to a particular group of proteins (based upon the type of chip) and its reproducibility has to be a concern [36, 37]. CE-MS is another sensitive system with a high-throughput manner that requires a small volume of sample. However, it is not well suited for analysis of prote ins with molecular masses greater than 20 kDa [36- 38]. Microarray technology is one of the ideal methods for proteome profiling [39]. This approach allows the high-throughput profiling of multiple proteins in the sample and offers an opportunity to discover low molecular weight biomarkers that may be missed by other (more commonly used) techn iques [40]. However, its applications are still limited by the difficulty to make arrays to cover all the urinary proteins and the availability of antibodies or other ligands [40]. Other limitations include the conservation of protein functionality during immobilization, as well as the provision of the required absolute and relative sensitivity [40]. Finally, assessing the turnover rates of individual proteins requires additional methods, such as the measurement of stable isotope labeling after infusion of isotope-labeled substrates, e.g. 1,2,3,4,5,6-13C6-glucose , which in turn is incorporated into the protein after metabolization to a non-essential amino acid [41]. Recent Proteomics Studies Applied to Sepsis and AKI

To date, proteomics has been extensively applied to several fields of biomedical research. The major objectives of applications of proteomics to molecular medicine include: (i) Better understanding of normal physiology and pathophysiology of diseases; (ii) identification of novel therapeutic targets and drugs; (iii) biomarker discovery (for early diagnosis, prediction of therapeutic outcome and prognosis) ; and (iv) vaccine discovery (for successful prevention of diseases). Compared to other subdisciplines , the field of proteomics applied to sepsis and AKI has just started recently. Although the field is at an early phase, proteomics in sepsis and/or AKI has made good progress. Table 1 summarizes all the recent proteomics studies applied to sepsis and/or AKI, as well as acute renal failure. These studies in humans and animal models (cat, rat, and mouse) have applied a wide range ofproteomic techniques to various biological samples, including plasma, serum, urine , amniotic fluid, liver, and kidney [42- 51]. Within only a few years, a relatively large amount of data has been generated , making more feasible further exploratory studies to better under stand the molecular mechanisms and pathophysiology of sepsis and AKI.

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M. Matejovic, P. Radermacher, and V. Thongboonkerd Table 1. Summary of recent proteomics studies applied to sepsis, acute kidney injury (AKI), and acute renal failure Publi- Studied cation by date

Proteomic technique

Sample

Disease model

Findings

Sepsis and septic shock

Complement factor B, haptoglobin and c1usterin had lower serum levels in the non-survivors, whereas alpha-l -B glycoprotein level was lower in the survivors.

Sepsis 2006

Kalenka, 2-DE fol- Human lowed by serum et al. [42) MALDI-TOF MS

2006

Crouser, et al. [43]

2-DE followed by LC-MS/MS

2006

Holly, et al. [44]

2-D DIGE Rat followed urine by MALOITOF MS

2007

Buhimschi, et al. [4S)

2007

2007

Cat liver Endotoxemitemia inchondria duced by Iipopolysaccharide from E. coli

During endotoxemia, mitochondrial levels of urea cycle enzymes, heat shock protein (HSP) 60, and manganese superoxide dismutase were increased, whereas HSP70, F1 -ATPase and key enzymes regulating lipid metabolism were decreased.

Sepsis induced by cecal Iigation and puncture

Sepsis-induced acute renal failure caused changes in urinary excretion of several proteins including albumin, brush-border enzymes (e.g. meprin-1-alpha), and serine protease inhibitors. Using the meprin-l-alpha inhibitor actinonin, animals treated with actinonin had lower serum creatinine level compared to the vehide-treated animals after an induction of sepsis.

SELOI-TOF MS

Human Early-onset amniotic sepsis in fluid premature neonates

Calgranulin C had the highest association with clinically significant funisitis, while calgranulin A had the strongest association with earlyonset sepsis. Women with mass restricted scores 3-4 were more likely to have histologic funisitis, and to deliver neonates with earlyonset sepsis.

Ren, et al. [46)

2-DE followed by MALOITOF/TOF

Mouse plasma

Sepsis induced by cecal Iigation and puncture

Plasma levels of transferrin, hemopexin, kininogen, alpha-l -antitrypsin precursor, leucine-rich alpha-2-glycoprotein, alpha-2-HS glycoprotein, alpha-l -acid glycoprotein, transthyretin, serum amyloid protein P, apolipoprotein A-I precursor, and complement C3 were altered during sepsis in mice. Most of these altered proteins remained in N-glycosylation status, but had changes of their N-glycans during sepsis.

Dear, et al. [47)

2-D DIGE Mouse liver followed byMALOITOF/TOF

Sepsis induced by cecal ligation and puncture

Several liver proteins had changes in abundance during sepsis, including proteins involving in acute phase response, coagulation, endoplasmic reticulum stress, oxidative stress, apoptosis, mitochondrial electron transfer, and nitric oxide metabolism. When CD147 or a receptor of cyclophilin (which was increased during sepsis) was inhibited, sepsis-induced renal dysfunction and cytokine production were reduced.

From Hemodynamics To Proteomics: Unraveling the Complexity of Acute Kidney Injury in Sepsis Table 1. ((ont.) Publication date

Studied by

Proteomic technique

Sample

Disease model

Findings

Human urine

ARF after Urinary proteins with masses of 6.4, 28.5, cardiopulmo- 43, and 66 kDa had increased levels during nary bypass acute renal failure.

AKI and acute renal failure 2005

Nguyen, et al. [48]

SELDI-TOF MS

2006

Zhou, et al. [49]

2-D DIGE Rat followed by urine MALDI-TOF/ TOF and LC-MS/MS

Cisplatininduced AKI

Urinary exosomal levels of 18 proteins were increased, whereas other 9 were decreased 8 h after induction of AKI with cisplatin. Among these, the increase in fetuin-A was confirmed in both AKI animal models and human subjects using Western blot analysis.

2007

Van-

SELDI-TOF MS

Human urine

Mild ischemic AKI after CABG surgery

A set of SELDI spectra (with massed ranges of 3- 70 kDa) could differentiate patients with early AKI after CABG surgery from healthy individuals.

2-DE followed by LC-MS/MS

Human urine

Mild ischemic AKI after CABG surgery

Retinol-biding protein, agrine, regenerating protein, Iipocalin, Zn-alpha-2-glycoprotein, gelsolin, carbonic anhydrase, actin, haptoglobin, perlecan, immunoglobulins, prostaglandin, amylase, transferrin, Bence-Jones protein, and cystatin had increased levels in the urine of CABG patients with AKI.

2-DE followed by LC-MS/MS

Mouse kidney

5-(1 , 2-dichlorovinyl)L-cysteineinduced acute renal failure

A number of kidney proteins involving in stress response, protein repair, turnover and translation, anti-oxidation, fatty acid transport, and energy production were altered during acute renal failure.

houtte,

et al. [50] 2007

Van-

boutte,

et al. [50]

2007

Korra-

pati,

et al. [51]

2-DE: two-dimensional gel electrophoresis; 2-D DIGE: two-dimensional difference gel electrophoresis; CABG: coronary artery bypass graft; HSP: heat shock protein; LC-MS/MS: liquid chromatography coupled to tandem mass spectrometry; MALDI-TOF MS: matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; MALDI-TOF/TOF: matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry; SELDI-TOF MS: surface-enhanced laser desorption/ionization coupled to time-of-flight mass spectrometry

Conclusion Undoubtedly, the process of AKI in sepsis involves multiple, dynamically interacting factors and it is clear that renal dysfunction, similar to dysfunction of other organs in sepsis, is not caused by a single mechanism . Limited ability to exactly analyze the renal molecular mechanisms and pathophysiology in humans emphasizes the need for complex, dynamic and clinically relevant animal studies. Implementing new, powerful technologies of molecular biology into research protocols should markedly enhance our understanding and should allow data to be put into a relevant complex picture. By applying proteomics to clinically relevant models of sepsis important

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gaps in our understanding of AKI in sepsis and other conditions can be filled, ultimately resulting in improved diagnosis and care of critically ill patients suffering from AKI. Acknowledgement: This work was supported by a research grant MSM 0021620819 (Replacement of and support to some vital organs). References 1. Schrier RW, Wang W (2004) Acute renal failure and sepsis . N Engl J Med 351:159-169 2. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP (1995) The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273:117-123 3. Bagshaw SM, Uchino S, Bellomo R, et al (2007) Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Invest igators . Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2:431-499 4. Chertow GM, Soroko SH, Paganini EP, et al (2006) Mortality after acute renal failure: models for prognostic stratification and risk adjustment. Kidney Int 70:1120-1126 5. Abuelo JG (2007) Normotensive ischemic acute renal failure. N Engl J Med 357:797-805 6. Gill N, Nally JV Ir, Fatica RA (2005) Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management. Chest 128:2847- 2863 7. Langenberg C, Bellomo R, Maz C, Wan L, Moritoki E, Morgera S (2005) Renal blood flow in sepsis . Crit Care 9:R363-R374 8. Bellomo R, Bagshaw S, Langenberg C, Ronco C (2007) Pre-renal azotemia: a flawed paradigm in critically ill septic patients? Contrib Nephrol 156:1- 9 9. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138-50 10. Langenberg C, Bellomo R, May CN, Egi M, Wan L, Morgera S (2006) Renal vascular resistance in sepsis. Nephron Physiol 104:1-11 11. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup (2004) Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-R212 12. Langenberg C, Wan L, Egi M, May CN, Bellomo R (2006) Renal blood flow in experimental septic acute renal failure. Kidney Int 69:1996-2002 13. Langenberg C, Wan L, Egi M, May CN, Bellomo R (2007) Renal blood flow and function during recovery from experimental septic acute kidney injury Intensive Care Med 33:1614- 1618 14. Di Giantomasso D, Morimatsu H, May CN, Bellomo R (2003) Intrarenal blood flow distribution in hyperdynamic septic shock: effect of norepinephrine. Crit Care Med 31:2509-2513 15. Wan L, Bellomo R, Di Giantomasso D, Ronco C (2003) The pathogenesis of septic acute renal failure. CUff Opin Crit Care 9:496- 502 16. Vincent JL, De Backer D (2005) Microvascular dysfunction as a cause of organ dysfunction in severe sepsis. Crit Care 9 (suppl 4):S9-S12 17. Lugon JR, Boim MA, Ramos OL, et al (1989) Renal function and glomerular hemodynamics in male endotoxemic rats . Kidney Int 36:570- 575 18. Friedrich JO, Adhikari N, Herridge MS, Beyene J (2005) Meta-analysis: low-dose dopamine increases ur ine output but does not prevent renal dysfunction or death. Ann Intern Med 142:510-524 19. De Vriese AS, Bourgeois M (2003) Pharmacologic treatment of acute renal failure in sepsis. Curr Opin Crit Care 9:474-480 20. Patel BM, Chittock DR, Russell JA, Walley KR (2002) Beneficial effects of short-term vasopressin infus ion during severe septic shock. Anesthesiology 96:576-582 21. Yamaguchi N, [esrnin S, Zaedi S, et al (2006) Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat. Peptides 27:2258-2270 22. Matejovic M, Radermacher P, Joannidis M (2007) Acute kidney injury in sepsis : Is renal blood flow more than just an innocent bystander? Intensive Care Med 33:1498-1500

From Hemodynamics To Proteomics: Unraveling the Complexity of Acute Kidney Injury in Sepsis 23. Brezis M, Rosen S (1995) Hypoxi a of the renal medulla-its implications for disease. N Engl J Med 332:647 -655 24. Molitoris BA, Sutton TA (2004) Endothelial injur y and dysfunction: role in the extension ph ase of acute renal failure. Kidney Int 66:496 -499 25. Tiwari MM, Brock RW, Megyes i JK, Kaushal GP, Mayeux PR (2005) Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure : role of nitric oxide and caspases, Am J Physiol Renal Physiol 289:FI324-F1332 26. Yasuda H, Yuen PS, Hu X, Zhou H, Star RA (2006) Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects . Kidney Int 69:1535-1542 27. Wu L, Tiwari MM, Messer KJ, et al (2007) Peri tubular capillary dysfunction and renal tubular epithelial cell stress follow ing lipopolysaccharide administration in mice . Am J Physiol Renal Physiol 292:F261-F268 28. Gupta A, Rhodes GJ, Berg DT, Gerlitz B, Molitoris BA, Grinnell BW (2007) Activated protein C ameliorates LPS-induced acute kidney injury and down-regulates renal iNOS and angiotensin 2. Am J Physiol Renal Physiol 293:F245 - 54 29. Wu L, Gokden N, Mayeux PR (2007) Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. J Am Soc Nephrol 18:1807 -1815 30. Matejovic M, Krouzecky A, Martinkova V, et al (2004) Select ive inducible nitric oxide syn thase inhibition during long-term hyperdynamic porcine bacteremia. Shock 21:458-465 31. Matejovic M, Krouzecky A, Martinkova V, et al (2005) Effects of ternpol, a free radical scaven ger, on long -term hyperdynamic porcine bacteremia. Crit Care Med 33:1057 -1063 32. Heemskerk S, Pickkers P, Bouw MP, et al (2006) Upregulation of renal inducible nitric oxide synthase during human endotoxemia and sep sis is associated with proximal tubule injury. Clin J Am Soc Nephrol 1:853-862 33. Horbelt M, Lee SY, Mang HE, et al (2007) Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am J Physiol Renal Physiol 293:F688-F695 34. Barth E, Bassi G, Maybauer M, et al (2008) Effects of ventilation with 100 % oxygen during early hyperdynamic porcine fecal peritonitis. Crit Care Med (in press) 35. Peng J Gygi SP (200l) Proteomics: the move to mixtures. J Mass Spectrom 36:1083-1091 36. Fliser D, Novak J, Thongboonkerd V, et al (2007) Advances in urinary proteome analysis and biomarker discovery. JAm Soc NephroI18:1057-1071 37. Thongboonkerd V (2007) Recent progress in urinary proteomics. Proteomics Clin Appl I: 780- 791 38. Mischak H, Julian BA, Novak J (2007) High-resolution proteome/peptidome analysis of peptides and low-molecular-weight proteins in urine. Proteomics Clin Appl 1:792-804 39. Liu BC, Zhang L, Lv LL, Wang YL, Liu DG, Zhang XL (2006) Application of antibody array technology in the analysis of urinary cytokine profile s in patients with chronic kidney d isease. Am J Nephrol 26:483-490 40. Angenendt P (2005) Progress in protein and antibody microarray technology. Drug Discov Today 10:503-511 41. Vogt JA, Hunzinger C, Schroer K, et al (2005) Determination of fract ional synthesis rates of mouse hepatic proteins via metabolic l3C-labeling, MALDI-TOF MS and analysis of relative isotopologue abundances using average masses. Anal Chern 77:2034 - 2042 42. Kalenka A, Feldmann RE, [r., Otero K, Maurer MH , Waschke KF, Fiedler F (2006) Changes in the serum proteome of patients with sepsis and septic shock. Anesth Analg 103:15221526 43. Crouser ED, Julian MW, Huff JE, Mandich DV, Green-Church KB (2006) A proteomic analysis of liver mitochondria during acute endotoxemia. Intensive Care Med 32:1252 -1262 44. Holly MK, Dear JW, Hu X, et al (2006) Biomarker and drug-target discover y using proteomics in a new rat model of sepsis-induced acute renal failure. Kidney Int 70:496-506 45. Buhimschi CS, Buhimschi lA, Abdel-Razeq S, et al (2007) Proteomic biomarkers of intraamniotic inflammation: relationship with funi sitis and early-onset sepsis in the premature neonate. Pediatr Res 61:318-324 46. Ren Y, Wang J, Xia J, et al (2007) The alterations of mouse plasma proteins during septic development. J Proteome Res 6:2812-2821 47. Dear JW, Leelahavanichkul A, Aponte A, et al (2007) Liver proteomics for therapeutic drug

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48. 49. 50. 51.

discovery: Inhibition of the cyclophilin receptor CD147attenuates sepsis-induced acute renal failure. Crit Care Med 35:2319-2328 Nguyen MT, Ross GF, Dent CL, Devarajan P (2005) Early prediction of acute renal injur y using urinary proteomics. Am J Nephrol 25:318-326 Zhou H, Pisitkun T, Aponte A, et al (2006) Exosomal Fetuin-A identified by proteom ics: a novel urinary biomarker for detecting acute kidney injury. Kidney Int 70:1847 -1857 Vanhoutte KJ, Laarakkers C, Marchiori E, et al (2007) Biomarker discovery with SELDI-TOF MS in human urine associated with early renal injury: evaluation with computational analytical tools. Nephrol Dial Transplant 22:2932-2943 Korrapati MC, Chilakapati J, Witzmann FA, Chundury R, Lock EA, Mehendale HM (2007) Proteomics of S-{1, 2-dichlorovinyl)-L-cysteine-induced acute renal failure and autoprotection in mice. Am J Physiol Renal Physiol 293:F994 -1006

Section XV

XV Hemodynamic Assessment and Management

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Towards Optimal Central Venous Catheter Tip Position W. SCHUMMER, Y.

SAKR,

and C. SCHUMMER

Introduction Central venous catheters (CVCs) are required in many critically ill patients. They are usually inserted through the subclavian or internal jugular veins. As with most invasive procedures, central venous catheterization is associated with numerous potential complications, many of which are associated with the access procedure . The use of ultrasound guidance during CVC placement is among the top 10 evidence-based tools that health care providers can use to improve patient safety [I]. However, serious complications may also occur due to catheter tip malposition. Generally, these complications have only been reported in small studies or case reports, thus underreporting is likely. As a result, exact figures regarding the magnitude of risk of specific complications are not available. Venous or right heart perforations, causing pericardial tamponade or hemothoraces, are associated with a high mortality rate of 65 to 91 % [2]. Despite the low incidence of severe complications, there is a wide range of clinically relevant drawbacks related to catheter tip malposition (e.g., venous thrombosis, catheter dysfunction). In this chapter, we discuss optimal catheter tip position, review the possible complications related to catheter tip malposition, and demonstrate the available methods used to confirm catheter tip position.

Optimal Position for Catheter Tip The optimal position of the CVC tip remains the subject of debate because no position is absolutely safe [3]. Conclusions drawn in the current chapter are based mainly on data gained from adults; therefore, these results cannot be extrapolated to the pediatric population. Three zones for catheter tip position were proposed by Fletcher and Bodenham ( Fig. 1) [3]. Zone 1 (mid-point of innominate vein), the most distal position in the venous system which ensures an extrapericardial CVC-tip position, is prone to vessel thrombosis [4- 7] or extravasation through the proximal port of a multilumen catheter. Zone 2 (upper superior vena cava) is prone to abutment in left sided catheters [4]. Therefore, we believe that in most cases the CVC tip should be positioned at the junction between the superior vena cava and the right atrium, which approximately matches zone 3 (lower superior vena cava/upper right atrium). In this position, catheters inserted from either side will run parallel with the long axis of the superior vena cava.

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L

Fig. 1. Schematic diagram of optimum catheter tip position (see text for explanation of zones). SVC: superior vena cava (Adapted from [31 with permission)

Complications Related to CVC misplacement Perforation The US Food and Drug Administration (FDA) strongly advises that the tip of a CYC should not be placed in the heart or allowed to migrate into the heart [3, 8]. These guidelines are based on the fear of pericardial tamponade. But one has to remember that it is also possible for pericardial tamponade to occur with perforations of the superior vena cava below the pericardial reflection. The high variability of the cephalic limit of the pericardial reflection means that a catheter has to end in the middle of the brachiocephalic vein to ensure placement outside the pericardium. Apart from improper catheter function (e.g., inadequate flow through hemodialysis catheters) [9], patients are prone to extravasation injury and vessel thrombosis at this CYC-tip position [5, 9-11] . These complications and their sequelae are real problems for patients - far more relevant than the hypothetical extra risk of pericardial tamponade if the catheter is placed in the lower superior vena cava. In addition, perforations above the pericardial reflection are quite dangerous. In the American Society of Anesthesiologists database of closed claims 1970- 2000, 13 of 16 cardiac tamponades and 14 of 15 hemothoraces resulted in death [12]. The incidence of CYC-induced vessel perforation seems to be about 0.25 to 0.4 % [2, 13-15], but there are no reliable data on the incidence of cardiac tamponade after CYC placement [3]. However, this is true for all CYC-position related complications.

Towards Optimal Central Venous Catheter Tip Position Thrombosis

Thrombosis is not a benign and self-limiting condition, but can be the cause of serious complications, such as pulmonary embolism, loss of vascular access, superior vena cava syndrome, and post-thrombotic venous insufficiency. Contr ibuting factors for catheter-induced thrombosis include route of venous access, biocompatibility of the catheter material, size and length of the catheter, and the length of time the catheter stays in place. Other factors promoting venous thrombosis include a hypercoagulable state, hypovolemia, venous stasis, infection, and frequency and type of medication infused through the catheter. These etiologies follow the well-known dictum of the triad of Virchow: Venous stasis, endothelial damage, and hypercoagulability. In rats, it was shown that thrombus occurred in those areas where the catheter was in contact with the vein wall [16]. Constant injury to the vein wall by rubbing, caused by respiratory, cardiac, or body movements resulted in denudation of endothelial cells and activation of smooth muscle cells, thus thrombus formation [16]. This is in line with the findings of a human autopsy study ( Fig. 2) [17]. Initially, a clot forms around the catheter - a catheter sleeve can be formed as early as 24 h after catheterization [18] - because of mechanical injury of the catheter on the vein wall and then transforms into vascularized connective tissue after 5- 14 days [16]. The sleeve is mainly formed by smooth muscle cells migrating from the injured vein wall into the early peri catheter thrombus and is permanently attached to the vein wall, making it a very unlikely cause of embolism [16]. However, other reports have shown that these fibrin sleeves may, in rare cases, cause pulmonary embolism spon taneously or after fibrin sheath stripping [19]. The degree of peri catheter sleeve and clot formation is related to the type of catheter material used. Polyurethane catheters carry a high risk for pericatheter sleeve formation, while silicone catheters have the lowest risk [20]. In some devices, the

IN

Left subclavian

---=::o;;;:.;;....-:/~-- eve

Fig. 2. Absolute numbers of thrombi (single and multiple) demonstrated in 58 post mortem examinations with a diagnosis of thrombus formation after CVC placement. IN: internal jugular vein, EN: external jugular vein; SVC: superior vena cava (Adapted from [17] with permission)

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W. Schummer, Y. Sakr, and C. Schummer Table 1. Catheter tip position in relation to the development of thrombosis [7]. Catheter tip position

Right atrium and superior vena cava junction Superior vena cava Junction between superior vena cava and the innominate veins Innominate (or brachio-cephalic) veins Aberrant topography, including right atrium and jugular veins

Number of patients with thrombosis

Thrombosis %

3/62 2/2S 5/7 5/12 2/7

5 8 71

42

29

catheter tip is fashioned from a silicone elastomer in order to soften it further, potentially aiding in preventing possible endothelial damage. From studies on silicone catheters, evidence is emerging that catheter tip placement high in the superior vena cava and above is associated with a higher risk of thrombosis formation ( Table 1) [4- 7]. The morbidity and mortality caused by thrombus formation from high lying catheter tips may quantitatively exceed that related to perforation. Extravasation

xv

Extravasation is an unintentional injection or leakage of fluid into the perivascular or subcutaneous space. Extravasation mayor may not be associated with tissue injury. Extravasation injury results from a combination of factors, including solution cytotoxicity, osmolality, vasoconstrictor properties, infusion pressure, regional anatomical peculiarities, and other patient factors [21-23]. Extravasation injury has been frequently described in patients undergoing cancer chemotherapy; thus, oncologists and related medical personnel are well aware of the severe untoward effects when cytotoxic drugs leak into the perivascular space. For CVCs, extravasation is less frequent but potentially more dangerous because of the vulnerable anatomical structures and because extravasation may easily escape attention. Depending on insertion depth, an extravasal position of the proximal port can occur when a multilumen catheter is inadvertently withdrawn just a few centimeters . In triple-lumen catheters for adults, the distance between the proximal and the distal port varies between 4 and 7.3 em (PreSep Central Venous Oximetry Catheter, Edwards Lifesciences LLC, Irvine, CA,US) [24]; this increases up to 8.75 ern in 5-lumen catheters [25]. When situated at a relatively long distance from the catheter tip, correct placement of the proximal port may present a practical challenge and it may be better to advance the catheter tip into the lower superior vena cava [3,5, 26]. Health personnel should be aware of the position of ports relative to the tip and total length of the catheter, especially when CVCs are to be introduced through the right subclavian vein, where the proximity to the right atrium may favor this complication. Arrhythmia

Contact of a guide wire or catheter with the endocardium may induce arrhythmias or heart block. A significant number of patients experience atrial (41 %) or ventricular (25 %) dysrhythmias when CVCs are placed without imaging guidance [27]. Dysrhythmias encountered in such settings are usually transient and asymptomatic. However, in patients with severe aortic stenosis, acute myocardial ischemia, and left bundle bran ch block, inducing arrhythmias may result in life-threaten ing situations

Towards Optimal Central Venous Catheter Tip Position

[28, 29). Importantly, intraatrial CVC tips may induce arrhythmias during patient positioning maneuvers , e.g., rolling from supine to prone [30). However, CVC-tip migration is of clinical relevance only in peripherally inserted catheters. Chest wall CVCs (subclavian vein, jugular vein) may be falsely judged to be migrating into the heart due to misinterpretation of the bedside radiograph (projection phenomena) (unpublished observation).

Methods to Determine

eve Tip Position

Chest Radiography

Since the first placement of a CVC by ForBmann in 1929, chest radiography has been used to control its position [31). Today, the American College of Radiology recommends portable radiographs in critically ill patients following placement of support and monitoring devices such as endotracheal tubes, CVCs, etc. Radiographs obtained routinely or following placement of a tube or catheter show significant abnormalities not suspected clinically in 35 to 65 % of patients in the ICU, and these findings often result in an intervention or change in treatment [32). Thus, bedside radiography helps to ensure correct placement of these devices and facilitates rapid detect ion of complications. Bedside chest radiography differs from standard erect radiography in several critical aspects. It is characterized by far greater variability in positioning and technique (e.g., due to rotation, lordotic or reverse lordotic positioning, extent oflung inspiration). This has profound effects on the interpretation of the radiograph. It should also be noted that in portable radiography the apparent heart size is particularly affected by anterior-posterior positioning, as this causes substantial magnification of the heart compared to the posterior-anterior positioning which is used in upright radiography. The CVC may be improperly placed in many venous structures, reflecting the complex mediastinal venous anatomy. Chest radiography (possibly in two plains or with contrast media) is the ideal tool to image these malpositions . Chest radiography can also detect complications such as pneumothorax or hemothorax. On the other hand, the junction of the superior vena cava with the right atrium or the pericardial reflection cannot be seen directly on a bedside chest X-ray [33]; instead, various radiographic landm arks are used ( Table 2) [33- 40). However, these landmarks are prone to parallax effects caused by the angle variance of incident X-rays and may account for 20 up to 47 % of incorrect intra-atrial classified CVC tips [33). In a recent transe sophageal echocardiography (TEE) controlled study with 20 patients, neither the intersection of the curvilinear lines representing the mediastinum and the right heart border, nor the thoracic vertebral bodies, were reliable landmarks for the superior vena cava/right atrium junction [41). In a magnetic resonance imaging (MRI) study on 42 patient s CVCs placed less than 29 mm below the right tracheobronchial angle guaranteed an extra-atrial position [33). In a recent study (unpublished data), we noted that the right tracheobronchial angle was not reliable as a reference as it was visible on only 32 % of chest X-rays. The carina , however, was identified in 96 % of all chest X-rays. One explanation for this finding could be that the carina projects onto homogeneous mediastinal tissue, whereas the right tracheobronchial angle projects onto different tissues (lung, vessels, and mediastinal tissue). Schuster et al. [39) suggested placement of CVCs with their tips above the carina as a reliable landmark to avoid pericardial tamponade. However, at the level of the

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carina left-sided catheters are prone to abutment on the lateral wall of the superior vena cava with potential thrombus generation or perforation [3, 5, 42]. Measuring the vertical distance of the CVC tip to the carina (TC-distance) is a not yet a widely used technique. This radiologic marker was evaluated by a TEE controlled study in 213 patients undergoing cardiac surgery. Here a TC-distance of < 55 mm was determined for adults more than 160 ern in height (unpublished data) . The introduction of the TC-distance as a radiological marker will allow the inexperienced to diagnose intra-atrially sited CVCs with the same accuracy as even an experienced radiologist ( Fig. 3). Nevertheless, none of the radiographic landmarks ( Table ~l used for excluding intra-atrial CVC tip position is 100 % reliable [43]. Apparently, bedside radiogra-

Fig. 3.Chest X-ray depicting a central venous catheter inserted from the left subclavian vein correctly sited in the lower superior vena cava. The vertical distance from the catheter tip to the carina is 34.9 mm. Table 2. Various radiographic landmarks used by radiologists to define extra-atrial position of central venous catheters (CVC) Author Greenall et aI., 1975 [35]

Radiographic landmarks for extra-atrial CVC tip position

Under the lower part of the clavicle, because the superior vena cava has its origin at this place. Between the fifth and the eighth thoracic vertebra. Defa lque and Cambell, 1979 [34] Vail and Ravin, 1992 [38] In the first anterior intercostal space. Collier et al., 1998 [36] Outside of the heart silhouette. Aslamy et al., 1998 [33] Maximal 29 mm below the right tracheobronchial angle. Hobbs and Mahajan, 2000 [37] In an area between the beginni ng of the first and the thi rd rib. Catheters above the level of the carina. Schuster et al., 2000 [39] Stonelake and Bodenham, 2006 [40] Left-sided catheters below the level of the carina, right-sided catheters above the level of carina

Towards Optimal Central Venous Catheter Tip Position

phy cannot serve as the gold standard in assessing a eve tip position with respect to the right atrium. Multiplane Transesophageal Echocardiography

Multiplane TEE, in contrast to chest radiography, allows the eve tip to be visualized along with its relation to anatomical structures, especially the lower superior vena cava/right atrium junction [41, 44-46]. TEE is the most reliable bedside imaging technique for confirming eve tip position [43,44,46,47]; however, TEE is an invasive procedure with inherent risks. For evaluation of a eve, it should only be employed where bedside chest X-ray or fluoroscopy are inconclusive. Nevertheless, if a TEE is performed for other reasons, it should be a matter of routine to check the eve tip position. Electrocardiogram (EKG}-guidance

EKG-guidance is one of the options available to guide eve positioning in patients in sinus rhythm. In many clinical studies it has been shown that EKG-guidance during eve placement is an adequate tool to reduce malpositioning [48]. With an intraluminal wire or saline as an electroconductive medium, the tip of the catheter serves as an electrode (Einthoven lead II) to obtain the intravascular EKG. When a guide wire technique is used, a black mark on the proximal end of the guide-wire indicates the point at which the tip of the wire levels with the port of the distal catheter lumen . A sterile connection cable is clamped to the guide-wire at the marked position in order to connect it with an adapter that allows the operator to switch from a surface (Einthoven Lead II) to an intravascular EKG. However, EKG-guidance is not widely used, possibly because of the technique advocated by the manufacturer: Insertion of the catheter, then withdrawal of the eve under EKG-guidance a few centimeters beyond a normalized P-wave amplitude. If EKG-guidance is applied in this manner, the results are disappointing; arrhythmias occur frequently, and the eve tip often ends up in the upper superior vena cava or even in the innominate veins. There is also a risk of extravasation from the proximal port of multilumen catheters, abutment with the vessel wall (superior vena cava), and thrombus formation. A safe method for EKG-guidance involves positioning of the guide-wire in the vein to a depth not exceeding 10-12 cm. After introducing the catheter over the wire up to the black mark the catheter is advanced carefully together with the guidewire. It has been demonstrated that the first increase in P-wave amplitude relates to the pericardial reflection. This is, therefore, the only reliable bedside method that allows the pericardial reflection to be identified during eve placement and herewith allows a eve to be placed reliably outside the pericardium. The P wave amplitude increases to its maximum once the catheter tip levels with the superior vena caval right atrial junction. Further advancement of the catheter tip results in a decrease in P wave amplitude or a biphasic P wave [45,47] . We suggest placing the eVe-tip at the maximal P wave amplitude. EKG guidance is not reliable for detecting whether a eve is positioned intravenously, intra-arterially, or extravascularly [49, 50]. Other methods should be applied where there is doubt about intra-arterial placement, including blood gas analysis or pressure tracing [51]. Therefore, the failure of EKG guidance to differentiate between arterial and venous eve position appears to be only a hypothetical disadvantage.

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Unfortunately, EKG guidance cannot provide information regarding the angle of CVCs with the vessel wall [49J. Typically, CVCs placed at the maximal P-waveamplitude end in the lower superior vena cava at the junction with the right atrium. At this position catheters - even inserted from the left - will run parallel with the vessel wall.

Conclusion Placement of a CVC is always associated with risks. Prudence dictates that CVCs be positioned in such a way that they function properly and that the risk for perforation is low (i.e., no angles> 40° with the vessel wall). This position is close to the superior vena caval right atrial junction, which can be accomplished easily by using EKG-guidance to the maximal P-wave amplitude. In clinical practice, radiologists and intensivists typically have to decide whether the CVC tip is in an acceptable position using the least sophisticated imaging procedure available - a bedside chest X-ray. However, traditional reading of a bedside chest X-ray alone is inadequate to decide whether a catheter ends in the right atrium. Nevertheless, chest X-ray may help in identifying CVC malposition or complications such as pneumothorax. TEE is the most reliable method in assessing CVC tip position, but is limited in that it is invasive and requires trained personnel. The introduction of the TC-distance as a radiological marker should allow the inexperienced user to detect CVCs that are placed intra-atrially with the same accuracy as an experienced radiologist, ultimately contributing to patient safety. Acknowledgment: The authors thank Donald 1. Bredle, PhD, Assistant Professor of Kinesiology, University of Wisconsin, Eau Claire for editorial assistance. References 1. Rothschild J (2001) Ultrasound guidance of central vein catheteriz ation. In: Markowitz A (ed)

On Making Health Care Safer: A critical analysis of patient safety practices. AHRQ Publications, Rockville, MD, pp 245- 255 2. Booth SA, Norton B, Mulvey DA (2001) Central venous catheterization and fatal cardiac tamponade. Br J Anaesth 87:298-302 3. Fletcher SJ, Bodenham AR (2000) Safe placement of central venous catheters: where should the tip of the catheter lie? Br J Anaesth 85:188- 191 4. Kim FM, Burrows PE, Hoffer FA, Chung T (1996) Interpreting the results of pediatric central venous catheter studies. Radiographies 16:747 -754 5. Puel V, Caudry M, Le Metayer P, et al (1993) Superior vena cava thrombosis related to catheter malposition in cancer chemotherapy given through implanted ports . Cancer 72:2248 2252 6. Pithie A, Soutar JS, Pennington CR (1988) Catheter tip position in central vein thrombosis. JPEN J Parenter Enteral Nutr 12:613-614 7. Luciani A, Clement 0, Halimi P, et al (2001) Catheter-related upper extremity deep venous thrombosis in cancer patients : a prospective study based on Doppler US. Radiology 220:655 - 660 8. Food and Drug Administration (1989) Precautions necessary with central venous catheters . FDA Task Force. FDA Drug Bulletin:15-16 9. Vesely TM (2003) Central venous catheter tip posit ion: a continuing controversy. J Vase Interv Radiol 14:527- 534 10. Schummer W, Schummer C, Bayer 0 , Muller A, Bredle D, Karzai W (2005) Extravasation injury in the perioperative setting. Anesth Analg 100:722 - 727

Towards Optimal Central Venous Catheter Tip Position 11. Wu X, Studer W, Skarvan K, Seeberger MD (1999) High incidence of intravenous thrombi after short -term central venous catheterization of the internal jugular vein. J Clin Anesth 11: 482-485 12. Domino KB, Bowdle TA, Posner KL,Spitellie PH, Lee LA, Cheney FW (2004) Injuries and liability related to central vascular catheters: a closed claims analysis. Anesthesiology 100: 1411-1418 13. Schummer W, Schummer C, Rose N, Niesen WD, Sakka SG (2007) Mechanical complications and malpositions of central venous cannulations by experienced operators : A prospective study of 1794 catheterizations in critically ill patients. Intensive Care Med 33:1055-1059 14. Robinson JF, Robinson WA, Cohn A, Garg K, Armstrong JD 2nd (1995) Perforation of the great vessels during central venous line placement . Arch Intern Med 155:1225-1228 15. Mukau L, Talamini MA, Sitzmann JV (1991) Risk factors for central venous catheter-related vascular erosions. JPEN J Parenter Enteral Nutr 15:513-516 16. Xiang DZ, Verbeken EK, Van Lommel AT, Stas M, De Wever I (1998) Composition and formation of the sleeve enveloping a central venous catheter. J Vase Surg 28:260-271 17. Muller K (1981) Komplikation durch Kava-Katheter und ihr pathologisch-anatomisches Substrat. In: Lawin P, Hartenauer U (eds) Der intravasale Katheter. Thieme, Stuttgart, pp 73-81 18. Hoshal VL, [r., Ause RG, Hoskins PA (1971) Fibrin sleeve formation on indwelling subclavian central venous catheters . Arch Surg 102:253-258 19. Winn MP, McDermott VG, Schwab SJ, Conlon PJ (1997) Dialysis catheter 'fibrin-sheath stripping' : a cautionary tale! Nephrol Dial Transplant 12:1048-1050 20. Borow M, Crowley JG (1985) Evaluation of central venous catheter thrombogenicity. Acta Anaesthesiol Scand Suppl 81:59-64 21. Gault DT (1993) Extravasation injuries . Br J Plast Surg 46:91-96 22. Upton J, Mulliken JB, Murray JE (1979) Major intravenous extravasation injuries. Am J Surg 137:497-506 23. Yosowitz P, Ekland DA, Shaw RC, Parsons RW (1975) Peripheral intravenous infiltration necrosis. Ann Surg 182:553-556 24. Wallenborn J, Kuhnert I (2002) [Do position control methods for central venous catheters prevent complications! Hydromediastinum caused by an initially correctly placed tri-Iumen subclavian catheter by using intra-atrial ECG recording - a case report] . Anaesthesiol Reanim 27:131-137 25. Walker C, Jackson D, Dolan S (1997) The potential for extravasation using a new five lumen catheter. Anaesthesia 52:716-717 26. Chalkiadis GA, Goucke CR (1998) Depth of central venous catheter insertion in adults: an audit and assessment of a technique to improve tip position. Anaesth Intensive Care 26: 61-66 27. Stuart RK, Shikora SA, Akerman P, et al (1990) Incidence of arrhythmia with central venous catheter insertion and exchange. JPEN J Parenter Enteral Nutr 14:152-155 28. Morris D, Mulvihill D, Lew WY (1987) Risk of developing complete heart block during bedside pulmonary artery catheterization in patients with left bundle-branch block. Arch Intern Med 147:2005-2010 29. Sprung CL, Elser B, Schein RM, Marcial EH, Schrager BR (1989) Risk of right bundle-branch block and complete heart block during pulmonary artery catheterization. Crit Care Med 17:1-3 30. Garden AL, Laussen PC (2004) An unending supply of 'unusual' complications from central venous catheters. Paediatr Anaesth 14:905 - 909 31. ForBmann W (1929) Die Sondierung des rechten Herzens. Klin Wochenschr 8:2085-2087 32. Webb W (2005) Pulmonary edema , the acute respiratory distress syndrome and radiology in the intensive care unit. In: Webb W (ed) Thoracic imaging: Pulmonary and cardiovascular radiology. Lippincott Williams & Wilkins, Philadelphia , pp 331- 355 33. Aslamy Z, Dewald CL, Heffner JE (1998) MRI of central venous anatomy : implications for central venous catheter insertion. Chest 114:820- 826 34. Defalque RJ, Campbell C (1979) Cardiac tamponade from central venous catheters. Anesthesiology 50:249- 252 35. Greenall MJ, Blewitt RW, McMahon MJ (1975) Cardiac tamponade and central venous catheters. BMJ 2:595- 597

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W. Schummer, Y. sakr, and C. schummer 36. Collier PE, Blocker SH, Graff OM, Doyle P (1998) Cardiac tamponade from central venous catheters. Am J Surg 176:212-214 37. Hobbs G, Mahajan R (2000) Radiology for Anesthesia. Churchill Livingstone, New York 38. Vail CM, Ravin CE (1992) Cardiovascular monitoring devices. In: Goodman LR, Putman CE (eds) Critical Care Imaging. W. B. Saunders, Philadelphia, pp 3-12 39. Schuster M, Nave H, Piepenbrock S, Pabst R, Panning B (2000) The carina as a landmark in central venous catheter placement. Br J Anaesth 85:192-194 40. Stonelake PA, Bodenham AR (2006) The carina as a radiological landmark for central venous catheter tip position. Br J Anaesth 96:335- 340 41. Hsu JH, Wang CK, Chu KS, et al (2006) Comparison of radiographic landmarks and the echo cardiographic SVC/RA junction in the positioning oflong-term central venous catheters. Acta Anaesthesiol Scand 50:731- 735 42. Gravenstein N, Blackshear RH (1991) In vitro evaluation of relative perforating potential of central venous catheters: comparison of materials, selected models, number of lumens, and angles of incidence to simulated membrane. J Clin Monit 7:1- 6 43. Reynolds N, McCulloch AS, Pennington CR, MacFadyen RJ (2001) Assessment of distal tip position oflong-term central venous feeding catheters using transesophageal echocardiology. JPEN J Parenter Enteral Nutr 25:39-41 44. Andropoulos DB, Stayer SA, Bent ST, et al (1999) A controlled study of transesophageal echocardiography to guide central venous catheter placement in congenital heart surgery patients. Anesth Analg 89:65- 70 45. Chu KS, Hsu JH, Wang SS, et al (2004) Accurate central venous port-A catheter placement: intravenous electrocardiography and surface landmark techniques compared by using transesophageal echocardiography. Anesth Analg 98:910-914 46. [eon Y, Ryu HG, Yoon SZ, Kim JH, Bahk JH (2006) Transesophageal echocardiographic evaluation of ECG-guided central venous catheter placement. Can J Anaesth 53:978-983 47. Schummer W, Schummer C, Schelenz C, Schmidt P, Frober R, Huttemann E (2005) [Modified ECG-gu idance for optimal central venous catheter tip positioning. A transesophageal echo cardiography controlled study] . Anaesthesist 54:983-990 48. McGee WT, Ackerman BL, Rouben LR, Prasad VM, Bandi V, Mallory DL (1993) Accurate placement of central venous catheters: a prospective, randomized, multicenter trial. Crit Care Med 21:1118-1123 49. Schummer W, Schummer C, Paxian M, Stock U, Richter K, Bauer M (2005) [Extravasal position of central venous catheters despite unsuspicious ECG-guidance] . Anasthesiol Intensivmed Notfallmed Schmerzther 40:91-96 50. Schummer W, Schummer C, Schelenz C, et al (2004) Central venous catheters - the inability of 'intra-atri al ECG' to prove adequate positioning. Br J Anaesth 93:193-198 51. Oliver WC Jr, Nuttall GA, Beynen FM, Raimundo HS, Abenstein JP, Arnold 11 (1997) The incidence of artery puncture with central venous cannulation using a modified technique for detection and prevention of arterial cannulation. J Cardiothorac Vase Anesth 11:851-855

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From Arterial Pressure to Cardiac Output M.

CECCONI,

A.

RHODES,

and G.

DELLA ROCCA

Introduction There are a number of companies that market devices for the monitoring of cardiac output from the arterial pressure waveform. These devices all share a number of characteristics that need to be understood if they are to be used appropriately. This chapter aims to describe the underlying history and physics behind these computer based algorithms.

Background Physiology The history of pulse contour techniques dates back more than 100 years and is based on obtaining continuous cardiac output from the analysis of the arterial waveform. In 1899, Otto Frank developed the Windkessel (air chamber) model to simulate the heart-vessel interaction [1, 2]. This model comprised a circuit in which fluid was pumped in tubes through chambers. Frank found similarities between the circulatory system and the pumps used by firemen, in which a pulsatile pump was provid ing continuous flow. The tubes were completely fluid-filled but the chambers contained some air. As the fluid was not compressible, the behavior of the air was thought to mimic aortic distension, or compliance, in blood vessels. Frank also deduced that the stroke volume could be calculated from the change in pressure. In 1904, Erlanger and Hooker described a correlation between stroke volume and change in arterial pressure and suggested there was a correlation between cardiac output and the contour arterial pulse pressure wave (3). This eventually led to the development of algorithms that relate the arterial pulse contour to cardiac output; only with the recent advent of computer technology has it been possible to develop these algorithms to a level useful for clinical practice. The ideal situation to calculate cardiac output would be one in which all the information is obtained from a site very proximal to the aorta ; however, in clinical practice this is rarely possible. Indeed it is often desirable not to cannulate large central arteries; therefore, many clinicians prefer to utilize distal arterial access, for instance from the radial artery. This brings several new problems into the equation when trying to extrapolate changes in pressure to changes in flow: Wave reflection, system damping , and changing relationships between flow and pressure in the periphery when compared to the central vasculature [4). Damping is a common problem in clinical practice . When recording an intravascular pressure, tubes filled with fluid are used. These systems have got spontaneous

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oscillations that can affect the quality of the analyzed signal. The performance of such a resonant system is determined by the frequency of oscillation and by the damping coefficient. Resonance frequency is the frequency of the oscillation of the system itself. If a signal has got a frequency similar to the resonance frequency of the system, the two oscillations can interact leading to a phenomenon called damping. If the system amplifies the signal, the phenomenon is called underdamping, if the system fades the signal, the phenomenon is called overdamping. Underdamping and overdamping lead to abnormal measurement of arterial pressure. The relationship between flow and pressure depends on the intrinsic characteristics of the cardiocirculatory system. Systole generates two kinds of waves: Pressure waves and flow waves. Pressure waves are those recorded from the arterial trans ducer. Although in the proximal aorta the flow wave and the pressure wave occur almost synchronously, peripherally the pressure wave is transmitted about 20 times faster. Furthermore, although flow in the proximal aorta is almost pulsatile, mostly in systole, the blood flows peripherally both in systole and in diastole. These problems create many issues with the development of algorithms that aim to convert arterial pressure perturbations into changes in stroke volume or cardiac output. Most companies marketing these technologies have come to the conclusion that it is impossible to reliably convert a pressure trace to a volume trace without an independent form of calibration, as many of these issues have proved to be difficult to overcome. Characteristics of an Ideal Algorithm for the Conversion of Pressure to Flow

The algorithm should: • work independent of the arterial site from where pressure is monitored despite changes in waveform shape and pressure through the arterial tree from the centre to the periphery • correct for non-linear compliance and take account of individual variations in aortic characteristics giving an absolute and accurate cardiac output • not be affected by changes in vascular resistance causing changes in reflected wave augmentation of the arterial pressure • not rely on identifying details of wave morphology • be only minimally affected by the damping often seen in arterial lines [4,5]. The Windkessel Model

When Otto Frank developed the famous model of air chambers in order to simulate the circulation in humans, properties about fluids in tubes were already known and some properties of the blood such as viscosity were also known too. The reason why the scientist developed it was that the pumping system in the human body is very complex. Indeed the pump (the heart) puts blood into the circulation in a pulsatile fashion, the arteries receive this blood and, thanks to elastic properties and to the ability to change the peripheral resistance, this system receives the blood in a pulsatile way and redistributes it in a more continuous fashion. The pulsatile inflow of the system is reflected by a pulse pressure that can be detected peripherally too. So, basically the Windkessel model was a model to describe the motion of the blood as a fluid moving into elastic compartments, and not in rigid tubes. The main components of this system are the pulsatile pump and the elastic vessels. Another important aspect of this system is time. Indeed volume and pressure in this system are

From Arterial Pressure to Cardiac Output

Heart

Fig. 1. Schematic representation of the forces in the cardiovascular system. The heart pumps the blood. Flow is regulated depending on the arterial compliance (the change in volume depends on compliance and time) and the peripheral resistance (mainly in the microcirculation).

Peripheral resistancesystem

Cha nge in volume (t ime dependent)

Compliance '---.r------'

Heart

'---.r------'

Arteries

Resistance Microcirculation

P

Fig. 2. Sinusoidal representation of changes in pressure over time. This property is used by algorithms of pulse pressure analysis in order to extrapolate changes in volume from changes in pressure.

dependent on time too [1, 6). Volume changes over time as the blood is pumped. This is similar to the proximal aorta which receives the stroke volume accommodating it and therefore changing its shape ( Fig. 1). At the same time, this change in volume is related to a change in pressure that can be simplified as sinusoid function over time ( Fig. 2). There are therefore two functions that are related to time: Pressure over time and volume over time. This means that even the cardiac output is a function that depends on time. It is important to note that the changes in volume are related to changes in pressure. But in this system we have mainly three factors. One is the pumping system, i.e., the heart, which pumps the blood intermittently. The second factor is the arterial system, which acts as a capacitor, getting blood during systole and then leaving it in diastole. The third factor is the peripheral vasculature , which contributes to the resistance. When studying the physics of fluids in motion, and comparing it to electricity, it is amazing how many similarities the two have. An electric circuit can be used to explain the Windkessel effect studied by Otto Frank (Fig. 3). In electric circuits when an alternating current and not a continuous one is applied, the total force that opposes the passage of the current is the impedance . Impedance is a measure of opposition to time-varying electric currents and derives from the combination of resistors and capacitors. Interestingly, when a direct cur-

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c

R

Fig. 3. Electric representation ofthe human circulation. The heart 'generates' power in an alternating fashion. ( represents the capacitor (i.e., the arterial tree), R represents the resistance of the system (l.e, the microcirculation).

rent is applied the effect of the capacitor is basically abolished and the only force that is relevant is the resistance. This is very similar to the cardiocirculatory system in which the pump is not continuous and needs to interact with the capacitor (i.e., the arteries) and the resistance (the microcirculation) beat by beat creating a sinusoid curve of pressure and a cycled behavior of the volume input [7,8]. The overall impedance depends on the combination of both of these two factors. Frank simulated compliance and resistance by using air chambers that simulated the physiologic behaviors of the cardiovascular system. As in electric circuits, impedance is a variable connected to time. We can imagine that the blood flows in a pulsatile way from the heart during systole (we can call this flow, Qin), this blood is accommodated in the arteries according to the compliance, from the arteries it flows during diastole (Qout) into the microcirculation where resistance has an effect ( Fig. 1). If we apply the concept of mass conservation, it is possible to quantify the speed of change in volume. The change in volume depends on time and is related to Qin - Qout with an exponential behavior. Time plays an important role in this model and this model explains that there is an exponential decay in the pressure and this is related to both resistance and compliance. From the law of conservation of mass: Qin - Qout = C x dPldt

where Qin is the inflow, Qout is the outflow in the periphery, C is the compliance, dP is the change in pressure, and dt the time interval. This is the Windkessel equation. This equation can also be expressed as: Qin - PIRs = C x dPidt

where P is pressure and R, is the systemic resistance If we imagine that Qin is constant during systole and equal to Qo (flow at the beginning of systole) then we can solve this for pressure during systole: pet) = RsQo - (RsQo - Po)e-( I1C)IRS

where t is 0 :5 t :5 t s' ts is the duration of systole, and Po is the pressure at the beginning of systole. If we solve the windkessel equation for pressure in diastole then Qin = 0 and so pet) = Pi!((JIC)/RsJ x (T-t) where t is ts :5 t :5 T, T is the duration of the cycle, and PT is the pressure at the end of diastole.

From Arterial Pressure to Cardiac Output

Following Frank's description of this system, new models have been developed, but every model has started from this background. It was only in 1983, thanks also to the computer era, that the first working algorithm based on these principles was made [6).

From Bench to Bedside Wesseling Algorithm The first algorithm used in clinical practice was the Wesseling algorithm, described in 1983. This algorithm is based on the hypothes is that the contour of the arterial pressure waveform is dependent on stroke volume, and that this can be estimated from the integral of the change in pressure over time, considering the interval between end of diastole to end of systole (Asys). The Wesseling algorithm has been described elsewhere in detail [6) and was the first successful attempt at converting the above theory onto a workable bedside system of measuring cardiac output.

Bedside Monitoring At the moment there are mainly three companies that sell devices able to monitor cardiac output from the analysis of the intravascular arterial pressure : Pulsion (Munich, Germany) with the PiCCOpius monitor, LidCO (Cambridge , UK) with the LiDCOTMplus System, and Edwards Lifesciences (Irvine , CA, USA) with the Flotrach technology and Vigileo Monitor.

Calibration Calibration is one of the strategies used by the first pulse pressure devices in order to tackle the problem of calculating the aortic impedance (compliance and resistance) . Calibration is the process in which an estimated continuous value of stroke volume is converted to a measured 'absolute' value. Basically in this way the impedance is calculated by obtaining a calibration factor that is equal to the ratio between the estimated stroke volume and the measured one. Cal = SVpulse/SVdilution

= calibration, SVpulse = pulse pressure algorithm stroke volume, and SVdilution = dilution measured stroke volume.

where Cal

The commercially available systems use different approaches to this problem. PiCCO uses a dilution technique based on cold injection (similar to the thermodilution method of the pulmonary artery catheter [PAC)), while LiDCO uses a lithium dilution technique.

PiCCO In clinical practice, the first pulse contour method using a Wesseling based algorithm was PiCCO (Pulsion Munich). PiCCO is a cardiac monitor that measures cardiac output through transpulmonary thermodilution, which is used to calibrate a pulse contour analysis algorithm. Over recent years, this algorithm has evolved through a number of steps into what is today integrated into the PiCCO monitor to measure cardiac output. The initial algorithm was a modification of the Wesseling

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approach. The second algorithm is more robust and analyzes even the diastolic part of the arterial pressure to tackle the problem of the non-linea r compliance [9-1 2] and the changing relationship between flow and pressure. Both algorithms use transpulmonary thermodilution to convert the continuous cardiac output der ived from the algorithm to a more accurate 'calibrated' value. The first algorithm utilized the following formula:

Stroke volume = cal (163 + 0.48HR x MAP) Asys

where cal = calibration factor, HR = heart rate, MAP = mean arterial pressure, and Asys = the systolic part of the area under the curve for the pressure over time curve. This algorithm is very similar to the Wesseling algorithm apart from the fact that age is not taken into consideration. The second algorithm is described according to:

Stroke volume = cal x JSYSlot.[P(t)ISVR + C(p)dPldtJdt

xv

where P = pressure, t = time, SVR = systemic vascular resistance, C(p) = compliance corrected for arterial pressure, and Asys = the systolic part of the area under the curve. This basically uses more information about the shape of the arterial pressure waveform. It also takes into account that during systole the pulsatile flow is the bigger part of the flow, with the aorta accommodating most of the stroke volume and little blood flowing away from it. In diastole, the blood leaves the aorta according to the total impedance (compliance and resistance). The systemic vascular resistance is calculated during the calibration by dividing the cardiac output by the mean arterial pressure. Compliance is then also calculated. The calibrated algorithm is then able to track stroke volume continuously. The PiCCO was for many years the only clinical available pulse contour device used in intensive care and in anesthesia. Continuous cardiac output measured by the PiCCO had been studied and validated against interm ittent thermodilution form the PAC in several conditions and has proven to be a reliable device, needing to be recalibrated only in cases of significant hemodynamic changes [13, 14]. The PiCCO system also measures several vascular volumes via the transpulmonary thermodilution technique, such as intrathoracic blood volume (ITBV) and extravascular lung water (EVLW) [15] ( Fig. 4). Before the advent of PiCCO, another system (COLD) by Pulsion was used to measure these volumes with a double indicator technique , using a thermal dye that spread inside and outside the vessels, and indocyanine green that remains only within the vascularature and is metabolized in the liver. The PiCCO system utilizes the data derived from the COLD machine to estimate these volumes without the second indicator injection. They have been partially validated against COLD volumes [16]. These volumes have been shown to better reflect preload status than filling pressures [17, 18].

LiDCO The LiDCO system is a new cardiac output monitor that measures cardiac output via lithium transpulmonary dilution. The lithium dilution technique is performed using 0.3 ml of lithium that is injected either into a central or a peripheral vein. At the same time a pump is connected to whatever arterial line is in place and a constant withdrawal of blood at a rate of 4 mllmin is generated. A lithium sensitive sensor, placed on the sampling line, detects the variation in the concentration of lithium

From Arterial Pressure to Cardiac Output

597

ETV

RAEDV RVEDV

PBV

LAEDV

LVEDV

PBV

1 L_-----.-------_~ + PTV

GEDV

1

ITTV

Fig. 4. Volumes as measured by PiCCO during thermodilution. RAEDV: right atrial end-diastolic volume; RVEDV: right ventricular end-diastolic volume; PBV: pulmonary blood volume; ElV: extravascular thermal volume; PTV: pulmonary thermal volume; LAEDV: left atrial end-diastolic volume; LVEDV: left ventricular end-diastolic volume; GEDV: global end-diastolic volume; ITTV: intrathoracic thermal volume.

and a concentration-time curve is generated. The Stewart-Hamilton curve allows the cardiac output to be measured from the indicator dilution curve. Being a transpulmonary technique, it is less affected by respiration than single measurements from the pulmonary artery and it has been said that a single lithium dilution curve is probably precise enough and accurate, without the requirement of averaging repeated measurements, to be used in clinical practice. This technique cannot be performed in patients receiving lithium therapy and is also difficult in the operating room, where the use of muscle relaxants containing quaternary ammonium ions can interfere with the lithium sensor. The LiDCOTMplus System contains an algorithm for continuous cardiac output monitoring which is calibrated with the lithium dilution curve. The continuous cardiac output is derived from the arterial pressure wave and it is normally classified as a pulse contour method, although strictly speaking it is not a pulse contour monitor. The LidCO approach can be defined as a pulse power analysis, as it is based on the hypothesis that the change in power in the system (arterial tree) during systole is the difference of the amount of blood entering the system (stroke volume) minus the amount of blood flowing out peripherally [4,19]. It is based on the principle of conservation of mass/power and an assumption that following correction for compliance and calibration there is a linear relationship between net power and net flow. This algorithm takes count of the entire beat, tackling in this way the problem of the reflected waves, and uses a so-called autocorrelation to define which part of the 'change in power' is determined by the stroke volume. Autocorrelation is a mathematical function used to analyze signals that tend to have repeated cycles over time (similar to a Fourier transformation). This is clearly the case of the stroke volume in human physiology. In this way all the curve is analyzed and the repeated stroke volume recorded . When this factor is identified then cardiac output is easily calculated, multiplying stroke volume by heart rate. Initially the algorithm transforms the arte-

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M. Cecconi, A. Rhodes, and G. Della Rocca

rial pressure wave to a standardized volume waveform (in arbitrary units) using the formula: ~ VI~p

= calibration

x 250 x e-k.p

where V = volume, P = blood pressure, and k = curve coefficient; 250 is the saturation value in ml, i.e., maximum additional value above the starting volume, at atmospheric pressure, that the aorta/arterial tree can fill to. Autocorrelation uses the volume waveform and derives the period of the beat plus a net effective beat power factor, proportional to the nominal stroke volume ejected into the aorta [4]. This nominal stroke volume is then calibrated to be equalized to a measured stroke volume. Basically, the algorithm takes the pressure over time wave and transforms it into a volume over time curve with autocorrelation. From the analysis of the curve the system needs to understand what the stroke volume is and how long each cycle lasts. To get the stroke volume (the nominal stroke volume) a sinusoidal relationship representing the oscillations of volume over time is created from the subtraction of the values around a mean value. Multiplying all values of the waveform by themselves will measure the mean deviation from zero. This multiplication creates positive waves for both the positive and negative oscillation, creating a double waveform. By averaging all these positive values a new number is obtained that represents the mean square of the original values. Backtransforming it with square root analysis will finally give a number proportional to the amplitude of the original waveform. This value is the nominal stroke volume and is related to the magnitude of the original waveform ( Fig. 5). Until the calibration is performed, the system behaves as if the calibration factor is 1. After calibration is done, a calibration factor derived from the ratio between the arbitrary cardiac output and the measured one is achieved. In theory, the calibration factor should be constant in the patient unless there are significant hemodynamic changes. The continuous cardiac output measured by LiDeo has been validated in several studies [20-22]. This new algorithm has so far proven to be reliable in surgical and intensive care patients [4].

Nom inal unit s

::!

3

ttl

Nomin al unit s

Fig. 5. Figure representing how autocorrelation obtains a nominal value for stroke volume from the analysis of the oscillations ofvolume obtained from the pressure wave. In the upper graph the sinusoidal oscillations are represented, obtained by subtracting the oscillations around the mean values from the mean value. In the lower graph, the transformation ofthe oscillation by multiplying them by themselves and then doing the square root is represented. The average ofthese values is a nominal stroke volume.

From Arterial Pressure to Cardiac Output

599

Vigileo

FloTrac (Edwards Lifescience) is the name of the specific transducer incorporated into the Vigileo mon itor. The most interest ing characteristic of this device is that it does not need to be calibrated and it needs just an arterial line to work. The underlying theory is that stroke volume is proportional to pulse pressure and that all the information about impedance can be achieved by demographic data and by the analysis of the arterial pressure waveform. According to the manufacturer, the algorithm is pr imarily based on the standard deviation of the pulse pressure waveform as follows:

Cardiac output = ftcompiiance, resistance) x

(Jp

HR

where (J p is the standard deviation of the arterial pressure, HR is the heart rate, and f(compliance, resistance) is a scale factor proportional to vascular compliance and peripheral resistance. This function is also referred as x; its calculation in the first version of the software was done every 10 minutes, while version 2 of the software recalculates it every minute. Cardiac outpout is computed every 20 seconds. The standard deviation of the arterial pressure waveform is computed on a beat-to-beat basis using the following equation: (Jp

= v[l/(N-I)

X L (N- l , k=oy(P(k)

- Pavgi']

where P(k) is k pulse pressure sample in the current beat, N is the total number of samples, and Pavg is the mean arterial pressure . Compliance and resistance are derived from the analysis of the arterial waveform. The hypothesis is that the shape of the arterial pressure wave, in terms of its kurtosis or skewness, can be used to calculate the effects of compliance and peripheral resistance on flow. Additional parameters, such as the pressure-dependent Windkessel compliance, C"" based on previous work [9-12, 23], heart rate, and the patient's body surface area (BSA) are also included to take other patient specific characteristics into account. This algorithm is currently under validation. Some authors state that the algorithm performs in an acceptable fashion [24- 26], while others have found that it is not reliable enough [27- 29]. th

Conclusion There are currently several commercially available monitors that can track changes in cardiac output or stroke volume from the arterial pressure waveform. PiCCOplus and LiDCOTMplus utilize an indep endent calibration technique for this purpose and have been well validated. They need some form of calculation that calibrates the arbitrary value to a specific value to compensate for vascular impedance. The Vigileo system tries to perform an 'internal' calibration. Data from the Vigileo technology are still under evaluation. In the meant ime, clinicians utilize validated methods of tracking cardiac output to manage their patients in order to improve outcomes.

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M. Cecconi, A. Rhodes, and G. Della Rocca References

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1. Baselli G, Porta A, Pagani M (2006) Coupling arterial windkessel with peripheral vasomotion: modeling the effects on low-frequency oscillations. IEEE Trans Biomed Eng 53:53-64 2. Finkelstein SM, Cohn IN (l992) First- and third-order models for determining arterial compliance. J Hypertens Suppl l0:S11-S14 3. Erlanger J, Hooker DR (l904) An experimental study of blood-pressure and of pulse-pressure in man. Johns Hopkins Hosp Rep 12:145-378 4. Rhodes A, Sunderland R (2004) Arterial pulse pressure analysis: The LiDCOpius System. In: Pinsky MR, Payen D (eds) Functional Hemodynamic Monitoring. Spinger, heidelberg, pp 183-192 5. Cecconi M, Wilson J, Rhodes A (2006) Pulse pressure analysis. In Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg, pp 176-184 6. Wesseling KH, Jansen JR, Settels H, Schreuder H (l993) Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 74:2566-2573 7. Chen CW, Shau YW, Wu CP (1997) Analog transmission line model for simulation of systemic circulation. lEEE Trans Biomed Eng 44:90-94 8. Cole RT, Lucas CL, Cascio WE, Johnson TA (2005) A LabVlEW model incorporating an openloop arterial impedance and a closed-loop circulatory system. Ann Biomed Eng 33:1555 -1573 9. Langewouters GJ, Wesseling KH, Goedhard WJ (l984) The static elastic properties of 45 human thoracic and 20 abdominal aortas in vitro and the parameters of a new model. J Biomech 17:425- 435 10. Langewouters GJ, Goedhard WJ, Wesseling KH (1985) [The effect of aging and sclerosis on the viscoelastic properties of the human thoracic aorta) . Tijdschr Gerontol Geriatr 16:61-70 11. Langewouters GJ, Zwart A, Busse R, Wesseling KH (l986) Pressure-diameter relationships of segments of human finger arteries. Clin Phys Physiol Meas 7:43- 56 12. Langewouters GJ, Wesseling KH, Goedhard WJ (l985) The pressure dependent dynamic elasticity of 35 thoracic and 16 abdominal human aortas in vitro described by a five component model. J Biomech 18613-620 13. Della RG, Costa MG, Coccia C, et al (2003) Cardiac output monitoring: aortic transpulmonary thermodilution and pulse contour analysis agree with standard thermodilution methods in patients undergoing lung transplantation. Can J Anaesth 50:707-711 14. Torgay A, Pirat A, Akpek E, Zeyneloglu P, Arslan G, Haberal M (2005) Pulse contour cardiac output system use in pediatric orthotopic liver transplantation: preliminary report of nine patients . Transplant Proc 37:3168-3170 15. Hofer CK, Furrer L, Matter-Ensner S, et al (2005) Volumetric preload measurement by thermodilution: a comparison with transoesophageal echocardiography. Br J Anaesth 94:748- 755 16. Sakka SG, Ruhl CC, Pfeiffer UJ, et al (2000) Assessment of cardiac preload and extravascular lung water by single transpulmonary thermodilution. Intensive Care Med 26:180-187 17. Della RG, Costa MG, Coccia C, Pompei L, Pietropaoli P (2002) Preload and haemodynamic assessment during liver transplantation: a comparison between the pulmonary artery catheter and transpulmonary indicator dilution techniques . Eur J Anaesthesiol 19:868 -875 18. Della RG, Costa GM, Coccia C, Pompei L, Di MP, Pietropaoli P (2002) Preload index: pulmonary artery occlusion pressure versus intrathoracic blood volume monitoring during lung transplantation. Anesth Analg 95:835 - 843 19. Pearse RM, Ikram K, Barry J (2004) Equipment review: an appraisal of the LiDCO plus method of measuring cardiac output. Crit Care 8:190-195 20. Hamilton TT, Huber LM, Jessen ME (2002) PulseCO: a less-invasive method to monitor cardiac output from arterial pressure after cardiac surgery. Ann Thorac Surg 74:S1408-S1412 21. Pittman J, Bar-YosefS, SumPing J, Sherwood M, Mark J (2005) Continuous cardiac output monitoring with pulse contour analysis: a comparison with lithium indicator dilution cardiac output measurement. Crit Care Med 33:2015 -2021 22. Tsutsui M, Mori T, Aramaki Y, Fukuda I, Kazama T (2004) [A comparison of two methods for continuous cardiac output measurement: PuiseCO VS CCO). Masui 53:929-933 23. Langewouters GJ, Settels H, Roelandt R, Wesseling KH (l998) Why use Finapres or Portapres rather than intra-arterial or intermittent non-invasive techniques of blood pressure measurement? J Med Eng Technol 22:37- 43

From Arterial Pressure to Cardiac Output

601

24. Manecke GR (2005) Edwards FloTrac sensor and Vigileo monitor: easy, accurate, reliable cardiac output assessment using the arterial pulse wave. Expert Rev Med Devices 2:523 - 527 25. Button D, Weibel L, Reuthebuch 0, Genoni M, Zollinger A, Hofer CK (2007) Clinical evaluation of the FloTraclVigileo system and two established cont inuous cardiac output mon itoring devices in pat ients undergoing cardiac surgery. Br J Anaesth 99:329-336 26. de Waal EE, Kalkman CJ, Rex $, Buhre WF (2007) Validation of a new arterial pulse contourbased cardia c output device. Crit Care Med 35:1904-1909 27. Mayer J, Boldt J, Schollhorn T, Rohm KD, Mengistu AM, Suttner S (2007) Semi-invasive monitoring of cardiac output by a new device using arterial pressure waveform analysis: a comparison with intermittent pulmonary ar tery thermodilution in pat ients undergoing cardiac surgery. Br , Anaesth 98:176-182 28. Opdam HI, Wan L, Bellomo R (2007) A pilot assessment of the FloTrac cardiac output monitoring system. Intensive Care Med 33:344-349 29. Guarracino F, Stefani M, Lapolla F, et al (2007) Monitoring cardiac output with Flo Trac Vigileo. Br J Anaesth 99:142-143

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602

Hemodynamic Monitoring: Requirements of Less Invasive Intensive Care - Quality and Safety A. VIEILLARD-BARON

Introduction: Some Definitions Monitoring is rather a general term which defines the set of techniques used to analyze, check, and monitor the quality of a recording in electronics, or the pathophysiologic reactions of a patient in medicine [1]. The definition of monitoring does not necessarily imply the notion of continuity. Applied to hemodynamics, monitoring records the main parameters of cardiac function, such as cardiac output, right and left filling pressures, contractility of the left ventricle, and systolic function of the right ventricle. Hemodynamic monitoring can be used to check filling requirements and also to assess how cardiovascular function impacts on metabolism, by determining venous oxygen saturation, lactate, and base deficit. Medical dictionaries label a technique invasive when the body is entered by a puncture or an incision [2], as with pulmonary arterial catheterization and many other monitoring techniques (see invasiveness scale on Figu re 1). Monitoring techniques are not equivalent, since some essentially enable measurement of cardiac output while others provide a more complete hemodynamic picture (see below for more details).

Historical Outline From the early 1970s, hemodynamic monitoring seemed indispensable in intensive care medicine. Swan and Ganz proposed a technique of right heart catheterization for bedside measurements of cardiac output and right and left filling pressures [3]. Such was the impact, that some intensivists rightly wrote that the pulmonary artery catheter (PAC) was not only important for intensive care, but also its very foundation [4]. From the use of the PAC stemmed a whole range of physiological and pathophysiologic studies of the cardiovascular system [5, 6]. At this time, such a hemodynamic monitoring tool, which necessitated the placement of a particular catheter in the pulmonary artery, seemed much less invasive than the intensive techniques used in management of acute respiratory insufficiency [7] or acute renal failure. With hindsight, it is apparent that the prognosis of a good many patients was intimately tied to the harmful consequences of unsuitable mechanical ventilation. However, by the end of the 1970s, certain intensivists were questioning the impact of intensive care on the prognosis of patients [8]. Scant attention was paid at the time to the risks of monitoring techniques and to the erroneous interpretations that they engendered, and this without doubt ran counter to any clinical benefit [9].

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Remarkable progress achieved over the last thirty years in understanding pathophysiologic phenomena and in technological improvements has considerably altered our perception of monitoring, particularly hemodynamic. The respirator became central to intensive care; its purpose, of course, being to ventilate, but also to oversee, monitor, and ensure the safety of patients. Ventilation is now deemed 'good' when it is minimally aggressive for the lungs [10]. Hemodialysis has been simplified and made safer, and strict control of renal function seems to be associated with a better prognosis [11]. In parallel to these developments, several studies, whose methodology was admittedly open to criticism, questioned the safety and even the value of the PAC [12] . Subsequent work in intensive care [13], cardiology [14], and the perioperative period [15] has confirmed these doubts. All these data imposed the idea that the prerequisites of monitoring are quality and safety and that systematic use of pulmonary artery catheterization in the management of circulatory failure was no longer justifiable. The Cub-Rea survey of the epidemiology of septic shock in the Paris Ilede-France region between 1993 and 2000 confirmed this tendency [16]. Yet every intensivist understands that the management of a state of shock cannot be limited to clinical evaluation, which is often inadequate, as in the detection of hypovolemia or the evaluation of cardiac output and filling pressure [17]. Such is the interplay between the various mechanisms of circulatory failure in complex conditions like septic shock that it is essential to obtain objective hemodynamic parameters to guide treatment. It would perhaps be an exaggeration to say that there was a revolutionary transition from the age of oil lamps to the age of electricity [18], but a new way of viewing hemodynamics and its monitoring emerged over the following years.

The Requirements for Quality Monitoring

xv

At the 2006 American Thoracic Society Congress in San Diego, Martin Tobin presented, in the context of the management of acute respiratory insufficiency, his definition of monitoring and the characteristics of quality monitoring. His reflections apply perfectly to hemodynamic monitoring, which should allow us to understand the mechanisms of circulatory failure: Hypovolemia, heart failure, vasoplegia, pericardial effusion. Hemodynamic monitoring thus enables treatment to be perfectly adapted to the circumstances, by prescribing filling, an inotropic agent, a vasoconstrictor, pericardial drainage. Good monitoring gathers pertinent physiological data. The following questions then arise: Is it relevant to measure filling pressures when seeking to predict the response to filling? Is it pertinent to define cardiac dysfunction of septic shock as the combination of a low cardiac output and high filling pressures? And is it relevant to measure and compare left and right heart filling pressures when wanting to detect right ventricular failure? A great many publications, which will not be cited here, have shown that these questions should be answered in the negative. Many of the monitoring techniques presented in Figure 1 virtually measure just cardiac output. This is, naturally, too restrictive when making a diagnosis and adapting treatment, as pointed out by the 2006 International Consensus Conference on the treatment of shock [19]. Lastly, good monitoring must be easy and quick to use, widely available, and of no danger to the patient , and thus minimally invasive. In all cases, the risk-benefit ratio must be low. More recently, evidence has emerged that hemodynamic monitoring must be coupled with a coherent therapeutic protocol, if appropriate quality and safety require-

Hemodynamic Monitoring: Requirements of Less Invasive Intensive Care - Quality and Safety

605

ments are to be met [20). The study by Rivers et al. was a reminder that by acting fast, using physiologically relevant findings, and implement ing a coherent treatment protocol, it is possible to diminish mortality significantly among patients with severe sepsis and septic shock [21). It is doubtless one of the great shortcomings of pulmonary artery catheterization that there is no consensual and effective management algorithm. This is a limitation inherent to the technique . Hemodynamic monitoring in 2008 must be tried and trusted, safe, minimally invasive or non-invasive, and directly coupled to a simple and effective treatment protocol. This is more or less the definition of the relatively recent concept of 'functional hemodynamic monitoring' [22). Even though certain techniques are more suitable than others, functional hemodynamic monitoring is not linked to one or another tool, but rather reflects a simpler (but not simplistic) view of hemodynamics: A question raised should prompt a reliable diagnosis and generate a clearsighted therapeutic response.

So, Which Tool? Perusal of the above, and of Figure 1, shows that in 2008 certain techniques do not meet the requirements for efficient, reliable, and safe hemodynamic monitoring. This is because their approach to the problem is piecemeal (measurement of cardiac output alone is useless), or because they monitor physiological variables lacking relevance, or because the risk-benefit ratio is unacceptable, at least in the current state of knowledge. It is, nonetheless, important to use the tool one masters best and to incorporate it as effectively as possible in management protocols used in practice or acknowledged in the literature . Continuous monitoring of arterial blood pressure is essential in a great many cases of shock, as recalled by the 2006 International Consensus Conference [19]. This does not mean that the resulting techniques for measuring cardiac output ensure safe and reliable monitoring. Taking sides somewhat, it is the author's view that echocardiography is probably at present the method that best meets the requirements enunciated above. It is also the tool that during utilization best clarifies the concept of functional hemodynamic monitoring and so facilitates its application. In a single examination , echocardiography yields a whole set of cardiac function parameters, reliable filling criteria have been defined, it is non-inv asive, or almost, can be mastered relatively easily, at least in terms of hemodynamics, and is accessible to everyone [23).

Conclusion In conclusion, over the last thirty years, from the advent of the PAC to the concept of functional hemodynamic monitoring, there has been a revolution in the devices and methods used in hemodynamic monitoring. Invasive and quantitative monitoring has given way to less invasive, even non-invasive, more qualitative monitoring. This change is explained by technological ameliorations, better pathophysiologic understanding, and numerous clinical studies that questioned the safety and utility of pulmonary artery catheterization. Among other tools, echocardiography seems best suited to meet the new requirements of efficacy, quality, and safety.

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606

A. Vieillard-Baron References 1. Centre National de Ressources Textuelles and Lexicales. http://www.cnrtlJr/lexiquesl 2. Definition of invasive. Available at: http ://www.hyperdic.net/dic/invasive.htm. Accessed Dec 2007 3. Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D (1970) Catheterization of the heart in man with use of a flow-directed balloon -tipped catheter. N Engl J Med 283:447-451 4. Marino PL (1997) The ICU Book. 2nd ed. Lippincott, Williams & Wilkins, Philadelphia 5. Jardin F, Farcot JC, Boisante L, Curien N, Margairaz A, Bourdarias JP (1981) Influence ofpositive end-expiratory pressure on left ventricul ar performance . N Engl J Med 304: 387- 392 6. Lemaire F, Regnier B, Simoneau G, Harf A (1980) Positive end-expiratory pressure (PEEP) ventilation suppresses the increase of shunting caused by dopamine infusion. Anesthesiology 52: 376-377 7. Colice GL (2006) Historical perspective on the development of mechanical ventilation. In: Tobin MJ (ed) Principles and Practice of Mechanical Ventilation. McGraw-Hill, New-York, pp 1-36 8. Robin ED (1983) A critical look at critical care. Crit Care Med 11:144-148 9. Spodick DH (1980) Physiologic and prognostic implications of invasive monitoring: undetermined risk/benefit ratios in patients with heart disease. Am J Cardiol 46:173-175 10. Hickling K, Henderson S, Jackson R (1990) Low mortality associated with low volume/pressure limited ventilation with permi ssive hypercapnia in severe adult respiratory distress syndrome . Intensive Care Med 16:372-377 11. Ronco C, Bellomo R, Hamel P, et al (2000) Effects of different doses in continuous venovenous haemofiltration on outcomes of acute renal failure: a prospective randomized trial. Lancet 355:26-30 12. Connors AF, Speroff TS, Dawson NV, et al (1996) The effectiveness ofright-heart catheterization in the initial care of critically ill patients . JAMA 276:889- 897 13 Richard C, Warszawski J, Anguel N, et al (2003) Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distre ss syndrome: a randomized controlled trial. JAMA 290: 2713-2720 14. The ESCAPE Investigators and ESCAPE Study Coordinators (2005) Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness. The ESCAPE trial. JAMA 294:1625-1633 15. Sandham JD, Hull RD, Brant RF, et al (2003) A randomized, controlled trial of the use of the pulmonary-artery catheters in high-risk surgical patients . N Engl J Med 348:5-14 16. Annane D, Aegerter P, [ars-Guincestre MC, Guidet B (2003) Current epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med 168:165-172 17. Eisenberg PR, Jaffe AS, Schuster DP (1984) Clinical evaluation compared to pulmonary artery catheterization in the hemodynamic assessment of critically ill pat ients. Crit Care Med 12: 549-553 18. Jardin F (2005) Acute leftward septal shift by lung recruitment maneuver. Intensive Care Med 31:1148- 1149 19. Antonelli M, Levy M, Andrews PJ, et al (2007) Hemodynamic monitoring in shock and implications for management. International Consensus Conference, Paris, France, 27- 28 April 2006. Intensive Care Med 33:575- 590 20. Pinsky MR, Vincent JL (2005) Let us use the pulmonary artery catheter correctly and only when we need it. Crit Care Med 33:1119-1122 21. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl J Med 345:1368-1377 22. Hadian M, Pinsky MR (2007) Functional hemodynamic monitoring. Curr Opin Crit Care 13:318-323 23. Charron C, Prat G, Caille V, et al (2007) Validation of a skills assessment scoring system for tran sesophageal echocardiographic mon itoring of hemodynamics. Intensive Care Med 33: 1712-1718

607

Minimally Invasive Cardiac Output Monitoring: Toy Or Tool? G.

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Introduction Cardiac output measurement is still regarded as one of the key hemodynamic variables in the assessment of cardiac function and as an essential measure for guiding the therapy of critically ill patients. In order to achieve adequate oxygen delivery (D0 2 ) , hemodynamic monitoring is necessary in order to provide appropriate cardiovascular support [1]. Although measurements of regional perfusion and oxygenation are gaining increasing attention, cardiac output measurement is still regarded as the key hemodynamic variable in the assessment of cardiac function and to guide therapy. Flow, as gauged by cardiac output, is the key measure of how well the circulation is delivering oxygen and nutrients to the vital organs and is the focus of all resuscitation efforts. Traditionally a pulmonary artery catheter (PAC) has been used for measuring pulmonary arterial pressures and cardiac output by thermodilution techniques in order to guide fluid therapy and hemodynamic manipulation. There have been serious concerns about the risk-benefit ratio of using pulmonary artery occlusion pressure (PAOP) as a measure of cardiac preload and recent studies have suggested a lack of benefit in some patient groups using the PAC [2-4] . Recently, in a cohort of patients undergoing major non-cardiac surgery, it was demonstrated that the use of the PAC provides no benefit [5]. Among patients with severe sepsis, PAC placement was not associated with a change in mortality rate or resource use, although small non -significant trends towards a lower resource use were present in the PAC group [6]. In a consensus statement of the National Heart, Lung, and Blood Institute (NHLBI) and the Food and Drug Administration (FDA) PAC use was not recommended for elective major surger y [7]. Thus, there is considerable controversy surrounding the use of a PAC for measuring cardiac output, since its use may be associated with an increase in morbidity and mortality [2, 8]. As a result, there is increasing interest in less invasive cardiac output measurement techniques, such as applications of the Fick principle, esophageal Doppler, thoracic bioimpedance, and pulse wave analysis, since none of these techniques requires the placement of a PAC. Pulse wave analysis provides a continuous display of cardiac output. The first algorithm used in clinical practice was suggested by Wesseling et al. [9]. This algorithm calculates the stroke volume derived by determining the area under the curve of the systolic part of the arterial pressure. Continuous arterial waveform analysis has been validated in recent years as a continuous cardiac output measurement method while other measured and derived parameters enable the simultaneous estimation of the cardiac preload [10]. Before clinicians accept or even adopt a new monitoring device they need to be convinced that it compares favorably with the existing 'gold' standard. However, as there is no true clinical gold standard in mea-

608

G. Marx and T. Schuerholz

suring cardiac output the accuracy of new cardiac output measuring devices is often determined by comparison with the PAC. It is important to realize that the thermodilution technique itself has some technical limitations resulting in sources of inaccuracy. The accuracy of PAC cardiac output measurement by thermodilution is affected to an extent by the transient decrease in the heart rate at the time of cold injection. The right ventricular (RV) cardiac output measured by thermodilution is unequal to the left ventricular (LV) cardiac output in the presence of intra - or extra-cardiac shunts. Valvular regurgitation gives inaccurate results as well. Thus, it is possible that, as newer devices are validated, some of these will become more appropriate reference methods than thermodilution. A clinical method for monitoring cardiac output should be continuous, minimally invasive, and accurate. However, none of the conventional cardiac output measurement methods possesses all of these characteristics. On the other hand, peripheral arterial blood pressure may be measured reliably and continuously with little invasiveness. This chapter will focus on the clinically available techniques using pulse wave analysis in order to measure cardiac output.

Pulse Wave Analysis

xv

Pulse wave analysis measures the variations in the arterial pressure waveform to predict vascular flow. With arterial pulse-based hemodynamic monitoring systems, determination of stroke volume is essential for determining cardiac output because of the interaction between stroke volume and systemic vascular compliance. Vascular compliance and changes in vascular resistance at the site of detection are important to enable accurate measurements. These different methods calculate stroke volume on a beat-to-beat basis or over a 20-30 sec period . It is imperative that these systems account for patient-to-patient differences as well as real time changes in factors affecting an individual patient's hemodynamics. Due to principles used to assess cardiac output, there are several major limitations applying to all pulse wave analysis devices [l l ]. All devices are dependent on an optimal arterial pressure signal. The limitations of pulse contour analysis include the presence of low arterial signal quality, rapid changes in vascular tone, severe arrhythmias, and significant aortic insufficiency causing flow reversal in the abdominal aorta. The use of an intraaortic balloon pump precludes reliable measurements, because intraaortic counter pulsation may give inaccurate results. Currently there are three devices commercially available using pulse wave analysis to determine cardiac output: PiCCOplus" (Pulsion Medical Systems, Munich, Germany); PulseCOTM (LiDCO Ltd, London, UK); FloTraclVigileo™ (Edwards LifeSiences). This chapter will focus on these clinically available devices, addressing the specific features and specific limitations .

PiCCO The PiCCOplus™ device was the first clinically introduced device using arterial thermodilution and pulse wave analysis for the continuous measurement of cardiac output. Based on the same principles as pulmonary thermodilution, cardiac output can also be measured by arterial thermodilution (12) . This less invasive technique needs a special arterial thermistor tipped catheter and a central venous line. Based on the algorithm first described by Wesseling et al. an integrated pulse wave method

Minimally Invasive Cardiac Output Monitoring: Toy Or Tool?

calculates cardiac output continuously [9]. According to this algorithm, LV stroke volume is computed by measuring the area under the systolic portion of the arterial pressure waveform and dividing this area by the aortic impedance. A subsequent mult iplication by the heart rate yields pulse-wave cardiac output. Nowadays, the PiCCOplus™ system uses a more sophisticated developed pulse-wave algorithm [13]. This formula analyzes the actual shape of the pressure waveform in addition to the area under the systolic portion of the pressure wave. Furthermore, the software takes into account the individual aortic compliance and systemic vascular resistance . Both arterial thermodilution cardiac output and continuous arterial waveform analysis of the PiCCO device have been validated within the last few years [14, 15], but sur prisingly in septic shock, there has been a lack of data comparing their accuracy and reliability. We compared arterial thermodilution with the physiological standard, indirect calorimetry, in a porcine septic shock model using fecal peritonitis [16]. Correlation between indirect calorimetry derived cardiac output estimation and transpulmonary cardiac output was high (r = 0.91, r 2 = 0.83, P < 0.00l). Bias was 0.75 mllkg/min (95 % confidence interval: -3.8 to 5.3 mllmin/kg with limits of agreement of -39.7 to 41.2 mllkg/min). The results suggest that even during hemodynamic instability in septic shock, arterial thermodilution provides accurate cardiac output measurements. Using the same experimental model we demonstrated the reliability of continuous cardiac output using the PiCCOTMdevice [17]. We connected two PiCCO moni tors to each animal and compared the results from an hourly-recalibrated monitor with the results from a non -recalibrated monitor. Correlation between recalibrated and non-recalibrated cardiac output 3 h after sepsis induction was r = 0.74, P < 0.01, at 5 h r = 0.59, P < 0.05, and at 9 h r = 0.02, n.s. Bias ± SD (limits of agreement) between both groups 3 h after sepsis induction was 1.6 ± 15.5 (-29.4 - 32.6) ml/kg/ min, at 5 h -15.0 ± 24.3 (-63.6 - 33.7) ml/kg/rnin, and at 9 h -87.0 ± 90.8 (-268.5 - 94.6) mllkg/min (Fig. 1). Thus, continuous cardiac output determination by pulsewave analysis is a clinically acceptable method to assess cardiac output up to five hours without recalibration in porcine septic shock . Spohr et al. confirmed our experimental data in sept ic shock patients [18]. They found a significant correlation between continuous cardiac output by PAC and by pulse-wave analysis (r 2 = 0.714, P < 0.000l), accompanied by a bias of 0.1 lImin and a precision of 2.7 lImin. Recently, studies revealed conflicting results on the agreement between the PiCCOplus™ device and the rmodilution cardiac output during cardiac surgery in the presence of rapid change s in vascular compliance and resistance . Halvorsen et al. reported a good agreement between the PiCCOplus™ device and thermodilution cardiac output in a hemodynamically unstable situation dur ing off-pump coronary artery bypass surgery [19], wherea s considerable variations were shown using the PiCCOplus™ device during off-pump coronary artery bypas s [20] and after weaning from cardiopulmonary bypass [21]. Thus, frequent recalibration of the device is recommended [11]. Despite early recalibration, Button et al. found a decreased agreement of the PiCCOplus™ in the postoperative period of cardiac surgery in comparison with intermittent pulmonary artery thermodilution [22]. In a multicenter epidemiological study, the use of hemodynamic monitoring with either a PAC or the PiCCfrplus" was evaluated in 331 criticall y ill patients [23]. In this study, invasive hemodynamic monitoring with PiCCO or PAC appeared to be applied to different patient populations. Whereas in patients with vasodilatory shock PiCCO was used more frequently, PAC was applied more often to patients requiring inotropic support. The authors found that the use of PiCCO was associated with a greater pos-

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xv

itive fluid balance and fewer ventilator-free days. After the adjustment for confounding variables, the choice of monitoring technique did not predict outcome, but a positive fluid balance was a significant predictor of greater mortality. The PiCCOplus™ device incorporates, in addition, the measurement of stroke volume variation (SVV), a continuous parameter of ventricular fluid responsiveness in mechanically ventilated patients in sinus rhythm. SVV has been shown to be a precise predictor of volume responsiveness in neurosurgery [24), cardiac surgery [25), and in septic shock [26). In addition, transpulmonary thermodilution measures the global end-diastolic heart volume (GEDV) at the end of diastole, facilitating the estimation of cardiac preload [27). Furthermore the transpulmonary thermodilution derived parameter, extravascular lung water (EVLW), enables the detection of pulmonary edema [28). The limitations of the PiCCOplus™ device include the need for a special arterial femoral or axillary catheter. Using the femoral catheter, complications related to the femoral puncture, like ischemia or bleeding, may occur. LiDCO

The LiDCO system offers a thermodilution technique to measure cardiac output using lithium as an indicator. The system requires a peripheral, or better a central venous, access for injection of the lithium plus any arterial line to which a lithium

Minimally Invasive Cardiac Output Monitoring: Toy Or Tool?

sensitive electrode needs to be attached. This electrode is located in a flow-through cell and attached to the arterial line via a three-way tap. Initially, a bolus of lithium chloride needs to be injected intravenously and then detected by the lithium sensitive electrode. The cardiac output is calculated from the lithium dose and the area under the concentration curve prior to recirculation [29]. Based on the lithium ther modilution cardiac output, the LiDCO device calibrates a pulse wave analysis software providing a continuous pulse wave cardiac output (PulseCOTM) by analyzing the arterial pulse wave [30]. Whereas the PiCCO algorithm uses only the area of the systolic part of the curve, PulseCO™ uses the complete area of the arterial pulse wave to calculate the change in stroke volume by power analysis. Agreement of the device compared to cardiac output measured by other techniques has been demonstrated in cardiac surgical patients [31] and pediatric critically ill patients [32]. Of note, there is one study comparing the LiDCO derived cardiac output with an electromagnetic flow probe , indicating that LiDCO is a reliable cardiac output measurement [33]. The continuous cardiac output of LiDCO has been validated in several studies showing it to be accurate and reliable in surgical and intensive care patients [34, 35]. LiDCO offers in addition pulse pressure, systolic pressure variations, and SVV to predict fluid responsiveness . Beside the general situations of limited accuracy that apply to all pulse wave analysis devices, the use of lithium is the major limitation of this method. Compared to the PiCCO system, LiDCO is not temperature sensitive, but is influenced by electrolyte and hematocrit concentrations allowing only limited injections per time unit [11]. The use of intravenous lithium chloride is not recommended in patients weighing less than 40 kg, pregnant women, or patients receiving oral lithium therapy. However, no additional side effects of the administration of lithium to measure cardiac output have been reported. Recently the LiDCO system was used in an interventional randomized study of postoperative goal-directed hemodynamic therapy [36]. Pearse et al. showed that post-operative goal-directed hemodynamic therapy guided by pulse-wave continu ous cardiac output was associated with reductions in post -operative complications and duration of hospital stay. FloTracNigileo™

The FloTrac™ device includes a special transducer that attaches to any existing arterial cannula and then connects to a monitoring system (Vigileo'P') [37]. The FloTrac™ device uses arterial pressure waveform analysis and an algorithm to provide continuous cardiac output in real-time without the need for prior calibration. The FloTrac algorithm does not calculate the area under the pressure waveform. Instead, cardiac output is correlated with the variance between systolic and diastolic pressure. Real-time analysis of waveform characteristics is also integrated, compensating for changes in vascular physiology affecting the pressure waveform. The algorithm uses the basic equation (1) for measuring cardiac output with heart rate being determined from the pressure waveform using conventional methods: cardiac output = heart rate x stroke volume

(1)

The FloTrac algorithm utilizes arterial pressure, age, gender, body length, and height to calculate stroke volume. The basis for the algorithm is the physiological premise that pulse pressure is proportional to stroke volume. The contribution of pulse pres-

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sure to stroke volume is proportional to the standard deviation (SD) of arterial pulse pressure (op)' The arterial pulse waveform is assessed at 100 Hz and the SD of the pulse pressure is determined over a 20-s window. The algorithm takes two additional factors into account: Vessel compliance (influenced by age, gender, height, and weight) and peripheral resistance effects (determined from arterial waveform characteristics). Statistical correlations were found that provided a mathematical model for providing a quantitative assessment of vascular resistance and compliance effects on stroke volume integrated into a single conversion factor, Khi (X ). Derivation of the variable X, incorporates different factors of the blood pressure [38] utilized in equation (2) from a multivariate regression model (M). These include Langewouter's aortic compliance [39] (Cp), mean arterial pressure (MAP), the variance, skewness, and kurtosis of the pressure wave curve. Body surface area (BSA) also appears in the model. Further details of this proprietary algorithm are not disclosed by Edwards Lifesciences. X = M(cp, MAp, variance, skewness, kurtosis, BSA)

(2)

Thus, it is possible to calculate stroke volume by the following equation (3): Stroke volume =

op

xX

(3)

Finally cardiac output is calculated as follows: Cardiac output = heart rate x

xv

op

xX

After early clinical experience with this algorithm, the rate of the adjustment of X has been reduced from the initial interval of 10 min to 1 min in the latest version of the software. Patient specific stroke volume and cardiac output are updated every 20 seconds. Initially, there were conflicting results in respect to the accuracy and precision of the FloTraclVigileo™ device. In postoperative cardiac surgical patients, Manecke and Auger reported a mean bias of 0.55 (limits of agreement 1.96) lImin between the Plo'Irac/Vigileo" device and intermittent pulmonary artery thermodilution [37]. Furthermore, they showed a good agreement between femoral and radial arterial measurement site using the Flo'Irac/Vigileo" device; the bias was -0.15 l/min combined with the precision of 0.56 lImin. De Waal et al. compared FloTraclVigileo™ with transpulmonary thermodilution and pulse contour cardiac output (PiCCOplus" device) in 22 patients undergoing coronary artery bypass graft (CABG) surgery [40]. De Waal et al. found a mean bias of 0.00 (limits of agreement 1.74) lImin combined with a precision of 0.87 lImin between the Flo'Irac/Vigileo" device and transpulmonary thermodilution (Fig. 2). The authors concluded that the FloTracl Vigileo" enables clinically acceptable assessment of cardiac output, whereas Sander et al. found a bias of 0.6 lImin combined with a wide range of limits of agreement between the FloTraclVigileo™ system and intermittent thermodilution in 30 cardiac surgery patients [41]. Mayer et al. showed in the same group of patients a large mean bias of 0.46 lIminl m2 (limits of agreement 1.15) concluding that there was no acceptable agreement of FloTraclVigileo™ cardiac output measurement in comparison to intermittent pulmonary arterial thermodilution-derived cardiac output [42]. In patients with septic shock, Sakka et al. compared Plo'Trac/Vigileo'I'<derived cardiac output with the transpulmonary thermodilution technique and showed that the Plo'Irac/Vigileo" underestimated cardiac output values [43]. As a consequence, the FloTraclVigileo™ software with its underlying algorithm was improved and the time window for vas-

Minimally Invasive Cardiac Output Monitoring: Toy Or Tool?

c:

2

E Fig. 2. Bias ± 2 SD according to Bland-Altman comparing FloTrac/ Vigileo™ and transpulmonary thermodilution cardiac output (TePO) for pooled data of 22 patients undergoing cardiac surgery excluding data obtained at 15 mins after weaning from cardiopulmonary bypass. From (40) with permission.

o

~'5> 0 t--------::~~~~~~#-"-"''-----

Bias

:> -1

6

u

:=

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2.5

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(TPCO+VigileoCOj/2 (l/ rnin')

cular adjustment was reduced from the initial interval of 10 min to 1 min in the latest version of the software. Using the new software, Mayer et al. repeated their initial study comparing FloTrac/Vigileo™ cardiac output measurement to intermittent pulmonary arterial thermodilution-derived cardiac output intra- and postoperatively in 40 ASA III patients scheduled for elective CABG (44). According to Critchley and Critchley [45], a percentage error of 30 % or less was determined for method interchangeability in this study. Mayer et al. (44) found good intraoperative and postoperative agreement of the FloTrac/Vigileo™ with intermittent pulmonary arte ry thermodilution cardiac output measurements proving a significant and clinically relevant improvement in the FloTrac/Vigileo™ software. Bias and precision (1.96 SD of the bias) were 0.19 l/rnin/rn? and ± 0.6 l/rnin/rn? (r = 0.82) resulting in an overall percentage error of 24.6 %. Subgroup analysis revealed a percentage error of 28.3 % for data pairs obtained intraoperatively and 20.7 % in the ICU. Other investigations in postoperative cardiac surgical patients using the new software confirmed the accuracy and precision of the FloTrac/Vigileo™. Breukers et al. investigated 20 patients up to 24 hours after cardiac surgery and compared card iac output measured by FloTrac/Vigileo™ with that measured by bolus thermodilution using a PAC (46). The mean cardiac output (PAC) ranged between 2.8 and 10.3 lImin and for the FloTrac/Vigileo" between 3.3 and 8.8 lImin. The coefficient of variation for pooled measurements was 7.3 % for the PAC and 3.0 % for the FloTrac/Vigileo™. For pooled data , the r 2 was 0.55 (p < 0.001), with a bias of -0.14, precision of 1.00 lImin, and 95 % limits of agreement between -2.14 and 1.87 lImin in a Bland-Altman plot. Changes in cardiac output correlated (r 2 = 0.52, P < 0.001). The authors concluded that FloTrac/Vigileo™ is a clinically applicable method for cardiac output assessment without calibration after cardiac surgery. Using the improved software, Prasser et al. confirmed recently that Plo'Irac/Vigileo" measures cardiac output accurately in postoperative cardiac surgery pat ients (47). The results of their study revealed a minimal bias and limits of agreement of 0.01 ± 1.63 lImin ( Fig. 3). The limits of agreement were below 30 % between the two methods, which is within the recommended value propo sed by Critchley (45) to accept a new technique that has been compared to the reference method. Button et al. evaluated FloTrac/Vigileo™ compared to continuous cardiac output using a PAC and the PiCCOplus™ system in 31 patients undergoing cardiac surgery (22). Cardiac output measurements were compared to intermittent pulmonary

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G. Marx and T. Schuerholz

4

~

2

~

0' u

0

~

-1

0-

u

Mean 0.01 (l/ rnin)

...

-2 -3

-4 1

2

4 7 5 6 8 (CO PAC + CO AP) / 2 (I/ min)

9

10

11

Fig. 3. Bland-Altman plots for comparison between the intermittent thermodilution-derived cardiac output (CO PAC) and the arterial pressure-based cardiac output (COAP) of 20 postoperative cardiac surgical patients undergoing elective coronary artery bypass grafting. Solid line, mean difference (bias); dashed lines, limits of agreement (bias ± 1.96 SD). From [47] with permission

artery thermodilution. Interestingly, the performance according to the Bland-Altman analysis was comparable for all tested continuous cardiac output monitoring devices with a decreased agreement in the postoperative period ( Fig. 4). The FloTrac/Vigileo™ system provides a clinically acceptable accuracy of continuous cardiac output measurements. Its algorithm compensates for the continuously changing effects of vascular tone via analysis of waveform characteristics directly correlated with vascular tone. Benefits of the system include a rapid and easy set-up and that it can be attached to any arterial line, even post hoc if the clinical situation of a patient unexpectedly deteriorates. Flo'Irac/Vigileo" system does not require an external reference method for calibration or subsequent correction. Therefore, it minimizes operator dependency and its automatic adjustment for the changes of vascular tone may eliminate drift phenomena. It offers SVV as an indicator of fluid responsiveness. Taking into account the vast number of publications on the FloTracl Viglleo" system within the last 12 months, it seems probable that further studies in different groups of patients like septic shock will be available shortly.

Conclusion There remains little doubt that measuring cardiac output in high risk surgical patients and critically ill patients is important. Minimally invasive cardiac output monitoring using pulse wave analysis allows continuous measurement of cardiac output and is a less invasive alternative to the PAC for the assessment of cardiac output. Three different devices that use pulse wave analysis to determine cardiac output are commercially available: PiCCOplus™ (Pulsion Medical Systems, Munich, Germany); PulseCOTM (LiDCO Ltd, London, UK); Plo'Irac/Vigileo" (Edwards LifeSiences). All three devices are sufficiently accurate for clinical practice, providing cardiac output measurements continuously, offering additional variables and, hence, showing promise to be robust and practical for the widespread ICU and operating room usage. Thus, it seems clear that minimally invasive cardiac output monitoring using pulse wave analysis is not a toy but a tool. It enables the clinician at the bedside to assess cardiac output continuously, thereby immediately detecting unpredictable,

Minimally Invasive Cardiac Output Monitoring: Toy Or Tool?

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Fig. 4. Bland- Alt man analysis for cardiac output measurements in 31 patients undergoing cardiac surgery during the postoperative period using the Holrac/viqileo! system, the PiCCOplus™ system, and the PAC! Viqilance" monitoring compared with intermittent pulmonary artery thermodilution. T4 = after transfer to the ICU, T5 -6 = during ICU stay; FCO: cardiac output by the FloTracNigileo™ device; PCO: cardiac output by the PiCCOplus™ system; CCO: continuous cardiac output measured by PAC using Vigiiance™ monitoring; ICO: cardiac output by intermittent pulmonary artery thermodilution (iced water bolus method). Solid line, mean bias; dashed lines: limits of agreement. From [22] with permission.

rapid changes in the hemodynamic status. As a consequence, minimally invasive cardiac output monitoring offers the opportunity of early, specific ther apeutic interventions in cardiovascular insufficiency. However, it is not enough to measure cardiac output; the implementation of the data into treatment algorithms is necessary in order to potent ially improve outcomes in high risk surgical and critically ill patie nts.

615

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G. Marx and T. Schuerholz References

xv

I. Pinsky MR (2003) Hemodynamic monitoring in the intensive care unit. Clin Chest Med 24:549-560 2. Connors AF [r, Speroff T, Dawson NV, et al (1996) The effectiveness of right heart catheteri zation in the initial care of critically ill patients . SUPPORT Investigators. JAMA 276:889-897 3. Weil MH (1998) The assault on the Swan-Ganz catheter : a case history of constrained technology, constrained bedside clinicians, and constrained monetary expenditures. Chest 113:1379-1386 4. Harvey S, Harrison DA, Singer M, et al (2005) Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet 366:472-477 5. Polanczyk CA, Rohde LE, Goldman L, et al (2001) Right heart catheterization and cardiac complications in patients undergoing noncardiac surgery: an observational study. lama 286: 309-314 6. Yu DT, Platt R, Lanken PN, et al (2003) Relationship of pulmonary artery catheter use to mortality and resource utilization in patients with severe sepsis. Crit Care Med 31:2734-2741 7. Bernard GR, Sopko G, Cerra F, et al (2000) Pulmonary artery catheterization and clinical outcomes: National Heart, Lung, and Blood Institute and Food and Drug Administration Workshop Report. Consensus Statement. lama 283:2568-2572 8. Sandham JD, Hull RD, Brant RF, et al (2003) A randomized, controlled trial of the use of pulmonary-artery catheters in high-r isk surgical patients . N Engl J Med 348:5-14 9. Wesseling KH, de Wit B, Weber J, Smith N (1983) A simple device for the continuous measurement of cardiac output. Adv Cardiovasc Physiol 5:16-52 10. Goedje 0, Hoeke K, Lichtwarck-AschoffM, et al (1999) Continuous cardiac output by femoral arterial thermodilution calibrated pulse contour analysis: comparison with pulmonary arterial thermodilution. Crit Care Med 27:2407- 2412 II. Hofer CK, Ganter MT, Zollinger A (2007) What technique should I use to measure cardiac output? Curr Opin Crit Care 13:308-317 12. Hoeft A, Schorn B, Weyland A, et al (1994) Bedside assessment of intravascular volume status in patients undergoing coronary bypass surgery. Anesthesiology 81:76-86 13. Godje 0, Hoke K, Goetz AE, et al (2002) Reliability of a new algorithm for continuous cardiac output determination by pulse-contour analysis dur ing hemodynamic instability. Crit Care Med 30:52- 58 14. Felbinger TW, Goepfert MS, Goresch T, et al (2005) Accuracy of pulse contour cardiac index measurements during changes of preload and aortic impedance. Anaesthesist 54:755- 762 15. Bein B, Worthmann F,Tonner PH, et al (2004) Comparison of esophageal Doppler, pulse contour analysis, and real-time pulmonary artery thermodilution for the continuous measurement of cardiac output. J Cardiothorac Vase Anesth 18:185-189 16. Marx G, Schuerholz T, Sumpelmann R, et al (2005) Comparison of cardiac output measurements by arterial trans-cardiopulmonary and pulmonary arterial thermodilution with direct Fick in septic shock. Eur J Anaesthesiol 22:129-134 17. Schuerholz T, Meyer MC, Friedrich L, et al (2006) Reliability of continuous cardiac output determination by pulse-contour analysis in porcine septic shock. Acta Anaesthesiol Scand 50:407-413 18. Spohr F, Heurich P, Bauer H, et al (2007) Comparison of two methods for enhanced continuous circulatory monitoring in patients with septic shock. Intensive Care Med 33:1805-1810 19. Halvorsen PS, Espinoza A, Lundblad R, et al (2006) Agreement between PiCCO pulse-contour analysis, pulmonal artery thermodilution and transthoracic thermodilution during off-pump coronary artery by-pass surgery. Acta Anaesthesiol Scand 50:1050-1057 20. Yamashita K, Nishiyama T, Yokoyama T, et al (2005) Cardiac output by PulseCO is not interchangeable with thermodilution in patients undergoing OPCAB. Can J Anaesth 52:530-534 21. Sander M, von Heymann C, Foer A, et al (2005) Pulse contour analysis after normothermic cardiopulmonary bypass in cardiac surgery patients. Crit Care 9:R729-734 22. Button D, Weibel L, Reuthebuch 0, et al (2007) Clinical evaluation of the FloTraclVigileo system and two established continuous cardiac output monitoring devices in patients undergoing cardiac surgery. Br J Anaesth 99:329-336

Minimally Invasive Cardiac Output Monitoring: Toy Or Tool? 23. Uchino S, Bellomo R, Morimatsu H, et al (2006) Pulmonary artery catheter versus pulse contour analysis: a prospective epidemiolog ical study. Crit Care 10:R174 24. Berkenstadt H, Margalit N, Hadani M, et al (2001) Stroke volume variation as a predi ctor of fluid responsiveness in patients und ergoing brain surge ry. Anesth Analg 92:984 - 989 25. Reuter DA, Felbinger TW, Schmidt C, et al (2002) Stroke volume variation s for assessment of cardiac responsiveness to volume loading in mechan ically ventilated patients after cardiac sur gery. Intensive Care Med 28:392- 398 26. Marx G, Cope T, McCrossan L, et al (2004) Assessing fluid responsiveness by stroke volume variation in mechanically ventilated patients with severe sepsis. Eur J Anaesthesiol 21:132138 27. Wiesenack C, Prasse r C, Keyl C, Rodig G (2001) Assessment of intr athoracic blood volume as an indicator of card iac preload: single transpulmonary thermodilution techniqu e versus assessment of pressure preload par ameters derived from a pulmonary art ery catheter. J Cardioth orac Vase Anesth 15:584-588 28. Fernandez-Mond ejar E, Rivera-Fernandez R, Garcia-Delgado M, et al (2005) Small increases in extravascular lung water are accurat ely detected by transpulmonary th erm odilution. J Traum a 59:1420-1423 29. Band DM, Linton RA, O'Brien TK, et al (l997) The shape of indicator dilut ion curves used for card iac output measurement in man. J Physiol 498 ( Pt 1):225- 229 30. Pearse RM, Ikr am K, Barry J (2004) Equipment review: an appraisal of the LiDCO plus method of measur ing cardiac output. Crit Care 8:190- 195 31. Linton R, Band D, O'Brien T, et al (l 997) Lithium dilut ion cardiac output measurement: a compa rison with therm odilution. Crit Care Med 25:1796 - 1800 32. Linton RA, [onas MM, Tibby SM, et al (2000) Card iac output measured by lithium dilution and transpul monar y thermodilution in patie nts in a paediatric intensive care un it. Intensive Care Med 26:1507- 1511 33. Kurita T, Morita K, Kato S, et al (l997 ) Comparison of the accura cy of the lithium dilution techn ique with the thermodilution technique for measurement of cardi ac output. Br I Anaesth 79:770- 775 34. Ham ilton TT, Huber LM, lessen ME (2002) PulseCO: a less-invasive meth od to monitor cardiac outp ut from arterial pressure after cardiac surgery. Ann Tho rac Surg 74:S1408- 1412 35. Pitt man I, Bar-Yosef S, SumPing J, et al (2005) Continuo us cardiac output monit orin g with pulse contour ana lysis: a comparison with lithium indicator dilution cardiac output measurement. Crit Care Med 33:2015-2021 36. Pearse R, Dawson D, Fawcett J, et al (2005) Early goal-directed therapy after major surgery redu ces complications and duration of hospital stay. A rand omised, controlled trial [ISRCTN38797445]. Crit Care 9:R687-693 37. Manecke GR, [r., Auger WR (2007) Cardiac output determination from the arterial pressure wave: clinical testin g of a novel algorithm that does not require calibration. J Cardiothorac Vase Anesth 21:3- 7 38. Wesseling KH, Weber H, de Wit B (l 973) Estimated five component viscoelastic model parameters for hum an arterial walls. J Biomech 6:13- 24 39. Langewouters GJ, Wesseling KH, Goedha rd WJ (l985) The pressure dependent dynamic elasticity of 35 thor acic and 16 abdominal hum an aortas in vitro described by a five component model. J Biomech 18:613- 620 40. de Waal EE, Kalkm an C/, Rex S, Buhre WF (2007) Validation of a new art erial pulse contourbased cardiac output device. Cri t Care Med 35:1904- 1909 41. Sander M, Spies CD, Grubitzsch H, et al (2006) Comparison of uncalibrat ed art erial waveform analysis in cardiac surgery patients with therm odilut ion cardiac output measurements. Crit Care 10:R164 42. Mayer J, Boldt J, Schollhorn T, et al (2007) Semi-invasive monitoring of cardi ac output by a new device using arterial pressure waveform analysis: a comparison with inter mitten t pulmonary artery therm odilution in patients und ergoing cardiac surgery. Br J Anaesth 98: 176-182 43. Sakka SG, Kozieras J, Thueme r 0, van Hout N (2007) Measur ement of cardiac output: a comparison between tra nspulmonary thermod ilution and uncalibrated pulse contour analysis. Br J Anaesth 99:337- 342

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G. Marx and T. Schuerholz 44. Mayer J, Boldt J, Wolf M, Suttner S (2007) Second generation arterial waveform analysis for less Invasive determination of the cardiac output. Anesthesiology 107:A1531 45. Critchley LA, Critchley JA (1999) A meta-analysis of studies using bias and precision statistics to compare cardiac output measurement techniques. J Clin Monit Comput 15:85-91 46. Breukers R, Sepehrkhouy S, Spiegelenberg S, Groneveld J (2007) Cardiac output measured by a new arterial pressure waveform analysis method without calibration compared with thermodilution after cardiac surgery. J Cardiothorac Vase Anesth 21:632-635 47. Prasser C, Trabold B, Schwab A, et al (2007) Evaluation of an improved algorithm for arterial pressure-based cardiac output assessment without external calibration . Intensive Care Med 33:2223- 2225

619

Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring P.

SQUARA

Introduction Although measurement of oxygen consumption in the clinical setting is hampered by numerous technical difficulties, the objective of hemodynamic resuscitation is to ensure that oxygen consumption balances the metabolic needs of the body [1 - 3]. When the hemoglobin level is stable, oxygen consumption is determined by three interrelated variables: Cardiac output, arterial oxygen saturation, and mixed venous oxygen saturation (Sv0 2 ) . This explains the considerable efforts that have been devoted to develop tools to measure and monitor each of these three variables. Such tools are important for diagnosis, optimization of treatment, and tracking progress of patients with hemodynamic compromise [4]. The gold standard for cardiac output measurement in clinical practice is the thermodilution technique which requires invasive placement of a right heart, pulmonary artery catheter (PAC) [5 - 7]. Recognition of the risks associated with PAC insertion and with the long catheter dwell times typically encountered in the intensive care setting have contributed to the more restricted use of invasive monitoring over recent years [8 - 10]. Therefore, cardiac output is only measured in a small proportion of patients in whom it could be helpful. Consequently, clinicians have long sought accurate non-invasive methods for measuring cardiac output. Several less invasive monitoring methods have been proposed recently, including arterial pulse contour analysis via an arterial catheter [11-14]; an intra-tracheal tube for lung capillary blood flow derivation using partial CO2 re-breathing [15], and an intra-esophageal probe for continuous Doppler velocity flow assessment [16]. Thoracic bioimpedance is currently the most widely used truly non-invasive method for cardiac output monitoring [17, 18). Although early studies in controlled settings yielded interesting results, and despite the development of progressively more complex algorithms [19, 20], recent studies have yielded mixed results concerning the accuracy of this approach. This is especially true in more complex cardiac patients, as typically found in the intensive care and post-operative settings [21, 22]. The variability and lack of consistent accuracy identified in these studies may be in part due to the inherently low signal-to-noise ratio of this approach. Consequently, although available for use, this technique is not widely used in the intensive care unit (lCU ). Standard bioimpedance systems apply a high frequency electrical current of known amplitude and frequency across the thorax and measure changes in voltage. The ratio between voltage and current amplitudes is a measure of transthoracic direct current resistance (more generically referred to as impedance, Zo) and this varies in proportion to the amount of fluid in the thorax. In addition to changing

620

P. Squara

the amplitude of an electrical signal passing through the thorax, changes in thoracic blood volume also produce changes in electrical capacitive and inductive (i.e., bioreactance) properties of the electrical signal as it traverses the thorax. This change in bioreactance can be detected as changes in frequency of the received signal. Traditionally, techniques for accurate measurement of modulation of frequencies are inherently more accurate and robust (i.e., less prone to noise) than techniques to measure changes in signal amplitudes. There is a direct analogy here to the differences between AM and FM radio . Accordingly, a bioreactance-based system (NICOM) has recently been developed and validated for continuous monitoring of cardiac output [23, 24]. This chapter summarizes the basic principles of the bioreactance technology, the basic assumptions and mathematical simplifications of the model that underlies estimation of cardiac output from change in bioreactance, and the main experimental and clinical results that indicate validity of this technique.

What Is Bioreactance? This first section summarizes the electric principles of bioreactance leading to abetter signal/noise ratio than traditional bioimpedance systems.

Electric Principle in Steady States The response of an electric circuit to a sinusoidal voltage (V) oscillating at a frequency F = wl2n is a sinusoidal current (I) oscillating at the same frequency, but with a phase shift, 8. The ratio VII is the impedance (Z). These relations can be symbolized mathematically by the following set of equations: V=Vo·e j oot I = 10 • e j (oot-8) Z = VII = VjIo . e j

8

Or using Euler's formula: A . e j f) = A . (cos ~ + j sin ~) :

Z = VjIo . (cos 8 + j sin 8 ) where Vo is the amplitude of the oscillating voltage signal, 10 is the amplitude of the current. V is in volts, I is in ampere, Z is in ohms , co is in radians/sec, F is in Hz, and 8 is in radians. Z is composed of a resistance (R), its real part, and of a reactance (X), its time-dependent part following: Z = R + jX. Since j = e j "12, j is indicative that R and X are in 90° of phase.

The above relationships are valid under steady states conditions when the impact of transient changes has been completely dissipated. However, during transients, for example when Z is varying, frequency and phase are also changing transiently. The formulas linking Z, Vo' 10 and 8 become more complicated and it is not possible to recalculate Z simply from V and 1 measurements. To circumvent this issue, a different circuit can be created ( Fig. 1) to make the change in 10 negligible in a given part of the circuit. Then, from this constant 10 , changes in Vo and 8 can be measured in order to calculate Z.

Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring

Zl

Z3

Fig. 1. When Zl and Z3 > > Z2, the changes in the alternative current through varying Z2 can be considered negligible, then changes in Vo (~V) are representative of Z2 changes.

621

AC generator

In a double circuit as shown in Figure 1, the current through Z2 and the voltage across Z2 is represented by the following equations, if /:.t" V is the specific change in Vo for a given period T and if we set the steady state phase to zero: I = 10

•

e j oi t

V = Va . e j wt + /:.t" V . e j (wt + t. wt + S) then, V = [Va + /:.t" V · e j (t. wt+ S)]. e j wt Leading to /:.t"Z = /:.t" Vila · el (t. wt + S)

The sum of all periods T (k = 1 to end) gives the final set of equations

Vet) Leading to Zit) or Z(t) then R(t) X(t)

= [Va + L K /:.t" VK • e j(t.WKt+ SK)] = L K /:.t" VIl a · et (t.UIKt+ SK) = L K /:.t" VIl a · [cos (/:.t" w Kt+8 J = L K /:.t" VIl a · cos (/:.t" w Kt+8 K) = L K /:.t" VIla · sin (/:.t"w Kt+8 K )

(1)

• e j wt

+ j sin (/:.t"w

(2)

Kt+8 K ]

(3)

This shows the physical links between Z(t), the time change in Z, its amplitude modulation component (AM) as seen by detecting the Vo envelope /:.t"Vtt) and its frequency modulation component (FM) as seen by detecting ~w(t) ( Fig. 21. As a consequence, the AM signal and the FM signal as seen on the receiving side have the same shape.

Electrical impedance measurements for the estimation of cardiac output have been developed in aeronautical and space medicine considering the chest as a varying impedance as symbolized in Figure 1 [18]. In practice, standard bioimpedance-based medical systems apply a high frequency electrical current of known amplitude and frequency acro ss the thorax via four electrodes and measure resulting changes in voltage using four other electrodes placed in adjacent regions. The ratio Vo/Io is a measure of the steady state transthoracic impedance. Conventionally, Z; = Vo/Io when there is no blood flow. In the presence of flow through the aorta, Z(t) decreases periodically from Zo following equation (2) in proportion to the increase of iron in the thorax, and thus, in proportion to the increase in blood volume. Traditional bioimpedance systems use the amplitude modulation V(t) as signal. The bioreactance system use the frequency modulation w(t) signal. Although the curves depicting the time variations in the changes in frequency and amplitudes have the same shape after appropriate scaling , analysis of the change in frequency yields a better signal -to-noise ratio . The level of noise (N) is given by KTeB where K

xv

622

P. Squara

10 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - _. A I

I

I I

I

Vo - -

1

-j- --------------,-,-,'" ~ : ~: ------------------. t1V

/

",

-:

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I]DDnnn~:~nODnD:

" "" ~~-[--""'" 1========:::=~'-'-- ---- -- -- -- - --'-'::::===== =:::: . • i

FM signal = t1w (t) Time

Fig. 2. Upper part, in light blue, the input constant alternating current: 10 = 5 mA, frequency 75 KHz (ev = 150 n radians/sec.); in dark blue, output voltage. V(t) = 200 ± 2 mVolts, frequency F(t) = 75 KHz ±5 Hz. In the middle, the Vo envelope (AM component) is extracted from the original signal figuring ~ V = 4 mY, corresponding to M = 4/5 = 0.8 n. Below, the corresponding changes in frequency are extracted from the original signal. In the lower part, the time variations in the changes in frequency are the final FM signal figuring ~F = 10 Hz corresponding to ~oo = 20n radians/sec. Using appropriate scaling, the shape of the AM and FM signals is the same.

is Boltzmann's constant , T, the absolute temperature and B the bandwidth in Hz. The probability of interferences (noise due to other electronic devices) is also proportional to the bandwidth. Then, in a signal as shown in equation (1) and Figure 2, we can see that Vet) is a high frequency signal (00 = 2:rrF = 150,000 n radians/sec.), associated with a high level of noise. The challenge is to isolate its FM (LlOO = 20 n radians/sec.) component associated with a lower level of noise. In practice, the low frequency signal is extracted from an autocorrelation method multiplying the input current carrier by the received voltage signal. First a limiter is applied to the output voltage that saturates the real part of the signal as shown in equation (1). To magnify the FM component when multiplying voltage by current, the current carrier phase is shifted to an angle of 90°. Then I = 10 • e j WI becomes I = 10 • e j (WI + :t12). When multiplied by the output voltage as shown in equation (1) we obtain a power signal (P): P = [Va + Ll V . e j (~Olt + S)] . e j 001 .10 , el (WI + :t12) that can be rearranged as P = [I; Va + 10 Ll V · e! (~ Oll + S)] . el (2001 + :t12) (4)

Since 200t » Lloot, it is easy to filter the part of the equation (4) containing 200t to optimally eliminate noise ( Fig. 3). If the lowpass filters reject frequencies near 2oot, the filtered mixer output becomes: P = loll V . e j (~ wI + S) and for the sum of T (k pet) = L K loll V k • e j (~ OlKt + SKY.

=I

to end) ,

From Euler's formula, this can be written pet) = L K loll Vk

•

[cos (LlooKt + OIC) + j sin (,10V + OJ].

When divided by the known value 10 2, this signal is equivalent to Zlt) as shown in (2) with a real part, R and an imaginary part, X. The limiter, applied before entering

Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring

Filter FM signal

Fig. 3. The signal coming from equation (4) as it can be seen using an oscillator. Noise is proportional to the bandwidth. AM is located in a bandwidth with high level of noise as opposed to FM. Aselective filter can be applied to keep only the FM signal

AM signal Nois:

---,----L.---,---'- -

10 '

.>

- - , - - - r -- - - , - ---.---_ 105 Hz

V(t) in the multiplier, has saturated the real part of the signal, L K ~ VkIlo . cos (~O)Kt+e K)' then has fixed it to a constant envelope C that can also be filtered (F = 0 Hz). The final signal, formulated L K~ VkIlo' sin (~O)Kt+e K)' is that of the bioreactance signal X(t) seen in (3) and schematized in the lower part of Figure 2.

From Chest Bioreactance to Cardiac Output Bioreactance systems are based on the general anatomic model linking the change in aortic volume and the change in chest impedance [17, 18). This model is based on the impedance law applied to the aorta considered as a conductor Z = pLlA where p = specific resistivity, L = length, and A = cross-sectional area of the tube. Ten anatomic assumptions and mathematical simplifications are necessary to derive the stroke volume from the change in impedance ~Z. • Assumption 1 (confidence high) : If we introduce and simultaneously sense an alternating current, the change in thoracic impedance is due to pulsatile blood flow. • Assumption 2 (confidence high): The effect of ventilation on blood flow can be averaged. • Assumption 3 (confidence moderate): The blood volume of low-pressure vessels is relatively constant and ventricles are electrically isolated by their thick walls. Then , change in impedance is mostly due to the variation of aortic blood volume. The variation of impedance that is not due to the variation of aortic blood volume is also linked to stroke volume. Therefore, a coefficient of proportionality can be determined to interrelate changes in impedance with changes in aortic blood volume. • Assumption 4 (confidence high): The aorta is a cylinder. • Assumption 5 (confidence moderate): Blood resistivity is constant so that hemoglobin concentration is stable during the measurements. When hemoglobin is stable, the impact of high or low levels can be corrected. From the five first assumptions and from Z = pLlA, at any time Z(t) = pLlA(t). Because A(t)= Va(t)/L where Va(t) is the instantaneous aortic volume. Then Z(t) = pLlA(t) = pLlVa(t) . L and at any time : Va(t) = pUIZ(t)

(5)

623

624

P. Squara It is impossible to measure the change in aortic impedance Z(t) non-invasively. We

can only measure easily the change in thoracic impedance Zr(t). Deriving Z(t) from Zr(t) requires 3 new assumptions. • Assumption 6 (confidence high): p of blood and thoracic tissues are similar. • Assumption 7 (confidence moderate): we can consider the thorax as a cylinder. • Assumption 8 (confidence moderate) : we can consider the thorax as a unique chamber C in parallel with the aorta with constant impedance Ze.

With these added assumptions, 1/Zr (t ) = l/Ze + l/Z(t). Solving this for Z(t) gives: Z(t) = Zr(t) . ZdfZc - Zy(t)) (6) Two additional assumptions are required to complete the derivation of cardiac output from impedance measurement: • Assumption 9 (confidence high): if aortic impedance is small compared to tissue impedance, Zr(t) is close to Ze and to the basic impedance Zoo Then, Zr(t) x Zc == Z0 2. Similarly, the denominator [Ze - Zr(t)] would be zero. This is impossible, so, let Zc - Zr(t) == Zo - Zr(t) = ~Z(t). Then equation (6) can be written Z(t) = Z0 2 I ~Z(t) and equation (5) becomes Va(t) = pL 2/Z02 x ~Z(t) . From the end of filling to the end of ejection, we arrive at: ~ Va

= pU/Z0 2

• ~Z

~ Va is the pulsatile change of aortic volume. This quantity is linked to stroke volume by: ~ Va = stroke volume - aortic output flow. Because output flow is unknown, it is necessary to extrapolate stroke volume using another assumption. One approach requires apnea and an independent assessment of aortic valve closure, which is not available in clinical practice. An alternative method requires the final assumption:

• Assumption 10: it is hypothesized that ~ V: (the change in aortic volume that would occur if there was no output flow) can be extrapolated according to stroke volume = ~ Vo'= pUIZ0 2 • ~Z'. The final formula for stroke volume is derived by substituting ~Z' by VET· dZ/dt max (see explanations in Figure 4), then stroke volume = pL 2/Z02 • VET · dZ/dt max. In a bioreactance-based system, the assumptions are the same. We have seen that the shape of the AM and FM signal is the same, then dZ/dt max can be replaced by dX/dt max, A transformation constant, C, is simply added to pU which is also constant for each individual patient, so that stroke volume = CpUIZ0 2 • VET· dXldt max and cardiac output = heart rate ' CpUIZ0 2 • VET· dX/dtmaxSeveral approaches have been suggested to limit the impact of the 10 assumptions and to improve the reliability of cardiac output derivation . For example, a truncated cone has been proposed instead of a cylinder to model the thorax [25]. More generally, each of the 10 assumptions may lead to individual discordances. To circumvent this issue, a multivariate calibration factor (CF) has been established using a reference method that is based on the age, gender, height, weight, body surface area, body mass index and, if available, hematocrit and pulmonary artery pressure. The final bioreactance formula for cardiac output is then:

cardiac output = heart rate ' CF/Zo2 • VET · dX/dt max.

Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring

Fig. 4. The upper part shows !'1Z; the extrapolation in Ztt) if the aorta was a capacitor without output flow. !'1Z' can be calculated by the product of the maximum Z(t) slope (in !1Isec.) by its duration (in sec.). The duration to reach !'1Z' is the left ventricle ejection time (VET) and the maximum Z(t) slope is given by the maximum of its timederivative (dZ/dt max). Then M ' = VET . dZ/dt max. In this figure, the x axis is conventionally inverted so that the bioimpedance signal mimics the aortic pressure curve.

625

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Z (tl 1- -:-:=,------ 1 - - - - - - - - - - - - - - - - -

Zo

dZ/dt max -- - - - - - - - - - 0 ~

Time

Experimental Validation One may be sceptical of the reliability of bioimpedance and/or bioreactance derivedcardiac output due to the multiple underlying assumptions and simplifications. However, bioimpedance-based systems have been of interest in various settings and bioreactance, in a way, is an advanced form of bioimpedance system based on similar assumptions and simplifications but based on a signal that has a better signal-tonoise ratio, thus providing a theoretically more reliable result. An experimental study in animals showed very interesting results [23]. In open chest pigs, total cardiac output was controlled using a right heart bypass (using an extracorporeal cardiopulmonary bypass [CPB] pump) while maintaining pulsatility in the pulmonary artery and aorta. Cardiac output was varied in increments by adjusting the CPB pump. Results from one animal are shown in Figure 5 As seen, bioreactance-derived cardiac output closely tracked the cardiac output imposed by the CPB. Inter-animal variability of results was moderate and the overall

~

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~ 3 .~ 2 '0 ;0

u

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versus bioreactance (open circles) cardiac output in I/min.

1

O-h,......,---r-r--.-r-r--.-,.,.-r, ,---...,., 1

3

5

7

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13

15

17

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12

~ 10 8

g u

06

6

~ 4 2 0 -1--1-,--....., -,--....., -,--....., -,--....., -,--....., -,--,......,---,,......,--,---,

7

9

11 13 15 17 19 21 Time

23 25

Fig. 6. Transonic (triangles) versus bioreaetance (open circles) cardiac output in l/mln.

results from nine animals in this series showed a strong correlation between bioreactance cardiac output and CPB: r = 0.90 ± 0.09, range 0.75 - 0.99. Another experiment was done under the same conditions but comparing the bioreactance cardiac output with that of a well accepted reference method in experimental studies: A Transonic ultrasound flow probe positioned directly around the pulmonary artery. Cardiac output was varied by sequential increases and decreases in dobutamine infusion. Results from one animal are shown in Figure 6. Again, bioreactance-derived cardiac output closely tracked the reference Transonic cardiac output. The overall results of nine animals show a strong correlation between the two modalities of cardiac output measurement: r = 0.64 ± 0.19, range 0.41 to 0.96. In these experimental studies, the bioreactance cardiac output did not include a calibration factor. Initial cardiac output value was simply adjusted to the baseline cardiac output of the reference method. Therefore, only the relative changes in cardiac output were investigated. However, due to the number of standpoints for each animal, the perfect correlation sometimes found cannot be due to chance alone and validates the model. Although acceptable, the imperfect results observed in several animals can be attributable to the different assumptions and mathematic simplifications of the model. Indeed, each assumption may be more or less valid for each individual animal and may occasionally introduce errors . It is the objective of the multiparametric calibration factor to adjust the model to individual characteristics in order to derive acceptable cardiac output values in any case.

Clinical Validation An auto-calibration process was determined in initial clinical studies, including a calibration factor based on 40 initial patients using continuous thermodilution as the reference. Then, two validation studies were performed in post-cardiac surgical patients . The first study included a cohort of 119 patients and the bioreactance cardiac output (NICOM) was compared to PAC alone [24] . In a second study including 29 patients, the NICOM was compared to PAC and to a pulse-contour system (Vigileo) [26]. In the first study, the bias was optimally analyzed during 40 periods of stable PAC cardiac output to minimize the effects of both natural changes in cardiac output and time responsiveness differences of the two devices. This part of the study included more than 9000 minute-by-minute cardiac output values. The study averaged bias

Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring _ 2

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u

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a

.....

• •• . y.. . •

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iii -,

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• ------------------ --.----'-fF------------.~

- - - -- - -- ---- - - - -

•

•
... - --- - - -•- - - - - - - - - - - - -•

-2 +----,_--,-_,----,-_ -,----,_--,----, 2 4 6 7 8 o Mean cardiac out put

Fig. 7. On the left panel, the relationship between NICOM and pulmonary artery catheter (PAC) cardiac output (in I/min.), r = 0.87, NS from the identity line (dotted line). The right panel shows the corresponding Bland & Altman representation. Upper and lower limits: 2SD = 1.0 I/min. Mean bias = 0.16 IImin. 38/40 patients (95 %) were inside the limits of agreement. In 37/40 (92.5 % of cases), the bias was < 1 I/min Table 1. Changes in cardiac output after hemodynamic challenges (from [24] with permission). NICOM

PAC-cardiac output

p

Negat ive cardiac output challenge n = 14 Lag time (min) Amplitude (l/rnin) Am plitude (%)

3.4 ± 1.3 - 1.7 ± 1.0 - 28 ± 14

7.1 ± 3.1 - 1.7 ± 1.2 - 34 ± 20

0.01 0.25 0.25

Positive cardiac output challenge n = 23 Lag time (min) Amplitude (I/min) Amplitu de (%)

4.0 ± 2.2 1.5 ± 0.9 40 ± 26

6.8 ± 3.2 1.7 ± 1.3 50 ± 33

0.003 0.07 0.07

PAC: pulmonary artery catheter

was negligible (0.16 IImin.) and most of the individual patient averaged biases were inside the limits of agreement (see Fig. 7). When all minute-by-minute cardiac output values were considered, 8004 % of them had a bias < 20 %. The precision assessed by the variability of measurements around the trend line slope (2SD/mean) was always better for the NICOM than for the PAC. When a hemodynamic challenge was imposed, the time responsiveness of the NICOM was 3 minutes faster than the PAC and the amplitude of response was comparable ( Table 1). Finally, the sensitivity for detecting significant cardiac output directional changes was 93 % and specificity 93 %. The second study showed similar correlations between NICOM and Vigileo, taking PAC as the reference. During recording periods when PAC cardiac output values were stable, including 4100 minute-by minute cardiac output values, the averaged bias was negligible for both NICOM and Vigileo (0.0 and -0.1 IImin. respectively). When cardiac output values were averaged during all periods of PAC cardiac output stability, the relationship between NICOM and PAC was closer than for PAC and Vigileo ( Fig. 8). The precision was not significantly different between the two modalities of measurement. The responsiveness was not significantly different in amplitude, although Vigileo was slightly faster (1.10 ± 0.3 min. vs. 1.35 ± 0.3 min.) (see an example in Fig. 9).

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.

_.-- - - - - --

....

-------------------------

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o -2 -f----,o

--.--

2

.----,--

~

.....-' --._--.-----,

4

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Fig. 8. On the left panel, the relationship between averaged values of NICOM (solid diamonds and solid line, R=0,77, NS from identity line) and Vigileo (open circles and dashed blue line, R=0.69, P< 0.05 from identity line) with pulmonary artery catheter (PAC)-cardiac output during periods of stable PAC-cardiac output. Cardiac output is in IImin. The right panel shows the corresponding Bland and Altman representation. NICOM bias and Vigileo biases are = 0.01 I/min. Upper and lower limits: 2SD = 1.68 Ilmin for NICOM in black dotted lines and 1.6 Umin for Vigileo in blue dotted lines, 32/34 patients were inside the limits of agreement for NICOM and 33/34 for Vigileo

4

o

u

3

2

m EEP

20

15

15

30

-' >.

NICOM -- - - PAC ------, f---=----, 10

45

60 Time

75

-

Vigileo

90

105

Fig. 9. Minute-by-minute monitoring of cardiac output using three different devices. At minute 5, a 20 cmH 20 positive end-expiratory pressure (PEEP) was applied for a recruitment test, then sequentially reduced by decrements of 5cmH 20 .

limitations Limitations are likely to be found when the assumptions made to derive cardiac output from chest variations in impedance and reactance are not valid. This is especially the case when the relationship between change in aortic volume and stroke volume is very different from what is expected, as in patients with aortic thoracic prosthesis, large thoracic aortic aneurysm, and/or dissection. The model also predicts that extreme values of hematocrit and of pulmonary pressures may affect the reliability of cardiac output measurement. The clinical studies have confirmed these expected limitations but have also allowed compensatory factors to be determined. These factors may be introduced into the system if necessary. Other limitations such as extreme abnormal body shape, extreme overhydration or dehydration, are also likely to affect the reliability of measurement.

Bioreactance: A New Method for Non-invasive Cardiac Output Monitoring

629

Conclusion Bioreactance is an advanced form of bioimpedance technology which has provided significant improvements in the signal-to-noise ratio and in principle provides a superior means of measuring non-invasive cardiac output assessment. Although numerous assumptions and mathematical simplifications underlie the theoretical model linking chest bioreactance and cardiac output, experimental results prove that this method is sound. The first bioreactance-based monitor (NICOM) shows acceptable clinical results in a great majority of cases. In circumstances when a discrepancy in cardiac output between NICOM and PAC is found, external artefacts, and/or uncertainty about the calibration factor encountered in patients having unusual characteristics must be considered as the root cause. There is no doubt that these issues will be solved in the future by optimizing the hardware and by using a larger database of patients for calibration. Clinical characteristics that most frequently lead to discrepancies include severe anemia and severe pulmonary hypertension. Once these factors can be overcome, bioreactance is arguably the most promising technology to definitively solve the difficult issue of providing a totally non-invasive method of cardiac output monitoring. Because NICOM only requires positioning of four sets of thoracic electrodes, it is plausible that in the near future, electrocardiograph (EKG) monitoring will be coupled with cardiac output monitoring. Acknowledgements: The author gratefully acknowledges Dr Hanan Keren for outstanding assistance in simplifying and writing the basic principles, Dr Nicolas Borenstein for realizing the experimental studies, Pr Jean Daniel Chiche for his permission to reproduce some of the clinical results and Pr Daniel Burkhoff for reviewing the manuscript. References 1. Gilbert EM, Haupt MT, Mandanas RY, Huaringa AJ, Carlson RW (1986) The effect of fluid 2. 3. 4. 5. 6. 7. 8. 9. 10.

loading , blood transfusion, and catecholamine infusion on oxygen delivery and consumption in pat ients with sepsis. Am Rev Respir Dis 134:873 - 878 Russell JA, Phang PT (1994) The oxygen delivery/consumption controversy. Approaches to management of the critically ill . Am J Respir Crit Care Med 149:533-537 Squara P (2004) Matching total body oxygen consumption and delivery; a crucial objective? Intensive Care Med 30:2170 - 2179 Cruz K, Franklin C (2001) The pulmonary artery catheter: uses and controversies . Crit Care Clin 17:271-291 Boldt J, Menges T, Wollbruck M, Hammermann H, Hempelmann G (1994) Is continuous cardiac output measurement using thermodilution reliable in the critically ill patient? Crit Care Med 22:1913-1918 Rubini A, Del Monte D, Catena V, et al (1995) Cardiac output measurement by the thermodilution method: an in vitro test of accuracy of three commercially available automatic cardiac output computers. Intensive Care Med 21:154-158 Haller M, Zollner C, Briegel J, Forst H (1995) Evaluation of a new continuous thermodilution cardiac output monitor in critically ill patients: a prospective criterion standard study. Crit Care Med 23:860-866 Sandham JD, Hull RD, Brant RF, et al (2003) A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 348:5-14 Frezza EE, Mezghebe H (1998) Indications and complications of arterial catheter use in surgicalor medical intensive care units : analysis of 4932 patients. Am Surg 64:127 -131 Kac G, Durain E, Amrein C, Herisson E, Fiemeyer A, Buu-Hoi A (2001) Colonization and infection of pulmonary artery catheter in cardiac surgery patients: epidemiology and multivariate analysis of risk factors. Crit Care Med 29:971- 975

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P. Squara II. Gratz I, Kraidin J, Jacobi AG, deCastro NG, Spagna P, Larijani GE (I992) Continuous noninvasive cardiac output as estimated from the pulse contour curve. J Clin Monit 8:20-27 12. Spohr F, Hettrich P, Bauer H, Haas U, Martin E, Bottiger BW (2007) Comparison of two methods for enhanced continuous circulatory monitoring in patients with septic shock. Intensive Care Med 33:1805-1810 13. de Wilde RB, Schreuder JJ, van den Berg PC, Jansen JR (2007) An evaluation of cardiac output by five arterial pulse contour techniques during cardiac surgery. Anaesthesia 62:760-768 14. de Waal EE, Kalkman CJ, Rex S, Buhre WF (2007) Validation of a new arterial pulse contourbased cardiac output device. Crit Care Med 35:1904-1909 15. Rocco M, Spadetta G, Morelli A, et al (2004) A comparative evaluation of thermodilution and partial C02 rebreathing techniques for cardiac output assessment in critically ill patients during assisted ventilation . Intensive Care Med 30:82-87 16. Su NY, Huang CJ, Tsai P, Hsu YW, Hung YC, Cheng CR (2002) Cardiac output measurement during cardiac surgery: esophageal Doppler versus pulmonary artery catheter. Acta Anaesthesiol Sin 40:127 - 133. 17. Bernstein DP (1986) Continuous noninvasive real-time monitoring of stroke volume and cardiac output by thoracic electrical bioimpedance. Crit Care Med 14:898- 901 18. Kubicek W, Patterson R, Witsoe D (1966) Development and evaluation of an impedance cardiac output system. Aerosp Med 37:1208-1212 19. Barin E, Haryadi D, Schookin S, et al (2000) Evaluation of a thoracic bioimpedance cardiac output monitor during cardiac catheterization. Crit Care Med 28:698- 702 20. Spiess B, Patel M, Soltow L, Wright I (2001) Comparison ofbioimpedance versus thermodilution cardiac output during cardiac surgery : evaluation of a second-generation bioimpedance device. J Cardiothorac Vase Anesth 15:567 -573 21. Leslien S, McKee S, Newby D, Webb D, Denvir M (2004) Non-invasive measurement of cardiac output in patients with chronic heart failure. Blood Press Monit 9:277- 280 22. Engoren M, Barbee D (2005) Comparison of cardiac output determined by bioimpedance, thermodilution, and the Fick method. Am J Crit Care 14:40-45 23. Keren H, Burkhoff D, Squara P (2007) Evaluation of a noninvasive continuous cardiac output monitoring system based on thoracic bioreactance . Am J Physiol Heart Circ Physiol 293:H583 - 589 24. Squara P, Denjean D, Estagnasie P, Brusset A, Dib JC, Dubois C (2007) Noninvasive cardiac output monitoring (NICOM): a clinical validation. Intensive Care Med 33:1191 -1194 25. Sramek B (I981) Non invasive technique for measurements of cardiac output by mean of electrical impedance. Proceedings of the fifith international conference on electric bioimpedance, Tokyo, 39- 42 26. Squara P, Marque S, Cariou A, Chiche JD (2007) Non invasive cardiac output monitoring (NICOM) compared to minimally invasive monitoring (VIGILEO). Anesthesiology 107:A1527 (abst)

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Goal-directed Hemodynamic Therapy for Surgical Patients P. MORGAN and A.

RHODES

Introduction The population is aging with inherent co-morbidity and patients undergo evermore extensive surgical procedures. The burden of these changes is being felt on the intensive care unit (lCU). The National Confidential Enquiry into Patient Outcome and Death for the United Kingdom (NCEPOD) has reported the 30-day mortality following all classes of operation to be less than 1 %. When the examined population is limited to the elderly with impaired physiological function and requisite emergency surgery the mortality rate rises to 50 % [1- 3). The physiological response to surgical stress is to increase oxygen delivery (DOl)' An inability to achieve this is associated with a worse outcome, especially the failure to mount an adequate cardiac output (4). It has been suggested that the development of tissue hypoxia is associated with an increase in peri operative morbidity and mortality. This can be due to increased demand from surgical metabolic stress, reduced supply due to inadequate DOl' or a combination of the two. This chapter will discuss the therapeutic strategies available to improve the hemodynamic status of high-risk patients and hence improve their outcome.

Epidemiology In a recent analysis of over four million surgical procedures from the UK, a subgroup of high risk patients was identified (5). The mortality in this group of 513,924 patients was 12.3 %. The overall mortality rates were 0.44 % for elective and 5.4 % for emergency surgery. This high-risk group of patients accounted for 83.8 % of all deaths but only 12.5 % of procedures. For the 31,633 patients admitted to ICU electively there was a mortality rate of 10.1 % and the 24,764 emergency surgical cases carried a mortality of 28.6 %. All admissions to the ICU were associated with a longer duration of hospital stay. Despite the high mortality rates fewer than 15 % of these patients were admitted to the ICU and the highest mortality rate (39 %) was found in patients who required ICU admission following initial care in a ward environment.

Identification of the High-risk Patient The early identification of the high-risk patient and subsequent appropriate management is vital to reduce the associated morbidity and mortality. The evidence

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Table 1. Criteria for identification of patients at 'high risk' of postoperative morbidity and mortality (8) Current or previous severe cardiorespiratory illness Acute intra-abdominal catastrophe with hemodynamic instability Acute renal failu re (blood urea > 18 rnrnol/l, blood creatinine > 265 mmolll) Multiple trauma Age over 70 with evidence of limited reserve of one or more organs Cardiovascular shock Respiratory failure Sepsis with hemodynamic instability Extensive surgery for malignancy

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from published trials strongly suggests that the instigation of goal-directed hemodynamic therapy confers no benefit once organ failure is established. To define a high-risk patient depends on both patient oriented factors and the type of surgery they are to undergo. The American Society of Anesthesiologists' scoring system for pre-operative patient assessment is a consistently good predictor of perioperative mortality [6]. The Goldman Cardiac Risk Index [7] also provides an accurate risk of perioperative mortality and morbidity from cardiac causes. Shoemaker and colleagues provided a list of criteria following their investigation into the physiological response to surgery and the possible causes of post-operative morbidity and mortality [8]. Shoemaker's criteria, as shown in Table 1, are intuitive to most clinicians; of note is the absence of weighted scoring to each parameter. Whether the disease processes described are chronic or acute they increase risk. Included in the criteria is the nature of the surgery, including acute cases such as perforated viscus, gastrointestinal bleeding, and pancreatitis. The criterion for multiple trauma is that three or more organs are involved or that two body cavities have been opened. The elderly patient is more susceptible to complications, especially if they have evidence of limited physiological reserve. Shock is further defined as a mean arterial pressure (MAP) less than 60 mmHg, central venous pressure (CVP) less than 15 mmHg and a urine output less than 0.5 ml/kg/h, Respiratory failure, for example PaOz < 60 mmHg on FiOz > 0.4, includes patients with a shunt fraction greater than 30 % and those who require mechanical ventilation for more than 48 h. The diagnosis of septicemia requires positive blood cultures or a clear septic focus. It should be noted that not all patients undergoing surgery for malignancy should be deemed high risk and that the degree of surgery should be extensive, for example esophagectomy, total gastrectomy. Elective surgical patients can be further assessed by cardiopulmonary exercise testing [9-10]. A strong correlation has been demonstrated between anaerobic threshold and perioperative mortality. The anaerobic threshold is the point where aerobic metabolism fails to provide adequate adenosine triphosphate (ATP) and anaerobic metabolism starts to reduce the resultant deficit. The threshold is determined by monitoring inhaled and exhaled levels of oxygen and carbon dioxide during escalating levels of exercise. Once the high-risk patient has been identified, plans should be instigated to arrange suitable levels of care for that patient during the perioperative period. Usually these patients will require their initial postoperative period to be in a critical care or high dependency setting. The identification must be a priority to enable efficient and effective use of resources. The initiation of goal directed hemodynamic therapy must take place before the onset of organ dysfunction to lead to any benefit [Ll].

Goal-directed Hemodynamic Therapy for Surgical Patients

The Process of Goal-directed Hemodynamic Therapy Resuscitation of the perioperative surgical patient is based around certain targets or goals. These will clearly depend on the patient in question and the type of surgery involved, becoming more or less complex depending on the circumstances. Shoemaker and colleagues showed that high-risk patients who ultimately survived surgery exhibited certain 'supranormal' hemodynamic variables : cardiac index (Cl) > 4.5 l/min/rrr', DOl index (DOlI) > 600 ml/min/m/ and oxygen consumption index (VOll) > 170 ml/min/m-. These investigators also showed that the measurement of more simple parameters such as blood pressure, heart rate, CVP, and urine output were of limited prognostic value. Further studies by Shoemaker and colleagues tested the hypothesis that the median value of these variables in the survivors could be taken as goals of therapy in the perioperative period. These authors determined that the physiological values were appropriate goals for high-risk patients as they were associated with reduced mortality rate, duration of mechanical ventilator dependency and duration of ICU stay [8, 12, 13]. Boyd and colleagues continued these finding s in a randomized controlled trial of perioperative patients with clear, protocol-driven management of the intervention and control arms . Patients were allocated to either 'best conventional therapy' or fluids and dopexamine to achieve a DOlI > 600 ml/min/rn- [14]. All patients were undergoing major vascular or general surger y and were admitted to the lCU and monitored using a pulmonary artery catheter (PAC). The main outcome measures were 28-day mortality and the number of complications; these were both reduced significantly in the intervention group: mean number of complications 0.68 vs. 1.35, mortality 5.7 % vs. 22.2 %, P = 0.015. Wilson and colleagues carried out a further randomized controlled trial of 138 elective major surgical patients [15]. The patients had PACs inserted and fluids infused to achieve a pulmonary artery occlusion pressure (PAOP) of 12 mmHg . Blood was transfused to maintain a hemoglobin concentration greater than 11 g/dl. The patients assigned to intervention received infusions of dopexamine or epinephrine to achieve the goal of D0 21 > 600 ml/min/rn- , The group receiving dopexamine had a significant reduct ion in morbidity and length of hospital stay. The epinephrine group exhibited a trend towards a reduction in morbidity. Seventeen percent of patients receiving conventional therapy died compared with 2 % of the epinephrine group and 4 % of the dopexamine group . The early studies investigating the concept of goal-directed hemodynamic therapy employed the PAC, the use of which is becoming rare outside of the cardiothoracic ICU and its safety and efficacy has been questioned in several recent papers. Many of these researchers admitted their patients to a critical care setting prior to surgery. This has proven difficult to translate into routine clinical practice due to the scarcity of critical care beds, so subsequent researchers have tried to answer the question of whether similar protocols can still be beneficial if started in the intra- or even postoperative periods.

Intraoperative Goal-directed Therapy The initial work investigating goal-directed hemodynamic therapy required the admission of patients to the ICU preoperatively on some occasions . The current pressure for bed availability in most lCUs, coupled with times of patient admission

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for surgery, will in most instances preclude the instigation of preoperative invasive monitoring and intervention. Intra-operatively there are a number of methods of monitoring hemodynamic parameters to guide therapy as discussed below. There is extensive published use of esophageal Doppler monitoring as a minimally invasive tool for hemodynamic monitoring during the perioperative period. Wakeling and colleagues published the results of a randomized controlled trial comparing CVP and esophageal Doppler monitoring in patients undergoing colorectal resection [16). Patients were allocated to either conventional cardiovascular monitoring aiming for CVPs of between 12 and 15 mmHg. The intervention group followed a dynamic, esophageal Doppler-guided fluid protocol. The intervention group achieved significantly higher D0 2I , cardiac output, and stroke volume intraoperatively. The intervention group subsequently displayed significantly reduced gastrointestinal morbidity (9 patients [14.1 %) vs, 29 [45.3 %J, P < 0.001) and overall morbidity (p = 0.05). A shorter length of hospital stay was demonstrated with postoperative days reduced from I l.S to 10 days, p < 0.05. Recent work by Noblett et al. on esophageal Doppler-guided fluid management in patients undergoing elective colorectal resection also showed a significant reduction in morbidity and length of hospital stay [17). The study design involved the intervention arm receiving colloid boluses to maintain a descending aortic corrected flow time (FTc) greater than 0.35 seconds. Further colloid boluses were administered to optimize the stroke volume. Once these parameters had been achieved, colloid was given in the event of stroke volume deviation of greater than 10 % or to maintain a FTc greater than 0.35 seconds. In this study, the authors found that the volume of fluid received by both groups was similar but the intervention arm colloid boluses were predominantly given in the first quarter of the operating time, suggesting that the timing of adequate fluid administration is important. The intervention arm also had significantly higher stroke volume, FTc, and cardiac index but comparable blood pressure at the end of surgery suggesting that blood pressure monitoring alone is inadequate to assess fluid status during the perioperative period. This study also recorded interleukin (IL)-6) levels for 48 hours following surgery. The intervention arm displayed a significantly reduced peak level of IL-6. The authors concluded that this may be a result of improved splanchnic perfusion and a reduced inflammatory response to surgery. Some of the patients in the above mentioned studies achieved their hemodynamic goals with just fluids and no further inotropic therapies. Several studies have tried to answer the question of whether similar benefits can be accrued using proto colized fluid boluses only. In patients undergoing proximal femoral fracture repair, Sinclair and colleagues [18) used esophageal Doppler monitoring to guide fluid administration. Those who were allocated to Doppler-guided fluid management exhibited a median cardiac output increase of 1.2 IImin compared to a decrease of 0.4 l/rnin when fluids were given in a conventional manner (p < 0.05). The study also showed a significant reduction in hospital stay of 12 days vs. 20 days (p < 0.05).

Postoperative Goal-directed Therapy The implementation of goal-directed therapy postoperatively has been successful in cardiac surgical patients [19). McKendry et al. allocated patients to either conventional or esophageal Doppler-guided therapy following cardiac surgery targeting a maximal stroke volume with fluid challenges and then a predetermined value of

Goal-directed Hemodynamic Therapy for Surgical Patients

stroke volume index with inotropes. The authors had already identified the predetermined value in previous work as being the most suitable value for their cohort of patients. They reported a reduced length of hospital stay from 9 to 7 days, p = 0.02 and a 23 % reduction in ICU bed usage. Pearse and colleagues investigated the process of postoperatively applying goaldirected therapy to general surgical patients [20]. One hundred and twenty-two patients were enrolled in this randomized controlled trial and allocated either to conventional therapy or goal directed therapy to attain a D0 21 > 600 ml/min/m-, The intervention group had fewer complications (44 % vs. 68 %, P = 0.003) and a shorter duration of hospital stay (11 days vs. 14 days, p = 0.001). There was no statistical difference in mortality between the two groups. Colloid boluses were admin istered to produce a sustained rise of 2 mmHg in CVP in the control group and a sustained 10 % increase in stroke volume in the intervention group . The intervention group also received dopexamine to achieve the target D0 2, monitored via lithium indicator dilution and pulse power analysis.

Future Advances There has been recent interest in a variety of parameters that dynamically challenge the cardiovascular system and can thus predict which patients will be volume responsive. This is of particular value as it would prevent inappropriate fluid challenges potentially leading to inadvertent volume overload. Lopes and colleagues investigated the use of minimizing the arterial pulse pressure variation (PPV) caused by mechanical ventilation as a hemodynamic goal in surgical patients [21]. The intervention arm received fluid boluses aimed at minimizing and maintaining the PPV below 10 %. A PPV at this level is associated with further fluid loading being unlikely to produce an increase in stroke volume greater than 10 %. The intervention group received more fluid during the perioperative period and had fewer postoperative complications (1.4 vs, 3.9, P < 0.05) and a shorter duration of hospital stay (7 vs. 17 days, p < 0.05). Although this was a small study and patients were restricted to those receiving mechanical ventilation , the use of PPV as a hemodynamic goal may become more Widespread depending on further studies. PPV is interesting as it is predictive of the benefit of further fluid administration rather than revealing the outcome of the fluids given.

Conclusion The implementation of goal-directed therapy to manage surgical patients leads to improved outcomes. The methods used to achieve the target goals are probably unimportant. The hemodynamic end-point to target, i.e., stroke volume, CI, D02I, will depend on available monitoring techniques and experience. The evidence suggests that hemodynamic flow compared to pressure monitoring is superior. An important aspect of this monitoring is that it should not only guide fluid resuscitation but also prevent fluid overload in those patients with a slimmer margin for error. The process of optimizing the patient to attain the hemodynamic goals is what conveys the benefit. All the studies have demonstrated similarities in fluid management, such that prevention of hypovolemia, early fluid resuscitation, and optimal fluid loading with

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stroke volume monitoring is vital. Some studies have shown additional benefit from further increases in stroke volume with inotropic support; the precise stroke volume increase goal for each patient is unclear. The protocolization of therapy targeting the cardiovascular system in surgical patients is associated with significant outcome benefits. This has now been demonstrated in a large number of studies. Routine use of these protocols has the potential for significant benefits in individual patients but also for dramatic improvements in efficiency of health care resource use for limited critical care facilities. References

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1. Adams AP, Cashman IN, Grounds RM (2003) Reducing mortality and complications in patients undergoing surgery at high risk for post-operative complications and death. Recent Adv Anaesth Crit Care 22:117-133 2. Edwards AE, Seymour DG, McCarthy JM, Crumplin MK (1996) A 5-year survival study of general surgical patients aged 65 years and over. Anaesthesia 51:3- 10 3. Cook TM, Day C] (1998) Hospital mortality after urgent and emergent laparotomy in patients aged 65 years and over. Risk and prediction of risk using multiple logistic regression analysis. Br J Anaesth 80:776-781 4. Clowes GH, Del Guercio LRM (1960) Circulatory response to trauma of surgical operations. Metabolism 9:67- 81 5. Pearse RM, Harrison DA, James P, et al (2006) Identification and characterisation of the highrisk surgical population in the United Kingdom. Crit Care 1O:R81 6. Vacanti C], VanHouten RJ, Hill RC (1970) A statistical analysis of the relationship of physical status to postoperative mortality in 68,388 cases. Anesth Analg 49:564-566 7. Goldman L, Caldera DL, Nussbaum SR, et al (1977) Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 297:845-850 8. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS (1988) Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients . Chest 94:11761186 9. Older P, Smith R, Courtney P, Hone R (1993) Pre-operative evaluation of cardiac failure and ischaemia in elderly patients by cardiopulmonary exercise testing. Chest 104:701-704 10. Older P, Hall A (2004) Clinical review: how to identify high-risk surgical patients. Crit Care 8:369-372 11. Kern JW, Shoemaker WC (2002) Meta-analysis of hemodynamic optimisat ion in high-risk patients. Crit Care 30:1686- 1692 12. Shoemaker WC, Appel PL, Bland R, Hopkins JA, Chang P (1982) Clinical trial of an algorithm for outcome prediction in acute circulatory failure. Crit Care Med 10:390 - 397 13. Shoemaker WC, Appel PL, Waxman K, Schwartz S, Chang P (1982) Clinical trial of survivors' cardiorespiratory patterns as therapeutic goals in critically ill postoperative patients. Crit Care Med 10:398-403 14. Boyd 0, Grounds RM, Bennett ED (1993) A randomized clinical trial of the effect of deliberate peri-operative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 270:2699-707 15. Wilson J, Woods I, Fawcett J, et al (1999) Reducing the risk of major elective surgery: rando mised controlled trial of preoperative optimisation of oxygen delivery. BMJ 318:1099- 1103 16. Wakeling HG, McFall MR, Jenkins CS, et al (2005) Intraoperative esophageal Doppler guided fluid management shortens postoperative hospital stay after major bowel surgery. Br J Anaesth 95:634-642 17. Noblett SE, Snowden CP, Shenton BK, Horgan AF (2006) Randomised clinical trial assessing the effect of Doppler - optimised fluid management on outcome after elective colorectal resection. Br J Surg 93:1069-1076 18. Sinclair S, James S, Singer M (1997) Intraoperative intravascular volume optimisation and length of hospital stay after repair of proximal femoral fracture: randomised controlled trial. BMJ 315:909-912

Goal-directed Hemodynamic Therapy for Surgical Patients 19. McKendry M, McGloin H, Saberi D, Caudwell L, Brady AR, Singer M (2004) Randomised controlled trial assessing the impact of a nurse delivered, flow monitored protocol for optimisation of circulatory statu s after cardiac surgery. BMJ 329:258 20. Pearse R, Dawson D, Fawcett j, Rhodes A, Grounds RM, Bennett ED (2005) Early goaldirected therapy after major surgery reduces complications and duration of hospital stay. Crit Care 9:687- 693 21. Lopes RL, Oliveira MA, Pereira VOS, Lemos IPB, Auler [r JOC, Michard F (2007) Goaldirected fluid management based on pulse pressure variat ion monitoring during high-risk surgery : a pilot randomised controlled trial. Crit Care 1l:RI00

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Section XVI

XVI Tissue Oxygenation

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Use of Mixed Venous Oxygen Saturation in ICU Patients M . LEONE,

V. BLASCO, and C. MARTIN

Introduction The hemodynamic resuscitation of patients in shock is aimed at fulfilling therapeutic goals that are predetermined. Classically, these goals are arterial pressure (MAP), urine output, and central venous pressure (CVP) [1]. Despite normalization of these parameters, tissue hypoxia can persist when the cardiorespiratory system is not adapted to metabolic requirements [2]. Prolonged hypoxia must be avoided since it is the main risk factor for multivisceral failure [3]. It is difficult to evaluate tissue hypoxia at the patient's bedside [1]. It is therefore of great interest to be able to evaluate it with an easy-to-monitor parameter. Mixed venous oxygen saturation (Sv0 2) depends on the balance between arterial oxygen transport (D0 2) to tissue and its consumption (V0 2) [4]. However, Sv0 2 measurement requires the placement of a pulmonary artery catheter (PAC) with a benefit/risk ratio that remains controversial. No study has reported a favorable impact on survival in patients with the use of this type of catheter [5-7]. Moreover, placement of a PAC is not always possible. Measurement of central venous oxygen saturation in the superior vena cava blood (Scv0 2) is possible with the use of a central venous catheter equipped with an optic fiber or using repeated venous samples with traditional catheters. There is a physiological relationship between Sv0 2 and Scv02 values with the latter always a little lower (2 - 3 %) in physiologic conditions than the former. Monitoring of SCV02 is therefore an attractive alternative to that of Sv0 2 [4]. The aim of this chapter is to define the interest and limit s of this hypothesis.

Physiology The Transport and Use of Oxygen

D0 2 is the product of cardiac output and the arterial oxygen content. The tissues extract a percentage of the oxygen available for cellular respiration: V0 2. With the remaining oxygen, the blood returns to the heart through the venous circulation. The oxygen saturation of the venous blood can be measured either at the level of the pulmonary artery (Sv0 2), at the level of the inferior vena cava, the superior vena cava, or the right atrium (Scv0 2). ScvOz reflects the balance between supply (D0 2) and demand (V0 2) and, therefore, tissue oxygen extraction.

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M. Leone, V. Blasco, and c. Martin Sv02 Detenninants The determinants of Sv0 2 value are inferred from equations defining the three parameters of oxygen metabolism for an entire organism: V0 2, D0 2, and oxygen extraction. V0 2 (mlJmin) can be expressed according to the Fick Equation: V02 = cardiac output x (Ca0 2 - CvO~,

where Ca02 and Cv02 are the oxygen content of the arterial blood and the mixed venous blood, respectively. Cv0 2 is a combined fraction (Sv0 2 x 1.34 x Hb) where Hb is the concentration of Hb and a dissolved fraction (P0 2 x 0.003). Since the dissolved fraction is quantitatively negligible, one can write the Fick equation in the following form: V02 "" cardiac output x 1.34 Hb x (Sa0 2 -

SvO~,

under these conditions: SV02 = Sa02 - (V0 2/cardiac output x 1.34 x Hb) The value of Sv0 2 therefore depends on the values of four variables: V0 2, cardiac output, Sa02, and Hb. Arterial oxygen transport, D02 (ml/min), represents the quantity of oxygen that the left ventricle sends each minute into the arterial circuit and that is, therefore, made available to the organism: D02 = cardiac output x CaOl'

The peripheral extraction coefficient for oxygen is expressed according to the formula: Oxygen extraction = V02/D0l' This parameter can also be written as: Oxygen extraction

= (Sa02 -

SvO~/SaOl'

If Sa02 is close to 100 %, the previous equation becomes: oxygen extraction = 1 - SV02'

Under these conditions: Sv02 = 1 - oxygen extraction = 1 - V021D0l' from the expression: SV02 = Sa02 - (VOjcardiac output x 1.34 x Hb).

Therefore, in normoxia (Sa0 2 = 100 %), at rest (cardiac output = 5 l/min, V0 2 = 250 mllmin) and in the absence of anemia (Hb = 15g1dl), the value of SV02 is close to 75 %: under these conditions, the organism only uses 25 % of the available oxygen. An isolated variation in Sa02' V0 2, cardiac output, or Hb will modify the value of Sv0 2. In practice, if one observes a variation in SV02, one must verify the values of each of these four determinants in order to determine the cause. From the expression: SV02 = 1 - VOiD0 2, one can infer that any variation in the peripheral extraction coefficient for oxygen will determine a variation in the opposite direction of SV02' The monitoring of Sv0 2 is, therefore, that of the tissue extraction of 02' In a healthy subject at rest with a normal Sa02 and a normal Hb concentration, the value of SV02varies between 70 % and 75 %. There is an increase in oxygen during physical exercise that is principally at skeletal muscle levels. The result is an increase in V0 2 fulfilled by an increase in cardiac output and extraction of oxygen by the skeletal muscles to which the blood flow was preferentially redistributed. One can thereby observe Sv0 2 values as low as 45 % in a healthy subject during physical effort [8]. However, when SV02 reaches such low values, anaerobic metabolism may

Use of Mixed Venous Oxygen Saturation in leu Patients Table 1. Mixed venous oxygen saturation (Sv0 2) and oxygen metabolism

SV02 level

Consequences

Sv0 2 > 75 %

Normal extraction 002 > V02 Compensatory extraction J, 002 or r V02 Exhaustion of extraction 002 < V02 Onset of lactic acidosis

75 % > SV02 > 50 % 50% > Sv02 > 30 %

002: oxygen delivery; V02: oxygen consumption

30% > SV02 > 25 %

Severe lactic acidosis

SV02 < 25 %

Cellular death

SCV02 Algo rithm (Non-hemodynamic events)

Consider cellular hypoxia

Anemia?

-. Yes: correct it

Hypothermia

Hypoxemia?

-. Yes: correct it

Coma/deep sedation

Agitation?

-. Yes: analgesia sedation

Hyperthermia? -. Yes: normalize

a

SCV02 Algorithm (Hemodynamic events)

b

Sepsis

Decreased venous return

Other distributive shock

Cardiogenic shock

Excessive cardiac output

Obstructive shock

Fig. 1. Interpretation of Scv0 2 according to non-hemodynamic a and hemodynamic b events.

occur. This value from which anaerobic metabolism (or dysoxia) appears, corresponds to the extraction limit of oxygen (or critical extraction) by the tissue ( Table 1). The SvOz to which the threshold of dysoxia corresponds is called the criti cal SvOz' A critical SvOz of approximately 40 % corresponds to a 'critical' oxygen

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extraction of approximately 60 % [9]. In pathological situations, SvOz is the consequence of complex interactions among these four determinants which can all potentially be altered to varying degrees by the pathology as well as its treatment. The four determinants are interdependent. Compensatory mechanisms come into play when one of them is altered. Two adaptive mechanisms intervene to ensure a balance between DOz and VOz: An increase in DOz which essentially depends on the elevation of cardiac output, and an increase in the purely tissular oxygen extraction mechanism. Cardiac output, therefore, increases in order to compensate for a fall in SaOz or Hb and returns to normal after their normalization. It should always be remembered that a variation in SvOz is rarely due to the variation in only one of these determinants (Fig. 1).

Limits in Sv02 Interpretation There are three general limiting factors for the interpretation of an SvOz value. First, it is an overall value which only provides information on the oxygen extraction of a given territory (Fig. 2). From one tissue to another, the ability to extract oxygen varies considerably. Thus the oxygen saturation of coronary venous blood is physiologically lower (37 %) than that of renal venous blood (92 %) ( Fig. 2).

Fig. 2. Arterial and venous oxygen saturations in various vascular regions.

Use of Mixed Venous Oxygen Saturation in leU Patients

The value of SvOz depends on the position of the affinity curve for Hb (Barcroft curve). For the same PvOz value, the SvOz will be lower in case of an acidosis responsible for a displacement to the right of the Barcroft curve. In certain patho logic situations, such as septic shock, peripheral oxygen extraction is altered; SvOz can be elevated whereas hyperlactatemia shows insufficient tissue oxygenation.

SV0 2 Measurement Measurement Sites

The oxygen content of venous blood is measured at the outlet of any organ or tissue but certain locations have easier access in clinical practice: The pulmonary artery (SvOz), the inferior vena cava, the superior vena cava, or the right atrium (ScvO z)' Measurement of SvOz is a reflection of the level of venous oxygenation in the entire body. SvOz is not easily measurable without a PAC. Measurement of ScvOz indicates the level of venous oxygenation of the brain and the upper part of the body. It is measurable by central venous catheter at the level of the superior vena cava or the right atrium [10]. As Figure 2 shows, venous oxygen saturation differs according to the organs since they extract different quantities of oxygen. Most of the studies that have analyzed the relationship between ScvOz and SvOz have shown that ScvOz is an average of 5 % higher than SvOz' This is linked to deoxygenation of the blood in the coronary sinus. Tables 2 and summarize the principal Table 2. Mixed venous oxygen saturation (SV02) versus central venous oxygen saturation (Scv0 2) Authors, year [ref]

Type of patients (n)

Tahvanainen et al. 1982 [11] Wendt et al. 1990 [12] Kong al. 1990 [13] Berridge et al. 1992 [14]

ICU (42) ICU (19) End-stage renal failure (8) ICU according to cardiac index (51)

Herrera et al. 1993 [15] Pieri et al. 1995 [16] Ladakis et al. 2001 [17]

Anesthesia for thoracic surgery (23) Postoperative period (major surgery) (39) ICU (mechanical ventilation) (61)

Michael et al. 2005 [18]

Anesthesia for neurosurgery (70)

Conclusions

SCV02 = SV02 Scv0 2 = Sv0 2 Scv0 2 = Sv0 2 SCV02 = SV02(minimal influence of cardiac index) Scv0 2 = Sv0 2 SCV02 "* SV02 SCV02 = Sv0 2 (independent of cardiac index) SCV02 "* Sv0 2 (values), identical trends

ICU: intensive care unit

Table 3. Mixed venous oxygen saturation (Sv0 2) and central venous oxygen saturation (Scv0 2) by BlandAltman analysis during septic shock Authors, year [ref]

Number of patients

Samples

Bias

Confidence interval 95 %

Martin et al. 1992 [19] Edwards et al. 1998 [20] Tumaoglu et al. 2001 [21] Chawla et al. 2004 [22] Reinhart et al. 2004 [23] Varpula et al. 2006 [24]

7 11 41 13 11 16

580 30 41 53 150

1.1 % 2.9% 6.4 % 5.5 % 7.1 % 4.2 %

-18 .9 to 21 .1 - 14.4 to 21.6 - 7.1 to 14.1 -5.2 to 15.5 - 0.9 to 15 - 8.1 to 16.5

72

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M. Leone, V. Blasco, and C. Martin

(%)

80 70

60 50 40

- scvo, - - - Svo,

. . . . .,- ....-----.-r--.--.-- r--.---,-o 5 10 15 20 25 30 35 40 Time (m in)

Fig. 3. TIme course of continuously measured central (Scv0 2) and mixed (Sv02) venous oxygen saturation in a patient with acute respiratory distress syndrome who developed tension pneumothorax which was treated by insertion of a chest tube.

studies that have compared Scv0 2 and SV02' The results of these studies are contradictory. They are difficult to compare because they differ in the number of patients studied, the number of comparisons carried out, and the statistical methods that were employed [11- 24]. Scv02 and Sv02 are not numerically equivalent but the variations in these two parameters usually occur in a parallel manner ( Fig. 3) [25]. Two recent studies, respectively in anesthesia and intensive care, are of particular interest. In a prospective study, Michael et al. compared Sv0 2 and SCV02 values in 70 neurosurgical patients in a seated position. There was a bias of 6.8 ± 9.3 % but the Scv0 2 and Sv0 2 evolved in the same direction in 75 % of the cases [18]. Reinhart et al. compared the graphs of SV02 and Scv0 2 in 32 ICU patients (postoperative, sepsis, traumatology). Scv02 evolved in the same manner as SV02 in 90 % of the 1,498 events (SD ± 5 % Sv0 2) [23].

Measurement Techniques Measurements are either intermittent by blood sample and analysis in a co-oximeter or continuous by optic fiber. However, the beneficial effects of this monitoring have only been reported within the framework of continuous SCV02 measurement [26]. Discontinuous measurement by in vitro (transmission) spectrometry The measurement principle is based on the change in color of the corpuscles from red to purple as their oxygen content gradually decreases. When one lights a blood sample with a light source that has several wave lengths, the light absorbed for a given wave length depends on the color of the blood and consequently the oxygen content of this blood. A venous blood sample taken from a PAC or a central venous line is placed between a light source and a photoelectric detector which measures its absorption at different wave lengths. Since oxyhemoglobin, desoxyhemoglobin, carboxyhemoglobin, and methemoglobin have different absorption profiles for each wave length crossing a red corpuscle, it is possible to determine with precision the oxygen saturation of each hemoglobin fraction (SV02 for mixed venous blood). Measurement of SV02 and Scv0 2 by co-oximetry causes blood loss and infections linked to frequent handling of catheters.

Use of Mixed Venous Oxygen Saturation in leu Patients

Continuous measurement by in vitro optic fiber (reflection) spectrometry The PACs or central venous lines that monitor SV02 are equipped with optic fibers that measure hemoglobin saturation by reflection spectrometry. It is no longer the transmitted light but the reflected light that is analyzed. In the last few decades, SV02 has been measured by continuous reflection spectrometry with PACs equipped with optic fibers. The accuracy and reproducibility of continuous Sv0 2 monitoring are obtained thanks to the use of several wave lengths (27). The red and infrared light sends different wave lengths through the PAC optic fiber and lights the blood passing through the pulmonary artery. The light reflected by the red corpuscles is retransmitted by a second optic fiber with a photo detector. The reflected light is read by a computer which calculates the Sv0 2. In order to obtain reliable SV02 measurements, an in vitro calibration must be performed according to the manufacturer's instructions before insertion of the PAC. A new in vivo calibration is carried out by a pulmonary artery blood sample every time continuous Sv0 2 monitoring displays suspicious or false values. There are still no recommendations concerning daily recalibration . The precision of Sv0 2 monitoring depends strictly on the good positioning of the catheter in the pulmonary artery (not too distal). The precision of Sv0 2 measurements claimed by the manufacturer is ± 2 %. But compared with cooximetry, the mean precision of continuous Sv0 2 monitoring systems is only 9 % in vitro (28). In a clinical context, the acceptable limits between the two measurement techniques vary by ± 9 % (29). However, discrepancies between laborato ry measurements and the Sv0 2 values obtained by continuous in vivo monitoring are more often due to poor use of SV02measurement systems rather than to their poor quality (30). False Sv0 2 interpretations can, therefore, be minimized by repositioning the PAC and recalibrating the measurement system.

The Current Place of Sv0 2 in Clinical Practice Severe Sepsis and Septic Shock In cases of severe sepsis and septic shock, hypoxia is the principal risk factor in the occurrence of multivisceral failure (3). Rivers et al. reported that in patients with severe sepsis, early and aggressive intensive care guided by continuous monitoring of SCV02' CVP, and MAP reduced mortality from 46.5 % to 30.5 % at the 28th day (26). Compared with the control group, the group whose Scv0 2 was monitored had vascular filling, a number of transfusions and greater recourse to dobutamine in the first six hours . However, no study has reported the interest of SCV02 monitoring after the initial phase of intensive care (the first 6 h). No study has shown that intermittent measurement by gasometry is as effective as continuous measurement. Sv0 2 makes it possible to predict mortality in sepsis (31). Gattinoni et al. reported that therapy with the aim to obtain an SV0 2 superior to 70 % during the first five days had no effect on mortality when compared with the control group (32). In a single-center retrospective study, Varpula et al. evaluated the impact of hemodynamic variables in III patients in septic shock by identifying optimal threshold values (33); mortality was 33 %. At the 48th hour, a MAP < 65 mmHg and an Sv0 2 < 70 % were predictive of mortality. These threshold values confirmed recent French Consensus Conference guidelines [34-36) .

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Anemia, Hemorrhage, and Transfusion During anesthesia, a fall in SV02 from 88 to 78 % can be observed with 15 % less blood mass. Sv0 2 variation is significant, beginning at a blood loss of 2.5 % [37]. The monitoring of Sv0 2 in cases of hemorrhage is of particular interest given the differences in hemodynamic tolerance to hemorrhage depending on a patient's cardiac function. In fact, this parameter includes the combination of an increase in cardiac output and a decrease in Hb concentration. Anesthesia disturbs normal adaptation to these variations. Classic monitoring methods are, therefore, insufficient to predict the adaptation reserve necessary for proper tissue oxygenation [38]. SCV02 monitoring is justified in this case. Being an early indicator of bleeding, it plays a role in the decision to transfuse. According to currently available data, it would appear to be reasonable to transfuse in order to maintain an Scv0 2 ~ 70 %, with the knowledge that this value includes the cardiocirculatory adaptability of the patient and that the tolerated decrease in Hb is as proportionally lower as cardiac output is higher (Fig. 4) [39].

Trauma and Hemorrhagic Shock Scalea et al. showed that SCV02 monitoring was a sensitive and reliable method to detect blood loss in severe trauma patients. Their study included 26 severe trauma patients who were initially stable but with a potential risk of bleeding. Despite the stability of their vital signs, 39 % of the patients (n = 10) had an Scv02 < 65 %. These patients had more severe lesions with bleeding and greater transfusion requirements compared with the patients with Scv0 2 > 65 %. Statistical analysis showed the superiority of Scv0 2 for the prediction of bleeding compared with other parameters: MAP, CVP, urine output, and hematocrit [40].

Mechanical Ventilation SV02 monitoring makes it possible to optimize ventilator settings for patients whose pulmonary status is altered. It also helps in the decision to wean a patient from the ventilator. Through heart-lung interactions, mechanical ventilation provokes a decrease in venous return and cardiac output. The addition of positive end-expiratory pressure (PEEP) increases this effect. Sv0 2 measurement helps set PEEP to an optimal level in order to meet peripheral tissue oxygenation requirements [41]. This level corresponds to the highest figure for SV02.

~

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Fig. 4. SvOihemoglobin (Hb) relation for V0 2 at 200 ml Oimin. The variations in cardiac output (0) are accompanied by large variations in SV02' For Hb = 7 g/dl, SV02 can be at 70 % if 0 = 5 11m in, or reach the critical threshold (40 %) if = 2.5 I/min.

o

Use of Mixed Venous Oxygen Saturation in ICU Patients 90 80 70

Fig. 5. Sv02/cardiac index (CI) relation according to the equation of Fick. The Sv02/Ci is curvilinear. Thus, for constant V0 2, the variations in CI induce large variations in Sv0 2 if the initial (I value is low. By contrast, if the initial CI value is high, the variations have only slight impact on SV02' These relations are altered if the variations in (I are associated with variations in oxygen consumption (V0 2)·

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At the circulatory level, ventilator weaning provokes an increase in left ventricular (LV) preload and afterload [42]. Resumption of respiratory work increases VOz' In addition, there is a catecholaminergic discharge provoked by stress and hypercapnia. Weaning often partially induces a decrease in PaOz. All of these factors contribute to a decrease in DOz and an increase in VOz which can be at the origin of weaning failure in patients with altered cardiac function. A value of 60 % for SvOz has been given as a weaning threshold by certain authors [43]. [ubran et al. studied the evolution of tissue oxygenation parameters in 19 patients . Weaning failure (n = 8) was correlated with a reduction in SvOz and an increase in extraction with more rapid arte rial desaturation. In the patients with successful weaning (n = 11), the authors noted an increase in the cardiac index associated with an increase in DOz [44]. Mechanical ventilator weaning is particularly difficult in patients with cardiac dysfunction with limited potential to increase cardiac output and in whom the increase in oxygen requirements is satisfied by an increase in oxygen extraction. An inappropriate hemodynamic response leads to weaning failure. SvOz redefines weaning in terms of tissue oxygenation. It would appear to be reasonable to optimize cardiac output in order to maintain an SvOz above the weaning threshold (60-70 %) . One should also remember that this value combines the cardiocirculatory adaptability of the patient and that the increase in VOz following the resumption of respiratory work is better tolerated when cardiac output can increase (Fig. 5). Anesthesia Recovery

Anesthesia has a profound effect on tissue oxygenation parameters. It causes a decrease in VOz that, at the same time, is accompanied by a decrease in DOz. The postoperative recovery period is similar to muscular exercise. In the first two hours following coronary surgery, VOz increases up to 50 % of the maximum VOz. For an SvOz of 60 % and 40 %, the VOz is respectively 25 % and 50 % of the maximum VOz [45]. In these patients whose cardiac function is normal, the critical VOz value is 68 % of maximum VOz which corresponds to the occurrence of anaerobic metabolism. This metabolic stress during recovery does not only concern major surgery. After minor orthopedic surgery, 20 minutes after isoflurane has been stopped, VOz goes from 173 to 473 ml/rnin and ventilation from 6.8 to 16.6 l/rnin, During intense shivering, V0 2 can reach 800 mllmin and ventilation 30 lImin [46]. The recovery period, particularly when it is accompanied by shivering or agita-

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c. Martin

tion, is characterized by an elevation in V0 2. This is compensated for by an increase in cardiac output and an increase in the arteriovenous oxygen difference. In a cardiac patient whose output reserves are decreased, the increase in oxygen requirements is achieved mostly by an increase in the arteriovenous difference in oxygen; the result may be a reduction of SV02by approximately 60 %. Placing the patient on spontaneous ventilation aggravates the phenomenon if it causes hypoxia. Moreover, when confronted with a sudden decrease in Sv0 2 during the change to spontaneous ventilation, one can delay tracheal extubation of a cardiac patient in order to correct the cause of V0 2 elevation and optimize cardiac output.

Perioperative Period Goal-directed therapy has been applied with success in the perioperative period. Several studies have reported reductions in morbidity and mortality. In a single center study that included 107 patients, Boyd et al. [47] showed that optimization of D0 2 reduced morbidity and mortality. Two groups of high-risk surgical patients were randomized: A control group (n = 54); and a protocol group (n = 53), which received goal-directed therapy of an indexed D0 2 optimized to 600 rnl/rnin/m- by the administration of dopexamine. Pre- and postoperative D0 2 values were higher in the protocol group. Mortality decreased from 22 % to 5.7 %. There was half the number of complications in the treatment group compared to the protocol group [47]. Wilson et al. reported a reduction in mortality in a single center study that included 138 high-risk surgical patients. There was 3 % mortality in the group optimized by catecholamines (epinephrine or dopexamine) versus 17 % in the control group [48]. In a randomized single center study that included 50 high-risk surgical patients, Lobo et al. showed that per- and postoperative optimization of DO z (first 24 hours) with dobutamine reduced mortality to 15.7 % in the protocol group versus 50 % in the control group. Morbidity was reduced respectively to 31 % versus 67 % [49]. In another randomized single center study that included 50 high-risk surgical patients, the same authors demonstrated that per- and postoperative optimization (first 24 hours) guided by a PAC (D0 2 optimized at 600 ml/min/rrr') byadministering dobutamine provided better results with fewer cardiovascular complications compared with the control group (volemic expansion) [50].

Postoperative Period Major surgery and SCV0 2 In a single center study that included 118 patients, Pearse et al. showed that goaldirected therapy could be implemented in the ICU after major surgery [51]. The aim of treatment consisted in optimizing DO z index to a target of 600 ml/min/rn? during the first eight postoperative hours. The target was reached in 80 % of the cases in the goal-directed therapy group versus 45 % in the control group. Mortality at 28 days was similar in both groups. On the other hand, the patients in the goal-directed therapy group developed fewer postoperative complications and were hospitalized for shorter periods than the patients in the control group. During this study, SCV02 was studied in order to evaluate the efficacy of goal-directed therapy [52]. This parameter turned out to be independently associated with the occurrence of postoperative complications at a threshold value of 64 % (sensitivity: 67 %, specificity: 56 %). In the first hour after surgery, significant reductions in Scv02 occurred in

Use of Mixed Venous Oxygen Saturation in ICU Patients

both groups that were not associated with variation s in cardiac output or D0 2. It is of interest to note that the patients who maintained their Scv0 2 at a mean of 75 % during the first eight postoperative hours did not develop complications. In these same patients, the lowest Scv0 2 was 67 % versus 63 % in the group with postoperative complications. Cardiac surgery and Sv0 2 Sv0 2 monitoring in cardiac surgery patients is of particular interest given the low margin of circulatory adaptation that these patients have. Polonen et al. [53] compared two treatment protocols: Standard treatment (n = 197) which consisted of volemic expansion to maintain pulmonary artery occlusion pressure (PAOP) at between 12 and 18 mmHg, associated with dobutamine (if the cardiac index was less than 2.5 l/min/m') with the addition of vasopressors or vasodilators (for a MAP between 60 and 90 mmHg) , and hemoglobin greater than 100 g/I [53]. Treatment of the protocol group (n = 196) included the above but in addition, had optimization of Sv0 2 above 70 % and lactatemia less than 2 mmolli. Patients in the SV02 group received more crystalloids and colloids and inotropes, and fewer vasopressors. Postoperative morbidity was lower in the protocol group (1.1 % versus 6.1 %; P < 0.001) . Hospitalization was six days in the protocol group versus seven days in the standard group.

Conclusion The use of a PAC has never been shown to have an impact on morbidity/mortality in the ICU or during anesthesia . It is, nevertheless, indispensable for the monitoring of Sv0 2. It is standard to consider that SV02values are an average of 5 % lower than SCV02 values and that the changes in these two parameters usually occur in a parallel manner. Clinical interest in venous oximetry monitoring has been demonstrated for Scv0 2 postoperatively following major surgery, in severe sepsis or septic shock, and for SV02postoperatively following cardiac surgery. SCV02 monitoring is possible in any pat ient with a central venous line. Further studies are required in order to demonstrate the value of venous oximetry in patients with severe trauma or cardiac arrest. It also remains to be seen if interm ittent measurement is as effective as continuous measurement by fiberoptic catheters, especially in patients with severe sepsis or septic shock. References 1. Dellinger RP, Carlet JM, Masur H, et al (2004) Surviving sepsis campaign guidelines for man -

agement of severe sepsis and septic shock. Crit Care Med 32:858-873 2. Reinhart K (1989) Monitoring 02 transport and tissue oxygenation in critically ill patients. In: Reinhart K, Eyrich K (ed) Clinical Aspects of Oxygen Transport and Tissue Oxygenation. Springer, Heidelberg, pp 195-211 3. Marshall JC (2001) Inflammation , coagulopathy, and the pathogen esis of multiple organ dysfunction syndrome. Crit Care Med 29:S99-S106 4. Reinhart K, Bloos F (2005) The value of venous oximetry. Curr Opin Crit Care 11:259-263 5. Harvey S, Harrison DA, Singer M, et al (2005) Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled tr ial. Lancet 366:472- 477 6. Sakr Y, Vincent JL, Reinhart K, et al (2005) Use of the pulmonary artery catheter is not associated with worse outcome in the ICU. Chest 128:2722-2731

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M. Leone, V. Blasco, and C. Martin 7. Sandham JD, Hull RD, Brant RF, et al (2003) A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 348:5-14 8. Weber KT, AndrewsV, Janicki JS, et al (1981) Amrinone and exercise performance in patients with chronic heart failure. Am J Cardiol 48:164-169 9. Vincent JL, De Backer D (2004) Oxygen transport: the oxygen delivery controversy. Intensive Care Med 30:1990-196 10. Rivers EP, Nguyen HB, Huang DT, et al (2002) Critical care and emergency medicine. Curr Opin Crit Care 8:600-606 11. Tahvanainen J, Meretoja 0, Nikki P (1982) Can central venous blood replace mixed venous blood samples? Crit Care Med 10:758 - 761 12. Wendt M, Hachenberg T, Albert A, et al (1990) Mixed venous versus central venous oxygen saturation in intensive medicine. Anasth Intensivther Notfallmed 25:102 -106 13. Kong CH, Thompson FD, Imms FJ (1990) Cardiac output and oxygen uptake in patients with renal failure. Clin Sci 78:591- 596 14. Berridge JC (1992) Influence of cardiac output on the correlation between mixed venous and central venous oxygen saturation. Br J Anaesth 69:409-410 15. Herrera A, Pajuelo A, Morano MJ, et al (1993) Comparison of oxygen saturations in mixed

venous and central blood during thoracic anaesthesia with selective single-lung ventilation. Rev Esp Anestesiol Reanim 40:349-353 16. Pieri M, Brandi LS, Bertolini R, et al (1995) Comparison of bench central and mixed pulmonary venous oxygen saturation in critically iII post surgical patients . Minerva Anestesiol 61:285-291 17. Ladakis C, Myrianthefs P, Karabinis A, et al (2001) Central venous and mixed venous oxygen saturation in critically iII patients . Respiration 68:279 - 285 18. Michael H, Dueck M H, Klimek M, et al (2005) Trends but not individual values of central

venous oxygen saturation agree with mixed venous oxygen saturation during varying hemodynamic conditions. Anesthesiology 103:249-257 19. Martin C, Auffray JP, Badetti C, et al (1992) Monitoring of central venous oxygen saturation versus mixed venous oxygen saturation in critically ill patients. Intensive Care Med 18:101-

110 20. Edwards JO, Mayall RM (1998) Importance of the sampling site for measurement of mixed venous oxygen saturation in shock. Crit Care Med 26:1356-1360 21. Turnaoglu S, Tugrul M, Camci E, et al (2001) Clinical applicability of the substitution of

mixed venous oxygen saturation with central venous oxygen saturation. J Cardiothorac Vase Anesth 15:574-579 22. Chawla LS, Zia H, Gutierrez G, et al (2004) Lack of equivalence between central and mixed venous oxygen saturation. Chest 126:1891-1896 23. Reinhart K, Kuhn HJ, Hartog C, et al (2004) Continuo us central venous and pulmonary artery oxygen saturation monitoring in the critically ill. Intensive Care Med 30:1572-1578 24. Varpula M, Karlsson S, Ruokonen E, et al (2006) Mixed venous oxygen saturation cannot be estimated by central venous oxygen saturation in septic shock. Intensive Care Med

32:1336 - 1343 25. Rivers E (2006) Mixed versus central venous oxygen saturation may be not numerically equal, but both are still clinically useful. Chest 129:507 - 508 26. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368 - 1377 27. Cernaianu AC, Nelson LO (1993) The significance of mixed venous oxygen saturation and 28. 29. 30. 31.

technical aspects of continuous measurement. In: Edwards JO, Shoemaker WC, Vincent JL (ed) Oxygen Transport: Principles and Practice. WB Saunders Company, London, pp 99-124 Janvier G, Guenard H, Lomenech AM (1994) In vitro accuracy of 3 blood 02 saturation optic catheter systems. Intensive Care Med 20:480 - 483 Scuderi PE, bowton DL, Meredith JW, et al (1992) A comparison of three pulmonary artery oxymetry catheters in intensive Care Unit Patients. Chest 102:896-905 Nelson LD (1987) Mixed venous oximetry. In: Snyder JV, Pinsky MR, (ed) Oxygen Transport in the Critically III. Year Book Medical Publishers, Chicago, pp 235 - 248 Heiselman 0, Jones J, Cannon L (1986) Continuous monitoring of mixed venous oxygen saturation in septic shock. J Clin Monit 2:237 - 245

Use of Mixed Venous Oxygen Saturation in leu Patients 32. Gattinon i L, Brazzi L, Pelosi P, et al. A tr ial of goal-oriented hemodynamic therapy in critically ill patients. Sv02 Collaborative Group. N Engl J Med 1995333:1025-1032 33. Varpula M, Tallgren M, Saukkonen K, et al (2005) Hemodynamic variables related to outcome in septic shock. Intensive Care Med 31:1066-1071 34. Lepape A (2007) Septic shock: from recommendations to bedside. Ann Fr Anesth Reanim 26:376- 380 35. Martin C, Brun-Buisson C (2007) Initial management of severe sepsis in adults and children . Ann Fr Anesth Reanim 26:53- 73 36. Martin C, Garnier F, Vallet B (2005) Recommendations for management of severe sepsis and septic shock. Surviving sepsis campaign. Ann Fr Anesth Reanim 24:440- 443 37. Cheung AT, Savino JS, Weiss SJ, et al (1994) Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventr icular function . Anesthesiology 81:376-387 38. Van der Linden P, Gilbart E, Engelman E, et al (1991) Effects of anesthesic agents on systemic critical 02 delivery. J Appl Physiol 71:83-93 39. Vallet B (2003) Effect of blood transfusion on oxygen transport, oxygen consumption and microcirculation. Reanimation 12:549 - 556 40. Scalea TM, Hartn ett RW, Duncan AO, et al (1990) Central venous oxygen saturat ion: a useful clinical tool in trauma patient s. J Trauma 30:1539-1 543 41. Suter PM, Fairley HB, Isenberg MD (1975) Optimum end-expiratory airway pressure in pat ients with acute pulmonary failure. N Engl J Med 292:284-289 42. Teboul JL (1992) Hernodynamique ventriculaire gauche et sevrage : consequences. Rean Med Urg 1:191-195 43. Armaganidis A, Dhainaut JF (1989) Sevrage de la ventilation artificielle : interet du monitorage de la Sv02. Ann Fr Anesth Reanim 8:708- 715 44. [ubran A, Mathru M, Dries D, et al (1998) Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 158:1763-1769 45. Viale JP, Annat G, Lehot JJ, et al (1994) Relationship between oxygen up lake and mixed venous saturation in the immediate postoperative per iod. Anesthesiology 80:278- 279 46. Ciofolo MJ, Clergue F, Devilliers C, et al (1989) Changes in ventilation, oxygen up lake, and carbon dioxide out up during recovery from anaesthesia . Anesthesiology 70: 737-741 47. Boyd 0 , Grounds RM, Bennett ED (1993) A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high- risk surgical patients. JAMA 270:2699- 2707 48. Wilson J, Woods I, Fawcett J, et al (1999) Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery. BMJ 318:1099-1103 49. Lobo SM, Salgado PF, Castillo VG, et al (2000) Effects of maximizing oxygen delivery on morbidity and mortality in high-risk surgical pat ients. Crit Care Med 28:3396-3404 SO. Lobo SM, Lobo FR, Polachini CA, et al (2006) Prospective, random ized trial comparing fluids and dobutam ine optimization of oxygen delivery in high-risk surgical patients . Crit Care1O: R72

51. Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM, Bennett ED (2005) Early goaldirected therapy after major surgery reduces complications and durat ion of hospital stay. A randomised, controlled trial. Crit Care 9:R687- 693 52. Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM, Bennett ED (2005) Changes in central venous saturation after major surger y, and association with outcome. Crit Care 9:R694699 53. Polonen P, Ruokonen E, Hippelainen M, et al (2000) A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical pat ients. Anesth Analg 90:1052-1059

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Early Optimization of Oxygen Delivery in High-risk Surgical Patients S.M. LOBO, E. REZENDE, and

F.

SUPARREGUI DIAS

Introduction Total tissue perfusion relies on adequate arterial oxygen saturation, cardiac output, and hemoglobin concentration, and global perfusion is usually assessed by calculation of the oxygen delivery index (D0 2I) [1]. More than 20 years ago Shoemaker et al. reported that perioperative alterations in D0 2 were closely correlated to the development of multiple organ failure (MOF) and death [2]. Since then goal-directed therapy, defined as the use of the cardiac output or a surrogate to guide intravenous fluid and inotropic therapy, has been used in an attempt to improve outcome in surgical patients [1].

Why Early Goal-directed Therapy for Certain Surgical Patients? Both hypovolemia and myocardial dysfunction may be easily undetected before, during, and after surgery in high-risk patients. Special attention to volume status and cardiovascular function is, therefore, required if low tissue perfusion and organ dysfunction are to be avoided. Nonetheless, hypovolemia is the major cause of cardiovascular dysfunction in critically ill patients. A very important consideration in the management of the critically ill is that the treatment for heart failure is usually the opposite to the treatment of hypovolemia. Mean arterial pressure (MAP) does not reflect blood flow and hypovolemia may be present, despite normalization of the physiologic variables and filling pressures. Hypovolemia results in inadequate blood flow to meet metabolic requirements. Occult hypoperfusion is associated with increased mortality in hemodynamically stable, high-risk surgical patients [3]. Prolonged lactate clearance is related to increased mortality in surgical ICU patients [4]. Additional therapy to increase central venous oxygen saturation (SCV02) and decrease serum lactate concentrations may be necessary to restore adequate systemic oxygenation after initial resuscitation [5]. In surgical patients, fluid deficits may occur in the absence of obvious fluid losses because of vasodilation or alterations in capillary permeability. Conventional fluid therapy usually considers that operative trauma causes a contraction of the extracellular fluid volume (ECV) beyond the measured fluid losses [6]. However, this concept seems to be based on weak evidence and some argue that ECV is actually increased during surgical trauma and inflammatory response [7]. Actually, a range of different physiological situations may occur in different types of surgery. Ideally, at the present time, we should use the necessary tools to correctly evaluate fluid sta tus and cardiac function individually.

Early Optimization of Oxygen Delivery in High-risk Surgical Patients

Assessment of Fluid Status and Fluid Challenge: Important Concepts during Goal-directed Therapy The first fundamental question regarding the cardiovascular system during resuscitation from shock is whether blood flow will increase with fluid resuscitation? It is not an easy task to define 'optimal fluid resuscitation'. Traditionally, cardiac filling pressures have been used to assess volume status in critically ill patients. But it is important to recognize that hypovolemia can exist despite normal values of central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP). Despite their validity to guide fluid therapy in less complicated patients, their use may overestimate filling pressures in more complex patients with external or intrinsic positive end-expiratory pressure (PEEP) and abdominal hypertension, conditions very commonly seen in the intensive care unit (lCU). CVP and PAOP are also highly dependent on left ventricular (LV) compliance which is frequently decreased in ICU patients with sepsis, ischemic, or hypertrophic cardiopathy. Nevertheless, accurate assessment of filling pressures or end-diastolic volumes (preload) responsiveness ('Frank-Starling' curve) can better predict the individual response to fluid loading than static indices [8]. According to the Frank-Starling relationship, a patient is a 'responder' to volume loading only if both ventricles are preload dependent. The goal is to reach the point where a certain preload is obtained and after which no further increase in cardiac output is observed with further fluid infusion. Step-by-step, incremental volume loading is used to identify the optimal point in the curve. Many studies of goal-directed therapy have used repeated boluses of artificial colloids [9- 15]. A fluid challenge causing an increase in stroke volume suggests that subsequent fluid challenges are unlikely to result in overfilling (ascending portion of the Frank-Starling curve). Conversely, further fluid challenges are inappropriate and could decrease ventricular performance resulting in pulmonary or tissue edema. Fluid challenge-induced responses in MAP, heart rate, ScvOz, serum lactate, and urine output, have been used as surrogates for stroke volume. Uncovering and correcting hypovolemia is a crucial step that should be performed before other therapies likely to increase DO z, such as blood transfusions or inotropes, are used. During surgery, dynamic indices appear to be more useful in evaluating fluid needs in mechanically ventilated patients [16]. The arterial pulse pressure variation (PPV) induced by cyclic changes in intrathoracic pressure can result in concurrent changes in stroke volume in preload-dependent, but not in preload-independent patients. In patients operating on the flat portion of the Frank-Starling curve, PPV is low and volume loading does not result in a significant increase in stroke volume. In patients operating in the steep portion of the preload -stroke volume relationship, PPV is high and volume loading leads to a significant increase in stroke volume. Importantly, preload and afterload are also influenced by vascular tone determined by several endogenous vasoactive mediators, in both venous and arterial systems. We must, therefore, look carefully at two other steps after adequate fluid resuscitation. First, if the patient is not preload responsive and is still hypotensive or not fully resuscitated (signs of tissue hypoperfusion), vasomotor tone will probably be reduced and vasopressors will be necessary. Second, if the patient is neither preload responsive, nor exhibiting reduced vasomotor tone and hypotension, then the problem is the heart, and action must be taken to diagnosis and treat cardiac failure.

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How to Decrease Mortality? Certainly, fluid management strategies based on simple filling pressure targets are less successful than those in which blood flow or perfusion is target. For many years, pulmonary artery catheters (PAC) have been considered the gold standard for monitoring critically ill patients. PAC use helps to evaluate filling pressures, cardiac function, and the adequacy of oxygen delivery and consumption. Many single center studies have demonstrated an impressive reduction in morbidity and mortality associated with a treatment strategy aimed at preemptive 'optimization' by increasing DOlI to levels greater than 600 ml/min/m- [17- 20). Consistently, these studies had the following circumstances in common: They were carried out preemptively in high-risk patients (expected mortality rate higher than 20 %); they started before and continued some hours after surgical trauma; and, in addition to fluids, they used inotropes, blood, and vasodilators if necessary ( Fig. 1). In other interventional studies, either preoperatively or intraoperatively, different goals, such as normal values for cardiac index (CI), ScvOl, serum lactate, and maximum stroke volume were used, usually in low-risk patients, and mainly using fluid resuscitation [21-25]. These studies did not show a reduction in mortality, however, they demonstrated decreases in the rate of complications or the length of hospitalization. One study using DOlI oriented optimization therapy during the first 8 h after operation showed a significant decrease in post -operative complications but no differences in mortality rates [26). Despite the unquestionably better results seen when resuscitation is preemptively DOl oriented, the target of 600 ml/rnin/m? is perplexing in terms of rationality.

Mortali ty

Complications Shoemaker, 1988 ...

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- - Post-operative

Fig. 1. Mortality and morbidity differences between goal-directed therapy and control groups. Note for each study the first author's name, the year of publication, the therapeutic goal, and the type of therapy (preemptive or post-operative). PPV: pulse pressure variation; CI: cardiac index; SV: stroke volume

Early Optimization of Oxygen Delivery in High-risk Surgical Patients Severe trauma patients in whom the goal was a D0 21 greater than 500 ml/rnin/mwere able to achieve the same perfusion goals as patients with a higher DOlI target [27). In fact, in this group, supranormal resuscitation was associated with infusion of more lactated Ringer's solution, more complications, and more cases of abdominal compartmental syndrome. We, therefore, still have to learn how to tailor the DOl to the actual demand and to avoid unnecessary therapies. Another issue is why goal-directed therapy works in the early phase and not in the late phase [28)? It seems that it works when the host can manifest an increased cardiac output response [29). In the late phase, cardiac injury commonly occurs with critical illness due to associated hypotension and secondary decreased coronary perfusion, and myocardial injury. An impaired reserve may be masked by the pathological vasodilatation that sustains a decreased LV afterload. Goal-directed therapy may be inappropriate or even dangerous at this phase. In addition, in the late stages after onset of organ failure no amount of extra -oxygen will restore dead cells [30).

(an Goal-directed Therapy be Performed in High-Risk Patients with Fluids Alone or is Inotropic Support Necessary? Major surgical trauma increases oxygen requirements from an average of 110 mIl min/m- at rest to an average of 170 ml/min/m- in the postoperative period [31). This increase in oxygen demand could be considered equivalent to sustained exercise and is normally met by increases in cardiac output and tissue oxygen extraction. There is, in fact, an operative anaerobic threshold, which, if exceeded during surgery or in the postoperative period, results in the development of circulatory failure or myocardial ischemia [31]. Patients that cannot meet the increased oxygen demand by increasing cardiac output will be more likely to have a poor outcome after major surgery [17]. Patients with chronic heart failure can face a series of events during prolonged surgery that may end in acute decompensation. In the immediate preoperative evaluation period, 40.5 % of a group of high -risk surgical patients had a CI less than 2.S l/rn in/rrr' and or a DOlI less than SSO ml/min/m- [20). Even critically ill patients without preexisting myocardial contractile dysfunction may sustain severe perioperative complications with subsequent acute heart failure [32). Anesthetic induction still result s in increases in systemic vascula r capacitance and, to a certain extent, in myocardial depression [33]. In a study of plasma dilut ion during open abdominal surgery, the infusion of a bolus of crystalloids unexpectedly decreased CI in 60 % of the patients [34). Supportive treatment with inotropes would be a very reasonable approach for these patients. However, their use is not without consequence. Inotropes may alter regional blood flow and cause tissue hypoxia with the potential to cause myocardial ischemia. In previous randomized controlled trials in high-risk surgical patients, after adequate recovery of volemia, dobutamine or dopexamine have been used with the objective of opt imizing DOl [17- 20]. The effects of D0 21 optimization (> 600 ml/min/rn-) with fluids or with fluids and dobutamine on the 60-day mortality in high-risk general surgery patients were evaluated in a randomized controlled trial [33]. The patients were treated according to sequentially applied therapies with intervention thresholds: packed red blood cells (RBCs) if hematocrit less than 30 % and fluids if PAOP < 16 mmHg. Dobutamine

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Fig. 2.Oxygen delivery index (0021) during surgery and postoperatively for the volume group (.) and the dobutamine group (.) . Results presented as the mean and standard error. 0, preoperative; 1, 30 min intraoperatively (10); 2, 2 hours 10; 3, 4 hours 10; 4, 6 hours 10; 5, 8 hours 10; 6, 0 hours postoperatively (PO); 7, 4 hours PO; 8, 8 hours PO; 10, 12 hours PO; 11, 16 hours PO; 12, 24 hours PO. *p < 0.05 versus volume group, #p < 0.05 versus baseline. From [33] with permission

was given for the 'dobutamine group' after a first cycle of fluids and further fluids were given only in the presence of signs of hypovolemia. The cardiovascular depression was an important component of the hemodynamic response in the perioperative period in this group of patients. The temporal pattern of the DOzI ( Fig. 2) shows an important reduction seen after the start of anesthesia in both groups. A higher DOzI was seen in patients in the dobutamine group. PAC-guided hemodynamic optimization using dobutamine and fluids determines better outcomes, whereas fluids alone increase the incidence of cardiovascular postoperative complications in highrisk patients.

Goal-directed Therapy: Necessity or Futility? Dobutamine is an inotropic agent with predominant ~1-adrenergic properties used to increase blood flow. The role of inotropes in optimization of high-risk surgical patients may exceed their effects on oxygen transport variables. Dobutamine or dopexamine may have anti-inflammatory properties and a role in increasing splanchnic or microvascular perfusion, thereby protecting this area from further injury [35, 36]. Three studies have investigated the use of fixed doses of dopexamine or dobutamine in surgical patients [36-38] . In the first, low-dose dopexamine was given blindly for esophageal Doppler-guided fluid resuscitated patients undergoing major abdominal surgery [36]. No significant differences in the incidence of postoperative complications or the length of ICU and hospital stay were seen. The second, multicenter study, used relatively normal values as goals and two fixed dosage levels of dopexamine, but the outcome was not significantly improved [37]. A third randomized, placebo-controlled study investigated the effects of a fixed dose of dobutamine (5 Ilg/kg/h) in 82 surgical patients admitted to a step-down unit [38]. If, in response to study drug administration, the patient presented tachycardia or hypotension, additional fluids were given, and if persistent, the study drug was interrupted. Fixed dose dobutamine after surgery had no effects on perfusion variables, serum C-reactive protein (CRP), or on the prevalence of postoperative complications. Interestingly, morbidity and mortality were significantly higher in patients in whom dobutamine was interrupted before completing 12 h. These patients had more complica-

Early Optimization of Oxygen Delivery in High-risk Surgical Patients

tions (75 % vs 40.6 %), higher mortality rate (62.5 % vs 12.5 %), and lower ScvOz (55 % ± 15 % vs 70 % ± 16 %) than those who received more than 12 h of dobutamine. The infusion of dobutamine likely unmasked the presence of occult hypoperfusion by inducing tachycardia or hypotension, therefore, identifying a group of more severely ill patients. These studies suggest that vasoactive agents should not be given blindly to surgical patients.

Is a Minimally Invasive Technique Suitable for Intraoperative Optimization Therapy? Perioperative cardiovascular optimization using a PAC in a selected group of patients has been shown to reduce mortality when commenced before surgery, but this approach has proved impractical outside clinical trials. The use of a minimally invasive technique may help to make the implementation of optimization of DO z widespread, which remains a major factor in reducing mortality. The rationale for using a less invasive hemodynamic tool is to manage an unstable patient with the same key information offered by the PAC but, possibly, without the risks and drawbacks of more aggressive or complex monitoring. Esophageal Doppler and pulse contour analysis have been used by anesthesiologists and intensivists in goaldirected therapy studies [39, 40). In five studies, esophageal Doppler was used for goal-directed therapy guiding repeated bolus of colloid solution to maximize stroke volume during surgery and was associated with improved or faster recovery from surgery. In the first study, gastrointestinal perfusion was improved and ICU and hospital length of stay were reduced in patients undergoing coronary artery revascularization [9). Two studies were carried out on orthopedic surgical patients and showed a reduction in the time spent in hospital [11, 12). Finally, goal-directed therapy made possible an earlier return to tolerating solid food and earlier discharge from hospital in moderate-risk general surgical patients and a reduction in the need for ICU admission after elective major bowel surgery [10, 15]. In spite of some utility in aiding assessment and therapy, this technology has been slow to be adopted likely because of a less than ideal accuracy of the cardiac output measurements, the learning curve, and problems related to the presence of the probe in the esophagus [40). Pulse contour analysis is based on the concept that the contour of the pulse pressure is proportional to stroke volume and inversely related to vascular compliance. The potential of continuous pulse contour analysis over other methods for intermittent cardiac output determination is the possibility to immediately detect any change in unstable patients. The technique requires only an arterial line and a central or peripheral venous access that will probably already have been inserted in critical care patients [46]. In addition, the presence of an arterial line allows the estimation of the PPV and, therefore, an accurate evaluation of fluid responsiveness. The LiDCO system uses the arterial pulse power analysis for measuring and monitoring stroke volume on a beat to beat basis from the arterial pulse pressure waveform. Cardiac output is measured by lithium indicator dilution and pulse power analysis. It is based on the assumption that the net power change in a heart beat is the balance between the input of a mass of blood (stroke volume) minus the blood mass lost to the periphery during the beat. Following correction for compliance and calibration there is a linear relationship between net power and net flow. A recent

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study used the LiDCO system to guide D0 21 optimization therapy post-operatively during an 8 h period [26]. Patients in the goal-directed therapy group received more fluids, had a higher D0 2I, and a significant decrease in postoperative complications. We are undertaking a study on D0 21 optimization therapy during major elective surgery using the LiDCO system in high-risk patients. 'Restrictive' strategies for fluid administration have been shown to improve certain outcomes in surgical patients [42, 43]. In a randomized controlled trial (ISRCTN94984995), we plan to enroll 156 patients to evaluate whether a 'restrictive' strategy of fluid resuscitation can be done safely, during optimization therapy with dobutamine. We have analyzed the hemodynamic and perfusion patterns associated with both regimens (conventional versus restrictive) of fluid replacement in 50 patients (median age 69 years) receiving dobutamine to evaluate the safety of the treatment algorithm guided by the un CO system. The D0 21 for both groups during surgery and for 8 h postoperatively are shown in Figure 3. The goal for D0 21 was achieved intra-operatively by 61 % of the patients in the 'conventional' group and by only 32 % of the patients in the restrictive group. Postoperatively, 68 % and 73 % of the patients were goal-achievers in conventional and restrictive groups , respectively. Importantly, and very interestingly, in spite of the lower proportion of goal-achievers intraoperatively in the restrictive group, both groups had similar patterns of perfusion variables (serum lactate and SCV02) on admission to the ICU and 24 h postoperatively. There were no significant differences in serum creatinine, hemoglobin, or acid-base status between the two groups. The current rates for major complications and mortality rate are 20 % and 2 %, respectively. Apparently, optimization does not necessarily mean achieving a supra-normal pre-defined goal but is the logical development of the concept that tailoring the goal to the best achievable values in a patient will, of course, decrease his/her chance of having an oxygen debt. Our preliminary results do suggest that the LiDCO system is a useful and pragmatic tool to undertake intraoperative optimization of D0 2 and substantially improves outcomes. Calibration alerts occurred a few times after arrhythmias and new calibrations were done without impeding the goal-directed therapy. In only one patient with recurrent acute atrial fibrillation, already in the ICU, was the goalPostoperative

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Fig. 3.Oxygen delivery index (D021) during surgery and postoperatively for the conventional and the restrictive group. Results presented as the mean and standard deviation. 0, preoperative; 1, 30 min intraoperatively (10); 2, 1 hour 10; 3, 2 hours 10; 4, 3 hours 10; 5, 4 hours 10; 6, 5 hours postoperatively (PO); 7, 0 hour PO; 8, 1 hour PO; 9, 2 hours PO; 10, 3 hours PO; 11 , 4 hours PO; 12, 5 hours PO; 13, 6 hours PO; 14, 7 hours PO; 15, 8 hours PO. *p < 0.05 versus restrictive group

Early Optimization of Oxygen Delivery in High-risk Surgical Patients

directed therapy interrupted due to uncertainties about the measurements. This less invasive alternative to the tradit ional PAC technique appears to offer a reliable tool for monitoring cardiac output and guiding DOj-oriented therapy dur ing surgery and in the immediate postoperative period in high-risk pat ients.

Who is the High-risk Patient likely to Benefit From Goal-directed Therapy? High-risk patients spend a significant amount of healthcare resources. Several attempts have been made to detect patients at risk, and to reduce the risk of postoperative morbidity and mortality by improving peri-operative care. The vast majority of postoperative deaths, mainly due to sepsis and MOF, occur in older patients who undergo non -elective surgery, and have coexisting cardio-respiratory disease [44]. A meta-analysis of 21 studie s of hemodynamic optimization in high-risk surgical patients demonstrated beneficial results when the mortality in the control group was higher than 20 %. Low control mortalities suggest that the patients were not very ill and, therefore, may not respond as clearly to increased DO z; at the same time, much larger numbers of patients may be required to show statistical significance [30]. It is easy to underestimate individual risk, and not to recognize high-risk patients. Just a few patients undergoing major surgery have an increased risk of severe postoperative complications and high mortality rates. A large observational British study with more than 4 million surgical patients has shown that this population accounts for only 12.5 % of the surgical procedures but, also for more than 80 % of the deaths [45]. Despite high mortality rates, fewer than 15 % of these patients are admitted to the ICU. In a recent Brazilian multicenter epidemiological study of 587 surgical patients admitted to 21 ICUs (unpublished) the ICU and hospital mortality rates were 15 % and 25 % respectively. The commonest complication was sepsis (48 %). Myocardial ischemia was diagnosed in only 1.9 %. The main causes of death were MOF (53 %) and card iovascular failure (12.5 %) . A total of 122 patients died; 66.5 % of the cases underwent non-elective surgery, 84.3 % underwent major surgery, 77 % were older than 60 years and 39 % older than 70 years old; 72 % had sepsis. In addition, 34 % of the patients who died were classified as having a poor functional capacity (inability to climb two flights of stairs), 30 % had diabetes, and 21 % had malnutrition. In spite of the multifactorial origin of post-operative complications, compromised physiologic reserves in combination with extensive surgery seem to be a hallmark of a high complication rate. Major body cavity surgery causes a strong inflammatory response , which in turn causes a marked increase in oxygen requi rements. The highrisk patient cannot spontaneously elevate their cardiac output to match the demand, and we may be able to identify these patients through cardiopulmonary exercise testing, which examines the ability of the cardiorespiratory system to deliver oxygen to tissues under stress [31, 46]. During cardiopulmonary exercise testing , the oxygen consumption at which the energy demands outstrip the supply of oxygen, and aerobic metabolism is supplemented by anaerobic metabolism with the consequent generation of lactate is known as the anaerobic threshold. Patients submitted to major abdom inal surger y who had an anaerobic threshold below 11 mllkg/min had a mortality of 18 % compared to 0.8 % in those who had an anaerobic threshold above 11 ml/kg/rnin [46]. The risk of

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S.M. Lobo, E. Rezende, and F. Supanegui Dias death was increased ten times when a poor ventricular function, as measured by the anaerobic threshold, was coupled with myocardial ischemia. The anaerobic threshold was used to stratify risk and direct h igher risk patients (low anaero bic threshold) to perioperative monitoring with a PAC, causing a significant reduction in the mortality rate from 18 % to 8.9 %. The subjective evaluation of exercise tolerance from the patient's history may also have prognostic value [47]. Exercise tolerance or physical fitness can be assessed in metabolic equivalents, which is a validated method of determining the functional capacity. The inability to climb two flights of stairs is related to an 89 % chance of developing post-surgical complications [48]. Decreased functional capacity may be multifactorial, including inadequate cardiopulmonary reserve, deconditioning, transient myocardial ischemia, diastolic dysfunction, presence of co-morbidities, and advanced age . Postoperatively, perfusion variables such as blood lactate and venous oxygen saturation were demonstrated as predictors of mortality. Significant reductions in SCV02 or a single measure less than 64.4 % were both independently associated with postoperative complications [49]. In cardiac surgery patients, the presence of a serum blood lactate concentration at ICU admission higher than 3 mmolll was predictive of death [50].

Conclusion In conclusion, sepsis and MOF are by far the main causes of death after general surgery. Nevertheless, in the risk assessment and pre-operative evaluation, usually only the risk of cardiac ischemic events is considered. A score to evaluate the risk of MOF and infe ctious complications is, therefore, warranted. Peroperative management might influence the outcome, and the identification of high-risk patients will thus only be of value if there is a change in management prompted by abnormal findings. It is time to implement a strategy for wide spread optimization of D0 2 in high -risk surgical patients. This strategy should consider the physiological reserve, the method of cardiovascular monitoring, and the therapy adopted to reach a safe threshold of D0 2.

References 1. Tote SP, Grounds RM (2006) Performing perioperative optimization of the high-risk surgical

patient. Br J Anaesth 97:4-11 2. Shoemaker WC, Montgomery ES, Kaplan E, Elwyn DW (1993) Physiologic patterns in surviving and nonsurviving shock patients. Use of sequential cardiorespiratory variables in defining criteria for therapeutic goals and early warning of death. Arch Surg 106:630-636 3. Meregalli A, Oliveira RP, Friedman G (2004) Occult hypoperfusion is associated with increased mortality in hemodynamically stable, high-risk, surgical patients. Crit Care 8: R60 -65 4. McNelis J, Marini CP, Jurkiewicz A, et al (2001) Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg 182:481-5 5. Rady MY, Rivers EP, Nowak RM (1996) Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med 14:218- 225 6. Shires GT, Brown F (1961) Acute changes in extracellular fluids associated with major surgical procedures. Ann Surg 154:803-810 7. Brandstrup B, Svensen C, Engquist A (2006) Hemorrhage and operation cause a contraction of the extracellular space needing replacement - evidence and implications? A systematic review. Surgery 139:419-4 32

Early Optimization of Oxygen Delivery in High-risk Surgical Patients 8. Vincent JL, Weil MH (2006) Fluid challenge revisited. Crit Care Med 34:1333-1337 9. Mythen MG, Webb AR (1995) Perioperative plasma volume expansion reduces the incidence of gut mucosal hypoperfusion during cardiac surgery. Arch Surg 130:423- 429 lO. Gan TJ, Soppitt A, Maroof M, et al (2002) Goal-directed intraoperative fluid adm inistration reduces length of hospital stay after major surgery. Anesthesiology 97:820-826 11. Sinclair S, James S, Singer M (1997) Intraoperative intravascular volume optimization and length of stay after repair of proximal femoral fracture: Randomized control trial. BMJ 315:909- 912 12. Venn R, Steele A, Richardson P, Poloniecki J, Grounds M, Newman P (2002) Randomized controlled trial to investigate influence of the fluid challenge on duration of hospital stay and perioperative morbidity in patients with hip fractures. Br J Anaesth 88:65- 71 13. McKendry M, McGloin H, Saberi 0, Caudwell L, Brady AR, Singer M (2004) Randomised controlled trial assessing the impact of a nurse delivered, flow monitored protocol for optimisation of circulator y status after cardiac surgery. BMJ 329:258 14. Polenen P, Ruokonen E, Hippelainen M, Poyhonen M, Takala J (2000) A prospective randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients. Anesth Analg 90:lO52 -1059 15. Conway DH, Mayall R, Abdul-Latif MS, Gilligan S, Tackaberry C (2002) Randomised controlled trial investigating the influence of intravenous fluid titration using oesophageal Doppler monitoring during bowel surgery. Anaesthesia 57:845-849 16. Solus-Biguenet H, Fleyfel M, Tavernier B, et al (2006) Non-invasive prediction of fluid responsiveness during major hepatic surgery. Br J Anaesth 97:808-816 17. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS (1988) Prospective trial of supra normal values of survivors as therapeutic goals in high-risk surgical patients . Chest 94: 1176-1186 18. Boyd 0 , Grounds M, Bennett 0 (1993) Preoperative increase of oxygen delivery reduces mortality in high-risk surgical patients. JAMA 270:2699-2707 19. Wilson J, Woods I, Fawcett J, et al (1999) Reducing the risk of major surgery: Randomized controlled trial of preoptimization of oxygen delivery. BMJ 318:1099-1103 20. Lobo SMA, Salgado PF, Castillo VGT, et al (2000) Effects of maximizing oxygen delivery on morbidity and mortality in high risk surgical patients. Crit Care Med 28:3396 - 3404 21. Berlauk JF, Abrams JH, Gilmour 1), O'Connor SR, Knighton DR, Cerra FB (1991) Pre-operative optimization of cardiovascular hemodynamics improves outcome in peripheral vascular surgery. Ann Surg 214:289 - 297 22. Bender JS, Smith-Meek MA, Jones CE (1997) Routine pulmonary artery catheterization does not reduce morbidity and mortality of elective vascular surgery: results of a prospective, random ized trial. Ann Surg 226:229 - 236 23. Valentine RJ, Duke ML, Inman MH, et al (1998) Effectiveness of pulmonary artery catheters in aortic surgery: A randomized trial. J Vase Surg 27:203 - 212 24. Ziegler OW, Wright JG, Choban PS, Flancbaum L (1997) A prospective randomized trial of preoperative "optimization" of cardiac funct ion in patients undergoing elective peripheral vascular surgery. Surgery 122:584- 592 25. Lopes M, Lopes MR, Oliveira MA, et al (2007) Goal-directed fluid management based on pulse pressure variat ion monitoring during high-risk surgery: a pilot randomized controlled trial. Crit Care 11:RI00 26. Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM, Bennett ED (2005) Early goaldirected therapy after major surgery reduces complications and duration of hospital stay. A randomised, controlled trial [TSRCTN38797445) . Crit Care 9:R687-693 27. Balogh Z, McKinley BA, Cocanour C, et al (2003) Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg 138:637 -643 28. Gattinoni L, Brazzi L, Pelosi P, et al (1995) A trial of goal-oriented hemodynamic therapy in critically ill patients. Sv02 Collaborative Group. N Engl J Med 333:1025-1032 29. Pinsky MR (2007) Heart failure as a co-morbidity in the ICU. In: J L Vincent (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg, pp llO-118 30. Kern JW, Shoemaker WC (2002) Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med 30:1686-1692 31. Older P, Hall A, Hader R (1999) Cardiopulmonary exercise testing as a screening test for per ioperative management of major surgery in the elderly. Chest 116:355-362

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S.M. Lobo, E. Rezende, and F. Suparregui Dias 32. Toller WG; Metzler H (2005) Acute perioperative heart failure. Curr Opin Anesthesiol 18: 129-135 33. Lobo SM, Lobo FR, Polachini CA, et al (2006) Prospective, randomized trial comparing fluids and dobutamine optimization of oxygen delivery in high-risk surgical patients [ISRCTN42445141] . Crit Care 10:R72 34. Svensen CH, Olsson J, Hahn R (2006) Intravascular fluid administration and hemodynamic performance during open abdominal surgery. Anesth Analg 103:671-676 35. De Backer D, Creteur J, Dubois MJ, et al (2006) The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 34:403-408 36. Stone MD, Wilson RJ, Cross J, Williams BT (2003) Effect of adding dopexamine to intraoperative volume expansion in patients undergoing major elective abdominal surgery. Br J Anaesth 91:619-624 37. Takala J, Meier-Hellmann A, Eddleston J, Hulstaert P, Sramek V (2000) Effect of dopexamine on outcome after major abdominal surgery: a prospective, randomized, controlled multicenter study. European Multicenter Study Group on Dopexamine in Major Abdominal Surgery. Crit Care Med 28:3417 - 3423 38. Arantes AS, Christiano AC, Abreu SP, et al (2007) Low-doses dobutamine and fluids in highrisk surgical patients: Effects on tissue perfusion, inflammatory response and morbidity. Revista Brasileira de Terapia Intensiva 19:5-13 39. Chaney JC, Derdak S (2002) Minimally invasive hemodynamic monitoring for the intensivist: current and emerging technology. Crit Care Med 30:2338 - 2345 40. Marik PE, Baram M (2007) Noninvasive hemodynamic monitoring in the intensive care unit. Crit Care Clin 23:383-400 41. Jonas MM, Tanser SJ (2002) Lithium dilution measurement of cardiac output and arterial pulse waveform analysis: an indicator dilution calibrated beat-by-beat system for continuous estimation of cardiac output. Curr Opin Crit Care 8:257- 261 42. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al (2003) Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 238:641-648 43. Nisanevich V, Felsenstein I, Almogy G, Weissman C, Einav S, Matot I (2005) Effect of intraoperative fluid management on outcome after intraabdominal surgery. Anesthesiology 103: 25-32 44. Cullinane M, Gray AJ, Hargraves CM, Lansdown M, Martin IC, Schubert M (2003) The 2003 Report of the National Confidential Enquiry into Peri-Operative Deaths NCEPOD, London 45. Pearse RM, Harrison DA,James P, et al (2006) Identification and characterisation of the highrisk surgical population in the United Kingdom. Crit Care 10:R81 46. Older P, Smith R, Courtney P, Hone R (1993) Preoperative evaluation of cardiac failure and ischemia in elderly patients by cardiopulmonary exercise testing. Chest 104:701-704 47. Hlatky MA, Boineau RE, Higginbotham MB, et al (1989) A brief self-administered question naire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 64:651-654 48. Girish M, Trayner E [r, Dammann 0, Pinto-Plata V, Celli B (2001) Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery. Chest 120:1147 -1151 49. Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM, Bennett ED (2005) Changes in central venous saturation after major surgery, and association with outcome. Crit Care 9: R694-699 SO. Maillet JM, Le Besnerais P, Cantoni M, et al (2003) Frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery Chest 123:1361-1366

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The Influence of Packed Red Blood Cell Transfusion on Tissue Oxygenation S. SUTTNER and

J.

BOLDT

Introduction: Indications for Perioperative Transfusions The Physiologic Transfusion Trigger for Red Blood Cells In recent years, the role of packed red blood cell (RBC) transfusion has come under intense scrutiny, with an expanding body of literature indicating that the risks of such therapy may be greater than , and the benefits less than, what has been traditionally believed. However, transfusion of packed RBCs is a potentially life-saving therapy in cases of major bleeding and remains an essential and frequently performed medical intervention. The American Association of Blood Banks reports that in 2004 nearly 29 million units of blood components were transfused, including 14 million units of packed RBCs [1]. Up to 80 % of these transfusions are administered to surgical and critically ill patients. With an aging population and further advances in medical treatments and procedures requiring blood transfusions, the demand for blood continues to increase. Despite the widespread use of packed RBC transfusions for a variety of reasons, the number of indications in which such transfusions are appropriate is quite limited. In an analysis of nine studies assessing the appropriateness of RBC transfusions, inappropriate rates of 18-55 % were reported [2]. However, substantial variation was found in the criteria for an appropriate or an inappropriate transfusion. In an effort to reduce the perceived overtransfusion of blood and blood components, guidelines for blood transfusion have been issued by several organizations [3-6] ( Table 1). These guidelines recommend that packed RBCs should be administered only when the hemoglobin (Hb) concentration is low (e.g., less than 6 g/dl in a young, healthy patient), especially when the anemia is acute. RBCs are usually unnecessary when the Hb concentration is more than 10 g/dl. The determination of whether intermediate Hb concentrations (i.e., 6 -10 g/dl) justify or require packed RBC transfusion should be based on any ongoing indication of organ ischemia, potential or actual ongoing bleeding (rate and magnitude), the patient's intravascular volume status, and the patient's risk factors for complications of inadeTable 1. American Society of Anesthesiology Guidelines for Transfusion of Red Blood Cells in Adults [6]

• Transfusion for patients with hemoglobin level of less than 6 g/dl is indicated, especially when anemia is acute • Transfusion is rarely indicated when the hemoglobin concentration is greater than 10 g/dl • For stable patients with hemoglobin level between 6 g/dl and 10 g/dl, the benefit of transfusion is unclear • The use of a single hemoglobin "trigger" for all patients is not recommended • Indications for transfusion of autologous RBCs may be more liberal than for allogeneic RBCs

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quate oxygenation [6]. The use of a single arbitrary Hb based transfusion trigger for all patients (e.g., Hb of 10 g1dl) is not recommended [6]. Useful transfusion triggers should rather consider signs of inadequate tissue oxygenation that may occur at various Hb concentrations depending on the patient's underlying disease(s). These 'physiological' transfusion triggers can be based on signs and symptoms of impaired global or regional tissue oxygenation. However, before transfusion decisions based on physiological transfusion triggers are made, maintenance of strict normovolemia by the use of crystalloid and colloids has to be ensured [7].

Physiology of Oxygen Transport Knowledge of the basic principles of oxygen transport and the physiology of anemia is a prerequisite for meaningful RBC transfusion decisions [8]. The main function of RBCs is oxygen transport from the atmosphere to the mitochondria. The transport of oxygen from the atmosphere to the cell involves two biophysical principles : Convection (i.e., bulk flow of blood) and diffusion (i.e., random movement of oxygen molecules). As blood passes through the lung, oxygen diffuses down its partial pressure gradient from the alveoli into the bloodstream where it combines with Hb in the RBCs and is carried by convective transport through the heart and large and small arteries to the microcirculatory vessels where the partial pressure gradient favors diffusion from the RBC to the tissue [9]. The microcirculation is usually defined as that part of the vascular tree comprising blood vessels smaller than 100 urn, including arterioles, capillaries, and venules. Its many branches, which expand the oxygen exchange area, and its close proximity to the cells, make the microcirculation ideal for oxygen exchange with surrounding tissue. Within individual organs, a heterogeneous distribution of blood flow, and thus RBC supply, is physiological [9, 10]. Blood flow heterogeneity continues down the arteriolar tree into the microcircu lation, where the distribution of flow is actively regulated by changes in vascular resistance and perfusion pressures which originate primarily from arterioles. Even changes in the resistance of the smallest, terminal arterioles may be followed by substantial redistribution of RBC flow within the capillary networks [9, 10]. Blood flow within the microcirculation is also subject to passive control, for example, when altered by rheologic influences and network geometry ( Table 2). Table 2. Factors influencing the microcirculation • • • • • • • •

Global oxygen transport Hematocrit Endothelial function Blood viscosity Vascular sclerosis Tissue temperature Mediators of inflam mation Activation of leukocytes

The Influence of Packed Red Blood Cell Transfusion on Tissue Oxygenation

The Concept of Critical Oxygen Delivery/Critical Hb Level The amount of oxygen available to the cell is determined by the adequacy of cardiorespiratory function, Hb concentration, the distribution of cardiac output to the various organs, and the regulation of the microcirculation. The amount of oxygen delivered, either to the whole body or to specific organs, is the product of blood flow and arterial oxygen content. For the whole body, oxygen delivery (D0 2) is the product of total blood flow or cardiac output and arterial oxygen content (Ca0 2) . The Ca0 2 is expressed by the following formula : Ca0 2 = (Hb . 1.39 . Sa0 2) + (0.0031 . Pa0 2) where Hb is the hemoglobin concentration (in g/dL), 1.39 is the oxygen carrying capacity of Hb (in ml O/gram Hb), Sa0 2 denotes arterial oxygen saturation, and Pa0 2 denotes arterial partial pressure of oxygen; 0.0031 is the solubility coefficient of oxygen in plasma at 37°C (mL 02/mmHg p02) ' In terms of Ca02' more than 99 % of O2 is transported by Hb and only a negligible amount is dissolved in the plasma fraction at ambient Pa0 2 in room air. Thus, under most circumstances, D0 2 can be calculated by D02 = CaD2 • cardiac output It is important to note that blood flow, which is one of the key determinants of D0 2,

is regulated not only at the level of the central circulation (as represented by cardiac output in the formula above), but also at the regional level and the microcirculatory level. The latter is primarily determined by the autonomic control of vascular tone and local microvascular responses and to the degree of affinity of the Hb molecule for oxygen. Under physiological conditions D0 2 exceeds V0 2 by a factor of up to 4, resulting in an oxygen extraction ratio (02ER) of 20-30 %. Consequently, even a marked isolated decrease in Hb concentration, with all other determinants remaining constant, will still result in sufficient D0 2 to meet tissue oxygen requirements. However, below a critical threshold of Hb concentration there will be a decrease not only in D0 2 but also in V0 2. This relationship between V0 2 and D0 2 is referred to as the concept of critical D0 2 or critical Hb level. Above the critical DO/critical Hb level, tissue oxygenation is sufficient as represented by a constant V0 2 which is thus 'D0 2 independent'. In contrast, below the critical D0 2/critical Hb level oxygen demands are no longer met, resulting in a decrease in V0 2. This state is characterized by a 'V0 2-D02 dependency' and the development of tissue hypoxia [11, 12]. This whole body shift to anaerobic metabolism might be the absolute indicator for RBC transfusion. From a physiological point of view, the expected benefit of RBC transfusion at this threshold would be an increase in V0 2 and D0 2 and prevention of irreversible cellular injury. The point of systemic critical D0 2/critical Hb level, however, may vary according to the individual patient's ability to tolerate and compensate for anemia [7, 8, 11]. Factors affecting a patient's response to decreased hemoglobin concentration, and thus the factors that should influence the physician's decision to transfuse, include the patient's cardiopulmonary reserve (determined by the presence or absence of cardiac and/or pulmonary disease), the rate and magnitude of blood loss (actual and anticipated), oxygen consumption (affected by body temperature, drugs/anesthetics, sepsis, muscular activity), and atherosclerotic disease (cerebrovascular, cardiovascular, peripheral, renal) [6].

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The critical Hb level cannot be defined in a generally applicable way, but it is intriguing to learn that even extreme acute normovolemic hemodilution (ANH) to a Hb concentration of 5 g/dl was well tolerated in otherwise healthy humans [13]. No signs of compromised D02, such as a decrease in V0 2 or an increase in lactate, were observed, not even after further compromising D02 by acute ~-blockade suggesting that a Hb concentration of 5 g/dl was not yet critical [13]. The critical Hb level can only be defined for certain organs, specific situations and disease states, and particular age groups [14]. Anemia is believed to be less well tolerated in older patients, in the critically ill, and in patients with clinical conditions such as coronary, cerebrovascular, or respiratory disease. Patients with coexisting cardiac diseases may be at particular risk of developing inadequate oxygenation and cardiac complications at low hemoglobin levels even when normovolemic. Anesthetized patients with severe coronary artery disease tolerated acute normovolemic hemodilution to a Hb concentration of 9.9 ± 0.2 gldl without evidence of myocardial ischemia [IS]. Increases in cardiac output and oxygen extraction completely compensated for the decrease in arterial oxygen content due to acute normovolemic hemodilution. However, the exact Hb level associated with myocardial ischemia is variable and depends on the degree of coronary stenosis and whether there is one- or multivessel coronary artery disease [14, 15]. Elderly patients (65-88 yr of age) without known cardiac disease tolerate moderate acute normovolemic hemodilution to a mean Hb concentration of 8.8 g/dl well and were capable of fully compensating the decrease in arterial oxygen content by increases in cardiac output and oxygen extraction [16]. None of these patients was hemodynamically unstable or showed evidence of myocardial ischemia before retransfusion. Thus, hemodynamic tolerance of low Hb levels was well preserved in elderly patients without clinical evidence of cardiac disease. However, the above results do not exclude the possibility that tissue ischemia could develop earlier in some areas due to a higher regional critical D0 2, especially in acute blood loss and when hypovolemia complicates anemia.

Measuring Tissue Oxygenation and Microcirculatory Flow As mentioned earlier, assessment of the adequacy of oxygen supply to organs and tissues is essential to guide transfusion decisions. Whether RBC transfusion actually restores tissue oxygenation is difficult to determine due to the lack of appropriate clinical monitoring techniques [17, 18]. Monitoring of tissue oxygenation and organ function in the clinical setting is largely based on measuring traditional variables of resuscitation, such as global hemodynamics, pulse oximetry, capillary refill, urine output, or indirect biochemical markers. However, these parameters remain insensitive indicators of dysoxia and are considered to be poor surrogates for the oxygen availability at tissue levels, since tissue oxygenation is determined by the net balance between cellular oxygen supply and oxygen demand [18, 19]. Furthermore, the fact that continuing regional tissue dysoxia can persist despite the presence of an apparently normal adequate systemic blood flow, pressure, and arterial oxygen content, highlights the need for specific indices of oxygenation at tissue level [20]. Methodologies to detect tissue dysoxia and oxygen debt can be grossly subdivided into two groups: techniques directed at the assessment of oxygenation at the systemic level, and monitoring techniques for measurements at the organ level ( Table 3).

The Influence of Packed Red Blood Cell Transfusion on Tissue Oxygenation

Table 3. Clinical techniques to monitor tissue oxygenation and microcirculatory flow

Monitor

Method

Variables

Global! regional

Invasive/ noninvasive

Systemic oxygenation

Pulmonary artery catheter

VOiD0 2/02ER

global

Invasive

Mixed venous O2 saturation

Pulmonary artery catheter blood gas analyses

Sv0 2

global

Invasive

Lactate

Laboratory - enzymatic testing

Lactate

global

Invasive

Gastrointestinal tonometry

Measurement of PC0 2 in an PrCOiPC02gap pHi air- or saline-filled balloon

regional

Minimally invasive

Near-infrared spectroscopy

Absorbance analysis of near- Hb/0 2Hb cytochrome infrared light aa,

regional

Non-invasive

Oxygen electrodes

Polarographic probes

P02

regional

Minimally invasive

Orthogonal polarizetion spectral imaging

Scattered polarized light

Diameter of vessels Velocity of red blood cells Functional capillary density

regional

Non-invasive

V0 2: oxygen consumption; D0 2: oxygen delivery; 02ER: oxygen extraction ratio; Sv02: mixed venous oxygen saturation; PrC02: regional gastric CO 2 tension; PC0 2gap: arterial-to-intramucosal PC0 2 difference; pHi: gastric intramucosal pH; Hb/0 2Hb: deoxygenated/oxygenated Hb; P02: partial pressure of oxygen

002' V02, 02ER

The relationship between D0 2 and V0 2can be used to assess the adequacy of tissue oxygenation. However, measurement of D0 2 and V0 2 requires right heart catheterization to measure cardiac output or is technically demanding and expensive if metabolic carts are used to measure V0 2 • Moreover, the interpretation of D0 2/V0 2 relationships has been criticized because of mathematical coupling [21]. Sv02 Mixed venous oxygen saturation (Sv0 2) can be readily measured from blood gas analysis derived at the bedside either intermittently, or continuously with fiberoptic pulmonary artery catheters. Since the pulmonary artery carries blood from all vascular beds of the organism, mixed venous blood may represent the amount of oxygen in the systemic circulation that is left after passage through the tissues. Thus, Sv0 2 might serve as a parameter of global oxygenation. Determinants of SV02 are Sa0 2, systemic V0 2, cardiac output, and Hb concentration, with Sv0 2 = Sa0 2 - V0 2 / 1.39 . Hb . cardiac output Accordingly, an increase in V0 2 and a decrease in Hb, cardiac output and arterial oxygenation will result in a decrease in Sv0 2. Interpretation of Sv0 2 values might be difficult in conditions where DOz/V0 2 relationships are altered. For example, in sepsis , arterial-venous microcirculatory shunting may increase Sv0 2, thus suggest-

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ing adequate tissue oxygenation, while regional tissue dysoxia is actually present [22]. Arterial Lactate

Lactate is formed from pyruvate by the cytosolic enzyme, lactate dehydrogenase, and lactate concentrations > 2 mmolll are generally considered as a biochemical indicator of inadequate oxygenation [23]. Circulatory failure and impaired tissue perfusion is the most common cause of lactic acidosis in intensive care patients. However, a number of mechanisms other than impaired tissue oxygenation may cause an increase in blood lactate, including activation of glycolysis, reduced pyruvate dehydrogenase activity, or liver failure [24]. Therefore, understanding the complex process of tissue lactate production and utilization is important to understand the usefulness and potential limitations of monitoring blood lactate levels. Measurement of global DOz, VOz, OzER, SvOz, and blood lactate may all provide means of assessing global oxygenation . They are not sufficient parameters, however, to indicate abnormalities in regional perfusion and oxygen balance . Gastric Mucosal Tonometry

The introduction of gastric or sigmoid mucosal tonometry for the measurement of intraluminal carbon dioxide (COz) enabled the clinician to change focus from global oxygen transport to regional tissue oxygenation. Measuring the regional gastric CO2 tension (PC0 2) photometrically with infrared spectrometry via a special gastric tube and calculating the arterial-to-intramucosal PCO z difference (PC0 2gap) and gastric intramucosal pH (pHi) provide valuable information about splanchnic perfusion [25]. Thus, tonometer measurements might provide an insight in a region of the body that is among the first to develop an inadequacy of tissue oxygenation in circulatory shock and the last to be restored by resuscitation [26]. Gastrointestinal tonometry has been evaluated in various situations during surgery and intensive care [26, 27]. As a result, it has been shown that prolonged acidosis in the gastric mucosa might be a sensitive but not specific predictor of outcome in critically ill patients [26, 27]. NIRS

Near-infrared spectroscopy (NIRS) is a continuous non-invasive method that uses the principles of light transmission and absorption to determine tissue oxygen saturation. NIRS measures oxygenated and deoxygenated Hb as well as the redox state of cytochrome aa3 (cyt aa3) as an average value of arterial, venous, and capillary blood according to the law of Lambert-Beer. Cyt aa3, the terminal cytochrome of the respiratory chain, is responsible for approximately 90 % of cellular oxygen consumption through oxidative phosphorylation [28]. Since the redox state of cyt aa3 is primarily determined by available oxygen, a decrease in cellular D0 2 results in a reduction of oxidative phosphorylation and a decreased oxidation level of cyt aa3. Monitoring the redox state of cyt aa3 might, therefore, be a key indicator of impaired cellular oxidative metabolism and tissue dysoxia. Although NIRS may be applied to almost any organ, it has mainly been used in studies investigating cerebral or muscle oxygenation after various hypoxic injuries [28, 29]. The main limitation of NIRS in the clinical setting is the inability to make quantitative measurements because of the con-

The Influence of Packed Red Blood (ell Transfusion on Tissue Oxygenation

tamination of light by scatter and absorption [28, 29]. Moreover, normal values for regional tissue oxygen saturation in organs like the brain or skeletal muscle have not yet been established.

Tissue Oxygen Tensions Monitoring tissue oxygen tensions for clinical use has become feasible with the development of miniaturized implantable Clark electrodes. These polarographic oxygen sensors enable us to measure oxygen partial pressure in tissues (Pti0 2) , organs , and body fluids directly and continuously. Pti0 2 values correspond to oxygen availability on a cellular level and provide information about oxygen supply and utilization in specific tissue beds [20]. Pti0 2 has been measured successfully in intensive care patients as well as during surgical procedures [30-35]. Studies on the critical threshold of Pti0 2 after traumatic brain injury showed that the absolute level of oxygenation in the cerebral white matter was a reliable predictor of neurological outcome [31,32] . However, organs like the brain are not readily accessible and thus not suitable for clinical routine monitoring. Monitoring muscle P0 2 might provide an early and reliable indicator of stagnant blood flow and tissue dysoxia. Moreover, it is easily accessible and reacts to hemorrhage, resuscitation, and shock on a similar time scale to that of the gastrointestinal tract, as has been shown clinically and in experimental studies [34, 35]. Limiting factors in the use of polarographic oxygen probes are the dependence of electrode currents on tissue temperature, errors in Pti0 2 readings due to tissue trauma and edema by electrode insertion, or intravascular misplacement of the oxygen sensors. OPS

Orthogonal polarization spectral (OPS) imaging is a newly developed non-invasive technique that allows direct visualization of the microcirculation [36]. Polarized light is used to illuminate the area of interest. The light is scattered by the tissue and collected by the objective lens. A polarization filter or analyzer, oriented orthogonal to the initial plane of the illumination light, is placed in front of the imaging camera, eliminating the reflected light scattered at or near the surface of the tissue that retain s its original polarization or glare. Depolarized light scattered deeper within the tissues passes through the analyzer. High contrast images of the microcirculation are formed by the absorbing structures of blood vessels that , for example, are close to the surface and are illuminated by the depolarized light coming from deeper structures. Because of its specific characteristics, this device is particularly convenient for studying tissues protected by a thin epithelial layer, such as mucosal surfaces. In critically ill patients, the sublingual area is the most easily investigated mucosal surface. Using OPS imaging in the sublingual area of patients in shock states, several investigators have recently observed that microcirculatory alterations are frequent in critically ill patients [37, 38]. Compared with healthy volunteers, patients with cardiogenic and septic shock presented a decrease in capillary density and a decrease in the proportion of perfused capillaries [37]. Current studies are ongoing to determine the effects of various interventions on the microcirculation in humans. The limitations of the OPS imaging technique include movement artifacts and the presence of various secretions such as saliva and blood. Because OPS imaging techniques use light absorbance by Hb, vessels can be visualized only when these are

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s. Suttner and J. Boldt filled by RBCs. In addition, patients need to be cooperative or adequately sedated to prevent them from biting the device. A major problem with using monitors of regional tissue oxygenation in clinical practice is that normal and critically abnormal values have not been established. Moreover, heterogeneity in microvascular blood flow and oxygenation, which exists between organs as well as at the level of each organ, may further increase during shock, sepsis, or other states of critical illness. Consequently, a common dysoxic threshold in vitally important organs such as the brain, the myocardium, the gastrointestinal tract, or any given tissue remains unclear.

Effect of RBC Transfusion on Tissue Oxygenation in Experimental and Clinical Studies Clinical and animal studies have reported contradictory findings about the oxygenation capacity of stored RBCs [32,39-45] ( Table 4). In a recent clinical study, Suttner et al. used systemic oxygen transport variables and skeletal muscle POz to assess global and regional oxygenation status of 51 volume-resuscitated, mechanically ventilated patients after elective coronary artery bypass grafting following transfusion of one or two units of allogeneic RBCs [30]. The authors further tested the hypothesis that increasing the oxygen-carrying capacity by ventilation with 100 % oxygen would be equally effective or even superior to RBC transfusion in improving tissue oxygenation in the immediate postoperative period. Tissue POz was measured conTable 4. Clinical studies evaluating the effect of blood transfusion on tissue oxygenation Author

Patient group

No. of Tissue O2 patients monitor

Leal-Noval [32]

Hemodynamically stable, non-bleeding patients with severe traumatic brain injury

60

Brain P0 2

Transfusion of 1- 2 units of RBCs improved cerebral P02

Marik [42]

Critically ill patients with sepsis

23

Gastric rnucosal tonometry

Transfusion of 3 units of RBCs led to a decrease of pHi

Sakr [46]

Critically ill patients with severe sepsis

35

OPS

Transfusion 1- 2 units of RBCs had no effect on microcirculatory flow

Smith [45]

Volume-resuscitated patients with subarachnoid hernorrhage

35

Brain P0 2

Transfusion of RBCs improved cerebral P0 2

Silverman [41]

Critically ill patients with sepsis

21

Gastric mucosal tonometry

Transfusion of 2 units of RBCs had no effect on pHi

Suttner [30]

Volume-resuscitated patients after elective coronary artery bypass grafting

51

Skeletal rnusele P0 2

Transfusion of 2 units of RBCs had no effect on skeletal rnusele P0 2

Walsh [44]

Critically ill patients with significant organ failure, but no evidence of hemorrhage

22

Gastric mucosal tonometry

Transfusion of 2 units of RBCs had no effect on global and regional oxygenation

OPS: Orthogonal polarization spectral imaging; pHi: intramucosal pH

Effect of blood transfusion

The Influence of Packed Red Blood Cell Transfusion on Tissue Oxygenation

tinuously using implantable polarographic microprobes. Transfusion of stored allogeneic blood was only efficacious in improving systemic DOz, whereas VOz and skeletal muscle POz remained unchanged. Augmentation of blood Oz content by 100 % Oz ventilation also failed to increase VOz, but was followed by an immediate increase in systemic DOz and skeletal muscle POz. This improved oxygenation status was due an increase in convective oxygen transport with an increased driving gradient for diffusion of plasma-dissolved oxygen into the tissues. However, the study was restricted to hemodynamically stable, low-risk patients without excessive bleeding. Therefore, the results of this study may not be extended to patients who exhibit a pathological oxygen supply dependency or have perfusion failure (e.g., circulatory or septic shock) . Other clinical investigations used gastric tonometry to study the effects of transfusions on pHi [41,42,44] . In these studies, a large inter individual variability in the response to RBC transfusions was observed. Silverman and Tuma compared the effectiveness of dobutamine administration with the effectiveness of transfusion in increasing pHi [41]. Although dobutamine administration significantly increased a low baseline pHi, transfusion with packed RBCs failed to have any effect on pHi in the patients evaluated. A study by Marik and Sibbald also failed to show a beneficial effect of RBC transfusion on measured systemic oxygen uptake and pHi in septic patients with elevated lactate levels [42]. On retrospective analysis these authors found a decrease in pHi after transfusion of three RBC units that were stored for more than 15 days, reflecting an inadequacy of splanchnic oxygenation . They concluded that poorly deformable cells cause micro circulatory occlusions, and further postulated that these occlusions lead to tissue ischemia. Thus, the age of RBC units may be an important factor influencing the efficacy of RBC transfusion to improve tissue oxygenation . Long-term blood storage decreases RBC concentrations of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG), resulting in decreased erythrocyte membrane deform ability and increased affinity of Hb for oxygen [43]. These 'storage' effects may interfere with the ability of RBCs to transport and unload oxygen at the capillary level [43]. Therefore, it has been proposed that fresh rather than stored erythrocytes should be transfused. Contradictory results were reported by Walsh et al., who evaluated changes in tonometric indices of gastric mucosal oxygenation and global oxygenation parameters in 22 ventilated critically ill patients with significant organ failure, but no evidence of hemorrhage [44]. The patients received, in a doubleblind, randomized fashion, two units of leukodepleted RBCs that were either fresh (stored < 5 days) or had a prolonged storage time (> 20 days). In this study, the authors did not detect any adverse consequence s on pHi or changes in the arterialgastric mucosal COzgap with a storage time > 20 days as compared to patients receiving RBCs with a storage time < 5 days. Possible explanations for the differences in results are that the patients in the study by Marik and Sibbald were at an earlier stage of sepsis and more oxygen supply dependent, or that Walsh et al. used leukodepleted RBCs and transfused only two RBC units, whereas Marik and Sibbald used three. Recently, Weiskopf et al. showed that transfusion of erythrocytes stored for less than 5 hours ("fresh") or more than 3 weeks ("old") to increase hemoglobin from 5 to 7 gldl equally reversed neuropsychological deficits in unmedicated healthy volunteers [47]. This equal efficacy of fresh blood and blood stored for 23 days was present despite significant decreases in 2,3-DPG and P50, the POz at pH 7.4 and PCOz 40 mmHg at which the oxyhemoglobin saturation is 50 %. This study strongly indicates that "old" and "fresh" RBCs are equally efficacious in restoring inadequate oxygenation .

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Only two clinical stud ies have reported beneficial effects of RBC transfusion on tissue oxygenation [41,45]. In a prospective observational study, Smith et al. continuously monitored local brain tissue P0 2 during transfusion of allogeneic RBC units to volume-resuscitated patients with subarachnoid hemorrhage or traumatic brain injury, without cardiac disease [45]. An increase in brain tissue P0 2 was observed in 26 of the 35 patients (74 %). The mean increase in brain tissue P0 2 for all patients was 3.2 ± 8.8 mm Hg, a 15 % change from baseline. This mean increase appeared to be independent of cerebral perfusion pressure, Hb oxygen saturation, and inspiratory fraction of oxygen. In nine patients, brain tissue P0 2 decreased after RBC transfusion. Another prospective observational study investigated the long-term influence of erythrocyte transfusion on cerebral oxygenation in hemodynamically stable, non bleeding patients with severe traumatic brain injury and monitored through intracranial pressure and brain tissue P0 2 catheters [41]. Transfusion of 1- 2 units of RBCs was associated with a variable increase in brain tissue P0 2 during a 6-h period, with a peak at 3 h in 78 % of the patients. Low baseline brain tissue P0 2 « 15 mmHg) defined those patients who benefited the most from erythrocyte transfusion.

Conclusion 1. Transfusion of allogeneic packed RBCs is a frequently performed and potentially

life-saving therapy. 2. RBC transfusions are indicated only to avoid or to treat tissue hypoxia. 3. Whether RBC transfusion actually restores tissue oxygenation is difficult to determine due to the lack of appropriate clinical monitoring techniques. 4. Clinical and animal studies report contradictory findings about the oxygenation capacity of stored RBCs. 5. Including measures of tissue oxygenation into transfusion decisions may enable a more individual use of allogeneic packed RBCs in specific situations. References 1. AABB. About blood and cellular therapies . At: www.aabb.orglContent/AbouCBlood/FAQ/

bloodfaq .htm. Accessed December 2007 2. Hasley PB, Lave JR, Kapoor WN (1994) The necessary and the unnecessary transfusion: A critical review of reported appropriateness rates and criteria for red cell transfusions. Transfusion 34:110-115 3. Office of Medical Applications of Research, National Institutes of Health (1988) Perioperative red blood cell transfusion. JAMA 260:2700-2703 4. American College of Physicians (1992) Practice strategies for elective red blood cell transfusion. Ann Intern Med 116:403- 406 5. Ferraris VA, Ferraris SP, Saha SP, et al (2007) Perioperative blood transfusion and blood conservation in cardiac surgery : the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg 83:S27 - 86 6. American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies (2006) Practice guidelines for perioperative blood transfusion and adjuvant therapie s: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 105:198-208 7. Madjdpour C, Spahn DR, Weiskopf RB (2006) Anemia and perioperative red blood cell tr ansfusion: a matter of tolerance. Crit Care Med 34:S102- 108

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S. Suttner and J. Boldt 34. McKinley BA, Ware DN, Marvin RG, Moore FA (1998) Skeletal muscle pH, pC0 2, and p02 during resuscitation of severe hemorrhagic shock. J Trauma 45:633- 636 35. McKinley BA, Butler BD (1999) Comparison of skeletal muscle P0 2' pC0 2, and pH with gastric tonometric pC0 2 and pH in hemorrhagic shock. Crit Care Med 27:1869-1877 36. Groner W, Winkelman JW, Harris AG, et al (2000) Orthogonal polarization spectral imaging: A new method for study of the microcirculation. Nat Med 5:1209-1213 37. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166:98-104 38. Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL (2004) Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 32:1825-1831 39. Van der Linden P, De Hert S, Belisle S, et al (2001) Comparative effects of red blood cell transfusion and increasing blood flow on tissue oxygenation in supply-dependent conditions. Am J Respir Crit Care Med 163:1605-1608 40. Fitzgerald RD, Martin CM, Dietz GE, et al (1997) Transfusing red blood cells stored in citrate phosphate dextrose adenine-l for 28 days fails to improve tissue oxygenation in rats. Crit Care Med 25:726- 732 41. Silverman H, Tuma P (1992) Gastric tonometry in patients with sepsis: Effects of dobutamine infusions and packed red blood cell transfusions. Chest 102:184- 188 42. Marik PE, Sibbald WJ (1993) Effect of stored -blood transfusion on oxygen delivery in patients with sepsis. JAMA 269:3024 - 3029 43. Chin-Yee I, Arya N, D'Almeida M (1997) The red cell storage lesion and its implications for transfusion. Transfus Sci 18:447 -458 44. Walsh TS, McArdle F, McLellan SA, et al (2004) Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients? Crit Care Med 32:364-371 45. Smith MJ, Stiefel MF, Magge Set al (2005) Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med 33: 1104-1108 46. Sakr Y, Chierego M, Piagnerelli M, et al (2007) Microvascular response to red blood cell transfusion in patients with severe sepsis. Crit Care Med 35:1639-1644 47. Weiskopf RB, Feiner J, Hopf H, et al (2006) Fresh blood and age stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans. Anesthesiology 104:911-920

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Recent Advancements in Microcirculatory Image Acquisition and Analysis R.

BEZEMER,

M.

KHALILZADA,

and C.

INCE

Introduction Since the introduction of orthogonal polarization spectral (OPS) imaging by Slaaf et al. and its implementation into a clinically-applicable hand-held microscope [1, 2], clinical microcirculation investigations have been carried out in various clinical scenario s on exposed organ and tissue surfaces [3-9]. OPS imaging has proved to be a useful modality to predict patient outcome , during disease and therapy, especially in intensive care and emergency medicine [4,9] . OPS imaging has made an important clinical impact by assessment of the sublingual microcirculation during sepsis, shock, and resuscitation [10]. OPS imaging can be applied on numerous sites, ranging from the nailfold and sublingual microcirculation to the brain microcirculation [3,11]. Very recently, OPS imaging was used to reveal microcirculatory alterations in malaria patients [12]. For this purpose, the investigators focused on the rectal microcirculation, since bruxism, a common feature of cerebral malaria, prevented oral introduction of the OPS probe. Additional applications of OPS imaging include wound healing and cancer and tumor development [11, 13]. Studies by several medical centers have shown that OPS observation of sublingual microcirculatory alterations (i.e., particularly changes in capillary perfusion) provided more sensitive information about patient outcome than conventional clinical parameters, such as systemic hemodynamic and oxygen derived variables [4,6, 7, 9, 10]. In OPS imaging, light from an external light source is guided to the OPS device by an optical fiber [1, 2]. The light, collimated by a lens, is filtered at 548 nm and linearly polarized by the first polarizer. The illumination light is reflected by a half pass mirror to provide dark field illumination. The reflected and backscattered light travels through the hole in the mirror to the second polarizer, termed the analyzer, with orthogonal orientation to the first polarizer. The analyzer blocks the reflected light and transmits the backscattered light, which is imaged onto a charge-coupled device (CCD) camera. Despite the major success of OPS imaging, the technique still has several weaknesses [14]. These include the need for an external high power light source, since a large portion of the initial light is blocked by the first polarizer ( Fig. la). Another drawback is the remaining interference of internal reflections by depolarizing optical components (i.e., lenses and filters) with the microcirculatory image. Additionally, the continuous illumination limits the resolvability of individual, flowing red blood cells (RBCs) as a result of smearing of moving features over video frames. Besides technical shortcomings, the complex video sequences of moving cells in a highly heterogeneous microcirculatory network require analysis to quantify the flow patterns and morphology so that comparison between different conditions and

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OPSdevice

SDFdevice

a

Fig. 1. aThe orthogonal polarization spectral (OPS) imaging device. Light from an external light source is guided to the OPS device by an optical fiber. The light, collimated by a lens, is filtered at 548 nm and linearly polarized by the first polarizer. The illumination light is reflected by a half pass mirror to provide dark field illumination. The reflected and backscattered light travel through the hole in the mirror to the second polarizer, termed the analyzer, with orthogonal orientation to the first polarizer. The analyzer blocks the reflected light and transmits the backscattered light, which is imaged onto a (CD camera. bThe sidestream dark field (SDF) imaging device. Light emitting diodes (LEDs) provide stroboscopic sidestream dark field illumination at 530 nm. The lens system in the core of the light guide is optically isolated from the illuminating outer LED ring, to prevent the microcirculatory image from contamination by tissue surface reflections.

patients can be made. To this end different scoring systems to (semi-)quantify microcirculatory morphology and perfusion have been developed. This chapter discusses the most recent advances in microcirculatory imaging, including the introduction and validation of a novel microcirculatory imaging modality, called sidestream dark field (SDF) imaging [10, 14], the development of specialized software to analyze OPS and SDF images for functional microcirculatory geometry and RBC velocities, and a consensus on microcirculatory image acquisition and analysis to standardize OPS- and SDF-mediated assessment of microcirculatory alterations and functioning. Furthermore, additional applications of OPS and SDF imaging that are currently under development will be discussed and directions for future research suggested.

Sidestream Dark Field (SDF) Imaging Driven by the success of OPS imaging and the remaining technical shortcomings it has, we developed a novel microcirculatory imaging modality, which we have termed "Sidestream Dark Field" imaging [10, 14]. For SDF imaging, light emitting diodes (LEDs) are employed to provide stroboscopic sidestream dark field illumina-

Recent Advancements in Microcirculatory Image Acquisition and Analysis

tion (Fig. 1b). The lens system in the core of the light guide is optically isolated from the illuminating outer LED ring, preventing the microcirculatory image from contamination by tissue surface reflections. The SDF probe, consisting of both the LED ring and the light guide, can be placed on organ and tissue surfaces when covered with a sterilized disposable cap. The LEDs emit at a central wavelength of 530 nm, chosen to correspond to an isosbestic point in the absorption spectra of deoxy- and oxyhemoglobin for achieving optimal optical absorption by the hemoglobin-containing RBCs, independent of the oxygenation state. Pulsed illumination in synchrony with the CCD frame rate enables intravital stroboscopy to (partially) prevent smearing of flowing RBCs, which improves imaging of the granular nature of flowing cells in the larger vessels, thereby allowing more accurate flow determination. In a recent study [14], SDF imaging was validated in comparison to OPS imaging. For this purpose, equal nailfold and sublingual microcirculatory areas were imaged at the same location using both techniques. Measured nailfold capillary diameters and RBC velocities gave equal quantitative results when measured by the different techniques . Image quality (separated into venular and capillary image quality) was determined employing a specially-developed image quality quantification system. Venular quality was shown to be comparable for both techniques . Capillary quality, however, was shown to be significantly better using SDF imaging with respect to OPS imaging. As can be seen in Figure 2, OPS image contrast suffers from underlying vascular (and thus light absorbing) structures, which darken the image and, thereby, lower image contrast. In addition to the superior capillary quality, SDF images also showed increased resolvability of the granular nature of flowing RBC columns in venules, compared to OPS images. These basic findings validate the use of SDF imaging for (clinical) assessment of microcirculatory geometry and blood flow velocities. Dubin et al. [8] recently employed SDF imaging to investigate the relationship between villus hypoperfusion and intramucosal acidosis during endotoxemia in sheep. These investigators imaged the microcirculation in the sublingual mucosa and the intestinal mucosa and serosa. At each imaging site, they imaged three different areas to account for the inter- and intraorgan microcirculatory flow heterogeneity. In this study, the authors showed that endotoxic shock decreased microcirculatory flow at all imaging sites and fluid resuscitation restored sublingual and serosal intestinal flow to baseline values; however, resuscitation failed to normalize mucosal

Fig. 2. Unedited orthogonal polarization spectral (OPS) a and sidestream dark field (SDF) b image of the same sublingual microcirculatory area in a human volunteer. The SDF image shows higher capillary contrast with respect to theOPS image. The OPS image contrast suffers from underlying vascular (and thus light absorbing) structures, which darken the image. Note the slight magnification difference between the two devices.

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intestinal flow. Furthermore, this study revealed that the PC0 2 gap, between the intramucosal PC0 2 (measured using a tonometer) and the arterial PC0 2 (measured using a blood gas analyzer), during shock and resuscitation correlated significantly with the percentage of perfused intestinal villi but not with superior mesenteric artery blood flow. Hence, the percentage of perfused intestinal villi was found to be the main determinant of intramucosal acidosis in this model. In addition to the comparable quantitative results for microcirculatory parameters, such as vessel diameters and RBC velocities, and the superior image quality, SDF imaging has the benefit oflow-power LED illumination, enabling battery and/or (portable) computer operation [14]. This is a major advantage in clinical settings where mains power supply needed for an external high power illumination source is not always available. Furthermore, battery operation allows microcirculatory recordings to be made in conditions such as ambulances and emergency medicine , where high mobility is of great importance.

Automated Image Analysis Once microcirculatory recordings are made, images must be (semi-)quantified to assess (alterations in) the functionality of the microcirculation to separate between health and disease and to evaluate the effects of interventions and (drug) therapy [IS]. For this purpose, several scoring systems have been developed for measurement and calculation of microcirculatory functionality determinants, such as capillary density and perfusion [4, 5, 16, 17]. To objectify microcirculatory image analysis and to minimize user input, specialized software packages have been developed. CapImage was, for a long time, the only commercially available software program for the analysis of microcirculatory images, for which there was a detailed description in the literature [18]. CapImage provides a quant itative method for the estimation of vessel diameter and length and RBC velocity [19]. However, vessel segment selection and vessel geometry determination are made manually by drawing lines in the vessels, requiring a large degree of user interaction, which is very time consuming and increases observer bias. A validation study has shown that the newer version, CapiScope, provides comparable results for vessel geometry and RBC velocities as those obtained using CapImage [20]. Although these software programs enable the semi-automated analysis of microcirculatory blood flow from consecutive images, the analysis is restricted to straight vessel segments. Recently, Dobbe et al. (unpublished data) developed a novel software package for microcirculatory analysis, called AVA (Automated Vascular Analysis). This software automatically determines vessel center lines in both straight and curved vessel segments, in order to measure vessel geometry and RBC velocities. The first step in the microcirculatory analysis procedure is image sequence stabilization using 2D crosscorrelat ion. Then, by time-averaging an image sequence, interruptions in capillaries (e.g., plasma gaps and leukocytes) are filled in, which enhances capillary geometry detection. Vessel center lines are subsequently determined by a technique previously described by Steger [21]. The vessel wall is detected at each center line pixel as the point at which the steepness in the grayscale intensity profile normal to the center line is maximal. After center line and vessel wall detect ion, the software automatically cuts vessels at bifurcations for determination of RBC velocities in separate vessel segments. The user is allowed to interact with the above mentioned segmentation process by deleting, cutting, or connecting vessel segments. The novel RBC velocity

Recent Advancements in Microcirculatory Image Acquisition and Analysis determination technique, as Dobbe et al. introduce it, maps the randomly distributed vessel center line pixels onto the equidistant intervals of the space-time diagram using linear interpolation [22]. RBC velocity can then be determined by automatic detection (based on the grayscale Hough transform [23]) or manual detection of the slope of the line structure in the space-time diagram [19]. Using this new algorithm, the software is able to (automatically) estimate the orientation and hence velocity of RBC flow. AVA was validated using video simulations of a microcirculatory network with known diameters and RBC velocities (Dobbe et al., unpublished data). The simulation movie was also analyzed with CapiScope, using the default factory settings as advised by the software. To illustrate clinical utility, sublingual SDF recordings were acquired from a healthy volunteer and from a patient during cardiac luxation in open-heart surgery (the simulation videos and sublingually-acquired SDF recordings can be downloaded from the website : www.sdfimaging.net). There was close agreement between the two software packages for vessel diameters and lengths. However, using AVA, vessel density measurements (= total vessel length [umj/field of view [f.lm 2 ]) were performed in 67 % of the time needed with CapiScope. Moreover, determining vessel diameter distribution took approximately 4 hours with CapiScope and only 10 minutes using AVA. Manual RBC velocity analysis with AVA was shown to be very accurate (i.e., a standard deviation < 4 % in the range from 2.5 to 1000 prn/s) and assessment of blood velocity in all vessels within the recording was performed in approximately 10 % of the time required using CapiScope. Automatic velocity assessment with AVA was > 95 % accurate for velocities up to 750 um/s , Additionally, validation and comparison has also shown that Capis cope seemed to overestimate relatively low blood velocities and was unable to detect velocities < 50 um/s, Dobbe et al. (unpublished data) have made the first step towards automated RBC velocity assessment in curved vessels. Compared to CapiScope, their software increases accuracy and reduces user interaction and analysis time radically. However, visual inspection of the results superimposed onto the microcirculatory images and possible interaction during selected phases in the analysis remains necessary. Future OPS and SDF research should be aimed at improving image quality (in terms of contrast and sharpness), increasing video frame rate and resolution, and reducing illumination intervals, to enhance software-based microcirculatory image analysis for vessel geometry and RBC velocity.

Consensus on Microcirculatory Image Acquisition and Analysis As mentioned in the introductory section, microcirculatory alterations may play an important role in the development of (multiple) organ failure in critically ill patients, especially in sepsis and shock. The rapid development of image acquisition technology and semiquantitative analysis scoring systems has led to great variation in image acquisition and analysis between the (medical) research centers investigating the microcirculation. This, in conjunction with the importance of the analysis-mediated conclusions on microcirculatory functioning, led to the organization of a round table conference aiming to achieve a consensus on microcirculatory image acquisition and analysis to standardize the (clinical) assessment of the microcirculation [15]. In the consensus [15] it is described that, due to the heterogeneous nature of the microcirculation, ideally five sites of an organ must be imaged and analyzed to draw

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reliable conclusions on microcirculatory functionality. The recommended optical magnification for the human sublingual microcirculation is 5x, since the heterogeneity of the microcirculation cannot be taken into account when using higher magnification. Additionally, acquisition issues might occur due to the magnification of small movement artifacts, which will result in an unstable and unanalyzable image. A very important aspect of microcirculatory image acquisition, for both OPS and SDF imaging, is prevention of the pressure artifact. Pressure on the imaged microvasculature might induce perfusion alterations and thereby lead to unreliable analysis and conclusions. All authors contributing to the round table discussion have reported that venular flow always remains unaltered and that (patho)physiologicallyinduced microcirculatory alterations occur mainly at the capillary level. Therefore, venular perfusion is a good indicator of the pressure artifact. Trzeciak et al. recently proposed a standard operating procedure for microcirculatory image acquisition, which serves as a guide to prevent the pressure artifact [4]. Briefly, the microscope (OPS or SDF device) should be advanced to the microvasculature till flow is (partially) obstructed. Then, the probe should be gently withdrawn until contact with the mucosa is lost. Finally, the probe should be advanced again to the point at which contact is regained . When analyzing microcirculatory images, one should first identify the capillary microvessels, which are vessels with a diameter < 20 Jlm (as decided in the consensus conference [15]). Geometrical and perfusion analysis will mainly be performed on capillaries, as they are the primary determinants of tissue perfusion. An important thing to realize when analyzing microcirculatory images is that software-mediated image stabilization implies a slight reduction in image size and, thus, in microvascular geometry and RBC velocities . Additionally, different display standards (e.g., NTSC and PAL) use display dimensions that probably affect the presentation of the microcirculatory image on a screen. This should be taken into account when using a scoring system worldwide. Another factor which might affect image magnification, although hard to correct for, is focus ing of the OPS and SDF devices, since both devices fine-tune the depth of focus by adjustment of the axial distance between the lens system and the CCD camera. In the consensus conference [15], three parameters were agreed upon which comprehensively describe microcirculatory alterations seen in sepsis: 1) perfused vessel density (PVD, also known as the De Backer score [16]), representing an estimate of the functional capillary density (FCD); 2) microcirculatory flow index (MFI, also known as the Boerma score [17]), giving information about the mean flow properties present; and 3), derived from the MFI calculation, the perfusion heterogeneity [4], as a crucial parameter for identifying the oxygen extracting capabilities of the tissue embedding the microcirculation. Accordingly, a homogeneously-distributed sluggish flow might be better tolerated than a heterogeneous flow/no flow distribution, even when the cumulative homogeneous flow is lower. A summary of the measurements and calculations to be performed to assess these parameters can be found in Table 1. The main advantage of the PVD score is that it accounts for most variables involved in tissue perfusion, including vascular density and proportion of perfusion. However, a disadvantage is that RBC velocity is not accounted for in continuously perfused capillaries. MFI scoring is relatively easy to perform, however, the score does not provide any information on the FCD. Additionally, the score is discontinuous: a change from 1 to 0 might have different implications than the change from 2 to I, complicating the interpretation of the MFI score. The consensus is that all indi-

Recent Advancements in Microcirculatory Image Acquisition and Analysis Table 1. Microcirculatory image analysis. Score

Imaging sites

Vascular density (VD)

Analysis grid

Measurements

Calculations

3 horizontal and 3 vertical lines

Vessel-line intersections (VLI).

VLI

TLL

Total length of analysis grid lines (TLL).

Proportion of perfused vessels (PPV)

Total number of capillaries (#T).

Perfused vessel density (PVD)

VD

100 * #C 7 #T

Number of capillaries where flow is continues (#C). VD * PPV

PPV

Microcirculatory flow index (MFI)

Flow heterogeneity index (Hetlndex)

7

3-5

4 quadrants

Value of predominant flow type in each quadrant, where value a = absent, 1 = intermittent, 2 = sluggish, and 3 = continuous flow.

4 quadrants per imaging site

All site flow velocities, including highest site flow velocity (Vhigh), lowest site flow velocity (Vlow), and the mean site flow velocity (vmean)·

Average values over all four quadrants.

(Vhigh - Vlow) 7

vmean

ces (i.e., proportion of perfused vessels [PPV], PVD, and MFI) should be measured to comprehensively describe the functional state of the microcirculation. PPV, although it does not distinguish between flow types, does provide information on flow heterogeneity within the imaged microva sculature. PVD provides an accurate estimate of the FCD. Additionally to distinguish between perfusion and non-perfusion, the MFI score, provided that flow is homogeneously distributed within the image, can differentiate between flow types and might thereby provide further information. In a recent study by Trzeciak et al., early sublingual microcirculatory perfusion derangements were studied in patients with severe sepsis/septic shock [4]. These investigators semiquantified the MFI in five imaging sites and calculated a flow heterogeneity index (Hetlndex), defined as the highest site flow velocity minus the lowest site flow velocity, divided by the mean flow velocity across all 5 sublingual sites. Septic patients had more heterogeneous flow, with respect to the control group. Moreover, non- surviving patients had a more heterogeneous flow distribution than surviving patients. Thus, flow velocity, capillary density, and flow heterogeneity might independently contribute to the risk of organ dysfunction in sepsis. Conclusively, the scoring of the microcirculation should include a vascular density index, capillary perfusion index, and a heterogeneity index; hence, the consensus advice on reporting of PPV, PDV, MFI, and HetIndex to describe microcirculatory perfusion. It must be emphasized, however, that these scoring systems have been developed and validated for identification and quantification of microcircula tory networks during sepsis and septic shock. Their use for scoring microcirculatory

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alterations during other disease states, although applicable, should be validated for each particular condition.

Microcirculatory Glycocalyx Thickness Measurement In addition to the assessment of the microcirculation, microcirculatory imaging is currently being used for identification and measurement of the thickness of the capillary glycocalyx, a physiological compartment important for endothelial function and maintaining a barrier function between the circulation and the tissue cells [24]. The endothelial glycocalyx, a negatively charged gel-like layer, composed of proteoglycans, glycosaminoglycans, glycoproteins, and glycolipids, is considered to protect the vascular wall by prevention of direct contact with flowing blood . Hence, the glycocalyx in both micro- and macrovasculature contributes to vascular homeostasis by maintaining the vascular permeability barrier, regulating the shear stress -induced release of nitric oxide (NO) and by inhibition of leukocyte and thrombocyte adhesion to the vascular wall [25- 29]. The latter is predominantly due to the fact that the endothelial glycocalyx harbors a wide array of enzymes and proteins mediating these vasculoprotective effects. An impaired or damaged glycocalyx is accompanied by a number of vascular wall alterations known to be the earliest characteristics of atherogenesis, a major cause of cardiovascular diseases [30-34] . In spite of these findings, it would be premature to claim that glycocalyx disruption is causally involved in these vascular diseases. Nevertheless, systematic glycocalyx measurements may hold promise as a diagnostic tool to estimate cardiovascular risk as well as to evaluate the impact of cardiovascular risk-lowering or even glycocalyx-restoring therapeutic interventions [35,36]. Recent investigations using OPS/SDF imaging have identified glycocalyx shedding associated with diabetes type 1 and endotoxin infusion in healthy volunteers [37, 38]. Visualization of the glycocalyx plays a prominent part in proving the causality of this vasculoprotective paradigm. Various microscopic techniques have been used to visualize the endothelial glycocalyx, such as conventional electron microscopy and intravital microscopy [39, 40]. Using OPS imaging of the sublingual microcirculation, estimations of individual capillary glycocalyx dimensions have been obtained [41]. Currently, sublingual glycocalyx measurements are being performed clinically using SDF imaging, which allows more detailed visualization of the sublingual microcirculation and higher resolution of leukocytes with respect to OPS imaging. Provided that leukocytes are sufficiently stiff to (temporarily) damage the endothelial glycocalyx during their passage in small capillaries (i.e., < 10 11m), while the glycocalyx in turn is stiff enough to deform RBCs, the RBC column width before and after leukocyte passage can be used to estimate glycocalyx thickness; such an estimation is shown in Figure 3. First, it is important to distinguish leukocytes from plasma gaps, which can be done by following the leukocyte/plasma gap to a capillary-venule junction ( Fig. 3a-3d). At this junction, leukocytes will tend to roll against the venular wall, while plasma gaps will dissolve in the larger blood stream ( Fig. 3d). Once an image is captured from before and after the leukocyte passage, an estimation of the glycocalyx thickness can be made, by subtracting the initial RBC column diameter from the diameter after leukocyte passage ( Fig. 3e and 3f).

Recent Advancements in Microcirculatory Image Acquisition and Analysis

Fig. 3. a Sublingually-acquired microcirculatory image using sidestream dark field (SDF) imaging. The white square indicates the region of interest, which isenlarged in panels b-f; band (Leukocyte flowing through a capillary (indicated with arrows); d Same leukocyte, rolling against venular wall; eEnlarged view of the capillary without (left side) and with (right side) the leukocyte, obtained from panel a and b respectively; fSame as panel e, with enhanced contrast for more clear observation of the widening of the red blood cell column after the leukocyte passage (indicated with arrows and bars).

Microcirculatory Imaging in Conjunction with Tissue Capnography In addition to microcirculatory imaging, tissue capnography has been proposed as a modality to assess the functionality of the microcirculation and tissue oxygenation [42-45] . Alterations in partial pressure of local tissue carbon dioxide (PtC0 2) have been observed in numerous stud ies in crit ically ill patients using various techniques, such as sublingual tissue capnography and gastric tonometry [42- 45]. Results have shown that these alterations might serve as early and reliable indicators of tissue hypoxia [42,44]. However, whether PtC0 2 changes result from a local microcirculatory perfus ion deficit, hypoxia, or an inability of the mitochondria to utilize avail-

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able oxygen remains a source of debate. Fick's equation dictates that PtC0 2 is determined by two factors: Metabolic CO2 production and microcirculatory blood flow [43]. In low-flow states, hypercapnia will occur, since metabolic CO2 production will remain , but blood flow-mediated CO2 clearance will decrease. To investigate the mechanisms behind PtC0 2 alterations in septic patients, Creteur et al. designed an elegant study in which they correlated sublingual and gastric PtC0 2 changes to sublingual microcirculatory perfusion, using sublingual capnography, gastric tonometry, and OPS imaging [43]. Their results revealed a good correlation between raised PtC0 2 levels and the proportion of non-perfused sublingual capillaries, indicating that during sepsis, PtC0 2 is determined by microcirculatory perfusion. In a recent preliminary study by our group [46], we investigated the feasibility of spatially-confined measurements of PtC0 2 at the site of microcirculatory imaging using an SDF imaging device in conjunction with a CO2 microelectrode. For this purpose, a special probe holder was engineered , which ensured a 0.1 mm spacing between the tip of the SDF probe and the tissue surface to capture diffused tissue CO2 from the imaging site ( Fig. 4). Additionally, the spacing between the SDF probe and the tissue surface omits any pressure-induced alterations in microvascular hemodynamics. The CO2 probe was secured adjacent to the SDF probe and was in direct contact with the air-filled space (height = 0.1 mrn, diameter = 0.9 mm) between the SDF probe and the tissue, in which the CO2 content could equilibrate with the tissue CO2, For in vivo validation of the system, measurements were performed on a rat kidney undergoing ischemia/reperfusion. After anesthetization and ventilation of the rat, the left kidney was exposed, decapsulated, and placed in a Lucite kidney cup as described previously [47]. The Lucite kidney cup prevented the kidney from respi-

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Fig. 4. Left: Sidestream dark field (SDF) probe and the CO2 microelectrode mounted in a probe holder. Upper right corner: SDF image of the superficial microcirculation of a rat kidney. Lower right corner: Tissue PC0 2 values during ischemia (from 4 to 43 min) and reperfusion.

Recent Advancements in Microcirculatory Image Acquisition and Analysis

ratory-induced movement and thereby enabled microcirculatory images to be made. Figure 4 shows the experimental setup and the main preliminary results. Immediately after induction of kidney ischemia, PtCOz levels raised slightly (probably due to the lack of microcirculatory blood flow for COz wash-out) , followed by a decrease to approximately 25 % of the initial PtCOz value (probably due to the lack of oxygen for the metabolic COz production). Reperfusion caused an increase to the initial PtCOz level. The number of perfused capillaries dropped to zero during ischemia and was restored to roughly 75 % during reperfusion. This preliminary study shows the feasibility of spatially-confined measurements of PtCOz at the site of microcirculatory imaging, employing the described probe holder. Furthermore, it emphasizes that for the kidney the predominant determinant of tissue COz is microcirculatory blood flow.

Future Directions Future improvement of microcirculatory imaging will be made by incorporation of more advanced camera technology in terms of resolution and frame rate, which will enable RBC velocity measurements in high flow (i.e., > 1000 um/s) vessels and more accurate vessel geometry determination. This, in conjunction with completely automated software, with (new) microcirculatory scoring systems, will lead to faster and more exact determination of microcirculatory functioning in clinical and experimental settings. For that purpose, future research should also be dedicated to the precise role of vessel diameter and RBC velocity on the oxygen delivery to tissue cells. For further improvement of (clinical) utility, microcirculatory imaging would greatly benefit from on-site, (near) real time image analysis. For instance, on-site image contrast and sharpness determination would improve the quality of microcirculatory recordings , making OPS and SDF stud ies more efficient (i.e., less recording time and improved image analysis). However, on-site microcirculatory measurements, such as vessel length, diameter, and RBC velocity, would be hard to realize, since images must be stabilized and time-averaged to obtain these parameters. Ideally, a device would be envisaged that could be left behind in the patient (e.g., on the sublingual mucosa) to continuously provide images of the patient's microcirculatory perfusion. A further point of concern for OPS and SDF imaging is the pressure artifact, induced by application of the SDF probe onto organ and tissue surfaces [4, 48]. These pressure-induced effects might lead to false interpretation of the actual microcirculatory perfu sion. To prevent this pressure artifact, a suction device has been engineered by Lindert et al., which can be placed around an OPS probe to stabilize it onto the tissue [48]. Suction applied via small holes in the device prevented the OPS probe from applying pressure onto the tissue and additionally reduced movement during microcir culatory recordings. However, in order to objectify the assessment of the microcir culatory perfusion, the pressure artifact should be characterized, i.e., distortion of the microcirculatory perfusion should be measured as a function of the applied pressure. Another clinically favorable feature would be a microcirculatory oxygenation imaging modality implemented into a hand-held device. This imaging modality would provide clear images of the microcirculation, where the oxygenation in each pixel is expressed in false colors (e.g., blue to red represents a % to 100 % blood oxygenation) [49]. This imaging modality would allow on-site assessment of microcirculatory (and tissue) oxygenation, which would be especially of use in emergency

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medicine, where quick assessment of microcirculatory function ing is desired. A potential technique to acquire oxygenation images is multi-wavelength imaging (MWI), which enables mapping of the oxygen saturation of the imaged vasculature by imaging the microcirculation at three or more wavelengths [49]. The principles of MWI are based on reflectance spectrophotometry: The ratio of the absorption at the multiple wavelengths is used to calculate the hemato crit and the HbIHb0 2 ratio. A software module should be designed, which analyzes the reflected light intensities per wavelength per pixel and calculates the oxygen saturation per pixel by fitting the measured reflection spectra to the absorption spectra of Hb and Hb0 2•

Conclusion Microcirculatory image acquisition and analysis has rapidly developed over the last few years. The introduction of SDP imaging improved microcirculatory image quality and enabled assessment of the microcirculation in scenarios where high mobility is required [10, 14]. Recently developed software has greatly improved the analysis of OPS and SDP images, in terms of reduced analysis time and user input and the capability of analyzing curved vessel segments. Consensus on microcirculatory image acquisition and analysis has furthermore standardized OPS and SDP proto cols to enable the comparison of microcirculatory alterations among different studies [15]. This is of major importance, since conclusions based upon the analysis of the microcirculation are used to distinguish between health and disease and to evaluate the impact of interventions and (drug) therapy [4, 10]. References 1. Slaaf DW, Tangelder GJ, Reneman RS, Jager K, Bollinger A (1987) A versatile incident illuminator for intravital microscopy. Int J Microcirc Clin Exp 6:391 - 397 2. Groner W, Winkelman JW, Harris AG, et al (I999) Orthogonal polariz ation spectral imaging: a new method for study of the microcir culation . Nat Med 5:1209-121 2 3. Mathur a KR, Alic L, Ince C (2001) Initial clinical experience with OPS imaging for observ ation of the human microcirculation. In: Vincent JL (ed) Yearbook of Intensive Care and Emergen cy Medicine, 2001. Springer-Verlag, Berlin, pp 233 -245 4. Trzeciak S, Dellinger RP, Parrillo JE, et al (2007) Early microcirculatory perfusion derangement s in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med 49:88 -98 5. Spronk PE, Ince C, Gardien MJ, et al (2002) Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 360:1395-1396 6. Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL (2004) Persistent microcirculatory alterat ions are associated with organ failure and death in patients with septic shock. Crit Care Med 32:1825 -1831 7. De Backer D, Creteur J, Dubois MJ, Sakr Y, Vincent JL (2004) Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 147:91-99 8. Dubin A, Kanoore EVS, POlO M, et al (2007) Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia . Crit Care Med (in press ) 9. Sakr Y, Chierego M, Piagnerelli M, et al (2007) Microvascular response to red blood cell tran sfusion in patients with severe sepsis. Crit Care Med 35:1- 6 10. Ince C (2005) The microcirculation is the motor of sepsis. Crit Care 9 (suppl 4):13- 19 11. Mathur a KR, Bouma GJ, Ince C (2001) Abnormal microcirculation in brain tumors during surgery. Lancet 358:1698-1699 12. Dondorp AM, Ince C, Tipmanee P, et al (2007) Direct in-vivo assessment of microcirculatory dysfunction in severe falciparum malaria. J Infect Dis (in press)

Recent Advancements in Microcirculatory Image Acquisition and Analysis 13. Lindeb oom JAH, Mathura KR, Aartm an IH, Kroon F, Ince C (2007) The influence of the applic ation of platelet enriched plasmas in oral mucosal wound healing. Clin Oral Impl Res 18:1 33 -139 14. Goedhart PT, Khalilzada M, Bezemer R, Merza J, Ince C (2007) Sidestream Dark Field (SDF) imaging: a novel stroboscopic LED ring -based imaging modality for clinical assessment of th e microcirculat ion. Opt Express 15:15101 -1 5114 15. De Backer D, Hollenb erg S, Boerm a C et al. (2007) How to evaluate the microc irculation? Report of a round table conference. Crit Care 11:101-110 16. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microvascular blood flow is altered in patient s with sepsis. Am J Respir Crit Care Med 166:98-1 04 17. Boerma EC, Mathura KR, Van der Voort PHJ, Spronk PE, Ince C (2005) Quantifying bed sidederived imaging of microcirculat or y abnormalities in septic pat ients: a prospective validation study. Crit Care 9:601- 606. 18. Klyscz T, Junger M, lun g F, Zeint! H (1997) Cap Image - ein neuartiges computerunterstutztes Videobild analysesystem fur die dyn amische Kapillarmikroskopie. Biomed Technik Band 42 Heft 6:168-1 75 19. Ellis CG, Ellsworth ML, Pittman RN, Bur gess WL (1992) Application of image analysis for evaluat ion of red blood cell dynamics in capillaries. Microvasc Res 44:214-225 20. Schaudig S, Dadasch B, Kellam KR, Christ F (2001) Validation of an analysis software for OPS imaging used in hum ans. Proceedin gs of the 7th World Congress for Micro circulation: 2 - 59 21. Steger C (1998) An un biased detector of curvilinear struc tures. IEEE T Pattern Anal 20: 113- 125 22. Iahne B (2005) The structure tenso r. In: Iahne B (ed) Digital Image Processing, 6th editio n. Sringer-Verlag, Berlin, pp 364-368 23. Lo RC, Tsai WH (1995) Gray-scale Hough tr ans form for thick line detection in gray-scale images. Int J Pattern Recog 28:647 - 661 24. Nieuwdorp M, Meuwese MC, Vink H, Hoekstr a JB, Kastelein JJ, Stroes ES (2005) The end othelial glycocalyx: a potent ial barrier between health and vascular disease. Curr Opin Lipidol 16:507-511 25. Henr y CB, Duling BR (1999) Perme ation of the lum inal capillary glycocalyx is determined by hyaluronan. Am J Physiol 277:508-5 14 26. Weinbaum S, Zhang X, Han Y, Vink H, Cowin SC (2003) Mechanotransduction and flow across the endothelial glycocalyx. Proc Nat! Acad Sci USA 100:7988 - 7995 27. Mochizuki S, Vink H, Hiramatsu 0, et al (2003) Role of hyaluronic acid in shear induced endothelium derived nitri c oxide release. Am J Physiol 285:722 - 726 28. Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbe ll JM (2003) Heparan sulfate proteoglycan is a mechan osensor on endothelial cells. Circ Res 93:136 - 142 29. Thi MM, Tarbell JM, Weinbaum S, Spray DC (2004) The role of the glycocalyx in reorg anizatio n of the actin cytoskeleton und er fluid shear stress: a bumper-car model. Proc Nat! Acad Sci USA 101:16483-1 6488 30. Libby P (2002) Inflammation in atherosclero sis. Nature 420:868-874 31. Van den Berg BM, Spaa n JAE, Rolf TM, Vink H (2006) Atherogenic region and diet diminish glycocalyx dim ension and increase intim a media rat ios at the murine carotid artery bifurcation. Am J Physiol 290:915-920 32. Wang S, Okano M, Yoshida (1991) Ultras truc ture of endothelial cells and lipid depo sit ion on the flow dividers of branchiocephalic and left subclavian arterial bifur catio ns of the rabb it aor ta. J lpn Ath eroscler Soc 19:1089- 1100 33. Constanti nescu AA, Vink H, Spaan JAE (2003) Endoth elial cell glycocalyx modulates immobilization of leukocytes at th e endo thelial surfac e. Arter ioscler Thr omb Vase Bioi 23: 1541-1 547 34. Henr y CB, Duling BR (2000) TNF-a increases entry of macromolecules into luminal endothelial cell glycocalyx. Am J Physiol 279:2815-2823 35. Subrama nian SV, Fitzgerald ML, Bernfield M (1997) Regulated shedding of syndecan-1 and 4 ectod omains by thrombin and growth factor receptor activation. J Bioi Chern 272: 14713-14720 36. Gouveneur M, Van den Berg BM, Nieuwdorp M, Stroes E, Vink H (2006) Vasculoprotective

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37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

properties of the endothelial glycocalyx: effects of fluid shear stress. J Intern Med 259: 393-400 Nieuwdorp M, Holleman F, de Groot E, et al (2007) Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis. Diabetologia 50:1288 1293 Nieuwdorp M, Mooij HL, Kroon J, et al (2006) Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55:1127 -1132 Van den Berg BM, Nieuwdorp M, Stroes E, Vink H (2006) Glycocalyx and endothelial (dys)function : from mice to men. Pharmacol Rep 58:75- 80 Luft JH (1966) Fine structure of capillary and endocapillary layer as revealed by ruthenium red. Microcirc Symp Fed Proc 25:1773- 1783 Vink H, Duling BR (1996) Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ Res 79:581- 589 Marik PE, Bankov A (2003) Sublingual capnometry versus traditional markers of tissue oxygenation in critically ill patients. Crit Care Med 31:818-822 Creteur J, De Backer D, Sakr Y, Koch M, Vincent JL (2004) Sublingual capnometry tracks microcirculatory changes in septic patients. Crit Care Med 32:516-523 Wei! MH, Nakagawa Y, Tang W, Sato Y, Ercoli F, Finegan R (1999) Sublingual capnometry: a new non invasive measurement for diagnosis and quantification of severity of circulatory shock. Crit Care Med 27:1225-1229. Marik PE (2001) Sublingual capnography: a clinical validation study. Chest 120:923-927 Bezemer R, Legrand M, Ince C (2007) Simultaneous sidestream dark field imaging of the microcirculation and spatially-confined tissue capnography on a rat kidney undergoing ischemia/reperfusion. Microcirculation 14: 475 (abst) Johannes T, Mik EG, NoM B, Raat NJH, Unertl KE, Ince C (2006) Influence of fluid resuscitation on renal microvascular P02 in a normotensive rat model of endotoxemia. Crit Care 10:R88 Lindert J, Werner J, Redlin M, Kuppe H, Habazettl H, Pries AR (2002) OPS imaging of human microcirculation: a short technical report. J Vasc Res 39:368-372 Styp-Rekowska B, Disassa NM, Reglin B, et al (2007) An imaging spectroscopy approach for measurement of oxygen saturation and hematocrit during intravital microscopy. Microcirculation 14:207- 221

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The Beneficial Effects of Increasing Blood Viscosity B.Y.

SALA ZAR V AZQ UEZ ,

P. CABRALES, and M.

INTAGLIETTA

Introduction Increased hematocrit above normal levels is usually associated with the elevation of mean systemic arterial blood pressure (MAP) due to increased blood viscosity as shown in studies where hematocrit was increased by 40 % or more above baseline [1, 2]. This effect is related to the behavior of pressure in rigid tubes subjected to constant flow, in the presence of varying viscosity. Clinically and physiologically, this situation is encountered with pathologically high hematocrits [3] and in individuals adapted to high altitude with hematocrit levels of75 -91 % [4]. Moderate hemat ocrit changes (and , therefore, changes in blood viscosity) due to variability in the normal population do not appear to affect MAP. A study by Martini et al. [5] in experimental animals showed that MAP only increased when hematocrit increa sed by 20 % above baseline. Below this threshold, the effect is reversed and an increase in hematocrit of up to about 10 % greater than normal causes blood pressure to decrea se, cardiac output to increase, and peripheral vascular resistance is significantl y lowered [5, 6]. This paradoxical effect appears to be due to the increase in shear stres s on the endothelium due to the increase in blood viscosity, a phenomenon that may also be due in part to the decreased cellfree layer (plasma layer) width at the blood and vessel endothelium interface .

The Link between Blood Viscosity and Nitric Oxide The increase of shear stress in the circulation augments endothelial production of vasodilators [7]. In awake hamsters treated with L-NAME (N (G)-nitro-L- arginine methyl ester) and knock-out mice deficient in endothelial nitric oxide (NO) synthases (eNOS) MAP did not decrease when hematocrit was increased to the level where wild type mice and untreated hamsters presented a maximal reduction in blood pressure [5]. Thus it can be concluded that the noted vasodilation is due to an NO-mediated effect. Lowering of peripheral vascular resistance is initially proportional to the increase in hematocrit; however, the related increase in blood viscosity eventually counteracts the effect of vasodilatation on MAP. At this point , the vasodi lator effect of increased shear stress no longer compensates for the increased viscosity, and peripheral vascular resistance and blood pressure increase above baseline . Evidence for a direct link between blood viscosity, shear stress, the production of NO, and vasodilation was reviewed by Smiesko and Johnson [8], who showed that increasing flow locally in arterioles (and, therefore, shear stress) caused "flow dependent vasodilation". This mechanism has strong implications for all conditions

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in which blood viscosity changes, such as in hemodilution and hemoconcentration, and for the management of hemorrhagic shock. Tsai et al. [9] showed that increasing plasma viscosity in extreme hemodilution in the hamster window chamber model increased shear stress, flow, and perivascular NO (measured with microelectrodes). Shear stress also elicits the production of prostacyclin [10]; however, this mediator appears to provide residual vasodilatory effects in comparison to those that are NO-mediated in normal tissues.

Blood Viscosity, Hemodilution, and Microvascular Function Introduction of a plasma expander reduces hematocrit and, unless its fluid viscosity is similar to blood , blood viscosity is reduced. The resulting hemodilution has long been regarded as beneficial. The limit of hemodilution (or plasma expansion) is reached when perfusion and oxygen delivery no longer maintain tissue metabolism, a point termed the transfusion trigger, where restoration of blood oxygen carrying capacity is considered necessary. Studies by Tsai et al. [11] show that as blood viscosity is reduced by hemodilution, microvascular funct ion is progressively impaired, jeopardizing tissue survival due to the local microscopic maldistribution of blood flow. These effects take place at hematocrits and intrinsic oxygen availability that are greater than those defining the oxygen supply limitation. This indicates that, in principle, the limit of hemodilution could be significantly decreased if the process of plasma expansion maintains microvascular function . Recent studies show that microvascular function can be maintained in extreme hemodilution by increasing either blood or plasma viscosity [11-13]. Restoration of blood viscosity during hemodilution and hemorrhage is desirable, because it maintains functional capillary density (FCD, the number of capillaries with passage of red blood cells [RBCs] in the field of view of a microscopically observed tissue). FCD was shown to be critical in defining tissue survival in a study by Kerger et al. [14], which showed the direct correlation between maintenance of FCD above a specific threshold and survival in extended hemorrhagic shock. FCD is determined by the maintenance of capillary pressure, which in extreme hemodilution is obtained by using high viscosity plasma expanders. The relevance of maintaining adequate FCD is not fully appreciated in medicine, where capillary perfusion is linked to tissue oxygen delivery (DOz), assuming that maintenance of adequate tissue POz is the hallmark of normal tissue function. We have shown, however, that tissue POz is an elusive target. Systematic studies of DOz to the tissue by the microcirculation show that most of the oxygen in blood is delivered to the tissue by arterioles (skeletal muscle at rest and connective tissue) prior to blood arriving at the capillaries [15]. Capillaries may not be the primary conduits for transferring oxygen to the tissue in normal circumstances , and maintaining normal levels of FCD is tied to the necessity of extracting from tissue the products of metabolism, which otherwise create toxic local conditions. The products of metabolism such as lactate, with the exception of the hydrogen ion, are less diffusible than oxygen and their clearance requires a functional capillary network. Our results show that in extreme hemodilution, acid base balance is positive if FCD is > 50 % of normal, and becomes negative when it is lower. Furthermore acid base balance, although seldom negative when tissue POz is above 3 - 4 mmHg, may be either negative or positive at low POzs depending on whether FCD is below the 50 % threshold. Extreme hemodilution studies show that

The Beneficial Effects of Increasing Blood Viscosity

FCD is the most direct predictor of homeostasis; however, FCD is not clinically observable, and does not have the diagnostic relevance associated with tissue P0 2 •

Elevated Plasma Viscosity Although most investigations of blood rheology demonstrate that increased blood and/or plasma viscosity results from, or may lead to, pathological conditions, there is increasing evidence supporting the opposite. Chen et al. [16] elevated plasma viscosity fourfold, and reported vasodilation reflected by a reduction in vascular hindrance in several vital organs. We showed that the reduction in FCD observed after reducing the systemic hematocrit by 75 % from baseline with low viscosity plasma expanders was prevented by continuing hemodilution with a high viscosity fluid [11]. Waschke et al. [17] found that cerebral perfusion was not changed when blood was replaced with fluids with the same oxygen carrying capacity and viscosities varying from 1.4 to 7.7 centipoise (cP). Krieter et al. [18] varied the viscosity of plasma by adding dextran (500 kDa) and found that the medians in tissue P0 2 in skeletal muscle were maximal at 3 cP plasma viscosity, while for liver the maximum occurred at 2 cPo In general, these authors found that a 3-fold increase in blood plasma viscosity had no effect on tissue oxygenation and organ perfusion when blood was hemodiluted. Endogenous NO release reduced total peripheral resistance during moderate hemodilution [19]. De Wit et al. [20] elevated plasma viscosity causing sustained NO-mediated dilatation in the hamster muscle microcirculation.

Blood Rheology and Hemodilution Substitution of RBC with a colloid or crystalloid solution is safe up to exchanges of 50 % of the RBC mass, as validated on a systemic basis. A 50 % substitution of RBCs brings the hemoglobin concentration to the transfusion trigger, generally accepted to be in the neighborhood of 7 g/dl. At this hematocrit, healthy organisms can autoregulate to compensate for this change, and tissue oxygenation, blood pressure, and FCD remain unchanged. Microvascular conditions deteriorate when this threshold is passed [13,21]. Blood viscosity is a function of hematocrit, plasma viscosity, cell deform ability, and cell aggregation. A 50 % reduction in RBCs brings the viscosity of systemic blood to about 2 cPo Microvascular viscosities are lower than systemic viscosity because of the presence of a low viscosity plasma layer that occupies a greater portion of the vessel lumen in microscopic vessels. Microvascular viscosities are a weak function of systemic hematocrit [22] because this parameter is regulated in the microcirculation [23]. Decreased blood viscosity due to hemodilution with an isooncotic colloid solution reduced venous pressure losses, elevated right atrial pressure, and increased filling of the heart, enhancing heart contractility, cardiac output, and blood flow velocity [24]. Increased cardiac output delivers fewer RBCs more rapidly maintaining D0 2 to the capillaries [25]. Capillary hematocrit does not fall as rapidly as systemic hematocrit in hemodilution in skeletal muscle and subcutaneous connective tissue [26]; therefore, microvascular D0 2 tends to remain nearly constant up to a hematocrit reduction of 50 % [27]. In addition, Buerk [28] showed that a reduced hematocrit due to hemodilution increases NO availability in the circulation since NO-scavenging hemoglobin is

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decreased. This effect is eventually overcome when the reduction in hematocrit limits D0 2 to the heart, lowering cardiac output and FCD. The blood viscosity threshold that causes the decrease in FCD appears to coincide with the decision to transfuse blood. Therefore, the transfusion trigger may also be a 'viscosity' trigger, and some of the results obtained with a blood transfusion may also be achieved by increasing plasma viscosity. Thus, use of RBCs for the purpose of increasing blood viscosity is unnecessary if a material is introduced that increases plasma viscosity in the circulation. In this context, it would seem that a desirable property for plasma expanders is that of increasing blood viscosity. Changes in hematocrit may also affect NO bioavailability due to changes in NO scavenging by hemoglobin. The width of the plasma layer should decrease when increase in hematocrit brings RBCs closer to the endothelial surface, enhancing NO scavenging and counteracting the effects of increased NO production [29]. Increasing hematocrit with non-oxygen carrying and, therefore, non-NO scavenging, RBCs, should extend the positive balance of vasodilation and the range over which increasing hematocrit lowers MAP in comparison with the same effect with normal RBCs. NO scavenging by hemoglobin should also playa role in this regulatory process.

Viscogenic Plasma Expanders A variety of visco genic plasma expanders are available ( Table 1).

Hydroxyethyl Starch (HES) These solutions (Pentaspanw [10 %,200 kDa], Hextendw [6 %,500 kDaJ) are viscogenic but their effect is of relatively short duration due to their high colloid oncotic pressure (COP). HES is available commercially in several molecular weight distributions. Table 1. Solution properties of plasma expanders as a function of viscosity Plasma Expander Ringer's lactate Human serum albumin Human serum albumin PEG-HSA PEG-BSA Dex 70 HES* HES** Dex 500 Alginate***

%

Concentration

Molecular weight kDa

Viscosity cp

COP mmHg

5 10 4 2.5 6 10 6 6 0.7

66 66 96 126 70 200 550 500 450-1200

0.8 0.9 1.5 2.2 2.7 2.8 3.0 3.4 6.5 8.0

0 21 47 48 38 50 85 29 32 0

PEG-HSA, polyethylene glycol conjugated human serum albumin (supplied by Dr. Acharya, Albert Einstein College of Medicine, Bronx, NY, and Sangart lnc, San Diego, CA.); PEG-BSA, PEG bovine serum albumin (supplied by Dr. Acharya, Albert Einstein College of Medicine, Bronx, NY); *Pentaspan (B. Braun Medical, Irvine CAl; **Hextend (BioTIme, Berkeley, CAl; ***(NovamatrixlFMCBiopolymer, Sandvika, Norway)

The Beneficial Effects of Inaeasing Blood Viscosity Polyvinylpyrrolidone (PVP; -1.1 MDa)

PVP has been used as a plasma expander and in studies of the brain circulation [30].

It is inexpensive; however, it causes immune and inflammatory reactions related to

the distribution of molecular weights in the compound, and it is no longer approved for human use in the USA. Dextran

This is a branched polysaccharide available in various molecular weights (i.e., 40, 70, 500 kDa). Dextran presents a small probability of causing anaphylactic shock [31]. Dextran > 250kDa causes RBC aggregation when the blood hematocrit is near normal. Alginate

This is a polysaccharide derived from seaweed with near ideal characteristics. A 0.7 % solution has a viscosity of 8 cPoAt present, alginates present a mixture of M (manuronic acid) and G (guluronic acid), and their applicability depends on optimizing their relative composition [12,32] . This polysaccharide is used extensively in biotechnology due to its water-binding and viscosifying properties and the fact that it has no COP. Keratins

Alpha-keratin, derived from human hair, has been proposed as a plasma expander and has been used successfully in exchange transfusions in dogs [33]. Pegylated proteins

These protein s are generated by the attachment of polyethylene glycol (PEG) to the surface amino groups of the protein using succinimidyl chemistry and extending vascular retention [21].

Resuscitation from Hemorrhagic Shock The responses of the hamster chamber window model to resuscitation using plasma expanders of different viscosities following hypovolemic hemorrhagic shock have been extensively studied . This experimental model allows systemic and microvascular parameters to be investigated in the awake condition, in a tissue isolated from the environment. Comparisons based on this model avoid consideration of species differences, methodologies, and laboratory procedures. Fluids that serve as a benchmark comparison for investigating the effect of increasing blood and plasma viscosity are Ringer's lactate, dextran, and blood. In a standard 2-hour shock model [34], resuscitation was implemented with 50 % volume restoration for shed blood and dextran , and 100 % volume restoration for Ringer's lactate. Blood significantly improved initial recovery of all parameters, particularly MAP, which was immediately restored by blood, and FeD, with full restoration at 24 hours with all fluids; however, both dextran 70 kDa and Ringer's lactate caused prolonged flow impairment and tissue hypoxia.

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B.Y. Salazar Vazquez, P. Cabrales, and M. Intaglietta Low Viscosity PEG-albumin Versus Hydroxyethyl Starch Resuscitation PEG conjugated bovine serum albumin (12 copies of PEG 5 kDa, PEG-Alb, 2.5 g/dl) and HES (200 kDa HES, 10 % wlvol in 0.9 % saline, Pentaspan, B. Braun Medical, Irvine, CA) delivered as 50 % of the shed volume were used to resuscitate in a one hour standard shock model [35]. PEG-Alb restored systemic and microvascular parameters throughout the observation period (90 min) . HES had the same effects as PEG-Alb during the initial 10-15 min but the effects were not sustained. Recovery of MAP with HES was present after both FCD and tissue pH decreased, thus early microvascular dysfunction was not predicted by MAP. In this experiment, final plasma viscosity was 1.4 cP for PEG-Alb, and 1.1 cP for HES [35].

Hyperviscous and Hyperoncotic HES Solutions: Hemorrhagic shock Wettstein et al. [36] studied the effects of different concentrations of HES in hamster shock resuscitation . Fifty percent hemorrhage was resuscitated with 25 % of the estimated blood volume with a 5, 10, or 20 % solution of HES (Pentaspan , B. Braun Medical Inc., Irvine , CA). Increasing concentration led to increased COP (from 20 to 70 to 194 mmHg) and viscosity (from 1.7 to 3.8 to 14.4 cP). Cardiac index, microcirculatory and metabolic recovery were improved with HES 10 and 20 % when compared to 5 % HES. Oxygen delivery and consumption in the dorsal skin fold chamber was more than doubled with HES 10 % and 20 % when compared to HES 5 %. This was attributed to the restoration or increased plasma COP and plasma viscosity obtained with HES 10 % and 20 % leading to improved microcirculatory blood flow early in the resuscitation period. Increased COP led to an increase in blood volume as shown by a reduction in hematocrit. MAP improved significantly in animals receiving 10 and 20 % solutions. Therefore, increased concentrations of HES, leading to hyperoncotic and hyperviscous solutions, are beneficial for resuscitation from hemorrhagic shock since normalization of COP and viscosity causes the rapid recovery of microcirculatory function .

Hyperviscous and Hyperoncotic HES Solutions: Hemorrhagic Shock and Continuous Bleeding Resuscitation from hemorrhagic shock (50 % of blood volume) was followed by bleeding at the rate of 20 % of blood volume per hour, with blood losses equaling 100 % of total blood volume [37]. Resuscitation was implemented via a volume infusion 50 minutes after hemorrhage using 25 % of blood volume with 10 % HES (HES 200, group HES4) , or a mixture of HES 200 with 0.3 or 0.6 % wtlvol alginate (group HES7 and HESIO, respectively, COP 84 to 87 mmHg and viscosities in the range of 3.8 to 9.8 cp). Alginates (NovamatrixlFMCBiopolymer, Norway) are very high molecular weight materials with comparatively high viscosities at very low concentrations that have minimal (a few mmHg) oncotic activity. All solutions caused similar initial (10-15 min) effects that diverged thereafter. Viscosity-enhanced solutions showed improved and longer lasting (90 min) maintenance of MAP, microvascular flow, FCD, and laboratory parameters than low viscosity solutions. Low (conventional viscosity) resuscitation caused all microvascular parameters to return to the shock level after 90 min [37]. It is apparent that viscosity per se improved resuscitation since blood volume changes were not a factor affecting the extent of recovery in the presence of continuous bleeding.

The Beneficial Effects of Increasing Blood Viscosity PEG-Albumin vs. PEG-Alb plus Red Blood Cells The hamster model was used to asses the effects of viscosity only versus the contribution of oxygen carrying capacity provided by RBCs plus enhanced viscosity [38]. Hamsters subjected to 50 % hemorrhage were resuscitated with 25 % of blood volume with solutions containing 6 % PEG-albumin only (PEG-BSA 0), and 6 % PEGBSA mixed with autologous RBCs to reach 4 g/dl of Hb (PEG-BSA 4) and 8 gldl of Hb (PEG-BSA 8). PEG-BSA (6 %) had a viscosity of 4.2 cP and a COP of 116 mmHg. Arterial base excess was lower than baseline for PEG-BSA 0 and PEG-BSA 4 (ns), whereas base deficit remained significantly decreased for PEG-BSA 8 (p < 0.05 vs. baseline). Oxygen extraction was 91 ± 2 % of the DO z for PEG-BSA 0 compared to 85 ± 2 % for PEG-BSA 8 (p < 0.05), and FCD was 61 %, 47 %, and 45 % for PEGBSA 0 (p < 0.05 vs. other groups), PEG-BSA 4, and PEG-BSA 8, respectively. Therefore, arterial base excess and oxygen extraction ratio were better restored when more PEG-BSA and less RBCs were used. This result suggests that the transfusion trigger in hemorrhagic shock may be shifted towards lower hemoglobin concentrations when using highly viscous and oncotic solutions [38].

The Role of RBC-related Oxygen Carrying Capacity in Hemorrhage Resuscitation Experimental results support the hypothesis that resuscitation can be improved via the restoration of plasma viscosity. Given the strong dependence of blood viscosity on hematocrit it is also possible to increase blood viscosity using additional RBCs. This approach requires isolating the effects due to changes in oxygen carrying capacity which per se modulate cardiac output and MAP. Accordingly resuscitation is implemented by the rein fusion of RBCs whose oxygen carrying capacity was annulled by conve rsion of their hemoglobin to methemoglobin, or saturation with carbon monoxide.

Shock Resuscitation with Carbon Monoxide-saturated Blood The response of transfusion with carbon monoxide-saturated RBCs on microvascular function in hemorrhagic shock resuscitation was investigated in the conventional model with decrease of 50 % of blood volume, and restoration one hour after hemorrhage with a single volume infusion of 25 % blood volume with fresh RBCs saturated or unsaturated with carbon monoxide suspended in human serum albumin [39]. Systemic and microcirculatory restoration were initially the same for resuscitation with or without carbon monoxide for up to 90 min after resuscitation. Carbon monoxide concentration decreased over 90 min, increasing the oxygen carrying capacity and gradually reoxygenating the tissue [39].

Shock Resuscitation with Methemoglobin RBCs Some of the beneficial effects noted with carbon monoxide-hemoglobin RBCs could be attributed to the systemic and microvascular flow improvements noted following the top load infusions of carbon monoxide-saline reported by Hangai-Hoger et al. [40]. To explore this possibility, oxygen carrying capacity was inactivated by con verting RBC hemoglobin to methemoglobin by exposure to nitrate. Resuscitation

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was implemented with fresh RBCs used in the standard shock model as in previous experimental approaches. Results were directly compared to either fresh plasma or blood . Blood viscosities at the end of the 90-min period were 2.4 cP after resuscitation with plasma and 2.9- 3.0 cP after blood transfusion (baseline: 4.2 cP). Resuscitation with RBCs, with or without oxygen carrying capacity, resulted in a greater MAP than resuscitation with plasma . FCD was substantially higher for RBC transfusions (56 ± 7 % of baseline) versus plasma (46 ± 7 % of baseline), and the use of methemoglobin RBCs (MetRBCs) did not change FCD or microvascular hemodynamics. As expected DO z and oxygen extraction were significantly lower for resuscitation with plasma and MetRBCs compared to oxygen carrying RBCs. Systemic and microvascular conditions after volume restitution with plasma were notably worse than with RBC-related recovery [41].

Conclusion Resuscitation from hemorrhagic shock can be achieved by volume restoration with a fluid with rheological properties similar to those of blood, independently of oxygen carrying capacity. Therefore, the transfusion of stored RBCs, which does not necessarily raise the effective oxygen capacity of blood upon transfusion, still provides beneficial effects, since the process increases blood viscosity, improving perfusion, allowing DO z by the remaining RBCs, and flushing out metabolites produced during shock. This physiological mechanism also becomes operational by increasing plasma viscosity in extreme hemodilution. The basis for these effects is the need to maintain an adequate level of shear stress in the circulation, insuring the production of NO by the endothelium. Limited shock resuscitation can in part be due to the decrease in blood viscosity, a condition that may also result from low plasma viscosity in hemodilution. Conversely, restoration of blood rheological properties improves resuscitation independently of the restitution of oxygen carrying capacity. Acknowledgments: These studies were funded in part by NIH grants R01HL064395 and BRP grant R24-HL64395 (Intaglietta) and P01HL071064-05 (Friedman). References 1. Richardson TQ, Guyton AC (1959) Effects of polycythemia and anemia on cardiac output and

other circulatory factors. Am J PhysioI197:1167-1170 2. Lindenfeld J, Weil JV, Travis VL, Horwitz LD (2005) Regulation of oxygen delivery during induced polycythemia in exercising dogs. Am J Physiol Heart Circ Physiol 289:HI821-1825 3. Bertinieri G, Parati G, Ullian L (1998) Hemodilution reduces clinic and ambulatory blood pressure in polycythemic patients . Hypertension 31:848- 853 4. Jefferson JA, Escudero E, Alfaro RT, Schoene RB (2002) Excessive erythrocytosis, chronic mountain sickness, and serum cobalt levels. Lancet 359:407 - 408 5. Martini J, Carpentier B, Chavez Negrete A, Frangos JA, Intaglietta M (2005) Paradoxical hypotension following increased hematocrit and blood viscosity. Am J Physiol Heart Circ Physiol 289:H2136 - 2143 6. Martini J, Tsai AG, Cabrales P, Johnson PC, Intaglietta M (2006) Increased cardiac output and microvascular blood flow during mild hemoconcentration in hamster window model. Am J Physiol Heart Circ Physiol 291:H310-317 7. Kuchan MJ, Io H, Frangos JA (1994) Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells. Am J Physiol 267:C753-C758 8. Smiesko V, Johnson PC (1993) The arterial lumen is controlled by flow related shear stress. News Physiol Sci 8:34-38

The Beneficial Effect5 of Increasing Blood Viscosity 9. Tsai AG, Acero C, Nance PR, et al (2005) Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion. Am J Physiol Heart Circ Physiol 288:H1730-1739 10. Frangos JA, Eskin SG, McIntire LV, Ives CL (1985) Flow effects on prostacyclin production in cultured human endothelial cells. Science 227:1477-1479 11. Tsai AG, Friesenecker B, McCarthy M, Sakai ti, Intaglietta M (1998) Plasma viscosity regulates capillary perfusion dur ing extreme hemodilution in hamster skin fold model. Am J PhysioI275:H2170-H2180 12. Cabrales P, Tsai AG, Intaglietta M (2005) Alginate plasma expander maintains perfusion and plasma viscosity during extreme hemodilution. Am J Physiol 288:HI708-1716 13. Cabrales P, Tsai AG, Intaglietta M (2004) Microvascular pressure and functional capillary density in extreme hemodilution with low and high plasma viscosity expanders. Am J PhysioI287:H363-H373 14. Kerger H, Saltzman DJ, Menger MD, Messmer K, Intaglietta M (1996) Systemic and subcutaneous microvascular p02 dissociation during 4-h hemorrhagic shock in conscious hamsters. Am J Physiol 270:H827-H836 15. Tsai AG, Johnson PC, Intaglietta M (2003) Oxygen gradients in the microcirculation. Physiol Rev 83:933- 963 16. Chen RYZ, Carlin RD, Simchon S, Jan K-M, Chien S (1989) Effects of dextran-induced hyperviscosity on regional blood flow and hemodynamics in dogs. Am J Physiol 256:H898-H905 17. Waschke KF, Krieter H, Hagen G, Albrecht DM, van Ackern K, Kuchinsky W (1994) Lack of dependence of cerebral blood flow on blood viscosity after blood exchange with a Newtonian O2 carrier. J Cereb Blood Flow Metab 14:871-876 18. Krieter H, Bruckner VB, Kafaliakis F, Messmer K (1995) Does colloid induced plasma hyperviscosity in haemodilution jeopardize perfusion and oxygenation of vital organs? Acta Anaest Scand 39:326-244 19. Doss DN, Estafanous FG, Ferrario CM, Brum JM, Murray PA (1995) Mechanism of systemic vasodilation during normovolemic hemodilution. Anes Analg 81:30-34 20. de Wit C, Schafer C, von Bismark P, Bolz S, Pohl U (1997) Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo. Pflugers Arch 434:354- 361 21. Cabrales P, Tsai AG, Winslow RM, Intaglietta M (2005) Extreme hemodilution with PEGhemoglobin vs. PEG-albumin . Am J Physiol 289:H2392- 2400 22. Lipowsky HH, S. U, Chien S (1980) In vivo measurements of apparent viscosity and microvessel hematocrit in the mesentery of the cat. Microvasc Res 19:297-310 23. Mirhashemi S, Breit GA, Chavez RH, Intaglietta M (1988) Effects of hemodilution on skin microcirculation. Am J Physiol 254:H411-H416 24. Messmer K (1975) Hemodilution. Surg Clin N Am 55:659-678 25. Fan FC, Schuessler GB, Chen RYZ, Chien S (1980) Effect of hematocrit alteration on the regional hemodynamics and oxygen transport. Am J Physiol 238:H545-H552 26. Lipowsky HH, Firrell JC (1986) Microvascular hemodynamics during systemic hemodilution and hemoconcentration. Am J Physiol 250:H908-H922 27. Messmer K, Kreimeier U, lntaglietta M (1986) Present state of intentional hemodilution. Europ Surg Res 18:254-263 28. Buerk DG (2001) Can we model nitric oxide biotransport? A survey of mathematical models for a simple diatomic molecule with surprisingly complex biological activity. Ann Rev Biomed Eng 3:109-143 29. Liao JC, Hein TW, Vaughn MW, Huang KT, Kuo L (1999) Intravascular flow decreases erythrocyte consumption of nitric oxide. Proc Nat! Acad Sci V S A 96:8757-8761 30. Rebel A, Lenz C, Krieter H, Waschke KF, Van Ackern K, Kuschinsky W (2001) Oxygen delivery at high blood viscosity and decreased arterial oxygen content to brains of conscious rats . Am J Physiol Heart Circ Physiol 280:H2591- 2597 31. Michelson E (1968) Anaphylactic reaction to dextrans. N Engl J Med 278:552 32. Ertesvag H, Hoidal HK, Schjerven H, Svanem BI, Valla S (1999) Mannuronan C-5-epimerases and their application for in vitro and in vivo design of new alginates useful in biotechnology. Metab Eng 1:262- 269 33. Ewald RA, Anderson P, Williams HL, Crosby WH (1964) Effects of intravenous infusions of

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34. 35.

36. 37. 38. 39. 40. 41.

feather keratin: Preliminary characterization and evaluation as a plasma expander. Proc Soc Exp Bioi Med 115:130-133 Kerger H, Tsai AG, Saltzman OJ, Winslow RM, Intaglietta M (1997) Fluid resuscitation with O2 vs. non-O, carriers after 2 h of hemorrhagic shock in conscious hamsters . Am J Physiol 272:H525-H537 Cabrales P, Nacharaju P, Manjula BN, Tsai AG, Acharya SA, Intaglietta M (2005) Early difference in tissue pH and microvascular hemodynamics in hemorrhagic shock resuscitation using polyethylene glycol-albumin - and hydroxyethyl starch-based plasma expanders. Shock 24:66-73 Wettstein R, Erni 0, Intaglietta M, Tsai AG (2006) Rapid restoration of microcirculatory blood flow with hyperviscous and hyperoncotic solutions lowers the transfusion trigger in resuscitation from hemorrhagic shock. Shock 25:641-646 Cabrales P, Tsai AG, Intaglietta M (2004) Hyperosmotic-hyperoncotic vs. hyperosmotichyperviscous small volume resuscitation in hemorrhagic shock. Shock 22:431-43 7 Wettstein R, Tsai AG, Erni 0, Lukyanov AN, Torchilin VP, Intaglietta M (2004) Improving microcirculation is more effective than substitution of red blood cells to correct metabolic disorder in experimental hemorrhagic shock. Shock 21:235-240 Cabrales P, Tsai AG, Intaglietta M (2007) Hemorrhagic shock resuscitation with carbon monoxide saturated blood. Resuscitation 72:306 - 318 Hangai-Hoger N, Tsai AG, Cabrales P, Suematsu M, Intaglietta M (2007) Microvascular and systemic effects following top load administration of saturated carbon monoxide-saline solution. Crit Care Med 35:335 - 237 Cabrales P, Tsai AG, Intaglietta M (2007) Is resuscitation from hemorrhagic shock limited by blood oxygen-carrying capacity or blood viscosity? Shock 27:380-389

Section XVII

XVII Anticoagulants in Organ Failure

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N.C.M.

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Introduction Activation of blood coagulation is a common observation in patients with sepsis. The clinical manifestations of an activated coagulation system depend on the degree of pro-coagulant conditions and may lead to overt disseminated intravascular coagulation (DIC), consumption coagulopathy, defibrination syndrome, and purpura fulminans . The protein C anticoagulant pathway regulates thrombin formation, prevents microvascular thrombosis, and has anti-inflammatory and profibrinolytic properties. Decreased plasma levels of antithrombin and protein C can occur in a variety of clinical conditions associated with DIC, such as sepsis, trauma, and after surgical interventions. Recent data suggest that in surgical patients admitted to the intensive care unit (ICU), antithrombin and protein C levels are low, and it has been suggested that antithrombin and protein C levels may have a potential role as predictors of outcome in critically ill patients.

Blood Coagulation: The Basic Science The coagulation system is a host defense mechanism that maintains the integrity of the vessels after an injury. When the hemostatic system is activated, a platelet plug is formed through the process of platelet adhesion and aggregation. A series of reactions initiate s the formation of the fibrin clot (Fig. 1). The generation of thrombin and the formation of a fibrin clot are achieved through two pathways, the intrinsic and extrinsic pathways [1). In the intrinsic pathway, the contact system is activated by surface contact . This pathway is initiated by the activation of factor XII by kallikrein . The activated factor XII (factor XIIa), catalyzes the conversion of factor XI to its active enzyme form, factor Xla. In the presence of calcium, factor Xla activates factor IX. Factor IXa binds to the cofactor VIlla, and acts on factor X. This complex converts factor X to its enzyme form, factor Xa, Factor Xa binds to factor Va and generates a complex with enzymat ic activity known as prothrombinase. This complex converts prothrombin to thrombin. Thrombin acts on fibrinogen to generate the fibrin monomer, which rapidly polymerizes to form the fibrin clot. The extrinsic pathway is initiated by the formation of a complex between tissue factor on cell surfaces and factor VIla. When tissue factor is in contact with plasma after vascular injury, this factor VIla complexes with tissue factor to form an enzyme complex that activates factor X. In turn, factor Xa can feed back to convert more factor VII to factor VIla. Factor Xa binds to the cofactor Va and, in the presence of calcium, generates the prothrombinase complex which converts prothrombin to thrombin.

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Protein ( Pathvvay The protein C anticoagulant pathway regulates thrombin formation and prevents microvascular thrombosis [2]. This pathway is initiated when thrombin binds to the endothelial cell surface protein, thrombomodulin, leading to the activation of protein C. Binding of thrombin to thrombomodulin increases the rate of protein C activation and simultaneously blocks the ability of thrombin to catalyze fibrin formation, factor XIII activation, platelet activation, and feedback activation of the coagulation cofactors (Fig. 2). Protein C activation is enhanced approximately 20-fold in vivo when protein C is bound to the endothelial cell protein C receptor (EPCR) [3]. Once activated protein C (APC) dissociates from EPCR, it binds to protein 5, and this complex then inactivates factors Va and VIlla. In addition, APC acts on the fibrinolytic system enhancing endogenous fibrinolytic activity by inhibiting plasminogen activator inhibitor (PAI-l) [3]. The thrombin-thrombomodulin complex is a potent activator of thrombin activatable fibrinolysis inhibitor (TAFI), a procarboxypeptidase. This enzyme removes terminal Arg and Lys residues from fibrin, slowing clot lysis and inhibiting C5a [3]. The APC-EPCR complex induces the cleavage of protease-activated receptor (PAR-I) which is one of the cell-signaling mecha-

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nisms related to antiapoptotic activity. APC-EPCR can be inactivated by plasma protease inhibitors (a I-antitry psin and protein C inhibitor) at approximately the same rate as free APC [3].

Interactions between Coagulation and Inflammation Activation of blood coagulation is a common observat ion in patients with sepsis [4]. Clinical man ifestation s depend on the degree of procoagulant state and may lead to overt DIC, consumption coagulopathy, defibrinat ion syndrome, and purpura fulminans. DIC is an acquired disorder ar ising from a heterogeneous group of disorders , such as sepsis, trauma, cancer, obstetrical complications, vascular disorders, reactions to toxins, immunologic disorders [5]. It is characterized by an unregulated and excessive generation of thrombin that results in the consumption of coagulation factors and large-vessel thrombosis leading to multiple organ dysfunction. The systemic formation of fibrin results from increased generation of thrombin, suppre ssion of physiologic anticoagulation mechanisms, and the delayed removal of fibrin as a consequence of impaired fibrinolysis. Overt DIC is characterized by elevated levels of fibrin-related markers, prothrombin time prolongation/elevated international norm alized ratio (INR), decreased platelet count, and decreased levels of antithrombin, protein C, and fibrinogen [5]. Consumption syndrome has the same laborator y criteria as DIC associated with bleedin g. Defibrination syndrome is a very specific type of consumption coagulopathy characterized by the combination of very low plasma fibrinogen levels, with high levels of fibrin degradation products as well as fibrinogen degradation products in plasma. Purpura fulminans is characterized by microvascular thrombosis of the skin and various organs (especially the kidne ys and adrenal glands). All the major physiologic anticoagulants - antithrombin, prote in C, and tissue factor-pathway inhibitor (TFPI) - appear to be affected in patients with Die. Antithrombin is synthesized in the liver and has a long half-life (» 48 h). It inactivates

705

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Y. Sakr, N.C.M. Youssef, and K. Reinhart

thrombin and inhibits factors IXa, Xa, Xla, Xlla, plasmin, kallikrein, and trypsin. Plasma levels of antithrombin, the most important inhibitor of thrombin, are markedly reduced as a result of the ongoing coagulation, degradation by elastase released from activated neutrophils, and impaired synthesis . A marked impairment of the protein C system occurs and is caused by a combination of impaired protein synthe sis, a cytokine-mediated decrease in the activity of endothelial thrombomodulin, and a decline in the level of the free fraction of protein S. Activation of the coagulation system may affect the inflammatory response in sepsis and vice versa [6). Inflammation induced coagulation activation is characterized by tissue factor mediated thrombin generation and simultaneous depression of protein C and S systems. In inflammation, activated platelets bind to neutrophils and mononuclear cells that result in activation of nuclear factor kappa B (NF-KB), and enhance the production of interleukin (lL)-I, IL-8, tumor necrosis factor (TNF)-a and monocyte chemotactic protein (MCP)-1 [6). Finally, tissue factor is induced and interacts with factor VII to activate the coagulation pathway. Endotoxin has a direct positive effect on tissue factor synthesis; likewise the formation of IL-l, 11-6, and TNF-a stimulates tissue factor formation. IL-6 is an important mediator of pro coagulant effects, while TNF-a is involved in the fibrinolytic response [6). Thrombin amplifies the inflammatory response, which in turn amplifies the coagulation response [6). Thrombin has many pro-inflammatory actions, including inducing the surface expression of P-selectin on the endothelium, being an agonist for the synthesis of platelet activating factor (PAF), being chemotactic for leukocytes, inducing the production of MCP-l and IL-6 in fibroblasts and of IL-6 and IL-8 in endothelial cells [6). The protein C pathway is uniquely poised to prevent this autoamplification. Thrombomodulin has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion [2). APC retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (TNF-a and IL-6). The anti-inflammatory activities of APC include inhibition of TNF-a release from monocytes, inhibition of tissue factor expression, and prevention of leukocyte adhesion. APC's anti-apoptotic activity appears to be mediated by the APC-EPCRcomplex [3). Factor Xa, thrombin and tissue-factor VIla elicit complex pro-inflammatory activities [6).

Protein C and Antithrombin Levels in Surgical ICU Patients Decreased plasma levels of antithrombin and protein C can occur in a variety of clinical conditions in the ICU, including sepsis [7 -9), acute lung injury (ALI) [10), neutropenia after cytostatic chemotherapy [U), post-surgical intervention [12, 13], and traumatic injury [14, 15). Patients with severe sepsis/septic shock and trauma have low levels of antithrombin and protein C due to activation of the coagulation system in these situations [14, 16). Neurosurgical patients were reported to have higher levels of antithrombin than trauma and septic patients [14). In patients after cardiac surgery, antithrombin activity was significantly lower compared to preoperative values [17). In 327 surgical ICU patients, we [13) reported that antithrombin levels were below the lower limit of normal in 84.1 % of patients and increased significantly by

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48 hours following admission to reach normal values by the 7th ICU day in patients who never had sepsis (Fig. 3). This increase in antithrombin levels was delayed in patients with sepsis. Patients with severe sepsis had consistently lower antithrombin levels compared with the other patients. Patients with lower antithrombin levels were more likely to need blood products and had a greater maximum degree of organ dysfunction in the ICU than other patients. Likewise, we [12] reported that plasma protein C concentrations were generally low in critically ill surgical patients, were associated with organ dysfunction/failure, and were independently associated with a higher risk of ICU mortality. Protein C concentrations were below the lower limit of normal in 50.6 % of patients on admission and decreased to a nadir within 3-4 days after admiss ion before almost normalizing by 2 weeks thereafter, irrespective of the presence of sepsis (Fig. 4). The minimum protein C concentration was lower in patients with severe sepsis/septic shock than in those with sepsis and those who never had sepsis, and was negatively correlated to the maximum sequential organ failure assessment (SOFA) score.

707

Fig. 4. Box plot representingthetime course of protein e concentrations (%) during the 2 weeks following admission to the leu in patients who never had sepsis in the leu (pale blue boxes), those with sepsis (mid blue boxes), and those with severe sepsis (including septic shock; dark blue boxes). The dashed line represents the lower limit of normal for protein e activity (70 %). Friedman test: p < 0.05 in each group over time. Multifactorial ANOVA; P< 0.05 between groups. *p < 0.05 compared with no sepsis group (MannWhitney U test with Bonferroni correction). $p < 0.05 compared with sepsis group (Mann-Whitney U test with Bonferroni correction). From [12] with permission

Prognostic Value of Protein ( and Antithrombin levels It has been suggested that antithrombin and protein C levels may have a role as predictors of outcome in patients with septic shock [7, 8, 16, 18-22]' and low antithrombin levels have also been found to be associated with an increased risk of infections and death in patients after trauma [15). However, the association between antithrombin levels and subsequent morbidity and mortality in the ICU is not consistent in the literature [9, 17]. Our recent data [13] showed that although antithrombin levels were consistently lower in non-survivors than survivors over the 2 weeks following ICU admission , in a receiver operating characteristic (ROC) curve analysis, simplified acute physiology II score (SAPS II) discriminated ICU mortality (area under the curve [AUC] : 0.78; 95 % confidence interval [CI]: 0.7-0.85) more efficiently than the antithrombin level on admission (AUC: 0.62; 95 % CI: 0.52-0.7l) or the minimum antithrombin level in the ICU (AUC: 0.72; 95 % CI: 0.64-0.8). In a multivariable analysis with ICU mortality as the dependent variable, only SAPS II score (odds ratio [OR) = 1.5; 95 % CI: 1.08-2.12, p = 0.017), maximum SOFA score (OR = 1.32; 95 % CI: 1.12-1.56, p = 0.00l), and the presence of severe sepsis (OR = 2.73; 95 % CI: 1.01-7.4, p = 0.001) were independent risk factors for ICU death, and not antithrombin levels. On the contrary [12), the AUC for ICU mortality prediction was 0.78 (95 % CI 0.71-0.85, p< 0.01) for minimum protein C concentration. Importantly, in the multivariate analysis with ICU mortality as a dependent variable, a

Protein Cand Antithrombin Levels in Surgical and Septic Patients

minimum protein C concentration less than 45 % was independently associated with a higher risk of death in the ICU (OR 4.02; 95 % CI, 1.43- 11.34, P = 0.008). A potential role for antithrombin levels as a predictor of outcome in septic shock patients was first suggested two decades ago [23] and several reports have supported this observation [8, 16, 19]. However, evaluation of the predictive value of a single laboratory test or model requires strict methodological criteria [24]. Significant differences in a single laboratory value between survivors and non-survivors may be present but not necessarily clinically relevant. Paradoxically, using larger sample sizes to detect possible differences in main outcome measures may actually increase the detection of clinically non-significant differences in secondary end points or demographic data (9). It should not be surprising, therefore, that despite the persistently lower antithrombin levels in non-survivors than in survivors over the 2 weeks following ICU admission, these were not associated with an increased risk of ICU death in the final multivariable analysis, after adjusting for baseline characteristics, severity of illness, and degree of organ dysfunction/failure. Similar observations have been reported in other studies [9, 17).

Protein Cand Antithrombin Deficiency: Clinical Implications In animal models, antithrombin administration prevents endotoxin-induced pulmonary accumulation of leukocytes and inhibits the increase in pulmonary vascular permeability (25); reduces hepatic ischemia/reperfusion-induced injury via prostacyclin-induced increased hepatic blood flow and reduced neutrophil activation (26); prevents and reverses leukocyte recruitment in ischemia/reperfusion injury [27]; reduces ischemia/reperfusion-induced renal injury by inhibiting leukocyte activation through promotion of prostacyclin production [28]; and improves outcome in severe sepsis (29). Unfortunately, success in animal models does not necessarily predict success in clinical trials . In a large, multicenter, double blind, placebo-control, randomized phase III trial, Warren et al. [30] did not demonstrate a survival benefit of antithrombin administration in 2314 patients with severe sepsis and the overall mortality rates at 28, 56, and 90 days were similar in patients who received antithrombin and those who were treated with placebo. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase, the 28-day mortality was non-significantly lower in the antithrombin group than in the placebo group and this trend became significant after 90 days. The overall incidence of bleeding complications was significantly more common in the antithrombin treatment group than in the placebo group (22 % x 12.8 %); this difference was most marked in those patients who received concomitant heparin therapy. Recently, a post-hoc analysis [31] demonstrated that patients with a higher degree of severity of illness (30-60 % predicted mortality according to the SAPS II score) who received antithrombin had increased 90-day survival, especially those who were not concomitantly treated with heparin. In a meta-analysis [32] and post-hoc reports [31] supplementation with antithrombin was shown to improve survival , but these data were not confirmed by a large phase III study [30), and the role of antithrombin is still unclear. Our data [13] should not necessarily be interpreted as a case against anti thrombin supplementation. The anti -inflammatory effect of antithrombin is thought to be independent of its anticoagulation activity [25-27] . Nevertheless, the current evidence does not support the routine use of antithrombin therapy in patients with sepsis.

709

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Y. Sakr, N.C.M. Youssef, and K. Reinhart

In surgical ICU patients, we [12) reported that the minimum protein C concentration correlated negatively with the SOFAmax (R2 = 0.345, P < 0.001; Fig. 5). All patients with a SOFAmaxgreater than 16 and 91 % of those with a SOFAmaxbetween 8 and 16 had a minimum protein C concentration below the lower limit of normal. Moreover, the minimum protein C concentration was also lower according to the degree of organ dysfunction/failure as assessed by the SOFAmax subscores for the cardiovascular, respiratory, renal, hepatic, and coagulation systems. The tight relation ship we observed between protein C concentrations and organ dysfunction/failure as assessed by the SOFA score [12) may explain the results of therapeutic studies [33- 36) targeting the protein C pathway. A benefit of treatment with recombinant human APC (drotrecogin alfa [activated)) was reported in patients with severe sepsis who had a higher degree of organ dysfunction [33) and those with overt DIC [34). The Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) study [36) provided supportive evidence for the favorable risk/benefit rat io observed previously in the Recombinant Human Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) study [33) and suggested that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier. However, no beneficial effect was dem onstrated in patients with severe sepsis who were at low risk of death, such as those with single-organ failure or an APACHE II score less than 25 [35). These observations support the hypothesis that organ failure, and not sepsis per se, is the major determinant of protein C deficiency. Whether targeting the protein C pathway could improve outcome in pat ients with multiorgan failure of non-septic origin remains an unanswered question. Further studies are needed to confirm or negate this hypothesis. 24

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Fig. S. Scatter plot representing the minimal protein Cconcentration (%, Xaxis) and maximum SOFA score during the ICU stay (Y axis) in patients with nosepsis (circles), those with sepsis (squares), and those with severe sepsis (including septic shock, triangles). The solid line represents the best fit (quadratic) with 9S % confidence interval (dashed lines). R2 = 0.345, P < 0.001. From [12) with permission.

Protein ( and Antithrombin Levels in Surgical and Septic Patients

Conclusion In surgical ICU patients, antithrombin levels are low on admission to the ICU regardless of the presence of sepsis syndromes. Despite being associated with the degree of organ dysfunction and the severity of sepsis, antithrombin levels poorly predicted ICU mortality and were not independently associated with worse outcomes in this group of surgical ICU patients. Protein C concentrations are generally low in critically ill surgical patients, with a more pronounced decrease during the ICU stay in the presence of severe sepsis/septic shock. Protein C levels are also associated with organ dysfunction/failure, and are independently associated with higher risk of ICU mortality. Protein C concentrations could be a good prognostic marker in these patients . References 1. Hoffman (2005) Hematology: Basic Principles and Practice, 4th ed. Churchill Livinsgstone, Philadelphia 2. Esmon C (2000) The protein C pathway. Crit Care Med 28:S44-S48 3. Esmon CT (2003) The protein C pathway. Chest 124:26S-32S 4. Dempfle CE (2004) Coagulopathy of sepsis. Thromb Haemost 91:213 -224 5. Levi M, ten Cate H (1999) Disseminated intravascular coagulation. N Engl J Med 341: 586-592 6. Levi M, Keller TT, van Gorp E, ten Cate H (2003) Infection and inflammation and the coagulation system. Cardiovasc Res 60:26- 39 7. LaRosa SP, Opal SM, Utterback B, et al (2006) Decreased protein C, protein S, and antithrombin levels are pred ictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudo mallei. Int J Infect Dis 10:25- 31 8. Karamarkovic A, Radenkovic D, Milic N, Bumbasirevic V,Stefanovic B (2005) Protein C as an early marke r of severe septic complications in diffuse secondary periton itis. World J Surg 29:759-765 9. Pettila V, Pentti J, Pettila M, Takkunen 0 , [ousela I (2002) Predictive value of antithrombin III and serum C-reactive protein concentration in critically ill patients with suspected sepsis. Crit Care Med 30:271- 275 10. Matthay MA, Ware LB (2004) Plasma protein C levels in patients with acute lung injury: prognostic significance. Crit Care Med 32:S229-S232 11. Mesters RM, Helterbrand J, Utterback BG, et al (2000) Prognostic value of protein C concen trations in neutropenic patients at high risk of severe septic complications. Crit Care Med 28:2209 - 2216 12. Brunkhorst F, Sakr Y, Hagel S, Reinhart K (2007) Protein C concentrations correlate with organ dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology 107:15-23 13. Sakr Y, Reinhart K, Hagel S, Kientopf M, Brunkhorst F (2007) Antithrombin levels, morb idity, and mortality in a surgical intensive care unit . Anesth Analg 105:715-723 14. Boldt J, Papsdorf M, Rothe A, Kumle B, Piper S (2000) Changes of the hemostatic network in critically ill patients - is there a difference between sepsis, trauma, and neurosurgery patients? Crit Care Med 28:445-450 IS. Wilson RF, Mammen EF, Tyburski JG, Warsow KM, Kubinec SM (1996) Antithrombin levels related to infections and outcome. J Trauma 40:384- 387 16. Fourrier F, Chopin C, Goudemand J, et al (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101:816- 823 17. Ranucci M, Frigiola A, Menicanti L, Ditta A, Boncilli A, Brozzi S (2005) Postoperative anti thromb in levels and outcome in cardiac operations. Crit Care Med 33:355- 360 18. Mammen EF (1998) Antithrombin: its physiological importance and role in DIe. Semin Thromb Hemost 24:19-25

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Y. Sakr, N.C.M. Youssef, and K. Reinhart 19. Dhainaut JF, Shorr AF, Macias WL, et al (2005) Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med 33: 341-348 20. Kinasewitz GT,Yan SB, Basson B, et al (2004) Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569). Crit Care 8:R82-R90 21. Macias WL, Nelson DR (2004) Severe protein C deficiency predicts early death in severe sepsis. Crit Care Med 32:S223-S228 22. Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR (2001) Low levels of protein C are associated with poor outcome in severe sepsis. Chest 120:915-922 23. Mammen EF, Koets MH, Washington BC, et al (1985) Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 11:281- 292 24. Randolph AG, Guyatt GH, Calvin JE, Doig G, Richardson WS (1998) Understanding articles describing clinical prediction tools. Evidence Based Medicine in Critical Care Group. Crit Care Med 26:1603-1612 25. Uchiba M, Okajima K (1997) Antithrombin III (ATIII) prevents LPS-induced pulmonary vascular injury: novel biological activity of AT III. Semin Thromb Hemost 23:583- 590 26. Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K (1999) Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 93:157-164 27. Ostrovsky L, Woodman RC, Payne D, Teoh D, Kubes P (1997) Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion. Circulation 96:2302- 2310 28. Mizutani A, Okajima K, Uchiba M, et al (2003) Antithrombin reduces ischemia/reperfusioninduced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. Blood 101:3029-3036 29. Mammen EF (1998) Antithrombin III and sepsis. Intensive Care Med 24:649-650 30. Warren BL, Eid A, Singer P, et al (2001) Caring for the critically ill patient . High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869 -1878 31. Wiedermann CJ, Hoffmann IN, Juers M, et al (2006) High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med 34:285-292 32. Eisele B, Lamy M, Thijs LG, et al (1998) Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with ant ithrombin III in severe sepsis. Intensive Care Med 24:663 - 672 33. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699- 709 34. Dhainaut JF, Laterre PF, Janes JM, et al (2003) Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 29:894 - 903 35. Abraham E, Laterre PF, Garg R, et al (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353:1332-1341 36. Vincent JL, Bernard GR, Beale R, et al (2005) Drotrecogin alfa (activated) treatment in severe sepsis from global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Crit Care Med 33:2266-2277

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Thrombophilia as a Risk Factor for Outcome in Sepsis J.-J.

HOFSTRA, M. SCHOUTEN, and M. LEVI

Introduction Virtually all patients with sepsis have coagulation abnormalities. These abnormalities range from subtle activation of the coagulation system that can only be detected by sensitive markers for coagulation factor activation , to somewhat stronger coagulation activation detectable by a small decrease in platelet count and sub-clinical prolongation of global clotting times, to fulminant disseminated intravascular coagulation (DIC), which is characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites [1]. Septic patients with severe forms of DIC may present with manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction [2-5]. Clinically relevant coagulation abnormalities are present in 50- 70 % of patients with severe infection or sepsis, whereas about 35 % of patients will actually meet the criteria for DIC [1,6].

Sepsis and Coagulation There is ample evidence that activation of coagulation in concert with inflammatory activation can result in microvascular thrombosis and thereby contributes to multiple organ failure (MOF) in patients with severe sepsis [7]. First, extensive data have been reported on post-mortem findings of patients with severe infectious diseases and coagulation abnormalities or DIC [8,9] . These autopsy findings include hemorraghic necrosis of tissue, microthrombi in small blood vessels, and thrombi in mid-size and larger arteries and veins. In these studies, ischemia and necrosis were invariably associated with fibrin deposition in small and mid-size vessels of various organs [10]. Second, experimental animal studies of DIC show fibrin deposition in various organs. Experimental bacteremia or endotoxemia causes intra- and extravascular fibrin deposition in kidneys, lungs, liver, brain, and various other organs. Amelioration of the hemostatic defect by various interventions in these experimental models appeared to improve organ failure and, in some but not all cases, survival [11-14]. Interestingly, some studies indicate that prevention of systemic coagulation activation reduces local fibrin deposition and organ failure [15, 16]. Last, clinical studies support the notion of coagulation as an important denominator of clinical outcome. DIC has been shown to be an independent predictor of organ failure and mortality in patients with sepsis [2, 17]. In a consecutive series of patients with severe sepsis the mortality of patients with DIC was 43 %, compared with 27 % in those without DIC [18]. In this study, the severity of the coagulopathy was also directly related to mortality.

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Since the prohemostatic state in severe infection and sepsis seems to be relevant for the pathogenesis of organ dysfunction and mortality, it may be hypothesized that a pre-existent prothrombotic state in patients would aggravate the coagulation derangement during infection and sepsis and thereby affect outcome. Such a prothrombotic state may be present in patients with congenital thrombophilia. In this chapter, we will briefly review experimental and clinical evidence on the relationship between thrombophilia and the outcome of severe infection and sepsis.

Coagulation Factor Gene Polymorphisms and Outcome in Infection and Sepsis Congenital thrombophilia is mostly due to a genetic variation in a gene encoding a coagulation factor or - in general clinically less relevant - a fibrinolytic protein. Such gene polymorphisms have been described for the coagulation factors prothrombin, factor V, fibrinogen, and factor XIII and for the coagulation inhibitors antithrombin, protein C and protein S. In the latter case, these mutations cause a deficiency of these natural anticoagulant factors. In the fibrinolytic system the most relevant polymorphism is the 4G/5G variation in the gene encoding plasminogen activator inhibitor type I (PAl-I). This polymorphism results in mildly elevated levels of PAl-1 and is related to an increased risk of myocardial infarction and ischemic stroke. Anecdotal reports have indicated that the presence of congenital thrombophilia may exacerbate the coagulopathy associated with severe infection and may even result in purpura fulminans [19-23]. Indeed, various coagulation defects seem to be associated with an aggravated coagulation response to infectious agents or sepsis, although a systematic overview is missing [24]. Prospective studies on the incidence or outcome of severe infections and sepsis in patients with a prothrombotic polymorphism or coagulation inhibitor deficiency are not available. However, some casecontrol studies have reported on the prevalence of thrombophilic abnormalities in cohorts of patients with severe sepsis. Moreover a substantial number of animal studies have been performed. These studies have particularly focused on deficiencies in the protein C and antithrombin pathways, the factor V Leiden mutation, and genetic polymorphisms in the fibrinolytic system. The association between these defects and outcome from severe infection and sepsis will be discussed in more detail in the following paragraphs.

Genetic Variation in the Protein C and Antithrombin Pathways and Outcome in Infection and Sepsis There are several indications that the protein C system plays an important role in sepsis. An impaired function of the protein C system is directly related to the severity and outcome of sepsis [25]. The most compelling evidence comes from experimental studies showing that administration of activated protein C (APC) to septic animals resulted in amelioration of Die and improved survival [14]. Clinical studies confirm the beneficial effect of APC in sepsis [26]. Severe (congenital) protein C deficiency in mice results in thrombophilia as well as a pro-inflammatory phenotype with higher total white blood cell (WBC) counts and higher basal interleukin (IL)-6 levels as compared with wild type mice [27]. Further protein C deficiency was

Thrombophilia as a Risk Factor for Outcome in Sepsis

shown to affect endotoxemia in a mouse model. In these experiments, mice with a one allele targeted deletion of protein C, resulting in heterozygous protein C deficiency [28], were subjected to endotoxemia [29]. Levels of protein C activity in these mice dropped from 61 ± 5 % to 18 ± 7 % compared with a drop from 98 ± 4 % to 38 ± 5 % in wild-type mice (Fig. 1). Mice with a heterozygous deficiency of protein C had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger reduction in platelet count. In addition, thrombin-antithrombin complex levels were 3.4-fold higher in protein C+I- mice compared with wild type mice and histologic examination showed more fibrin deposition in lungs and kidneys in these mice. Survival at 12 hours after the endotoxin injection was diminished in the protein C+I- group. Interestingly, protein C+I- mice had significantly higher levels of the pro-inflammatory cytokines , tumor necrosis factor (TNF)-a, IL-6, and IL-l~, indicating an interaction between the protein C system and the inflammatory response . This latter observation is consistent with many other studies indicating cross-talk between effects of protein C on coagulation and inflammatory modulation [30]. Similar findings were reported in studies in mice genetically predisposed to a severe protein C deficiency [31]. Interestingly, reconstitution of prote in C levels in these mice with recombinant human APC resulted in less severe inflammatory responses and an improved survival. In a model of severe abdominal infection through cecal ligation and puncture, mice with a heterozygous deficiency of protein C had more profound organ dysfunction and an enhanced mortality in comparison to wild-type mice [32]. Taken together, these data suggest that preexistent protein C deficiency aggravates the coagulopathic response to severe infection and sepsis and is related to

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a worse outcome. It is not clear whether this observation may be extended to the clinical situation, mostly due to the fact that deficiency of protein C in humans is relatively rare. Therefore it is hard to establish a relationship between this condition and the incidence of or outcome from sepsis. Antithrombin is the cardinal inhibitor of thrombin and factor Xa activity and, like the protein C pathway, a central regulator of coagulation activation in vivo. There is ample evidence that antithrombin is unable to adequately regulate these coagulation proteases in sepsis. Clinical studies show mean levels of antithrombin as low as 30 % of normal values in patients with severe sepsis, whereas in selected individuals these levels may be even lower [17, 33]. Low levels of antithrombin have been shown to be associated with a higher mortality in septic patients in several prospective studies [17]. Restoration of antithrombin levels in experimental DIC in animals has been demonstrated to adequately block the systemic activation of coagulation and was also associated with improved outcome in terms of less organ failure and a reduction in mortality in these studies [12, 34]. In mice with a heterozygous deficiency of antithrombin, endotoxemia leads to greater deposition of fibrin in various organs, including kidneys, liver, and heart, as compared with endotoxemic wild-type mice [35]. There are no clinical data that point to a role of antithrombin deficiency in the outcome from sepsis or severe infection in humans.

Factor V Leiden and Sepsis In view of the central role of the protein C pathway in sepsis, a lot of attention has been given to the presence of factor V Leiden mutation, which leads to resistance to APC, and the severity of and outcome from sepsis or severe infection. In a clinical study in 259 children with meningococcal sepsis, factor V Leiden carriers had more profound coagulopathy and purpura fulminans, but their carrier status had no significant effect on survival [36]. Unfortunately, both experimental and clinical studies in sepsis have not shown unequivocal results regarding the presence of the factor V Leiden mutation so far. In one study, endotoxemic mice carrying a heterozygous factor V Leiden mutation had a surprisingly lower mortality (19 %) compared to their wild-type controls (57 %) [37]. In these experiments, factor V Leiden mice produced more thrombin than normal controls, indicating a more profound activation of coagulation. In contrast, factor V Leiden mice did not differ significantly in their response compared to wild-type mice in a model of septic peritonitis, as reflected by similar degrees of activation of coagulation, inflammation, organ dysfunction, and survival [38]. Moreover, mice with both one or two factor V Leiden alleles had the same bacterial outgrowth and inflammatory response as wild type mice in a model of pneumococcal pneumonia (unpublished data). Clinical studies also show variable results. The presence of the factor V Leiden mutation was analyzed in large cohorts of patients with severe sepsis that had been included in intervention studies with recombinant human APC [26, 39]. In this study of 3894 patients, the prevalence of factor V Leiden heterozygosity was 3.9 % which is slightly higher than the predicted allelic frequency of 2.5 % [40]. The 28day mortality in those with factor V Leiden was not significantly different from the control population (19.3 % versus 26.2 %, risk ratio 0.74; 95 % confidence interval 0.53-1.03). Moreover, there were no differences in the incidence of serious bleeding or thrombotic events between factor V Leiden carriers and non-factor V Leiden carriers. In another publication in which the data of only one of these two studies were

Thrombophilia as a Risk Factor for Outcome in Sepsis

presented [37) patients with a heterozygous factor V Leiden mutation were shown to have a lower mortality (l3.9 %) than those without this mutation (27.9 %, P = 0.013) [37]. There was no different effect of treatment with recombinant human APC between the two groups. In the Copenhagen City Heart study, 9253 individuals were screened for the presence of the factor V Leiden mutation and followed for a period of more than 7 years to establish the risk of hospitalization for any infectious disease and the subsequent risk of progression of disease to death [41]. The relative risk of any infection in carriers of the factor V Leiden mutation was 1.08 (95 % confidence interval 0.87 -1.35) as compared with non-carriers (after adjustment for age, sex, smoking, alcohol consumption, income, and level of education). In contrast with the previously mentioned study, patients with the factor V Leiden mutation in this study had a higher risk of death from infection as compared with patients who did not have this mutation (adjusted relative risk 4.41, 95 % confidence interval 1.42-13.67). In conclusion, both experimental and clinical studies show inconsistent results in relation to whether carriers of the factor V Leiden mutation have different survival from sepsis or severe infection than non-carriers. Although it may be biologically plausible that the factor V Leiden mutation and the ensuing APC resistance would aggravate the response to sepsis, the opposite may also be true as it has been speculated that a balanced and moderate increase in thrombin generation, as may be caused by a heterozygous factor V Leiden mutation, might be protective during severe infection and sepsis by means of generating slightly more APC [42]. Additional analyses in larger cohorts of septic patients or long-term prospective studies in patients with a known factor V Leiden mutation will be required to clarify this issue.

Gene Polymorphisms in the Fibrinolytic System and Outcome in Infection and Sepsis At the time of maximal activation of the coagulation system in sepsis, the fibrinolytic system is largely shut down. The acute fibrinolytic response to inflammation is the release of plasminogen activators, in particular tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), from storage sites in vascular endothelial cells. However, this increase in plasminogen activation and subsequent plasmin generation is counteracted by a delayed but sustained increase in PAl-1 [43, 44]. The resulting effect on fibrinolysis is a complete inhibition and, as a consequence, inadequate fibrin removal which contributes to microvascular thrombosis. Experiments in mice with targeted disruptions of genes encoding components of the plasminogen-plasmin system confirm that fibrinolysis plays a major role in inflammation-induced coagulation. Mice with a deficiency of plasminogen activators had more extensive fibrin deposition in organs when challenged with endotoxin, whereas PAI-l knockout mice, in contrast to wild-type controls, had no microvascular thrombosis upon endotoxin challenge [45, 46). Of interest, two studies showed that a functional mutation in the PAI-l gene, the 4G/5G polymorphism, not only influenced the plasma levels of PAl-I, but was also linked to clinical outcome from meningococcemia [47]. Patients with the 4G/4G genotype had significantly higher PAI-l concentrations in plasma and an increased risk of death [48). Further investigations demonstrated that the PAI-l polymorphism did not influence the risk of contracting meningitis as such, but probably increased the likelihood of developing septic shock from meningococcal infection [49,50) .

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Conclusion Activation of coagulation seems to playa pivotal role in the pathogenesis and outcome of severe infection and sepsis. Hypothetically, a preexisting prohemostatic state, as seen in congenital thrombophilia, may aggravate the severity of this coagulopathy and may thereby affect outcome. Experimental animal studies show that deficiencies in protein C or antithrombin will indeed worsen sepsis-induced coagulopathy and result in increased morbidity and mortality. The interaction between the presence of the factor V Leiden mutation and the outcome of severe infection and sepsis is less clear, as both experimental and clinical studies show divergent results. In the fibrinolytic system, in particular the 4G/5G polymorphism in the PAI-l gene seems to have a significant impact on the clinical outcome of severe sepsis. Additional studies involving larger cohorts of patients with severe infection or sepsis and long-term prospective follow-up studies in patients with congenital thrombophilia are required to further elucidate the relationship between thrombophilic defects and outcome in severe infection and sepsis. References 1. Levi M (2004) Current understanding of disseminated intravascular coagulation . Br J Haematol 124:567- 576 2. Levi M, ten Cate H (1999) Disseminated intravascular coagulation. N Engl J Med 341: 586-592 3. Colman RW, Robboy 5J, Minna JD (1979) Disseminated intravascular coagulation: a reappraisal. Annu Rev Med 30:359-374 4. Levi M, van Gorp E, ten Cate H (2002) Disseminated intravascular coagulation. In: Handin R I, Lux S E, Stossel T P (eds) Blood: Principles and Practice of Hematology. JB Lippincott, Philadelphia, pp 1275-1302 5. Levi M, Marder VJ (2006) Coagulation abnormalities in sepsis. In: Colman RW, Marder VJ, Clowes AW, George IN, Goldhaber SZ (eds) Hemostasis and Thrombosis: Basic principles and Clinical. Practice Lippincott William and Wilkins, Philadelphia, pp 1601-1613 6. Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340:207- 214. 7. Levi M, Keller TT, van Gorp E, ten Cate H (2003) Infection and inflammation and the coagulation system. Cardiovasc Res 60:26-39. 8. Robboy 5J, Major MC, Colman RW, Minna JD (1972) Pathology of disseminated intravascular coagulation (DIC). Analysis of 26 cases. Human Pathology 3:327- 343. 9. Shirnamura K, Oka K, Nakazawa M, Kojima M (1983) Distribution patterns of microthrombi in disseminated intravascular coagulation. Arch Path Lab Med 107:543-547 10. Coalson 11 (1986) Pathology of sepsis, septic shock, and multiple organ failure. In: Sibbald WJ (ed) Perspective on Sepsis and Septic Shock. Society of Critical Care Medicine, Fullerton, pp 27-59 11. Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FBJ, Hinshaw LB (1993) Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 91: 2850-2856 12. Kessler CM, Tang Z, Jacobs HM, Szymanski LM (1997) The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity. Blood 89:4393-4401 13. Taylor FBJ, Chang A, Ruf W, et al (1991) Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 33:127-134 14. Taylor FBJ, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79:918-925

Thrombophilia as a Risk Factor for Outcome in Sepsis 15. Welty-Wolf KE, Carraway MS, Miller DL, et al (2001) Coagulation blockade prevents sepsisinduced respiratory and renal failure in baboons. Am J Respir Crit Care Med 164:1988-1996 16. Miller DL, Welty-WolfK, Carraway MS, et al (2002) Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. Am J Respir Cell Mol Bioi 26:650- 658 17. Fourr ier F,Chopin C, Goudemand J, et al (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation . Compared patterns of antithrombin 1lI, protein C, and protein S deficiencies. Chest 101:816- 823 18. Dhainaut JF, Yan SB, Joyce DE, et al (2004) Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2:1924-1933 19. Inbal A, Kenet G, Zivelin A, et al (1997) Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. Thromb Haemost 77:1086-1089 20. Dogan Y, Aygun D, Yilmaz Y, et al (2003) Severe protein S deficiency associated with heterozygous factor V Leiden mutation in a child with purpura fulminans. Pediatr Hematol Oncol 20:1-5 21. al Ismail S, Collins P, Najib R, James-Ellison M, O'Hagan M (1999) Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210A and acquired protein S resistance. Pediatr Hematol Oncol 16:561- 564 22. Woods CR, Johnson CA (1998) Varicella purpura fulminans associated with heterozygosity for factor V leiden and transient protein S deficiency. Pediatrics 102:1208-1210 23. Sackesen C, Secmeer G, Gurgey A, et al (1998) Homozygous Factor V Leiden mutation in a child with meningococcal purpura fulminans . Pediatr Infect Dis J 17:87 24. Texereau J, Pene F,Chiche JD, Rousseau C, Mira JP (2004) Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis. Crit Care Med 32:S313-S319 25. Levi M, de Ionge E, van der Poll T (2001) Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation. Crit Care Med 29 (Suppl 7):S90-94 26. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699- 709 27. Lay AJ, Liang Z, Rosen ED, Castellino FJ (2005) Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilit ies. J Clin Invest 115:1552-1561 28. Jalbert LR, Rosen ED, Moons L, et al (1998) Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 102:1481-1488 29. Levi M, Dorffler-Melly J, Reitsma PH, et al (2003) Aggravation of endotoxin-induced disseminated intravascular coagulation and cytok ine activation in heterozygous protein C deficient mice. Blood 101 :4823-4827 30. Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation . Circulation 109:2698-2704 31. Lay AJ, Donahue D, Tsai MJ, Castellino FJ (2007) Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency. Blood 109:1984-1991 32. Ganopolsky JG, Castellino FJ (2004) A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model. Am J Pathol 165:1433-1446 33. Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J (1996) Factor VIla and antithrombin 1lI activity during severe sepsis and septic shock in neutropenic patients. Blood 88:881-886 34. Minnema MC, Chang AC, Jansen PM, et al (2000) Recombinant human antithrombin 1lI improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli. Blood 95:1117- 1123 35. Yanada M, Kojima T, Ishiguro K, et al (2002) Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice. Blood 99:2455 - 2458 36. Kondaveeti S, Hibberd ML, Booy R, Nadel S, Levin M (1999) Effect of the Factor V Leiden mutation on the severity of meningococcal disease. Pediatr Infect Dis J 18:893-896

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J.-J. Hofstra, M. Schouten, and M. Levi 37. Kerlin BA, Yan SB, Isermann BH, et al (2003) Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 102:3085 - 3092 38. Bruggemann LW, Schoenmakers SH, Groot AP, Reitsma PH, Spek CA (2006) Role of the factor V Leiden mutation in septic peritonitis assessed in factor V Leiden transgenic mice. Crit Care Med 34:2201 - 2206 39. Bernard GR, Margolis BO, Shanies HM, et al (2004) Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 125:2206 - 2216 40. Yan SB, Nelson DR (2004) Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med 32:S239-S246 41. Benfield TL, Dahl M, Nordestgaard BG, Tybjaerg-Hansen A (2005) Influence of the factor V Leiden mutation on infectious disease susceptibility and outcome: a population-based study. J Infect Dis 192:1851-1857 42. Weiler H, Kerlin B, Lytle MC (2004) Factor V Leiden polymorphism modifies sepsis outcome: evidence from animal studies . Crit Care Med 32:S233-S238 43. van der Poll T, Levi M, Buller HR, et al (1991) Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 174:729-732 44. Biemond BJ, Levi M, ten Cate H, et al (1995) Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Colch ) 88:587- 594 45. Yamamoto K, Loskutoff OJ (1996) Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator. J Clin Invest 97:2440- 2451 46. Pinsky OJ, Liao H, Lawson CA, et al (1998) Coordinated induction of plasminogen activator inhibitor-I (PAl-I) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 102:919-928 47. Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S, Levin M (2003) Role of functional plasminogen-activator-inhibitor-I 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children . Crit Care Med 31:2788-2793 48. Hermans PW, Hibberd ML, Booy R, et al (1999) 4G/5G promoter polymorphism in the plasrninogen-activator-inhibitor-I gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 354:556-560 49. Westendorp RG, Hottenga 11, Slagboom PE (1999) Variation in plasminogen-activator-inhibitor-I gene and risk of meningococcal septic shock. Lancet 354:561- 563 50. Geishofer G, Binder A, Muller M, et al (2005) 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia. Eur J Pediatr 164:486-490

721

The Effects of Activated Protein ( on the Septic Endothelium S.E.

ORFANOS,

N.A.

MANIATIS ,

and A.

KOTANIDOU

Introduction Sepsis is a serious disorder with high morbidity and mortality worldwide and an increasing incidence [1). Sepsis is the result of an overwhelming and maladaptive response of the host organism to the invasion of pathogenic microorganisms, which generates an uncontrolled and auto-destructive inflammatory process [2). The septic syndrome carries various degrees of severity, and critically ill patients often develop sepsis-induced acute organ dysfunction (i.e., severe sepsis) and fluid-refractory hypotension (i.e., septic shock) . Extensive research performed during the past two decades has greatly improved our understanding of the mechanisms underlying sepsis pathophysiology: Widespread devastating inflammation and microvascular coagulation are common denominators in severe sepsis, while endothelial cell dysfunction appears to be a key determinant in the development of the syndrome [3, 4). The intimal lining of all blood vessels is a single layer of functionally and structurally heterogeneous endothelial cells depending on organ and vascular bed location [5). Microvascular endothelium is a metabolically active organ essential for the maintenance of adequate cardiovascular homeostasis [5, 6). Endothelial cells regulate permeability, and modulate vascular tone, hemofluidity, and interactions with blood-borne cells. Sepsis induces an endothelial phenotypic shift accompanied by secretion of inflammatory and chemotactic substances, expression of adhesion molecules, increased permeability and loss of anticoagulant functions, resulting in loss of endothelial cell functional and structural integrity [4, 6]. Endothelial dysfunction and microvascular functional impairment appear to be major determinants of organ dysfunction and death in sepsis [2). Of particular interest is the role of the pulmo nary microvascular endothelium in preserving both pulmonary and systemic homeostasis [6]; pulmonary endothelial cell injury will lead to the development of acute lung injury (ALI) and will additionally promote distal organ dysfunction. For a detailed analysis of endothelial cell metabolic properties and their response to injury, the reader is referred to reference [6). The protein C system has been shown to playa major role in sepsis, being both an important regulator of the coagulation system (anticoagulant protein C pathway) and a cytoprotector of several cell-types (cytoprotective protein C pathway), including the endothelium [7, 8]. Activated protein C (APC) administration in patients with severe sepsis has been one of the most promising and widely discussed topics in the Critical Care setting. In contrast to other anticoagulant agents, the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) randomized trial [9) docu mented a clinical benefit of recombinant human (rh)APC administration in patients with severe sepsis, which could be due to drug-induced cytoprotection. Although

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S.E. Orfanos, N.A. Maniatis, and A. Kotanidou

the mechanisms of APC action are still under intense investigation, numerous studies performed over the past few years have provided evidence for a direct APC protective effect on the endothelium, a short overview of which will be presented in this chapter.

Protein ( Pathway Protein C is a vitamin K-dependent plasma glycoprotein, synthesized by the liver, and circulating as a two-chain biologically inactive zymogen. Protein C concentration in plasma is 70 nM, while concentrations of its activated form, the serine protease, APC, average 40 pM (-2.3 nglmL) in normal plasma [7]. Thrombin induces protein C proteolytic activation on the endothelial cell surface to produce APC, with the aid of two membrane receptors, namely thrombomodulin and endothelial protein C receptor (EPCR) (Fig. 1). Thrombomodulin amplifies the protein C to APC conversion by > lOOO-fold compared with thrombin acting alone. Protein activation is further enhanced - 20-fold in vivo when protein C is bound to EPCR (Fig 1). EPCR is expressed on endothelial cells, leukocytes, immature hematopoietic stem cells, and as a biologically active soluble form, while expression of functional receptors has been recently identified on vascular smooth muscle cells. Besides its contribution to APC generation, EPCR appears to possess additional inflammatory func-

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Fig. 1. Schematic representation of protein C(PC) activation and activated protein C(APC) cytoprotective activities. The endothelial cell receptors, thrombomodulin (TM) and endothelial protein Creceptor (EPCR), are required for maximal PC activation by thrombin. Induction ofthe cytoprotective effects ofAPC requires the activation of protease activated receptor-t (PAR-l), while EPCR serves as a coreceptor, PAR-l is activated by proteolytic cleavage within the extracellular N-terminal tail. APC cytoprotective activities include: i. Alteration in gene expression, which promotes upregulation of anti-inflammatory pathways and downregulation of pro-inflammatory pathways, resulting among others in reduced nuclear transcription factor lCB (NF-lCB) expression and functional activity, and inhibition of cell surface adhesion molecule induction and inducible nitric oxide synthase (iNOS) expression; ii, Anti-inflammatory activities; iii. Anti-apoptotic activity; and iv. Endothelial barrier stabilization.

The Effects of Activated Protein Con the Septic Endothelium

tions, such as regulating leukocyte-endothelial cell adhesion [10- 12]. Recent work performed in EPCR knockout mice challenged with lipopolysaccharide (LPS), provides evidence that the EPCR-related coagulation and inflammatory responses induced during endotoxemia are mostly regulated by non-hematopoietic rather than hematopoietic receptors [13]. Loss of thrombomodulin and EPCR from the cell surface is related to decreased prote in C activation, a phenomenon implicated in sepsis pathogenesis [14]. Two recent investigations have provided additional information related to this issue: Villegas-Mendez et al. [15] provided evidence that activated neutrophils and purified neutrophil proteinase 3 (PR3) decrease endothelial EPCR by proteolysis suggesting an addit ional mechanism that could downregulate the protein C pathway during inflammation. It should be additionally noted that binding of soluble EPCR to activated neutrophils occurs via PR3 [15]. In a second report, Weijer et al. demonstrated that mice with a mutation in the thrombomodulin gene that impairs APC generation have uncontrolled lung inflammation dur ing tuberculosis [16). It should be noted that loss of endothelial EPCR and thrombomodulin expression may also contribute to the pathophysiology of inflammatory diseases other than sepsis. Such appears to be the case in the intestinal mucosal microvasculature in Crohn's disease and ulcerative colitis [17).

Anticoagulant Protein C Pathway Increasing evidence has suggested the existence of two modes of action of APC that appear distinct from each other : An anticoagulant and a cytoprotective role. The former mainly involves the irreversible proteolytic inactivation of factors Va and VIlla, with the contribution of various protein and lipid cofactors [7]. Further analysis of anticoagulant APC properties is beyond the scope of this chapter. It should be noted, however, that the APC anticoagulant pathway also exerts an indirect antiinflammatory cytoprotective effect by inhibiting thrombin generation and consequently decreasing the pro-inflammatory sequence of events related to the latter. In fact, the beneficial effect of APC at the cellular level was previously attributed solely to the aforementioned indirect action, until clinical and basic research findings pointed to the existence of a direct cytoprotective protein C pathway [7).

Cytoprotective Protein C Pathway Numerous investigations have provided evidence that APC exerts direct cytoprotective effects on various cell-types, and more specifically on endothelial cells. These cytoprotective effects are mostly related to: i) gene expression alteration; ii) antiinflammatory activities ; iii) antiapoptotic activity; and iv) endothelial cell barrier stabilization [7, 18). A schematic presentation of these actions is provided in Figure 1. Most cytoprotective effects require the activation of protease activated receptor-I (PAR-I) [7,8, 18, 19], while EPCR serves as a co-receptor. PAR-I is a G-protein coupled receptor, activated by proteolytic cleavage within the extracellular N-terminal tail (Fig. 1). An apparent paradox exists in that the beneficial pharmacological effects of APC require PAR-I, while at the same time PAR-I is the receptor via which thrombin mainly exerts its pro-inflammatory actions. It appears that PAR-I can mediate either pro- or anti- inflammatory signals, depending on the activating prote-

723

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S.E. Orfanos, N.A. Maniatis, and A. Kotanidou

ase, the protease concentration, and the cell type where the receptor is expressed [20,21].

APC-related Endothelial Cell Gene Expression Alteration and Anti-inflammatory Activity Several stud ies have provided evidence that cell treatment with APC results in modulation of gene expression related to the major pathways of inflammation and apoptosis: Pro-inflammatory and proapoptotic pathways are downregulated, while antiinflammatory and anti-apoptotic pathways are upregulated. There is thus a substan tial overlap between APC-induced endothelial cell genomic alterations and APCrelated anti-inflammatory activity. A detailed list of such genes is provided in ref [7]. In this respect, Joyce et al. have shown that rhAPC directly modulates patterns of endothelial cell gene expression clustering into anti-inflammatory and cell survival pathways: rhAPC reduced nuclear transcription factor lCB (NF-lCB) expression and functional activity, while it additionally inhibited cytokine signaling, including tumor necrosis factor-alpha (TNF-a)-related induction of cell surface adhesion molecules [22]. The same group provided further information on several immune response modulating genes whose activation is suppressed by APC [23]. The anti-inflammatory activity of APC on endothelial cells is mainly related to the inhibition of pro-inflammatory mediator release and the downregulation of adhesion molecules. It should be noted that APC exerts an additional endothelial cell-protective effect, through its action on leukocytes: APC has been shown to inhibit leukocyte cytokine release, chemotaxis, and migration in vivo [7]. The combined APC action on both cell types reduces leukocyte-endothelial cell adhesion and the consequent leukocyte parenchymal infiltration, thus attenuating tissue injury. Several studies have addressed the anti-inflammatory action of APC on endothelial cells. Brueckmann et al. showed that treatment of human umbilical vein endothelial cells (HUVEC) with supra -therapeutic concentrations of rhAPC upregulated the expression of the inducible cyclooxygenase (COX) isoform to produce the antiinflammatory and platelet aggregation-inhibitor, prostacyclin [24]. Similarly, Isobe et al. demonstrated that APC prevented endotoxin-induced hypotension in rats. The beneficial APC effect was associated with inhibition of the endotoxin-induced increases in TNF-a and inducible nitric oxide (NO) synthase (iNOS) levels in the lung, as well as with decreases in TNF-a and iNOS mRNA expression [25]. The authors concluded that APC appears to inhibit iNOS induction by decreasing TNF-a production.

Anti-apoptotic Activity Apoptosis is the process responsible for programmed cell death. Apoptotic signals coming from inside the cell activate the intrinsic pathway, while the extrinsic apoptotic pathway gets signals from the extracellular environment and is dependent on cell membrane 'death' receptors [7]. Joyce et al. demonstrated that rhAPC inhibited endothelial cell apoptosis induced by the potent inducer staurosporine [22], while Mosnier and Griffin provided evidence that inhibition of staurosporine-induced endothelial cell apoptosis by APC requires the presence of EPCR and PAR-1 [26]. Further studies confirmed that APC anti-apoptotic activity requires the presence of

The Effects of Activated Protein Con the Septic Endothelium

the enzymatically active site on APC, and both EPCR and PAR-l [7]. Similarly, Cheng et al. provided evidence that APC prevents apoptosis in the hypoxic brain endothelium, offering neuroprotection [27].

Endothelial Cell Barrier Stabilization Endothelial barrier disruption and subsequent increased endothelial cell permeability are central components of the inflammatory process and key contributors to the pathobiology of severe sepsis and organ failure. Edothelial cell barrier disruption in the septic lung is of particular importance, since it will lead to development of ALI and acute respiratory distress syndrome (ARDS) [6]. Therapeutic rhAPC concentrations have been shown to attenuate human microvascular endothelial cell hyperpermeability induced by thrombin and interleukin (IL)-I~ [28]. In a more recent study, APC has been shown to induce endothelial cell barrier protection via cytoskeletal rearrangement mediated by sphingosine l -phopshate receptor transactivation, combined with EPCR ligation [29]. The aforementioned crossactivation appears to be mediated by PAR-l [30]. It should be noted that contrary to the APC-mediated protective effect, PAR-l signaling by thrombin induces endothelial cell barrier destabilization. For a more detailed analysis on the effects of APC on endothelial cell barrier function and the underlying signaling pathways, the reader is referred to ref [7].

APC in Acute lung Injury Severe sepsis is manifested in the lung by the induction of the ALI continuum and its most severe extreme, ARDS. Sepsis is the commonest cause of ALI/ARDS development, while pulmonary endothelial cells appear to be the first lung cells altered in ALII ARDS generated by sepsis [31]. Endothelial cell dysfunction has profound effects on pulmonary and systemic vascular homeostasis and further promotes development of ALI [6]. The fact that 75 % of the patients participating in the PROWESS study [9] were intubated and ventilated, supports the hypothesis that APC may be beneficial in sepsis-induced ALI. A National Heart, Lung and Blood Institute workshop has suggested the exploration of novel therapies targeting pulmonary microvascular inflammation and thrombosis in ALIIARDS [31], strengthening the rationale for investigating APC administration in such patients. In the mid-90s, Murakami et al. [32] studied the effect of intravenous APC pretreatment on rat pulmonary vascular injury induced by intravenous LPS administration. In this report, APC prevented the increase in pulmonary vascular permeability, as well as the interstitial edema and leukocyte infiltration induced by LPS. The authors concluded that the protective effect of APC was related to its ability to inhibit leukocyte lung accumulation, but the exact mechanism(s) remained elusive. Nick et al. [33] have more recently examined the effect of rhAPC in human volunteers with local lung inflammation secondary to bronchial LPS installation; simultaneous intravenous administration of rhAPC attenuated the LPS-induced leukocyte accumulation in the airspaces, although not reducing either LPS-induced protein concentrations in bronchoalveolar lavage (BAL) fluid, or cytokine and chemokine levels. Further ex vivo and in vitro analyses revealed that APC decreased neutrophil chemotaxis along chemokine concentration gradients. Interestingly, no differences in gene expression, kinase activation, cytokine release, cell survival, or apoptosis

725

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S.E. Orfanos, N.A. Maniatis, and A. Kotanidou

were detected in neutrophils recovered in the presence or absence of rhAPC [33]; rhAPC additionally attenuated the LPS-induced pro-coagulant activity in these patients [34]. We have recently investigated the effect of inhaled rhAPC in a murine model of direct ALI [35]. Our choice to study topical APC administration in the septic lung was based on the rationale that such a treatment, if effective, might carry fewer side effects than systemic intravenous administration. Animals inhaled 10 mg of pseudo monas LPS in 3 ml normal saline (NS); 30 min prior to LPS, mice were pretreated with inhaled rhAPC (4 mg/3 ml NS; APC + LPS group) or NS (LPS group). A control animal group inhaled vehicle (NS) twice. Twenty-four hours later, total cells and celltypes, protein content, and the cytokines, TNF-a, interleukin (lL)-6, macrophage inflammatory protein (MIP)-la, and mouse keratinocyte-derived chemokine (a homolog of human IL-8) were estimated in BAL fluid. Lung pathology, wet/dry lung weight ratios, and lung vascular cell adhesion molecule (VCAM)-1 expression were additionally assessed [35]. Pre-treatment of the mice with inhaled rhAPC attenuated the aerosolized LPSinduced increases in total cell-, neutrophil- and macrophage counts in BAL fluid (Fig. 2), as well as the LPS-induced lung tissue inflammation; rhAPC inhalation did not, however, attenuate either the LPS-induced increases in total protein and cytokine levels in BAL fluid, or the LPS-induced increases in wet/dry ratios. Thus, in agreement with the results obtained in the clinical study by Nick et al. [33], inhaled rhAPC was effective in reducing the cellular infiltration component of the inflammatory response, but it lacked an effect on lung vascular permeability and BAL fluid cytokines. We then sought to investigate whether the inhibitory action of APC on leukocyte chemotaxis into the alveolar compartment is related to a downregulation of endothelial cell-leukocyte adhesion that would lead to decreased transendothelial migration. We chose to examine VCAM-l expression since several reports have depicted the role of this endothelial adhesion molecule in sepsis. rhAPC inhalation reduced

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The Effects of Activated Protein ( on the Septic Endothelium Control

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LPS-induced lung VCAM-l expression by half (Fig. 3) implying that the observed attenuation of pulmonary cellular infiltration was at least partly related to a reduction in VCAM-l [35]. These findings, taken together with the reported inhibitory action of rhAPC on neutrophil chemotaxis observed by Nick et al. [33], point to a protective effect of APC associated with leukocyte trafficking modifications at the level of both the leukocytes and the endothelial cell [35]. The beneficial effect of inhaled APC in attenuating direct lung injury has been additionally shown in a recent report by Slofstra et al. [36]; in contrast with our study, however, this effect appeared to be leukocyte-independent, a fact that can be partly attributed to study protocol and drug regimen differences.

APC Variants In an effort to determine: i) the importance of the anticoagulant versus cytoprotective actions of APC; and ii) their relative contributions to the beneficial effects of APC and the observed side-effects (such as the increased risk of bleeding), APC variants have been engineered with decreased anticoagulant and normal cytoprotective activity or vice versa [18]. Such techniques could allow a better understanding of the related APC pathways and probably allow synthesis of safer and more efficient compounds. Kerschen et al. have recently shown that a recombinant APC variant with normal signaling but < 10 % anticoagulant activity was as effective as wild type APC in reducing mortality after LPS challenge in mice [37].

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S.E. Orfanos, N.A. Maniatis, and A. Kotanidou

Conclusion Despite ongoing discussion about the use of APC in the treatment of the septic patient, rhAPC has thus far been the sole drug, in addition to antimicrobials, that has been shown to decrease mortality in severe sepsis [9}. Numerous studies have demonstrated a cytoprotective effect of APC on the endothelium, a phenomenon of great importance since endothelial cells have a central role in sepsis pathobiology. It should be noted, however, that in most basic studies APC is delivered as a pre-treatment, prior to the sepsis-related harmful stimulus. Consequently, and in contrast with the clinical reality, the findings obtained reflect the capability of APC to offer endothelial protection rather than endothelial therapy [38}. New experimental approaches and the use of APC variants may improve our understanding of the beneficial effects of APC on the septic endothelium. References 1. Martin GS, Mannini DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546-1554 2. Cinell, Dellinger RP (2007) Advances in pathogenesis and management of sepsis. Curr Opin Infect Dis 20:345-352 3. Abraham E, Singer M (2007) Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35:2408-2416 4. Aird WC (2004) Endothelium as an organ system. Crit Care Med 32:S271-S279 5. Aird WC (2007) Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 100:174-190 6. Orfanos SE, Mavrommati I, Korovesi I, Roussos C (2004) Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med 30:1702 -1714 7. Mosnier La, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109: 3161-3172 8. Looney MR, Matthay MA (2006) Bench-to-bedside review: The role of activated protein C in maintaining endothelial tight junction function and its relationship to organ injury. Crit Care 10:239 9. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699- 709 10. Esmon CT (2004) Structure and functions of the endothelial cell protein C receptor. Crit Care Med 32 (suppl):S298-S301 11. Thiyagarajan M, Cheng T, Zlokovic BV (2007) Endothelial cell protein C receptor. Role beyond endothelium? Circ Res 100:155 -157 12. Bretschneider E, Uzonyi B, Weber AA, et al (2007) Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 100:255-262 13. Zheng X, Li W, Song Y, et al (2007) Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 5:1394-1400 14. Bastarache JA, Ware LB, Bernard GR (2006) The role of the coagulation cascade in the continuum of sepsis and acute lung injury and acute respiratory distress syndrome. Semin Respir Crit Care Med 27:365-376 IS. Villegas-Mendez A, Montes R, Ambrose LR, Warrens AN, Laffan M, Lane DA (2007) Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. J Thromb Haemost 5:980-988 16. Weijer S, Wieland CW, Florquin S, Van der Poll T (2007) A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis. Blood 106:2761-2768 17. Scaldaferri F, Sans M, Vetrano S, et al (2007) Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 117:1951-1960 18. Griffin JH, Fernandez JA, Gale AJ, Mosnier La (2007) Activated protein C. J Thromb Haemost 5 (suppl 1):73-80

The Effects of Activated Protein ( on the Septic Endothelium 19. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W (2002) Activation of endothelial cell protea se activated receptor 1 by the protein C pathway. Science 296:1880-1882 20. Coughlin SR, Camerer E (2003) Participation in inflammation. J Clin Invest 111:25 -27 21. Ruf W (2005) Is APC activation of endothelial cell PARI important in severe sepsis]: Yes. J Thromb Haemost 3:1912-1914 22. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW (2001) Gene expression profile of anti thrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Bioi Chern 276:11199-11203 23. Joyce DE, Grinnell BW (2002) Recombinant human activated prote in C attenuates the inflammator y response in endothelium and monocytes by modulating nuclear factor-xls. Crit Care Med 30 (suppl):S288-S293 24. Brueckmann M, Horn S, Lang S, et al (2005) Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activat ion of protease-activated receptor-I, Thromb Haemost 93:743- 750 25. Isobe H, Okajima K, Uchiba M, et al (2001) Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation 104: 1171-11 75 26. Mosnier LO, Griffin JH (2003) Inhibit ion of staurosporine-induced apoptosis of endothelial cells by activated protein C require s protease-activated receptor -1 and endothelial cell protein C receptor. Biochem J 373:65- 70 27. Cheng T, Liu 0, Griffin JH (2003) Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 9:338-342 28. Zeng W, Matter WF, Yan SB, Urn SL, Vlachos CJ, Liu L (2004) Effect of drotrecogin alfa (activated) on human endothelial cell permeability and Rho kinase signaling . Crit Care Med 32 (suppl):S302-S308 29. Finigan JH, Dudek SM, Singleton PA, et al (2005) Activated protein C mediates novel lung endothelial barrier enhancement. Role of sphingosine I-phopshate receptor tran sactivation . J BioI Chern 280:17286- 17293 30. Feistrit zer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR-I-dependent sphingo sine I-phopshate receptor-1 crossactivation. Blood 105:3178-3184 31. Matthay MA, Zimmerman GA, Esmon C, et al (2003) Future research direct ions in acute lung injury. Summary of a National Heart, Lung and Blood Institute working group. Am J Respir Crit Care Med 167:1027-1035 32. Murakami K, Okajima K, Uchiba M, et al (1996) Activated protein C attenuates endotoxininduced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 87: 642-647 33. Nick JA, Coldren CD, Geraci MW, et al (2004) Recombinant human activated protein C reduces human endo toxin-induced pulmonary inflammation via inh ibition of neutrophil chemotaxis. Blood 104:3878-3885 34. Van der Poll T, Levi M, Nick JA, Abraham E (2005) Activated protein C inhibits local coagulation after intrapulmonar y delivery of endotoxin in humans. Am J Respir Crit Care Med 171:1125-1128 35. Kotanidou K, Loutrari H, Papadornichelakis E, et al (2006) Inhaled activated protein C atten uates lung injury induced by aerosolized endotoxin in mice. Vascul Pharmacol 45:134-140 36. Siofstra SH, Groot AP, Maris NA, et al (2006) Inhalation of activated protein C inhibits endo toxin-induced pulmonary inflammation in mice independent of neutrophil recru itment. Br J Pharmacol 149:740- 746 37. Kerschen EJ, Fernandez JA, Cooley BC, et al (2007) Endotoxernia and sepsis mortality reduction by non-anticoagulant-activated protein C. J Exp Med 204:2439-2448 38. Regnault V, Levy B (2007) Commentary. Recombinant activated protein C in sepsis: endothelium protection or endothelium therapy? Crit Care 11:103

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Improvement in Hemodynamics by Activated Protein ( in Septic Shock X.

MONNET,

H.

KSOURI,

and

J.-L.

TEBOUL

Introduction Recombinant human activated protein C (rhAPC) has been approved by the US Food and Drug Administration (FDA) for treating patients with sepsis or septic shock with an APACHE II score of more than 25 and by the European Agency for the Evaluation of Medicinal Products for multiple organ failure (MOF) related to sepsis. Furthermore, guidelines of the Surviving Sepsis Campaign recommend rhAPC as a standard-of-care for patients with severe sepsis and septic shock [1]. These approvals and recommendations were mainly supported by the results of the worldwide Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study [2], in which rhAPC was demonstrated to increase the survival rate of patients with the most severe forms of septic shock. This seminal study was focused on the overall mortality as the main criterion of judgement. Nevertheless in the following years, experimental and clinical studies suggested that rhAPC induces a specific improvement in the cardiovascular failure during septic shock. In this chapter, we will review these studies and the underlying mechanisms that are supposed to explain the effects of APC.

What is the Clinical Evidence for the Hemodynamic Effects of rhAPC? In human beings, the effects of rhAPC on macrohemodynamic variables were initially investigated in a model of endotoxin-induced hypotension in healthy volunteers. Kalil and co-workers induced mild hypotension in 16 subjects by the intravenous administration of low-doses of endotoxin [3]. rhAPC (24 Ilg/kg/h) or placebo infusion was started 2 hours before endotoxin injection and prolonged over 8 h. As compared to placebo, rhAPC enabled mean arterial pressure (MAP) to be better maintained, the statistical significance being reached at 3 h after endotoxin exposure. Nevertheless, this study was unable to demonstrate any significant antithrombotic, profibrinolytic, or anti-inflammatory effects with rhAPC. Moreover, the MAP was already reduced before endotoxin administration in the placebo group . In a similar manner, Derhaschnig and coworkers found no effect of rhAPC on lipolysaccharide (LPS)-induced hypotension in healthy subjects as compared to placebo [4]. In this latter study also, rhAPC had no effect on fibrinolytic activity or inflammation. In these two studies, beneficial effects of rhAPC on sepsis-induced hypotension were not evidenced, but these studies suffered from the major flaw that the model of septic hypotension in healthy subjects only poorly mimics the septic shock in which rhAPC was demonstrated to improve survival [2].

Improvement in Hemodynamics by Activated Protein ( in Septic Shock

Analyzing data from the seminal PROWESS trial [2], two time-to-event analyses reported that respiratory and cardiovascular failure resolved more rapidly in patients receiving rhAPC than in those receiving placebo [5, 6]. At 7 days after the onset of rhAPC administration, Dhainaut et al. reported that the cardiovascular failure (defined as a low arterial pressure or the need for vasopressors) had resolved in 61 % of patients treated with rhAPC vs. in 54 % of controls [6]. A similar faster recovery of cardiovascular function with rhAPC in the PROWESS trial was reported in a comparable report by Vincent et al. [5]. Nonetheless, these studies were post-hoc analyses of the PROWESS data such that they did not enable the effects of rhAPC on hemodynamic variables to be investigated in more detail. In a clinical study, we evaluated the effects of rhAPC administration on the hemodynamic status of patients with severe septic shock [7]. We compared 22 patients with septic shock who received rhAPC with a historical group of septic shock patients who were not treated with rhAPC. These patients were matched for age, SAPS II score, MAP, and norepinephrine dose at baseline. The blood lactate level, the number of organ failures, the number of patients treated with corticosteroids, and renal replacement were also similar between groups at baseline. In all patients, the norepinephrine dose was adjusted to achieve and maintain a MAP value of 65 mmHg. As a result of hemodynamic treatment, MAP was restored and maintained stable over the study period in a similar manner between groups. However, over the 24 h following the start of rhAPC administration, the dose of norepinephrine that was required to maintain MAP decreased by 33 % in patients receiving rhAPC while it increased by 38 % in the control subjects (Fig. 1). Interestingly, this beneficial effect of rhAPC on the hemodynamic status appeared as quickly as 4 h after the onset of rhAPC administration. Additionally, the blood lactate level tended to decrease in the rhAPC group while it tended to increase in the control group [7]. In a recent study reviewing the 53 patients treated in our unit with rhAPC from 2003 to 2007, we confirmed theses results by observing, a few hours (as soon as 4 h) after the start of rhAPC infusion, a significant decrease in the dose of norepinephrine

Without rhAPC

80 60 40

~

20

:r: E

0

OJ

0

0

0

..= Fig. 1. Time-course of the norepinephrine dose (% change from the value at HO, mean [interquartile range]) in patients receiving recombinant human activated protein C (rhAPC) and in matched control patients. The norepinephrine dose was measured at the start of rhAPC administration (treated patients) or at the time of its theoretical administration (control patients) (HO) and 4, 10 and 24 h later (H4, H10 and H24, respectively). * p< 0.05 (adapted from [7]).

0>

I I HO

H4

H1 0

C

~ -20 u

-40 -60 -80 -100

With rhAPC

1 H24

l

731

732

X. Monnet, H. Ksouri, and J.-L. Teboul

while arterial pressure remained stable [8]. A significant improvement in the PaOz: FiOz ratio and a significant decrease in the blood lactate level were also observed concomitantly [8]. De Backer and colleagues compared 20 patients with septic shock and receiving rhAPC with a control matched group of patients with a contra-indication for its administration [9]. They showed that in the group of patients treated with rhAPC, vasopressor support was reduced more rapidly than in the control patients after 4 h of rhAPC administration. Blood lactate level increased at 4 h in the control group while it had decreased at this time in the rhAPC group. In addition, the Sequential Organ Failure Assessment (SOFA) score decreased during the first 24 h in the rhAPC group but not in the control group [9]. The obvious limits of these studies were that they enrolled a limited number of patients and that they were not randomized. Nonetheless, they suggest a specific and rapid benefit of rhAPC on sepsis-induced hypotension. They raise the question of which mechanisms could explain this 'macro circulatory' effect of rhAPC?

Animal Studies and Underlying Mechanisms APC Prevents Endotoxin-induced Hypotension in Animals A preliminary study suggested that APC could exert beneficial effects on endotoxininduced shock [10]. In baboons, APC administration was able to attenuate the fall in systolic arterial pressure induced by the injection of Escherichia coli endotoxin [10]. Interestingly, while the fall in arterial pressure was negligible if the dose of endotoxin was low, it became of large magnitude if antibodies to APC were injected into the animals. Years later in a rat model of septic shock, Isobe and colleagues demonstrated that the administration of APC (l00 ug/kg i.v.) prevented endotoxin -induced hypotension as compared to saline [11]. This effect was observed if APC was administered just before endotoxin injection as well as 30 min later. However, lower doses of APC had no effect on the decrease in MAP. In addition to this improvement in arterial pressure, interesting results were obtained about the pathophysiological pathway of these APC effects. In fact, APC administration prevented the increase in the plasma nitrates/nitrites (indicators of nitric oxide [NO] synthesis) and reduced the expression of tumor necrosis factor (TNF)-a mRNA that followed endotoxin injection. In addition, inhibition of TNF-a by leukocytopenia and treatment with anti-TNF-a antibodies produced similar effects to those of APC, suggesting that the effects of APC on arterial pressure were linked to a decreased TNF-a production. Interestingly in this study, the administration of a selective inhibitor of thrombin generat ion mimicking the antithrombotic properties of APC was unable to prevent the effects of endotoxin [11]. This suggests that the hemodynamic effects observed with APC were specifically related to its ant i-inflammatory rather than to its antithrombotic potent. Thus, this animal study demonstrated that APC could prevent endotoxin-induced hypotension and strongly suggested that this effect on macrohemodynamics was related to an inhibition of NO production through reduced TNF-a expression [11]. This inhibition of TNF-a production may be linked to an inhibition of the nuclear translocation of nuclear factor-kappa B (NF-KB) [12].

Improvement in Hemodynamics by Activated Protein ( in Septic Shock

APC also Improves Cardiac Function in Septic Animals The results reported by Isobe et al. were nicely confirmed in a recent study by Favory et al. [13). In a model of endotoxin-induced shock in rats, APC administration (240 ug/kg, i.v.) prevented the fall in arterial pressure while saline did not. Importantly, by using an ex vivo isolated heart preparation, this study was designed to explore cardiac function independent from the concomitantly altered loading conditions. The authors demonstrated that APC not only increased arterial pressure, but also improved the contractility of the left ventricle that had been depressed by the endotoxin injection. The deficit in the perfusion of the small intestine muscularis layer was also partially prevented, suggesting an improvement in microvascular function. In line with this latter result, adhesion and rolling of leukocytes to the mesenteric venule endothelial surface were reduced in animals in which APC was added to LPS. Finally, the infiltration of intestine and heart by leukocytes was reduced by APC. Production of nitrates/nitrites and TNF-a were largely limited in rats receiving APC as compared to control animals [13]. In summary, this study confirmed that the beneficial effects of APC on endotoxin-induced hypotension are probably linked to its blunting effects on NO and TNF-a production. Moreover, this study evidenced a beneficial effect of rhAPC on sepsis-related cardiac hypocontractility. It is noteworthy that the consequences of APC administration on cardiac function variables have not been investigated in human beings to date.

Effects of APC on Multiple Organ Failure in Septic Animals In a recent study, Wang and colleagues interestingly demonstrated that the benefit of APC is not limited to the hemodynamic failure but is clearly extended to other organ dysfunctions [14). The authors induced septic shock in sheep by the intraperitoneal injection of feces. Ringer's lactate was infused to maintain the pulmonary artery occlusion pressure (PAOP) but no vasopressor was administered. Two hours after the induction of sepsis, animals were randomized to receive either saline or APC (24 ug/kg/h) . The effects of APC on the different organ failures were extensively investigated. The decreases in systemic arterial pressure and in urine output were less profound in animals receiving APC than in controls . A beneficial effect on respiratory function was also evidenced: The PaOz: FiOz ratio and the thoraco-pulmonary compliance were greater in animals which received APC, and the lung wet/dry ratio, estimated at post-mortem examination, was significantly lower in the APC group than in the control group. Blood lactate increase and disseminated intravascular coagulation (DIC) were attenuated in APC-treated sheep. Finally, survival was significantly improved by APC as compared to saline. This study takes its advantage from the fact that it used a sheep model that enables a relevant exploration of different organ dysfunctions related to sepsis. Furthermore, the dose of APC administered to the treated group was the dose used in patients, while in the previous animal studies higher doses of the drug were administered. Finally, APC was administered 2 h after the induction of the septic shock, i.e., with greater clinical relevance than if it is administered as a preventive treatment. Clearly, this experimental study must be considered as high level evidence of the beneficial effects of APC on multiple organ failure in animals [14].

733

734

X. Monnet, H. Ksouri, and J.-L. Teboul

Effects of APC on the Microcirculation The hemodynamic effects of APC have been investigated not only at the macrocirculatory level but also at the microcirculatory level. In skinfold preparations in hamsters challenged with endotoxin, Hoffmann et al. showed that APC decreased leukocyte adhesion to arterioles and venules and improved capillary density [15]. Another animal study in endotoxemic rats reported that APC inhibited the adhesion of leukocytes on the endothelium of mesenteric microvessels [16]. Favory and colleagues also observed these microvascular effects in their experimental study [13]. The first clinical confirmation of such effects was recently reported by De Backer et al. [9]. Using the Orthogonal Polarization Spectral (OPS) imaging technique, these investigators studied the sublingual microcirculation of septic shock patients who received rhAPC compared to patients who did not. They reported that 4 h after rhAPC infusion, the proportion of perfused capillaries increased in rhAPC treated patients (from 64 % to 84 %) but not in the control group. Thus, it is likely that APC improves microcirculatory function during septic shock.

Putative Mechanisms In the pathway of sepsis-related circulatory failure, NO is believed to playa key role [17, 18]. During sepsis, NO is produced in an excessive amount by the inducible isoform of NO synthase (iNOS) expressed within the vasculature. iNOS can be stimulated by TNF-a [19], a pro-inflammatory cytokine produced by monocytes . As a result of the massive NO production, the intracellular calcium concentration is decreased and the vasculature reactivity to vasopressors is impaired . The myocardial depression, which is in part related to the excessive NO production, actually participates in the cardiovascular failure. Another aspect of this pathway implicates the microcirculation. The release of cytokines induces widespread endothelial and neutrophil activation. Due to the expression of secondary adhesion molecules on leukocytes, the neutrophil emigrates through the endothelium and releases toxic substances that participate in the MOF of septic shock. The way in which APC could interact with the pathway of septic cardiovascular failure is still a matter of debate. Indeed, the anti-inflammatory effects of APC have been clearly evidenced in animal studies in which APC was demonstrated to reduce the production of NO by iNOS and to reduce TNF-a production [11 , 13]. However, human studies were unable to show any decrease in the plasma levels of TNF-a or any cytokines [2-4, 20]. The anti-inflammatory properties of APC may rather be related to a modulation of the interaction of leukocytes with the activated endothelium. APC was demonstrated to reduce the rolling of leukocytes on the wall of arterioles [15] and venules [13, 15]. As a consequence, the infiltration of tissues by leukocytes was found to be diminished by APC administration [13] . The beneficial effect of APC on the microcirculation may be related to a reduction in white blood cell rolling and adhesion to the activated endothelium, although the antithrombotic effect of this drug cannot be ruled out. Such a modulation of leukocyte function may play an important role by which APC improves vascular function [21]. Finally, in a recent experimental study in a rabbit E. coli endotoxin-induced shock, APC treatment was shown to restore the endothelium -dependent sensitivity to phenylephrine in LPS-treated aortic rings in spite of persistence of monocyte tissue factor expression, suggesting that APC has vascular protective effects independent ofits action on coagulation [22]. This favorable effect of APC on endothelial

Improvement in Hemodynamics by Activated Protein Cin Septic Shock

modulation in the phenylephrine response was associated with decreased endothelial injury in LPS-treated animals maybe via an anti-apoptotic effect [22]. It is noteworthy that APC failed to restore acetylcholine-induced relaxation in LPS-treated animals, suggesting that APC acts differently in the relaxant and contractile signaling pathways [22]. The effects of APC on the macro- and microcirculations should not be artificially separated. Indeed, it is reasonable to hypothesize that an improvement in arterial tone and in cardiac function promotes a better microcirculation by an increase in the blood flow at this level. It is also likely that an improvement in microvascular function participates to a reduced production of NO. This may reduce the systemic inflammatory response to sepsis and thus reduce sepsis-related vasoplegia and cardiac dysfunction. However, the integrative pathway by which APC alters global hemodynamic homeostasis during sepsis is still to be elucidated.

Conclusion A reasonable amount of evidence corroborates the efficacy of APC for preserving cardiovascular homeostasis during septic shock. Nonetheless, definite clinical proof should come from studies that may re-perform the direct comparison between rhAPC and placebo in critically ill patients. In these studies, assessment of hemodynamic effects would be of importance to further investigate by which mechanism rhAPC improves global survival. It must be kept in mind that during septic shock with MOF, death most often occurs from hypotension refractory to high doses of vasopressors. In line with this paradigm, restoring vascular reactivity allowing a reduction in vasopressor requirements would be a therapeutic target of tremendous importance. References I. Dellinger RP, Cadet JM, Masur H, et al (2004) Surviving Sepsis Campaign guidelines for man -

agement of severe sepsis and septic shock. Intens ive Care Med 30:536- 555 2. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699- 709 3. Kalil AC, Coyle SM, Urn JY, et al (2004) Effects of drotrecogin alfa (activated) in human endo toxemia. Shock 21:222-229 4. Derhaschnig U, Reiter R, Knobl P, Baumgartner M, Keen P, [ilma B (2003) Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 102: 2093-2098 5. Vincent JL, Angus DC, Artigas A, et al (2003) Effects of drotrecogin alfa (act ivated) on organ dysfunct ion in the PROWESS trial. Crit Care Med 31:834-840 6. Dhainaut JF, Laterre PF, Janes JM, et al (2003) Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Inten sive Care Med 29:894- 903 7. Monnet X, Lamia B, Anguel N, Richard C, Bonmarchand G, Teboul JL (2005) Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients. Intensive Care Med 31:1573-1576 8. Ksouri H, Cour M, Monnet X, Richard C, Teboul JL (2007) An observational study of the use of activated protein C in septic shock patients with emphasis on hemodynamic effects. Intensive Care Med 33 (suppl 2):SI66 (Abst) 9. De Backer D, Verdant C, Chierego M, Koch M, Gullo A, Vincent JL (2006) Effects of drotrecogin alfa activated on microcirculatory alterations in patients with severe sepsis. Crit Care Med 34:1918-1924

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X. Monnet, H. Ksouri, and J.-L. Teboul 10. Taylor FB [r, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79:918- 925 II. Isobe H, Okajima K, Uchiba M, et al (2001) Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation 104:Il71Il75 12. White B, Schmidt M, Murphy C, et al (2000) Activated protein C inhibits lipopolysaccharideinduced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol IlO: 130-134 13. Favory R, Lancel S, Marechal X, Tissier S, Neviere R (2006) Cardiovascular protective role for activated protein C during endotoxemia in rats. Intensive Care Med 32:899-905 14. Wang Z, Su F, Rogiers P, Vincent JL (2007) Beneficial effects of recombinant human activated protein C in a ewe model of septic shock. Crit Care Med 35:2594-2600 IS. Hoffmann IN, Vollmar B, Laschke MW, et al (2004) Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia. Crit Care Med 32:IOIl-1017 16. Iba T, Kidokoro A, Fukunaga M, Nagakari K, Shirahama A, Ida Y (2005) Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model. Crit Care Med 33:368-372 17. Young JD (2004) The heart and circulation in severe sepsis. Br J Anaesth 93:Il4-120 18. Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63-78 19. Drapier JC, Wietzerbin J, Hibbs JB Ir (1988) Interferon-gamma and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol 18:1587-1592 20. Nick JA, Coldren CD, Geraci MW, et al (2004) Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 104:3878-3885 21. Sennoun N, Desebbe 0, Levy B (2007) Hemodynamic effects of activated protein C in septic shock. In: Vincent JL (eds) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg, pp 75- 80 22. Wie1 E, Costecalde ME, Lebuffe G, et al (2006) Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock. Crit Care 10:R47

Section XVIII

XVIII Acute Bleeding

737

739

Gastrointestinal Hemorrhage on the Intensive Care Unit S.J. THOMSON,

M.L. COWAN,

and

T.M. RAHMAN

Introduction Gastrointestinal bleeding in the critical care environment is a relatively common clinical event with an incidence of approximately 100/100,000 population per year in both the UK and the USA [I, 2]. Of these bleeding events, 14 % occur in patients already hospitalized. Gastrointestinal bleeding can be the primary reason for admission or can develop as a secondary co-morbid factor. Patients with this complication can have an increased length of stay on the intensive care unit (lCU) and up to a four-fold rise in mortality [3]. This chapter will describe the nature of gastrointestinal bleeding in critical care, the etiologies and risk factors that may predispose to gastrointestinal bleeding, and the variety of therapeutic options available to the clinician. Upper gastrointestinal stress-related mucosal disease, variceal hemorrhage, and lower gastrointestinal bleeding will be considered separately.

Stress-related Mucosal Disease Upper gastrointestinal bleeding is defined as that originating from a source within the upper gastrointestinal tract proximal to the ligament of Treitz, i.e., esophagus, stomach , and duodenum. It commonly presents as fresh hematemesis and/or melena. 'Coffee ground' vomiting is an unreliable clinical sign. Upper gastrointestinal bleeding may occasionally be mistaken for feculent vomiting which is associated with bowel obstruction. It is not, however, uncommon for patients in the critical care setting to have fresh or altered blood in their nasogastric tube. Bleeding from the nasopharynx should also be excluded. A brisk, significant upper gastrointestinal bleed can reveal itself as hematochezia (fresh blood per rectum) but this usually suggests a colonic source. Mucosal ulceration can be superficial (erosions) and characterized histologically by loss of surface epithelium, coagulation necrosis of the mucosa, and hemorrhage from superficial mucosal capillaries, which leads to a more occult blood loss and is generally not amenable to endoscopic therapy, or deep (ulcers), eroding through to larger vessels causing acute severe bleeding. Critical illness may lead to decreased cardiac output, increased vasoconstriction, and subsequent release of pro-inflammatory cytokines. This leads to severe stress on normal mucosal physiological processes. Subsequent splanchnic hypoperfusion induces gastrointestinal mucosal ischemia, reduces gastric motility, impairs protective mucous production, and reduces the ability to neutralize hydrogen ions. Drugs, including opiates and sedatives, can also have a similar deleterious effect on hemo-

740

SJ. Thomson, M.L. Cowan, and T.M. Rahman

dynamics. Clinical risk factors for the development of stress ulcers are well established with the most significant being coagulopathy and mechanical ventilation for > 48 h; 3.7 % of patients with these risk factors experience gastrointestinal bleeding compared to only 0.1 % of those without [4]. Esophageal motility is reduced in sedated critically ill patients [5], nocturnal gastroesophageal reflux disease and in-patient esophagitis are related to supine positioning, and prolonged use of wide bore nasogastric tubes has also been suggested as an etiological factor in esophagitis amongst hospital in-patients. Critical care patients are, therefore, not only at risk of esophageal mucosal erosive disease, but also of chemical lung injury and nosocomial pneumonias. The increasing use of antiplatelet agents in the setting of acute coronary syndrome and coronary intervention should also be considered. Aspirin (acetylsalicylic acid) inhibits platelet cyclooxygenase-l (COX1) activity thereby preventing the synthesis of thromboxane A2, a promoter of platelet activation. It also inhibits the cytoprotective effects of prostaglandin E2 on the gastric mucosa. These two factors contribute to the increased risks of peptic ulceration . Clopidogrel blocks the ADPdependent pathway of platelet activation by binding to the P2Y12 receptor and is a more potent platelet inhibitor than aspirin. It appears to carry less of a risk of inducing gastrointestinal bleeding when compared to aspirin presumably because it has no effect on the gastric mucosa, although it is still more likely to trigger gastrointestinal bleeding in patients with a previous history of gastrointestinal bleeding than in those without (22 vs 0 %, P = 0.007) [6]. The antithrombotic benefits and bleeding risks of antiplatelet therapy should be balanced in a manner analogous to anticoagu lation; however, the higher the vascular risks the more benefit there is to be gained thereby outweighing the risk of bleeding. Proton pump inhibitor therapy is a useful precaution in patients with a recent history of ulceration or bleeding [7]. The relative merits of COX2 inhibitors in reducing gastrointestinal side effects are reduced when balanced against the reported increase in cardiovascular complications [8] and the anyway frequent collateral usage of antiplatelet therapy. As with antiplatelet agents, the incidence of recurrent gastrointestinal bleeding in patients taking COX2 inhibitors is also reduced in patients on proton pump inhibitor dual therapy [9]. The implication of Helicobacter pylori in the pathogenesis of stress-related mucosal disease is unclear. The incidence of H. pylori seropositivity has been shown to be increased in lCU patients versus controls (67 versus 39 %, P < 0.001) [10]. Although there appeared to be no relation to the incidence of gastrointestinal bleeding there was an association between seropositivity and severity of bleeding. This study seemed to support a relationship between H. pylori and extent of mucosal injury, however, this is not supported by the data [l l]. Although a consensus on best practice in this setting remains unclear it is recommended that H. pylori eradication should be employed empirically for duodenal ulcers and after confirmation of infection in gastric ulcers [12]. Although urea breath tests and biopsy based methods of H. pylori diagnosis are highly specific and sensitive, on balance, the most practical tests for the critical care population are stool antigen and serology, which have a similar diagnostic performance [13]. Treatment regimens normally consist of 'triple therapy' containing a proton-pump inhibitor and two antibiotics for one week, although more recently evidence has suggested improved efficacy with a staggered sequential course of dual then triple agent therapy over ten days [14]. Although reduced pH is only one factor contributing to stress-related mucosal disease, controlling excess luminal acid levels in at risk patients is an important factor in the reduction of bleeding episodes. The incidence of overt gastrointestinal

Gastrointestinal Hemorrhage on the Intensive Care Unit

bleeding is reduced with the use of prophylactic agents including antacids, sucralfate and Hz blockers versus no therapy [15). Proton-pump inhibitors are known to be effective in the general treatment of acid-related disease. They are, however, not yet formally approved as prophylaxis against stress ulceration . They have been favorably evaluated in isolated intensive care gastric pH studies; however, these studies used small numbers of patients and lacked control groups. The few trials that have directly compared Hz blockade with proton-pump inhibitor therapy suggest that proton -pump inhibitor therapy is associated with reduced bleeding episodes [16). Patients exhibit less tolerance to proton-pump inhibitor therapy compared to Hz blockers and there are also theoretical concerns that Hz blockers can induce the cytochrome P450 system and accumulate in renal failure. With these patterns in mind the use of proton-pump inhibitors as stress ulcer prophylactic agents has increased in recent years. Intravenous proton-pump inhibitor therapy now routinely accompanies endoscopic therapy for treatment of bleeding peptic ulcers [17). Blood clots are less stable in an acid environment and a pH > 6 is necessary for platelet aggregation. Rebleeding rates, blood transfusion requirements and duration of hospital stay are all reduced in patients who receive intravenous omeprazole (80 mg stat followed by an infusion of 8 mg hourly for 72 hours) vs placebo [17). More recent evidence demonstrated that a pre-endoscopy intravenous infusion of a proton -pump inhibitor accelerated the resolution of signs of bleeding in ulcers (ulcer with clean base p = 0.001) and reduced the need for endoscopic therapy (p = 0.007) when compared to placebo [18). The initial assessment of the patient with active gastrointestinal bleeding should focus on the general principles which are applied to any life-threatening condition . Evaluation of airway patency and respiratory compromise and management of circulatory dysfunction are the primary goals. A number of scoring systems exist for the calculation of severity and risk of mortality from acute upper gastrointestinal bleeding. Perhaps the best known of these was devised by Rockall et al. in 1996 (Table 1) [19). A simple numerical scoring system using five clinical features stratifies patients into different levels of mortality risk ( Table 2). In the setting of critical care, all patients, by definition, should have intensive physiological monitoring. Gastrointestinal bleeding can often be underestimated Table 1. Risk assessment after acute upper gastrointestinal hemorrhage - The Rockall score [19] Score

0

1

2

Age

< 60

60- 79

> 80

HR > 100 HR > 100, SBP < 100

Shock

No shock

Co-morbidity

Nil

Cardiac failure, ischemic heart disease

Diagnosis

Mallory Weiss, no All other lesion, no stigmata of diagnoses recent hemorrhage

Malignancy of upper gastrointestinal tract

Major stigmata of recent hemorrhage (endoscopy findings)

None or dark spot

Fresh blood, adherent clot, visible or spurting vessel

HR: heart rate; SBP: systolic blood pressure

3

Renal failure, liver failure, disseminated malignancy

741

742

SJ. Thomson, M.L. Cowan, and T.M. Rahman Table 2. Re-bleeding and mortality rates based on the Rockall score [19] Score Total (%) Re-bleed (%) Death (non re-bleed) (%) Death (re-bleed) (%) Death (total) (%)

0

1

2

3

4

5

6

7

8+

4.9 4.9 0 0 0

9.5 3.4 0 0 0

11.4 5.3 0.3 0 0.2

15 11.2 2.0 10.0 2.9

17.9 14.1 3.5 15.8 5.3

15.3 24.1 8.1 22.9 10.8

10.6 32.9 9.5 33.3 17.3

9.0 43.8 14.9 43.4 27.0

6.4 41.8 28.1 52.5 41.1

Table 3. Clinical assessment of shock. (Adapted from [20]) Blood loss (ml) Blood loss (% cire. blood volume) Heart rate Systolic Diastolic Respiratory rate Urine output (ml/h) Extremities Mental state

Class I 750 ml

Class II

Class III

Class IV

< 15%

750-1500 ml 15- 30 %

1500 -2000 ml 30-40 %

> 2000 ml > 40 %

< 100

> 100

> 120

< 20

> 20 20-30

> 30 10- 20

No change No change > 30

Normal Alert

No change Raised Pale Anxious

> 140

Reduced Reduced

Very low Unrecordable

Pale Aggressive/drowsy

Cold Confused/unconscious

> 40 < 10

because unlike a traumatic or operative source of bleeding it cannot be 'seen'. Resuscitation is, therefore, guided by clinical and physiological parameters, although they do not always correlate with the degree of shock. Mismatch may be seen in the case of the young, the elderly, and patients on beta-blockade, and these groups can sometimes be inadequately resuscitated . Table 3 presents a clinical guide to the assessment of patients with hypovolemic shock [20]. There is ongoing debate regarding the timing and volume of fluid admin istration for patients with bleeding. It can be difficult to strike a balance between restoration of blood pressure and the potential for disrupting clots, reopening bleeding points, and hence worsening bleeding. Resuscitation should be focused on restoring parameters to normal limits. Crystalloids and volume expanders should be used initially, with addit ional blood produ cts in the setting of class III/IV shock, active hematemesis, or for initial hemoglob in concentr ations of less than 10 g/dl [21]. In pat ients with a large bleed and/or cardiac co-morbidities, it is commonly accepted that central venous access is a necessary adjunct to management, although this has not been the subject of a formal clinical trial. The presence of shock, agitation , hematemesis , and other clinical factors may influence the decision to protect the airway and intubate promptly or to re-assess at a later stage. There is no definitive evidence to support rout ine intub ation [22]. However, if there is any concern about adequate airway protection then this is the preferred action. Coagulopathy will exacerbate any kind of hemorrhage. Elevation of the INR (International Normalized Ratio) should be reversed with fresh frozen plasma or clotting factor concentrates in the setting of active hemorrhage [23]. Parenteral vitamin K should be supplemented in jaundiced patients. Few studies have defined the optimum doses of these produ cts or indeed the relative evidence for one over the other. The use of recombinant factor VII in the setting of uncontrollable gastrointes-

Gastrointestinal Hemorrhage on the Intensive Care Unit

tinal bleeding is still under assessment. The only randomized clinical trial assessed by the Cochrane database failed to demonstrate a reduction in the risk of death from gastrointestinal bleeding in patients with cirrhosis treated with recombinant factor VII [24]. This treatment should, therefore , only be considered in patients who are unresponsive to standard treatment. The incidence of thrombotic events with use of factor VII has been reported at 1.5 % in a stud y of 11,000 patients. Almost all of these events occurred in non -hemophiliac patients and those with other underlying risk factors for thrombosis. All case mortality was 0.3 % [25]. Endoscopic Therapy

Esophagogastroduodenoscopy plays an important part in the management of gastrointestinal bleeding . It can offer both diagnostic information (Table 4) and the opportunity for therapeutic intervention. Esophagogastroduodenoscopy should be undertaken within 24 h in low risk patients and as soon as blood pressure has normalized in those with massive bleeding. Patients undergoing endoscopy within the first 24 h of admission demonstrate a reduction in re-bleeding, surgical intervention, and length of hospital stay [26]. If required for ventilated pat ients, the endoscopy can take place in the critical care unit itself. It is, however, preferable for those patients who can move, to have the procedure in the normal specialist surroundings of a dedicated endoscopy unit. The endoscopist should be assisted by trained endoscopy nursing staff who are familiar with the equipment and techniques required. If emergency surgery is possible then it can be beneficial to undertake the procedure in the operating room. This allows for surgical involvement and immediate procession to laparotomy if required. Endoscopic evaluation of mucosal ulcerat ive disease should be straightforward; however, excessive active bleeding or residual blood pooling can obscure adequate views of the mucosal surfaces. Changing patient position (prone, right lateral), or pre-endoscopic administration of erythromycin [27] as a pro-motility agent, can help to clear the fundus of residue if requ ired. The highest risk, and most commonly missed, sites of ulceration , are high on the gastric lesser curve and on the posterior wall of the second part of the duodenum. These areas should be carefully inspected before the esophagogastroduodenoscopy can be considered complete. Indeed, one should consider the use of a side viewing duodenoscope for greater assessment and management of lesions in these areas. Endoscopic therapeutic option s are epinephrine injection, heat treatment/diathermy, endoscopic clips, and argon plasma coagulation. Injection therapy with epinephrine aims to provide local tamponade with the additional advantage of vessel and tissue vasoconstriction. Saline can be used for emergency tamponade; however, Table 4. Incidence of different endoscopic diagnoses in acute upper gastrointestinal hemorrhage. (Adapted from [1])

Diagnosis

%

None made Peptic ulcer Malignancy Varices Mallory Weiss tear Erosive disease Esophagitis Other

25 35 4 4 5 11

10 6

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SJ. Thomson, M.L. Cowan, and T.M. Rahman

it is likely that the lesion will re-bleed once this effect is lost. The newest and preferred modality for heat treatment is bipolar electrocoagulation via a 'Gold' probe (Boston Scientific). The alternat ive 'heater' probe technique is still used widely. This uses direct application of thermal energy (- 30 J) rather than an electrical source. The bipolar 'Gold' probe catheter also has a needle in the central channel through which injection therapy can be applied. This obviates the need to change catheters when applying dual injection and heat therapy. In summary, for the treatment of ulcers, if there is evidence of fresh bleeding, adherent clot or a visible vessel in the ulcer base then intervention is indicated as these lesions confer a high risk of re-bleeding [28]. Attempts should be made before treatment to remove adherent clot from the ulcer base with either a water jet or a cold snare . If it is not possible to remove the overlying clot during the initial endoscopy then repeated assessment can be undertaken after a trial of pro-motility agents. This may help the clot to move on if stability has been achieved. A clean ulcer base or one with black or red spots can be safely left alone and managed conservatively as these ulcers have a low risk of re-bleeding. Epinephrine injection (5-10 ml of 1:10,000) should be applied in four quadrants around the bleeding point before finally injecting into the central vessel itself. Thermocoagulation should then be applied repeatedly until bleeding has stopped and a blackened area has formed [21]. The use of 'dual' therapy, that is, epinephrine injection and thermocoagulation together, is now recommended best practice [29]. Endoscopic clips are a relatively recent adjunct to current therapies . In practice , endoscopic clips are best targeted at larger visible vessels where it is actually possible to obtain an effective mechanical grip on the vessel. This is not always achievable in the setting of a large fibrotic ulcer base. It should be acknowledged that this technique is more technically demanding and requires both a skilled operator and assistant. In patients in whom initial endoscopic techniques have failed (5-20 %) one further attempt at endoscopic therapy should be tried before progressing to open surgical intervention [30). Radiological Management

Interventional radiology techniques may be useful if endoscopy is unsuccessful in either locating the bleeding site or in the application of its therapy. The methods for diagnosis and treatment are broadly similar for both upper and lower gastrointestinal bleeding [31]. The role of imaging is to locate the site of hemorrhage. The main modalities are conventional angiography, labeled red cell imaging, and computed tomography (CT) angiography. Angiography involves selective catheterization of the celiac artery, the superior mesenteric artery (SMA), and the inferior mesenteric artery (IMA) with a radiological catheter. Conventional angiography detects hemorrhage if patients are bleeding at a rate of 1 ml per minute or more. A positive result in a patient who is not bleeding at the time of the study is uncommon, therefore, angiography should generally only be performed in patients with ongoing hemorrhage. Acute bleeding is visualized angiographically in 37- 97 % of cases and is more common in upper than lower gastrointestinal bleeding. Red cell imaging is sensitive at lower rates of bleeding than angiography and may be used in stable patients when angiography is negative. With the development of multislice CT scanners, the ability of CT to image small vessels has improved substantially. Although, the technique continues to

Gastrointestinal Hemorrhage on the Intensive Care Unit

evolve, it appears that CT angiography can locate sites of bleeding in a significant proportion of patients and where available should probably be used early on in the diagnostic evaluation of patients. Embolization in gastrointestinal bleeding is one of the most technically demanding procedures performed by interventional radiologists. The aim of embolizat ion is to occlude the vessel supplying the site of hemorrhage. The main embolic agents used to treat gastrointestinal bleeding are coils, particulate matter (PVA or polyvinyl alcohol), and gelatin sponge (gelfoam). Gelfoam is a temporary occluding agent and dissolves after a few days, while the other agents are permanent. The choice of agent depends on the anatomical site of the bleed and the ability to pass a catheter to the bleeding site. Most recent series report successful embolization in around 85 - 90 % of patients . These success rates are achieved in upper and lower gastrointestinal bleeding [32, 33]. Recurrent hemorrhage occurs in 10-20 % of cases and can be treated by repeat embolization procedures in the majority of patients. Re-bleeding is more common in patients with angiodysplasia , and the presence of multiple lesions in many patients is usually an indicat ion for surgery. Although ischemic complications were feared by interventionalists and clinicians alike in the early experience of embolization, they are actually very uncommon, occurring in 1- 2 % of patients. In most patients, small ischemic or infarcted areas of bowel visible endoscopically are asymptomatic and do not requir e surgery. Transient abdominal pain occurs in around 10 % of patients [34].

Variceal Hemorrhage Portal hypertension is a complication of cirrhosis and is the etiological factor behind gastroesophageal varices and subsequent bleeding. Portal hypertension generates reversal of portal venous flow (hepatofugal), which diverts venous blood in a cephalic direction through the left gastric vein to the venous plexus of the esophagus. Therefore, portal hypertensive varices are more common in the lower third of the esophagus, especially at the gastroesophageal junction. Gastric fundal varices can also develop in this setting but can also rarely be caused by splenic vein thrombosis. Variceal hemorrhage is often associated with clinical stigmata of chronic liver disease (spider nevi, gynecomastia, palmar erythema, etc). At the time of diagnosis, 40 % of patients with compensated cirrhosis and 60 % of those with ascites have varices [35]. A small number (4.41100,000 per year) of patients with cirrhosis suffer with variceal bleeding as their first presenting feature [36]. Due to advances in pharmacotherapy and endoscopic intervention there has been a significant reduction in in-hospital mortality over the past two decades, from 42 to 14 % [37]. Immediate mortality from uncontrolled bleeding is between 5-8 % [38]. The poor prognostic indicators related to failure to control bleeding include active bleeding at endoscopy, hepatic venous pressure gradient > 20 mmHg, and bacterial infection. Infection can also act as a precipitating factor in the patient with variceal bleeding and affects between 35-66 % of patients within 2 weeks of the event [39]. A combination of reduced small bowel motility, bacterial overgrowth and increased permeability also gives rise to higher levels of gut bacterial translocation and hence endotoxemia and spontaneous bacterial peritonitis. Prophylactic broad spectrum antibiotic adminis tration at the time of bleeding has been shown to reduce the risk of re-bleeding . The most frequently studied and successfully used antibiotics are those that are active against enteric bacteria [40].

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SJ. Thomson, M.L. Cowan, and T.M. Rahman The use of vasopressin analogs (terlipressin) to affect splanchnic vasoconstriction and thus reduce the hepatic venous pressure gradient and variceal pressure is now common practice in the acute management of bleeding varices. Terlipressin has been shown to be superior to placebo in the control of variceal bleeding, to reduce mortality [41], and to have fewer of the systemic side effects (myocardial infarction, mesenteric ischemia) that were a concern with vasopressin. In situations where endoscopy is unavailable, terlipressin should be given; however, the benefits of combining the two therapies have still not been demonstrated in the literature. Somatostatin (octreotide) has also been shown to be better than placebo in controlling variceal bleed ing [42] and of equivalent efficacy to vasopressin [41]. It is probably best reserved as a second line therapy for patients intolerant to terlipressin. Historically, the endoscopic therapy of choice was sclerotherapy (submucosal injection of a sclerosant, e.g., ethanolamine); however, over the last ten years the technique of endoscopic variceal band ligation has taken preference. Meta-analysis [43] appears to suggest that variceal band ligation is superior to sclerotherapy on its own and in conjunction with vasoactive therapy in controlling bleeding, and in reducing rates of re-bleeding, mortality, and complications. The data discussed so far relate to the treatment of esophageal varices . Gastric varices, however, present a slightly different technical challenge. The evidence for band ligation in this setting is not as strong; however, the emerging use of endoscopic glue therapy (cyanoacrylate) appears especially useful [44]. The glue polymerizes on contact with the hydroxyl ions present in water and, thereby, physically occludes the lumen of the varix . Anecdotal risks of embolization to lung, spleen or brain have been reported. Patients with variceal bleeding are more likely to require airway protection due to the volume of blood, associated encephalopathy, and potential insertion of a Sengstaken-Blakernore tube. In contrast to upper gastrointestinal bleeding from other sources, resuscitative efforts for variceal bleeding should probably be more controlled. There is limited evidence to support the theoretical concerns that rapid volume resuscitation has a detrimental effect on portal pressure and hence bleeding. An alternative strategy is to maintain the hematocrit between 25 - 30 % [45]. Insertion of a Sengstaken-Blakemore tube can act as an effective bridge to definitive treatments in the case of massive uncontrollable bleeding. This technique was first described in 1950 and remains highly temporarily effective, arresting variceal bleeding in 90 % of cases [46]. It is not a definitive measure however, as up to 50 % of patients will re-bleed after deflation of the balloon at 24 h [46]. Patients should ideally be intubated before insertion. The tube can be passed nasally or orally although the latter is the more logical route in the intubated patient. Once fully passed, the gastric balloon should be inflated with 150-200 ml of air, water or contrast, and traction applied and maintained. Confirmation of correct placement preinsufflation can be obtained either endoscopically or with ultrasound, and post insufflation by chest radiographs if a contrast agent was used. The gastric balloon alone is sufficient for compression of the gastric cardia thereby tamponading the variceal supply. The esophageal balloon is not routinely inflated as concerns exist regarding pressure necrosis. Once in situ, traction should be applied by fixing the tube to the patient's cheek using a waterproof medical adhesive tape. Linton-Nachlas tubes are an alternative for effective control of gastric varices. This tube has a larger gastric balloon (600 ml) which provides tamponade throughout the gastric fundus. The evidence for their use is limited and historical but does seem to suggest an advantage over the Sengstaken-Blakemore tube in this setting.

Gastrointestinal Hemorrhage on the Intensive Care Unit

Establishing a mechani cal connection between the portal venous system and the systemic supply (hepatic vein) allows for decompression of raised portal venous pressure. This phenomenon was first described in 1969 although has only really featured as a formal clinical intervention over the past 10 years. The technique, known as transjugular intrahepatic portosystemic shunt (TIPSS), is a radiologically guided insertion of a self-expanding metallic stent into the liver parenchyma via the internal jugular vein, to connect the portal and hepatic veins. This technique is indicated as a rescue therapy in patients with uncontrollable acute variceal bleeding who have failed conventional endoscopic therapy, or for recurrent bleeding in patients intolerant to standard medical treatments. In patients with a hepatic venous pressure gradient > 20 mmHg TIPSS has been shown to reduce early re-bleeding risk and 6week mortality [47]. The main complication s of Trpss include stent failure, either due to thrombosis or intimal hyperplasia, and worsening encephalopathy. Stent thrombosis occurs in 10 % of cases [48], generally within the first 24 h post -insertion. Blockage can be identified with Doppler ultrasound and released with repeat radiological catheterization. Procedural related complications such as intra -peritoneal bleeding, hepatic infarction, and formation of biliary-venous or arterio-venous fistulas are rare. TrpSS is not widely available and is generally only performed in dedicated hepatology units. The indications for insertion and decision to proceed should normally take place under the direction of a specialist hepatologist. Other mucosal vascular abnormalities implicated in gastrointestinal bleeding include portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE). Both of these are more likely to produce chronic blood loss and are associated with patients with hepatic cirrhosis. There are other rarer lesions such as Dieulafoy's ulcer, an abnormally large submucos al artery, which erodes into the stomach lumen. This anomaly is usually found in the proximal stomach and accounts for up to 4 % of upper gastrointestinal bleeding. Initial endoscopic hemostasis (injection therapy and hemoclipping) is largely successful with overall mortality < 10 % [49].

lower Gastrointestinal Bleeding The incidence of lower gastrointestinal bleeding is 22 per 100,000 adults in the United States [50) and it accounts for 24 % of all gastrointestinal bleeding episodes. Ninety percent of cases of lower gastrointestinal bleeding stop spontaneously although 35 % require transfusion and 5 % acute surgical intervention [51]. Lower gastrointestinal bleeding generally occurs in older patients [50]. The most common etiology in the western world is diverticular disease (40 %), followed by inflamma tory bowel disease (20 %), malignancy (15 %), and benign anorectal disease (hemorrhoids) (10 % ). Up to 5 % of apparent lower gastrointestinal bleeding actually arises from the small bowel [51]. The role of urgent colonoscopy in these cases is controversial. Endoscopic views may be obscured by blood or stool and, as mentioned previously, 90 % of cases settle spontaneously. Urgent colonoscopy identifies the cause of bleeding significantly more often (odds ratio 2.6) than standard management [52]. There is, however, no significant difference in mortality, hospital stay, transfusion requirements, or rebleeding rates between urgent and planned cases [52]. Therapeutic options vary depending on the pathology demonstrated. The treatment of bleeding from divertic ular disease will depend on the stigmata of hemorrhage but is essentially identical to that of mucosal ulcerative disease in the upper gastrointestinal tract (epinephrine

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injection, heat therapy, hemoclipping). Hemorrhoidal bleeds can be managed with thermocoagulation, however, band ligation has recently found favor. A discussion of the radiological techniques involved in management of lower gastrointestinal bleeding is included in the earlier section. Surgical intervention is required in 18- 25 % of patients who require a blood transfusion [53]. A segmental colectomy is the preferred operation providing a bleeding point can be identified pre-operatively; if not then subtotal colectomy should be performed. The average mortality rate for segmental colectomy is 10 % and 20 % for subtotal colectomy [53] . Case series have described the role oflaparoscopic surgery in an 'acute setting' but within these series there was no description of the role of this technique in the management of colonic hemorrhage. Open surgery, therefore, remains standard practice.

Conclusion As we have highlighted, gastrointestinal bleeding is a significant and challenging problem when encountered in the critical care setting. The potential etiologies are numerous but core aspects of clinical management remain constant. The evidence base for specific therapeutic interventions is large and ongoing. Progress within the field of endoscopic and drug therapy has advanced to the extent that requirements for emergency gastroduodenal surgery are increasingly rare in modern practice. Perhaps the most significant of these advances was the advent of proton-pump inhibitors which has revolutionized the management of peptic ulcer disease. Falling mortality rates for variceal bleeding over the past two decades is also a victory for developments in endoscopic technique (variceal band ligation) and pharmacological intervention (vasopressin analogs). Specialist training in endoscopy is gaining prominence in the UK with recently established national training centers and educational programs bringing a much needed formal and standardized approach to training. More hospitals are establishing emergency 24 h endoscopy rotas as evidence demonstrates improved outcomes with earlier intervention. The interface between critical care medicine and the medical specialities is increasing. The specialist knowledge and practical contribution provided by physicians trained in gastroenterology should not be underestimated and demonstrates the importance of multi-disciplinary working. References 1. Rockall TA, Logan RFA, Devlin HB. Northfield TC (1995) Incidence of and mortality from acute upper gastrointestinal hemorrhage in the United Kingdom. BMJ 311:222- 226 2. Arlt GD, Leyh M (2001) Incidence and pathophysiology of peptic ulcer bleeding. Langenbecks Arch Surg 386:75-81 3. Cook DJ, Griffith LE. Walter SD. et al (2001) The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 5:368-375 4. Cook DJ. Fuller HD, Guyatt GH, et al (1994) Risk factors for gastrointestinal bleeding in criti cally ill patients. Canadian Critical Care Trials Group. N Engl J Med 330:377-381 5. Kolbel CB, Rippel K. Klar H. Singer MV, van Ackern K. Fielder F (2000) Esophageal motility disorders in critically ill patients: a 24-hour manometric study. Intensive Care Med 26:1421-7 6. Ng FH, Wong SY. Chang CM. et al (2003) High incidence of clopidogrel-associated gastrointes-

Gastrointestinal Hemorrhage on the Intensive Care Unit tinal bleeding in pat ients with previou s peptic ulcer disease. Aliment Pharmacol Ther 18: 443-449 7. Liberopoulous EN, Elisaf MS, Tselepis AD, et al (2006) Upper gastrointestinal haemorrhage complicat ing antiplatelet treatment with aspirin and/or clopidogrel : where we are now? Platelets 17:1-6 8. Kearney PM, Baigent C, Godwin J, Halls H, Emberson jR, Patrono C (2006) Do selective cyclo-oxygenase-2 inhibitors and tradi tional non -steroidal anti-inflammatory drugs increase the risk of atherothro mbosis? Meta-analysis of rando mised tr ials. BMj 332:1302- 1308 9. Chan FK, Wong VW, Suen BY, et al (2007) Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double -blind, randomised trial. Lancet 369:1621 -1626 10. Robertson MS, Cade JF, Clancy RL (1999) Helicobacter pylori infection in intensive care: increased prevalence and a new nosoco mial infection. Crit Care Med 27:1276-80 11. Halm U, Halm F, Thein D, Mohr FW, Mossner J (2000) Helicobacter pylori infection: a risk factor for upper gastroi ntesti nal bleeding after cardiac surgery? Crit Care Med 28:110- 113 12. Ong SP, Duggan A (2004) Eradic atio n of Helicobacter pylori in clinical situations. Clin Exp Med 4:30-8 13. Gisbert JP, Abraira V (2006) Accuracy of Helicobacter pylori diagnostic tests in patients with bleeding peptic ulcer: a systematic review and meta analysis. Am J Gastroen teroll0 l :848-63 14. Zullo A, De Francesco V, Hassan C, Morin i S, Vaira D (2007) The sequent ial therapy regimen for Helicobacter pylori eradication :a pooled data ana lysis. Gut 56:1353-1 357 15. Cook D], Reeve BK, Guyatt GH, et al (1996) Stress ulcer prophy laxis in critically ill patie nts: resolving discordant meta-analyses. JAMA 275:308-14 16. Stollman N, Metz DC (2005) Pathophysiology and prophylaxi s of stress ulcer in intensive care unit patients. I Crit Care 20:35-45 17. Lau JY, Sung JJ, Lee KK, et al (2000) Effect of intravenous omep razole on recurrent bleed ing after endo scopic treatment of bleeding peptic ulcers. N Engl J Med 343:310-316 18. Lau JY, Leung WK, Wu JC, et al (2007) Omeprazole before endosco py in patients with gastrointestinal bleeding. N Engl J Med 356:1631-1640 19. Rockall TA, Logan RF, Devlin HB, Northfield TC (l996) Risk assessment after acute upper gastrointestinal haemorrhage. Gut 38:316- 21 20. American College of Surgeons (1997) Advanced Trauma Life Support Course, Chicago 21. British Society of Gastroenterology Endoscopy Comm ittee (2002) Non variceal upper gastro intestinal haemorrhage: guidelines. Gut 51 (supp l iv): iv1- 6 22. Rudolph S], Landsverk BK, Freeman ML (2003) Endotracheal intubation for airway protection during endoscopy for severe upper GI haemorrhage. Gastroin test Endosc 57:58-6 1 23. Love DG (l999) Manageme nt of hemorr hagic events in patie nts receiving anticoagu lant therapy. j Thromb Thrombolysis 7:149-152 24. Bosch j, Thabut D, Bendsten F, et al (2004) Recombinant factor VIla for upper gastroi ntest inal bleeding in patients with cirrhosis: a randomized, double-blind trial. Gastroente rology 127:1123 - 1130 25. Hedner U (2007) Recombinant factor VIla: its background, development and clinical use. Curr Opin Hematol 14:225 - 229 26. Cooper GS, Chak A, Way LE, Hammar P], Harper DL, Rosenthal GE (l999) Early endosco py in upper gastro intestinal haemor rhage: associations with recur rent bleeding, surgery and length of hospita l stay. Gastro intest Endosc 49:145 - 152 27. Winstead NS, Wilcox CM (2007) Erythromycin prior to endosco py for acute upper gastro intestinal haemorrhage: a cost effectiveness analysi s. Alimen t Pharm acol Ther 26:13711377 28. Cook DJ, Gayatt GH, Salena BJ, Laine LA (l992 ) Endoscopic therapy for acute non-variceal upper haemorrhage: a meta analysis. Gastroenterology 102:139- 148 29. Chung SS, Lau JY, Sung JJ, et al (l997 ) Randomised comparison between adre nalin e injectio n alone and adrenaline injection plus heat probe treatment for actively bleeding peptic ulcers. BMJ 314:1307- 1311 30. Lau JY, Sung JJ, Lam YH, et al (l999 ) Endoscopic retreatment compared with surgery in patients with recur rent bleeding after initial endoscopic control of bleeding ulcers. N Engl I Med 340:751-756

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SJ. Thomson, M.L. Cowan, and T.M. Rahman 31. Lefkovitz Z, Cappell MS, Lookstein R, Mitty HA, Gerard PS (2002) Radiologic diagnos is and treatment of intestinal haemorrhage and ischaemia. Med Clin North Am 86:1357-1399 32. Schenker MP, Duszak R Ir, Soulen MC, et al (2001) Upper gastro intestinal haemorrhage and trans catheter embolotherapy: clinical and technical factors impact in success and survival. J Vasc Interv Radiol 12:1263-1271 33. D'Othee BJ, Surapaneni P, Rabkin D, Nasser I, Clouse M (2006) Microcoil embolization for acute lower gastrointestinal bleeding. Cardiovasc Intervent Radiol 29:49- 58 34. Silver A, Bendick P, Wasvary H (2005) Safety and efficacy of superselective angio embolisation in control of lower gastro intestinal haemorrhage. Am J Surg 189:361-363 35. Schepis F, Camma C, Niceforo D, et al (2001) Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection? Hepatology 33:333- 338 36. Bosch J, Grozmann R (1994) Portal hypertension in cirrhosis: Natural history. In: Bosch J (ed) Portal Hypertension: Pathophysiology and Treatment. Blackwell Scientific, Cambridge , pp 72-92 37. Carbonell N, Pauwels A, Serfaty L, Fourdan 0 , Levy VG, Poupon R (2004) Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 40: 652-659 38. de Franchis R, Primignani M (2001) Natural history of portal hypertension in pat ients with cirrhosis. Clin Liver Dis 5:645-663 39. Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs A (1998) Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal haemorrhage. Hepatology 27:1207 -1212 40. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L (2002) Antibiotic prophylaxis for cirrhotic pat ients with gastrointestinal bleeding. Cochrane Database Syst Rev CD002907 41. Ioannou GN, Doust J, Rockey DC (2003) Systematic review: terlipres sin in acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther 17:53- 64 42. Avgerinos A, Nevens F, Raptis S, Fevery J (1997) Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial. Lancet 350:1495 -1499 43. Gross M, Schiemann U, Muhlhofer A, Zoller WG (2001) Meta-analysis: efficacy of therapeutic regimens in ongoing variceal bleeding. Endoscopy 33:737-746 44. Seewald S, Sriram PV, Naga M, et al (2002) Cyanoacrylate glue in gastric variceal bleeding. Endoscopy 34:926- 932 45. Abraldes JG, Dell'Era A, Bosch J (2004) Medical management of variceal bleeding in pat ients with cirrhosis. Can J Gastroenterol 18:109-113 46. Panes J, Teres J, Bosch J, Rodes J (1988) Efficacy of balloon tamponade in treatment of bleeding gastric and esophageal varices. Results in 151 consecutive episode s. Dig Dis Sci 33: 454-459 47. Monescillo A, Martinez -Lagares F, Ruiz-del-Arbol L, et al (2004) Influence of Portal hyper tension and its early decompression by TIPS placement on the outcome of variceal bleeding. Hepatology 40:793-801 48. Rossle M, Siegerstetter V, Huber M, Ochs A (1998) The first decade of the tran sjugular intrahepatic portosystemic shunt (TIPS): state of the art. Liver 18:73- 89 49. Romaozinho JM, Pontes JM, Lerias M, Ferreira M, Freitas D (2004) Dieulafoy's lesion: Management and long-term outcome. Endoscopy 36:416-420 50. Longstreth GF (1997) Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 92:419-424 51. Vernava AM 3rd, Moore BA, Longo WE, Johnson FE (1997) Lower gastrointestinal bleeding. Dis Colon Rectum 40:846- 858 52. Green BT, Rockey DC, Portwood G, et al (2005) Urgent colonoscopy for evaluation and management of acute lower gastrointestinal hemorrhage: a randomized controlled trial. Am J Gastroenterol 100:2395-2402 53. Edelman DA, Sugawa C (2007) Lower gastrointestinal bleeding : a review. Surg Endosc 21: 514-520

751

Recombinant Activated Factor VII: The Delicate Balance between Efficacy and Safety S.

BELISLE,

J.-F.

HARDY,

and P.

VAN DER LINDEN

Introduction Endogenous activated factor VII (FVIIa) plays a crucial role in the effective coagulation process. The clotting drug NovoSeven® (Novo Nordisk A/S, Bagsvaerd, Denmark) is structurally nearly identical to endogenous FVIIa and is produced by recombination from a baby hamster kidney cell line. Supra-physiologic concentrations of FVIIa are achieved by the administration of pharmacological doses of recombinant FVIIa (rFVIIa). To generate thrombin, rFVIIa needs either tissue factor or activated platelets (tissue factor-independent generation). Consequently, rFVIIa is approved for the prevention and the treatment of bleeding in patients with a range of congenital hemostatic disorders, mainly hemophilia. Its high efficacy in various hemostatic defects has oriented its application to the perioperative setting, trauma, and ICU patients. Over the last five years, the estimated number of patients treated with rVIIa has grown rapidly, mainly for off-license indications. Previous to any clinical use, a new treatment has to be proven effective and safe. The gold standard in establishing benefits and harms is the randomized controlled trial (RCT). In this chapter, we reassess all published RCTs that have evaluated the hemostatic efficacy and safety of rFVIIa in non-hemophiliac patients. In total, at the time of writing, 14 placebo-controlled, double-blind RCTs have been published on the use of rFVIIa to control bleeding in patients either as a prevention (8 RCTs, 874 patients) [1- 8] or as a cure (6 RCTs, 1086 patients) [9 -14].

Efficacy in Prophylaxis Trials Prevention of excessive bleeding and transfusion can be achieved by the implementation of different alternatives and modalities in high-risk patients undergoing surgery. The balance between the efficacy and the safety of a treatment is tremendously important before considering its large-scale use. The ratio of this balance is different when curative or prophylactic approaches are considered. The safety of a cure has simply to be superior to the risk associated with the disease, which makes the treatment better than the disease. However, this ratio is quite different when a prophylactic intervention is considered. As the efficacy of preventive measures is exceptionally more than 50 %, the majority of the exposed population, only at risk for the disease, will not benefit from the protective treatment. Therefore, an innoxious prophylaxis is essential to preserve an acceptable risk-benefit ratio for the entire population. Eight RCTs have estimated the blood-sparing effect of rFVIIa during various elective surgical procedures. Table 1 summarizes the outcomes of these studies. Six of

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the trials were included in a recent meta-analysis [15). Stanworth et al. [15) coneluded th at 'no advantage was observed when rFVIIa was compa red to placebo. The inclusion of the two more recent trials should not modify these conclusions. Many limitat ion s of these RCTs need to be considered, including the large variation in the dosage (from 20 to 120 fig/kg and number of doses from 1 to 3) and the timing of the administration of rFVIIa. Noticeably, the optimal dose to obtain a clinical effect is still unknown. Crucially for the generalization of these results, patients with important co-morbidities were always excluded from the se tr ials. Table 1. Results of prophylactic trials using rFVlla

First author [ref]

Number of Prevenpatients tion analyzed during: for primary outcome

Outcome with significant difference, rFVlla versus control

Outcome with no significant difference

Diprose [1] 20

Adult cardiac surgery

Ekert [3]

76

Children cardiac surgery

Friederich [2]

36

Prostatec- Total blood 1055 1089 Length of stay, number of adverse tomy ml versus 2688 ml events p = 0.001; number of transfused patients 0 % versus 58 % P =0.001;

Number of transfused patients, number of units transfused, total blood loss, length of stay, number of adverse events Time to chest closure Number of transfused patients, number 98 min versus 55 min of units transfused, total blood loss, p = 0.026 (in favor of number of adverse events placebo)

number of units transfused 0 versus 1.5 unit p = 0.0003 Lodge [4]

204

Hepatectomy

Lodge [5]

182

Number of transfused Liver transplan- patients 90% versus tation 100 %, P = 0.03

Number of units transfused. total blood loss, length of stay, number of adverse events

Planinsic [6]

87

Liver transplantation

Number of units transfused, total blood loss, length of stay, number of adverse events

Raobaikady [7]

48

Traumatic fracture

Number of transfused patients, number of units transfused, total blood loss, length of stay, number of adverse events

5hao [8]

221

Hepatectomy

Number of transfused patients, number of units transfused, number of adverse events

reduction in hematocrit Number of transfused patients, total -3.7 % versus -6.7 %, blood loss, number of units transfused. number of adverse events p = 0.04

Recombinant Activated Factor VII: The Delicate Balance between Efficacy and Safety

When considered individually, these trials show inconsistent effects of rFVIIa. Ekert et al. observed a significantly faster time to close the chest with the placebo [3]. rVIIa was associated with a 10 % reduction in the rate of transfusion during liver transplantation [5]. The most impressive results were reported by Friederich et al. in patients undergoing retropubic prostatectomy [2]. rFVIIa, at a dose of 40 fig/kg, reduced the rate of transfusion from 58 % to 0 % (p = 0.001), the mean number of red blood cell (RBC) units from 1.5 to 0 unit (p = 0.0003), and the mean total blood loss from 2688 ml to 1089 ml (p = 0.001). However, this trial [2] only included 36 patients and the blood loss reported in the control group was unexpectedly high, particularly when we consider recent advancements in minimally invasive surgical techniques. All other trials have shown no significant improvement in the perioperative blood loss and the rate and number of RBC transfusions. Based on these stud ies, rVIIa has no blood-sparing or transfusion-saving properties in patients undergoing elective high-risk surgery, and clinicians should consider other available and well-validated alternatives in this setting.

Efficacy in Curative Trials Conventional management of active bleeding would typically include the optimiza tion of the hemostatic environment, early surgical hemostasis or interventional radi ology procedure, and the transfusion of appropriate blood components. From its potent effect in hemophil ia and its various mechanisms of action, rFVIIa may be considered as a potential universal hemo static agent. Case reports and case series suggest that rFVIIa is effective in the management of uncontrolled bleeding of diverse origins in patients with an acquired coagulopathy. While such results are interesting and suggest possible efficacy, more recent papers raise questions about its efficacy and its safety [16 - 18]. In six RCTs, aFVIIa was used to control hemo rrhage in diverse cases of severe bleeding. These studies showed either no gain [9-11, 13], significant benefits [9, 12], or even an advantage for the placebo group [14]. The main results of these studies are summarized in Table 2. The six RCTs available have been included in a meta-analysis [15]. Limitations for appropriate meta-analys is, however, are the small cohorts, the variety of hemostatic defects causing the hemorrhage, the non-standardized bleeding management, and the large variation in the mort ality rate of the placebo groups (0 %-30 %). The most salient result is the equivalent rate of bleeding control in the two groups (3 RCTs, rVIIa: 75 % [range 43 %-94 %], placebo: 76 % [range 44 %-84 %]) . Overall, no significant improvement in the mortality rate, use of RBC transfusion, or the number of patients transfused could be attributed to rFVIIa over placebo. When considered individually, the majority of the RCTs have not been able to demonstrate a convincing beneficial impact of rFVIIa. However, three trials require further discussion . The first study included a SUb-group of patients with severe blunt trauma, defined by the requirement of more than 6 units of RBCs within 4 h of admission [9]. A significant reduction in the rate of massive transfusion (> 20 units of RBCs) from 33 % to 14 % (p = 0.03) was observed . On the other hand , the estimated reduction of 2.6 RBC units at 48 hours (p = 0.02) seems relatively small and concerns only patients with blunt trauma surviving more than 48 h. The subgroup with penetrating trauma did not benefit from the infusion of rFVIIa. A positive trend in favor of rFVIIa was observed in the survival rate of the two sub-groups. This may reflect the reduction of late complications, such as acute lung injury and

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S. Belisle, J.-F. Hardy, and P. Van der Linden Table 2. Results of therapeutic trials using rFVlla First author [ref]

Number of Bleeding patients associated analyzed with: for primary outcome

Outcome with significant difference rFVlla versus control

Outcome with no significant difference

Boffard [9] 143

Blunt trauma

Number of units trans- Serious adverse events, length of stay, fused estimated reduc- mortality tion of 2.6 units, p = 0.02; number of massively transfused patients 14% versus 33 %, P = 0.03

Boffard [9] 134

Penetrating trauma

Number of massively transfused patients, number of units transfused, serious adverse events, length of stay, mortality

Bosch [10] 237

Upper gastrointestinal bleeding with cirrhosis

Chuansumrit

Dengue hemorrhagic fever

Clinical control of bleeding, recurrence of bleeding, number of transfused patients, number of units transfused, number of adverse events, mortality

Mayer [12] 399

IntracereRankin Scale score + bral hernor- mortality 54% versus rhage 69%, p = 0.004; mortality 18% versus 29 %, P = 0.02

Serious adverse events

Mayer [13] 48

Intracerebral hemorrhage

Number of adverse events, serious adverse events, mortality

Pihusch [14]

Stem cell Excluding hemorrhagic transplanta- cystitis: number of tion units transfused higher with increasing doses of rFVlla p = 0.04 and 0.02 (in favor of placebo)

Clinical control of bleeding, number of units transfused (all patients), length of stay, number of adverse events, mortality

25

[11]

100

clinical control of vari- Clinical control of bleeding (all ceal bleeding Child B patients), recurrence of bleeding, or C number of units transfused, number 92 % versus 77 %, of adverse events, length of stay, p = 0.03 mortality

multiple organ failure. Finally, no difference was observed between groups with respect to the transfusion of hemostatic blood . A large confirmatory Phase III study is ongoing since 2005 and is expected to include 1502 patients with severe trauma injuries (F7TRAUMA-1648 www.clinicaltrials.gov NCT00184548). The second study reported a significant advantage only in a selected group of patients after a post-hoc analysis [10]. In active acute upper gastrointestinal bleed-

Recombinant Activated Factor VII: The Delicate Balance between Efficacy and Safety

ing in patients with cirrhosis (Child-Pugh B and C), the administration of eight doses of rFVIIa improved the rate of bleeding control at 24 h in the sub-population of variceal bleeders. However, in bleeding of non-variceal origin, the failure rate was higher with rFVIIa (19 % versus 7.7 % in the placebo group (no statistical analysis provided by the authors). Further studies are required to confirm these exploratory analyses. In a phase II trial, the impact of early treatment with different dosages of rFVIIa in patients with spontaneous intracerebral hemorrhage was particularly impressive [12]. This treatment significantly reduced intracranial bleeding, mortality at 90 days (18 % versus 29 % for placebo, p = 0.02), and the incidence of severe incapacity (53 % versus 69 %, P = 0.004). The recent publication by the American Heart Association/American Stroke Association of updated guidelines on the management of spontaneous intracerebral hemorrhage in adults recommends that before its use in patients with intracranial bleeding, the efficacy and safety of rFVIIa must be confirmed by phase III trials [19]. The placebo-controlled rFVIIIa in Acute Hemorrhagic Stroke Treatment (FAST) Trial was designed to validate these results and included 821 patients. Although not formally published at the time of writing, this study failed to confirm any benefit in terms of reduced mortality or severe disability at day 90 [20). The massively bleeding patient, although challenging and associated with higher morbidity and mortality, represents less than 15 % of the usual civilian and military case load [21- 23). Conventional but standardized modalities to achieve control of massive bleeding continue to be the cornerstone of effective management. Until appropriately validated by positive trials, liberal administration of rFVIIa is not justified outside licensed uses. Nevertheless, rFVIIa may be considered in selected cases of life-threatening hemorrhage unresponsive to standard management and as an adjunctive treatment. To be effective, prior to its utilization, conditions such as hypothermia, acidosis, high vascular pressure, low ionized calcemia, anemia and low concentrations of platelets and fibrinogen need to be corrected.

Safety: Thrombo-embolic Complications When administered at pharmacological doses, blood levels of FVIIa are at a concentration 1000 times greater than normal. rFVIIa augments thrombin generation by different pathways (tissue factor-dependent and -independent), enhances the adhesion, deposition, and activation of platelets (thrombin dependent) and inhibits fibrinolysis [24-26). Any therapy able to promote hemostasis can induce thromboembolic complications as well. Therefore, the balance between benefit and harm may be quite delicate. A risk for thromboembolic events after the administration of rFVIIa can be inferred from RCTs, large retrospective studies, and spontaneous reports of adverse events for licensed and off-label indications.

Safety Profile: Volunteers and Licensed Indications The administration of rFVIIa in volunteers results in increased endogenous thrombin potential, plasma concentrations of F1+2 and D-dimer, and a reduction in the thrombin-generation time, activated partial thromboplastin time (aPTT), and prothrombin time, all signs of thrombin generation and transformation of fibrinogen to

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S. Belisle, J.-F. Hardy, and P. Van der Linden fibrin [27, 28]. A large interindividual vanation in the thrombin burst is also observed although has not yet been correlated with the clinical response [29]. No serious thromboembolic adverse event has been reported in healthy, non-bleeding volunteers. , In hemophiliac patients, control bleeding by rFVIIa is achieved in more than 80 % of episodes [30, 31]. The rate of efficacy is similar to the older activated prothrombin complex concentrate treatment. The incidence of serious adverse events associated with rFVIIa in this population of patients with hemostatic disorders is less than 1 % [32]. In a recent comprehensive pharmacovigilance assessment, the occurrence of reported thromboembolic complications was estimated at 0.02 % per infusion (l event spontaneously described after each 4065 infusions), mainly cerebrovascular thrombosis and myocardial infarction [33]. These complications seem to be related to the underlying risk for atherosclerosis. Although ra re and probably underestimated, the incidence of thrombotic adverse events with rFVIIa is significantly, roughly three-times, higher when compared with factor VIII inhibitor bypass activity (FEIBA®) [33].

Safety Profile: Off-label Indications Levy et al. have reviewed the critical safety data obtained from 10 studies in patients or volunteers with acquired coagulopathy who received rFVIIa (n = 1178) [34]. Based on the an alysis of nine studies, including five placebo-controlled RCTs, and one abstract, the incidence of thrombotic adverse events was 6.0 %, equivalent to the 5.3 % in the control groups. More robust results are derived from the meta-analysis of Stanworth et al. which includes 12 RCTs [15]. Rates of cardiovascular complications and stroke were 3.3 % (rFVIIa) versus 0.7 % (placebo) and 3.6 % (rFVIIa) versus 0.6 % (placebo), respectively. The relative risk of developing each complication was not significant (cardiovascular events: 2.18 (95 % CI 0.82 to 5.79), stroke: 2.0 (95 % CI 0.57 to 7.17). The pooled relative risk for thromboembolic events was 1.28 (95 % CI 0.84 to 1.95), also not significant. Most of the included studies were not designed or powered to detect a significant risk of thromboembolic complications. Of note, Mayer et al. reported a significantly higher rate of thromboembolic complications (rFVIIa 7 % versus placebo 2 %, p< 0.05) in patients with intracerebral hemorrhage [12]. The publication of the results of the FAST trial should provide more information regarding these safety issues . Finally, it must be recognized that all studies had previously excluded patients with conditions associated with thrombosis and vaso-occlusive disease, thus greatly limiting any generalization. One other source of information is provided by the analysis of spontaneous reports of complications to the Food and Drug Administration (FDA) Adverse Event Reporting System. During the initial 5 years after the US licensure, unlabeled indications generated 151 reports, representing 90 % of all cases of thromboembolic complications associated with rFVIIa [35]. More than 75 % of the assessments of these reports concluded that there was a possible or probable relationship between rFVIIa and the adverse event . The reported mortality rate was high at 27 %, and in 72 % of fatal cases the cause of death was attributed to the thrombotic event. Thromboembolic complications occured at a median time of 24 h, and mostly during the first three days, after the last infusion. Th ese events involved locations other than the initial bleeding site , mainly arterial and venous thrombosis or occlusion of devices. A

Recombinant Activated Factor VII: The Delicate Balance between Efficacy and Safety

concomitant hemo static agent (usually platelets, fresh-frozen plasma or antifibrinolytic drugs) was used in 38 % of reports. Without knowing the denominator (total number of patients exposed), the real incidence cannot be calculated but it is higher than previously reported for licensed indications. Many recent publications have evaluated the safety of off-label rFVIIa in retro spective cohorts. In a comparison of two historical groups, Sugg et al. reported a 10 % incidence of myocardial infarction after administration of rFVIIa in patients with intracerebral hemorrhage versus 1 % in patients managed with conventional treatment (p = 0.01) [18]. Karkouti et al. retrospectively evaluated the incidence of serious thrombotic events and death in excessive bleeders after cardiac surgery [36]. This large study included 114 patients in the rFVIIa group, compared to 541 patients as controls. Patients were divided into early (:5 8 units) and late (> 8 units) treat ment groups according to the median number of RBC units received before therapy. The adverse event rates were 24 % in unexposed patients and 30 % and 60 % in the early and late rFVIIa group s, respect ively. After adjustment for different risk factors, the complication odds ratio was significantly lower in the rFVIIa group when given early. In light of these results, the authors suggest the use of rFVIIa very early after the onset of hemorrhage [36]. In a retrospective audit of 285 trauma patients who had received rFVIIa, Thomas et al. reported a 9.4 % rate of severe thromboembolic complications , which were thought to be involved as a cause of death in 71 % of cases [17]. A clear and progressively higher incidence of thromboembolic complications is observed when we consider volunteers , hemophiliac patients, low-risk populations included in RCTs, and high-risk patients in retrospective cohorts. However, this observation cannot establish a link of causality between these events and rFVIIa. In addition, the absence of significant differences in RCTs should not reassure us. Adequately powered RCTs are obviously required.

Conclusion In summary, at the present time, published RCTs do not support the efficacy of rFVIIa to control bleeding and reduce transfusions in various patient populations. In addition, the safety of rFVIIa remains a concern [35]. The lack of adequately powered, randomized studies evaluating rFVIIa limits drawing firm conclusions on its real place in our therapeutic armamentarium. Consequently and until the demonstration of benefits, confirmation of its safety, and determination of the optimal dosage and appropriate monitoring, the use of rFVIIa to prevent or to control bleeding in non-hemophiliac patients cannot be recommended. However, rFVIIa could be considered, with caution , in patients with refractory life-threatening hemorrhage when conventional measures have failed. It should be considered as an adjunct to, rather than instead of, such measures. To express its full clotting potential, rFVIIa requires an optimal hemostatic environment (pH, temperature at the site of action, vascular pressure, ionized calcium and hemoglobin concentration), and adequate circulating levels of platelets and fibrinogen . As these conditions are prerequisites for treatment, rFVIIa must be considered late in the management of excessive bleeding; early introduction will expose a large number of patients unnecessarily.

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S. Belisle, J.-F. Hardy, and P. Van der Linden References 1. Diprose P, Herbertson MJ, O'Shaughnessy D, Gill RS (2005) Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: random ized double-blind placebo-controlled pilot study. Br J Anaesth 95:596-602 2. Friederich PW, Henny CP, Messelink EJ, et al (2003) Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a doubleblind placebo-controlled randomised trial. Lancet 361:201- 205 3. Ekert H, Brizard C, Eyers R, Cochrane A, Henning R (2006) Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double-blind, parallel group, placebo-controlled study of rFVIIa and standard haemostat ic replacement therapy versus standard haemostatic replacement therapy. Blood Coagul Fibrinolysis 17:389- 395 4. Lodge JP, Jonas S, Oussoultzoglou E, et al (2005) Recombinant coagulation factor VIla in major liver resection: a randomized, placebo-controlled , double-blind clinical trial. Anesthesiology 102:269- 275 5. Lodge JP, Jonas S, Jones RM, et al (2005) Efficacy and safety of repeated perioperative doses of recombinant factor VIla in liver transplantation. Liver Transpl11 :973-979 6. Planinsic RM, van der Meer J, Testa G, et al (2005) Safety and efficacy of a single bolus administration of recombinant factor VIla in liver transplantation due to chronic liver disease. Liver Transpl11 :895-900 7. Raobaikady R, Redman J, Ball JA, Maloney G, Grounds RM (2005) Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum : a double-blind, randomized, placebo-controlled trial. Br J Anaesth 94:586-591 8. Shao YF, Yang JM, Chau GY, et al (2006) Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Am J Surg 191:245-249 9. Boffard KD, Riou B, Warren B, et al (2005) Recombinant factor VIla as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials . J Trauma 59:8- 15 lO. Bosch J, Thabut D, Bendtsen F, et al (2004) Recombinant factor VIla for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial. Gastroenterology 127:1123 -1130 11. Chuansumrit A, Wangruangsatid S, Lektrakul Y, et al (2005) Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study. Blood Coagul Fibrinolysis 16:549-555 12. Mayer SA, Brun NC, Begtrup K, et al (2005) Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352:777- 785 13. Mayer SA, Brun NC, Broderick J, et al (2005) Safety and feasibility of recombinant factor VIla for acute intracerebral hemorrhage. Stroke 36:74-79 14. Pihusch M, Bacigalupo A, Szer J, et al (2005) Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation. J Thromb Haemost 3:1935- 1944 15. Stanworth SJ, Birchall J, Doree CJ, Hyde C (2007) Recombinant factor VIla for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev: CD005011 16. Conen A, Weisser M, Tsakiris DA, Siegemund M (2007) Failure of recombinant factor VIla in a patient with severe polymicrobial sepsis and postoperative uncontrolled intraabdominal bleeding. BMC Infect Dis 7:34 17. Thomas GO, Dutton RP, Hemlock B, et al (2007) Thromboembolic complications associated with factor VIla administration. J Trauma 62:564- 569 18. Sugg RM, Gonzales NR, Matherne DE, et al (2006) Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIla. Neurology 67:1053-1055 19. Broderick J, Connolly S, Feldmann E, et al (2007) Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart

Recombinant Activated Factor VII: The Delicate Balance between Efficacy and Safety AssociationlAmerican Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 38:2001- 2023 20. Mayer SA, (2007) Complications in patients with intracerebral hemorrhage treated with recombinant factor VIla. Neurology 69:319 - 320 21. Karkouti K, Beattie WS, Wijeysundera ON, et al (2005) Recombinant factor VIla for intractable blood loss after cardiac surgery : a propensity score-matched case-control analysis. Transfusion 45:26-34 22. Huber-Wagner S, Qvick M, Mussack T, et al (2007) Massive blood transfusion and outcome in 1062 polytrauma patients : a prospective study based on the Trauma Registry of the German Trauma Society. Vox Sang 92:69- 78 23. Perkins JG, Schreiber MA, Wade CE, Holcomb JB (2007) Early versus late recombinant factor VIla in combat trauma patients requiring massive transfusion. J Trauma 62:1095-1099 24. Hedner U, Ezban M (2007) Tissue Factor and Factor VIla as Therapeutic Targets in Disorders of Hemostasis. Annu Rev Med [Epub ahead of print] 25. Gerotziafas GT, Chakroun T, Depasse F, Arzoglou P, Samama MM, Elalamy I (2004) The role of platelets and recombinant factor VIla on thrombin generation, platelet activation and clot formation . Thromb Haemost 91:977- 985 26. Lisman T, Adelmeijer J, Cauwenberghs S, Van Pampus EC, Heemskerk JW, De Groot PG (2005) Recombinant factor VIla enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. J Thromb Haemost 3:742-751 27. Bijsterveld NR, Moons AH, Boekholdt SM, et al (2002) Ability of recombinant factor VIla to reverse the anticoagulant effect of the pentasaccharide fondapari nux in healthy volunteers. Circulation 106:2550 - 2554 28. Fridberg MJ, Hedner U, Roberts HR, Erhardtsen E (2005) A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects. Blood Coagul Fibrinolysis 16:259-266 29. Wegert W, Harder S, Bassus S, Kirchmaier CM (2005) Platelet-dependent thrombin generation assay for monitoring the efficacy of recombinant Factor VIla. Platelets 16:45- 50 30. Arkin S, Blei F, Fetten J, et al (2000) Human coagulation factor FVIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven emergency-use programme in patients with severe haemophilia or with acquired inhibitors. Blood Coagul Fibrinolysis 11:255- 259 31. Negrier C, Hay CR (2000) The treatment of bleeding in hemophilic patients with inhibitors with recombinant factor VIla. Semin Thromb Hemost 26:407-412 32. Roberts HR, Monroe OM, 3rd, Hoffman M (2004) Safety profile of recombinant factor VIla. Semin Hematol 41:101-108 33. A1edort LM (2004) Comparative thrombotic event incidence after infusion of recombinant factor VIla versus factor VIII inhibitor bypass activity. J Thromb Haemost 2:1700- 1708 34. Levy JH, Fingerhut A, Brott T, Langbakke IH, Erhardtsen E, Porte RJ (2006) Recombinant factor VIla in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 46: 919-933 35. O'Connell KA, Wood JJ, Wise RP, Lozier IN, Braun MM (2006) Thromboembolic adverse events after use of recombinant human coagulation factor VIla. JAMA 295:293- 298 36. Karkouti K, Yau TM, Riazi S, et al (2006) Determinants of complications with recombinant factor VIla for refractory blood loss in cardiac surgery. Can J Anaesth 53:802-809

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Section XIX

XIX Hepatic Disease

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leu Management of the Liver Transplant Patient G.

DELLA ROCCA,

M.G.

COSTA,

and P. CHIARANDINI

Introduction The perioperative care of patients undergoing liver transplantation is a crucial clinical situation encountered by surgeons, anesthetists, and critical care physicians. Great strides have been made in the field of liver transplantation since the time when it was considered just an experimental procedure [1]. Liver transplantationrelated mortality and complication rates have significantly decreased and the mean l-year survival rate is now more than 90 % as a result of improved techniques, the consolidation of basic knowledge and experience, better patient selection and preparation, and the use of innovative drugs and technologies [2]. Morbidity after liver transplantation results in suffering, prolonged hospitalization, and increased health care expenditure. Associated conditions, such as acute lung injury (ALI), renal dysfunction, infection, and gastrointestinal tract dysfunction, increase hospital length of stay and costs. Graft-related complications, such as primary non-function, poor (or delayed) early graft function , and early rejection, can result in the loss of the donor organ reducing dramatically the outcome or necessitating retransplantation. Complications after liver transplantation are likely to be multifactorial in origin. Some of the morbidity may be due to a patient's underlying condition, for example, their preoperative renal function, the United Network for Organ Sharing (UNOS) status, and their model for end-stage liver disease (MELD) score. We will discuss some particular aspects of the early intensive care unit (lCU) management of the liver transplanted patient that reflect the current challenges associated with this procedure including early extubation and non -invasive ventilation; hemodynamic management, splanchnic perfusion, and graft function; fluid management and transfusion; lung and liver function; renal function; and neurological status and sedation.

Early Extubation and Non-invasive Ventilation Ever since a deleterious impact of mechanical ventilation on post-transplant liver graft recovery was reported [3], early postoperative extubation ('fast tracking') has been applied in liver transplant recipients (Table 1) [4]. Several reports on fast tracking in clinical liver transplantation have now been published, essentially demonstrating that this technique merits the increased interest in many transplant centers worldwide [5- 7]. Consequently, the postoperative ventilation time has markedly decreased, and postoperative extubation is performed mostly in the operating room and not in the ICU. Mandell et al. applied fast tracking to liver transplant recipents

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G. Della Rocca, M.G. Costa, and P. Chiarandini Table 1. Absolute and relative criteriafor early extubation and/or for non-invasive (NIV) or invasive ventilation in liver transplanted patients. Criteria

Early Extubation Preoperative

NIV Postoperative

Absolute 1. No acute liver 1. PaO/ Fi02 > 200 failure

Relative

ETI-MV

1. PaO/Fi0 2 < 150 1. Tracheal intubation for CPR, respiratory arrest, and/or PaC0 2 > 60 mmHg severe hemodynamic instability, decreased level of consciousness, NIV-non responder

2. No encephalopathy

2. No cardiovascular 2. RR > 35 drug support at breaths/min theend ofsurgery and body temperature > 36 °C

2. Respiratory fai lure caused by neurological disease or status asthmaticus

3. No other rna-

3. < 10 units of packed RBC administered

3. More than 1 new organ fai lure

jor coexisting diseases or retransplantation

3. Active contrac-

tion of the accessory muscles of respiration

4. Age < 65 years 4. Graft function

recovery

CPR: cardiopulmonary resuscitation; Ell: endotracheal intubation; MV: mechanical ventilation

and found that patients who were extubated before leu admission had a reduced length of stay in the leU, decreased need for certain leU services, and overall lower leu costs [4]. Glanemann et al. and Biancofiore et al. achieved immediate or very early « 3 hours) extubation in patients after liver tr ansplantat ion without an increase in the incidence of reintubation compared with patients in whom extubation occurred late [5, 6]. Although encouraging, none of these studies were conducted in a randomized, prospective manner. Findlay and colleagues demonstrated that when used with an leu care plan and ventilator weaning protocol, fast track anesthetic can result in earlier extubation in patients after liver transplantation [7]. However, in their institution, reduced ventilation time did not translate into a reduction in length of leu stay. Also in this study, fast track anesthesia was not associated with an increased requirement for reintubat ion or with complications related to reintubation . Mechanical ventilation does not always benefit all post-surgic al patients because the lower intrapleural pressure during spontaneous ventilation facilitates venous return and favors end-d iastolic filling of the heart, cardiac output, and hepatic flow, and this can improve venous drainage and liver circulation especially when it is used to create the best hemodynamic conditions for functional graft recovery [3]. Another central question is the possibility of predicting which patients can be extubated immediately and, therefore, also which can be potentially transferred to a ward or high dependency unit rather than to the leu [6]. Liver transplant candidates generally enter surgery with multiorgan disease, including encephalopathy, renal insufficiency, and so on. Postoperatively, the patient receiving a liver transplant can experience graft dysfunction and severe coagulopathy, and generally requires considerable amounts of blood and fluid. As immediate extubation is possi-

leu Management of the Liver Transplant Patient

ble only if the patient is in a very stable condition at the end of surgery, some preop erative (recipient selection) and intraoperative factors (excellent and quick surgical technique, correct management of blood coagulation, maintenance of good thermal and metabolic homeostasis , use of short-acting anesthetic drugs) playa fundamental role in determining who may successfully undergo immed iate extubation [7]. Successful immediate extubation could, therefore, be considered a significant indicator of the quality of intraoperative care and one of the main principles governing the management of anesthesia for liver transplantation. Common sense suggests that spont aneous ventilation may be beneficial in the hemodynamically stable patient, promoting hepatic venous drainage and donor graft circulation [6]. However, patients with acute liver failure, retransplantation, and complicated surgery (in terms of increased intraoperative bleeding, more than 6 units of red blood cells [RBCsj) may not be eligible for fast-tracking protocols and may have an increased risk of prolonged postoperative mechanical ventilation [4-5]. Approximately 5 % of patients undergoing renal, hepatic, cardiac, or pulmonary transplantation develop pneumonia in the period after transplantation, which has an associated crude mortality of 37 % [8]. It has been reported that early application of non-invasive ventilation (NIV) in solid organ transplant recipients and in immuno suppressed patients could eliminate the need for intubat ion [9]. In acute respiratory failure, when NIV is effective in avoiding endotracheal intubation, the incidence of bacterial pneumonia is extremely low [9]. Antonelli et al. performed a prospective randomized study in patients undergoing solid organ transplantation in which NIV or standard treatment with supplemental oxygen was administered to patients who developed acute respiratory failure [9). The authors demon strated that early administration of NIV was well tolerated and associated with a significant reduction in the rate of endotracheal intubation, fatal complications, and ICU mortality. Based on their results, these authors suggested that active transplantation programs should consider NIV in the treatment of eligible patients with acute respiratory failure who have no contraindications and who can be monitored safely in the appropriate environment. More recently Chin and colleagues admin istered NIV in pediatric patients undergo ing liver transplantation with subsequent pulmonary complications and demonstrated the efficacy of NIV also in this patient population [10].

Hemodynamic Management The cardiovascular system in patients with cirrhosis and portal hypertension is abnormal. The circulation becomes hyperdynamic, characterized by increased cardiac output and decreased peripheral vascular resistance and arterial pressure [11]. Moreover, despite the increased cardiac output at rest, under stressful situations such as hemorrhage, surgery, or vasoactive drug administration, the ventricular response is blunted, a condition known as cirrhotic cardiomyopathy [11]. The mechanisms of cirrhotic cardiomyopathy include altered physicochemical properties of the cardiomyocyte plasma membrane, impairment of beta-adrenergic receptor signaling pathways, and overactivity of nitric oxide (NO), carbon monoxide, and endocannabinoid systems [11]. Whether the central blood volume is increased in cirrhosis remains controversial [12). Patients with cirrhosis have a substantially reduced total blood volume index as showed by Henriksen et al. who reported that central blood volume was significantly smaller in patients with cirrhosis than in controls

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[12]. Because of this relative hypovolemia, adequate volume management is a cornerstone of treatment during liver transplantation. Tissue hypoperfusion during surgery has been shown to be a cause of poor outcome [13]. Hence, fluid management in these patients requires a balance between preload optimization and avoidance of pulmonary edema particularly during the post-anhepatic phase, when post-reperfusion syndrome can occur. Since the first liver transplant procedure, extended monitoring including a pulmonary artery catheter (PAC) for cardiac index (CI) determination, and monitoring of central venous pressure (CVP), pulmonary artery pressure (PAP) and pulmonary artery occlusion pressure (PAOP), has been used during anesthesia for liver transplantation. Conventionally, 'preload pressure parameters', such as PAOP and CVP, used to estimate intravascular volume status, have been widely shown to correlate poorly with changes in cardiac output in the critically ill patient [14]. In 1993, De Wolf and co-workers observed a hyperdynamic hemodynamic system in patients with end-stage liver disease with high right ventricular ejection fraction (RVEF), heart rate (HR) and CI, and low systemic vascular resistance (SVR) [15]. Their study was performed with the first generation of PACs for measurement of right heart volumes and function, and found a significant correlation between stroke volume index (SVI) and end diastolic volume index (EDVI) over a wide range of EDVI (60-185 ml/m-): the authors concluded that in patients undergoing liver transplantation with normal RV function, CVP is a less reliable clinical indicator of RV preload than EDVI. In order to evaluate volumes rather than pressures, a modified PAC equipped with a rapid response thermistor has been recently introduced into clinical practice. This new PAC (Vigilance system, Edwards Laboratories, Santa Ana, CA USA) can measure RV end-diastolic volume (RVEDV) continuously, calculating it from RVEF and SVI. Recently, De Simone and colleagues demonstrated that intraoperative assessment of RV volume by means of thermodilution and three-dimensional echocardiography is feasible and that these techniques are able to provide a useful estimation of RV function, which is immediately available in the operating room [16]. This modified PAC offers the opportunity of having a volumetric preload index but it is much more expensive than the classical PAC and this is a limitation for the use of such a device. Moreover, methodological errors may cause misleading values due to the position of the PAC and due to arrhythmia and alteration of R waves that make it impossible to calculate accurate end-diastolic volumes. Over the last 10 years, the transpulmonary indicator dilution technique has been used to directly measure circulating blood volumes [17- 19]. Krenn and colleagues observed that an increase in post-reperfusion intrathoracic blood volume index (ITBVI) influenced pulmonary function, as demonstrated by the increase in venous admixture (QS/QT) without changes in extravascular lung water index (EVLWI) or oxygenation impairment [17]. We analyzed hemodynamic-volumetric data in cirrhotic patients before and after liver transplantation to evaluate intravascular blood volume status [18]. Results from this study demonstrated that the hyperdynamic circulation of cirrhotic patients coexists with a hypovolemic status when evaluated with volumetric monitoring. Total blood volume index (TBVI) was markedly reduced compared to ITBVI, probably because of the hepatic disease, which greatly increases the 'third space' (intra and extra vascular). We also used the transpulmonary indicator dilution technique to compare the value of each preload variable during anesthesia for liver transplantation [19]. The main finding of this study was a good correlation between ITBVI and SVI and CI while no consistent correlation could be established between PAOP and SVI or CI. Statistically significant correla-

leU Management of the Liver Transplant Patient

tions were obtained analyzing preload data at predefined steps. These results confirm the validity of ITBVI as a preload index also during phases characterized by major hemodynamic changes, bleeding, and surgical manipulation [18, 19]. During the last decade, tr ansesophageal echo cardiography (TEE) has been used increasingly for the assessment of cardiac shape, performance, and preload [20,21]. The left ventricular end dia stolic area index (LVEDAI) provides a measure of left ventricular filling that has been shown to correlate well with changes in SVI during volume therapy, even though changes in LVEDAI during surgery can be due to variations in the preload only if the compliance and contractility of the left ventricle remain unchanged. [22]. Standards for training in TEE are not yet universal and the documentation pattern still falls short of practice guidelines. Dependency on operator experience, low repeatability, and the high costs of th is procedure limit its interpretation and diffusion into clinical practice. Nevertheless, routine use of TEE monitoring is recommended during liver transplantation [20].

Splanchnic Perfusion and Graft Function Postoperative liver graft function in liver transplant patients is influenced by many factor s, such as ischemia, infection, drug toxicity, and acute rejection. The use of vasoactive drugs and mechanical ventilation with positive end expiratory pressure (PEEP) may also affect graft function [3]. Maintenance of adequate splanchnic perfusion seems to play a crucial role in graft function and prevention of multiple organ failure (MOF). Tietge et al. showed that in patients with cirrhosis, splanchnic oxygen uptake (V0 2 ) decreased, while whole-body V0 2 increased [23]. In the clinically stable, longterm course after liver transplantation, th ese parameters normalized, indicating the correction of hepatic and extrahepatic metabolic derangements. In cirrhosis, alterations occur in the hepatic microcirculation resulting in hepatic blood flow becoming limiting for splanchnic oxygen supply [23]. Moreover, patients undergoing liver transplantation are at risk of elevated intra-abdominal pressure (lAP) not only because of the pathophysiology of their preoperative chronic liver disease (tense ascites) but also because of the specific characteristics of the transplant procedure, which includes frequent intraperitoneal hemorrhage (surgical or due to coagulopathy), the use of perihepatic or retroperitoneal packs to control bleeding, bowel congestion due to portal hype rtension and/or massive fluid administration, and the use of a pneumatic antishock garment [24]. An acute increase in lAP has a series of 'dose-dependent' negative consequences that may affect many organs and functions because there is not enough time for any compensation mechanism to occur: cardiac output is progressively impaired, as are splanchnic and hepatic perfusions, and renal and respiratory functions. Under such conditions, hypovolemia aggravates the effect of intra-abdominal hypertension (lAH) . It has been suggested that loading patients with intravenous fluids may prevent the deleterious effects of IAH because it counteracts the reduced cardiac output caused by the diminished preload occulting as a result of the reduction in venous return caused by abdominal hypertension-induced inferior and superior venous cava compartment compression. Moreover, the increased abdominal pre ssure has been recognized as being associated with acute renal failure also in liver transplant recipients. Biancofiore et al. showed that IAH is a frequent finding after liver transplantation [24]. The authors of this study [24] did not provide any conclu sive evidence as to whether the increased lAP was mainly a

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severity marker and a consequence of a more complicated post-surgical condition or a 'disease' in itself.

Fluid Management and Transfusion During surgery, absolute or relative blood volume deficits often occur either due to bleeding (absolute hypovolemia) or vasodilatation mediated by various vasodilating substances (relative hypovolemia). During liver transplantation, the hyperdynamic circulation, cardiac function abnormality and relative hypovolemia could make fluid replacement arduous [25]. Moreover, the problem of massive blood loss during hepatic resection and liver transplantation is a daunting one for surgeon and anesthesiologist alike. As a result, various strategies have been developed to limit the degree of blood loss, including use of autotransfusion devices, acute isovolemic hemodilution, and a variety of surgical maneuvers [26]. Because major blood loss is a vital concern and transfusion requirements correlate significantly with morbidity and mortality after liver surgery, emphasis has been placed on blood-saving techniques [26, 27]. Recent studies showed that intraoperative transfusions of fresh frozen plasma (FFP) or packed RBC were associated with a significant decrease in the one year survival rate [27]. Improvements in surgical and anesthetic technique have greatly decreased the amount of blood products transfused; nevertheless, blood product use can still be occasionally massive. The "lowering CVP" debate is still continuing among hepatic surgeons. In several non-randomized, retrospective studies of liver resection, reducing CVP to less than 5 mmHg, with or without some sort of portal triad clamping, was associated with decreased intraoperative blood loss and even decreased morbidity and hospital stay [28]. Despite some conflicting results, this suggests that maintaining a low CVP during the parenchymal division phase of the hepatic resection may significantly reduce intraoperative blood loss and subsequent need for transfusion. Some centers have extended this same strategy to liver transplantation [27]. Schroeder and colleagues retrospectively reviewed the experience in two liver transplant centers, one using the low CVP method and the other using the normal CVP method , to assess the clinical safety of a low CVP fluid management strategy in patients undergoing liver transplantation [25]. The main finding of this study include an increased rate of transfusion in the normal CVP group but increased rates of postoperative renal failure and 30-day mortality in the low CVP group. The authors concluded that despite success in reducing blood transfusion requirements in liver resection patients, a low CVP should be avoided in patients undergoing liver transplantation. Recently Massicotte and coworkers performed an historical study in 98 liver transplanted patients. Decreasing CVP by fluid restriction, phlebotomy, and avoiding plasma transfusion, in order to reduce blood losses during liver resection before the anhepatic phase was effective [27]. This strategy did not yield more renal, cardiac or neurological complications, the hospital stay did not increase, and the one year survival rate improved in the low CVP group. Their results concur with statements by Reyle-Hahn and Rossaint that it is not necessary to correct coagulation defects or relative blood lost during the liver dissection before the anhepatic phase [29]. This discussion is still open and randomized studies are needed. Transfusion of plasma for the purpose of correcting coagulation deficiencies is not associated with a reduction in RBC transfusion during liver transplantation. In fact, the reverse often occurs. In most centers, the criteria used for the transfusion

leu Management of the Liver Transplant Patient

of blood products during liver transplantation are those recommended by the American Society of Anesthesiologists (threshold for RBC transfusion: 60 -100 gil; threshold for plasma transfusion: international normalized ratio [INR] > 1.5; threshold for platelet transfusion: < 50 x 109 platelets/I) [30].

Lung and Liver Function Liver disease affects the lungs. A minority (some 10 %) of patients exhibit a 'hepatopulmonary syndrome' defined by severe hypoxemia with arterial PaOz below 60 mmHg, dyspnea, cyanosis etc. The hepatopulmonary syndrome is incurable but resolves over time after liver transplantation [31]. An even lower proportion of patients, approximately 1 %, develop pulmonary hypertension. Clinically this 'portopulmonary hypertension' resembles primary pulmonary hypertension, with dyspnea and fatigue as the main symptoms, similar histopathology and response to prostacyclin therapy [31]. Portopulmonary hypertension is irreversible and the mortality rate in liver transplant patients with portopulmonary hypertension ranges from 50 to 100 %. The prognosis of hepatopulmonary syndrome is poor, with one year survival rates between 16 and 38 % once PaOz is less than 50 mmHg. No drug therapy has proved effective. Liver transplantation has been used for the treatment of hepatopulmonary syndrome and this syndrome is commonly seen in patients on a liver transplant waiting list. The success of liver transplantation in the treatment of hepatopulmonary syndrome is not uniformly documented. Reversal of hepatopulmonary syndrome after liver transplantation is slowest, and possibly incomplete, in patients with the largest preoperative shunts and pulmonary vascular dilatation [32]. Collisson et al. documented successful resolution of hypoxemia after liver transplantation in a pilot cohort study [33]. Their results support the newly implemented United Network for Organ Sharing (UNOS) criteria, that liver transplantation for hepatopulmonary syndrome may be extended to include patients with PaOz < 60 mmHg. Data were collected from 10 liver transplant centers from 1996 to 2001 that characterized the outcome of patients with either hepatopulmonary syndrome (n = 40) or portopulmonary hypertension (n = 66) referred for liver transplantation [31]. Key variables (PaOz for hepatopulmonary syndrome, mean PAP, pulmonary vascular resistance (PVR), and cardiac output for portopulmonary hypertension) were analyzed with respect to three definitive outcomes (those denied liver transplantation, transplant hospitalization survivors, and transplant hospitalization non -survivors). The authors concluded that patients with hepatopulmonary syndrome (based on a combination of low PaOz and non-pulmonary factors) and patients with portopulmonary hypertension (based on pulmonary hemodynamics) were frequently denied liver transplantation because of pre-liver transplantation test results and co morbidities. For patients who subsequently underwent liver transplantation, transplant hospital mortality remained significant for those with hepatopulmonary syndrome (16 %) and those with portopulmonary hypertension (36 %) [31]. However, even if stabilized or improved by prostacyclin or other therapy, pulmonary hypertension remains a serious contraindication to liver transplantation. Overall, the mortality of liver transplantation in patients with pulmonary hypertension is as high as 35 %. According to a study from the Mayo Clinic, cardiopulmonary mortality after liver transplantation is 100 % if the mean PAP exceeds 50 mmHg, and is as high as 50 % if the mean PAP is between 35 and 50 mmHg and PVR greater than

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G. Della Rocca, M.G. Costa, and P. Chiarandini 250 dyne/a/em", No regression of pulmonary hypertension has been reported after liver transplantation. It is not known whether combined liver-lung transplantation may be a reasonable option for some patients. Ashfaq et al. demonstrated that effective pharmacologic control of portopulmonary hypertension before liver transplant was associated with excellent post-transplant survival that was similar to patients transplanted for other indications [34]. These authors suggested that patients with moderate or severe portopulmonary hypertension who are able to decrease their mean PAP to < 35 mmHg with vasodilator therapy have excellent survival following liver transplantation. The authors cannot exclude the possibility that improved anesthetic and surgical techniques might also account for some of the observed survival benefit. Patients with portopulmonary hypertension on intravenous therapy are given a MELD exception of 25 points in Region 4 in order to reduce waiting list time. The authors concluded that transplant centers can no longer justify excluding portopulmonary hypertension patients from consideration for transplantation unless they fail vasodilation therapy or have other contraindications to transplantation [34]. There is still significant transplant hospitalization mortality associated with hepatopulmonary syndrome and portopulmonary hypertension despite improved screening and patient selection. Ideal pre-transplant treatment of portopulmonary hypertension remains problematic. Additional efforts to quantify the impact and consequences of hepatopulmonary syndrome and portopulmonary hypertension on liver transplantation should continue.

Renal Function It is well established that when acute renal failure develops either before or after liver transplantation, it has a major impact on the outcomes of the allograft and on patient survival, ultimately producing hepatorenal syndrome [35]. When preoperative renal failure is related directly to hepatorenal syndrome, patient survival is limited (10 % at 10 weeks) if orthotopic liver transplantation cannot be accomplished. After liver transplantation, acute renal failure continues to impact outcomes, as mortality increases from 5 to 41 % in those who develop perioperative acute renal failure. Several studies have indicated that reduced pre-transplant kidney function (reflected by glomerular filtration rate [GFR], usually expressed as creatinine clearance) is the single most consistent predictor of acute renal failure after transplant. Other predictors are less consistent, including the number of units of blood trans fused, the need for vasopressor support, early allograft dysfunction, and pre-transplant Child class. Immunosuppression based upon calcineurin inhibitors such as cyclosporine or tacrolimus routinely induces renal vasoconstriction, leading to a 30 to 40 % fall in GFR within the first few days and weeks, despite rising systemic arterial pressures. Whether the perioperative compromise of renal function in this setting can be influenced favorably and whether such maneuvers can improve outcomes is an important question. A major problem is the lack of a consensus definition of an acute renal failure. The Acute Dialysis Initiative (ADQI) group of experts have developed and published a consensus definition of acute renal failure. This definition goes under the acronym of RIFLE [35]. This definition classifies patients with renal dysfunction according to the degree of impairment into patient at risk (R), with injury (I), with failure (F),

ICU Management of the Liver Transplant Patient

with sustained loss (L), and with end-stage (E) status [35). The RIFLE criteria are based on changes in a patient's GFR andlor their urine output. In a recent study, O'Riordan et al. used the RIFLE criteria to try and determine the incidence and risk factors for acute renal failure and acute renal injury, and to evaluate any link with outcome, patient survival , and length of hospital stay [35). Three hundred patients who received 359 liver transplants, were analyzed retrospectively. By multivariate analysis, acute renal injury was associated with pre-liver transplantation hypertension and alcoholic liver disease and acute renal failure with higher pre-liver transplantation creatinine, inotrope and amino glycoside use. Acute renal failure, but not acute renal injury, had an impact on 30-day and l-year patient survival, and longer length of hospital stay. Acute renal injury and acute renal failure, as defined by the RIFLE criteria, are common complications of liver transplantation, with distinct risk factors and acute renal failure has serious clinical consequences . The development of a consensus definition is a welcome advance; however, these criteria do need to be validated in large studies in a wide variety of patient populations. Renal dysfunction was reported to be a strong and independent risk factor for major adverse cardiac events, as well as for cardiovascular and all-cause mortality, by 5-years post-transplant [36). Pawarode et al. identified risk factors that independently predict the need for immediate dialysis and the development of permanent renal dysfunction and severe renal failure after liver transplantation [36). A documented history of renal insufficiency (serum creatinine > 1.2 mg/dl) or a baseline GFR < 70 ml/min/1.73 m? predicted the development of permanent renal dysfunction. Diabetes mellitus, coronary artery disease and primary graft non-function predicted the development of chronic renal failure. From these observations, it seems that susceptible patients with microvascular disease (diabetes mellitus, coronary artery disease) are more likely to develop renal failure. It is possible that many of these patients may have had unrecognized pre-existing renal disease that progressed with time after liver transplantation. Another possibility is that susceptible subjects are more prone to renal failure because of surgical complications or because of the nephrotoxicity of calcineurin inhibitors. The maximum rate of decline in renal function was seen within the first month after transplantation, which was possibly related to surgery or to induction therapy, which invariably included nephrotoxic drugs . Pre-existing diabetes mellitus, major surgical infection, and a longer waiting tine on the transplant list were independent predictors for the need of immediate (within 1 month) post-transplant dialysis [36). Pretransplantation renal failure has been shown to decrease the survival of liver transplant recipients and to predict the risk of post-transplantation renal failure and infection. In this study, patients who developed severe renal failure after transplantation had a significantly shorter survival compared with tho se without renal failure, even after adjusting for other confounding variables such as diabetes mellitus and coronary artery disease [36). Acute tubular necrosis is a life-threatening complication in liver transplant patients occurring as the result of various concomitant causes: renal hypoperfusion and relatively reduced oxygen delivery, as well as the use of nephrotoxic drugs, antibiotics, and immunosuppressants. Strategies to avoid renal impairment include volume loading to correct hypovolemia, use of inotropes and vasopressor agents to optimize cardiac output and systemic blood pressure, use of renal vasodilators to augment renal blood flow, and use of diuretics to decrease medullar oxygen consumption [37). Because the low cardiac output state is a risk factor for postoperative acute renal failure, perioperative cardio-protection plays an important role in acute renal failure preventive strategies. Volume loading is probably the most effective

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preventive measure to avoid pre-renal renal failure as well as acute tubular necrosis. Monitoring with CVP and if necessary with PAC and/or volumetric monitoring as well as a PiCCO system, may guide the amount of fluid to be administered to optimize volemia and maintain an adequate cardiac output. It remains unresolved whether colloids or crystalloids are preferable for maintaining adequate volemia in critically ill patients. With the exception of dopamine there has been no randomized controlled trial of sufficient statistical power to detect differences in clinical outcome and renal protection using vasoactive drugs [38]. In critically ill patients, a continuous infusion of fenoldopam does not cause any clinically significant hemodynamic impairment and seems to be a new option to improve renal function compared with renal dose dopamine [38]. In early acute renal dysfunction, before severe renal failure has occurred, the attempt to reverse renal hypoperfusion with fenoldopam is more effective than with low-dose dopamine. Fenoldopam seems to play a role in preventing the progression to established acute renal failure or in accelerating the recovery of renal function in critically ill patients [38]. Landoni et al., in a recent study, suggested that fenoldopam reduces the need for renal replacement therapy and mortality in patients with acute renal injury [39]. We performed a randomized study to test the relative effects of low-dose dopamine (2 fig/kg/min) and fenoldopam (0.1 fig/kg/min) over 48 hours, starting with anesthesia induction, on serum creatinine, blood urea nitrogen (BUN), and urine output in 43 patients undergoing liver transplantation [40]. This study showed that on postoperative day 3, the median creatinine increase was significantly lower in the fenoldopam group and that the BUN increase was significantly higher in the dopamine group. No difference in urine output was observed; however, significantly fewer fenoldopam patients required furosemide compared with dopamine patients. Biancofiore et al. reported the results of a prospective trial of 140 consecutive liver transplantations, in which, during the first 96 hours after transplant, patients were randomized to receive fenoldopam (0.1 fig/kg/min), dopamine (3 fig/kg/min) or placebo [41]. Data were collected from the time of anesthesia induction. The placebo group experienced a moderate fall in creatinine toward the fourth day (-39 %), with a rise in blood cyclosporine A level from 0- 328 ng/dI. Although serum creatinine levels and cyclosporine A levels were identical in the dopamine and fenoldopam groups, no decrement in calculated creatinine clearance was apparent in the fenoldopam group on the fourth day. No differences were apparent regarding any other parameters, including urine output, diuretic requirements, incidence of acute renal failure requiring dialysis support, ICU stay, or mortality. Biancofioreet aI. argue that these results indicate a 'counterbalancing' of the renal vasoconstrict ive effects of cyclosporine A in the post-transplant state. Leung and Textor in an accompanying editorial commented that while this conclusion may be partially correct, it must be emphasized that the results presented did not include arterial pressures or renal blood flow [42]. Hence, whether true renal vasodilation occurred cannot be assessed. Most importantly, these results fail to support improved clinical outcomes in terms of early postoperative urinary output, hospitalization, or morbidity. Based on these observations, Leung and Textor suggest that it is hard to justify routine use of either fenoldopam or dopamine in this setting. It is still unclear what hemodynamic manipulation is appropriate to obtain renal protection and ameliorate renal perfusion. Currently the discussion is whether non-pharmacologic strategies are more effective than drug infusions to prevent acute renal failure or progression of renal dam-

ICU Management of the Liver Transplant Patient

age (43). Because the mortality from acute renal failure is so high in the setting of liver transplantation, further studies are needed to identify whether reversal of hemodynamic changes before transplant in higher risk patients (e.g., those with incipient hepatorenal failure) is warranted.

Neurological Status and Sedation in the ICU As reported by Saner et al., more than 27 % of patients requiring liver transplantation with a diagnosis of alcoholic cirrhosis, hepatitis Band C, or acute liver failure experienced severe neurological events after liver transplantation (44). Diffuse encephalopathy is the most common complication following liver transplantation (45). The underlying mechanism is unknown, although in a large prospective study the authors diagnosed diffuse encephalopathy (anoxic, septic, or metabolic) as being the most common complication occurring in 13/84 (15 %) pat ients (46). Seizures are common following liver transplantation, although the range of reported incidence is wide, varying from 0 to > 40 % and higher in some small series with larger numbers of repeat transplants [45 - 46). Several transplant centers avoid intravenous cyclosporine A loading and had a more positive experience with tacrolimus, which may contribute to a decreasing rate of seizures. About 13- 43 % of liver transplant patients experience severe neurological events with increased morbidity and mortality. Due to longer hospitality stays, healthcare costs increase. Patient health-related quality of life decreases. The causes of mental status changes post-liver transplantation include factors related to recipient pre-liver transplant status, intraoperative factors, and post-liver transplant factors. Drug-specific toxicity of immunosuppression is considered the main effect. Saner et al. suggested that routine preoperative neurological evaluation and careful postoperative examination should be conducted to help define the causes and consequences of serious neurological events in liver transplant recipients (44). Sedation is a crucial aspect in the management of all ICU patients and pain control is also essential for the optimal care of critically ill patients. The Society of Critical Care Medicine and the American College of Critical Care Medicine published the "clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult" [47]. Pain and sedation assessment and response to therapy should be performed regularly using appropriate scales such as the Ramsay score, the bispectral index for consciousness evaluation, and the visual analog score for pain assessment [47 - 48]. Midazolam, propofol, fentanyl, and morphine have been the most widely used drugs for sedation in the ICU for many years. Today, new drugs, with more predictable effects and rapid onset of action and with less collateral effects are available, such as remifentanil and sufentanil [49-50] . No alteration in the remifentanil dose is necessary with renal and hepatic disease [49-50] . These features of remifentanil make it an ideal agent for use in critically patients. Remifentanil is used as a continuous infusion with a starting dose of 0.05 Ilglkg/min. If sedation is excessive (Ramsay 4-6) the dose may be reduced by 0.01 ug/kg/rnin. Sufentanil is a highly selective agonist of III receptors and its lipid solubility produces a progressively increasing context-sensitive half-time related to the duration of administration [50). Sufentanil is used as a continuous infusion with a starting dose of 0.005 Ilglkg/min. If sedation is excessive (Ramsay 4-6) the dose may be reduced by 0.001 Ilg/kg/min. If the analgo-sedative infusion has to be interrupted for an evaluation, or in case of organ dysfunction, remifentanil may be preferable.

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Conclusion The perioperative care of patients undergoing liver transplantation is a critical clinical situation in which surgeons, anesthetists, and critical care physicians must do the best they can. The quality of care in the early lCU management of the liver transplanted patient is moving towards a new horizon through several modern approaches: A fast track program with early tracheal extubation and, if necessary NlV is preferable; accurate hemodynamic management to optimize liver and , more generally, organ perfusion is mandatory - splanchnic perfusion and graft function depend on this; fluid management with crystalloids and colloids to minimize blood product use without any coagulation disorders and use of fresh frozen plasma only when indicated should always be followed; lung function and renal function should be optimized; and a neurological status score followed with appropriate sedation. This list provides a summary of what an intensivist should do in the early lCU management of the liver transplanted patient. References 1. Carton GE, Tettke SR, Plevak DJ, Geiger HJ, Kranner PW, Coursin DB (1994) Perioperative care of the Liver Transplant Patient: part 1. Anesth Analg 78:120-133

2. United Network for Organ Sharing and Organ Procurement and Transplant Network, Richmond, VA. Current U.S. waiting list for liver transplantation. Available at http://www.optn. orgllatestdata/rptdata.asp Accessed Dec 2007 3. Brienza N, Revelly JP, Ayuse T, Robotham JL (1995) Effects of PEEP on liver arterial and venous blood flows. Am J Respir Crit Care Med 152:504-510 4. Mandell MS, Lockrem J, Kelley SD (1997) Immediate tracheal extubation after liver transplantation: experience of two transplant centers. Anesth Analg 84:249-253 5. Glanemann M, Langrehr J, Kaiser U, et al (2001) Postoperative tracheal extubation after orthotopic liver transplantation. Acta Anaesthesiol Scand 45:333-339 6. Biancofiore G, Romanelli AM, Bindi ML, et al (2001) Very early extubation without predetermined criteria in liver transplant recipient population. Liver Transpl 7:777- 782 7. Findlay JY, Jankowski q, Vasdev GM, et al (2002) Fast track anesthesia for liver transplantation reduces postoperative ventilation time but not intensive care unit stay. Liver Transpl 8:670-675 8. Mermel LA, Maki DG (1990) Bacterial pneumonia in solid organ transplantation. Semin Respir Infect 5:10- 29 9. Antonelli M, Conti G, Bufi M, et al (2000) Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation. JAMA 283:235-241 10. Chin K, Uemoto S, Takahashi K, et al (2005) Noninvasive ventilation for pediatric patients including those under l -year-old undergoing liver transplantation. Liver Transplll :188-195 11. Liu H, Gaskari SA, Lee SS (2006) Cardiac and vascular changes in cirrhosis: pathogenic mechanisms. World J Gastroenterol 12:837-842 12. Henriksen JH, Bendtsen F, Sorensen TIA, et al (1989) Reduced central blood volume in cirrhosis . Gastroenterology 97:1506-1513 13. Nasraway SA, Klein RD, Spanier TB, et al (1995) Haemodynamic correlates of outcome in patients undergoing orthotopic liver transplantation. Evidence for early postoperative myocardial depression . Chest 107:218-224 14. Kumar A, AneI R, Bunnell E, et al (2004) Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Crit Care Med 32:691- 699 15. De Wolf AM, Begliomini B, Gasior TA, Kang Y, Pinsky MR (1993) Right ventricular function during orthotopic liver tran splantat ion. Anesth Analg 76:562 - 8 16. De Simone R, Wolf I, Mottl-Link S, et al (2005) Intraoperative assessment of right ventricular volume and function. Eur J Cardiothorac Surg 27:988-33

ICU Management of the Liver Transplant Patient 17. Krenn CG, Plochl W, Nikolic A, et al (2000) Intrathoracic fluid volumes and pulmonary function during orthotopic liver transplantation. Transplantation 69:2394 - 2400 18. Della Rocca G, Costa MG, Coccia C, et al (2001) Intravascular blood volume in cirrhotic patients. Transplant Proc 33:1405-1407 19. Della Rocca G, Costa MG, Coccia C, Pompei L, Pietropaoli P (2002) Preolad and haemodynamic assessment during liver transplantation. A comparison between pulmonary artery catheter and transpulmonary indicator dilution technique. Eur J Anaesthesiol 19:868-875 20. De Wolf A (1999) Transesophageal echocardiography and orthotopic liver transplantation: general concepts . Liver Transpl Surg 5:339 - 340 21. Steltzer H, Blazek G, Gabriel A, et al (1991) Two-dimensional transesophageal echocardiography in early diagnosis and treatment of hemodynamic disturbances during liver transplantation . Transplant Proc 23:1957-1958 22. Cheung AT, Savino JS, Weiss SI, et al (2003) Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventricular function . Circulation 108:226- 229 23. Tietge UJF, Bahr MI, Manns MP, Boker KHW (2001) Decreased splachnic oxygen uptake and increased systemic oxygen uptake in cirrhosis are normalized after liver transplantation. Liver Transpl 7:1015-1022 24. Biancofiore G, Bindi ML, Romanelli A, et al (2003) Intra-abdominal pressure monitoring in liver transplant recipients: a prospective study. Intensive Care Med 29:30-36 25. Schroeder RA, Collins BH, Tuttle-Newhall E, et al (2004) Intraoperative fluid management during orthotopic liver transplantation. I Cardiothorac Vasc Anesth 18:438-441 26. Massicotte L, Sassine MP, Lenis S, Seal RF, Roy A (2005) Survival rate changes with transfusion of blood products during liver transplantation. Can I Anesth 52:148-155 27. Massicotte L, Lenis S, Thibeault L, Sassine MP, Seal RF, Roy A (2006) Effect of low central venous pressure and phlebotomy on blood product transfusion requirements during liver transplantations. Liver Transpl 12:117- 123 28. Wang WD, Liang LJ, Huang XQ, Yin XY (2006) Low central venous pressure reduced blood loss in hepatectomy. World I Gastroenterol 12:935-939 29. Reyle-Hahn M, Rossaint R (1997) Coagulation techniques are not important in directing blood product transfusion during liver transplantation. Liver Transpl Surg 3:659-663 30. American Society of Anesthesiologists Task Force on perioperative blood transfusion and adjuvant therapies (2006) Practice guidelines for perioperative blood transfusion and adjuvant therapies; an update report by the American Society of Anesthesiologists Task Force. Anesthesiology 105:198- 208 31. Krowka MJ, Mandell MS, Ramsay MAE, et al (2004) Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database . Liver Transpl 10:174-182 32. Naeije R (2003) Heaptopu lmonary syndrome and portopulmonary hypertension. Swiss Med Wkly 133:163-169 33. Collisson EA, Nourmand H, Fraiman MH, et al (2002) Retrospective analysis of the results of liver transplantation for adults with severe hepatopulmonary syndrome. Liver Transpl 8:925-931 34. Ashfaq M, Chinnakotla S, Rogers L, et al (2007) The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am I Transplant 7:1- 7 35. O'Riordan A, Wong V, Mcquillan R, McCormick PA, Hegarty IE, Watson AI (2007) Acute renal disease, as defined by the RIFLE Criteria, post-liver transplantation. Am I Transplant 7:168-176 36. Pawarode A, Fine DM, Thuluvath PI (2003) Independent risk factors and natural history of renal dysfunction in liver transplant recipients. Liver Transpl 9:741-747 37. Girbes AR (2004) Prevention of acute renal failure: role of vaso-active drugs , mannitol and diuretics . Int I Artif Organs 27:1049- 1053 38. Brienza N, Calcagni V, Dalfino L, et al (2006) A comparison between fenoldopam and lowdose dopamine in early renal dysfunction of critically ill patients. Crit Care Med 34:707 -714 39. Landon i G, Biondi-Zoccai GG, Tumlin [A, et al (2007) Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials . Am I Kidney Dis 49:56-68

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patients undergoing liver transplantation: a randomized, controlled pilot trial. Anesth Analg

99:1604-1609

41. Biancofiore G, Della Rocca G, Bindi L, et al (2004) Use of fenoldopam to control renal dysfunction early after liver transplantation. Liver Transpl 10:986-992 42. Leung N, Textor SC (2004) Acute renal failure after liver transplantation: the role of dopamine and fenoldopam. Liver Transpl 10:993- 994 43. Kellum JA, Leblac M, Gibney RT, Tumlin J, Lieberthal W, Ronco C (2005) Primary prevention of acute renal failure in the critically ill. Curr Opin Crit Care 11:537-541 44. Saner FH, Sotiropoulos GC, Gu Y, et al (2007) Severe neurological events following liver transplantation. Arch Med Res 38:75- 79 45. Lewis MB, Howdle PD (2003) Neurologic complications of liver transplantation in adults. Neurology 61:1174-1178 46. Pujol A, Graus F, Rimola A, et al (1994) Predictive factors of in-hospital CNS complications following liver transplantation. Neurology 44:1226-1230 47. Jacobi J, Fraser GL, Coursin DB, et al (2002) Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 30:119-141 48. Simmons LE, Riker RR, Prato BS, et al (1999) Assessing sedation during intensive care unit

mechanical ventilation with the bispectral index and the sedation -agitation scale. Crit Care Med 27:1499- 504 49. Costa MG, Chiarand ini P, Della Rocca G (2006) Sedation in the crit ically ill patient . Transpl Proc 38:803 - 804 50. Soltesz S, Biedler A, Silomon M, et al (2001) Recovery after remifentail and sufentanil for analgesia and sedation of mechanically ventilated patients after trauma or major surgery. Br J Anaesth 86:763 -768

777

Liver Support with Fractionated Plasma Separation and Adsorption and Prometheus® K.

RIFAI,

C. TETTA, and C.

RONCO

Introduction The liver performs multiple metabolic functions ranging from protein synthesis to gluconeogenesis, metabolism of amino acids, lipids and urea, and the detoxification of drugs and by-products of intermediate metabolism . The liver also acts in the regulation of the immune system and the metabolism of many hormones. As a consequence, liver insufficiency is catastrophic both at the metabolic and the clinical level, giving rise to a multiple organ failure (MOF) syndrome characterized by encephalopathy, jaundice, coagulopathy, and an imbalance of the immune system. At the same time, a multiplicity of toxic substances, both lipophylic and hydrophylic, are released into the systemic circulation, thus altering many enzymatic cellular pro cesses. The lipophylic substances interfere with structural cellular processes, such as the reconstruction of cellular membranes, while the hydrophilic ones alter and block functional processes both enzymatic and non-enzymatic in nature. To date, orthotopic liver transplantation (OLT) represents the most adequate treatment for such a complex and critical situation. Unfortunately, organ scarcity cannot match the needs for transplantation arising from acute and chronic liver diseases. Many patients with serious liver insufficiency do not survive long enough to find a liver suitable for them. Thus, the clinical demand for liver support therapies remains high.

The Concept of Albumin Dialysis A number of techniques of liver support have been proposed (reviewed in ref [1]). There is common agreement that in liver disease removal of both water soluble and water-unsoluble albumin-bound molecules is needed. The concept of albumin dialysis is based on the principle that albumin may drag hydrophobic compounds present in the plasma across a high permeability hemodialyzer. Albumin is the 'sink' for many of these compounds as it can non-covalently bind hydrophobic compounds such as bilirubin , salt acids, metabolites of aromatic amino acids, and fatty acids. More in general, plasma proteins, e.g., a2-macroglobulin, are able to bind, via specific domains, remarkable amounts of cytokines . Single-pass albumin dialysis (SPAD) is simply the use of an albumin-containing dialysate (such as bicarbonate dialysate) in a counter-directional flow, which is discarded after passing the hemodialyzer that is impermeable to albumin [2]. An evolution of this concept has been the Molecular Adsorbent Recycling System (MARS)® (Gambro, Rostock, Germany) [3]. Commercially available albumin is added into the

778

K. Rifai, C. Tetta, and C. Ronco secondary circuit and is regenerated via passage through anionic-exchange resin and charcoal cartridges.

FPSA and the Prometheus® System A pioneering evolution of the concept of albumin dialysis was made in 1999 whereby the patient's own albumin is used and regenerated via passage through two adsorption matrixes. The filtration of plasma proteins is a complex process that relies on the membrane cut-off, and biocompatibility, as well as on maintenance of low pressures at the operational flow rates. In some cases, the cut-off has been chosen as being intermediate between conventional high flux hemodialyzers and plasma separators to allow the filtration of albumin. This has led to the concept of fractionated plasma separation and adsorption (FPSA) [4, 5]. This concept was later translated into a commercially available unit with some modification (Prometheus>, Fresenius Medical Care, Bad Homburg, Germany) [6]. Therefore, FPSA and Prometheus's are extracorporeal blood purification techniques related to, but quite distinct, from MARS®. An exhaustive description of the different circuit design concepts and detoxification efficiency of MARS and Prometheus's can be found in recent comparisons [7 -9]. All these data show a superiority of Prometheus in comparison to MARS in terms of removal of most protein-bound toxins as well as water-soluble substances. Ever since its introduction, more than 3000 treatments with Prometheusw have been performed in patients with liver disease. It is increasingly important to define the patient population that is currently considered for treatment. Here we will review the present clinical indications to start therapy with Prometheusw, the operative aspects of this technique, and the clinical/biological responses during and after the therapy.

How to Prescribe the Prometheus® Therapy The Prometheus's system is controlled by the same unit, which ensures pressure and flow stability within the acceptable ranges. The FPSA system uses dialysis and adsorption for detoxification of water-soluble and albumin-bound toxins, like other extracorporeal liver support systems. However, in contrast to other systems, like MARS®, Prometheus's separates both procedures. A special, albumin-permeable filter (AlbuFloW®, Fresenius Medical Care), with a membrane cut-off close to 300,000 Da, is used. The albumin-rich endogenous filtrate enters the secondary circuit and is regenerated via two adsorbers (neutral resin , anion exchanger). In a second step, detoxification of water-soluble substances takes place by diffusion via passage into a high-flux hemodialyzer (see Fig. 1). Maintenance and monitoring of the extracorporeal circuit is performed by the Prometheus's unit. It is therefore a comprehensive 'all-in-one' extracorporealliver support system based on the Fresenius 4008H dialysis unit (Fresenius Medical Care) combining FPSA and hemodialysis integrated in one unit. In clinical practice, an operational time of 4 to 6 hours is recommended for each session of the Prometheus's device . Afterwards, the adsorption capacities decrease noticeably [10]. Using blood flow rates of around 200 ml/rnin, a total blood volume of around 60 liters is processed per session. Of course, the necessary number of Pro-

Liver Support with Fractionated Plasma Separation and Adsorption and Prometheus®

r-'-'-'-'-'-'-'-'-'-'-'-'-'-'- '- '- '- '

!I

i

~

·

"""-L.-+I_.--' JHIt"" · 3: 1.2

i '3 i :3 i
I ·

Prornethu t"

I

recirculation circuit Prornethu z"

I

FPSA

i i i i

i I

·L._ ._ ._ ._ ._ ._ ._ ._ ._ ._._ ._ ._ ._ ._ ._ ._ .-'i

Fig. 1. Schema of the Prometheus's system. The patient's blood passes through an albumin-permeable Fresenius polysulfone filter (AlbuFlow®). There, molecules up to the size of albumin are filtered from the blood side into the secondary circuit where the albumin fraction undergoes direct adsorption of albuminbound toxins by two different adsorbers (promethOl ® and prometh02®). The purified plasma is then returned into the primary circuit. There, hemodialysis is performed using a conventional high-flux dialyzer (F60 SO®) in order to eliminate water-soluble toxins. The dotted rectangle identifies FPSA (fractionated plasma separation adsorption) as originally described [4, 5]. metheusw sessions varies according to a patient's individual characteristics. However, there is a tendency to treat often in the early phase (e.g., begin with 5 days of treatment in a row) and then continue with maintenance treatments (e.g., 2-3 sessions per week) until recovery or (more often) until liver transplantation. Anticoagulation always represents a critical point for the application of extracorporeal systems in patients with liver failure. These patients regularly develop a significant coagulopathy and, therefore , have an increased bleeding risk. On the one hand, use of anticoagulation could further increase the risk of bleeding in these patients; on the other hand, insufficient anticoagulation may result in clotting of parts or the whole extra corporeal circuit. This risk is further augmented by the fact that due to the secondary circuit the extracorporeal volume is larger in Prometheus's than in conventional dialysis procedures. At first, anticoagulation during Prometheusw therapy was performed using unfractionated heparin. However, even though there were no treatment-related bleedings, some clotting events occurred within the secondary circuit. Therefore, other anticoagulation protocols have been evaluated. It is currently assumed that liver patients are unsuitable for citrate anticoagulation, because of a decreased capacity to metabolize citrate. Nevertheless, Prometheusv therapy in connection with regional citrate anticoagulation has been investigated as the potential advantages of regional anticoagulation (citrate) compared to systemic anticoagulation (heparin) are expected in patients with an elevated bleeding risk. At the University Hospital Essen, 14 consecutive patients with acute (n = 6) or acute-on-chronic (n = 8) liver failure were enrolled in this study. All patients had bilirubin values ~ 10 mg/dl and/or hepatic encephalopathy ~ grade 2. A total of 50 Prometheusw treatments were performed (3±2 treatments/patient, every other day). Detoxification (pre/post) performed by Prometheus's treatment was highly efficient and the

779

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K. Rifai, C. Yetta, and C. Ronco

therapy was not associated with bleeding complications. Patients were hemodynamically stable (blood pressure pre vs. post: 119/58 vs. 110/53 mmHg, pulse 89 vs. 911min) and all therapy sessions could be delivered for the prescribed 6 hour duration. Citrate was well tolerated despite liver failure, indicated by stable ionized calcium values (1.0 vs. 1.0), pH, and anion gap within the reference range during Prometheuss treatment. The dialyzer had to be changed due to clotting in only 2 out of 50 treatments. This study demonstrated the safety and efficacy of the Prometheuss therapy with regional citrate anticoagulation. Therefore, most centers now use this anticoagulation protocol when performing Prometheusw therapy. A small add-on module for the device has been introduced allowing automated citrate anticoagulation according to a standard protocol. Besides citrate anticoagulation, the additional application of small amounts of heparin to 'coat' the extracorporeal circuit is currently being discussed.

Who should be treated with Prometheus®? The following clinical conditions are considered possible indications for treatment with Prometheuse: Acute on chronic liver failure (including acute alcoholic steatohepatitis), acute liver failure, primary dysfunction after liver transplantation, bridging to liver transplantation, intoxication with protein-bound drugs, and refractory cholestatic pruritus (Table 1). Acute on chronic liver failure has become the commonest indication for Prometheuss. Acute on chronic liver failure is defined as deterioration of liver function in cirrhotic patients over a period of 2-4 weeks, usually precipitated by gastrointestinal bleeding, infection, binge drinking, or surgery [11]. Several case series reporting on a total of 36 patients with acute on chronic liver failure have been published [6, 7, 10]. In the pilot trial at the Hannover Medical School [6], 11 patients with acute on chronic liver failure of various etiologies were studied. Among the inclusion criteria were hyperbilirubinemia (> 250 umol/l) and hepatic encephalopathy of grade 2 or higher. All patients had concomitant renal failure necessitating extracorporeal renal replacement therapy. The average Child-Pugh score was 12. Prometheus's treatment resulted in significantly improved blood levels of conjugated bilirubin, bile acids, ammonia, creatinine, and urea. Clinical parameters such as the grade of hepatic encephalopathy and the Child-Pugh score did not improve, however, probably due to the fact that each patient was treated only twice. In-house mortality was 73 % (8 of 11 patients) without any evidence of treatment-related complications. In 2003, a systematic review concluded that artificial liver support systems might reduce mortality in patients with acute on chronic liver failure [12]. The HELlOS trial is a randomized European multicenter trial of Prometheus's versus standard medical treatment in more than 200 patients with acute on chronic liver failure (defined as severe deterioration of chronic liver disease, a Child - Pugh score > 10 and persistent bilirubin> 85.5 umol/l [5 mg/dl]). The primary end-points are survival after 28 days and after 3 months. Results are expected in 2008. A common complication of liver failure is hepatic encephalopathy which improves under Prometheus's therapy according to data from a pilot trial [13]. Hepatorenal syndrome is another prognostically important complication in patients with acute on chronic liver failure . If patients develop combined liver and renal failure, Prometheusw is able to support both organs efficiently as standard hemodialysis is performed parallel to liver support therapy [14].

Liver Support with Fractionated Plasma Separation and Adsorption and Prometheus®

Acute alcoholic steatohepatitis, which is usually subsumed to acute on chronic liver failure, seems to be a good indication for extracorporeal liver support therapies as patients have a high mortality and are not eligible for liver transplantation due to recent alcohol consumption. Furthermore, if the acute hepatic decompensation can be bridged and the patient stops alcohol drinking, the potential for liver regeneration is high. As a result a surprising stabilization of liver function can be observed in many cases. Even though most studies addressing acute on chronic liver failure include patients with acute alcoholic hepat itis, there are no publications available to date focusing on the treatment of acute alcoholic hepatitis with Prometheusw. Even though acute liver failure is rare, it is an attractive setting to evaluate the potential of liver support devices. Acute liver failure represents the highest medical emergency in hepatology with high dynamics including the risk of hepatic coma and MOE If liver transplantation is not available, mortality rates are very high. However, if extracorporeal devices are able to support the patient's potential to regenerate hisl her own liver, this would represent an important success as: 1) the patient would avoid transplantation with its lifelong sequelae, and 2) another patient could profit from the liver graft spared from the acute liver failure patient. Initial data on the use of Prometheus's in patients with acute liver failure are promising [15, 16] but not conclusive as controlled trials are lacking. The same rationale for the use of liver support therapies in acute liver failure can also be applied to patients who develop a primary dysfunction after liver transplantat ion. As primary dysfunction after liver transplantation impairs the patient's prognosis and often necessitates retransplantation, the chances of overcoming the initial liver insufficiency would increase with efficient supportive therapy of the liver graft . This could result in avoidance of retransplantation and again sparing one graft . If liver transplantation seems inevitable in patients presenting with acute on chronic liver failure, acute liver failure, or primary dysfunction after liver transplantation, these patients should be bridged to transplantation to improve their clinical condition and at the same time to improve post -transplant survival probability. There has been some clinical experience with Prometheusv for this indication [13], the most impressive being the case of a 38-year old male with acute on chronic liver failure. This patient was successfully bridged to transplantation over a period of 51 days using 23 Prometheus" treatment sessions [17]. As described above, the capacity of Prometheuss to clear the blood of even strongly protein-bound substances has been well demonstrated. Thus, if introduced early enough, an intoxication with protein-bound drugs could be another indication for the use of Prometheusw. In some patients, severe cholestatic pruritus represents an emergency. In a few cases where the various standard medical treatment options (including ursodesoxycholic acid, cholestyramine, histamine HI-antagonists, rifampicin, cannabinoid receptor agonists, serotonin receptor antagonists, and opioid antagonists) are ineffective, Prometheus's has been used as a successful last resort. In a recent paper, Rifai et al. treated seven patients with three to five Prometheusw sessions of at least 4 h duration [18]. Visual analog scale assessments of pruritus improved markedly from 9 ± 1 to 3 ± 3, and the concentration of total serum bile acids decreased from 248 ± 192 umol/l to 101 ± 85 umol/l, Overall, six of the seven patients responded to Prometheus's treatments; the response was sustained in four.

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K. Rifai, C. Tetta, and C. Ronco

Contraindications for Prometheusw Treatment As any extracorporeal treatment, particular attention has to be paid to an increased risk of bleeding as in the case of uncontrolled coagulopathy (disseminated intravascular coagulation [DIC]) or uncontrolled gastrointestinal bleeding. However, no report of bleeding related to the Prometheuss' treatment has ever been published. Nevertheless, uncontrolled bleeding, DIC, and severe thrombocytopenia, should be regarded as contraindications to Prometheusw. Other proposed contraindications include severe hemodynamic instability and uncontrolled septicemia. Hemodynamic instability is a potential contraindication because of the well-known effect of a decrease in the blood pressure during conventional hemodialysis. This effect can sometimes be observed during Prometheuse treatment where the extracorporeal volume is even higher [6). A comparison of several hemodynamic parameters, such as mean arterial pressure (MAP) and systemic vascular resistance index (SVRI), showed an improvement of these parameters only under MARS but not under Prometheusw treatment [19). The simultaneous decrease in several vasoactive substances, such as vasopressin and nitrate/nitrite levels, only under MARS was believed to be due to different removal characteristics of both systems. However, another possibility explaining these differences could be the setup of the two systems: In MARS, the secondary circuit is filled with albumin solution which is known to improve blood pressure and thus could downregulate the vasoactive substances. On the other hand, no external albumin is needed for the Prometheus's device and some slight losses even occur within the system [9). No differences have been reported for the two systems in terms of cytokine removal. Even though the removal of cytokines can be measured for both devices, their high rate of production prevents significant changes in serum cytokine levels [20,21). Recent data report a clotting of arterio-venous shunts in some patients who were treated for chronic renal failure but not liver failure [22). Further coagulation analyses revealed a removal of some pro- and anticoagulatory factors especially within the anion exchanger adsorber (Promethozw). This explains well the difference with a previous report, which found no removal of coagulation factors, but only used the first adsorber (Promethntw) [21). As often observed in unselective adsorption extracorporeal systems, proteins such as albumin, heparin, coagulation, and complement factors may be adsorbed. Prometheusw has been registered for a specific application, i.e., liver disease. In the context of this clinical condition, no adverse effects have

Table 1. Possible indications and contraindications for Prometheuss therapy Possible indications Acute liver failure Acute-on-chronic liver failu re Acute alcoholic hepatitis Hepatorenal syndrome Hepatic encephalopathy Bridging to liver transplantation Primary graft dysfunction after Olf Intoxication with protein-bound drugs Refractory cholestatic pruritus OLl

= Orthotopic liver transplantation

Contraindications Uncontrolled bleeding Disseminated intravascular coagulation (DIC) Severe thrombocytopenia Severe hemodynamic instability Uncontrolled septicemia Use of arteriovenous shunt for dialysis

Liver Support with Fractionated Plasma Separation and Adsorption and Prometheus®

been reported in the scientific literature or filed as such to the producer. No assumptions, however, can be made if patients with other conditions (e.g., chronic kidney disease, sepsis) are treated. In these cases, the application of Prometheusw should be considered as experimental.

Conclusion New therapeutic options are needed to improve the prospects of patients with liver failure, either of an acute or acute -on chronic type. Prometheus's offers promising perspectives in these patients by combining fractionated plasma separation and direct adsorption on one hand and high-flux hemodialysis on the other. This concept allows an effective and safe removal of both protein-bound and water-soluble substances without the need for external albumin. The detoxification produced by the Prometheusw device seems to be more effective than MARS. Possible indications and contraindications for Prometheus's therapy are summarized in Table 1.The anticoagulation protocol is optimized by using regional anticoagulation with citrate. A large randomized multicenter trial is currently evaluating hard clinical endpoints, such as survival, in patients with acute-on-chronic liver failure treated with Prome-

theusw.

References 1. Stadlbauer V, Ialan R (2007) Acute liver failure: Liver support therapies. Curr Opin Crit Care 13:215- 221 2. Kreymann B, Seige M, Schweigart U, Kopp KF, Classen M (1999) Albumin dialysis: effective rem oval of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins. J Hepatol 31:1080-1085 3. Stange J, Hassanein TI, Mehta R, Mitzner SR, Bartlett RH (2002) The molecular adsorbent recycling system (as a liver support system based on albumin dialysis: a summ ary of preclinical investigations, prospective randomized, controlled clinical trial, and clinical experience from 19 centre s. Artif Organs 26:103-110 4. Strobl W, Vogt G, Mitteregger R, Schonhofen M, Gerner FJ, Falkenhagen D (1998) [The fraction ated plasma separation and adsorption system (PFSA), a new membrane adsorptionassisted adjunctive extracorporeal blood purification system for liver failure]. Biomed Tech (Berl) 43 Suppl:168- 169 5. Falkenhagen D, Strobl W, Vogt G, et al (1999) Fractionated plasma separation and adsorption system. A novel system for blood pur ification to remove albumin-bound substances. Artif Organs 23:81-89 6. Rifai K, Ernst T, Kretschmer U, et al (2003) Prometheus - a new extracorporeal system for the treatment of liver failure. J Hepatol 39:984- 990 7. Krisper P, Haditsch B, Stauber R, et al (2005) In vivo quantificat ion of liver dialysis: Compari son of albumin dialysis and fractionated plasma separation. J Hepatol 43:451-457 8. Evenpoel P, Laleman W, Wilmer A, et al (2006) Prometheus versus Molecular Adsorbents Recirculating system: comparison of efficiency in two different liver detoxification devices. Artif Organs 30:276- 284 9. Krisper P, Stauber RE (2007) Technology insight: artificial extracorporealliver suppo rt: how does Prometheus compare with MARS? Nature Clin Practice Nephrology 3: 267- 276 10. Evenepoel P, laleman W, Wilmer A, et al (2005) Detoxifying capacity and kinetics of prome theus 'ta new extracorporeal system for the treatment of liver failure. Blood Purif 23: 349- 358 11. [alan R, Williams R (2002) Acute-on-chronic liver failure: pathophysiological basis of therapeutic opt ions. Blood Purif 20: 252- 261

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K. Rifai, C. Yetta, and C. Ronco 12. Kjaergard LL, Liu J, Als-Nielsen B, Gluud C (2003) Artificial and bioartificial support systems for acute and acute -on-chronic liver failure: a systematic review. JAMA 289:217-222 13. Rifai K, Manns MP (2006) Review article: clinical experience with Prometheus. Ther Apher Dial 10:132-137 14. Rifai K, Ernst T, Kretschmer U, et al (2005) The Prometheus's device for extracorporeal support of combined liver and renal failure. Blood Purif 23:298- 302 15. Kramer L, Bauer E, Schenk P, et al (2003) Successful treatment of refractory cerebral oedema in ecstasy/cocaine-induced fulminant hepatic failure using a new high-efficacy liver detoxification device (FPSA-Prometheus). Wien Klin Wochenschr 115:599-603 16. Skwarek A, Grodzicki M, Nyckowski P, et al (2006) The use Prometheus FPSA system in the treatment of acute liver failure: preliminary results . Transplant Proc 38:209- 211 17. [ung 0, Asbe-Vollkopf A, Betz C, et al (2007) Long-te rm therapy of acute chronic liver failure to successful transplantation with an extracorporealliver support system. Z Gastro 45:21- 24 18. Rifai K, Hafer C, Rosenau J, et al (2006) Treatment of severe refractory pruritus with fractionated plasma separation and adsorption (Prometheusw). Scand J Gastroenterol 41:12121217 19. Laleman W, Wilmer A, Evenepoel P, et al (2006) Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic hemodynamics and vasoactive agents in patients with acut-on-chronic alcoholic liver failure. Crit Care 10:R108 20. Stadlbauer V, Krisper P, Aigner R, et al (2006) Effect of extracorporealliver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure. Crit Care 1O:R169 21. Rifai K, Ernst T, Kretschmer U, et al (2006) Removal selectivity of Prometheus - a new extracorporeal liver support device. World J Gastroenterol 12:940-944 22. Meijers BKI, Verhamme P, Nevens F, et al (2007) Major coagulation disturbances during fractionated plasma separation and adsorption. Am J Transpl 7:2195-2199

785

Artificial Liver Support: Current Status F.

SALIBA,

P. ICHAI, and D.

SAMUEL

Introduction Orthotopic liver transplantation emerged during the 1980s and has become a standard approved therapeutic lifesaving procedure for the treatment of patients with end-stage liver disease. Patient and grafts have achieved 1 and lO-yearsurvival rates of 85 % and 70 %, respectively [1]. Despite great improvements in the field of transplantation, mortality in patients developing hepatic failure remains very high. Ten to 20 % of the patients are dying awaiting liver transplantation mainly due to scarcity of organ donors . In recent years, there has been considerable interest in replacement of the liver by extracorporeal systems that may provide a bridge until spontaneous recovery of the liver or until an appropriate donor is available. Many biological and non-biological liver support therapies, based essentially on detoxification of the patient's blood, have been developed. During the last decade, some of these have reached the phase of human application and are currently undergoing clinical trials. The results seem to be encouraging in some groups of patients with liver disease. In one meta-analysis mixing artificial (5 types of devices) and bioartificial liver support systems (2 types of devices) and including 483 patients, no significant effect on mortality compared with standard therapy was observed [2]. But in a subgroup analysis, support systems significantly decreased mortalit y in patients with acute-on-chronic liver failure (33 %, RR: 0.67; 95 %, CI 0.51-0.90) but not in patients with acute liver failure [2].

Early liver Support Devices Based on Hemodialysis, Hemadsorption, Blood and Plasma Exchange Most trials and reports on charcoal hemoperfusion, hemodialysis, hemofiltration, hemodiafiltration, plasma and blood exchange transfusion showed a transient neurological improvement in some patients but failed to show a beneficial effect on survival (Table 1). The causes of the failures of these treatments were probably multifactorial, including the severity of liver failure, severe coagulation disorders, and sepsis, but mostly related to the fact that liver regeneration is probably not a constant event after fulminant hepatic failure and is very poor if not absent in patients with endstage liver cirrhosis.

Hemodialysis and Hemofiltration Hemodialysis, the first reported of these devices, has the ability to remove molecules smaller than 500 Da. The dialysis membranes used in these studies were synthetic

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F. Saliba, P. Iehai, and D. Samuel Table 1. Main studies using artificial liver support before albumin dialysis era Liver support devices

Author/year [ref]

NumResults ber of patients

Hemodialysis

Opolon et ai, 1976 [4] 10

Hemofiltration

Knell et ai, 1976 [5] Denis et al, 1978 [3]

4 41

Total recovery of consciousness in 6/10 pts and partial in 2/10 pts Temporary small effect on consciousness Total recovery of consciousness in 43 %; overall survival of 22 %

Charcoal Gimson et al, 1982 hemoperfusion [6] O'Grady et al, 1988 [7]*

76

Biologic-DT System

Ash 2001 [11]*

10

Improvement in liver function and general health

Plasma exchange and continuous hemodiafiltration

Matsubara et at 1990 [16] Yoshiba 1996 [17]

16

Improvement in level of consciousness but no increase in survival Regained normal consciousness in 97 %, and 80.9 % had stable neurological status Improvement in HE and cerebral edema within 7 days but LDLT performed Control of ICP during treatment

Plasma exchange

29

67

Sadamori 2002 [51] Nakanishi et ai, 2005 [52]

13

Kondrup et al, 1992 [53]

11

Larsen et ai, 1995 [14] Clemmesen et al, 1999 [54] Mandai et ai, 2000 [55]

10

Singer et ai, 2001 [56]

14 5

49

Greater effect oncerebral edema with earlier treatment (grade 3 HE) than later therapy (grade 4 HE)* Identical survival between no perfusion group and hemoperfusion group

5/11 patients survived (all acetaminophen), temporary improvement in cerebral function in non-survivors and positive hemodynamic effect. Improvement in cardiac output, SVR and blood pressure Increase in hepatic blood flow and D02, V02 unchanged Effective treatment option for PNF (with ALF) immediately after LT and may obviate the need for retransplantation (restoration of liver function in 4/5 pts without LT) No effect on neurological complications or on ability of the liver to regenerate in children

* Controlled trials; D02: splanchnic oxygen delivery; V02: oxygen consumption; SVR: systemic vascular resistance; ALF: Acute liver failure, LT: liver transplantation; LDLT: living donor liver transplantation; HE: hepatic encephalopathy; ICP: intracranial pressure.

membranes such as polymethylmethacrylate or polyacrylonitrile with filtration of lower and middle molecular weight molecules of up to 40 kDA [3]. A preliminary report in patients with fulminant hepatitis showed total recovery of consciousness in 6/10 patients and partial recovery of consciousness in two patients [4]. In another report by the same author, the use of high-permeability membrane hemodialysis and hemofiltration in 39 patients led to total recovery of consciousness in 43.6 % of the pat ients; 9 patients survived [3]. Other authors described partial improvement with dialysis procedures [5]. But in all the cases, no improved survival was observed.

Artificial liver Support: Current Status

Charcoal Hemoperfusion With this system, charcoal is incorporated into a hemoperfusion circuit to increase its performance. In an early study in which charcoal hemoperfusion was performed in patients with fulminant hepatic failure, cerebral edema occurred significantly less frequently when hemoperfusion was started in patients with grade 3 hepatic encephalopathy than in those patients in whom the hemoperfusion was started when signs of grade 4 encephalopathy were already apparent (49 % and 78 %, respectively, p < 0.05) [6]. In a later controlled trial of charcoal hemoperfusion in 62 patients with grade 4 encephalopathy on admission, there was no significant difference in overall survival rate between patients treated by charcoal hemoperfusion (10 h daily) and patients not treated (34.5 % vs. 39.3 %) . In the same study in 75 patients with grade 3 encephalopathy, the overall survival rates for patients treated and not treated were similar (51.3 % vs. 50.0 %) [7].

The liver Dialysis Unit (formerly Biologic-DT) The Food and Drug Administration (FDA)-approved Liver Dialysis Unit uses a cation exchange resin in addition to charcoal. It is a device in which membranes of a cellulosic plate dialyzer actively pump blood through a single access at over 20 mil min. The dialysate contains a suspension of powdered activated charcoal (300 000 m- surface area) and cation exchangers (160 mEq capacity). In a prospective trial of 15 patients with acute deterioration of liver function, there was a statistically significant improvement (p < 0.01) in neurological status during individual treatments and over days of treatment (1- 12 daily treatments). For half the patients, treatment with the BioLogic-DT system served as a bridge to liver transplantation or liver recovery [8]. Wilkinson et al. conducted a randomized controlled study in 11 patients with hepatic failure and stage 3- 4 encephalopathy. After 5 days of treatment, the physiologic status of patients had significantly improved and improvement in outcome was shown for treated patients versus non-treated patients [9]. But in a randomized controlled trial in 10 patients with fulminant hepatic failure, there was a significant loss of platelets and decrease in plasma fibrinogen with a rise in blood activated clotting time, not seen in the controls. The authors concluded that removal of metabolites by treatment was limited with no significant effect on blood ammonia level [10]. Another large, controlled and randomized trial, conducted in several centers with the Biologic-DT sorbent-suspension dialyzer, enrolled 56 patients with acute hepatic encephalopathy (grade 2- 4). These patients had acute liver failure or acute-onchronic liver disease. The duration of each treatment course was 6 h. Liver dialysis significantly improved the incidence of positive outcome (recovery of hepatic function or improvement for liver transplantation) of patients with acute-on-chronic liver disease versus controls (71.5 % vs. 35.7 %, P = 0.036) . However, in the group of patients with fulminant hepatitis, there was no significant improvement in outcome versus the control group. The overall survival was 51.6 % [11].

The Plasma Filter Unit The plasma filter unit is another system which combines hemadsorption systems in series (BioLogic-DT) with two Gambro plasma filters downstream from the plate dialyzer, which allows most of the blood plasma to pass out of the blood, contact powdered charcoal in a suspension, and then return to the blood each second cycle,

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F. Saliba, P. leba'i, and D. Samuel

creating push-pull sorbent based pheresis [12). This system has been tested in patients with hepatic failure with grade 3 and 4 encephalopathy, respiratory and kidney failure. After treatment, blood pressure and encephalopathy improved. Bilirubin, aromatic amino acids, ammonia, creatinine, and interleukin (IL} -l~ decreased . Finally, according to the authors, the treatment appeared to be safe [11). Plasma Exchange With or Without Hemodiafiltration

Plasma exchange is based on the removal of the patient's plasma and its replacement with donor plasma free of 'cytokines and toxins' [13), The disadvantage of this method is the removal of molecules independent of their molecular weight and protein binding in contrast with hemodialysis or hemoperfusion; this could provide a deficiency in the immune system of the recipient, In addition, more complications could occur, such as pulmonary embolism, infection, and hemorrhage. A benefit of plasmapheresis is inconsistent in the different available studies and no controlled trials have been published. In a prospective study by Larsen et al., 10 patients with fulminant hepatic failure were treated with high-volume plasmapheresis (8 -15 I of fresh frozen plasma exchanged), Cardiac output, systemic vascular resistance, and arter ial blood pressure improved during phasmapheresis [14). Tygstrup et al. made similar findings with high volume plasmapheresis therapy in a review of 52 patients with liver failure treated until liver transplantation [15). A pilot study of continuous hemofiltration using a high-performance membrane alternately with plasma exchange (10-15 I per session) was conducted in 16 patients. Eight of the 16 patients had improvement in consciousness and were weaned from hemofiltration; three patients survived and 13/16 patients lived an average of 15 days [16]. Yoshiba et al. treated 67 patients with this system. Among these patients, 65 (97 %) regained consciousness and 55 patients (80.9 %) stayed alert during the treatment; the overall survival rate was 55.2 % [17). The authors concluded that hemofiltration in combination with plasma exchange might provide a means of life support for patients awaiting a liver transplantation. The SEPETTM Liver Assist Device

The SEPET (Arbios Systems) is a new selective plasma filtration therapy that uses a single cartridge containing hollow fibers capable of sieving substances with molecular weight of up to 100 kDa. The patient's blood plasma is expressed through the micropores, thereby cleansing the blood from toxins, such as ammonia and various mediators of inflammation and inhibitors of hepatic regeneration present in patients with hepatic failure. The system can be connected with most available kidney dialysis units. Preliminary results from a phase I clinical trial, in patients with acute decompensation of liver cirrhosis showed a beneficial effect on survival without liver transplantation [18].

Artificial Devices Using Albumin Dialysis Introduced in 1993, the concept of albumin dialysis aimed to specifically clear albumin-bound toxins from the blood of patients with liver failure [19]. Human serum albumin is an important antioxidant, drug carrier, and transporter for endogenous and physiological anions, like bilirubin, bile salts, long chain fatty acids, nitric oxide, and a variety of other substances . The transport function for liver toxins makes

Artificial liver Support: Current Status Table 2. Effects of different albumin dialysis devices in patients with acute liver failure or acute-on-chronic liver failure Author

Albumin Type of study dialysis used

Status of Num- Liver support effects patients ber of pts

Kreymann et al, 1999 [39]

SPAD® Clinical, biological and outcome

ALF

Mitzner et al (2000) [24]

MARS® Improvement in

ALCF

8

Improvement in hemodynamics, renal function, bilirubin, and survival

Ben Abraham et al (2001) [31]

MARS® Brain edema & cerebral perfusion pressure

ALCF

3

'\, ICp, .l' CPP

Heemann et al (2002) [2S]

MARS® Effective and safety study'"

ACLF

12

.l' 30-day survivalP, '\, renal dysfunction, '\, hepatic encephalopathy"

Catalina et al MARS® Systemic (2003) [57] hemodynamic

ACLF

4

'\, portal hypertension '\, hyperdynamic circulation (.l'MAp, .l' SVRI, '\, CO, '\, PRA & NE)

Novelli et al (2003) [58]

hepato-renal syndrome'!'

MARS® Systemic hemodynamic

Schmidt et al MARS® Systemic (2003) [32] hernodynarnk'"

ALF, PNF, 63 DG, ACLF

ALF

8

ACLF

11

Rifai et al (2003) [35]

Pome- Clinical, biologitheus® cal and outcome

Sauer et al (2004) [41]

MARS® Comparison of In vitro CVVHDF, MARS® study and SPAD® and SPAD®

Krisper et al (2005) [43]

MARS® vs Prometheus®

Comparison of MARS® and Prornetheusv on protein bound and water-soluble markers'"

Control of rhabdomyolysis, lactic acidosis and hemolysis. Improvement in renal function.

ACLF

- Bilirubin'', '\, NH4P, '\, GCSP - Correlation between improvement in neurological status and improvement in cerebral perfusion .l' SVRIP, » COP, .l' MAPP, .> HRP, '\, V02 P Outcome 2 months: 3/11 pts. Improvement in heart rate, 24 h diuresis and oxygen saturation. Significant improvement in bilirubin, bile acids and ammonia concentration levels. - Significantly greater decrease in ammonia levels with SPAD® and CVVHDF than MARS® - No significant differences on watersoluble substances with SPAD®, CVVHDF and MARS® - Significantly greater decrease in bilirubin levels with SPAD® than MARS® - Similar decrease in bile acid levels with SPAD® and MARS®

8

Clearance of ammonia, unconjugated bilirubin, urea significantly higher with FPS than MARS No significant difference between plasma levels of bilirubin, ammonia and urea

789

790

F. Saliba, P. Ichai, and D. Samuel Table 2. (Cont.) Author

Albumin dialysis used

Type of study

Status of N Liver support Effects patients pts

Laleman et al MARS® Comparison of ACLF (2006) [45] MARS® and Provs Prometheus® metheus® on systemic haemodynamics and vasoactive agents

Camus et al (2006) [33]

MARS®

Clinical, biological and outcome

ALF

12 - Significant improvement in bilirubin and bile acids by both MARS® and Prometheus, but Prometheus more effective than MARS® - Significant improvement in MAP and SVRI with MARS® - Significant decrease in PRA, aldosterone, norepinephrine, vasopressin and nitrate levels with MARS® 22 - Significant improvement in grade of hepatic encephalopathy and of Glasgow coma score. Significant decrease in conjugated bilirubin and INR - M - More frequent transplant recovery than expected

ALF: Acute liver failure; ACLF: Acute on chronic liver failure; ICP Intracranial pressure; CPP: Cerebral perfusion pressure; SPAD®: Single-pass albumin dialysis; MAP: Mean arterial pressure; SVRI: Systemic vascular resistance index; Cardiac output; NE: Norepinephrine; PRA: plasma renin activity; PNF: Primary nonfunction of the graft; DGF: dysfunction graft; NH4: ammonia; GCS: Glasgow Coma Score; V02: Oxygen consumption; HR: Heart rate; (1) prospective controlled trial. p: p < 0.05

co:

albumin an interesting target for liver detoxification research [20]. These therapies and their effects are described in Table 2.

Molecular Adsorbent Recycling System (MARS®) MARS® (Gambrow, Stockholm, Sweden) is a liver support system that uses an albumin-enriched dialysate to facilitate the removal of albumin-bound toxins. The system has three different fluid compartments: A blood circuit, a 600 ml of 20 % human serum albumin circuit with charcoal and anion exchange resin columns, and a dialysate circuit [21]. Blood is passed through a non-albumin-permeable high flux dialysis membrane (MARSFlux®). The human serum albumin dialysate is passed through the dialysate compartment of the blood dialyser and is regenerated by dialysis against a bicarbonate-buffered dialysate, followed by passage through two sequential columns of uncoated charcoal and anion exchanger resin. MARS® requires a standard dialysis machine or a continuous veno-venous hemofiltration device to control the blood and dialysate circuits. MARS® has been used in the intensive care un it (leU) in most clinical situations of hepatic failure [22, 23]. In uncontrolled and controlled trials, albumin dialysis was found to improve liver tests and clinical conditions in two major situations: 1. In patients suffering from acute decompensation on chronic liver disease, MARS® has already been the object of two prospective randomized studies evaluating the short-term benefits mainly in terms of survival at one month.

Artificial Liver Support: Current Status Mitzner et al. randomized 13 patients with hepato-renal syndrome, 8 in the MARS® group and 5 in a control group [24]. The mortality was 100 % in the control group and 75 % in the MARS® treated group (p < 0.01); effectiveness was also demonstrated by the increase in arterial pressure, the urinary volume, and the decrease in creatininemia and bilirubinemia. In the second clinical trial, Heemann et al. randomized 24 patients with severe cholestasis (bilirubin > 20 mg/dl) not improving after 3 to 5 days of standard medical therapy into two groups: standard medical therapy versus standard medical therapy + MARS'" [25]. The determining factors for acute decompensation were infection, drug intoxication, and hemorrhage or alcohol abuse. The results showed a significant difference (p < 0.05) in the 30-day survival rate in favor of the MARS®group: 6 deaths in the standard medical therapy group (survival = 50 %) aga inst only one in the MARS® group (survival = 91 %). Effectiveness was also demonstrated on hepatic-encephalopathy, bilirubinemia , biliary acids, arterial pressure, and creatininemia. Recently, the results have been presented of a prospective randomized multicenter study including 70 patients with grade 3 and 4 hep atic-encephalopathy with a primary objective of decreasing by two stages the degree of encephalopathy [26]. This study compared, at 5 days, treatment with MARS® with treatment with standard medical therapy. The study showed a significant improvement in the degree of encephalopathy in 64 % of the patients treated with MARS® and in 38 % of the control group (p = 0.04). In particular, MARS® significantly reduced ammonia levels Other uncontrolled studies have shown a beneficial effect of MARS® in severe cholestatic liver [27], acute alcoholic hepatitis [28], hypoxic liver [29], and graft dysfunction after liver transplantation [30]. 2. In patients with acute fulminant liver failure, several uncontrolled studies have been performed and showed improvements in encephalopathy, a decrease in intracranial pressure, and an increase in cerebral perfusion pressure, mean arterial blood pressure, systemic vascular resistance, and cardiac index [31, 32]. In 22 patients, who had acute liver failure with criteria for liver transplantation, Camus and colleagues observed a 32 % recovery after MARS® therapy avoiding the need for transplantation [33]. The main indications for treatment with MARS® are summarized in Table 3.

Table 3. Main indication groups for MARS®therapy Acute liver failure

Decompensated chronic liver disease (acute-on-chronic liver failu re) Complicated by progressive jaundice (i.e., acute alcoholic hepatitis) Complicated by hepatic encephalopathy Complicated by renal dysfunction (i.e., hepato-renal syndrome) After liver transplantation Primary non function of the graft Primary dysfunction of the graft Recurrent cirrhosis, chronic rejection, others After major hepatectomy Acute hepatic fail ure Intractable pruritus in cholestatic diseases Acute intoxication or overdose with substances potentially bound to albumin Secondary liver failure and multiple organ failure

791

792

F. Saliba, P. Ichai, and D. Samuel Fractionated Plasma Separation and Adsorption (FPSA, PrometheusQl»)

The Prometheusw system (Fresenius Medical Care AG, Homburg, Germany) is based on the concept of fractionated plasma separation and adsorption (FPSA). It is a new liver support system in which albumin-bound substances are directly removed from the blood by a special adsorber (albumin permeable polysulfon filter) [34]. The AlbuFlow membrane allows the passage of a plasma fraction containing patients' albumin. Molecules up to 68 kDa (size of albumin) pass from the blood into a secondary circuit. This fraction is passed over two sorbent columns (a neutral resin and an anion exchanger) to achieve removal of albumin-bound toxins from the albumin. The fraction is then passed back to the blood. The whole blood is then dialyzed while passed through a high flux-dialyser and returned to the patient [34]. Rifai and colleagues treated 11 cirrhotic patients with acute liver failure with Prometheusw. Baseline bilirubin was 446 ± 286 umol/l and the average treatment time was 5± 1 hours. There was an insignificant trend towards a decrease in total bilirubin (reduction rate 21 %), a significant decrease in creatinine, urea, ammonia, bile acids, conjugated bilirubin, while unconjugated bilirubin and cholinesterase increased significantly. No significant clinical changes were reported for hepatic encephalopathy or Child and Glasgow coma scores . Coagulation problems/clotting were reported in 36 % of cases (4/11). The thirty day-survival rate was 36 % (4111) and the hospitalsurvival rate was 27 % (3111) [35]. Evenepoel and colleagues treated nine patients with acute-on-chronic liver failure with Prometheus's for three consecutive days. A significant decrease in urea, creatinine, total bilirubin, and bile acids was observed and, particularly, a decrease in serum albumin concentration (30.2 ± 1.6 to 27.4 ± 1.7 giL, P = 0.055) [36]. Skwarek and colleagues treated 13 patients with acute liver failure and showed a significant decrease in total bilirubin and ammonia but no significant improvements in mean arterial pressure; seven pat ients were transplanted and only three patients survived at 6 months [37]. Recently, Meijers et al. reported repeated occlusive thrombosis of the arterio-venous conduit and severe loss of coagulation factors exceeding 50 % for factor II, factor X and protein C in FPSA-treated liver failure patients [38]. Single-pass Albumin Dialysis (SPADQI»)

Single-pass albumin dialysis (SPAD®) uses a standard renal replacement therapy system without an additional perfusion pump system [39]. The patient's blood flows through a circuit containing a high-flux hollow fiber hemodiafilter. The other side of this membrane is cleansed by an albumin dialysate flowing in the counter-direction; this solution is discarded after passing the filter. This solution is prepared in bicarbonate-buffered 4.5 liter bag; 1 liter is replaced by 1 liter of 20 % human albumin solution resulting in a 44 glalbumin concentration with a slow dialysate flow rate (1- 2 lIhour). This technique is similar to continuous veno-venous hemofiltration; the difference is the dialysate composition and the time of treatment. This technique was applied to a young patient with fulminant Wilson's disease. After the first six treatments, the authors observed improvement in the clinical condition, in renal function, and regression of hemolysis. In total, 35 treatments were performed in this patient before liver transplantation [38]. In another report, three cirrhotic patients were treated for long-term, resulting in two successful transplantations; one patient died from sepsis after 140 days [40].

Artificial Liver Support: Current Status

Comparison of Albumin Dialysis Techniques Sauer et al. compared in vitro MARS®, SPAD®, and continuous veno-venous hemodiafiltration (CVVHDF) [41]. SPAD® and CVVHDF induced a significantly greater reduction in ammonia levels than MARS®. No significant differences were found among SPAD®, MARS®, and CVVHDF with respect to other water-soluble substances. SPAD® induced a significantly greater reduction in bilirubin levels than MARS®. Reductions in bile acid levels were similar for SPAD® and MARS®. In another in vitro comparison between single pass albumin dialysis versus recirculation (MARS®), MARS® was the more effective kind of albumin dialysis for bile acids. In addition, with SPAD®, an improvement in efficacy can be reached only by dramatic increases in costs [42]. Krisper et al. compared 8 patients with acute-onchronic liver failure treated alternately in a cross over design with MARS® and Prometheusv. Clearance in ammonia, unconjugated bilirubin, and urea were significantly higher with FPSA than with MARS®. There were no significant differences in plasma levels of bilirubin, ammonia, or urea [43]. Evenepoel et al. compared retrospectively 18 patients with acute-on-chronic liver failure treated either with MARS® (9 patients) or Prometheusw (9 patients) for an identical duration, blood and dialysate flows [44]. For all markers, except bile acids , the reduction ratios obtained with Prometheus" were significantly higher compared to those obtained with MARS®; blood clearances of protein-bound substances declined overtime with MARS® but not with Prometheus's. Laleman et al. compared 18 patients with acute alcoholic hepatitis treated for 3 consecutive days either with MARS® (6 patients), or Prometheusw (6 patients), or standard medical care [45]. Both Prometheus's and MARS® decreased serum bilirubin levels, the Prometheus's device being more effective than MARS®. Only MARS® was associated with a significant improvement in mean arterial pressure and systemic vascular resistance index, while the cardiac index and central filling remained constant. This circulatory improvement in the MARS® group was paralleled by a decrease in plasma renin activity (p < 0.05), aldosterone (p < 0.03), norepinephrine (p < 0.05), vasopressin (p = 0.005), and nitrate/nitrite levels (p < 0.02) [45].

Artificial Liver Devices and Cytokines Serum pro- and anti -inflammatory mediators, particularly tumor necrosis factor (TNF)-a and other cytokines (IL-l, IL-6, IL-lO), in patients with acute liver failure might playa role in the pathophysiology of cerebral edema. In many studies, concentrations of circulating pro -inflammatory cytokines were increased significantly in patients with fulminant hepatic failure (lL-l is, TNF-a, IL-6, and IL-l receptor antagonist) or were associated with a fatal outcome (TNF-a and IL-lO) [13, 46]. These devices, and in particular plasma exchange, remove some of these inflammatory mediators from the circulation of patients with severe liver failure [13]. In vitro, bilirubin, endotoxins, and cytokines in the plasma of patients with hepatic failure can be effectively adsorbed by resins. Most cytokines and endotoxins in plasma can also be effectively removed by resin s in vivo. Ialan et al. showed the role of proinflammatory cytokines in the pathogenesis of intracranial hypertension in patients with fulminant hepatic failure [47]. In patients with acute-on-chronic liver failure, elevated serum levels of several cytokines, including TNF-a, sTNF-aRl, sTNF-aR2, IL-2, IL-2R, IL-4, IL-6, IL-8,

793

794

F. Saliba, P. Ichai, and D. Samuel

1L-lO, and interferon-y, have been reported [48, 49]. Continuous renal replacement therapy per se may remove cytokines from plasm a by convection and membrane adsorption. However, removal of cytokines is not sufficient to result in a significant and sustained effect on plasma concentrations. Stadlbauer et al. studied eight patients with acute-on-chronic liver failure who underwent alternating tre atments with either MARS® or Prometheusv in a randomized cross-over design. No significant changes in 1L-6, 1L-8, 1L-lO, TNF-a or sTNF-aRl serum levels could be found in the course of 6 h treatments with MARS® or Prometheuss', and there was no significant rebound 60 mins after the treatment for any of the tested cytokines . Cytokine levels were not different between survivors and non -survivors (day 30) at any time point, and no differences were found between the beginning and the end of the treatment series [50]. Other studies repo rted in the literature have shown contradictory result s (Table 4). The real capacity of these exchanges of cytokine removal has been poor and their potential risk and benefit rem ains unknown. Table 4. Main endotoxins and cytokines increased and removed by artificial liver devices in patients with acute liver failure Authors, years

Cytokines investigated

Patients

Results

Endotoxins and cytokines released in patients with acute liver failure Sen et al (1992) [59]

IL-6

SAH, AH, FHF, control

l' IL-6 in AH, l' IL-6 in SAH, l' IL-6 in FHF Significant correlation between serum IL-6 level and PT

Sekiyama et al (1994) [46]

IL-1 beta, TNF-a, IL-6, IL-1ra,

FHF vs SAH

l' IL-1 beta, ~ ratio IL-1ra/IL-1 beta in FHF pts died vs pts survived

Nagaki M et al (2000) [60]

IL-10, TNF-a, IL-1 beta, IL-6, IL-2, sTNFR p55 und p75

Pts with FHF vs SAH

TNF-a & IL-10 predictive of fatal outcomes

Tokushige et al (2000) [61]

TNF-a, sTNFR-I, sTNF-II

FHF, SAH, Healthy controls

l'sTNFR-I, l' TNF-a, l'sTNF-1i in FHF

Odeh M et al (2004) [62]

TNF-a

HE in pt with Significant positive correlation between chronic liver failure serum levels of TNF and severity of HE

Authors (years)

Cytokines investigated

Patients

Devices

Results

Hepatotoxic substances and cytokines removed by extracorporeal devices Bouman et al (1998) [63]

TNF-a, IL-6, IL-8

In vitro study

filtration and adsorption during pre-postdilution hemofiltration*

~ TNF-a, IL-6, IL-8/ adsorption polyacrylonitrile membrane ++

Sieberth et al (1999) [64]

Cytokines, TN F-a

Patients with ARF & sepsis

Continuous hemofiltration

Brief and transient drop in TNF-a level

Steczko et aI (1999) [65]

TNF-a, IL-1 beta, IL-6

In vitro study

BioLogic - DTPF

'\, TN F-a, IL-1 beta and IL-6

Artificial Liver Support: Current Status Table 4. (Cont.)

Authors (years) Cytokines investigated

Patients

Devices

Results

Ambrosino (2003) [66]

TNF-a, IL-6

Acute on chronic MARS® liver disease

Guo et al (2003) [49]

NO, TNF-a, IL-6, IL-8, IFN gamma

SAH with MODS

Wang et al (2004) [67]

Bilirubin, endotoxins, IL-1 beta, TNF-a

In vitro & in vivo Resin perfusion study

Significantly decrease endotoxin, IL-1 beta, TNF-a in vitro & in vivo

Di Campli et al (2005) [68]

TNF-a, IL-1 beta, IL-6

Acute on chronic MARS® liver disease

'\, TNF-a , IL-1 beta, IL-6

Acute on chronic MARS®and Prcmetheusv liver disease

Clearance of cytokines by both MARS®and Prometheus®. No change in serum cytokine levels after MARS®or Prometheus®treatment

Stadlbauer et al TNF-a , IL-6, IL-8, (2006) [50] IL-10, sTNFR-1

MARS®

7' IL-6, '\, TNF-a

Significant removal of NO and cytokines Improvement of clinical conditions

FHF: fulminant hepatic failure; SAH: severe acute hepatic; AH: acute hepatitis; PT: prothrombin time; IL-1RA: IL-1 receptor antagonist; sTNFR: soluble tumor necrosis factor receptor; sTNFR-I: soluble TNF receptor-I; sTNF-II: soluble TNF receptor-II; *: filtration and adsorption ofcytokines during hemofiltration in 4 different membranes (polysulfone, polyacrylonitrile, polyamide and cellulose triacetate); HE: hepatic encephalopathy; ARF: acute renal failure; NO: nitrous oxide; IFN: interferon; MODS: multiple organ dysfunction syndrome.

Conclusion Despite great improvements in the field of transplantation and better management of patients with liver disease, there remains a major need for artificial liver support devices. In recent years, there has been considerable interest in the use of newer forms of liver support that may provide a bridge until spontaneous recovery of the liver or until an appropriate donor is available. The concept of albumin dialysis has been a breakthrough in the development of artificial hepatic support devices. To date, the most widely developed system has been the MARS® system that uses albumin dialysis to replace the detoxification function of the liver. The MARS® system has given interesting results in controlled and uncontrolled tr ials in terms of improving short-term survival. It appears, at this stage, premature to compare albu min dialysis techniques and devices. Technical improvements, randomized controlled trials evaluating indications and timing of treatment, and cost-effectiveness studies, are still needed to evaluate the impact of these therapies in medical practice. References

Adam R, McMaster P, O'Grady JG, et al (2003) Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry. Liver Transpl 9:1231-1243 2. Kjaergard LL, Liu J, Als-Nielsen B, Gluud C (2003) Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA 289:217 - 222 1.

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F. Saliba, P. Ichai, and D. Samuel 3. Denis J, Opolon P, Nusinovici V, Granger A, Darnis F (1978) Treatment of encephalopathy during fulminant hepatic failure by hemodialysis with high permeability membrane. Gut 19:787-793 4. Opolon P, Lavallard MC, Huguet C (1976) Hemodialysis versus cross hemodialysis in experimental hepatic coma. Surg Gynecol Obst 142:845- 853 5. Knell AJ, Dukes DC (1976) Dialysis procedures in acute liver coma. Lancet 2:402-403 6. Gimson AES, Braude SE, Mellon PJ, Canalese J, Williams R (1982) Earlier charcoal hemoperfusion in fulminant hepatic failure. Lancet ii:681- 683 7. O'Grady JG, Gimson AES, O'Brien C], et al (1988) Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 94:1186-1192 8. Ash SR, Blake DE, Carr DJ (1992) Clinical effects of a sorbent suspension dialysis system in treatment of hepatic coma (The BioLogic-DT). Int J Artif Organs 15:151-161 9. Wilkinson AH, Ash SR, Nissenson AR (1998) Hemodiabsorption in treatment of hepatic failure . J Transpl Coord 8:43-50 10. Hughes RD, Pucknell A, Routley D, et al (1994) Evaluation of the BioLogic-DT sorbent-suspension dialyser in patients with fulminant hepatic failure. Int J Artif Organs 17:657- 662 11. Ash SR (2001) Powdered sorbent liver dialysis and pheresis in treatment of hepatic failure. Ther Apher 5:404-416 12. Ash SR, Blake DE, Carr DJ, Harker KD (1998) Push-pull sorbent based pheresis for treatment of acute hepatic failure: the bioLogic-detoxifier/plasmafilter System. ASAIO J 44:129-139 13. Iwai H, Nagaki M, Naito T, et al (1998) Removal of endotoxin and cytokines by plasma exchange in patients with acute hepatic failure. Crit Care Med 26:873- 876 14. Larsen FS, Ejlersen E, Hansen BA, Mogensen T, Tygstrup N, Secher NH (1995) Systemic vascular resistance during high-volume plasmapheresis in patients with fulminant failure: relationship with oxygen consumption. Eur J Gastroenterol Hepatol 7:887- 892 15. Tygstrup N, Larsen FS, Hansen BA (1997) Treatment of acute liver failure by high volume plasmapheresis. In: Lee WM, Williams R (eds) Acute Liver Failure. Cambridge University Press, Cambridge, pp 267- 277 16. Matsubara S, Okabe K, Ouchi K, et al (1990) Continuous removal of middle molecules by hemofiltration in patients with acute liver failure. Crit Care Med 18:1331-1338 17. Yoshiba M, Inoue K, Sekiyama K, Koh I (1996) Favorable effect of new artificial liver support on survival of patients with fulminant hepatic failure. Artif Organs 20:1169-1172 18. SEPET artificial liver assist device. http ://www.arbios.com/pipeline/sepet.htm. Accessed Dec 2007 19. Stange J, Mitzner S, Ramlow W, et al (1993) A new procedure for the removal of protein bound drugs and toxins. ASAIO J 39:M621 -625 20. Mitzner S, Klammt S, Stange J, Schmidt R (2006) Albumin regeneration in liver support comparison of different methods. Ther Apher DiaI1Q:108-117 21. Mitzner SR, Stange J, Klammt S, Peszynski P, Schmidt R, N6ldge-Schomburg G (2001) Extracorporeal detoxification using the molecular adsorbent recirculating system for critically ill patients with liver failure. J Am Soc Nephrol 12:S75-82 22. Novelli G, Rossi M, Pretagostini M, et al (2005) One hundred sixteen cases of acute liver failure treated with Mars. Transplant Proc 37:2557- 2559 23. Saliba F, Ichat P, Gonzales M, et al (2005) Extracorporealliver support using the MARS@ Albumin dialysis system: a rescue therapy in patients with end-stage liver disease and renal failure. Liver Transpl 1l :41C-lla (abst) 24. Mitzner SR, Stange J, Klammt S, et al (2000) Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl 6:277- 286 25. Heemann U, Treichel U, Loock J, et al (2002) Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 36:949-958 26. Hassanein T, Tofteng F, Brown R, et al (2004) Efficacy of albumin dialysis (MARS) in patients with cirrhosis and advanced grades of hepatic encephlopathy: a prospective, controlled, randomized multicenter trial. Hepatology 38:LB04-726a (abst) 27. Campli C, Gaspari R, Mignani V, et al (2003) Successful Mars treatment in severe cholestatic patients with acute on chronic liver failure. Artif Organs 27:565- 569 28. [alan R, Sen S, Steiner C, Kapoor D, Alisa A, Williams R (2003) Extracorporealliver support

Artificial Liver Support: Current Status with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis. J Hepatol 38:24- 31 29. Banayosy A, Kizner L, Schueler V, Bergmeier S, Cobaugh D, Koerfer R (2004) First use of the Molecular Adsorbent Recirculating System technique on patients with hypoxic liver failure after cardiogenic shock. ASAIO J 50:332-337 30. Kellersmann R, Gassel H-J, Buhler C, Thiede A, Timmermann W (2002) Application of Molecular Adsorbent Recirculating System in patients with severe liver failure after hepatic resection or transplantation: initial single-cent re experiences. Liver 22 (SuppI.2):56-58 31. Ben Abraham R, Szold 0, Merhav H, et al (2001) Rapid resolution of brain oedema and improved cerebral perfusion pressure following the molecular adsorbent recycling system in acute liver failure patients. Transplant Proc 33:2897- 2899 32. Schmidt LE, Wang LP, Hansen BAH, Larsen FS (2003) Systemic hemodynamic effects of treatment with the molecular adsorbents recirculating system in patients with hyperacute liver failure: a prospective controlled trial. Liver Transplant 9:290- 297 33. Camus C, Lavoue S, Gacouin A, et al (2006) Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation. Intensive Care Med 32:1817-1825 34. Falkenhagen D, Strobl W, Vogt G, et al (1999) Fractionated plasma separation and adsorption system: a novel system for blood pur ification to remove albumin bound substances. Artif Organs 23:81- 86 35. Rifai K, Er T, Kretschmer U, et al (2003) Prometheus a new extracorporeal system for the treatment of liver failure. J Hepatol 39:984- 990 36. Evenepoel P, Laleman W, Wilmer A, et al (2005) Detoxifying capacit y and kinetic s of Prometheus-a new extracorporeal system for the treatment of liver failure. Blood Purif 23:349- 358 37. Skwarek A, Grodzicki M, Nyckowski P, et al (2006) The use Prometheus FPSA system in the treatment of acute liver failure: preliminary results. Transplant Proc 38:209- 211 38. Meijers BKI, Verhamme P, Nevens F, et al (2007) Major coagulation disturbances during Fractionated Plasma Separat ion and Adsorption. Am J Transplant 7:2195-2199 39. Kreymann B, Seige M, Schweigart U, Kopp KF, Classen M (1999) Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of prote in-bound toxins. J Hepatol 31: 1080-1085 40. Seige M, Kreymann B, Jeschke B, Schweigart U, Kopp KF, Classen M (1999) Long-term treatment of pat ients with acute exacerbat ion of chronic liver failure by albumin dialysis. Transplant Proc 31:1371-1375 41. Sauer 1M, Goetz M, Steffen I, et al (2004) In vitro comparison of the Molecular Adsorbent Recirculation System (MARS) and Single-pass Albumin Dialysis (SPAD@). Hepatology 39:1408-1414 42. Peszynski P, Klammt E, Peters E, Mitzner S, Stange J, Schmidt R (2002) Albumin dialysis: single pass vs, recirculation (MARS). Liver 22:S40-42 43. Krisper P, Haditsch B, Stauber R, et al (2005) In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation. J Hepatol 43:451-457 44. Evenepoel P, Laleman W, Wilmer A (2006) Prometheus versus molecular adsorbents recircu lating system: comparison of efficiency in two different liver detoxification devices. Artif Organs 30:276-284 45. Laleman W, Wilmer A, Evenepoel P, et al (2006) Effect of the molecular adsorbent recircula ting system and Prometheus devices on systemic haemodynamics and vasoact ive agents in patients with acute-on-chronic alcoholic liver failure. Crit Care 10:RI08 46. Sekiyama KD, Yoshiba M, Thomson AW, et al (1994) Circulating proinflammatory cytokines (lL-l beta, TNF-alpha, and IL-6) and IL-1 receptor antagonist (lL-IRa) in fulminant hapatic failure and acute hepatitis. Clin Exp Immunol 98:71- 77 47. [alan R, Pollok A, Shah SHA, Madhavan KK, Simpson KJ (2002) Liver derived pro inflammatory cytokines may be important in producing intracranial hypertension in acute liver failure. J Hepatol 37:536- 538 48. Sen S, Davies NA, Mookerjee RP, et al (2004) Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study. Liver Transpl10:1109-1119 49. Guo LM, Liu JY, Xu DZ, et al (2003) Application of molecular adsorbents recirculating system

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50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68.

to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int 23:16-20 Stadlbauer V, Krisper P, Aigner R, et al (2006) Effect of extracorporealliver support by MARS and Prometheus on serum cytokines in acute-on -chronic liver failure. Crit Care 10:R16 Sadamori H, Yagi T, Inagaki M, et al (2002) High-flow-rate haemodiafiltration as a brain-support-therapy proceeding to liver transplantation for hyperacute fulminant hepatic failure. Eur J Gastroenterol Hepatol 14:435-439 Nakanishi K, Hirasawa H, Oda S, et al (2005) Intracranial pressure monitoring in patients with fulminant hepatic failure treated with plasma exchange and continuous hemodiafiltration. Blood Purif 23:113-118 Kondrup J, Almdal T, Vilstrup H, Tygstrup N (1992) High volume plasma exchange in fulminant hepatic failure. Int J Artif Organs 15:669-676 Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648 - 653 Mandai AK, King KE, Humphreys SL, Maley WR, Burdick JF, Klein AS (2000) Plasmapheresis: an effective therap y for primary allograft nonfunction after liver transplantation. Transplantation 70:216- 220 Singer AL, Olthoff, KM, Kim H, Rand E, Zamir G, Shaked A (2001) Role of Plasmapheresis in the Management of Acute Hepatic Failure in Children; Ann Surg 234:418- 424 Catalina MY, Barrio J, Anaya F, et al (2003) Hepatic and systemic haemodynamic changes after MARS in patients with acute on chronic liver failure. Liver Int 23 Suppl 3:39-43 Novelli G, Rossi M, Pretagostini R, et al (2003) A 3-year experience with Molecular Adsorbent Recirculating System (MARS): our results on 63 patients with hepatic failure and color Doppler US evaluation of cerebral perfusion. Liver Int 23 Suppl 3:10-15 Sen Y, Tokushige K, Isono E, Yamauchi K, Obata H (1992) Elevated serum interleukin-6 Ievels in patients with acute hepatitis . J Clin ImmunoI12:197-200 Nagaki M, Iwai H, Naiki T, et al (2000) High levels of serum interleukin-l0 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis. J Infect Dis 182:1103-1108 Tokushige K, Yamaguchi N, Ikeda I, Hashimoto E, Yamauchi K, Hayashi N (2000) Significance of soluble TNF receptor-I in acute-type fulminant hepatitis. Am J Gastroenterol 95: 2040-2046 Odeh M, Sabo E, Srugo I, Oliven A (2004) Serum levels of tumor necrosis factor-alpha correlate with severity of hepat ic encephalopathy due to chronic liver failure. Liver Int 24:110-116 Bouman CS, Van Olden RW, Stoutenbeek CP (1998) Cytokine filtration and adsorption durin preand postdilution hemofiltration in four different membranes . Blood Purif 16:261 - 268 Sieberth HG, Kierdorf HP (1999) Is cytokine removal by continuous hemofiltration feasible? Kidney Int Suppl 72:S79-83 Steczko J, Ash SR, Blake DE, Carr DJ, Bosley RH (1999) Cytokines and endotoxin removal by sorbents and its application in push-pull sorbent-based pheresis: the BioLogic-DTPF System. Artif Organs 23:310-318 Ambrosino G, Naso A, Feltracco P, et al (2003) Cytokines and liver failure: modification of TNF-and IL-6 in patients with acute on chronic liver decompensation treated with Molecular Adsorbent Recycling System (MARS). Acta Biomed Ateneo Parmense 74 Suppl 2:7-9 Wang YJ, Wang ZW, Luo BW, Liu HI, Wen HW (2004) Assessment of resin perfus ion in hepatic failure in vitro and in vivo. World J Gastroenteroll0:837-840 Di Campli C, Zocco MA, Gaspari R, et al (2005) The decrease in cytokine concentration during albumin dialysis correlates with the prognosis of patients with acute on chronic liver failure. Transplant Proc 37:2551-2553

Section XX

XX Neurological Crises

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Encephalopathy in Sepsis A.

POLITO, S . SIAMI,

and T.

SHARSHAR

Introduction - Definition Encephalopathy is a frequent neurological manifestation of sepsis. The term, sepsis encephalopathy, is certainly misleading. An encephalopathy can be a direct consequence of sepsis but it can also be secondary to various associated complications of sepsis, such as liver or renal failure, drug toxicity, or metabolic disturbances. Because of the difficulty in discriminating a septic from a non-septic origin, the terms "sepsis-associated encephalopathy" or "critical illness encephalopathy" may be more appropriate. In addition, a pathophysiological definition would be questionable as a multitude of pathogenic mechanisms are involved. Clinical [1], electrophysiological (e.g., electroencephalogram [EEG], bispectral index, somatosensory evoked potentials) [2, 3] and biochemical (e.g., neuron-specific enolase [NSE] , S-100 ~-protein) [4] definitions of encephalopathy have been proposed, but each has its own limits. Clinical criteria are not applicable in sedated patients, electrophysiological testing is too cumbersome or sophisticated to be used in routine practice, and the usefulness of biochemical markers needs to be confirmed. In addition, relationships between clinical, electrophysiological, and biochemical markers have never been properly assessed, to our knowledge. Encephalopathy is an acute, diffuse, and reversible phenomenon. However, sepsis can induce focal brain lesions and septic patients can develop psychological and cognitive disturbances. Therefore, one may argue that these disturbances are secondary to the acute brain dysfunctions induced by the sepsis. Behavior is a major component of the response to stress and may vary from aggressiveness, anxiety, or hyper-alertness to lethargy. Interestingly, it is mainly controlled by the amygdala and the hippocampus, which are susceptible to hemodynamic and metabolic (e.g., hypoxemia and hypoglycemia) insults. Therefore, interpretation of changes in behavior is difficult as it may be adaptive or maladaptive, physiological or pathophysiological.

Pathophysiology of Sepsis-associated Delirium Brain Signaling in Sepsis A balanced interaction between the central nervous system (CNS) and the immune system is necessary for homeostasis. The neuroendocrine and autonomic nervous systems modulate the immune response. Immune-competent cells express receptors to glucocorticoids, to catecholamines, but also to acetylcholine. It has been shown that stimulation of the vagus nerve decreases, and vagotomy increases, the release of

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cytokines from macrophages, indicating the existence of a "cholinergic anti-inflammatory pathway" [5]. The neuroendocrine, behavioral, and autonomic structures are highly interconnected. The connection between the paraventricular nuclei (where corticotrophin releasing factor [CRF] and vasopressin are synthesized) and the locus coeruleus (which is involved in arousal and cardiovascular autonomic centers), the so-called noradrenergic-CRF loop, is essential for the response to stress [6]. In order to generate an appropriate brain modulation of the immune response but also of the hemodynamic status, activation of the autonomic and neuroendocrine systems has to be adequate . This brain activation is triggered by an activating signal, which schematically encompasses anatomical, cellular, and molecular sequences. Although the blood-brain barrier (BBB) hampers entry of circulating inflammatory mediators , systemic inflammation can be detected by the brain via the vagus nerve and the circumventricular organs. The former is a sensor of visceral inflammation through its axonal cytokine receptors. The latter lacks a BBB and expresses components of innate and adaptive immune systems, such as Toll-like receptors (TLRs), CD14 and receptors for cytokines, notably interleukin- l beta (Il-Ip), IL-6 and tumor necrosis factor alpha (TNF-a) [7]. The circumventricular organs are either located in the vicinity of the neuroendocrine structures or close to brainstem autonomic centers (e.g., area postrema) [8]. Afferent vagal fibers terminate in the nucleus tractus solitar ius, which controls the baroreflex and is connected to other autonomic structures but also to the paraventricular nuclei. Once systemic inflammation is detected, the activating signal will spread to the deeper areas involved in controlling the behavioral, neuroendocrine, and autonomic response. Expression of CDI4, TLR2, 4, and 9 is initially detected in the circumventricular organs then in hypothalamic and medullary autonomic nuclei [9]. A similar pattern has been demonstrated for inflammatory cytokines and their receptors [10]. Interestingly, expression of inflammatory cytokines precedes that of inducible nitric oxide (NO) synthase (iNOS) [11] and is associated with that of anti-inflammatory cytokines. This suggests a sequential activation of inflammatory mediators and the existence of an immune counter-regulation within the brain [12]. This signal will also affect glial cells and neurons. Thus, glial cells and neurons exhibit CDI4, TLR2, 4, and 9 after lipopolysaccharide (LPS) challenge [7]. Furthermore, prostaglandins are key mediators in the brain response to inflammatory stimuli; LPS stimulates astrocyte release of prostaglandin E [13] and microglial expression of prostaglandin receptors [14] and cyclo-oxygenase 2 [15]. Finally, neuronal function, namely release of neurotransmitters and neurohormones, will be, directly or not, altered by these mediators . There is a body of evidence that NO, cytokines, and prostaglandins modulate ~-adrenergic, gamma-aminobutyric acid (GABA)ergic or cholinergic neurotransmission but also secretion of CRF, adrenocorticotrophin hormone (ACTH), and vasopressin [16, 17]. There are many other mediators that are involved in the brain response to sepsis: Chemokines, angiotensin II, endothelin 1, macrophage migrating inhibitory factor (MIF), platelet activating factor (PAF), superoxide radicals, and carbon monoxide [18]. When considering the multitude of the mediators and the complexity of their interaction and their effects on brain cells, it is not surprising that it is so difficult to precisely and clearly describe brain signaling during sepsis. Moreover, interactive cellular organization of the brain adds an additional level of complexity. For example, astrocytes can be protective by regulating local blood flow, transporting energy substrates from microvessels to neurones, preserving BBB properties, destroying pathogens, removing debris, and promoting tissue repair [19]. However, activated

Encephalopathy in Sepsis glial cells can be neurotoxic by releasing NO and glutamate [20) during cerebral trauma, inflammation and infection. In conclusion, while this brain signaling is necessary for an adapted response to sepsis, it may, if, for example, too intense, become deleterious for brain cells, by inducing mitochondrial dysfunction, oxidative stress and apoptosis, but also for the cerebral endothelium and the BBB. The deleterious effect of brain inflammation is illustrated by the report in a human immunodeficiency viru s (HIV)-negative septic patient of a multifocal necrotizing leukoencephalopathy, which was characterized by marked inflammatory lesion of the pons and associated with an excessive systemic inflammatory response [21).

Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis Oxidative stress is one of the pathophysiological consequences of sepsis. Formation of reactive oxygen species (ROS) compromises cell functions and survival. An early but transitory oxidative stress has been documented in various brain areas of septic rats, especially the hippocampus and the cortex [22). This oxidative stress may result from a decrease in ant i-oxidant factors (heat shock protein, ascorbate) [23), an imbalance between superoxide dismutase and catalase activity [22), and mitochondrial dysfunction [24). It is well established that NO induces oxidative stress, leading to formation of peroxynitrite. A recent study in septic rats has shown that hypotension is preceded by the subsequent expression of iNOS, dysfunction of mitochondrial complexes I and IV, and formation of superoxide anions in a medullar autonomic centre [25). Oxidative stress may also be induced by hyperglycemia and hypoxemia. Apoptosis may result from oxidative stress. Mitochondrial-mediated apoptosis has been demonstrated in septic rats' brains [26). In patients who died from septic shock, expression of iNOS was correlated with neuronal and microglial apoptosis, which was detected in paraventricular and supraotic nuclei but also in cardiovascular autonomic centers, locus coeruleus, and the amygdala [27). Many other pro-apoptot ic factors can be incriminated, notably glial cell dysfunction, glutamate, and TNF-a, although its expression did not correlate with apoptosis [27). But before linking brain dysfunction to oxidative stress and apoptosis, one should remember that there is no evidence that their blockade is beneficial [28).

Endothelial Activation and Blood-brain Barrier Breakdown Cerebral endothelial cells are activated by LPS and pro-inflammatory cytokines, which induce the expression of CD40, vascular cell adhesion molecule (VCAM)-l or intercellular adhesion molecule (ICAM)-l, and E-selectin, activate synthesis of cyclooxygenase 2 and stimulate the Ixls-c/nuclear factor-kappa B (NF-KB) pathway. LPS also triggers expression of IL-1 and TNF-a receptors and the production of IL-1~, TNF-a, and IL-6 [7). LPS activates endothelial and inducible NOS [29). These released pro -inflammatory cytokines and NO are then able to interact with surrounding brain cells, relaying into the brain inflammatory response. One consequence of endothelial activation is the breakdown of the BBB. This has been demonstrated in experimental models of sepsis [30, 31). A similar phenomenon also occurs in the hippocampus of septic rats [32). This endothelial dysfunction may impair the movement of oxygen, nutrients, and metabolites but also facilitates the passage of various neurotoxic factors. In patients with septic shock, brain mag-

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A. Polito, S. Siami, and T. Sharshar

netic resonance imaging (MRI) can reveal BBB breakdown. In one study, vasogenic edema was found to be localized in the Virchow-Robin space in all but one patient in whom it was diffuse [33]. In another study, the authors documented a posterior reversible encephalopathy syndrome (PRES), which is characterized by vasogenic edema in the posterior lobes and vasospasm of the cerebral arteries [34]. Finally, endothelial activation results in microcirculatory dysfunction, altered vascular tone and coagulation, which favor the development of ischemic or hemorrhagic lesions.

A prospective post-mortem study has shown that septic shock is associated with various brain non-inflammatory injuries, including ischemic lesions in all cases, hemorrhage in 9 % of cases and micro-abcesses in 9 % [35] (Fig. 1). Ischemic lesions were located in brain areas susceptible to low cerebral blood flow (CBF). However, changes in CBF and its autoregulation during sepsis are controversial. Hence, human sepsis studies found an unchanged or a reduced CBF, while experimental studies have found increased or decreased CBF. Autoregulation of CBF has also been reported as preserved or altered in human or experimental sepsis [36]. Microcirculatory alterations may contribute to ischemic but also to hemorrhagic lesions. Hypoxemia, hyperglycemia, and hypoglycemia are deleterious for the neuron . It is noteworthy that the amygdala and the hippocampus are highly susceptible to hypoxemia and hypoglycemia [37]. Insulin therapy increases the risk of hypoglycemia while reducing hyperglycemia-related mitochondrial dysfunction. While insulin therapy may improve the outcome of brain-injured patients, its effects on the incidence, severity, and outcome of sepsis-associated encephalopathy have never been assessed. Neurotransmitter synthesis is also altered by ammonium and tyrosine, tryptophan and phenylalanine [38]. Liver dysfunction increases plasma levels of ammonium and, in combination with muscle proteolysis and liver dysfunction , plasma levels of these amino-acids [39]. Finally, brain dysfunction may be worsened by hydroelectrolytic disturbances but also by a number of drugs commonly administered in septic patients, including hypnotics, analgesics, and antibiotics. Septic patients often develop renal or liver failures that are by themselves a cause of encephalopathy.

Diagnosis of Sepsis-associated Encephalopathy Patients with sepsis-associated encephalopathy can be disoriented, agitated, confused, or delirious but also somnolent, stuporous, or comatose. Agitation and somnolence can occur alternatively. Among various scores that have been validated for the diagnosis of confusion or delirium in intensive care unit (lCU) patients, the Confusion Assessment Method for the ICU (CAM-ICU) has been used most in clinical studies. This system enables assessment of various domains of mental status, including attention, thinking organization and consciousness [40]. We also consider that the Assessment to Intensive Care Environment (ATICE) [41], which has been developed for titrating sedation, is useful for monitoring awareness and elementary comprehension. Therefore, CAM-ICU and ATICE can be used in routine practice to detect changes in mental status in non - or slightly sedated patients. Once encephalopathy is identified, a focal neurological sign should be sought clinically. Presence

Encephalopathy in Sepsis

Fig. 1. Neuropathological changes in patients who died from septic shock. a Large leptomeningeal hemorrhage adjacent to the right fissure of Sylvius. b Recent petechial hemorrhage in the right nucleus paraventricularis; H&E, x 100. c Fibrinous microthrombi from disseminated intravascular coagulation; H&E, x 200. d Nonbacterial thrombotic endocarditis, gross appearance of the heart. e Distal fibrinocruoric emboli in small leptomeningeal arteries; recent ischemia in the underlying cortex; H&E, x 40. f Septic emboli within necrotic area; H&E, x 40. g Multifocal necrotizing leukoencephalopathy; horizontal section of the upper pons; Luxol fast blue/cresyl violet. h Multifocal necrotizing leukoencephalopathy, recent necrotic changes in the transverse pontine fibers; H&E, x 60 From [18] with permission.

of abnormal movement should suggest seizures. Although the EEG may be considered to be more sensitive than neurological examination for detecting sepsis-associated encephalopathy (2), it has, however, not been tested against these validated scores in septic patients . It has also been shown that the bispectral index fails to detect delirium (42) . In addition, circulating levels of S-lOOB-protein do not correlate with either the Glasgow coma scale (GCS) or the EEG pattern in patients with sepsis (43) . In heavily sedated patients, detection of brain dysfunction is challenging. The first step is to interrupt or reduce sedation in order to assess the patient's mental status . However, discontinuation of sedatives may not be possible or may induce agi-

80S

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A. Polito, S. Siami, and T. Sharshar

Y~

Interruption of sedation

Sedated

~

~o

Yes

~ ~

Focal neurological signs

Nol Abnormal motor responsesto sti muli or abnormal brainstem responses (cough reflex, grimacing, oculocephalic response)

No

. . .. Sepsis as~oc~ated delirium IS likely Sepsis associated delirium is unlikely

t

Yes

+--

Abnormal EEG-SEP S-l OO ~ protein/neuron specific enolase

MRI to evaluatethe nature and extent of brain damage

No

Fig. 2. Proposed decision tree forthediagnosis of sepsis-associated delirium. EEG: electroengephalography; SEP: somatosensory evoked potentials; MRI: magnetic resonance imaging; ATICE: Assessment to Intensive Care Environment; CAM-ICU: Confusion Assessment Method for the ICU. From [18] with permission.

tation, making sepsis-associated encephalopathy difficult to discriminate from an effect of sedative accumulation or withdrawal. In pat ients for whom sedation cannot be reduced, diagnosis of brain dysfunction currently relies on electrophysiology (i.e., EEG, bispectral index, or somatosensory evoked potentials) or biomarkers (i.e., NSE and S-lOO~-protein). It should be noted that sedatives may hamper interpretation of EEG abnormalities but do not alter somatosensory evoked potentials [3]. However, somatosensory evoked potentials are too cumbersome to be used routinely. Serum levels of NSE and S-lOO~-protein are increased in septic shock and are higher in non-survivors [4], suggesting that brain cell damage is a deleterious phenomenon. The relationship between NSE or S-100~-prote in levels and the nature and extent of neuroradiologicallesions remains to be assessed (Fig. 2).

Investigations in Sepsis-associated Encephalopathy Once brain dysfunction has been detected, complementary investigations must be considered. Metabolic disturbances must be ruled out and, whenever possible, neurotoxic drugs discontinued or tapered. An EEG should be performed as it enables to detect a subtle status epilepticus, which is a treatable cause of encephalopathy. In sepsis-associated encephalopathy, the EEG may be normal or show excessive theta or predominantly delta and, but less frequently, triphasic waves or burst suppression, which are associated with increased mortality [2]. If meningitis is suspected, a lumbar puncture is required; the cerebrospinal fluid analysis is usually normal in sepsisassociated encephalopathy.

Encephalopathy in Sepsis Brain imaging is clearly indicated in cases of focal neurological signs or seizure. Otherwise, the risks and benefits of brain imaging should be assessed. If the patient is transportable, we believe that brain imaging deserves to be performed as it may reveal brain lesions, the ir type, nature, and extension. Such findings may guide treatment and care. In comparison to computed tomography (CT) scanning, MRI allows an accurate exploration of the brain, especially of the white matter and the BBB. MRI can reveal ischemic or hemorrhagic lesions [33), white matter lesions, including PRES [34) or leukoencephalopathy related to BBB breakdown and predominating around the Virchow-Robin spaces [33), as well as, but less frequently, gray matter lesions involving the basal ganglia and thalami [44).

Risk Factors and Outcome There is a correlation between the severity of sepsis and the incidence of encephalopathy. Liver dysfunction, renal failure, and Gram-negative infection have been identified as risk factors for encephalopathy in septic patients [1). Mortality related to sepsis-associated delirium varies from 16 when the GCS is 15, to 63 % when it is less than 8 [1). Mortality also increases with the severity of electrophysiological abnormalities [2) and with plasma levels of biomarkers [4). Alteration of the GCS was retained as an independent prognosis factor [1). More importantly, any physician is aware that persistent or relapsing encephalopathy often indicates uncontrolled sepsis . Sepsis-associated encephalopathy is considered reversible with recovery from sepsis but septic patients may develop long-term cognitive disturbances. However, the relationships between acute (encephalopathy) and chronic brain dysfunction (i.e., long-term cognitive and psychological disorders) in septic patients remain to be assessed. However, when considering the neuropathological and neuroradiological findings in these patients, such a link is likely. All these observations support the need to detect and explore encephalopathy in septic patients and to control sepsis .

Treatment of Sepsis-associated Encephalopathy With a lack of any specific therapeutic approach, treatment of sepsis-associated encephalopathy currently consists of control of sepsis, management of organ failure and metabolic disturbances, and avoidance of neurotoxic drugs. The pathogenic role of iNOS suggests that its inhibition could be beneficial. However, it has been shown that consciousness is not improved in septic rats treated with an iNOS-selective inhibitor while LPS-induced neuronal apoptosis is reduced [28]. Moreover, brain ischemia is aggravated [45) and cardiovascular deaths increased by NOS inhibition [46). Similarly, the anti-inflammatory and endothelial effects of activated protein C in sepsis and experimental brain ischemia are also appealing. However, there is no evidence from clinical trials that activated protein C reduces the incidence and severity of sepsis -associated encephalopathy. Finally, other therapeutic options include serum amyloid P or magnesium [47, 48), which have been shown to reduce BBB permeability in septic animals, and antioxidants, which possess neuroprotective properties [49).

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Conclusion Sepsis is frequently complicated by brain dysfunction, the clinical manifestation of which varies from confusion to coma and which increases the morbidity and mortality from sepsis. The diagnosis of sepsis-associated encephalopathy is, therefore, crucial and relies essentially on neurological examination. Electrophysiological testing, biochemical markers, and brain MRI may provide useful information. The mechanism of sepsis-associated delirium is highly complex. It involves both inflammatory and non-inflammatory processes that affect endothelial cells, glial cells, and neurons, and that induce BBB breakdown, dysfunction of intracellular metabolism, and cell death. Currently, the treatment of sepsis-associated encephalopathy consists mainly of control of sepsis. The incidence and severity of sepsis-associated encepha lopathy warrants researches on its physiopathology in order to develop specific treatments. References 1. Eidelman LA, Putterman D, Putterman C, Sprung CL (1996) The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA 275:470-473 2. Young GB, Bolton CF, Archibald YM, Austin TW, Wells GA (1992) The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol 9:145-152 3. Zauner C, Gendo A, Kramer L, et al (2002) Impaired subcortical and cortical sensory evoked potential pathways in septic patients. Crit Care Med 30:1136-1139 4. Nguyen DN, Spapen H, Su F,et al (2006) Elevated serum levels of S-100~ protein and neuron specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 34:1967 -1974 5. Tracey KJ (2002) The inflammatory reflex. Nature 420:853-859 6. Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42: 33-84 7. Sharshar T, Hopkinson NS, Orlikowski D, Annane D (2005) The brain in sepsis - culprit and victim. Crit Care 9:37- 44 8. Roth J, Harre EM, Rummel C, Gerstberger R, Hubschle T (2004) Signaling the brain in systemic inflammation: role of sensory circumventricular organs. Front Biosci 9:290-300 9. Lacroix S, Feinstein D, Rivest (1998) The bacterial endotoxin lipopolysaccharide has the ability to target the brain in upregulating its membrane CD14 receptor within specific cellular populations. Brain Pathol 8:625- 640 10. Breder CD, Hazuka C, Ghayur T, et al (1994) Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc Nat! Acad Sci USA 91:11393-11397 11. Galea E, Reis DJ, Feinstein DL (1994) Cloning and expression of inducible nitric oxide synthase from rat astrocytes. J Neurosci Res 37:406-414 12. Heyen JR, Ye S, Finck BN, Johnson RW (2000) Interieukin(IL) -lO inhibits IL-6 production in microglia by preventing activation of NF-kappaB. Brain Res Mol Brain Res 77:138-147 13. Fontana A, Kristensen F, Dubs R, Gemsa D, Weber E (1982) Production of prostaglandin E and an interleukin-l like factor by cultured astrocytes and C6 glioma cells. J Immunol 129: 2413-2419 14. Caggiano AO, Kraig RP (1999) Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide -induced interleukin-lbeta production. J Neurochern 72:565 - 575 15. Elmquist JK, Scammell TE, Saper CB (1997) Mechansims of CNS resposne to systemic immune challenge: the febrile response . Trends Neurosci 20:565- 570 16. Kadoi Y, Saito S, Kunimoto F, Imai T, Fujita T (1996) Impairment of the brain beta-adrenergic system during experimental endotoxemia . J Surg Res 61:496-502

Encephalopathy in Sepsis 17. Pavlov VA, Ochani M, Gallowitsch-Puerta M, et al (2006) Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Nat! Acad Sci USA 103:5219 - 5223 18. Ebersoldt M, Sharshar T, Annane D (2007) Sepsis-associated delirium. Intensive Care Med 33:941-950 19. Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED (2000) Pathophysiology of septic encephalopathy: a review. Crit Care Med 28:3019- 3024 20. Kim WG, Mohney RP, Wilson B, Ieohn GH, Liu B, Hong JS (2000) Regional difference in susceptibility to lipopolysaccharide neurotoxicity in the rat brain: role of microglia. J Neurosci 20:6309- 6316 21. Sharshar T, Gray F, Poron F, Raphael JC, Gajdos P, Annane D (2002) Multifocal necrotiz ing leukoencephalopathy in septic shock . Crit Care Med 30:2371- 2375 22. Barichello T, Fortunato 11, Vitali AM, et al (2006) Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med 34:886-889 23. Christians ES, Van LI, Benjamin II (2002) Heat shock factor 1 and heat shock proteins: crit ical partners in protection against acute cell injury. Crit Care Med 30:S43- 50 24. Chuang YC, Tsai JL, Chang AY, Chan IY, Liou CW, Chan SH (2002) Dysfunction of the mitochondrial respiratory chain in the rostral ventrolateral medulla during experimental endotoxemia in the rat. J Biomed Sci 9:542- 548 25. Chan JY, Chang AY, Wang LL, Ou CC, Chan SH (2007) Protein kinase Codependent mitochondrial translocation of proapoptotic protein Bax on activation of inducible nitric-oxide synthase in rostral ventrolateral medulla mediates cardiovascular depression during experimental endotoxemia. Mol Pharmacol 71:1129-1139 26. Messaris E, Memos N, Chatzigianni E, et al (2004) Time-dependent mitochondrial-mediated programmed neuronal cell death survival in sepsis. Crit Care Med 32:1764-1770 27. Sharshar T, Gray F, Lorin de la Grandmaison G, et al (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362:1799- 1805 28. Kadoi Y, Goto F (2004) Selective inducible nitric oxide inhibition can restore hemodynamics, but does not improve neurological dysfunction in experimentally-induced septic shock in rats . Anesth Analg 99:212- 220 29. Wong ML, Rettori V, al-Shekhlee A, et al (1996) Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nat Med 2:581- 584 30. Clawson CC, Hartmann JF, Vernier RL (1966) Electron microscopy of the effect of gram-negative endotox in on the blood-brain barrier. I Comp Neurol 127:183-198 31. Papadopoulos MC, Lamb FJ, Moss RF, Davies DC, Tighe D, Bennett ED (1999) Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex . Clin Sci (Lond) 96:461-466 32. Kafa 1M, Ari 1, Kurt MA (2007) The peri-microvascular edema in hippocampal CAl area in a rat model of sepsis. Neuropathology 27:213- 220 33. Sharshar T, Carlier R, Bernard F, et al (2007) Brain lesions in sept ic shock: a magnetic resonance imaging study. Intensive Care Med 33:798- 806 34. Bartynski WS, Boardman JF, Zeigler ZR, Shadduck RK, Lister J (2006) Posterior reversible encephalopathy syndrome in infection, sepsis, and shock . AINR Am I Neuroradiol 27: 2179-2190 35. Sharshar T, Annane D, de la Grandmaison G, Brouland IP, Hopkinson NS, Gray F (2004) The neuropathology of septic shock. Brain Pathol 14:21 - 33 36. Pedersen M, Brandt CT, Knudsen GM, et al (2007) The effect of S. pneumoniae bacteremia on cerebral blood flow autoregulation in rats. J Cereb Blood Flow Metab 13:13 37. Mori F, Nishie M, Houzen H, Yamaguchi J, Wakabayashi K (2006) Hypoglycemic encephalopathy with extensive lesions in the cerebral white matter. Neuropathology 26:147-152 38. Sprung CL, Cerra FB, Freund HR, et al (1991) Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med 19:753-757 39. Monfort P, Munoz MD, EIAyadi A, Kosenko E, Felipo V (2002) Effects of hyperammonemia and liver failure on glutamatergic neurotransmission. Metab Brain Dis 17:237- 250 40. Ely EW, Inouye SK, Bernard GR, et al (2001) Delirium in mechanically ventilated patients. Validity and reliability of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). JAMA 286:2703-2710

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A. Polito, S. Siami, and T. Sharshar 41. de [onghe B, Cook D, Griffith L, et al (2003) Adaptation to the Intensive Care Environment (ATICE): development and validation of a new sedation assessment instrument. Crit Care Med 31:2344-2354 42. Ely EW, Truman B, Manzi DJ, Sigl JC, Shintani A, Bernard GR (2004) Consciousness monitoring in ventilated patients: bispectral EEG monitors arousal not delirium . Intensive Care Med 30:1537-1543 43. Piazza 0, Russo E, Cotena S, Esposito G, Tufano R (2007) Elevated S100B levels do not correlate with the severity of encephalopathy during sepsis. Br J Anaesth 24:24 44. Finelli PF, Uphoff DF (2004) Magnetic resonance imaging abnormalities with septic encephalopathy. J Neurol Neurosurg Psychiatry 75:1189-1191 45. Li H, Forstermann U (2000) Nitric oxide in the pathogenesis of vascular disease. J Pathol 190:244 - 254 46. Lopez A, Lorente JA, Steingrub J, et al (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32:21- 30 47. Veszelka S, Urbanyi Z, Pazmany T, et al (2003) Human serum amyloid P component attenuates the bacterial lipopolysaccharide-induced increase in blood-brain barrier permeability in mice. Neurosci Lett 352:57-60 48. Esen F, Erdem T, Aktan D, et al (2005) Effect of magnesium sulfate administration on bloodbrain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. Crit Care 9:RI8-23 49. Huang M, Liu W, Li Q, Wu CF (2002) Endogenous released ascorbic acid suppresses ethanolinduced hydroxyl radical production in rat striatum. Brain Res 944:90- 96

811

Multimodality Monitoring in Patients with Elevated Intracranial Pressure D.B. SEDER, r.M. SCHMIDT, and S.A. MAYER

Introduction Conventional paradigms for the management of elevated intracranial pressure (ICP) are in many ways imperfect. Clinicians respond to increases in ICP, or to worsening of the clinical neurological examination, after critical thresholds of brain ischemia have been crossed, at a point when irreversible injury may have already occurred and the window of opportunity for therapeutic intervention has closed. Even with the benefit of direct ICP monitoring, the true biochemical environment of the brain is unknown, so that measurable changes in blood pressure, cerebral perfusion pressure (CPP), circulating blood volume and rheology, blood oxygen and glucose levels, and other clinical parameters result in uncertain global or regional effects in areas of the brain at risk. The goal of multimodality monitoring is to titrate clinical therapy at the bedside to foster a biochemical environment that favors preservation of function and healing within the brain - a proactive, in place of a reactive, approach. This chapter suggests different ways in which ICP, brain tissue and jugular bulb oxygen content, microdialysis, continuous electroencephalography (EEG), and transcranial Doppler ultrasound data can be integrated into a practical management algorithm for patients with elevated ICP.

CPP is the Most Important Hemodynamic Parameter to Consider in the Treatment of Elevated ICP Because the intracranial compartment is of fixed volume, ICP increases exponen tially once added volume overwhelms the modest buffering capacity afforded by an extra cranial shift of cerebrospinal fluid (CSF) and venous blood. This increase in volume may result from global injury, such as cerebral edema after cardiac arrest or hepatic failure, or focal injury, such as hemorrhage, contusion, or tumor. The initial neurological injury can then be exacerbated and compounded by physiological derangements such as fever, hyper- or hypoglycemia, hypoxia, or hyponatremia, resulting in secondary injury in the hours and days after the original insult. As injury progresses, regional or global elevation of ICP may lead to tissue compression and ischemia, a downward spiral in which elevated ICP causes ischemia, provoking edema and infarction, which serve to increase ICP further. Early recognition of this deter ioration, before it becomes clinically apparent, is necessary, so that the injurious processes may be arrested, and intracranial homeostasis restored. Existing management paradigms for elevated ICP revolve around the critical concept of maintaining cerebral blood flow (CBF) to damaged tissues by attaining CPP

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goals. CPP is the primary determinant of CBF, defined by the equation CPP = mean arterial pressure (MAP)-ICP, and is a highly practical parameter against which common therapies like fluids, vasopressors, and osmotic diuretics can be titrated. Under conditions of reduced intracranial compliance, when CPP is inadequate, reflex cerebral vasodilation and globally increased cerebral blood volume (CBV) can lead to further increases in ICP (Fig. 1). These increases in Iep are based on 'vasodilatory cascade' physiology and can lead to a fatal increase in pressure if sustained. Treatment of this situation requires elevation of MAP and CPP. At the other extreme, excessive CPP in the setting of cerebral autoregulatory dysfunction can directly cause hyperemia and passive increases in CBV via hydrostatic forces. In this setting of 'perfusion pressure breakthrough', increased ICP can be treated by carefully reducing MAP and CPP. Thus, CPP optimization is a cornerstone of stepwise interventions for elevated ICP in monitored patients (Table 1). Table 1.Stepwise treatment protocol for elevated intracranial pressure (lCp' > 20 mmHg for > 10 minutes) in a monitored patient. From [1] with permission 1. Surgical decompression. Consider repeat Q scanning, and definitive surgical intervention or ventricular drainage 2. Sedation. Intravenous sedation to attain a motionless, quiet state 3. CPP optimization. Pressor infusion if CPP < 70 mmHg, or reduction of blood pressure if CPP is > 110 mmHg, 4. Osmotherapy. Mannitol 25-1.5 g/kg i.v, (repeat every 1-6 h as needed) 5. Hyperventilation. Target PC0 2 levels of 28 - 32 mmHg. 6. High dose pentobarbital therapy. Load with 5- 20 mg/kg, infuse 1- 4 mg/kg/hr. 7. Hypothermia. Cool core body temperature to 32 - 33 0(, Q : computed tomography; CPP: cerebral perfusion pressure

Multimodality Monitoring in Patients with Elevated Intracranial Pressure

Excessive MAP and CPP also results in increased left ventricular (LV) afterload, which can cause pulmonary congestion, oxygenation deficits, and reduced cardiac output, particularly when LV performance is already impaired at baseline or due to neurogenic myocardial stunning. Clinicians often strive to find the optimal CPP range through trial and error, titrating diverse factors such as ICP, cardiopulmonary status , and the neurological examinat ion. Unfortunately, improvement in hemodynamic parameters and notable changes in the neurological examination are insensitive endpoints. Changes in the neurological examination may be subtle or undetectable, and may be unrelated to CPP. Furthermore , hemodynamic parameters are insensitive measures of regional brain homeostasis. The brain is a heterogeneous environment in which one compartment or region may benefit from an increase in CPP, while another suffers from the same intervention. Furthermore, although critically important, CPP is only one piece of the homeostatic puzzle, where factors such as blood rheology, serum osmotic pressure, glucose and oxygen levels, and the systemic inflammatory state influence ongoing neuronal injur y and survival. Into this uncertainty, multimodality monitoring offers biochemical and electrical measurements which may allow for the earlier identification of problems, and faster, more accurate interventions to preserve a favorable biochemical milieu.

The ICP Waveform is a Reflection of Intracranial Compliance While knowing the absolute ICP is critically important for CPP calculations, the morphology of the ICP waveform has its own diagnostic importance. It is well known that the relationship between brain volume and ICP is parabolic, so that as volume increases toward a critical point, intracranial compliance decreases, and the increase in pressure per unit of volume becomes enormous (Fig. 2). This critical decrease in intracranial compliance is reflected in the ICP waveform. Under normal circum stances , arterial pulse pressure causes a small variation in intracranial blood volume, resulting in an ICP waveform with 2- 3 mmHg pressure variation between systole and diastole (Fig. 3). The normal waveform is characterized by PI, P2, and P3 components, with a progressive decrease in the size of each element. When intracranial compliance is low, however, the systolic increase in arte rial blood volume results in an increase in rcp pulse pressure (the quantitative difference between systole and diastole), as well as a change in morphology of the waveform, in which the second peak exceeds the first. A rising ICP pulse pressure, and a progressive increase in the P2-to-Pl ratio of the ICP waveform are strong indi-

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cations of critically reduced intracranial compliance, and clinicians should be aware that ischemia, hyperemia, fever, patient repositioning, or decreasing serum osmolarity at this juncture may result in critically high ICP, and potentially in brain herniation.

Lundberg A (Plateau) Waves Require Treatment with CPP Augmentation Lundberg A waves (plateau waves), are sudden increases in ICP of 20-100 mmHg, that last for minutes to hours, causing reduced CBF/CPP and brain ischemia. Lundberg B waves are smaller increases, usually of 5- 20 mmHg, lasting 1- 5 minutes, and characterized by a sharpened waveform. Both are markers of critically low intracranial compliance, and probably result from a spiral of tissue hypoperfusion, progressive arteriolar dilation, and increased CBV, which worsens ICP and feeds back to exacerbate the initial problem of hypoperfusion. The cycle can be ultimately broken by a sympathetic-mediated blood pressure surge known as the 'termination spike', which serves to restore CPP and break the cycle of progressive cerebral vasodilation [1]. Lundberg A waves should be treated aggressively by increasing CPP with vasopressors , and decreasing ICP with osmotic diuretics and hyperventilation.

Jugular Venous Oxygen Saturation is a Measure of the Adequacy of Cerebral Blood Flow and Cerebral Metabolic Activity Jugular venous oxygen saturation (Sjv0 2) monitoring is a method of evaluating the metabolic activity of the brain and the adequacy of CBF. Sjv0 2 is measured by an oximetric catheter inserted into the dominant internal jugular vein and positioned at the level of the jugular bulb. Sjv0 2 is a product of CBF, arterial oxygen content, and the cerebral metabolic rate. Its measurement allows for calculation of the arteriovenous oxygen difference (AVD02 ) . Like the systemic mixed venous oxygen saturation (SV02)' AVD02 widens either when CBF decreases or cellular metabolism increases, and narrows either when cellular metabolic activity decreases, or blood flow increases. The reliability of AVD02 is affected by changes in arterial oxygen content, the hemoglobin dissociation curve, and by hemodilution, but when these

Multimodality Monitoring in Patients with Elevated Intracranial Pressure

variables are constant, Sjv0 2 can reflect global supply-demand relationships between cerebral metabolism and blood flow. Specifically, AVD02 reflects CBF in relation to the cerebral metabolic rate for oxygen (CMR0 2). For patients with elevated ICP, Sjv0 2 monitoring should be interpreted in conjunction with direct ICP monitoring. When SjV02 drops below the threshold value of 55 % in the setting of elevated ICP, or when a trend of desaturation is identified, clinicians should first verify calibration of the device, a steady state of arterial oxygen content, systemic metabolic conditions, and intravascular volume status, and then determine whether oxyhemoglobin desaturation is due to low CPP, or to an increase in the CMR0 2. Low CPP causes low SjV02 because a longer transit time through the cerebral circulation leads to increased oxygen extraction at the tissue level, and can be corrected by increasing CPP through the use of fluids and vasopressor medications. If the CPP is adequate, then the possibility of increased CMR0 2 and its etiology should be considered. Common causes of increased CMR0 2 include fever, infection, seizure activity, shivering, and pain or agitation. Conversely, SjV02 above 75 % in the setting of high ICP should alert clinicians to the possibilities of decreased cerebral cellular metabolic activity, or to poor cerebral oxygen due to excessive flow [2]. Decreased cerebral metabolism is expected when patients are kept deeply sedated or hypothermic, but when Sjv0 2 rises without cause, clinicians should be alert to the possibility of neuronal cellular dysfunction commonly ischemia and a corresponding inability to extract oxygen. At high CPP, in the setting of impaired cerebral autoregulation, high rates of flow and pressure in the cerebral vasculature causes effective arteriovenous shunting, and are likely to drive ICP upward. SjV02 monitoring is recommended in patients with elevated ICP as an indirect method of evaluating the cerebral metabolic rate and adequacy of CPP. Advantages of Sjv0 2 monitoring include extensive collective experience in the neurocritical care community, low associated morbidity, and the availability of continuous data to guide clinicians at the bedside . The primary disadvantage is that dramatic changes in metabolism and blood flow must occur to affect the cerebral blood pool, making the technique insensitive to smaller local ischemic processes that still may be critical [31 .

Brain Tissue Oxygen Tension Reflects Local Brain Oxygen Supply and Demand in the Region of Catheter Placement Unlike Sjv0 2, which is an indirect and global measure of the cerebral metabolic environment, brain oxygen tens ion (Pbr0 2) is directly measured by an invasive catheter placed through a craniotomy, or through a multi-lumen bolt into an area of brain identified by clinicians to be at risk. This precise placement of the Pbr0 2 catheter is both the strength and weakness of the technique: The technology allows for highly sensitive monito ring of just less than 20 mm- of brain tissue. Thus, if the device is placed exactly within the area of interest, or if the area of placement reflects global conditions, then the probe is a sensitive measure of changes in tissue perfusion. Conversely, if the probe is outs ide of or isolated from a region of ischemia or dysmetabolism, then brain hypoxia will go undetected. Two commercially available devices allow for direct measurement of Pbr0 2. The Licox" device (Integra Neurosciences) measures tissue oxygenation using a Clark electrode, while the Neuro'Irend" (Codman, Johnson & Johnson) measures Pbr02' PbrC0 2, and pH using optical luminescence. Normal Pbr02 levels are typically

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Fig. 4. Real-time relationship of the physiological parameters, brain oxygen tension (PbrOz), cerebral perfusion pressure (CPP), and intracranial pressure (lCP) over 2 hours in a patient with intracerebral hemorrhage complicated by intracranial hypertension. Note the striking parallel relationship between PbrO z and CPp, indicative of autoregulatory failure. From [28] with permission

greater than 35 mmHg in the gray matter, and 20 mmHg in the white matter, but normal PbrOz varies regionally in the brain [4]. PbrOz levels of 8-25 mmHg have correlated with cerebral ischemia on single photon emission computed tomography (SPECT) scan and with SjvOz levels less than 50 % [5], and PbrOz levels persistently below 25 mmHg are associated with a poor neurological outcome [6]. PbrOz is a useful tool for the identification of regional ischemia, vasospasm, and the loss of vasomotor autoregulation (Fig. 4). One group of investigators used PbrOz > 25 mmHg as a secondary target for cerebral resuscitation in patients with severe traumatic brain injury (TBI), treating low PbrO, by increasing arterial oxygen tension, infusing fluids, red blood cells, and vasopressors, and aggressively treating fever, pain , and seizures . With this strategy, they found a trend toward better outcomes than patients in whom the standard resuscitation endpoints of ICP < 20 mmHg and CPP > 60 mmHg [7] were utilized. The same group has demonstrated that during early resuscitation after TBI, a significant number of patients in whom CPP and ICP goals are met continue to experi ence low PbrOz, and are at high risk of poor outcome [8]. Other investigators have recently demonstrated that if the PbrOz changes in tan dem with CPP, cerebral vasomotor autoregulation has been lost [9]. These investiga tors showed that a cerebral pressure-oxygen-reactivity index (COR) in the setting of malignant middle cerebral artery (MCA) infarction identified patients with impaired autoregulation at risk for hyper- or hypoperfusion. They calculated: %t.Pbr0 2 / %t.CPP = COR index

where the t.Pbr0 2 and t.CPP are the mean values during an early 30 min period of stable hemodynamics, ventilatory parameters, and microdialysis markers of cerebral ischemia [9]. Also predictive of failed autoregulation was an increased correlation coefficient between Pbrt) , and CPP.

Multimodality Monitoring in Patients with Elevated Intracranial Pressure

Because of consistently poor outcomes in patients with sustained PbrO, < 25 mmHg, maintaining the PbrOz above that threshold may be an important goal of cerebral resuscitation in patients with elevated ICP. Low PbrOz should provoke computed tomography (CT) evaluation of catheter placement if its location is unknown, and clinicians should then evaluate the response of PbrOz to an increase in inspired fraction of oxygen (FiOz), which indicates that the probe is functional. Whether simply maintaining an increased FiOz to correct reduced PbrOz levels is the equivalent of doing so by raising CPP and CBF is a topic of intense controversy. In our view, hemodynamic interventions using fluids and vasopressors should take precedence, as well as treatment of pain, fever, seizures or shivering, all of which can increase the rate of cerebral oxygen consumption. Finally, if PbrOz remains low, clinicians may consider the transfusion of red blood cells to a hemoglobin of 10.0g/dl, or a definitive surgical intervention such as decompressive craniectomy.

Microdialysis Technology Allows For Direct Evaluation of the Cerebral Biochemical Environment Some of the most compelling multimodality data relate to micro dialysis technology, which has the ability to directly measure levels of small soluble molecules in the extracellular matrix of the brain. The micro dialysis catheter is a semipermeable membrane, 0.62 mm in width, and is surgically inserted through a craniotomy and perfused with Ringer's or saline solution. Molecules less than 20,000 Da in size diffuse into the diasylate, and the fluid can be removed and analyzed at regular intervals. Solutes commonly measured for clinical purposes include glucose, glutamate, lactate, pyruvate, and glycerol; acetylcholine, choline, cytokines, antibiotics, anticonvulsans, and others can also be measured for research purposes. Like PbrOz technology, the recovery of useful information depends upon well-considered probe placement into an area of brain at risk, but unlike PbrOz technology, micro dialysis is a high maintenance endeavor requiring regular calibration, upkeep, and analysis at the bedside. The reward for this level of attention is real-time knowledge of the biochemistry of the brain. Microdialysis technology has clear and extensive research applications, and despite its labor-intensive nature, is useful at the bedside to direct the management of comatose patients with elevated ICP. Most helpful in clinical practice is the routine measurement of lactate and pyruvate, the ratio (LPR) of which is diagnostic of tissue ischemia and glycolytic metabolism [10], and has been shown to remain elevated around contusions in TEI despite the maintenance of 'adequate' CPP [11]. The normal range of this ratio is below 20, with levels above 40 strongly suggesting anaerobic metabolism and ischemia. Glutamate, released by ischemic neurons somewhat later in the metabolic cascade of ischemia, is another molecule which suggests active ischemia. Glutamate levels may rise from a mean value of 16 umol/l (normal) to 380 umol/l when neuronal membranes are disrupted [12] . Because brain glucose concentration is affected by many factors, the interpretation of and response to abnormal brain glucose levels can be challenging. Brain glucose levels respond to CBF, the systemic glucose level, insulin administration, and cellular metabolism, perfusion and glucose uptake. Normal brain glucose is widely variable, from 1000 to 4000 umol/l, Low brain glucose in TEI is associated with poor outcome [13], and low brain glucose in all should be addressed acutely by considering and treating the serum glucose level, evaluating the adequacy of CBF, and then addressing metabolic factors which might influence cellular glucose uptake and utilization.

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Continuous Electroencephalography Detects Subclinical Seizure Activity and Reveals Changes in Regional Brain Metabolic Activity in Real Time Continuous EEG monitoring is widely used in the intensive care unit (lCU) for the detection of non-convulsive seizures, for electrical characterization of 'spells' in patients with physical examination findings concerning for seizure activity, to assess the level of consciousness during sedation and paralysis, for the detection of ischemia in subarachnoid hemorrhage and for prognostication [14]. Because risk factors for seizures in the neurological lCU are similar to the causes of elevated lCP, there is significant overlap. Comatose patients with elevated lCP of any cause are at high risk for the development of subclinical seizures; the most important causes of seizures in the neurological lCU are stroke, trauma epilepsy, intracranial infection, tumor, neurosurgery, and hypoxic-ischemic encephalopathy [15]. Unless the patient is able to follow verbal commands, seizures are common enough in stuporous or comatose patients with elevated rcp that surveillance continuous EEG monitoring should be instituted for 24-48 hours [15, 16]. Regardless of the specific disease process, the yield of this strategy for detecting subclinical seizures or status is approximately 20 % [15]. Seizures are a well-described cause of acutely elevated lCP [17], probably due to neurotransmitter-mediated excitotoxicity and cytotoxic edema. One series of patients with intracerebral hemorrhage monitored with continuous EEG revealed an overall incidence of seizures of 28 %, and seizures were associated both with poor outcome and with increased midline shift, suggesting deleterious effects on intracranial volume and pressure [18]. Although not dramatic in nature, and as yet poorly characterized in terms of bedside utility, EEGslowing which is focal or acute in nature should be considered an acute event, and clinicians should seek an explanation for changes in the electrical baseline. Focal changes in EEG activity may relate to hemorrhage, ischemia, thrombosis, infarction, or other pathology, and should be responded to by clinicians at the bedside. Signal-processed graphical continuous EEG display of the alpha-delta ratio, total power, and other derivatives is an increasingly useful modality for demonstrating functional changes in brain electrical activity that van correlate with ischemia and injury.

Transcranial Doppler Ultrasound Allows for Bedside Assessment of Intracranial Pressure, Vascular Tone, Blood Flow, and Autoregulatory Reserves Although widely used for intermittent examinations, transcranial Doppler ultrasound technology is generally limited by the lack of continuous data output and the need for skilled and experienced technicians. Nonetheless, transcranial Doppler ultrasound is a versatile tool with many potential uses in the intensive care of patients with elevated rCp. Multiple investigators have suggested a role for transcranial Doppler ultrasound in non-invasive lCP monitoring and, for patients in whom invasive lCP monitoring is contraindicated, tissue resonance analysis (TRA) can provide adequate intermittent assessment of rcp based on the ultrasound-derived transcranial waveform [19]. TRA has also been used to detect unilateral mass effect in intracerebral hemorrhages greater than 25 ml in volume [20]. The cerebrovascular flow response to decreased [21] or to increased carbon dioxide levels [22] can be used to assess autoregulatory reserves, but caution should be

Multimodality Monitoring in Patients with Elevated Intracranial Pressure

employed in pat ients with poor intracranial compliance, who may experience a harmful rise in ICP after COz adm inistration. Alternatively, evaluation of cerebral autoregulation can be evaluated by various techniques such as looking for phase shift in MCA flow during respiratory and arterial blood pressure waves [23], by evaluating the CBF respon se to leg cuff decompression [24], or by evaluating for increased ispilateral MCA blood flow after the initial decrease caused by carotid compression [25].

Putting it all Together: Advanced Neuromonitoring Allows Clinicians to Identify and Respond to Events in the Brain Before Irreversible Damage Occurs Invasive ICP monitoring is the standard of care for patients with radiological evidence of intracranial mass effect who are comatose (Glasgow coma scale [GCS] :5 8), and whose prognosis supports aggressive treatment. In these patients, maintenance of adequate CPP is critical in preventing the spiral of ischemia and vasodilation which can cause lethal increases in ICP. CPP goals have traditionally been titrated to the neurological examination, but because the neurological examination is insensitive to subtle changes in the microenvironment of the brain, newer technologies which monitor cerebral metabolism, electrical activity, and subtle markers of ischemia should be employed. As each pat ient with elevated ICP is admitted to the neurological ICU, clinicians should make thoughtful decisions about monitoring goals, and tailor an individualized multimodali ty monitoring approach, based on the unique pathophysiology, risks, and prognosis of the disease, as well as the expertise and technology available to the clinician . The fundamental goal of advanced neuromonitoring is to detect and treat secondary neurological injury or deterioration prior to the development of permanent deficits. Figure 5 suggests an updated algorithm for the initial management of coma based on the fundamental principle of early recognition of hypoperfusion using multimodality monitoring techniques. Table 2 presents a suggested algorithm for the treatment of acute brain tissue perfu sion failure as detected by SjvOz, PbrOz, or microdialysis in comatose patients undergoing combined multimodality and conventional ICP monitoring. Table 2. Management algorithm for multimodality evidence of brain tissue perfusion failure Ougular venous oxygen saturation [Sjv0 2] < 55 %, brain oxygen tension [Pbr0 2] < 25 mm Hg, or lactate/pyruvate ratio > 40) 1. Verify/corroborate data source 2. Treat pain, anxiety/agitation, autonomic 'storm; fever, shivering 3. Verify CVP > 8, CPP> 70, Pa0 2> 100 mmHg, and pH 7.35-7 .45 4. Reduce ICP if > 20 mmHg with osmotherapy and hyperventilation 5. Consider repeat imaging to evaluate for anatomical change 5. Increase CPP by 20% and watch for improvement in parameter of concern 7. Consider measures to reduce cerebral metabolic rate: pentobarbital, hypothermia 8. Reconsider surgical options for decompression CVP: central venous pressure; CPP: cerebral perfusion pressure; ICP: intracranial pressure

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Early empiric management of ICP • Head elevation • Mannitol 1.0 - ,.5 g/kg • Hyperventilate to PC0230 mm Hg Stat head CT

Global brain injury · TBI • Hypoxic-ischemic injury .4• SAH • Other

1

j -

--''----

_

Focal brain inj ury ·IC H • Infarction • Neoplasm • Other

1

Consider Monitori ng algorith m: Monitoring algorit hm: EVDor • Invasive ICP • Invasive ICP --+ neurosurgical +-• SjV0 2or Pbr0 2 • Pbr0 2 • Microdialysis • Microdialysis interventio n

cEEG x 24 - 48h

Monitor neuro exam wit h serialsedative interruptions

Fig. 5. Suggested algorithm for the initial evaluation and management of coma with elevated intracranial

pressure (ICP). GCS: Glasgow Coma Scale; 181: traumatic brain injury; SAH: subarachnoid hemorrhage; ICH: intracerebral hemorrhage; EVO: external ventricular drain; Sjv02: jugular vein oxygen saturation; Pbr02: brain oxygen tension; cEEG: continuous electroencephalography

References 1. Mayer SA, Chong JY (2002) Critical care management of increased intracranial pressure. J

Intensive Care Med 17:55-67 2. Cormio M, Valadka AB, Robertson CS (1999) Elevated jugular venous oxygen saturation after severe head injury. J Neurosurg 90:9-15 3. White H, Baker A (2002) Continuous jugular venous oximetry in the neurointensive care unita brief review. Can J Anaesth 49:623 - 629 4. Sarrafzadeh AS, Kiening KL, Unterberg AW (2003) Neuromonitoring: brain oxygenation and micro dialysis. CUff Neurol Neurosci Rep 3:517- 523 5. Gopinath SP, Valadka AB, Uzura M, Robertson CS (1997) Comparison of jugular venous oxygen saturation and brain tissue P02 as monitors of cerebral ischemia after head injury. Crit Care Med 27:2337- 2345 6. Zauner A, Doppenberg EM, Woodward n, Choi SC, Young HF, Bullock R (1997) Continuous monitoring of cerebral substrate delivery and clearance: initial experience in 24 patients with severe acute brain injuries. Neurosurgery 41:1082-1091 7. Steifel MF, Spiotta AM, Gracias VH, et al (2005) Reduced mortality in patients with severe traumatic brain injury in patients treated with brain tissue oxygen mon itoring . J Neurosurg 103:805-811 8. Steifel MF, Udoetuk JD, Spiotta AM, et al (2006) Conventional neurocritical care and cerebral oxygenation after traumatic brain injury. J Neurosurg 105:568-575 9. Dohmen C, Bosche B, Graf R et al (2007) Identification and clinical impact of impaired cerebrovascular autoregulation in patients with malignant middle cerebral artery infarction. Stroke 38:56-61

Multimodality Monitoring in Patients with Elevated Intracranial Pressure 10. Goodman JC, Valadka AB, Gopinath SP, et al (1999) Extracellular lactate and glucose concentrations in the brain after head injury measured by microdialysis . Crit Care Med 27: 1965-1973 11. Vespa PM, O'Phelan K, McArthur D, et al (2007) Pericontusional brain tissue exhibits persis 12. 13. 14. 15.

tent elevation of lactate/pyruvate ratio independent of cerebral perfusion pressure. Crit Care Med 35:1153-1160 Bellander BM, Cantais E, Enblad P, et al (2004) Consensus meeting on microdialysis in neurocritical care. Intens ive Care Med 30:2166-2169 Vespa PM, McArthur D, O'Phelan K, et al (2003) Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysi s study. J Cereb Blood Flow Metab 23:865 - 877 Wartenberg KE, Schmidt M, Mayer SA (2007) Multimodality monitoring in neurocritical care. Crit Care Clin 23:507- 538 Claassen I. Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ (2004) Detection of electrophysiologic seizures with continuous EEG monitoring in critically ill patients. Neurology

62:1743 -1 748 16. Jordan KG (1995) Neurophysiologic monitoring in the neuroscience intensive care unit. Neurol Clin 13:579-626 17. Gabor AJ, Brooks AG, Scobey RP, et al (1984) Intrac ranial pressure during epileptic seizures. Electroencephalogr Clin Neurophysiol 57:497 - 506 18. Vespa PM, O'Phelan K, Shah M, et al (2003) Acute seizures after intracerebral hemorrhage: A factor in progressive midline shift and outcome . Neurology 60:1441-1446 19. Michaeli D; Rappaport ZH (2002) Tissue resonance analysis; a novel method for noninvasive monitoring of intracranial pressure . J Neurosurg 96:1132- 1137 20. Mayer SA, Thomas CE, Diamond BE (1996) Assymmetry of intracranial hemodynamics as an

indicator of mass effect in acute intracranial hemorrhage. A transcranial doppler study. Stroke 27:1788-1792 21. Coles JP, Minhas PS, Fryer TD, et al (2002) Effect of hyperventilation on cerebral blood flow in traumatic head injur y: clinical relevance and monitoring correlates . Crit Care Med 30:2619 - 2625 22. Steiger HI. Aaslid R, Stooss R, Seiler RW (1994) Transcranial doppler mon itoring in head 23. 24. 25. 26. 27. 28.

injury: relations between type of injury, flow velocity, vasoreactivity, and outcome. Neurosurgery 34:79 - 85 Diehl RR, Linden D, Lucke D, Berlit P (1995) Phase relationship between cerebral blood flow velocity and blood pressure. A clinical test of autoregulation. Stroke 26:1801-1804 Tieks FP, Lam AM, Aaslid R, Newell DW (1995 ) Comparison of static and dynamic cerebral autoregulation measurements. Stroke 26:1014-1019 Smielewski P, Czosnyka M, Kirpatrick P, Pickard JD (1997) Evaluation of the transient hyperemic response test in head-injured patients. J Neurosurg 86:773- 778 Rose JC, Mayer SA (2004) Optimizing blood pressure in neurological emergencies. Neurocrit Care 1:287 - 299 Wijdicks EFM (2003) The Clinical Practice of Critical Care Neurology. Oxford University Press, New York Wartenberg KE,Schmidt JM, Krieger DW (2006) The future of the brain support: Multimoda lity monitoring. Futur e Neurology 1:465-488

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Managing Critically III Patients with Status Epilepticus s. LEGRIEL, J.P. BED OS,

and E.

AZOULAY

Introduction Status epilepticus is a major medical emergency that is fatal in 7.6- 22 % of cases [1, 2]. The incidence per 100,000 population has been estimated at 9.9 episodes in Europe and 41 episodes in the USA [2]. Status epilepticus is a clinical and electrical entity in which the broad spectrum of clinical presentations may lead to over- or underdiagnosis. Status epilepticus may be convulsive, i.e., accompanied by motor activity, or nonconvulsive. Continuous or repeated electrical seizures without recovery of consciousness characterizes both forms of status epilepticus. Morbidity and mortality rates differ between convulsive and nonconvulsive status epilepticus, and each requires a specific treatment strategy. Knowledge of the current definition and electroclinical classification of status epilepticus, as well as familiarity with differential diagnoses, is essential to ensure appropriate treatment.

Diagnosis of Status Epilepticus Definitions Convulsive status epilepticus The working (operational) definition of convulsive status epilepticus proposed by Lowenstein et al. in 1999 [3] remains widely accepted, despite some degree of controversy. This definition was developed pragmatically based on findings from clinical and experimental studies [4]. Video-electroencephalographic (EEG) recordings have established that simple convulsive seizures have a mean duration of only 2 minutes, although longer durations of up to 11 minutes are observed occasionally [5]. As seizure duration increases, the likelihood of spontaneous resolution decreases, most notably beyond 30 min [6]. Seizures longer than 30 min are associated with a high rate of refractoriness to antiepileptic drugs [7] and with the development of neuronal damage. Therefore, a key treatment objective is to achieve seizure resolution within 30 minutes. There is a consensus that seizures lasting longer than 30 min constitute established status epilepticus [4]. A useful strategy focuses on imminent convulsive status epilepticus [4], defined as continuous seizures for longer than 5 min or three seizures not separated by recovery of normal consciousness or of the level of consciousness present before the seizures [1, 4]. Nonconvulsive status epilepticus The definition of nonconvulsive status epilepticus is actively debated. Members of an international workshop held by the Epilepsy Research Foundation [8] agreed on

Managing Critically III Patients with Status Epilepticus

a somewhat vague definition of nonconvulsive status epilepticus as "a range of conditions in which electrographic seizure activity is prolonged and results in nonconvulsive clinical symptoms". The electrographic seizure activity must meet complex electrophysiological criteria, among which some are defined clearly and others must be interpreted according to the clinical setting [8, 9). Because a working definition was needed, the workshop members agreed to include electrographic seizure activity for 30 min in the definition of nonconvulsive status epilepticus [8).

Classification The many definitions of status epilepticus in the literature vary according to whether the underlying approach was epidemiological, clinical, or electrophysiological [10). The result is considerable confusion. Ideally, all available parameters would be incorporated into a definition allowing clinicians in all relevant fields (emergency medicine, critical care, and neurology) to promptly determine the type of status epilepticus so that appropriate treatment can be initiated within the timeframe dictated by the prognosis of the specific type of status epilepticus type in any patient. The most widely accepted classification scheme distinguishes between convulsive status epilepticus, which is usually easy to recognize on clinical grounds, and nonconvulsive status epilepticus, in which the symptoms may be minimal and the role

Statusepilepticus

Nonconvulsive

t

Partial motor

l

Tonic-Clonic

!

l

+

l

Tonic

Myoclonic

Clonic

!

Generalized

!

!

Fig. 1. Classification of convulsive status epilepticus

Convulsive

Nonconvulsive

l Absence

Complex partial

Electrical

t

Subtle

Fig. 2. Classification of nonconvulsive status epilepticus

+

Coma

Partial simple

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for EEG is preponderant [11]. Subgroups are described within each of these two main categories. Thus, the motor activity in convulsive status epilepticus may consist of partial tonic-clonic seizures or of generalized seizures with tonic-clonic, tonic, clonic, or myoclonic activity (Fig. 1). Patterns of nonconvulsive status epilepticus include absence status epilepticus, complex partial status epilepticus, and electrical status epilepticus (including subtle status epilepticus) (Fig. 2).

Differential Diagnoses Pseudo-status epilepticus Pseudo-epileptic seizure is defined as paroxysmal motor or behavioral symptoms that simulate an epileptic seizure in the absence of detectable electrical seizure activity or bra in lesions [12]. The incidence of pseudo-epileptic seizure in patients with known epilepsy is about 15 %. Prolonged episodes of pseudo-epileptic seizure define pseudo-status epilepticus, which mimics status epilepticus. Of 85 patients with pseudo-epileptic seizures, 77.6 % reported at least one episode of pseudo-status epilepticus > 30 mins, and 27 % ICU admission for pseudo-status epilepticus [13]. Pseudo-status epilepticus may be misdiagnosed as refractory status epilepticus, which may lead to mechanical ventilation [14] and death. Distinctive features of pseudo-status epilepticus mimicking generalized convulsive status epilepticus have been identified . Anticonvulsant dosage requirements are higher than in refractory status epilepticus, and the time to induced respiratory depression is longer [15]. Eye opening and closing may be the best clinical feature for differentiating pseudo -status epilepticus from status epilepticus, although most studies focused on seizures as opposed to status. Eye opening is the rule during epileptic seizures (positive predictive value [PPV], 97 %), whereas the eyes are closed in most pseudo-epileptic seizures (PPV, 94.3 %) [16]. The serum creatine phosphokinase level may be normal in pseudo -status epilepticus [15], contrasting with the increase from 3 to 36 hours seen in convulsive status epilepticus. Elevated serum prolactin helps to differentiate epilepsy from pseudo -epileptic seizure but remains unproven for separating status epilepticus from pseudo-status epilepticus [17]. In contrast, a normal interictal EEG trace after clinical resolution of the seizure supports pseudo-status epilepticus, as abnormalities are consistently found just after convulsive status epilepticus [18].

Abnormal Movements and Neuropsychiatric Manifestations Many forms of abnormal motor activity may be confused with convulsive status epilepticus, including tetany, neuroleptic malignant syndrome, chills, drug-induced myoclonus, decerebration posturing, hemiballism, and athetosis. Whether postan oxic myoclonus is an epileptic manifestation remains highly controversial. Lesions located in the cerebral cortex cause epilepsy-like seizures in addition to myoclonic jerks. In contrast, myoclonus due to subcortical lesions (reticular substance or spinal cord) is characterized by absence of seizures and presence of burst -suppression patterns that are usually modified by movement artifacts related to the myoclonic jerks [19]. Therefore, the epileptic nature of the disorder cannot be established. Myoclonus consistently indicates severe damage to the central nervous system (CNS). Resistance to medications is marked and the prognosis consistently bleak [20]. The neurosensory manifestations of nonconvulsive status epilepticus deserve special attention, as they may be mistaken for psychiatric disorders. They include mood

Managing Critically III Patients with Status Epilepticus

disturbances, cortical blindness , elocution problems (mutism, impaired verbal fluency), echolalia, confabulation, behavioral disorders (inappropriate laughing, dancing, or singing), dissociative psychosis, and psychosensory disorders (e.g., heautoscopy and limb torsion). These manifestations, which are usually ascribed to psychiatric disease, should lead routinely to investigations for epilepsy [21]. Neurological manifestations that may simulate nonconvulsive status epilepticus [22] include metabolic encephalopathy, migraine with aura symptoms , and posttraumatic confusion. Here also, an EEG is needed to establish the diagnosis of nonconvulsive status epilepticus. Errors Related to the Recording and/or Interpretation of the Electroencephalogram

In addition to the artifacts inherent in the EEG recording technique, specific arti facts generated by ICU equipment have been described [23]. Sources of artifacts include oscillating water condensation in ventilator circuits and motors of continuous hemofiltration machines . Interpretation of some EEG patterns may also lead to over- or underdiagnosis of status epilepticus. EEG patterns that may be mistakenly ascribed to nonconvulsive status epilepticus include periodic lateralized epileptiform discharges, bilateral periodic epileptiform discharges, generalized periodic epileptiform discharges, and triphasic waves, the epileptic nature of which is widely debated [24]. These patterns should be interpreted with caution based on the clinical setting [8, 9, 22].

Advances in the Treatment of Status Epilepticus The paucity of randomized controlled studies is an obstacle to the development of treatment strategies for status epilepticus. The first-line and second-line treatment of status epilepticus relies on various short and long-acting antiepileptic agents, whereas refractory status epilepticus - defined as persistent clinical or electrical seizure activity - requires the administration of anesthetics. Some antiepileptics are old drugs that have been considerably improved over the years, whereas others are new drugs about which information is still limited. A number of nonconventional treatments are available for highly refractory forms of status epilepticus. New Indications for Old Drugs

Lorazepam, Diazepam, Clonazepam, Phenytoin, Phenobarbital There are few new developments in relation to these medications, which were used in the few evaluations of treatment strategies for status epilepticus. In a 1998 randomized double-blind trial in patients with generalized convulsive status epilepticus or subtle status epilepticus (electrical seizure activity with or without subtle convulsive movements), lorazepam was superior to phenytoin [25]. Lorazepam is a longacting intravenous benzodiazepine that is not available in all countries . No significant differences were found between lorazepam and phenobarbital or between diazepam plus phenytoin and phenobarbital in terms of clinical seizure resolution or adverse events (cardiovascular events, CNS depression, and respiratory events). A Cochrane review published in 2005 [26] failed to uncover new information about these medications.

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Sodium valproate The pharmacokinetic properties of sodium valproate are well suited to the treatment of status epilepticus, and the spectrum of antiepileptic activity is broad. Nevertheless, the role of sodium valproate in the management of status epilepticus was controversial for a long time. Studies in children and adults established that loading doses of up to 45 mglkg [27] at rates of up to 6 mglkglmin [28] were both effective and safe. A prospective randomized pilot study published in 2007 compared sodium valproate and phenytoin for the first-line or second-line treatment of convulsive status epilepticus in 68 patients [29]. When used as first-line treatment, sodium valproate produced clinical seizure resolution in 66 % of cases, compared to 42 % with phenytoin. Sodium valproate was given in a dose of 30 mg/kg in 100 ml of saline as an intravenous infusion over 15 minutes followed by a maintenance infusion of 2 mg/kglh . These highly promising results require confirmation in a study with sufficient statistical power to establish the superiority of sodium valproate over phenytoin. Nevertheless, sodium valproate deserves greater recognition as a first-line treatment for status epilepticus [30, 31]. Liver disease is a contraindication for sodium valproate use. Patients should be monitored for evidence of hyperammonemia encephalopathy, particularly when consciousness remains abnormal after initiation of the drug. Fosphenytoin Fosphenytoin is a prodrug of phenytoin that is easier to administer, as it does not need to be diluted and infused in saline exclusively, and neither does it cause peripheral venous toxicity. Although an up to 3 times faster infusion rate can be used compared to phenytoin, the time needed for conversion to phenytoin in the body cancels out any time-to-action advantage over administration of phenytoin [32]. Neither fosphenytoin nor phenytoin can be used in patients with absence status epilepticu s, and both drugs can exacerbate myoclonic status epilepticus. The high cost of fosphenytoin is a potential limiting factor. Expression of the dosage as phenytoin-equivalents has generated confusion, and excessively fast administration of fosphenytoin has been reported to cause cardiac arrest. Propofol, Midazolam, and Thiopental/Pentobarbital A systematic literature review published in 2002 reported efficacy and safety data from 193 patients given propofol, midazolam , or pentobarbital for refractory status epilepticus. Pentobarbital was more effective in producing a burst-suppression EEG pattern but failed to improve survival; in addition, pentobarbital was associated with a significantly higher rate of vasopressor use to correct hypotension [33]. Subsequently, two high-quality stud ies done by the same group provided detailed information on the optimal use of thiopental and propofol (see below) [34, 35]. The results support the use of midazolam and propofol as alterna tives to thiopental in patients with refractory status epilepticus [31]. Clinicians must be aware that continuous propofol infusion in the dosages required to control refractory status epilepticus may cause propofol infusion syndrome. Patients should be monitored closely for evidence of the syndrome, and the appropriateness of continued propofol use should be reappraised after 24 to 48 hours. Prolonged thiopental use induces immunosuppression, thereby increasing the risk of infection.

Managing Critically III Patients with Status Epilepticus

Ketamine Ketamine has been suggested as an adjunctive treatment for refractory status epilepticus. In addition to antiepileptic effects, ketamine may induce neuroprotection, an effect of considerable interest in patients with refractory status epilepticus [30, 36]. After a bolus of 1- 2 mg/kg, an infusion is given at rates of up to 7.5 mg/kg/h [36]. Because ketamine increases intracranial pressure, a space-occupying lesion must be ruled out before ketamine therapy, which should be reserved for a small minority of patients [4]. Cerebral toxicity due to prolonged ketamine administration for status epilepticus has been reported [31]. Isoflurane and Desflurane These inhalational anesthetics have been used in a few patients with refractory status epilepticus. Reported advantages included ease of titration, rapid action , and antiepileptic efficacy [36, 37]. Few data are available on these agents, which have not been compared to conventional treatments for refractory status epilepticus . Side effects included hypotension, atelectasis, paralytic ileus, and deep vein thrombosis [31]. New Drugs Contributing to the Management of Refractory Status Epilepticus

Levetiracetam Levetiracetam is a new drug with a poorly understood mechanism of action and a broad spectrum of antiepileptic activity [38]. An intravenous form is available and the drug can be diluted in saline or glucose solution. Dosages of up to 2500 mg over 5 min have been given without detectable adverse effects [38]. Levetiracetam was effective when used as adjunctive treatment in small case-series of patients with refractory convulsive or nonconvulsive status epilepticus, at a maximum dosage of 3000 mg/d [39,40] . A prospective study that is ongoing in the Netherlands may clarify the role for levetiracetam in patients with status epilepticus. Until then, levetiracetam should probably be reserved for the adjunctive treatment of refractory status epilepticus. Topiramate Topiramate has a complex mechanism of action and a broad spectrum of antiepileptic activity [38]. It is available only for oral administration. Similar to levetiracetam, topiramate was effective for the adjuvant treatment of small populations of patients with refractory status epilepticus complicating convulsive or partial complex nonconvulsive status epilepticus [31, 41]. These situations constitute the only indica tions for topiramate therapy at present. The daily dosage is 300 to 1600 mg per day via a nasogastric catheter. Drugs being developed Several drugs that are being developed are effective in experimental models of status epilepticus. They include brivaracetam, NS1209, retigabine, RWJ-333369, and talarnpanel. Their mechanisms of action differ from those of conventional antiepileptic agents, which may ensure better control of the epileptogenic process and afford a neuroprotective effect. Thus, in the future, these drugs may prove useful adjuvant treatments for refractory status epilepticus [38].

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Other Treatment Approaches Stimulation of the brain Electroconvulsive therapy has been used in a very small number of patients with refractory status epilepticus, to good effect [37]. However, it is important to bear in mind that many cases of nonconvulsive status epilepticus have been reported in patients treated with electroconvulsive therapy for depression. This fact is a major obstacle to considering electroconvulsive therapy as a potential tool for controlling status epilepticus. Vagus nerve stimulation Stimulation of the vagus nerve has been found to be effective in 20- 66 % of patients with status epilepticus refractory to medications. However, the number of reported cases is very small [37]. Therapeutic hypothermia Recent experimental data strongly suggest that therapeutic hypothermia exerts beneficial effects in patients with refractory status epilepticus, including potentiation of the antiepileptic activity ofbenzodiazepines [42]. Three children with refractory status epilepticus were managed successfully with therapeutic hypothermia, which was combined with thiopental [43]. These promising results require confirmation by further experimental work and by clinical trials. Neurosurgical resection Neurosurgery can be considered in patients with partial epilepsy that is refractory to medications. Some authors have suggested neurosurgery as a treatment of last resort in patients with highly refractory status epilepticus [31, 37].

Treatment Strategies A European consensus conference on the management of status epilepticus was held in 2006 [1]. The strategies suggested by the panel are easy to adapt according to whether lorazepam is available and in order to incorporate recent data.

General Measures Patients with status epilepticus require the symptomatic measures usually taken in the ICU. Hemodynamic stability should be ensured, particularly as many of the drugs used to treat status epilepticus can induce hypotension and/or heart failure. Catecholamines are often needed in patients with refractory status epilepticus. The need for upper airway protection should be evaluated continuously while bearing in mind that the primary treatment goal is seizure resolution with recovery of consciousness. Therefore, an initial phase of coma without life-threatening manifestations is acceptable if not unduly prolonged. If endotracheal intubation is performed, rapid-sequence induction with etomidate and succinylcholine can be used, provided there is no evidence of hyperkalemia. Propofol or thiopental are also good choices, since they have anticonvulsant effects. Neuromuscular agents may transiently mask the seizures. Hypoglycemia should be looked for routinely and corrected. If glucose is given, 100 mg of thiamine should be administered concomitantly, most notably

Managing Critically III Patients with Status Epilepticus

when there is evidence of vitamin Bl deficiency. Patients should be routinely evaluated for hyperthermia and metabolic disturbances, which require prompt correction. Metabolic and/or respiratory acidosis should be controlled, and tests for acute renal failure with rhabdomyolysis should be performed. Aspiration pneumonia may complicate the initial consciousness disorders [1,4] . Patients should be evaluated for injur ies such as head injury and shoulder dislocation. Antiepileptic treatment, appropriate for the electrical and clinical pattern in the patient (see below), should be initiated on an emergency basis. In addition to these symptomatic measures, the treatment strategy should include investigations for a cause of the status epilepticus, followed by etiological treatment [1].

Treatment Strategies for Convulsive Status Epilepticus Generalized convulsive status epilepticus (Fig. 3) Intravenous lorazepam is the first-line treatment for generalized convulsive status epilepticus. If the seizure persists, a second injection can be given 10 minutes later.

Lorazepam,4 mg i.v,bolus Repeatafter 10 min if needed

Phenytoin 18mg/kg (or fosphenytoin 15 mg/kg PEl

Diazepam 10 mg i.v, bolus or donazeparn1 mg i.v, bolus

or phenobarbital 10- 15 mg/kg

Repeat up to 3 timesif seizures persist

Consider Sodium valproate30 mg/kg

L Phenytoin 18 mg/kg or Fosphenytoin 15 mg/kg PE

1

± lorazepam 4 mg Lv. bolus

J

Additionaldoseof the long-acting antiepileptic drug used previously

1

+

If phenytoin add 12mg/kg If fosphenytoin add 10 mg/kg PE

L

~

If phenobarbital add 5- 10 mg/kg

+ If sodiumvalproate add 15 mg/kg

+

Refractory status epilepticus

Fig. 3.Treatment strategy for generalized convulsive status epilepticus. PE: phenytoin-equivalent

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Phenytoin or fosphenytoin is a good choice when lorazepam fails. Administration of an additional lorazepam dose can be considered. When lorazepam is not available, a short-acting benzodiazepine such as clonazepam or diazepam should be given in combination with a long-acting antiepileptic drug such as phenobarbital, phenytoin, fosphenytoin [32], or sodium valproate [29-31]. Factors that affect the choice of the antiepileptic agent include the spectrum of antiepileptic activity, contraindications, and expected side effects (Table 1). Patients with persistent seizuring at the end of the infusion can be given an additional dose of the same antiepileptic drug. Refractory status epilepticus is defined as either persistent seizures at the end of this treatment sequence or continuous seizures for 1 hour [I, 31]. Anesthetics should be used as the first-line treatment of refractory status epilepticus [25, 31]. When there is concern that this aggressive strategy may have limited benefits, for instance in elderly patients , addition of a second long-acting antiepileptic drug may deserve consideration [1, 9]. Partial motor convulsive status epilepticus The paucity of published data on this form of status epilepticus hinders the development of treatment strategies and probably explains the lack of consensus about the optimal treatment. In patients with altered consciousness, progression to generalized convulsive status epilepticus is common and the risk of progression to refractory status epilepticus high [44], supporting the use of the treatment strategy designed for generalized convulsive status epilepticus [4]. When consciousness is normal, an orally or rectally administered drug can be used initially [4]. Refractoriness should not be diagnosed until several lines of treatment fail (Fig. 4).

Treatment Strategies for Nonconvulsive Status Epilepticus Absence or simple partial nonconvulsive status epilepticus A benzodiazepine, such as clonazepam or diazepam, is usually sufficient [45]. Complex partial nonconvulsive status epilepticus (Fig. 4) The risk of neuronal damage and the high mortality rate associated with complex partial nonconvulsive status epilepticus support the use of the treatment strategy designed for generalized convulsive status epilepticus. However, refractory status epilepticus should be defined as failure of the second or even third line of antiepileptic therapy [1]. Subtle status epilepticus and electrical status epilepticus In the Veterans Affairs study published in 1998 [25], resistance to medication was common in subtle nonconvulsive status epilepticus, which carried a high mortality rate. These features warrant aggressive first-line treatment using the same strategy as in refractory status epilepticus (Fig. 5) [1].

Treatment Strategies for Refractory Status Epilepticus (Fig. 5) Anesthesia with propofol, thiopental, or midazolam is the cornerstone of the management of refractory status epilepticus [1, 31, 33, 37]. Regardless of the drug used, the dose should be titrated at 3- to 5-min intervals under EEG monitoring with the goal of obtaining a burst-suppression pattern with suppression for 5 to 10 seconds

If enteral route not ava ilable 2 to 3 mg /kg/24 h single slow Lv.::;; 5 mg/min

12 mg /kg Slow i.v. 1 mg/kg /min Rate no faster than 50 mg/min, in saline (precipitates in glucose solutions), such that the maximum concentration is 5 mg/ml 1000 mg in 200 ml saline Slow i.v, <: 20 min

Monitor during the infusion, decrease the rate if bradycardia occurs Induces respiratory and hemodynamic depression If enteral route not available 7- 10 mg/kg /24 h pump infusion start 6 to 12 h after the loading dose Phenytoin 2 to 6 mg/kg /24 h Divided in 1 to 2 doses Start within 12 h of the loading dose

10 - 20 Ilg/ml

15 mg/kg

Slow i.v. over 15 min in 100 ml saline

1800 mg in 100 ml saline Slow l.v. over 15 min No CNS, respiratory, or hemodynam ic depression Routinely, 1 to 5 mg/kg /h To maintain serum level at 75 mg/L then switch to oral route 20- 30 mg/kg /24 h Divided in 2- 3 daily doses Start during the maintenance infusion

50 - 100 mg/l

Additional dose

Administration

Example For a 60-kg patient

Monitoring during administration

Continuous pump infusion for maintenance

Switch to the oral route

Therapeutic concentration

i.v: intravenous; PE: phenytoin-equivalent ; CNS: central nervous system

Induces respiratory, CNS, and hemodynamic depression

10 mg/kg PE

Slow i.v, 100-1 50 mg /min PE, maximum rate 150 mg/min PE, in 5 % glucose or saline so that the maximum concentration is 25 mg PE/ml

18 mg/kg

30 mg/kg

Loading dose

If entera l route not available 4 to 5 mg/kg/24 h pump infusion or 1 to 2 doses/24 h s 100 mg/min PE

900 mg PE in 18 ml saline or 5 % glucose, Slow l.v, <: 6 min

15 mg/kg PE

Do not use for myoclonic convulsive status epilepticus or absence nonconvulsive status epilepticus

All patterns of status epilepticus Particularly myoclonic convulsive status epilepticus

Seizure type

Phenobarbital

15 - 40 Ilg/ml

Phenobarbital 2 to 3 mg /kg/24 h Once daily, preferably in the evening Start within 12 h after the loading dose

600 to 900 mg in 10 ml sterile water for i.v, Slow i.v, over 6 to 9 min

Slow Lv. s 100 mg/min, in 10 ml sterile water for l.v,

S to 10 mg/kg

10 to 15 mg/kg

All patterns of status epilepticus

Hypersensitivity to the drug Severe respi ratory failure Several cytotoxic drugs St John's wort, saquinavir, voriconazole

Hypersensitivity to the drug Acute or chronic hepatitis Family history of acute hepatitis Mefloquine, St John's wort

Fosphenytoin

Phenytoin Hypersensitivity to the drug Several cytotoxic drugs, St John's wort, saquinavir Sinus bradycardia, sinoatrial block, Atrioventricular block II and III, Stokes-Adams syndrome

Sodium va lproate

Contraindications

Table 1. Rules for using long-acting antiepileptic agents to treat status epilepticus

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III

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III

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== III :::I III loCI

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S. Legriel, J.P. Bedos, and E. Azoulay

Lorazepam,4 mg i.v, bolus Repeat after 10 min if needed

Phenytoin 18 mg/kg (or fosphenytoin 15 mg/kg PEl

Diazepam 10 mg i.v, bolus or clonazepam 1mg l.v, bolus

or phenobarbital 10-15 mg/kg

Repeat up to 3 times if seizures persist

Consider Sodium valproate 30 mg/kg

L

Additional doseof the long-acting antiepileptic drug used previously

Phenytoin 18mg/kg or

+

Fosphenytoin 15 mg/kg PE

!

± lorazepam

4 mg l.v. bolus

J

If phenytoin add 12 mg/kg If fosphenytoin add 10 mg/kg PE

~

..

L

i

•

If phenobarbital add 5-10 mg/kg

If sodium valproate add 15 mg/kg

Give long-actingantiepileptic drugsnot usedpreviously

Refractory statusepilepticus

Fig. 4. Treatment strategy for partial convulsive status epilepticus and complex partial nonconvulsive status epilepticus. PE: phenytoin-equivalent

[1, 34, 35]. Once this goal is reached, a continuous infusion is given to maintain the burst-suppression pattern for 12 to 24 h. Boluses should be given if the burst-suppression pattern is lost before the pre-specified time; after the boluses , the continuous-infusion dose should be increased gradually. Table 2 recapitulates the rules for using these anesthetic agents. The treatment-discontinuation modalities vary across agents, in relation to the differences in their half-life values. A 20 % reduction every 3 h is appropriate with pro-

Managing Critically III Patients with Status Epilepticus

General anesthesia with thiopental, midazolam, or propofol Goal: to titrate under EEG guidance until a burst-suppression patternisachieved then to continuethe maintenance doseto maintain this pattern for 12-24 h Simultaneously, start the antiepilepticdrug that will be continuedafter discontinuation of the anesthetics

Thiopental

Midazolam

Propofol

Initial bolus5 mg/kg Titrateby 1-2 mg/kg every3- 5 min Then maintenance 3- 5 mg/kg/h

Initial bolus 0.2 mg/kg Titratedby 0.2 mg/kg every 3-5 min Then maintenance 0.1-0.4 mg/kg/h

Initial bolus 2-3 mg/kg Titrated by 1-2 mg/kg every3-5 min Thenmaintenance 4mg /kg/h

Fig. S. Strategy for managing refractory status epilepticus Table 2. Rules for using anesthetic drugs to treat refractory status epilepticus Sodium thiopental Penthotal®

Midazolam Hypnovelv

Propofol Diprivan®

Loading dose

5 mg/kg slow i.v, 20 sec

0.2 mg/kg slow l.v,

2-3 mg/kg slow i.v,

Bolus titration under EEG guidance

1 - 2 mg/kg slow l.v., 20 sec every 3- 5 min

0.2 mg/kg slow Lv. every 3-5 min

1-2 mg/kg slow Lv. every 3-5 min

Maintenance dose, pump infusion

3-5 mg/kg/h ± 1 mg/kg/h

0.1 -0.4 mg/kg/h ± 0.1 mg/kg/h

4 mg/kg/h ± 1 mg/kg/h

Administration modalities

Dilute to 2.5 % or 5 %

No dilution needed

~ 48

Specific effects

Immunosuppressant

Tachyphylaxis

Risk of propofol infusion syndrome

h

Lv. intravenous

pofol and a 50 % decrease every 3 h with midazolam, whereas thiopental can be stopped with no prior dosage reduction. Should the seizures recur, the same anesthetic agent should be given in the dosage that was effective previously. A loading dose of one or two long-acting antiepileptic agents should be given routinely in combination with the anesthetic agent and continued after anesthesia withdrawal [1,34,35] .

Treatment Goals The immed iate treatment goals in pati ents with generalized convulsive status epilepticus are cessation of the clinical seizures and prevent ion of subtle status epilepticus. Subtle status epilepticu s has been reported to develop in 14 % [46] to 20 % [25] of patients with convulsive statu s epilepticus. The optim al time for obtaining an EEG is not known. In pract ice, an EEG should be obtained as early as possible and is particularly urgent in patients who fail to recover normal or pre-seizure levels of con-

833

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S. Legriel, J.P. Bedos, and E. Azoulay

sciousness after cessation of clinical seizuring [47]. In nonconvulsive status epilepticus, the goal of treatment is resolution of the critical EEG patterns accompanied with a return to normal of the patient's clinical status. When clinical abnormalities persist, their link to epilepsy should be reappraised [22]. According to current recommendations, the immediate treatment objective in patients with refractory status epilepticus is prompt generation of a burst-suppression pattern [1,37] . Resolution of the electrical seizures without a burst-suppression pattern is associated with a higher rate of recurrence than maintenance of a burstsuppression pattern for 12 to 24 h [33]. The desired characteristics and optimal duration of the trace remain debated. It has been suggested that a l-second burst followed by 10 seconds of suppression may be sufficient, although others have recommended suppression for 15 to 30 seconds [36]. Well-designed trials are not available to prove that this aggressive approach to the management of refractory status epilepticus translates into reduced mortality rates [48]. Regardless of the pattern of status epilepticus, continuous EEG monitoring has emerged as a crucial management tool [9,49] .

Conclusion This review highlights recent advances in the diagnosis and treatment of status epilepticus. Knowledge of the classification scheme that separates convulsive and nonconvulsive status epilepticus is crucial. Generalized convulsive status epilepticus carries a grim prognosis and requires early diagnosis and treatment. The diagnosis of nonconvulsive status epilepticus may be difficult, as it requires an EEG. The many diagnostic pitfalls are dominated by pseudo-status epilepticus, which should be considered routinely. The undeniable treatment advances achieved in recent years have resulted in the development of treatment strategies tailored to the type and severity of status epilepticus. Although old antiepileptic agents are still used, their indications have been refined. The role of new drugs needs further evaluation. A highly aggressive approach is appropriate in patients with refractory status epilepticus in order to improve survival. A number of last-resort methods may be used in patients with highly refractory status epilepticus. Mortality rates associated with status epilepticus remain high overall, indicating a need for new drugs and for randomized trials of new treatment strategies. References 1. Meierkord H, Boon P, Engelsen B, et al (2006) EFNS guideline on the management of statu s epileptic us. Eur J Neurol 13:445- 450 2. Chin RF, Neville BG, Scott RC (2004) A systematic review of the epidemiology of status epilepticus. Eur J Neurolll:800-810 3. Lowenstein DH, Bleck T, Macdonald RL (1999) It's time to revise the definition of status epilepticus. Epilepsia 40:120- 122 4. Chen JW, Wasterlain CG (2006) Status epilepticus: pathophysiology and management in adults. Lancet Neurol 5:246-256 5. Jenssen S, Gracely EJ, Sperling MR (2006) How long do most seizures last? A systematic comparison of seizures recorded in the Epilepsy Monitoring Unit. Epilepsia 47:1499-1503 6. DeLorenzo RJ, Garnett LK, Towne AR, et al (1999) Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes . Epilepsia 40:164-169 7. Eriksson K, Metsaranta P, Huhtala H, Auvinen A, Kuusela AL, Koivikko M (2005) Treatment delay and the risk of prolonged status epilept icus. Neurology 65:1316-1318

Managing Critically 1\1 Patients with Status Epilepticus 8. Walker M, Cross H, Smith S, et al (2005) Non convulsive status epilepticus : Epilepsy Research Foundation Workshop Reports. Epileptic Disord 7:253- 296 9. [irsch J, Hirsch LJ (2007) Nonconvulsive seizures: Developing a rational approach to the diagnosis and management in the critically ill population. Clin Neurophysiol 118:1660-1670 10. Coeytaux A, Iallon P (2000) The difficulty of defining and classifying status epileptic us. Neurophysiol Clin 30:133-138 11. Walker M (2005) Status epilepticus : an evidence based guide. BMJ 331:673- 677 12. AssaI F, Coeytaux A, [allon P (2000) Drug resistant status epilepticus. Neurophysiol Clin 30: 139-145 13. Reuber M, Pukrop R, Mitchell AJ, Bauer J, Elger CE (2003) Clinical significance of recurrent psychogenic nonepileptic seizure status . J Neurol 250:1355-1362 14. Walker MC, Howard RS, Smith SJ, Miller DH, Shorvon SD, Hirsch NP (1996) Diagnosis and treatment of status epilepticus on a neurological intensive care unit. QJM 89:913-920 15. Holtkamp M, Othman 1, Buchheim K, Meierkord H (2006) Diagnosis of psychogenic nonepi leptic status epilepticus in the emergency setting . Neurology 66:1727- 1729 16. Chung SS, Gerber P, Kirlin KA (2006) Ictal eye closure is a reliable indicator for psychogenic nonepileptic seizures. Neurology 66:1730- 1731 17. Chen DK, So YT, Fisher RS; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (2005) Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 65:668-675 18. Dworetzky BA, Mortati KA, Rossetti AO, Vaccaro B, Nelson A, Bromfield EB (2006) Clinical characteristics of psychogenic nonepileptic seizure status in the long-term mon itoring unit. Epilepsy Behav 9:335- 338 19. Thomke F, Marx 11, Sauer 0 , et al (2005) Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus. BMC Neurol 18:1-14 20. Wijdicks EF, Hijdra A, Young GB, et al (2006) Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 67:203-210 21. Riggio S (2005) Nonconvulsive status epileptic us: clinical features and diagnostic challenges. Psychiatr Clin North Am 28:653- 664 22. Meierkord H, Holtkamp M (2007) Non-convulsive status epilepticus in adults: clinical forms and treatment. Lancet Neurol 6:329-339 23. Young GB, Campbell VC (1999) EEG monitoring in the intensive care unit: pitfalls and caveats. J Clin Neurophysiol 16:40-45 24. Brenner RP (2002) Is it status? Epilepsia 43:103-113 25. Treiman DM, Meyers PD, Walton NY, et al (1998) A comparison offour treatments for generalized convulsive status epilepticus . Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 339:792- 798 26. Prasad A, AI-Roomi K, Krishnan PR, Sequeira R (2005) Anticonvulsant therapy for status epileptic us. Cochrane Database Syst Rev CD003723 27. Limdi NA, Shimpi AV, Faught E, Gomez CR, Burneo JG (2005) Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 64:353- 355 28. Venkataraman V, Wheless JW (1999) Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res 35:147-153 29. Misra UK, Kalita J, Patel R (2006) Sodium valproate vs phenytoin in status epilepticus: A pilot study. Neurology 67:340- 342 30. Van rijckevorsel K, Boon P, Hauman H, et al (2005) Standards of care for adults with convulsive status epilepticus : Belgian consensus recommendations. Acta Neurol Belg 105:111-118 31. Lowenstein DH (2006) The management of refractory status epilepticus : an update. Epilepsia 47:35-40 32. Lowenstein DH (2005) Treatment options for status epilepticus. Curr Opin Pharmacol 5: 334-339 33. Claassen J, Hirsch LJ, Emerson RG, Mayer SA (2002) Treatment of refractory status epilepti cus with pentobarbital, propofol, or midazolam : a systematic review. Epilepsia 43:146-153 34. Parviainen I, Uusaro A, Kalviainen R, Kaukanen E, Mervaala E, Ruokonen E (2002) High-

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35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 59:1249-1251 Parviainen I, Uusaro A, Kalviainen R, Mervaala E, Ruokonen E (2006) Propofol in the treat ment of refractory status epilepticus. Intensive Care Med 32:1075-1079 Dhar R, Mirsattari SM (2006) Current approach to the diagnosis and treatment of refractory status epilepticus. Adv Neurol 97:245 - 254 Holtkamp M (2007) The anaesthetic and intensive care of status epilepticus. Curr Opin Neurol 20:188-193 Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T (2007) Progress report on new antiepileptic drugs : a summary of the Eigth Eilat Conference (EILAT VIII). Epilepsy Res 73:1-52 Patel NC, Landan IR, Levin J, Szaflarski J, Wilner AN (2006) The use of levetiracetam in refractory status epilepticus. Seizure 15:137- 141 Rupprecht S, Franke K, Fitzek S, Witte OW, Hagemann G (2007) Levetiracetam as a treatment option in non-convulsive status epilepticus. Epilepsy Res 73:238 - 244 Reuber M, Evans J, Bamford JM (2002) Topiramate in drug -resistant complex partial status epilepticus. Eur J Neurol 9:111-112 Schmitt FC, Buchheim K, Meierkord H, Holtkamp M (2006) Anticonvulsant properties of hypothermia in experimental status epilepticus. Neurobiol Dis 23:689 - 696 Orlowski JP, Erenberg G, Lueders H, Cruse RP (1984) Hypothermia and barbiturate coma for refractory status epilepticus. Crit Care Med 12:367 - 372 Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF (2002) Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch NeuroI59:205-21O Thomas P (2000) Status epilepticus with confusional symptomatology. Neurophysiol Clin 30:147-154 DeLorenzo RJ, Waterhouse EJ, Towne AR, et al (1998) Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 39:833- 840 Thomas P (1997) Status epilepticus: indications for emergency EEG. Neurophysiol Clin 27:398-405 Rossetti AO, Logroscino G, Bromfield EB (2005) Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch NeuroI62:1698-1703 YoungGB (2006) Nonconvulsive seizures and electroencephalogram monitoring in the intensive care unit. Adv Neurol 97:221- 227

Section XXI

XXI Analgesia and Sedation

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Sedation with Inhaled Anesthetics in Intensive Care EJ.

BELDA, M . SORa,

and A.

MEISER

Introduction Sedation is an essential therapy in the intensive care unit (ICU). Patients admitted to the lCU receive sedation for many hours and even days, largely because of their dependence on mechanical ventilation but also because of their poor general condition, high treatment and monitoring invasiveness, nursing maneuvers, and many other factors such as isolation, sleep deprivation, communication impairment, etc. [1]. Adequate sedation hinders the reaction to stress, prevents anxiety, increases comfort, and improves tolerance to endotracheal intubation and mechanical ventilation, thus facilitating nursing work [2, 3]. However, sedation poses many problems. First, it is difficult to titrate . Inadequate, light sedation may lead to hypertension, tachycardia, and poor ventilator synchrony and produces stressful experiences. Patients not only remember the endotracheal tube but refer to discomfort, fear, anxiety, agitation , lack of sleep, hallucinations, nightmares, loneliness... [4]. These experiences seem to be responsible for long-term psychological effects and the so-called 'post-traumatic stress disorder', observed in 15- 27 % of patients after lCU discharge [5, 6] and substantially reducing quality of life [7]. However, in general, it seems that we oversedate our patients. In fact, recent studies have demonstrated that daily interruption of sedative infusions reduced the duration of mechanical ventilation and the mean lCU stay [8] and did not result in adverse psychological outcomes [9]. Titration of intravenous sedatives cannot be controlled from measurement of their plasma concentration, but from their effect. Subjective scoring indexes are imperfect and carry the potential for variability in measurements. The bispectral index can be useful for monitoring sedation in critical care but its use did not reduce the amount of sedation used, the length of mechanical ventilation, or the length ofICU stay [10]. Second, intravenous agents, which are the most commonly used sedatives in the lCU [11-13], seem to have severe disadvantages and side effects. For midazolam, a short-acting benzodiazepine, quick onset of tolerance and a ceiling effect are characteristic. Propofol, a relatively shortacting intravenous sedative, has become very popular in many countries . However, its use for lCU sedation was questioned after the report on the deaths of five children in 1992 and five adults in 2001 and many others since, all of them recently reviewed [14, 15]. "Propofol infusion syndrome" has been described as a severe metabolic acidosis with rhabdomyolysis and renal and myocardial failure. Warnings issued in most European Union countries state that propofol for lCU sedation should be restricted to patients over 16 years of age, for up to 7 days, and to a maximum dose of 4 to 5 mg/kg/h or less if possible. Many other side effects have been described when propofol is used for long-term sedation in lCU patients [16, 17].

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FJ. BeIda, M. Soro, and A. Meiser

Finally, opioids can depress respiration and intestinal motility. This interferes with current therapeutic guidelines, such as early enteral feeding and assisted spontaneous breathing in mechanically ventilated patients. For these reasons, we believe it is worth looking for alternative treatment options .

Sedation using Inhalational Anesthetics A feasible alternative today to intravenous drugs for sedation is inhalational anesthetics. A major advantage of this mode of sedation is that volatile agents give excellent control over their action. The end-tidal fraction of volatile anesthetics can be monitored, giving a good indication of the drug's concentration in the target organ, much more reliable than any target-controlled infusion algorithm. In fact, a recent paper demonstrated in non-paralyzed ICU patients sedated with isoflurane or mida zolam that end-tidal fraction of isoflurane appeared to be a better indicator of clinical sedation depth than the bispectral index [18]. The onset of action of inhalational anesthetics is usually quick and emergence times are shorter and more predictable than after intravenous sedation [19-22] . Volatile anesthetics accumulate very little, and elimination via the lungs is independent of liver and kidney function. Regarding psychological aspects, the hypothesis is that post-traumatic stress disorder will occur very rarely after inhalational sedation. A partly suppressed perception combined with hallucinations and disturbed information processing may result in frightening experiences related with post-traumatic stress disorder. Volatile anesthetics act primarily on the cerebral cortex, and even at low concentrations may completely depress consciousness while leaving many autonomic functions undisturbed (such as breathing, temperature control, and blood pressure regulation). We observed that return of consciousness with volatile anesthetics is usually brisk, and can be said to act like on/off switches for consciousness. Unlike the case with intravenous sedation, perception and integrat ion of information seem to be possible only after patients become clearly awake and responsive (Meiser et al. unpublished data). Another major advantage of inhalational anesthetics lies in their pharmacodynamic effects. First, volatile anesthetics are potent bronchodilators. Sedation with isoflurane became popular about 15 years ago and is still used to treat severe status asthmaticus when other therapies have failed [23,24]. Second, modern halogenated agents produce better hemodynamic stability than intravenous agents. Propofol, opioids, or uz-agonists, interfere with hemodynamic regulation by causing vasodilation, myocardial depression, or bradycardia. Ketamine increases the workload of the heart by increasing blood pressure and heart rate. In contrast, sevoflurane is renowned for its circulatory stability and in concentrations up to 1 minimum alveolar anesthetic concentration (MAC) does not produce any hemodynamic variation [25]. The sympathoadrenergic stimulation seen after a sudden increase in desflurane concentration from 1 to 1.5 MAC is not seen at concentrations around 0.5 MAC that are used for ICU sedation. In fact we reported that heart rate was more often in the normal range in patients sedated with desflurane compared to propofol [22]. At usual sedation doses, these characteristics make inhalational anesthetics an almost ideal sedative, as was reported in an Editorial in the British Journal of Anaesthesia [26]. Several studies have shown the superiority of inhaled anesthetics for sedation in ICU patients when compared to intravenous agents [19-22, 27, 28]. A new important advantage is organ protection against ischemic insults. Recent clinical evidence has shown that inhaled anesthetics have cardiovascular protective

Sedation with Inhaled Anesthetics in Intensive Care

effects associated not only with improved cardiac function in the postoperative period after cardiac surgery, but also with a reduced length of stay in the ICU [29,

30].

The reasons why inhalational sedation has not gained more widespread acceptance may be of a technical and educational nature. First, critical care ventilators do not allow an easy fitting of vaporizers and there are concerns about excessive agent consumption and environmental contamination which would require a gas scavenging system. Second, there is little room for an anesthetic machine in critical care units and such machines do not have all the new assisted ventilatory modes used in critical care patients. Finally, from a clinical management perspective, the ICU staff, in general, is not familiar with the pharmacology, physiologic effects, and handling of volatile anesthetics.

How to Administer Inhalation Anesthetics in the ICU: The Anaconda Device A new anestheti c conserving device (ACD - AnaConDa, Sedana Medical, Sundbyberg, Sweden) [31, 32], can be used for the administration of inhalational agents like isoflurane and sevoflurane with standard critical care ventilators. The ACD (Fig. 1) is a modified bacterial filter heat and moisture exchanger (HME) that incorporates an extra layer of activated carbon fibers, called the anesthetic reflector. The anesthetic is supplied in liquid status via a syringe pump into a porous rod (called the evaporator) inside the ACD on the patient side of the reflector. The anesthetic diffuses over the large surface of the rod being instantaneously dragged and vaporized by the inspiratory gas flow and delivered to the lungs. During expiration, 90 % of the volatile anesthetic molecules condense on the surface of the activated carbon fibers and are released again during the next inspiration [31]. Consequently, only 10 % of the anesthetic passes the filter and is released through the expiratory outlet of the ventilator. In spite of this small amount of anesthetic loss, scavenging of this gas should be performed from the expiratory outlet of the ventilator. In this way, a main advan-

2

2

3

7

4 5

6

Fig. 1. Schematic representation of the AnaConDa device. Left panel: 1. Ventilator side 15 mm male connector; 2. Bacterial and particle filter; 3. Carbon filter (reflector); 4. Agent supply line; 5. Evaporator; 6. Patient side 22 mm male/15 mm female connector; 7. Gas monitor sampling port. Right panel: 1. Sealing cap; 2. Agent supply line; 3. Anaconda housing; 4. Conical sealing cap; 5. Special 50 ml syringe; 6. Syringe cap; 7. Gas monitor port closure.

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FJ. Beida, M. Soro, and A. Meiser

tage when compared to an ICU ventilator (open circuit) with a vaporizer attached is that the ACD can be used as a vaporizer device with a standard critical care ventilator, saving anesthetic loss like a low flow anesthetic circle system [32]. In fact, the ACD reduces anesthetic consumption to a level equivalent to that produced in a circle system using a fresh gas flow of 1.5 lImin [32]. The ACD is a disposable device for use in a single patient. The manufacturer recommends change of the ACD after 24 hours of use. However, it is known that the anesthetic conserving properties of the device are maintained for at least 72 hours . We change the ACD according to the same protocol we use for anti-bacterial HME filters.

Setting up the ACD in Clinical Practice The clinical set up at the bedside is depicted in Figure 2. The ACD is placed between the Y piece of the breathing system of the ventilator and the patient's endotracheal tube . The ACD incorporates a line for conducting the liquid anesthetic to the evaporator that is connected to a 50 ml syringe filled with the liquid anesthetic. Liquid anesthetics are drawn into the syringe from the bottle with a specific adapter to prevent leaks and ambient pollution. Use of the syringe and line provided with the ACD is mandatory as volatile anesthetics may dissolve unsuitable plastic materials. A standard syringe pump drives the syringe adjusting a determined pump-rate. Care must be taken to avoid bubbles in the syringe . Due to their high vapor pressure, volatile anesthetics will evaporate into these bubbles and make them grow if the syringe is exposed to high temperatures. The growing bubbles may pump liquid volatile anesthetics into the ACD, which may lead to overdose [33]. Therefore, heat sources must always be kept away from the syringe and if bubbles are detected the device should be disconnected from the patient and the reason investigated. To monitor the effective concentration of the gas in the blood (equal to that of the brain), a gas analyzer for measuring end-tidal anesthetic concentration must be used. The sampling line is connected to the sampling port of the ACD and in order to prevent ambient pollution, the sampling flow (150 ml/min) should also be scavenged. Alternatively, mainstream gas monitors can be used. In any case, the analyzer should be provided with alarms for a high-anesthetic end-tidal concentration not just to detect predictable fluctuations from syringe refills, but as a defense against human error and equipment failure.

Sampling line

Gas monitor

Gas sourcefor ejection suction

+

t

Syringe pump containing isoflurane

t

Ventilator

+- Hospital waste gas system outlet

Ejector suction Gas reservoir

Fig. 2. Clinical positioning of the AnaConDa at the bedside (From [45) with permission).

Sedation with Inhaled Anesthetics in Intensive Care

843

v

Fig. 3. Ventilation cycle showing ventilatory flow (V'), capnogram (CO 2) and the fraction of the anesthetic vapor (FVA) as measured with a gas monitor connected to the AnaConDa. Due to the physiological dead space (1 ), CO 2 will only rise after the start of expiration (Exp). Due to the dead space inside the AnaConDa (2), CO 2 will continue to be sampled by the gas monitor during the start of inspiration (Insp). The peak FVA, although occurring during inspiration, will be interpreted by most gas monitors as end-tidal fraction, because it is mixed with a high CO 2, During expiration there is a plateau representing the realistic value for end-tidal fraction (From [44] with permission)

Insp.

Exp.

FVA

However, not all standard gas monitors display inspiratory and end-tidal concentrations correctly. Because of the constant infusion of the anesthetic to the ACD and the anesthetic retained by the filter during expiration, the inspiratory concentration is not constant (Fig. 3) and displayed values do not represent the mean inspired concentration and must be ignored. During the end-expiratory pause , for the same reason, a 'cloud' builds inside the device and an abnormally high end-tidal concentration can be displayed. Following the anesthetic concentration curve shown in Figure 3, during expirat ion there is a plateau representing the realistic value for end-tidal concentration. Fortunately, some commercially available analyzers offer correct endtidal concentration values, for example, the side-stream Vamosv monitor (Draeger, Lubeck, Germany) and the main -stream Veo® monitor (Phasein , Danderyd, Sweden) . In order to minimize occupational exposure , an anesthetic gas scavenging system should be connected to the expiratory port of the ventilator. Canisters filled with special adsorbents are suitable for this purpose and are commercially available (Adalsorb'", Contrafluran'"). A more common option is to use an active suction system applied to the gas outlet. Care must be taken that the suctioning does not interfere with the function of the ventilator. Suctioning should be performed with small negative pressures but should allow high flows.

Selecting the Anesthetic Agent for use with the ACO The ACD can be used with isoflurane or sevoflurane but not with desflurane; this is not reflected by the charcoal layer as not enough molecules will condense on its surface because of the higher vapor pressure. Sevoflurane has become the halogen agent of first choice in the operating room for its physical, chemical, and pharmacokinetic properties; perhaps the same could be applied for sedation at the ICU. The low blood -gas partition coefficient of sevof-

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FJ. Beida, M. Soro, and A. Meiser

lurane and its low liposolubility provide a faster velocity of induction, control, and recovery than those provided by isoflurane. Yet, sevoflurane is currently limited to anesthetic use and for sedative procedures lasting less than twelvehours in the operating room, since its theoretical toxicity to kidney and liver, due to inorganic fluoride (a waste product from its metabolism) remains a controversial issue for longterm procedures. The authors, in an experimental model of anesthesia of long duration (5 days), compared a group of 12 pigs anesthetized with sevoflurane (end-tidal concentration of 2.5 %) versus a control group anesthet ized with propofol. We observed no significant differences in serum concentrations of fluoride between the groups and all values were under 50 umol/l (unpublished results). Similar results are being noted in a clinical study that is not yet finished, in patients after cardiac surgery sedated with sevoflurane or propofol for up to 72 hours (Dr. C. Rhom, Klinikum Ludwigshafen, Germany, personal communication) . In another study, 12 patients were sedated with 0.9- 1.5 % sevoflurane for on average of 70 hours without any adverse effects and opened their eyes 17±18 minutes after discontinuation [34]. However, most studies on inhalational sedation have been performed with isoflurane and it may be the agent of choice for very long periods of sedation at the ICU.

Selecting the Anesthetic Concentration and Co-adjuvant Therapy The end-tidal concentration for inhalational sedation should be slightly above MAC. wake (the steady-state alveolar end-tidal concentration at which 50 % of subjects respond appropriately to command) , which for volatile anesthetics is about one third of the MAC at which 'purposeful movement to a supramaximal stimulus' is avoided. In patients, the MAC.wake for isoflurane and sevoflurane have been determined to be 0.4 and 0.6 %, respectively. Adjuvant therapy with low-dose opioids will allow reduction of the end-tidal concentration of the volatile anesthetic. However, if a patient who is sedated intravenously is going to inhale a volatile anesthetic, opioid requirements will be less than half, and it is wise to stop the opioid temporarily until the blood concentrations have fallen.

Adjusting the Syringe Pump-rate with the ACD The infusion line and the evaporator of the ACD have a 'dead' volume of 1.2 ml. Hence, when starting the infusion, a rate of 25 mllh is recommended until the volatile anesthetic reaches the evaporator (about 3 min); this can be detected by carefully watching the infusion line or by the first signal detected by the gas analyzer. Alternatively, a bolus of 1.1 ml is recommended for priming the line. Depending on the minute volume and the desired concentration, the rate should then be selected according to a dosing table provided by the manufacturer. After 1 h, the rate has to be lowered slightly dur ing the subsequent 2- 4 h but very few readjustments are needed thereafter. With isoflurane, rates of 2- 5 mllhour are usually enough to achieve an end-tidal concentration of 0.3- 0.5 %. In our experience over up to 28 days the infusion rate very rarely needs to be modified. If sedation is not adequate, a bolus of 0.5 mlliquid isoflurane can be injected and onset of action will be more rapid than with any intravenous drug.

Sedation with Inhaled Anesthetics in Intensive Care

With sevoflurane, rates of 4-8 mllhour achieve an end-tidal concentration of 0.5- 1.0 %. However, during the first 6- 8 hours, infusion rates have to be reduced hourly to maintain the adjusted concentration. After that period, as a rule of thumb, the maintenance rate will be half the starting rate. Bolus doses to increase the end tidal concentration of sevoflurane should be 0.1- 0.2 ml for adults of normal weight, repeating a second or third bolus if necessary. Decreasing the end-tidal concentration of isoflurane or sevoflurane may be achieved by stopping the syringe for a few minutes while the end-tidal concentration is closely observed in the gas-analyzer. A faster decrease is obtained by removing the ACD.

Target-controlled Infusion for liquid Anesthetics We have developed a very precise pump-driven, manually-adjusted infusion scheme for the syringe pump ensuring the desired alveolar concentration of sevoflurane but also allowing the concentration to be increased and decreased. A key objective was to make a single infusion rate change per hour, to facilitate its clinical use. The pharmacokinetic model was based on Lowe's classical model [35]. The loss produced by the ACD was added to the patient's uptake estimated by Lowe's model to obtain the total infusion volume per hour. In order to determine the predictive performance of the model, we performed a clinical study on 60 patients anesthetized for short surgical procedures and on another 50 patients sedated in the ICU for 6 hours. Patients received sevofturane at an end-tidal concentration of 1 to 2.5 % in both studies. Infusion scheme performance was evaluated in terms of accuracy (median absolute performance error) and bias (median performance error). The model showed an overall accuracy of 3-8 % with a negative bias of 2- 4 %. These results indicated the excellent predictive performance of the scheme for sevoflurane sedation with the ACD. With this easy-to-handle scheme, a computercontrolled system is no longer essential. In fact, for the same patient, the infusion rate reduction in the 6 h fluctuates from 5 to 15 % (depending on target % and weight) and decreases over time . Hence, forgetting to modify the infusion rate for 2- 3 h is not likely to cause clinically relevant variations in the sevoflurane end-tidal concentration. This feature also increases system safety. Finally, this target -controlled infusion for liquid anesthetics is much more accurate than any target-controlled infusion algorithm used for intravenous drugs [36-37]. Two main differences between the algorithms can account for these results: The effect of drug metabolism is almost zero with inhaled anesthetics and control of the blood concentration is readily measurable with inhaled anesthetics through the end-tidal concentration.

Pump Infusion Rate at Equilibrium There is another simple way for estimating infusion rate of the syringe pump to obtain a determined concentration at equilibrium (when the patient's uptake is close to zero). This technique is based on a bench study where we determined losses of anesthetic through the ACD. Losses were small and constant for 24 hours and we found a linear relationship between the concentration of the agent lost through the ACD (Closs) and the patient's concentration (Cpat) over the clinically relevant concentration range with no difference between sevoflurane and isoflurane. The concentration lost was only 10 % of the patient's concentration (R = Clos,lCpat = 0.10).

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At equilibrium, anesthetic infused to maintain patient concentration is used to compensate losses through the ACD, so that

V gas infused (ml) = V gas lost (ml) or the equivalent: PR x (F/60) = Closs

X

VB

where PR is the pump rate in mllhour, F is the factor for calculating the volume of anesthetic vapor from liquid anesthetic (value: 1 ml isoflurane: 219 ml vapor; 1 ml sevoflurane: 208) and VE is the minute ventilation. Dividing both sides by CpaI' and re-arranging the equation, it follows: Cpat

= PR x (F/60)lR x VB = 34.7 x PR/VB [I]

From this equation it can be observed that Cpa! (and, obviously, Closs) is directly proportional to the pump rate and inversely proportional to the minute ventilation. It follows from a practical point of view, that when the concentration is re-adjusted or the minute ventilation is changed, the infusion rate may need readjustments. From [1] it is derived that, for sevoflurane, PR (mllh) = 0.03 x Cpat

X

VB

For example, for an end-tidal concentration of sevoflurane of 1 % (0.01) with a minute volume of 7 lImin (7000 mllmin) the pump infusion rate at equilibrium will be 2.1 mllh. Given that the metabolism of sevoflurane is neglected, pump rate values with this approach will produce end-tidal concentrations slightly below the target. However in our bench study, at higher concentrations and/or minute ventilation, this ratio R: Clos/Cpa! of 10 % increased sharply indicating a much higher proportion of losses. That is to say, when the number of molecules reaching the ACD exceeded a threshold, spill over occurred. For example, if by mistake a pump rate of 50 mllh instead of 5 mllh were programmed, Cpa! instead of the intended end-tidal concentration would increase to over 15- 20 % if no spill over occurred and R was constant [38]. But in fact Cpa! will only approach about 4 %. This 'spill over effect' offers some protection against an inadvertent overdose if large tidal volumes are used. With small tidal volumes spill over will occur only at higher concentrations. This is because a small volume with a high concentration will contain the same number of molecules as a larger volume with a lower concentration. The spill over effect also adds to system safety. By decreasing the capacity of the device, it should be possible to make use of this protective effect for smaller tidal volumes. Likewise, this would reduce dead space making ACD more suitable for children.

Conclusion Providing adequate and appropriate sedation for critically ill patients is a difficult task. The actions and side-effects of intravenous drugs are difficult to control. A feasible alternative today is inhalational anesthetics, which have been used for sedation over the last two decades. Clinical experience has been described in adults and children for sedation from 10 minutes to 30 days with different inhaled agents [39-42]. The better performance of these agents when compared to intravenous drugs can be seen from the results of three randomized clinical studies [21,22,43] and from two

Sedation with Inhaled Anesthetics in Intensive (are

nice reviews [26, 44]. Today, to deliver inhaled anesthetics in the ICU, an anesthesia machine is no longer needed. Isoflurane and sevoflurane can be applied simply and efficiently via the ACD connected to a normal ICU ventilator. Titration of liquid anesthetics in clinical practice is easy because their blood concentration can be monitored on-line through the end-tidal concentration by means of a gas analyzer. Clinical experiences with the ACD since 2001 have been published [45-50] and its use is increasing in European countries. References 1. Fraser GL, Prato BS, Riker RR, Berthiaume D, Wilkins ML (2000) Evaluation of agitation in ICU patients: Incidence, severity, and treatment in the young versus the elderly. Pharmaco therapy 20:75- 82 2. Mazzeo Aj (1995) Sedation for the mechanically ventilated patient. Crit Care Clin 11:937955 3. Durbin CG jr (1994) Sedation in the critically ill patient. New Horiz 2:64-74 4. Rotondi A], Chelluri L, Sirio C, et al (2002) Patients' recollections of stressful experiences while receiving prolonged mechanical ventilation in an intensive care unit. Criti Care Med 30:746-752 5. Jones C, Griffiths RD, Humphris G, Skirrow PM (2001) Memory, delusions , and the development of acute post-traumatic stress disorder-related symptoms after intensive care. Crit Care Med 29:573- 80 6. Scragg P, Jones A, Fauvel N (2001) Psychological problems following ICU treatment. Anaesthesia 56: 9- 14 7. Schelling G, Stoll C, Haller M, et al (1998) Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 26: 651-659 8. Kress JP, Pohlman AS, O'Connor MF, Hall JB (2000) Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471-1477 9. Kress JP, Gehlbach B, Lacy M, et al (2003) The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med 168:1457 -1461 10. Weatherburn C, Endacott R, Tynan P, Bailey M (2007) The impact of bispectral index monitoring on sedation adm inistration in mechanically ventilated patients. Anaesth Intensive Care 35:204 - 208 11. Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ (2000) Sedation in the intensive care unit . JAMA 283:1451-1459 12. lzurieta R, Rabatin jT (2002) Sedation during mechanical ventilation: a systematic review. Crit Care Med 30:2644-2648 13. Payen JF, Chanques G, Mantz J, et al (2007) Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology 106:687 - 695 14. Fudickar A, Bein B, Tonner PH (2006) Propofol infusion syndrome in anesthesiaand intensive care medicine . Curr Opin Anaesthesiol 19:404-410 15. Wysowski DK, Pollock ML (2006) Reports of death with use of propofol (Diprivan) for nonprocedural (long-term) sedation and literature review. Anesthesiology 105:1047-1051 16. Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, de Smet AM, Kalkman CJ (2001) Longterm propofol infusion and cardiac failure in adult head-injured patients. Lancet 357:117-118 17. Khamiees M, Amoateng-Adjepong Y, Manthous CA (2002) Propofol infusion is associated with a higher rapid shallow breathing index in patients preparing to wean from mechan ical ventilation . Respir Care 47:150-153 18. Sackey PV, Radell PI. Granath F, Martling CR (2007) Bispectral index as a predictor of sedation depth during isoflurane or midazolam sedation in ICU patients. Anaesth Intensive Care 35:348-356 19. Kong KL, Willatts SM, Prys-Roberts C (1989) Isoflurane compared with midazolam for sedation in the intensive care unit. BMJ 298:1277-1289

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FJ. Beida. M. Soro, and A. Meiser 20. Millane TA, Bennet ED, Grounds RM (1992) Isoflurane and propofol for long-term sedation in the intensive care unit a crossover study. Anaesthesia 47:768-774 21. Spencer EM, Willatts SM (1992) Isoflurane for prolonged sedation in the intensive care unit; efficacy and safety. Intensive Care Med 18:415-421 22. Meiser A, Sirt! C, Bellgardt M, et al (2003) Desflurane compared with propofol for postoperative sedation in the intensive care unit. Br J Anaesth 90:273- 280 23. Johnston RG, Noseworthy TW, Friesen EG, YuleHA, Shustack A (1990) Isoflurane therapy for status asthmaticus in children and adults. Chest 97:698-701 24. Maltais F, Sovilj M, Goldberg P, Gottfried SB (1994) Respiratory mechanics in status asthma ticus. Effects of inhalational anesthesia. Chest 106:1401- 1406 25. De Hert SG (2006) Volatile anesthetics and cardiac function. Semin Cardiothorac Vase Anesth 10:33- 42 26. Kong KL, Bion JF (2003) Sedating patients undergoing mechanical ventilation in the intensive care unit. Winds of change? Br J Anaesth 90:267- 269 27. Halpenny D (2000) Sevoflurane sedation. Can J Anaesth 47:193-194. 28. Ibrahim AE, Ghoneim MM, Kharasch ED, et al (2001) Speed of recovery and side-effect profile of sevoflurane sedation compared with midazolam . Anesthesiology 94:87- 94 29. De Hert SG, Van der Linden PJ, Cromheecke S, et al (2004) Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 101:299-310 30. De Hert SG, Van der Linden PJ, Cromheecke S, et al (2004) Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 101:9- 20 31. Enlund M, Wiklund L, Lambert H (2001) A new device to reduce the consumption of a halogenated anesthetic agent. Anaesthesia 56:429-432 32. Tempia A, Olivei MC, Calza E, et al (2003) The anesthetic conserving device compared with conventional circle system used under different flow conditions for inhaled anesthesia . Anesth Analg 96:1056-1061. 33. Henning JDR (2004) Excess delivery of isoflurane liquid from a syringe driver. Anaesthesia 59:1251 34. Guzman RE, Zinker E, Horta E, et al (2003) Sevoflurane sedation in intensive care patients . Crit Care Med 30:158a (abst) 35. Lowe HJ (1981) The quantitative practice of anesthesia. Baltimore, Williams and Wilkins. 36. VeselisRA, Glass P, Dnistrian A, Reinsel R (1997) Performance of computer-assisted continuous infusion at low concentrations of intravenous sedatives. Anesth Analg 84:1049-1057 37. Swinhoe CF, Peacock JE, Glen JB, Reilly CS (1998) Evaluation of the predictive performance of a 'Diprifusor' TCI system. Anaesthesia. 53 (suppl 1):61-67 38. Berton J, Sargentini C, Nguyen JL, Belii A, Beydon L (2007) AnaConDa reflection filter: Bench and patient evaluation of safety and volatile anesthetic conservation . Anesth Analg 104:130-134 39. Arnold J, Truog R, Rice S (1993) Prolonged administration of isoflurane to pediatric patients during mechanical ventilation. Anesth Analg 76:520-526 40. Tanigami H, Yahagi N, Kumon K, et al (1997) Long-term sedation with isoflurane in postoperative intensive care in cardiac surgery. Artif Organs 21:21- 23 41. Mirsattari S, Sharpe M, Young G (2004) Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 61:1254-1259 42. Shankar V, Churchwell K, Deshpande J (2006) Isoflurane therapy for severe refractory status asthmaticus in children. Intensive Care Med 32:927- 933 43. Willatts SM, Prys-Roberts C, Kong KL, Spencer EM (1989) Isoflurane compared with midazolam in the intensive care unit. BMJ 299:389 44. Meiser A, Laubenthal H (2005) Inhalational anesthetics in the ICU: theory and practice of inhalational sedation in the ICU, economics, risk-benefit . Best Pract Res Clin Anaesthesiol 19:523-538 45. Sackey P, Mart!ing C, Granath F, Radell PJ (2004) Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device. Crit Care Med 32:2241- 2246. 46. Sackey P, Mart!ing C, Radell P (2005) Three cases of PICU sedation with isoflurane delivered by the 'AnaConDa'. Paediatr Anaesth 15:879-885

Sedation with Inhaled Anesthetics in Intensive Care 47. lung C, Granados M, Marso! P, Murat I, Gall 0 (2007) Use of sevoflurane sedat ion by the AnaConDa device as an adjunct to extubation in a pediatric burn patient. Burns [Epub ahead of print] 48. Soro M, Beida FJ, Badenes R, Alcantara MJ (2004) Use of the AnaConDa (Anestesia Conserving Device) with sevoflurane in critical care pat ients. Eur J Anaesthesio l 21 (supp l 32):708a (abst) 49. Sackey PV, Martli ng CR, Nise G, Radell PJ (2002) Sedation of ICU patients with isoflurane using the anest hetic conserving device. Intensive Care Med 28 (suppl l) :347a (abst) 50. Sackey PV, Martling CR, Nise G, Radell PJ (2005) Ambient isoflurane pollution and isoflurane consu mption duri ng intensive care unit sedation with the anesthetic conserving device. Crit Care Med 33:585- 590

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Section XXII

XXII Outcomes

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Time to Use Computerized Physician Order Entry in all ICUs? J.

ALI and A.

VUYLSTEKE

Introduction The adage "To Err is Human" has been recognized by many for a very long time, and gives a sense of the inescapable to our common mistakes. One could, therefore, argue that it might have been wrong to highlight that sense of unpreventable in a 1999 report by the Institute of Medicine (USA) telling us that between 44,000 and 98,000 patients die per year due to medical errors [1]. And, indeed, the Institute chose the more inspiring title of "Preventing Medication Errors" when it subsequently reported in 2006 that there is approximately one medication error per patient per day. This title at least suggested that it might be possible to act and decrease this burden [2]. The UK Department of Health went one step further when it reported that adverse events caused harm to patients in up to 16 % of admissions , and published 'An organization with a memory', urging us to learn from past mistakes to build a safer health care environment [3]. These numbers are worrying and it is not surprising that health organizations around the world have responded by setting up working groups, institutes, and new commissions. Amongst others, one can cite the Leapfrog group (http ://www.leapfroggroup.org) in the USA, and the National Patient Safety Agency (http://www. npsa.nhs.uk) in the UK. Both have similar aims in 'leveraging dramatic improvements in the safety and quality of healthcare'. The Leapfrog group specifically identified addressing intensive care unit (lCU) physician staffing, promoting evidence based hospital referrals and computerized physician order entry (CPOE) as 'safety leaps' to reduce preventable medical errors.

Medication Errors and Adverse Drug Events Medication Error

The National Coordinating Council for Medication Error Reporting and Prevention (http://www.nccmerp.orgl) defines medication error as: 'any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of health professional, patient or consumer'. By definition, these errors are preventable. Medication errors are an internationally recognized source of significant morbidity and mortality in hospitalized patients, and as such are highlighted in both of the aforementioned reports as a major cause of healthcare related deaths. The Institute of Medicine estimates at least 7,000 deaths per year are accounted for by medication errors in the US alone, and it is reported that medication use is responsible for at

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least 20 % of adverse events in hospitalized patients [4]. Medication errors are, therefore, common . One study of handwritten prescriptions in an ICU reported that 6.7 per 100 prescriptions contained a medication error [5], whilst another reported an error rate of 19.4 per 100 patient days [6]. The Intensive Care Society's Working Group on Adverse Incidents in Intensive Care reviewed prescription errors in the UK [7]. This review involved 24 critical care units contributing data on their prescription errors over a four week period. As many as 15 % of prescriptions were said to contain errors, with up to 20 % of those classified as significant, serious or potentially life threatening. Of the erroneous prescriptions, 60 % were for intravenous drugs, with unusual or irregularly timed prescriptions more commonly associated with errors. The most common incorrect prescriptions, accounting for 27 %, were for potassium chloride, heparin, magnesium sulfate, paracetamol and propofol. In this comprehensive survey, the four commonest categories of error were: Not writing the order according to the British National Formulary recommendations (14 %), ambiguous medication order (13 %), non-standard nomenclature (11 %) and illegible writing (10 %) [7]. Just to prove that this is not always your neighbor's problem, we investigated our own unit (25 beds with rigid protocols in place and consultant led ward rounds three times a day) and confirmed that medication errors are indeed common . Of 2707 regular drug prescriptions reviewed over a 2-week period, 4 % had no dose recorded, 8 % used non-generic drug names and 7 % had no allergy indication completed. From these data and others, it can be extrapolated that at least 1 % of inpatient medication errors leads to an adverse drug event - although 7 % have the potential to do so. Medication errors can occur at the prescribing, dispensing or administration stages. However, it is suggested that most preventable errors occur at the prescribing stage (estimated to be around 56 % of all errors) [6]. As such, it is this stage that has received the most focus with regard to reducing errors and improving patient safety. A study into the types of prescribing errors that occur identified that incorrect dose was responsible for 39 % of errors, with incorrect frequency, nomenclature, presence of drug allergy and incorrect medication following in decreasing frequency [8]. Lack of knowledge of how to appropriately use a medication (knowing indications, contraindications, or dosing guidelines of the drug) is the leading cause for prescribing errors (over 50 % of cases); followed by a lack of knowledge of the patient (including failure to adjust for patients pathological state such as renal failure or co-morbidities). Other, less frequent causes include mental slip, transcription errors, non-adherence to policy, and illegible handwriting [8]. Adverse Drug Event

An adverse drug event is defined by the World Health Organization (WHO) as: 'any response to a drug which is noxious, unintended, and occurs at doses used for prophylaxis, diagnosis or therapy'. Due, presumably, to the large number of drugs administered, the utilization of the intravenous route and the incidence of organ failure, the rate of actual and potential adverse drug events is said to be almost twice as high in critical care as compared to general care units [9]. An adverse drug event is a significant problem, both for the patient and hospital concerned. It may prolong hospitalization, increases mortality and morbidity, and increases cost. In the US alone, at least $1.5 billion is spent per annum and an extra 1.5 million hospital days accounted for because of adverse drug events, highlighting the enormity of this problem [10].

Time to Use Computerized Physician Order Entry in all ICUs?

Prevention of Medical Errors and Adverse Drug Events

One intervention that has been shown to reduce the incidence of adverse drug reactions in rcus, is the involvement of a clinical pharmacist with their skills of promoting the safe and effective use of medications [11]. The presence of a clinical pharmacist on rcu ward-rounds has a significant effect on reducing the incidence of adverse drug event and in preventing and intercepting errors. The main interventions leading to these effects include clarification or correct ion of an order, provision of drug information, and recommendation of alternative therapy. Others include identification of drug interaction, systems error or drug allergy, approval of non -formulary drug use, provision of special orders , and identification of adverse drug events. Further interventions are, however, required and organizational and environmental strategies, such as the use of information technology, are progressively imposing themselves as part of a solution.

Computerized Physician Order Entry to the Rescue! One highlighted use of information technology that is reported to have a substantial potential for improving the medication ordering process is CPOE. What is (POE?

At the most basic level, CPOE is a clinical software application designed specifically for use by physicians to write patient orders electronically rather than on paper charts and prescription pads [12]. At this basic level, CPOE immediately offers the advantage of guaranteed legibility of prescriptions, completeness of orders, and traceability. Nursing and pharmacy staff can then access the software to retrieve and execute the prescribed orders . The information can be reorganized to be presented in the most appropriate way to the task in hand: A nurse may want to see only all orders planned in the next hour, but a pharmacist may want to see the total number of doses planned for the duration of the patient stay. From this basic level, the system can evolve in complexity. The orders can be based on a pre-defined model , with pre-defined doses, quantity to mix, schedule and route of administration. Automatic adjustment to weight can be included. The amount of flexibility can be set so that the prescriber can or cannot modify what has been defined in the system. The system can alert the prescriber that an allergy recorded for the patient makes a specific medication inadequate, or ask for confirmation for the order, or sometimes prevent a specific order altogether. The system may ask for another healthcare worker to confirm an order out of the norm. The system can be linked to other electronic database s, allowing immediate access to guidelines and formularies, or even allowing interactive integration (e.g., flagging interactions, requesting automatic blood levels for specific drugs , suggesting dosages in case of renal failure...). Traceability is immediately enhanced and review of prescriptions is facilitated as the information can be aggregated and analyzed. Automatic counting and restocking is possible.

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What are the Benefits of (POE? Legibility Illegible prescriptions are a major cause of medication error. They force the person reading the prescription to make their own interpretation. If that interpretation is wrong the drug may be incorrectly transcribed by another doctor, incorrectly dispensed by the pharmacist or incorrectly administered by a nurse. In all instances the patient is at risk. The prescription should 'always be clear, unamb iguous and leave no doubt as to the prescribers intentions ' [13]. There are numerous cases where legibility issues have lead to harm particularly involving drug name misinterpretation and dose ambiguity. Examples can be found in abundance in the literature or the press. A simple but dramatic example is the prescription of 6 units of insulin, abbreviated as 6 'lU', and administered as 61 U [14]. CPOE has been shown to have a significant impact on legibility [15]. The very fact that drugs are usually selected from lists, with recommended route, frequency, and doses - with alerts if any of the fields are blank - and the fact they are displayed on the screen in a standard font removes any legibility issues resulting from handwritten prescr ibing and insures that all prescriptions are complete. From our own unit, an audit performed before implementation of a clinical information system demonstrated that from 2707 prescriptions the signature was legible on only 32 %. This increased to 100 % after the implementation due to the nature of the system requiring the prescriber to logon. Unambiguous record of administration Patients may suffer harm from not receiving a medication, or receiving the same medication twice in a short interval of time. A CPOE system can alert nurses that it is time for administration, or that a drug has indeed already been given. Clinical decision support However, where CPOE really comes into its own is with clinical decision support functionalities, where the application provides guidance and/or incorporates knowledge to assist the clinician in entering complete, accurate, and appropriate patient care orders . As described previously, clinical decision support ranges from the simple to the complex. The simplest level of clinical decision support should include: • Predefined completed prescriptions. • Time-management feature - both at prescribing and administration levels. • Preventing the prescription of drugs to which the patient is allergic, including cross-reactions such as cephalosporins with penicillin allergy. The next level includes integration of information recorded in the same information technology system: • Link to local prescribing guidelines, so that upon selecting a particular drug, a relevant guideline can easily be accessed, allowing the prescriber to insure that their prescribing is adhering with hospitals policy. • Assessing for drugs contraindicated in certain patients. • Presenting drug costs and recommending cheaper generic equivalents with equal efficacy, in an attempt to promote cost effectiveness. • Specific or expensive drug guidance, insuring use is within the hospital guidelines.

Time to Use Computerized Physician Order Entry in all ICUs?

• Presenting laboratory test costs and redundant laboratory warnings, which have been proven to reduce the ordering of laboratory tests. One author quotes a 4.5 % reduction in tests ordered after the presentation of an alert displaying the cost; and a 69 % cancellation rate of tests, when the prescriber was presented with an alert indicating that this test had been ordered recently. Combined, these were said to have lead to a cost saving over 10 years of $1.9 million [16, 17]. • Assessing laboratory values in determining suitability of a drug or dose, e.g., relevant blood results displayed on the ordering screen - such as therapeutic drug monitoring for variable dosing regimens , e.g., warfarin. • Corollary orders, e.g., when prescribing a loop diuretic, CPOE should suggest prescription of a potassium supplement and ordering of serum creatinine and potassium levels [18]. • Preventing duplicate prescription when different physicians may each take the responsibility of prescribing a drug, without checking to see whether it has already been prescribed [15]. • Suggesting appropriate doses in pediatric patients, where calculations are often required to ensure correct dose, based most commonly on weight, but also body surface area estimates. • Elderly dosing guidance, for drugs where a reduction in dose is commonly recommended in geriatric patients. • Adjusting doses for renal and/or hepatic impairment. • Suggesting appropriate antibiotic use. More complex clinical decision support requires interfacing the CPOE system with other information technology systems, either within the hospital, or located in remote locations: • Assessing for drug-drug interactions based on the pharmacy drug database. • Assessing national drug database . Standardization of care CPOE can promote the standardization of care of patients with similar conditions at the time of prescription ordering. This can be achieved in several ways: Standardized order sets where a predefined set of orders will be submitted due to the presence of a particular diagnosis; presentation of clinical guidelines for the optimal use of medications; and alerts recommending additional or adjunct orders [19]. While physicians usually understand and accept guidelines, they do not remember when the situation arises and CPOE can promote the adherence of physicians to a series of prescribing guidelines, using at least four mechanisms: • Medication selection - Upon attempted prescription of an alternative, an alert appears indicating the recommended choice (based on hospital pharmacy guidelines - lower cost, similar side effect profile and efficacy). A study demonstrated an increase in the use of the recommended drug from 12 % of Hj-blocking agents prescribed, to 95 %, an effect which persisted at 2-year follow up [20]. • Dosage guidance - The CPOE suggests a dose, by it being highlighted on the drop down list. Although the mean doses were similar before and after, there was an 11 % reduced standard deviation post-implementation of the CPOE, suggesting that more physicians were selecting the recommended dose. In addition, a 30 % reduction in the standard deviation of frequency of administration was also noted [20].

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• Frequency recommendations - Following a review of literature, a hospital decided that three times daily ondansetron would be as effective as four times daily. They attempted to implement this change in practice by education, which failed. They then highlighted the 'three times a day' in the frequency pull down list for ondansetron and assessed the effect on prescribing practice. A dramatic change was noted. Before the intervention 90 % orders were four times daily and 6 % three times daily. After the intervention, 14 % of orders were four times daily whilst 75 % of orders were three times daily [20). • Consequent orders - an intervention was implemented that gave the physician the opportunity to prescribe heparin after an order for bed-rest was placed. Before the intervention 24 % of orders for bed rest were accompanied by orders for heparin. After the implementation of this intervention, compliance with the guideline had increased to 47 % [20). Cost-effectiveness Cost of CPOE is one of the major impediments to the widespread implementation of this technology - in particular the large up-front investment [21). The 'total cost of ownership' can be defined as the total cost of acquiring, installing , using, maintaining, changing, upgrading, and disposing of an information technology system over its predicted useful lifetime. This takes into account the costs not only of the hardware, but aspects such as training all users which is a significant undertaking in itself. Calculating return on investment for a CPOE project may not be straightforward for several reasons. It may be difficult to determine costs of key processes; benefits may not be easily amenable to measurement - such as improved interdepartmental communication and strategic positioning - and many organizations do not measure rates of medication errors and adverse drug events [21). However, when looking in depth at the costs and financial benefits derived from the CPOE system at a nO-bed academic tertiary care centre in the US (Brigham and Women's Hospital), it was noted that the majority of savings were accrued from a small number of interventions [22). The areas in which the greatest cost benefits were observed were (in millions): renal dosing guidance ($6.3); nurse time utilization ($6.0); specific or expensive drug guidance - such as showing costs and suggesting alternatives for expensive antibiotics like vancomycin ($4.9); adverse drug event prevention ($3.7); and laboratory charge display and redundant laboratory test warnings ($1.9) [16). Another study, in an ICU, after the implementation of an antibiotic advisor function demonstrated a reduction in hospital stay by nearly 3 days and a 25 % reduction in costs per patient [22). Antimicrobial prescription guidance Antibiotics are said to be one of the costliest drug expenditures in hospitals, accounting for in excess of 25 % of total drug costs. It is also reported that as much as 50 % of antibiotic use is inappropriate. The consequences of such widespread inappropriate antibiotic use are threefold: Antimicrobial resistance, adverse drug reactions, and cost [23). A study was conducted in a hospital following the implementation of local clinician-derived consensus practice guidelines into CPOE. The results were very positive [23). The proportion of patients who received antibiotics increased from 32 % to 53 %. However, the proportion of the drug budget attributable to antimicrobials decreased from 25 % to 12 %. The average cost per treated patient decreased from $123 to $52. The authors noted that both antibiotic-associated adverse reactions and mortality had decreased. In addition, microbiology resistance patterns had been sta-

Time to Use Computerized Physician Order Entry in all ICUs?

ble, presumably due to improved use of antibiotics. Therefore, there was a demonstrated financial benefit attributable to this computer-assisted decision support function with positive clinical outcomes also [23]. Another study in a 648-bed tertiary referral center in the US, also reported their results after the implementation of such a function in the form of a randomized controlled trial [24]. The types of alerts made included: Use of restricted antimicrobial, oral equivalent indicated, double coverage of antimicrobial therapy, and use of specific antibiotic without specified organism (e.g., vancomycin without methicillin-resistant Staphylococcus aureus [MRSAJ). The authors reported that more patients had inappropriate or inadequate therapy in the control arm: 20 % compared with 10 % [24]. They claimed to have saved $84,000 on antimicrobials compared with the control group over this 3-month study, suggesting annual savings in the order of $672,000. They noted that patient outcomes were not significantly different, but tended toward more favorable outcomes in the intervention arm. Thus significant financial savings can be made with the implementation of such a system [24]. At Brigham and Women's Hospital, two antibiotic guidelines were implemented with significant savings associated. Vancomycin use was restricted to explicit indications, and prompts to discontinue after three days. This led to 32 % fewer vancomycin orders, saving $20,042 annually. The second guideline involved ceftriaxone being recommended as daily rather than twice daily dosing. An 80 % uptake of this guideline was reported to save $175,094 annually [16]. Dosing in renal insufficiency Physicians often do not adjust medications in the presence of renal insufficiency, which can lead to adverse events that are preventable, as the accumulation of a renally cleared drug is predictable in such patients. CPOE systems can use patient data - age, weight, sex, creatinine level - to calculate creatinine clearance as a correlate of renal insufficiency. This is usually based upon the Cockcroft and Gault equation [25]. At the Brigham and Women's Hospital they reported $6.3 million savings over 10 years due to the presence of such a renal dosing system [16]. CPOE can highlight drugs that are contraindicated in renal sufficiency and it was noted that after the implementation of alerts informing of the contraindication, the likelihood of a patient receiving a dose of a contraindicated drug reduced from 89 % to 47 % - mostly due to cancellation of orders based upon the alerts [26]. Avoidance of adverse dr ug events At least two studies demonstrate the ability of CPOE systems to reduce medication errors and thus improve patient safety. One group summarized a prospective time series analysis conducted at an academic tertiary care hospital [27]. Over four and a half years, four periods of data collection were conducted, with a baseline, and post-CPOE implementation, with increasing degrees of sophistication of their clinical decision systems functions. Their primary outcome was a measure of nonmissed dose medication errors - those they deemed most likely to cause harm (excluding missed-dose errors where the drug was not available to nursing personnel at the time of requested administration). The study showed an 81 % reduction in non-missed-dose error rate from 142 to 27 per 1000 patient days. Also notable was a reduction in the non-intercepted serious medication error rate, which consisted of preventable adverse drugs events and non-intercepted potential adverse drugs events, which fell from 8 to 1 per 1000 patient days. The authors reported that the non-missed-dose error rate fell more in the 1CU than in general units: 248 to 35 per 1000 patient days in the 1CU compared with 109 to 23 in the general units [27].

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Another group performed a prospective, controlled, cross-sectional trial in the ICU of a tertiary care university hospital comparing paper based and computer based units [28]. They presented their findings based on three levels of severity: Minor medication prescription errors , intercepted medication prescription errors, and serious medication prescription errors. These were then divided into: Non-intercepted potential adverse drug events and total adverse drug events. At each, the computerized unit had statistically significantly lower rates of error. Overall, the reduct ion in medication prescription errors was reported as 87 % (from 27 % to 3 %) of all orders. Minor medication prescription errors fell from 18 % to 1 % of orders. These were mainly errors of completeness and legibility and were deemed unlikely to be harmful. The intercepted medication prescription error rate fell from 4 % to 1 %. These are potential errors that did not reach the patient. Non-intercepted potent ial adverse drug events fell from 4 % to 2 % of all orders and were errors that reached the patient but caused no harm. Adverse drug events fell from 1 % to 0.15 %. When considering intercepted and serious medication prescription errors there was a 67 % decrease upon implementation of the CPOE system. Hence, these authors commented that the CPOEhad the greatest potential to eliminate errors at the lowest severity. The importance of this finding though, is that it is the more severe errors that have the greatest impact on morbidity and mortality, and it is these that appeared to be reduced the least, albeit by statistically significant amounts. The authors accept that with greater clinical decision support functionality, their system would likely be able to have prevented many more of the higher severity medication prescription errors [28]. Education Interestingly, it is unknown if such an interaction affects the learning experience in any way. A situation can be foreseen where physicians grow dependent on CPOE, due to the tasks it performs automatically, such as adjusting doses for renal insufficiency. On the other hand , it has also been proposed that the frequent presentation of guidelines and recommendations may enhance learning [20]. A study studied the impact of junior doctor tra ining by looking at the effect of a clinical decision support system that provided instant feedback if complex orders involving clearance calculations were deemed incorrect. With this system, the error rate was found to be approximately 23 % when initiated, which they suggest is low enough that it suggests that there is not dependence on dosing assistance by the system. The error was found not to change significantly between the end and start of the training year, which also suggests against dependence on the system, but might indicate no benefit in training [29]. This remains an area of future research.

(POE in Practice Shifting from Paper to Computer

The change from paper based prescriptions to a CPOE system, has many theoretical benefits, inasmuch rendering prescription readable by all and the availability of information at the point of need. Despite these recommendations, uptake has been slow and it has been estimated that only 15 % of US hospitals had even partially implemented CPOE by 2002. In the UK, the National Health Service Plan stated that 75 % of hospitals should have implemented electronic patient record systems by 2004 in order to make information available at the point of need [30]. This has not been achieved to date.

Time to Use Computerized Physician Order Entry in all ICUs?

Failure and delays in implementation are believed to be due to reasons including cost of implementation and hospitals waiting to see results of CPOE implementation at other institutions before committing themselves [31]. Many clinicians still need convincing that the investment in time, money, and training, and that the perceived inconvenience of change and interfacing through a machine at the patient bedside, are worthwhile. Implementation of (POE into Intensive (are Units

Clinical information systems with CPOE and clinical decision support are one of the newer technological advances in the ICU environment. ICU care routinely involves complexities that are rarely found elsewhere in the hospital. It has already been alluded to that there are many features of ICU patients that render them more susceptible to medication errors and adverse drug events. Hence, there is perhaps the most to gain by implementation of a system that has been demonstrated to reduce the incidence of such events in ICUs [32]. However, implementation of CPOE is not a simple undertaking, and the project should be well organized, as has been demonstrated by the cases where implementation failed. One important point that arose from these cases is that a system designed for general wards is unlikely to be adequate to accommodate the types of complex care found in the ICU environment. However, the reverse might be possible - ICU systems might meet the need of the wards if flexible enough. Research on physician attitudes has demonstrated that not all systems are equal, and so purchasers must assess the quality of systems and, most importantly, ensure that the system will not cause a disruption to the workflows present in the unit. In recognition of the differences required of CPOE systems within the ICU environment, the Society of Critical Care Medicine created a report, which describes the 'essential elements required for CPOE systems to be functional in the ICU: This covers areas such as: system and data access, special requirements for ICU orders, patient safeguards and order processing requirements [33]. Expert opinion suggests that successful implementation requires (Table 1): • Motivation for implementation - where will funding come from? What are the objectives of implementation? • Vision, leadership , and personnel - effective leadership for the duration is necessary. The project leader must have a realistic idea of what can be achieved and the enormity of the task ahead . There must be the support of physician leaders and other clinical staff, ensuring that an environment promoting constructive feedback exists. • Costs - ensure that 'total cost of ownership' is appreciated including the costs of training. • Integration of workflow, health care processes - clinicians resent disruption of their patient care activities and so CPOE must integrate into existing environments and workflows. Programs developed off site and introduced into the clinical environment often fail to meet clinician needs - systems should have enough flexibility to allow trouble free merging with existing clinical pathways [32]. • Value to users/decision support systems - users of the system must understand the benefits that will be provided by the system, and indeed be involved in the development of decision support and other benefits that affect their workflow. Indeed , it has been noted elsewhere that to obtain support, generate commit-

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•

•

•

•

ment, and ensure user-driven design and implementation users must be involved early, thoroughly, and systematically [34]. Project management and staging of implementation - implementation must be carefully planned. 'People issues' are of highest priority. Users must be kept informed, and there must be a critical mass of users ready and trained for the implementation. A plan with realistic milestones will go far. Technology - includes assessment of the quality of the application including ability to interface with current and future systems, customizability and user friendliness. Users should easily be able to modify the system on site. User acceptance is of utmost importance and speed is the essence. One author quotes: 'Any time a screen takes more than 2 seconds to appear the clinicians deem it unacceptable. If they have to page through more than 2 - 3 screens to get to what they want they turn away. If the system is not intuitive they will not take time to learn it' [32]. Training and support 24/7 - an important feature identified is the availability of live help 'at the elbow' at the time of implementation and for some time after. Support at the time of going live is thought to be more important to the success of implementation than pre-implementation training. Learning, evaluation and improvement - recognition that implementation is ongoing, and that feedback is essential for the molding of the system, particularly at the beginning [35].

Table 1. Key points required for successful implementation of a clinical information system in ICU

Motivation

Defined objectives of implementation.

Vision and leadership

Effective leadership. Realistic expectations. Support to and from all clinical staff. Environment promoting constructive feedback.

Costs

Identified funding. Correct estimation of 'total cost of ownership: Costs of training. Cost of maintenance.

Integration of workflow processes

Integration into existing environments. Allow flexi bility in design required for merging with existing clinical pathways [32].

Value to users

Users must understand benefits. Users involved in development [34].

Project management

Careful planning. Users must be kept informed. Realistic milestones.

Technology

Ability to interface with current and future systems. Customizability (on site, by user). User friendliness. Speed is the essence [32].

Training and support 24 7

Live help. Support at time of going live (important for success).

Learning and improvement

Customization to continue for ever. Feedback is essential for the molding of the system [35].

Time to Use Computerized Physician Order Entry in all ICUs? Impact on Staff

Nurses Nursing staff acceptance of clinical information systems and CPOE is of vital importance to the succes s of such projects, as nurse's workflow patterns are significantly altered in evolving from a paper based system of working. Several studies have looked at the impact of nursing activity and nursing attitudes to such systems. One report found that in an ICU there was a 10 % decrease in the nursing time spent charting from 16 % to 4 %, and a decrease in time spent gathering information from 7 % to 4 %. However, a significant amount of time was spent interacting with the computer terminals, approximately equal to the time saved on other activities suggesting no net time saving was made that could have been applied to other patient care activities [36). Similarly, another study demonstrated no increase in time devoted to direct patient care. However, these authors commented that nursing documentation was more complete and always legible [37). In contrast, a cardiothoracic ICU reported that although admission procedures were longer - 18.1 compared with 16.8 minutes - a 30 % reduction in documentation time led to a saving of 29 minute per 8 hour shift that was completely re-allocated to patient care [38). One study looked into the attitudes of nurses towards such systems: 78 % of nurses agreed that once learned, the system was easy to use and 63 % said that the system made their work easier, 13 % remained neutral [41). The greatest strength of the system that they identified was the legibility; 91 % reported that the system had not reduced their time with patients, 56 % agreed that overall quality of care had improved, 69 % reported high satisfaction, and 75 % were in favor of continuing with the system [39]. Physicians The importance of physician acceptance and willingness to evolve to computerized information systems is vital to the success of such systems. This is perfectly illus trated by the implementation of CPOE at the University of Virginia Medical Centre, where widespread discontent amongst physicians led to a boycott of the system [40]. One important issue that has been raised is the time taken for prescribing with the CPOE, compared with handwritten prescriptions. One study presented results that it takes approximately 20 seconds to handwrite a prescription compared with 55 seconds to prescribe the same drug on a CPOE system [15). This finding was confirmed in another study which noted that there was an increase in the proportion of time a physician spent ordering by 44 minutes for medical physicians and 79 minutes for surgical phy sicians per day [41). In contrast though, one study suggested that there was no significance in the time difference, and that experienced users are in fact time neutral with handwritten prescriptions [42). Although the data are not consistent, one author suggests that these calculations underestimate the time taken for handwritten prescribing, because they fail to take account of the true time needed which includes finding the chart, writing the order, delivering the order to the nurse, transmitting the order, or time sp ent fixing or clarifying errors resulting from handwriting or other errors common to handwritten orders. In which case it is likely that CPOE will save time overall for prescribing [43). Another important point to the success of the CPOE system is the motivation of the physicians to use it. In a study looking into physician attitudes towards a clinical information system, satisfaction was correlated with ratings of improved productivity, ease of use, reliability, improvement to patient care, and reducing error. The most liked aspects of the system included remote access, do ing all ordering on one

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place, prompts for default dosages and frequencies, ability to view recent laboratory data, and ease of use. Dissatisfaction, on the other hand , was correlated with the perception that CPOE had negative impacts on patient care and a reduction in pro ductivity due to slowing down of work. System downtime and slow response are key factors in system acceptance. Aspects that were accepted but could be improved on included increasing speed, reducing the number of steps/clicks to access specific screens, decreasing the number of options in order entry and improving help/support. Dissatisfaction was primarily related to technical issues, mainly downtime , and system response time [39,41]. User satisfaction is vital and it is noteworthy that nurses and physicians may have different attitudes, because success requires both groups of users to be satisfied. The needs and uses of both groups need consideration when designing or customizing such systems. Pharmacists The pharmacist has become an important member of the ICU multidisciplinary team. Their role in optimizing patient medication is greatly impacted upon with the implementation of CPOE. One study has looked into the way in which CPOE alters pharmacist work patterns [44]. The researchers discovered that the pharmacists spent significantly more time checking prescriptions, the majority of which was problem solving (5 % to 51 % of time), which the authors attributed to the fact that physicians were dealing with a range of issues that were new to them because of the system. The pharmacist spent significantly less time filling prescriptions (51 % to 17 % of time) . There was an insignificant change in the time that the pharmacist was interacting with physicians and patients. In this study, pharmacists embraced the computerized system, recognizing that it would increase their efficiency. In addition, they described the benefits of remote working, reduced need to complete prescriptions and to decipher illegible writing [44]. Unintended Adverse Consequences of (POE

A recent paper comprehensively identified a series of unintended adverse consequences of CPOE, by observation and questioning of users of CPOE systems at 176 major hospitals across the USA. The most common unintended adverse consequences involved increased workload for clinicians. This includes the need to enter new information such as justification for a treatment selection, and the need to respond to excessive alerts some of which may be of no help. This phenomenon has been reported elsewhere, where warnings against 'alert fatigue' were raised, causing clinicians to ignore decision support, potentially decreasing the effectiveness of the system. Clinicians report inappropriate alerts as highly frustrating nuisances [45]. The second unintended adverse consequences were unfavorable workflow issues, recognizing that modeling clinical workflow is difficult because clinical practice is so complex, interruption-driven and constantly changing. Hence, no CPOE is able to match all workflows of a hospital perfectly. Other unintended adverse consequences included changes in communication patterns with the system replacing previously interpersonal conversations, leading to a reduction in face-to-face communication; physicians reporting loss of professional autonomy when CPOE forces them to comply with guidelines they may not embrace; never-ending demands for system changes; problems related to paper persistence; negative emotions; generation of new kinds of errors and overdependence on technology [46].

Time to Use Computerized Physician Order Entry in all ICUs? High Profile Cases where things didn't go to plan... There have been several cases where CPOE implementation has been associated with significant enough adverse outcomes. Reviewing these is indispensable if one wants to avoid the same pitfalls. Increased mortality after implementation of CPOE in a pediatric ICU A 235-bed regional pediatric referral center reported an increase in unadjusted mortality rate from 2.8 % to 6.37 % coincident with the implementation of the CPOE system. The authors recognized that their results did not support the majority of studies on CPOE systems, which suggest a reduction in adverse drugs events. They suggested that there was an additional time required to place orders, and that there were changes in the health care dynamics and the manner by which bedside care was delivered [47]. The publication of these findings lead to a number of post publication peer reviews, which identified possible contributing factors that removes causation from the CPOE system directly, including 'delays in the administration of critical medication resulting from complete centralization of pharmacy services as a consequence of CPOE implementation' [48]; a short time span for the hospital-wide implementation of the CPOE system (6 days) [49]; and the use of a general medicalsurgical CPOE and clinical information system that may have been suboptimal for the ICU environment. Following this report, another study at a tertiary referral center pediatric ICU, attempted to verify or refute the claims in this initial paper, recognizing the potential importance of this finding of increased mortality. Their analysis did not show any significant change in mortality both immediately post-implementation, nor after an extended period. The pre-implementation mortality rate was 4.22 % and there was an insignificant reduction to 3.46 % in the post-implementation phase. The main difference was the implementation of a more ICU specific CPOE system into the pediatric ICU, with pre-completed order sets for their most frequently placed orders to reduce time taken for ordering [43]. Cases where CPOE implementation has been reversed There have been three notable cases where CPOE implementation has been reversed, both temporarily and permanently. The University of Virginia Medical Center began the implementation of a medical information system in 1985. There was a progressive implementation strategy starting with dietary and radiological orders, progressing to prescription orders, being completed in 1992 three years later than expected and three times the estimated cost. The project was described as provoking major confrontation between medical staff and hospital administration and the system was deactivated briefly. Four factors were believed to contribute to the problems encountered : Alteration of established workflow patterns, strict interpretation of rules by the computer, ambiguity of governance policies, and lack of understanding of the long term strategic value of the system by physicians. The issues were resolved by a senior management team representing important sectors of the hospital staff and administration, meeting regularly to address the institution wide issues that had been raised. They realized that 'information technology alone cannot fix problems that it did not create, but that such technology can accentuate existing problems by diverting attention from the root causes and fundamental issues involved' [40]. The Ohio State University Health System implemented CPOE between February and May 2000. There were a large number of problems noted early and persistently in the medical ICU, such as slowed ordering, lack of ICU specific CPOE content and

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lack of train ing. Due to the severity of these problems, the unit returned to paper orders temporarily. With consultation, several changes were made to the system and display and output to the bedside nurse were significantly simplified and order sets were revised to more appropriately meet the needs of the critically ill. The mod ified system was successfully implemented seven months later. Authors reporting on these events concluded that the unique workflow and clinical needs of a specialized environment such as an ICU, must be completely understood to ensure that addition of CPOE is not an encumbrance [50]. The Cedars-Sinai Medical Center in Los Angeles implemented a CPOE system in late 2002. Use of the system ceased just four months later after 400 physicians complained that it was too difficult and time consuming to use and suggested that it was posing a risk to patient safety. A hospital spokeswoman commented that after a year of internal evaluation, the project had been decommissioned for now, and that the hospital would be concentrating on other information technology projects [51].

Conclusion With the growing evidence base, and the increasing power of clinical decision support functions, is it now time to consider 'prescribing CPOE in all ICUs'. Benefits are many and the ability of CPOE systems to decrease medical errors must be acknowledged. Implementation of CPOE systems has now been made easier, thanks to advances in information technology and a better understanding of integration of the technology at the bedside, both its benefits and its shortcomings. References 1. Institute of Medicine (1999) To err is human : build ing a safer health system. Available at: http://www.iom.edu/object.fIie/Master/4/l17/ToErr-8pager.pdf. Accessed Dec 2007 2. Aspden P, Wolcott J, Bootman J, Cronenwett L (2006) Preventing Medication Errors: Quality Chasm Series. National Academy Press, Washington 3. Department of Health (2000) An organi sation with a memory. Available at: http://www.dh. gov.uklen/Publicationsandstatistics/public ation s/publicationspolicyandguidance/browsable/ dh_4098184. Accessed Dec 2007 4. Leape L, Brennan T, Laird NE (1991) The nature of adverse events in hospitalized pat ients: results from the Harvard Medical Practice Study. N Eng J Med 342:377- 384 5. Shulman R, Singer M, Goldstone J, Bellingan G (2005) Medication errors: a pro spective cohort study of hand-written and computerised physician order entry in the intensive care unit. Crit Care 9:R516-521 6. Bates DW, Cullen DJ, Laird N, et al (1995) Incidence of adverse drug events and potential adverse drug events. Implication s for prevention. ADE Prevention Study Group. JAMA 274: 29- 34 7. Ridley SA, Booth SA, Thompson CM (2004) Prescription errors in UK critical care unit s. Anaesthesia 59:1193-1200 8. Bobb A, Gleason K, Husch M, Feinglass J, Yarnold PR, Noskin GA (2004) The epidemiology of prescribing errors: the potential impact of computerized prescriber order entr y. Arch Intern Med 164:785 -792 9. Cullen D, Sweitzer B, Bates D, Burdick E, Edmondson A, Leape L (1997) Preventable adverse drug events in hospitalized patients: a comparative stud y of intensive care and general care units. Crit Care Med 25:1289-1297 10. Classen D, Pestotnik SL,Evans RS, Lloyd JE, Burke J (1997) Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 277: 301-306

Time to Use Computerized Physician Order Entry in all ICUs? 11. Horn E, Jacobi J (2006) The critical care clinical pharmacist: Evolution of an essential team member. Crit Care Med 34:S46-51 12. Leapfrog Group (2001) Computerized physician order entry: a look at the vendor marketplace and getting started. Available at: http ://www.leapfroggroup.org/newslleapfro!\-news/ 97902. Accessed Dec 2007 13. Department of Health (2004) Building a safer NHS for patients: Improving medication safety. Available at: http ://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/Browsable/D H_4097460 Accessed Dec 2007 14. Miles M, Sweeny S (2001) Insulin dose interpretation errors . Pharm J 267:193 15. Evans KD, Benham SW, Garrard CS (1998) A comparison of handwritten and computerassisted prescriptions in an intensive care unit. Crit Care 2:73- 78 16. Kaushal R, Iha AK, Franz C, et al (2006) Return on investment for a computerized physician order entry system. J Am Med Inform Assoc 13:261-266 17. Bates DW, Kuperman GJ, Rittenberg E, et al (1999) A randomized trial of a computer-based intervention to reduce utilization of redundant laboratory tests. Am J Med 106:144-150 18. Nebeker JR, Hoffman JM, Weir CR, Bennett CL, Hurdle JF (2005) High rates of adverse drug events in a highly computerized hospital. Arch Intern Med 165:1111-1116 19. Leapfrog Group (2003) Computerized physician order entry: costs, benefits and challenges. Available at: http ://www.leapfroggroup.org/media/file/Leapfrog-AHA_FAH_CPOE_Report. pdf. Accessed Dec 2007 20. Teich JM, Merchia PR, Schmiz JL, Kuperman GJ, Spurr CD, Bates DW (2000) Effects of computerized physician order entry on prescribing practices. Arch Intern Med 160:2741-2747 21. Kuperman GJ, Gibson RF (2003) Computer physician order entry: benefits, costs, and issues. Ann Intern Med 139:31 -39 22. Evans RS, Pestotnik SL, Classen DC, et al (1998) A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med 338:232 - 238 23. Pestotnik SL, Classen DC, Evans RS, Burke JP (1996) Implementing antibiotic practice guidelines through computer-assisted decision support: clinical and financial outcomes. Ann Intern Med 124:884- 890 24. McGregor JC, Weekes E, Forrest GN, et al (2006) Impact of a computerized clinical decision support system on reducing inappropriate antimicrobial use: a randomized controlled trial. J Am Med Inform Assoc 13:378-384 25. Cockcroft D, Gault M (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41 26. Galanter WL, Polikaitis A, DiDomenico RJ (2004) A trial of automated safety alerts for inpatient digoxin use with computerized physician order entry. J Am Med Inform Assoc 11:270-277 27. Bates DW, Teich JM, Lee J, et al (1999) The impact of computerized physician order entry on medication error prevention. J Am Med Inform Assoc 6:313-321 28. Colpaert K, Claus B, Somers A, Vandewoude K, Robays H, Decruyenaere J (2006) Impact of computerized physician order entry on medication prescription errors in the intensive care unit: a controlled cross-sectional trial. Crit Care 10:R21 29. Oppenheim MI, Vidal C, Velasco FT, et al (2002) Impact of a computerized alert during physician order entry on medication dosing in patients with renal impairment. Proc AMIA Symp:577- 581 30. Department of Health (2000) The NHS Plan, a plan of investment, a plan for reform UK. Available at: http://www.dh .gov.uk/en/Publicationsandstatistics/Publications/PublicationsP01icyAndGuidance/DH _4002960 Accessed Dec 2007 31. Ash JS, Gorman PN, Seshadr i V, Hersh WR (2004) Computerized physician order entry in U.S. hospitals : results of a 2002 survey. J Am Med Inform Assoc 11:95-99 32. Clemmer T (2004) Computers in the ICU: Where we started and where we are now. J Crit Care 19:201- 207 33. Bunnell M, Chalfin D, Hassan E, Shapiro B, Sweldow D, Weinfurt P (2002)CPOE system requirements for intensive care use. Available at: http://www.sccm.org/corporate_resources/ coalition_foccriticaLcare_excellence/Documents/cpoe.pdf. Accessed Dec 2007 34. Berg M (1999) Patient care information systems and health care work: a sociotechnical approach. Int J Med Informat 55:87-101

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J. Ali and A. Vuylsteke 35. Ash JS, Stavri PZ, Kuperman GJ (2003) A consensus statement on considerations for a successful CPOE implementation. J Am Med Inform Assoc 10:229-234 36. Pierpont G, Thilgen D (1995) Effect of computerized charting on nurs ing activity in intensive care. Crit Care Med 23:1067 -1073 37. Menke J, Broner C, Campbell D, McKissick M, Edwards-Beckett J (2001) Computerized clinical documentation system in the pediatric intensive care unit. BMC Med Inform Decis Mak 1:3 38. Bosman R, Rood E, Straaten HO-v, Spoel JVd, Wester J, Zandstra D (2003) Intensive care information system reduces documentation time of the nurses after cardiothoracic surgery. Intensive Care Med 29:83- 90 39. Weiner M, Gress T, Thiemann D, et al (1999) Contrasting views of physicians and nurses about an inpatient computer based provider order entry system. J Am Med Inform Assoc 6:234-243 40. Massaro T (1993) Introducing physician order entry at a major academic medical center: I Impact on organizational culture and behaviour. Acad Med 68:20- 25 41. Lee F,Teich J, Spurr C, Bates D (1996) Implementation of physician order entry : user satisfaction and self reported usage patterns. J Am Med Inform Assoc 3:42-55 42. Overhage J, Perkins S, Tierney W, McDonald C (2001) Controlled trial of direct physician order entry : effects on physicians time utilisation in ambulatory primary care internal medicine practices . J Am Med Inform Assoc 8:361- 371 43. Del Beccaro MA, Jeffries HE, Eisenberg MA, Harry ED (2006) Computerized provider order entry implementation: no association with increased mortality rates in an intensive care unit. Pediatrics 118:290-295 44. Murray M, Loos B, Tu W, Eckert G, Zhou X, Tierney W (1998) Effects of computer based prescribing on pharmacist work patterns. J Am Med Inform Assoc 5:546-553 45. Kilbridge PM, Welebob EM, Classen DC (2006) Development of the Leapfrog methodology for evaluating hospital implemented inpatient computerized physician order entry systems. Qual Saf Health Care 15:81-84 46. Ash JS, Sittig DF, Poon EG, Guappone K, Campbell E, Dykstra RH (2007) The extent and importance of unintended consequences related to computerized provider order entry. J Am Med Inform Assoc 14:415-423 47. Han YY, Carcillo JA, Venkataraman ST, et al (2005) Unexpected increased mortality after implementation of a commercially sold computerized physician order entry system. Pediatrics 116:1506-1512 48. Phibbs C, Milstein A, Delbanco S, Bates D (2005) No proven link between CPOE and mortality. Available at: http://pediatrics.aappublications.orglcgi/elettersIl16/6/1506. Accessed Dec 2007 49. Bej MD (2006) Response to response re: CPOE Available at: http ://pediatrics.aappublications. org/cgileletters/116/6/ 1506. Accessed Dec 2007 50. Allan EL, Barker KN (1990) Fundamentals of medication error research. Am J Hosp Pharm 47:555-571 51. Morrissey J (2004) Harmonic divergence. Cedars-Sinai joins others in holding off on CPOE. Mod Healthc 34:16

881

Quality of Life in Locked-in Syndrome Survivors M.-A. BRUNO, F. P ELLAS, and S. LAUREYS

Introduction "Thirty years ago a stroke left me in a coma. When I awoke I found myself completely paralyzed and unable to speak... I didn't know what paralysis was until I could move nothing but my eyes. I didn't know what loneliness was until I had to wait all night in the dark, in pain from head to foot, vainly hopingfor someone to come with a teardrop of comfort. I didn't know what silence was until the only sound I could make was that of my own breath issuing from a hole drilled into my throat" [1] Pseudocom a or locked-in syndrome was first described by Plum and Posner in 1966 [2]. The patient with locked-in syndrome is fully conscious but interaction with the external world is very limited due to anarthria, lower cranial nerve paralysis, and quadriplegia. Usually, but not always, the anatomy of the responsible lesion in the brainstem is such that locked-in syndrome patients are left with the capacity to use vertical eye mo vem ents and blinking to com municate. The earliest example of a 'locked-in patient' was des cribed in 1854 in Alexandre Dumas's novel "The Count of Monte Cristo". Some years later, Zola described a woman who was paralyzed and "bur ied alive in a dead body" but could communicate via eye movements in his book "Therese Raquin". Dumas and Zola thus described the locked-in syndrome before the medical community did. In France, the Association for Locked-In Syndrome (ALIS, http://alis-assoJr) currently groups over 400 locked-in syndrome survivors and aims to inform, help and advise them and their families. The ALIS was created in 1997 after the death of lok ked -in syndrome patient, Jean-Dominique Bauby. In 1995, Bauby, aged 43 and editor-in-chief of the magazine ELLE, survived a brain stem stroke leaving him with locked-in syndrome. He communicated with his left eyelid and managed to write his memoirs in a book "The Diving Bell and the Butterfly" (or iginal title in French: "Le Scaphandre et Ie Papillon") [3]. This book was adapted as a movie in 2007 (directed by Julian Schnabel who received the best director prize at the Cannes film festival). Bauby's book illustrates with poetry and humor his courage and determination, the caring patience of those who helped him, and the difficulties that patients with lok ked -in syndrome encounter in dail y life. Bauby is not the only one to have written his memoirs. Many locked-in syndrome survivors have shown through their writing that their lives can be meaningful, productive and creative ( Table 1). In the last 50 years, technological progress in intensive care medicine has considerably increased the number of patients surviving severe brain damage. The management of the patient with locked-in synd rom e remains challenging and medical professionals may have difficulties in assessing the remaining quality of life for

882

M.-A. Bruno, F. Pellas, and S. Laureys Table 1. Some books written by locked-in syndrome survivors Author (year)

Title

Publisher

Jean-Dominique Bauby (1998)

The Diving Bell and the Butterfly: A Memoir of Life in Death

Vintage

Julia Tavalaro (1997)

Look Up for Yes

Kodansha (NY)

Karl-Heinz Pantke (1999)

Locked-in. Gefangen im eigenen Kerper (Taschenbuch)

Mabuse-Verlag

Philippe and Stephane Vigand (2000)

Only The Eyes Say Yes (original title: Putain de silence)

LGF - Livre de Poche

Philippe Vigand (2002)

Promenade immobiles

Le Livre de Poche

Roland Boulengier (2002)

Solitaire, dans Ie silence

Imprimerie - Editions Demol

Vincent Humbert (2003)

Je vous demande Ie droit de mourir

Michel Lafon

Je parle: I'extraordinaire retour a la vie d'un Locked-In Syndrome

J.-c. Lattes

Leatitia Bohn-Derrien (2005)

patients with locked-in syndrome. In the present chapter, we will define the etiology and nosology of locked-in syndrome and discuss the existing scientific data on quality of life, cognitive functioning, and communication possibilities in patients with locked-in syndrome. We have reviewed the available medical literature and present some preliminary data from ongoing studies performed by the ALIS.

Definition, Etiology and (mis)Diagnosis The American Congress of Rehabilitation Medicine [4] defines locked-in syndrome as a syndrome characterized by the presence of sustained eye opening (bilateral ptosis should be ruled out as a complicating factor), intact cognitive function, aphonia or severe hypophonia, quadriplegia or quadriparesis, and a primary and elementary code of communication that uses vertical or lateral eye movement or blinking of the upper eyelid. Bauer et al. [5] classified the locked-in syndrome into three categories on the basis of the extent of motor impairment: (a) classical locked-in syndrome is characterized by quadriplegia and anarthria with preserved consciousness and vertical eye movement or blinking; (b) incomplete locked-in syndrome permits remnants of voluntary motion other than vertical eye movement; (c) total locked-in syndrome consists of complete immobility including all eye movements combined with preserved consciousness. Each of the three categories has been subdivided into transient and chronic forms. Most frequently, locked-in syndrome is caused by a bilateral ventral pontine lesion [6,7]. In rarer cases, it can also be due to mesencephalic lesions [8]. The most common etiology is cerebrovascular disease, either a basilar artery occlusion or a ventral pontine stroke. Following traumatic brain injury (TBI) [9], locked-in syndrome may be caused either directly by brain stem lesions, secondary to vertebroba-

Quality of Life in Locked-in Syndrome Survivors

silar arte ry damage or due to compression of the cerebral peduncles from tentorial herniation [10]. Locked-in syndrome has also been reported in case of brain stem tumor, subarachnoid hemorrhage and vascular spasm of the basilar artery, encephalitis, central pontine myelinolysis, brain stem drug toxicity, pont ine abscess, hypoglycemia, or vaccine reaction (reviewed in [ll ]). Transient peripheral locked-in syndrome has been reported after Guillain Barre polyradiculoneuropathy [12] and severe infectious polyneuropathy [13]. In these extensive peripheral disconnection syndromes, vertical eye movements are not selectively spared. Another important cause of complete locked-in syndrome is end-stage amyotrophic lateral sclerosis, i.e., motor-neuron disease [14]. Finally, general anesthesia can sporadically induce tran sient pharmacological locked-in syndrome (when patients receive muscle relaxants together with inadequate amounts of anesthetics). Such cases may be followed by post -traumatic stress disorder [15]. The diagnosis of locked-in syndrome may be easily missed and the patient may erroneously be considered as being in a coma, vegetative state, or akinetic mutism . Unambiguous signs of consciousness in severely bra in-injured patients are difficult to detect due to motor impairment and fluctuating levels of vigilance (for review see [16]). A study in collaboration with the ALIS showed that in 55 % of cases, it was a relative of the patient with locked-in syndrome and not the treating physician (23 % of cases) who first realized that the patient was conscious and could communicate via eye movements . On average, the time that elapsed between the insult and the diagnosis of locked-in syndrome was 78 days [17]. In clinical locked-in syndrome, structural brain imaging (magnetic resonance imaging, MRI) typically shows isolated lesions (bilateral infarction, hemorrhage, or tumor) in the ventral portion of the basis pont is or midbrain (reviewed in [18]). Bassetti et al. [19] reviewed electroencephalographic (EEG) recordings in six patients with locked-in syndrome. These autho rs noted normal or minimal baseline slowing and predominance of reactive alpha activity [19]. Other authors observed abnormal EEG findings, mostly slowing over the temporal or frontal leads or more diffuse slowing [7], unreactive EEG [20], or an "alpha coma" pattern (i.e., alpha rhythm unreactive to multimodal stimuli) [21]. These findings indicate that EEG recording cannot be taken as a sole measure of consciousness and thus cannot be used to disentangle locked-in syndrome from post-comatose unconsciousness [22]. Positron emission tomography (PET) scanning studies conducted by Levy et al. [23] showed significantly higher metabolic levels in brains of patients with locked-in syndrome compared to patients in a vegetative state. More recent studies have shown that in classical locked-in syndrome, regional cerebral metabolic rates for glucose are not significantly below normal values measured in healthy volunteers [24].

Prognosis and Quality of life The mortality rate for patients with acute locked-in syndrome is about 75 % for vascular etiologies with nearly 90 % of the deaths occurring in the first four months [7]. Once a patient has stabilized medically and had locked-in syndrome for more than a year, lO-year survival is over 80 % and 20-year survival is 40 % [25]. Classically, motor recovery of patients with locked-in syndrome is very limited [7, 25], but a recent study showed that intensive and early rehabilitative care improves outcome [26]. Often unknown to physicians caring for locked-in syndrome in the acute setting and despite the limited motor recovery, many locked-in syndrome patients can

883

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M.-A. Bruno, F. Pellas, and S. Laureys

return to live at home. The ALIS database shows that out of 245 patients nearly half returned home. Over 90 % of the studied patients recovered some degree of head movement, about two-thirds recovered some motor function in the upper limbs, and about half recovered mono-syllabic speech [11]. Is life worth living in locked-in syndrome? There is, at present, no generally accepted definition of quality of life, but it can be seen as the gap between our expectations of health and our experience of it [27]. In the field of neurology and neuro-critical care, studies on quality of life have been relatively slow to develop. Communication limitations make quality of life assessments in brain damaged patients particularly difficult [28]. One of the reasons behind the rapid development of quality of life measures in intensive care has been the growing recognition of the importance of understanding the impact of our medical interventions on patients' lives rather than just on their bodies [29]. The level of care required remains extensive in patients with chronic locked-in syndrome. Although medical, nursing, physical, and speech therapy occupy a major part of the day for a patient with locked-in syndrome, it is surprising to see that patients still have essential social interaction and lead meaningful lives. Patient activities include television, radio, music, books on tape, visiting with family, visit vacation home, e-mail, telephone, teaching, going to movies, shows, the beach, and bars [25]. In a study conducted by the ALIS and Leon-Carrion et al. [17], it was shown that about three-quarters of patients with chronic locked-in syndrome (73 %) enjoyed going out and met with friends at least twice a month. In collaboration with the ALIS, we have assessed 53 patients (locked-in syndrome durat ion 6±5 years) with the Reintegration to Normal Living Index [30]. The majority of patients (70 %) participated in recreational activities (i.e., hobbies, crafts, sports, reading, television, games, computers) in a satisfying manner. Most patients (68 %) also declared that they assumed a role in their family which met their personal needs and those of the family members. Doble et al. [25] were impressed by the social interaction of patients with locked-in syndrome and stated that it was clear that patients were actively involved in family and personal decisions and that their presence was valued at home. A study conducted by the ALIS assessed the quality of life in patients with chronic locked-in syndrome. Chronic locked-in syndrome survivors (n = 17, lockedin syndrome duration 6±4 years) who did not show major motor recovery (i.e., used eye movements or blinking as the major mode of communication) and who lived at home were asked to fill in the Short Fom-36 (SF-36) questionnaire [31] on quality of life. On the basis of the SF-36 questionnaire, these locked-in syndrome patients not surprisingly showed maximal limitations in physical activities (all patients scoring zero). Interestingly, self-scored perception of mental health (evaluating mental wellbeing and psychological distress) and personal general health were not significantly lower than values from age-matched French control subjects [11,32]. Note that perception of mental health and the presence of physical pain was correlated to the frequency of suicidal thought [11], highlighting the importance of managing pain in patients with chronic locked-in syndrome. Our results confirm earlier reports on quality of life assessments in patients with chronic locked-in syndrome. Leon-Carrion et al. [17] and the ALIS showed that about half of the assessed patients (n = 44) regarded their mood as good. Similarly, Doble et al. [25] studied 13 patients with locked-in syndrome and reported that more than half were satisfied with life in general. In 2007, we assessed the quality of life of 11 patients (locked-in syndrome duration 7±3 years) (unpublished data) using the ACSA scale (Anamnestic Comparative

Quality of Life in Locked-in Syndrome Survivors

-5

I

-4

Worst period in my life

-3

-2

-,

o

. 2

*

~ 3

I

4

5

~eri O d in my life

Fig. 1. Anamnestic Comparative Self Assessment [33] showing self-rated quality of life in 11 patients with locked-in syndrome (crosses; mean age 37±6 years; 8 males). Box and whiskers represents mean, SD, minimum and maximum of self-rated quality of life in 22 controls (mean age 43 ± 10 year; 8 males). Note that on average the self-rated quality of life in patients with locked-in syndrome patients is not significantly lower than that in controls (Bruno et ai, unpublished data).

Self Assessment) (33]. ACSA estimates overall wellbeing on a scale from -5 (worst period in the respondent's life) to +5 (best period). As show in Figure " the overall quality of life of the patients with locked-in syndrome was not significantly different from healthy matched controls.

End-ot-Iite Decisions As stated by The Amercian Academy of Neurology (AAN), patients with profound and permanent paralysis have the right to make health care decisions about themselves including to accept or refuse life-sustaining therapy (34]. In 2007, Bruno et al. (unpublished data) questioned 97 clinicians and found that 66 % answered "yes" and 34 % "no" to the affirmation: "Having locked-in syndrome is worse than being in a vegetative state or in a minimally conscious state?" The consequences of this finding may be that biased clinicians provide less aggressive medical treatment and influence the family in ways not appropriate to the situation (25]. Some health care professionals who have no experience with chronic locked-in syndrome survivors might believe that such patients want to die but many studies have shown that patients typically have a wish to live. In 1993, Anderson et aI. [35] reported that all questioned locked-in syndrome patients wanted life-sustaining treatment. A previous study by the ALIS showed that 75 % of patients with chronic locked-in syndrome without motor recovery rarely or never had suicidal thoughts. To the question: "would you like to receive antibiotics in case of pneumonia", 80 % answered "yes", and in reply to the question "would you like resuscitation to be attempted in case of cardiac arrest", 62 % said "yes" [11]. Similarly, in a recent survey conducted by Bruno et al. (unpublished data) nearly two-thirds of the studied locked-in syndrome patients (n = 54) never had suicidal thoughts (Fig. 2). In line with these findings, Doble et al. [25] reported that none of the questioned patients with chronic locked-in syndrome had a "do not resuscitate" order; more than a half had never considered or discussed euthanasia. These authors also noted that none of the 15 deaths in their study cohort of chron ic locked-in syndrome patients (n = 29) could be attributed to euthanasia. Since its creation, the ALIS has registered over 400 patients with locked-in syndrome in France; only five of the reported deaths have been related to the pat ient's wish to die.

885

886

M.-A. Bruno, F. Pellas, and S. Laureys

16 14

14 ~

C

'"

o Cii

.o

• Head communication (median duration 4 years) Verbal communication (median duration 5 years)

12

.~ 10 o,

• Eye communication (median duration 3 years)

10

8

8

E

6

Z

4

:::l

8

4

2 0

o Never

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0

Often

Fig. 2. Frequency ofsuicidal thoughts in 54 patients with chronic locked-in syndrome (age 22 - 60years); 14 communicate with their eyes, 18 have recovered some communication using their head, and 22 have recovered some verbal communication. Note that 33 patients never had suicidal thoughts, 20 occasionally had suicidal thoughts, and only 1 patient frequently had suicidal thoughts (Bruno et al., unpublished data),

In accordance with the principle of patient autonomy, physicians should respect the right of locked-in syndrome patients to accept or refuse any treatment. At least two conditions are necessary for full autonomy: Patients need to have intact cognitive abilities and they must be able to communicate their thoughts and wishes.

Cognitive Functioning and Communication In clinical routine, there is no systematic neuropsychological evaluation of cognitive functioning in locked-in syndrome survivors because most neuropsychological tests need a written or verbal response. Due to the lack of motor and verbal communication, the cognitive testing of locked-in syndrome patients is difficult and requires an adapted assessment. Some case reports have emphasized that cognitive abilities remain intact in locked-in syndrome (for review see [11]). Recently, Schnakers et al. (unpublished data) have assessed a cohort of locked-in syndrome survivors using a standard battery of neuropsychological testing (i.e., sustained and selective attention, working and episodic memory, executive functioning , phono logical and lexico-semantic processing and vocabulary knowledge) adapted to an eye-response mode for specific use in patients with locked-in syndrome. The authors did not detect any significant cognitive deficits in locked-in syndrome patients with an isolated brain stem lesion (Fig. 3). However, locked-in syndrome patients with additional supra-tentorial cortical lesions did show cognitive dysfunction. Most recently, Lakerveld at al. [36] investigated cognition in late-stage amyotrophic lateral sclerosis (l.e., neurodegenerative disease that progressively paralyzes limbs or bulbar musculature, or both). These authors showed that patients' cognitive performance (i.e., general intelligence, language, executive function, learning, and memory) was not significantly different from matched healthy controls. However, some individual patients displayed deficits in some aspects of executive functioning, learning, and memory. In the latter cases, the detection of cognitive deficits permitted the communication mode to be adapted in order to better fit the patient's

Quality of Life in Locked-in Syndrome Survivors

30

Executivefunctioning

I

25 20

ClJ '" (; 15 u

VI

40 (;

VI

10

LIS

0

Control subjects

Short term memory

100

8 a

VI

T

Control subjects

Verbal intelligence

'" 60 ClJ

(; u

4

VI

2 0

LIS

80

6 '" ~ u

20 10

5 0

T

10

Attent ion

50

40 20

LIS

Control subjects

0

LIS

Control subjects

Fig. 3. Neuropsychological testing data from six patients with locked-in syndrome (3 males; mean age 42 ± 16 years) and 40 healthy adults (matched according to age and level of education). Note that the cognitive functioning of the patients with locked-in syndrome did not differ significantly from that of the controls (5chnakers et aI., unpublished data).

preserved cognitive abilities and thus to facilitate commun ication and to increase patient autono my [37) The first method of establishing communication with locked-in syndrome patients is to use a yes/no code based on eyelid blinks or vertical eye movements (i.e., look up for "yes" and look down for "no"). Such a code will only permit to communicate via closed questions (i.e., questions requiring yes/no answers). The principal aim of re-education is to re-establish a genuine exchange with the lockedin syndro me pat ient by putti ng into place various codes to permit them to reach a higher level of communicatio n and thus to achieve an active part icipation in his/her management. Locked-in syndrome pat ients can also use alphabetical communication methods; the simplest metho d is to list th e alphabet and ask the locked-in syndrome patient to make a prearr anged eye movement to indicate a letter. Some patients prefer a listing of the letters sorte d as a func tion of the appearance rate in usual language, for example: French: E-S-A-R-I-N-T-U-L-O-M-D-P-C-F-B-V-H-G-J-Q-Z-Y-X-K-W English: E-T-A-O-I-N-R-S-H-L-D-C-U-M-F-P-G-W-Y-B-V-K-X-J-Q-Z The interlocutor pronoun ces th e letters and the locked-in syndro me pat ient blink s to indicate which one they want. An alternative meth od is the "vowel and consonant method" shown in Table 2.

887

888

M.-A. Bruno, F. Pellas, and S. Laureys V

Cl

C2

0

A

B

J

R

C

K

5 T

D

0

Table 2. Vowel and consonant communication method for locked-in syndrome. The alphabet is divided into 4 groups: "Vowel" (V), "Consonant 1" (Cl) (B-H), "Consonant 2" (0) (J-Q), and "Consonant 3" (0) (R-Z). The interlocutor says "Vowel" and then "Consonant 1, 2, 3" and the patient blinks to indicate the chosen group.

M

V

U

G

N

W

Y

H

P

X

Q

Z

The above discussed communication systems all require assistance from others. Recent developments in informatics are drastically changing the lives of patients with locked-in syndrome. Instead of passively responding to the requests of others, new communication facilitation devices coupled to computers now allow the patient to initiate conversations [11]. Experts in rehabilitation engineering and speech-language pathology are continuously improving brain-computer interfaces. Brain-computer interfaces (also named thought translation devices) are a means of communication in which messages or commands that an individual sends to the external world do not pass through the brain's normal output pathways of peripheral nerves and muscles [38] . These patient-computer interfaces such as infra-red eye movement sensors which can be coupled to on-screen virtual keyboards allowing the locked-in syndrome survivor to control his/her environment, use a word processor (which can be coupled to a text-to-speech synthesizer), operate a telephone or fax, or access the Internet and use e-mail. Wilhelm et al. [39] showed that mental manipulation of salivary pH may be an alternative way of documenting consciousness in acute brain computer interfaces (Fig. 4). Birbaumer et al. [40] reported that patients with chronic near-complete locked-in syndrome and end-stage amyotrophic lateral sclerosis were able to communicate without any verbal or motor report but solely by modulating their EEG. In the future, more widely available access to enhanced communication computer prosthetics should additionally enhance the quality of life of locked-in syndrome survivors.

0.6 0.4 ~

OJ

g' 0.2

±'"

s:

Q.

0+-- - -- - - - - - - - - - - -

T

»,

.~ -0.2 m VI

...L

-0.4

-0.6 + - - - - - - -Imagery of lemon

.,.-- - - - - - --, Imagery of milk

Task

Fig. 4. Communication method based on mental imagery and measurement of salivary pH changes. Imagery of lemon increases salivary pH and is used to communicate "yes" while imagery of milk decreases pH and communicates "no': Result obtained in one healthy volunteer. Box and whiskers represent mean, SD, and minimum/maximum measurements. Adapted from [41]

Quality of Life in Locked-in Syndrome Survivors

Conclusion The data in this chapter stress the need for critical care physicians who are confronted by patients with acute locked-in syndrome to recognize this infrequent syndrome as early as possible. Health care workers who take care of patients with acute locked-in syndrome need a better understanding of the long-term outcome of lokked-in syndrome. Contrary to the beliefs of many physicians, patients with lockedin syndrome self-report a meaningful quality of life and the demand for euthanasia exists but is uncommon. Studies emphasize the right of autonomy for patients with locked-in syndrome and demonstrate their ability to exercise it, including taking end-of-life decisions. The strength of medical and communication-technological progress for patients with severe neurological conditions is that it makes them more like the rest of us. Clinicians should realize that quality of life often equates with social rather than physical interaction. It is important to emphasize that only the medically stabilized, informed locked-in syndrome patient is able to accept or to refuse life-sustaining treatment. Locked-in syndrome patients should not be denied the right to die, but also, and more importantly, they should not be denied the right to live - and to live with dignity and the best possible care. Acknowledgements: This study was supported by the Fonds National de la Recherche Scientifique de Belgique (FNRS), the Special Funds for Scientific Research of the University of Liege, the Mind Science Foundation, the French Concerted Research Action (ARC 06/11- 340), the French Association for Locked-In Syndrome (ALIS), and the European Commission. References 1. Tavalaro J, Tayson R (1997) Look Up for Yes. Kodansha America, Inc, New York 2. Plum F, Posner JB (1966) The Diagnosis of Stupor and Coma, lst ed. FA Davis, Philadelphia 3. Bauby JD (1998) The Diving bell and the Butterfly: A Memoir of Life in Death (original title: Le scaphandre et Ie papillon). Vintage, New York 4. American Congress of Rehabilitation Medicine (1995) Recommendations for use of uniform nomenclature pertinent to patients with severe alterations of consciousness. Arch Phys Med Rehabil 76:205- 209 5. Bauer G, Gerstenbrand F, Rumpl E (1979) Varieties of the locked-in syndrome. J Neurol 221: 77 -91 6. Plum F, Posner JB (1983) The Diagnosis of Stupor and Coma, 3rd ed. FA Davis, Philadelphia 7. Patterson JR, Grabois M (1986) Locked-in syndrome: a review of 139 cases. Stroke 17:758-764 8. Dehaene I, Dom R (1982) A mesencephalic locked-in syndrome. J Neurol 227:255-259 9. Golubovic V, Muhvic D, Golubovic S (2004) Posttraumatic locked-in syndrome with an unusual three day delay in the appearance. Coli Antropol 28:923- 926 10. Keane JR (1986) Locked-in syndrome after head and neck trauma. Neurology 36:80-82 11. Laureys S, Pellas F, Van Eeckhout P, et al (2005) The locked-in syndrome : what is it like to be conscious but paralyzed and voiceless? Prog Brain Res 150:495-511 12. Ragazzoni A, Grippo A, Tozzi F, Zaccara G (2000) Event-related potentials in patients with total locked-in state due to fulminant Guillain-Barre syndrome. Int J PsychophysioI37 :99-109 13. O'Donnell PP (1979) 'Locked-in syndrome ' in postinfective polyneuropathy. Arch Neurol 36:860 14. Kotchoubey B, Lang S, Winter S, Birbaumer N (2003) Cognitive processing in completely paralyzed patients with amyotrophic lateral sclerosis. Eur J Neurol 10:551-558 15. Sandin RH, Enlund G, Samuelsson P, Lennmarken C (2000) Awareness during anaesthesia: a prospective case study. Lancet 355:707-711 16. Majerus S, Gill-Thwaites H, Andrews K, Laureys S (2005) Behavioral evaluation of consciousness in severe brain damage . Prog Brain Res 150:397-413

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M.-A. Bruno, F. Pellas, and S. Laureys 17. Leon-Carrion J, van Eeckhout P, Dominguez-Morales Mdel R, Perez-Santamaria FJ (2002) The locked-in syndrome: a syndrome looking for a therapy. Brain Inj 16:571- 582 18. Leon-Carrion J, van Eeckhout P, Dominguez-Morales Mdel R (2002) The locked-in syndrome: a syndrome looking for a therapy. Brain Inj 16:555-569 19. Bassetti C, Mathis J, Hess CW (1994) Multimodal electrophysiological studies including motor evoked potentials in patients with locked-in syndrome: report of six patients. J Neurol Neurosurg Psychiatry 57:1403-1406 20. Gutling E, Isenmann S, Wichmann W (1996) Electrophysiology in the locked-in- syndrome. Neurology 46:1092-1101 21. Jacome DE, Morilla-Pastor D (1990) Unreactive EEG: pattern in locked-in syndrome. Clin Electroencephalogr 21:31-36 22. The Multi-Society Task Force on PVS (1994) Medical aspects of the persistent vegetative state (1). N Engl J Med 330:1499-1508 23. Levy DE, Sidtis JJ, Rottenberg DA, et al (1987) Differences in cerebral blood flow and glucose utilization in vegetative versus locked-in patients. Ann Neurol 22:673-682 24. Laureys S, Owen AM, Schiff ND (2004) Brain function in coma, vegetative state, and related disorders. Lancet Neurol 3:537- 546 25. Doble JE, Haig AJ, Anderson C, Katz R (2003) Impairment, activity, participation, life satisfaction, and survival in persons with locked-in syndrome for over a decade: follow-up on a previously reported cohort. J Head Trauma Rehabil18:435 -444 26. Casanova E, Lazzari RE, Lotta S, Mazzucchi A (2003) Locked-in syndrome: improvement in the prognosis after an early intensive multidisciplinary rehabilitation. Arch Phys Med Rehabil 84:862-867 27. Carr AJ, Gibson B, Robinson PG (2001) Measuring quality of life: Is quality of life determined by expectations or experience? BMJ 322:1240-1243 28. Murrell R (1999) Quality of life and neurological illness: a review of the literature. Neuropsychol Rev 9:209- 229 29. Addington -Hall J, Kalra L (2001) Who should measure quality of life? BMJ 322:1417 - 1420 30. Wood-Dauphinee S, Williams II (1987) Reintegration to normal living as a proxy to quality of life. J Chronic Dis 40:491 - 502 31. Ware JE, Snow KK, Kosinski M (1993) SF-36 Health Survey Manual and Interpretation Guide. The Health Institute, New England Medical Center, Boston 32. Ghorbel S (2002) Statut fonctionnel et qualite de vie chez Ie locked-in syndrome a domicile. Universite Jean Monnet Saint-Etienne, Montpellier 33. Bernheim JL (1999) How to get serious answers to the serious question: "How have you been?": subjective quality of life (QOL) as an individual experiential emergent construct. Bioethics 13:272- 287 34. Ethics and Humanities Subcommittee of the AAN (1993) Position statement: certain aspects of the care and management of profoundly and irreversibly paralyzed patients with retained consciousness and cognition . Report of the Ethics and Humanities Subcommittee of the American Academy of Neurology. Neurology 43:222- 223 35. Anderson C, Dillon C, Burns R (1993) Life-sustaining treatment and locked-in syndrome. Lancet 342:867- 868 36. Lakerveld J, Kotchoubey B, Kubler A (2007) Cognitive function in late stage ALS patients. J Neurol Neurosurg Psychiatry (epub ahead of print) 37. Bruno MA, Bernheim JL, Schnakers C, Laureys S (2008) Locked-in: don't judge a book by its cover. J Neurol Neurosurg Psychiatry 79:2 38. Kubler A, Neumann N (2005) Brain-computer interfaces - the key for the conscious brain locked into a paralyzed body. Prog Brain Res 150:513-525 39. Wilhelm B, Jordan M, Birbaumer N (2006) Communication in locked-in syndrome: effects of imagery on salivary pH. Neurology 67:534- 535 40. Birbaumer N, Ghanayim N, Hinterberger T, et al (1999) A spelling device for the paralysed . Nature 398:297- 298 41. Vanhaudenhuyse A, Bruno MA, Bredart S, Pleneveux A, Laureys S (2007) The challenge of disentangling reportability and phenomenal consciousness in post-comatose states. Behavioral and Brain Sciences (in press)

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Post-traumatic Stress Disorder in Intensive Care Unit Survivors J.

GRIFFITHS,

A.M.

HULL,

and

B.H. CUTHBERTSON

Introduction Extended follow-up of survivors of intensive care unit (ICU) treatment has shown that many patients suffer long-term physical and psychological consequences that affect their quality of life [1]. One form of psychological morbidity, post-traumatic stress disorder, is increasingly reported in ICU survivors [2-4]. The aim of this chapter is to: (a) provide a brief summary of post-traumatic stress disorder and its diagnos is; (b) summarize existing research pertaining to ICU-related post-traumatic stress disorder and review the methodologies of the research; (c) provide an estimate of the prevalence of ICU-related post-traumatic stress disorder; (d) discuss the limitation s of the current research into ICU-related post-traumatic stress disorder; and (e) provide a summary of potential risk factors for ICU-related post-traumatic stress disorder.

A Brief Background of Post-traumatic Stress Disorder and its Diagnosis Post-traumatic stress disorder is a condition categorized by an individual experiencing or witnessing a traumatic event involving actual or threatened death or serious injury. The event itself elicits a reaction of intense fear, helplessness, and horror, and subsequently symptoms of intrusion, avoidance, and hyperarousal. Post-traumatic stress disorder was defined as a psychiatric disorder in 1980 [5] and has been traditionally associated with traumatic stresso rs such as rape, combat, and surviving a disaster or major incident. Since 1980, clinical experience and resulting research has resulted in revisions of the diagnostic criteria for post-traumatic stress disorder [6]. Indeed , the experience of medical illness, including critical illness and ICU treat ment, is now recognized as a potential traumatic event [7]. Post-traumatic stress disorder should ideally be diagnosed using consistent criteria and reliable instruments that exhibit high inter-rater reliability, are stable over time, and are able to assess individual patients presenting with wide symptom variance. At the current time the recognized gold standard for diagnosing post -traumatic stress disorder is a stan dardized clinical interview by a clinical psychologist or psychiatrist experienced in the assessment and treatment of post-traumatic stress disorder. Post-traumatic stress disorder diagnostic measures based on standardized interview formats include the Structured Clinical Interview for DSM (Diagnostic and Statistical Manual of Mental Disorders) -IV (SCID) [8] and the Clinician Administered Post-traumatic Stress Disorder Scale (CAPS) [9]. The current DSM-IV diagnostic criteria are given in Table 1. The CAPS and SCID provide a strategy for assessing a range of rele-

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J. Griffiths, A.M. Hull, and S.H. Cuthbertson Table 1 DSM-IV criteria for post-traumatic stress disorder [61 A The person has been exposed to a traumatic event in which both of the following were present: • the person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others • the person's response involved intense fear, helplessness, or horror. B The traumatic event is persistently re-experienced in one (or more) of the following ways: • recurrent and intrusive distressing recollections of the event, including images, thoughts, and/or perceptions • recurrent distressing dreams of the event • acting or feeling as if the traumatic event were recurring • intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event • physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event C Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by at least three of the following: • efforts to avoid thoughts, feelings, and/or conversations associated with the trauma • efforts to avoid activities, places, and/or people that arouse recollections of the trauma • inability to recall an important aspect of the trauma • markedly diminished interest or participation in significant activities • feeling of detachment or estrangement from others • restricted range of affect • sense of a fores hortened future

o

• • • • •

Persistent symptoms of increased arousal (not present before the trauma), as indicated by at least two of the following: difficulty falling or staying asleep irritability or outbursts of anger difficulty concentrating hypervigilance exaggerated startle response

E Duration of the disturbance (symptoms in Criteria B, C, and D) is more than one month F The disturbance causes clinically significant distress and/or impairment in social, occupational, and/or other important areas of functioning. Specify if:

Duration of symptoms is less than three (3) months • Acute Duration of symptoms is more than three (3) months • Chronic • Delayed Onset Onset of symptoms is at least six (6) months after the incident

vant experiences and symptoms . The standardized interview formats allow the clinician to query the patient, and occasionally collateral sources, about functioning across a number of relevant areas. Clinical ratings can be made based not only on patient report, but also on behavioral observations and include all symptom clusters necessary for the diagnosis of post-traumatic stress disorder. A systematic review of all symptom criteria decreases the likelihood that a clinician will improperly diagnose post-traumatic stress disorder when a more focused problem, such as a specific phobia, is presenting. By allowing a standardized assessment, structured interviews generally offer known reliability and validity coefficients. In contrast, self-report

Post-traumatic Stress Disorder in Intensive (are Unit Survivors

screening instruments provide an estimate of 'post-traumatic symptomatology' but not a conclusive diagnosis of post-traumatic stress disorder. Screening instruments for post -traumatic psychopathology include the Davidson Trauma Scale (DTS) [10], the Impact of Events Scale (IES) [11], the Impact of Events Scale-Revised (IES-R) [12], and the Post-traumatic Stress Syndrome lO-questions inventory (PTSS-lO) [13]. Self-report screening instruments such as the PTSS-IO have reported efficiency factors for the diagnosis of post -traumatic stress disorder. At a cut-off point of 35, the sensitivity and specificity for the diagnosis of post-traumatic stress disorder are 77 % and 97.5 %, respectively. In addition, the DTS has an odds ratio for the likelihood of a post-traumatic stress disorder diagnos is (or not) for each score [2, 13].

ICU Treatment as a Traumatic Stressor A modern day ICU harbors numerous potential stressors that would include acute cardiac and pulmonary dysfunction, severe pain , significant injury, anxiety, surgery, and repeated medical procedures. Many ICU patients require exogenously admin istered stress hormones, like epinephrine, norepinephrine, and dopamine, which may maintain and intensify the stress reaction. It is recognized that a mixture of physiological and psychological responses normally accompanies this stress reaction . It has been proposed that if these responses are abnormal or become exaggerated they may lead to post -traumatic stress disorder [14]. In addit ion, a proportion of patients will be admitted to ICU after a traumatic event, such as a road traffic accident or an assault. Several psychological factors have been documented to contribute to the intensity of the psychological response to a tr aumatic experience . Amongst these are controllability, predictability, and perceived threat. Few would argue that patients experiencing ICU treatment retain their autonomy, have a predictable course, or are under no threat of repeated injury, disability, or pain. Indeed, patients who have spent time on an ICU report nightmares, depression, and high levels of distress , and up to 40 % have recollection of pain. However, it is important to recognize that critical illness and its associated factors are not always traumatic stressors; the degree to which these events are experienced as traumatic may be mediated by age, severity of illness, abruptness of onset , religious faith, and individual interpretation [15). Among individuals who experience neither an acute emotional response nor interpret a potential stresso r as extremely disturbing and frightening, the likelihood of developing post -traumatic stress disorder is very low [15].

Methodologies of Studies of ICU-related Post-traumatic Stress Disorder Two recent reviews have looked at the association of ICU treatment and the development of post-traumatic stress disorder. Jackson et al. performed a literature review focusing exclusively on post-traumatic stress disorder following medically related critical illness, and included 16 studies in their review [16]. The systematic review by Griffiths et al. included all patients treated on medical, surgical, and trauma ICUs, and 30 stud ies met their inclusion criteria [17]. Combining the findings of these two recent literature reviews provides a comprehensive insight into the study of ICUrelated post-traumatic stress disorder.

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Study Characteristics A majority of studies into ICU-related post-traumatic stress disorder have been performed in Europe and the UK and have studied survivors of acute respiratory distress syndrome (ARDS), cardiac surgery, and general, medical, surgical, and trauma ICU treatment (Table 2). The median age of patients in the studies ranges from 35 to 69 years [18, 19] and the median ICU length of stay varies from 2 to 35 days [20- 22]. Half of the studies either exclude those patients with a history of personality factors or pre-existing psychological disorder or those with pre-existing neurological disease or those with traumatic brain injury. Although the majority of the studies are prospective in design sample sizes are universally small with the number of patients participating in follow-up ranging from 20 to 184 [21, 23].

Method and Timing of Post-traumatic Stress Disorder Assessment The majority of studies rely solely on the use of standardized self-report screening instruments in their assessment of post-traumatic stress disorder and post-traumatic stress disorder symptomatology (Table 2). A third of studies apply a combination of standardized clinical interview and a screening instrument whilst only two use standardized clinical interview alone [3, 24]. Diagnoses of post-traumatic stress disorder are repeatedly made entirely on the basis of information derived from screening tools. For example, a number of studies used a cut-off score of 35 on the PTSS-lO as opposed to standardized clinical interview to 'diagnose' post-traumatic stress disorder (Table 3). Few studies attempt to identify or quantify the clinical significance of post-traumatic stress disorder or to evaluate commonly studied outcomes in this regarding (for example, substance abuse, increased marital or family conflict, and days away from work) [16]. In addition, no diagnostic methodology was used that could potentially identify adjustment disorder. The mean time of assessment of post-traumatic stress disorder or post -traumatic symptomatology ranges between 10.7 days post-cardiac surgery [25] to 8 years after surviving ARDS [3] (Tables 3 and 4). Although DSM-IV stipulates that post-traumatic stress disorder symptoms must have been present for at least one month before the diagnosis of acute post-traumatic stress disorder can be considered (three months for chronic post-traumatic stress disorder), three studies assessed for posttraumatic stress disorder before this time criterion [21, 25, 26].

Reported Prevalence of Post-traumatic Stress Disorder and Post-traumatic Symptomatology The prevalence of post-traumatic stress disorder can only be provided by those studies that use standardized diagnostic clinical interview (Table 4). In the studies that used the CAPS, post-traumatic stress disorder prevalence decreased from 4.7 % at l-month to 1.9 % at 12 months in survivors of severe accidental injuries [24, 26, 27] and was found to be 17.6 % in survivors of abdominal aortic surgery assessed 6 to 24 months after surgery [28]. In the studies that used the SCID, post-traumatic stress disorder prevalence varied from 0-32 %. The lowest prevalence was noted in a cohort of medical patients who had undergone daily sedation with holding on the ICU [29]; the highest prevalence in those patients who received no sedation interruption [29].

Post-traumatic Stress Disorder in Intensive (are Unit Survivors Table 2. Patient cohort and method of post-traumatic stress disorder assessment studied in adult ICU survivors First author, Year

No*

Patient group

Patient age (years)' 39b

ICU LOS

Method of post-traumatic stress disorder assessment Postal self-report instrument Standardized clinical interview Postal self-report instrument Postal self-report instrum ent Face-to-face self-report instrum ent Standardized clinical interview and postal self-report instrument Standardized clinical interview and face-to-face self-report instrument Face-to-face self-report instrument Postal self-report instrument Posta l self-report instrument Posta l self-report instrument Face-to-face self-report instrument

Deja, 2006 [40] Kapfhammer, 2004 [3] Nelson, 2000 [45] Schelling, 1998 [19] Shaw, 2001 [47] Stoll, 1999 [13]

65 46 24 80 20 52

36.5 40b 35 N/s 36.5

47b n/s 20 35'1 n/s 30

Rothenhausl er, 2005 [25] Sch elling, 2003 [21 ] Schelling, 2004 [1 4] Stoll, 2000 [22] Weis, 2006 [18] Badia-Castello, 2005 [30] Capuzzo, 2005 [37] Cuthbertson, 2005 [2] Griffiths, 2006 [48] Jones, 2001 [4] Jones, 2003 [49] Perrins, 1998 [50] Rattray, 2005 [32] Scragg, 2001 [31]

34 Cardiac surgery 68b

3.1 b

ARDS ARDS ARDS ARDS ARDS ARDS

184 48 80 28 169

Cardiac surgery Cardiac surgery Cardiac surgery Cardiac Surgery General ICU

64 69',70 d 66',611 69', 68d 54.1 b

2 4', 3d 2el 6', 2d 6b

84 78 108 30 11 4 44 109 80

General ICU General ICU General ICU General ICU General ICU GenerallCU General ICU General ICU

69 58 56.9b 57 49b 55b

8.4b 5.6b

Girard, 2007 [35] Kress, 2003 [29]

43 Medical ICU 32 Medical ICU

Nickel, 2004 [33]

41 Medical ICU

Wehler, 2004 [34] Schelling, 1999 [20] Schelling, 2001 [23]

80 Medical !CU 27 Septic shock 20 Septic shock

liberzon, 2006 [28]

90 Surgical ICU

Mahler, 2005 [36] Richter, 2006 [51]

101 Surgical ICU 37 Surgical ICU

Hepp, 2005 [24] Schnyder, 2000 [26]

106 Trauma ICU 121 Trauma ICU

Schnyder, 2001 [27]

106 Trauma ICU

Face-to-face self-report instrument Telephone self-report instrument Face-to-face self-report instrument W Face-to-face self-report instrument 8' 13 b', 14bd Face-to-face self-report instrument Postal self-report instrument 6b 57.1 4.9 Face-to-face self-report instrument 54.1 b Majority Postal self-report instrument s 2 days Face-to-face self-report instrument 52 10 49.5bd, Standardized clinical interview and 12.8b', face-to-face self-report instrument 6.9bd 47.2b' 48.3 b n/s Standardized clinical interview and face-to-face self-report instrument 46b 12b Face-to-face self-report instrument Postal self-report instrument 53',54d 35'd 55',48 d 32', 23d Standardized clinical interview and face-to-face self-report instrument 68b n/s Standardized clinical interview and face-to-face self-report instrument Postal self-report instrument 58.3 n/s 41.7b 51 .9b Standardized clinical interview and face-to-face self-report instrument 37.9b Standardized clinical interview 5.5b 37.5b Standardized clinical interview and 5.7b face-to-face self-report instrument 37.9b Standardized clinical interview and 5.5b face-to-face self-report instrument

ICU: intensive care unit; LOS: length of stay; n/s: not stated; ARDS: acute respiratory distress syndrome; AVR: aortic valve replacement; CABG: coronary artery bypass grafting; *: sample size at first post-traumatic stress disorder assessment; ' : data are reported as median if not specified; b: mean; ': control group; d: study; ' : CABG group; I: AVR group;

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J. Griffiths, A.M. Hull, and B.H. Cuthbertson Table 3. Studies using self-report inventories to assess post-traumatic symptomatologyinadult ICU survivors

First author, Year

Study Design

Time of first post-traumatic stress disorder assessment eb

Post-traumatic symptomatology •

IES Capuzzo, 2005 [37] Jones, 2001 [4] Jones, 2003 [49] Badia-Castello, 2005 [30] Perrins, 1998 [50] Rattray, 2005 [32] Schnyder, 2000 [26] Schnyder, 2001 [27] Scragg, 2001 [31] Shaw, 2001 [47]

Prospective cohort Prospective cohort Prospective randomized Prospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort Cross-sectional survey Prospective cohort

1 month 8 weeks 8 weeks 12 months 6 weeks ICU discharge 13.7 days'd 12 months" n/s n/s

5% 10.89 to 43h 12.091to 29.09k 1.5i to 11.1 i 13.8 17% avoidance", 16% intrusion" 14.9 (avoidance 6.8, intrusion 8.3) 15.5 (avoidance 7.0,intrusion 8.7) 12% avoidance", 8 % intrusion" 35 % (IES score > 30)

IES-R Liberzon, 2006 [28]

Follow-up cohort

22.5

Kress, 2003 [29] Mahler, 2005 [36]

Prospective cohort Cross-sectional survey

6 months to 2 years 6 months 7.2 years

PTSS-l0 Deja, 2006 [40] Girard, 2007 [35] Mahler, 2005 [36] Kapfhammer, 2004 [3] Rothenhausler, 2005 [25] Schelling, 2003 [21] Schelling, 2004 [14] Schelling, 2001 [23] Nickel, 2004 [33] Schelling, 1998 [19] Schelling, 1999 [20] Stoll, 1999 [13] Stoll, 2000 [22] Wehler, 2004 [34] Weis, 2006 [18]

Retrospective cohort Prospective cohort Cross-sectional survey Retrospective cohort Prospective cohort Prospective cohort Prospective randomized Prospective randomized Follow-up cohort Retrospective cohort Retrospective cohort Follow-up cohort Follow-up cohort Follow-up cohort Prospective randomized

57 months 6 months 7.2 years 8 years' 10.7 days' 1 week 6 months 31 months 6.2 months' 4 years 4 years 5 years 20 weeks 18 months 6 months

29%** 14%** 28.0%**; 25.4 25.0 f 24.9 22.0f 20.0ft, 25.5fk 63.6 %** I, 11 .1 %** k 17.1 %** 27.5%** 38.9%** 19.0 %** 15.0 %** 12.5 %** 15.5fl, 25.5fk

DTS Cuthbertson, 2004 [2]

Prospective cohort

3 months

14% (DTS score> 27)

TSQ Griffiths, 2006 [48]

Follow-up cohort

6 to 12 months 52.8%

7-item tool Nelson, 2000 [45]

Cross-sectional survey

15 months

27.3 k, 11.21 31.0 % (IES-R score > 39); 28.5

39.1 to 56.5%

IES: Impact of Events Scale; IES-R: Impact of Events Scale Revised; PTSS-l0: Posttraumatic stress syndrome 10-questions inventory; DTS: Davidson trauma scale; TSQ trauma screening questionnaire. ': Data are reported as median if not specified; b: Time of assessment after ICU or hospital discharge if not specified; ': Mean; d: After accident; e: Data are reported as prevalence rate (%) or mean inventory score if not specified; f: Median; 9: patients with factual memory for ICU; h: patients with delusional memory for ICU; i: patients with delusional and factual memory for ICU; i: patients with no memory for ICU; k: control group; I: study group; ': IES score > 20; ": PTSS-l0 score > 35.

Post-traumatic Stress Disorder in Intensive (are Unit Survivors Table 4. Studies using standardized clinical interview to assess the prevalence of post-traumatic stress disorder in adult ICU survivors

First author, year

CAPS

Hepp, 2005 [24] Schnyder, 2000 [26] Schnyder, 2001 [27] liberzon, 2006 [28] SCID

Kapfhammer, 2004 [3] Kress, 2003 [29] Nickel, 2004 [33] Richter, 2006 [51] Rothenhausler, 2005 [25] Schelling, 2001 [23] Stoll, 1999 [13]

Study Design

Time of 1't post-traumatic stress disorder assessment ab

Post-traumatic stress disorder prevalence at 1't assessment

Prospective cohort Prospective cohort Prospective cohort Follow-up cohort

1 month 13.7 days'd 12 months"

6 months to 2 years

4.70%, (18.9") 4.70 %, (21.5") 1.90 %, (18.9") 17.60 %

Retrospective cohort Prospective cohort Follow-up cohort Follow-up cohort Prospective cohort Prospective randomized Follow-up cohort

8 years 6 months 6.2 months' 35 months 1 week 31 months 5 years

23.90 % 31.6 %1, 0 %9 9.80% 19 % 17.6 % 63.6 %1, 11.1 %9 25 %

CAPS: Clinician Administered Post-Traumatic Stress Disorder Scale; SClD: Structured Clinical Interview for DSM-IV; ' : Data are reported as median if not specified; b: Time of assessment after ICU or hospital discharge if not specified; ': Mean; d: After accident; ": Mean CAPS score; ': control group; 9: study group

Studies that apply screening instruments can only provide information on the prevalence of post -traumatic symptomatology. The most frequently used screening instruments were the IES and the PTSS-lO ( Table 3). The IES scores are reported either as a mean score or a percentage of patients scoring over a threshold score. The mean IES score ranges from 43 in those patients with only delusional memory for their ICU experience 8 weeks after ICU discharge [4], to 1.5 at 12 months postICU discharge in patients with no memory for ICU (30). The prevalence of patients scoring above 20 on the IES ranges from 12 % for avoidance and 8 % for intrusion [31], to 21 % for avoidance and 18 % for intrusion 12 months after treatment on a general ICU [32]. The studies using a cut-off threshold score of 35 or more on the PTSS-lO report a post-traumatic symptomatology prevalence of between 11 % and 64 % in survivor s of septic shock [13, 23], 12.5 - 17.5 % in survivors of a general medicallCU [33-35) , 15 % in survivors of cardiac surgery [22], 19-29 % in survivors of ARDS [13, 19], and 28 % in survivors of prolonged surgical ICU treatment (36).

Limitations of Existing Studies Comparability Issues

The studies of ICU-related post-traumatic stress disorder differ extensively in terms of casemix, inclusion and exclusion criteria as well as method and timing of posttraumatic symptomatology or post-traumatic stress disorder assessment. The studies are small and have often used the same cohort of patients [3, 13, 19, 24, 26, 27). In addition, most research has been conducted in tertiary, university -affiliated hospitals in differing health care systems across Europe, UK, and America. As ICUs can differ within the same area, among countries, and among teaching hospitals and

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non-teaching hospitals, patient outcomes and rates of psychological morbidity may also be expected to differ widely. Furthermore, the studies span a nine-year period during which considerable changes in ICU casemix, ICU therap ies, and training of ICU personnel has occurred. Taken together, all these factors limit the generalizability of study findings and question the merit of drawing conclusions from the current literature about true post-traumatic stress disorder prevalence in survivors of ICU treatment.

Study Design Ideally, studies should aim to recruit consecutive ICU admissions with limited exclusion criteria and undertake detailed follow-up of all enrolled patients, so that posttraumatic stress disorder prevalence can be determined for the ICU population as a whole. Although over half of the relevant studies enrolled consecutive patients, many experienced significant losses of study participants before the first assessment of post-traumatic psychopathology had occurred. When conducting studies to catalog post-traumatic stress disorder prevalence, any attrition or loss of data is a poten tial source of bias. Furthermore, any patients lost to follow-up should be subject to statistical comparison to those patients remaining in the study group to determine any significant differences (e.g., demographics, ICU length of stay, admission diagnosis, and severity of illness). The majority of studies focus on a particular ICU subgroup (e.g., cardiac, ARDS, sepsis) and apply extensive inclusion and exclusion criteria. Pragmatically, studies that give post-traumatic stress disorder prevalence rates for survivors from general ICUs are probably the most relevant for intensivists and referring specialists. The prevalence of post-traumatic stress disorder and post-traumatic symptomatology of general ICU survivors was found to be 5-64 % [23,37] . These prevalence rates rival those of survivors of natural disasters (5 -60 %) and political refugee experience (4-44 %), and exceed those of survivors of cancer (1.9-39 %) or myocardial infarction (0-16 %) [16]. The wide variation in reported post-traumatic stress disorder prevalence after ICU treatment undoubtedly reflects the wide variation in study design and assessment of post-traumatic psychopathology.

Post-traumatic Stress Disorder Assessment The reliability and validity of the reported prevalence of post-traumatic stress disorder and post-traumatic symptomatology also depends on the method used to measure post-traumatic psychopathology and post-traumatic stress disorder [17]. For obvious reasons, standardized interview is not always practically possible at ICU follow-up, and the administration of self-report screening instruments allows the identification of post-traumatic symptomatology. However, the practice of using screening tools for diagnostic purposes is problematic. Although threshold scores are often proposed for self-report instruments so that they can be used diagnostically, the use of such cut-off scores reflects a dichotomous categorization of a continuous variable [38]. There will be little difference among patients just below or just above the cutoff score. Furthermore, appropriate cut-off points will vary with either the popula tion or ICU subgroup under investigation, so it is recommended that cut-off scores be used with caution [38]. Structured clinical interviews also have important limitations. Firstly, they may be vulnerable to negative reporting bias and to symptom over-reporting or malingering . Second, there exist problems with coding and scor-

Post-traumatic Stress Disorder in Intensive (are Unit Survivors

ing. Many interview-based post-traumatic stress disorder diagnostic measures are also scored dichotomously and not on a continuum. This approach portrays symptoms and diagnoses simplistically and fails to provide severity ratings that can track change over time. The CAPS addresses this by querying on a continuous scale the intensity of the symptoms. Perhaps the stronge st studies methodologically are those where researchers use self-report instruments in conjunction with standardized diagnostic clinical interviews. This approach ensures accurate diagnosis based on standardized criteria, and symptom severity based on the screening instrument. In addition, it enables the diagnostic sensitivity, specificity, and validity of the selfreport instrument and its cut-off threshold to be determined in an leu population. Indeed, the use of self-report instruments to 'diagnose' post-traumatic stress disorder is likely to elevate the reported prevalence rates. For example, a study of burn survivors conducted by Tedstone and Tarrier [39] revealed that whereas nearly 40 % of their cohort were classified as 'post -traumatic stress disorder cases' via the IES, only 2 % were found to actually have post-traumatic stress disorder when assessed with a comprehensive instrument, the Penn inventory. Where self-report instruments are used it is important that they have been validated. However, at the current time, most self-report instruments lack sufficient sensitivity and specificity in the ICU population. The commonly used IES and IES-R have not been validated against psychological diagnostic interview in the post -ICU population. Most psychomet ric evidence for the IES has been developed in populations with symptoms resulting from trauma/stressful events but without mental health diagnoses . Importantly, the IES only assesses two of the three post-traumatic stress disorder diagnostic criteria. Therefore, the merit of drawing any conclusions regarding post-ICU post-traumatic stress disorder prevalence based solely on IES assessment remains open to question. In critically ill patients, symptoms of post-traumatic stress disorder are likely to be expressed in nuanced and idiosyncratic ways and may not be captured through simple self-report questionnaires [16]. Additionally, self-report measures typically do not allow researchers to determine whether a constellation of symptoms reflect post-traumatic stress disorde r or another psychological disorder such as anxiety, depression , or adjustment disorder. For example, 75 % of the ICU patients in a study by Stoll et al. reported having nightmares [13]. The presence of nightmares often contributes significantly to a post-traumatic stress disorder score on a screening questionnaire and may suggest underlying post-traumatic stress disorder. However, the nightmares could be due to sleep disturbance, so often seen in patients recovering from critical illness, or anxiety, or be a side effect of medicat ion. The true importance of nightmares in this situation can only be determined through clinical interview. The timing of post-traumatic stress disorder assessment varied widely among the studies . However, the timing of assessment is crucial to the understanding of the reported prevalence of post -traumatic stress disorder. According to DSM-IV criteria it is necessary to specify both the duration of the post-traumatic stress disorder symptoms and their onset (Table 1). Acute post-traumatic stress disorder can be considered after symptom duration of at least one month after the stressor/event. Acute versus chronic post-traumatic stress disorder depends on whether the symptom duration is more or less than three months. Delayed onset is recognized if the post-traumatic stress disorder symptoms occur at least six months after the stressorl event. However, for a patient surviving ICU treatment the timing of the stressorl event is often confounded and requires the patient 'remembering' when the posttraumatic stress disorder symptoms first occurred. It follows that there needs to be

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some consistency in a particular study's definition of the traumatic event and timing of the post-traumatic stress disorder assessment in relation to this event if studies of ICU survivors are to be compared and results discussed in a comparable way [2].

Risk Factors for ICU-related Post-traumatic Stress Disorder Although risk factors have not been studied systematically across studies, a number of risk factors for ICU-related post-traumatic stress disorder have been reported. Demographic and historical variables associated with an increased risk of ICUrelated post-traumatic stress disorder include younger age [2,31,32], female gender [31, 35], and a lesser degree of perceived social support [40].

Pre-existing Patient Characteristics The general literature suggests that existing characteristics of the patient may predispose individuals to the development of post-traumatic stress disorder. These include personality factors [41], previous life adversity, and previous mental health difficulties [41]. Unfortunately, few studies of ICU-related post-traumatic stress disorder specifically measured lifetime post-traumatic stress disorder, and over half of the studies actively excluded patients with a history of personality factors or preexisting psychological problems. Ideally, screening should try to identify previously occurring post-traumatic stress disorder or any other pre-existing mental disorder. Ongoing ill health leading up to a traumatic illness event, and its sequelae (for example, repeated hospital visits, the worry of future ill health, and financial difficulties), may have an additive effect. This has been described as "cumulative adversity" [42]. The studies that sought a history of significant pre-existing personality and psychological disorders provide evidence that these disorders are indeed likely to be an important etiological factor in the development of future post-traumatic stress disorder. By applying the SCID, Nickel et al. demonstrated a post-traumatic stress disorder prevalence of 9.8 % (4 patients) 6-months after discharge from treatment in a medical ICU [33]. Interestingly, all four patients had a pre-existing mental illness: Two were addicted to alcohol, one had recurrent depressive disorder, and another borderline personality disorder. In comparison with the group without post-traumatic stress disorder, 35 % of the post-traumatic stress disorder patients had previous 'psychic stress'; the difference was significant (p = 0.025). In a small group of patients scheduled for elective cardiac surgery, Rothenhausler et al. discovered that a total of 41.2 % of the entire sample met the criteria for a current psychiatric diagnosis on the SCID [25]. Diagnoses included minor depressive episodes (11.8 %), undifferentiated somatoform disorder (8.8 %), dysthymic disorder (5.9 %), generalized anxiety disorder (5.9 %), agoraphobia without a history of panic disorder (5.9 %), and major depressive disorder (2.9 %). Prior psychiatric history revealed lifetime diagnoses of alcohol abuse (U.8 %), benzod iazepine abuse (U.8 %), and, importantly, post-traumatic stress disorder (8.8 %). In survivors of ICU treatment in the UK, Cuthbertson et al. demonstrated that patients who reported having visited their General Practitioner (GP) or a mental health professional for psychological distress prior to their ICU admission had significantly higher levels of post-traumatic stress disorder symptomatology 3-months after ICU discharge [2]. This is in agreement with the work in trauma populations that has demonstrated endorsement of the statement that "visited a GP for stress" prior to

Post-traumatic Stress Disorder in Intensive Care Unit Survivors

the accident is a more reliable predictor than asking about their pre-trauma psychiatric history [43). Recall of the ICU Experience

Currently, there is no standardized way of assessing perceptions of the ICU experience in survivors or relating it to long-term outcome. Methods that have been employed include the ICU memory tool [4], the ICE questionnaire [44], and recall for traumatic events [14, 20]. A particular issue for ICU patients appears to be the high prevalence of delusional memories for the period of critical illness. Jones et al. demonstrated much higher IES scores at 6-months following ICU discharge in patients having delusional memory without recall for factual events than those patients retaining some factual recall [4]. However, a proportion of patients after ICU treatment reporting factual, traumatic memories from their stay in the ICU have also been shown to be more likely to develop post-traumatic stress disorder [20,31). It has been postulated that stress hormones may influence the development of post-traumatic stress disorder through complex and simultaneous interactions on memory formation and retrieval and numerous studies have demonstrated that treatment with hydrocortisone is associated with a decreased risk of post-traumatic stress disorder [18, 20, 23). Therefore, the exact relationship between recall for the ICU experience, factual and delusional memory, and subsequent psychological morbidity remains uncertain at the present time. Sedation and Delirium

The long-term psychological effects of the sedative and analgesic drugs prescribed on the ICU are also not properly understood. High levels of ICU-related post-traumatic symptomatology could be related to lorazepam dose [35] or the duration of sedation and neuromuscular blockade prescribed on the ICU [45). Moreover, a lower prevalence of post -traumatic symptomatology has been demonstrated in patients whose sedative infusions are interrupted on a daily basis [29). It is postulated that intermittently withdrawing sedation from ICU patients enables them to become more conscious and aware of their environment. As a consequence of this they may be less prone to developing the delusional type of memory described by Jones et al. [4]. However, the exact relationship between the level of sedation, the development of delirium, and the later recall of delusional memories and post-traumatic stress disorder symptomatology remains largely undetermined [35]. Post-traumatic Stress Disorder and Co-morbid Psychological Disorder

Post-traumatic stress disorder, particularly in the more chronic forms, rarely occurs alone. The National Co-morbidity Survey found that approximately 80 % of patients with post-traumatic stress disorder met criteria for at least one other disorder defined in the DSM-IV [46). Post-traumatic stress disorder is most commonly associated with depression and this co-morbidity is associated with greater symptom severity and higher risk of suicidal behavior. Accurate prevalence rates for depression symptomatology associated with ICU-related post-traumatic stress disorder are difficult to ascertain because a wide variety of tools have been used by the individual studies. Moreover, these tools have been applied at different time points . Using the scm to diagnose depression, Rothenhausler et al. reported a prevalence rate of 10 %

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J. Griffiths, A.M. Hull, and B.H. Cuthbertson in survivors of cardiac surgery 6-months after hospital discharge [25]. Trait anxiety in patients recovering from ICU treatment has been found to be a predictor of possible post-traumatic stress disorder-related symptoms [4]. In the same study, patients demonstrating "delusional memory" for their ICU experience had significantly higher mean depression and anxiety scores at 2-weeks compared to those patients with factual memory [4]. In survivors of ARDS, Shaw et al. demonstrated a significant positive correlation between IES intrusion subscale score and the Weinberger Adjustment Inventory (WAI) Distress Score [47]. ARDS survivors with post-traumatic stress disorder commonly display psychiatric co-morbidities that include major depression, bulimia nervosa, alcohol abuse, and in 58 % of patients, undifferentiated somatoform disorder [3]. It is not surprising that an increased level of somatic symptoms has been found in patients with post-traumatic stress disorder or post-traumatic symptomatology after ICU treatment as the general literature suggests that there is an increased risk of somatization symptoms that is beyond that expected by the presence of co-morbid psychiatric disorders in individuals with post-traumatic stress disorder. The recognition of the existence of co-morbidity is essential to allow the appropriate formulation of treatment for each disorder and to clarify the respective roles each disorder may play in the maintenance of distress and dysfunction.

Conclusion There are an increasing number of studies pertaining to the study of post-traumatic stress disorder and post-traumatic symptomatology in survivors of critical illness. Although the studies reporting on the rates of post-traumatic stress disorder vary considerably in their design and methodological rigor, a number of conclusions can be drawn. First, there is little doubt that a population of adult ICU survivors does suffer significant psychological morbidity as a result of their ICU experience. Second, few rigorous longitudinal studies have been undertaken to establish the exact prevalence and natural time course of post-traumatic stress disorder in survivors of ICU treatment. Third, there is no clear evidence in the literature regarding the true etiology of post-traumatic stress disorder in survivors of lCU, but memory of the ICU experience and particularly the effects of sedation protocols on recall of the ICU experience may playa role . As with other patient populations, pre-existing psychological and personality disorders could predispose an individual to post-traumatic stress disorder after a traumatic event. Fourth, post-traumatic stress disorder is often associated with other psychological morbidity (notably depression and anxiety disorders) and also causes limitation of function above and beyond the impact of the primary critical illness to affect an individual patient's health-related quality of life. Finally, few studies have examined potential treatments and interventions in ICU survivors with post-traumatic stress disorder. Currently, there is a global lack of resources in ICU follow-up and access to mental health professionals, such as psychiatrists and clinical psychologists, is not universally regarded as an important facet of the follow-up process. Therefore, it is understandably difficult to achieve the gold standard for post-traumatic stress disorder diagnosis at time of ICU follow-up - clinical review by personnel trained in psychological assessment. This has been overcome by the use of screening instruments. These self-report questionnaires have highlighted patients suffering from psychological distress and allowed post-traumatic symptomatology to be measured. However,

Post-traumatic Stress Disorder in Intensive (are Unit Survivors Table S. Recommendations for future studies of post-trau matic stress disorder in survivors of ICU treat-

ment

Future studies should: • Be longitudinal in nature with multiple assessments made over a minimum of 12 months follow-up • Recruit consecutive ICU admissions • Include patients with pre-existing personality and psychological disorders • Determine baseline prevalence of post-traumatic stress disorder, anxiety, depression, and other co-morbid psychological conditions • Utilize both a structured clinical interview and self-report measure approach to diagnose post-traumatic stress disorder and its related symptoms, so that the diagnostic sensitivity and specificity and validity of the self-report measure can be determined in the post-ICU population • Collect detailed demographic and treatment data including ICUlength of stay, sedation policy, and delirium score • Collect longitudinal data on a patient's recall for their ICU experience and health-related quality of life and the prevalence of depression, anxiety and other co-morbid psychological disorders

the majority of these instruments have been introduced without enough attention given to their tru e psychometric properties. Few have been validated against psychological diagnost ic interview in survivors of ICU treatment. Moreover, when follow-up studies have used a screening tool, rath er than a diagnostic interview, to determine post-traumatic stress disorder-related symptoms, this fact is rarely empha sized in the literature when the rates of post-traumatic stress disorder are quoted. As a result, the prevalence rates that exist in the literature for post -traumatic stress disorder in pat ients recovering from critical illness are inaccurate as no distinction is made between post-traumat ic psychopathol ogy and the distinct diagnostic entity that is post-traumatic stress disorder. Complications ar ise with regard to which classification system is used as diagnostic inter views comply with the stricter criteria of DSMIV and thus the rates of post-traumatic stress disorder quoted from these studies are likely to be over-inflated with regard to DSM-IV. The diagnosi s of post-traumatic stress disorder is an important psychiatric disorder, with significant and recognized morbidity for an individual patient, and it is essential that such a label is only given when appropriate [38]. There is a need for future studies to incorporate a rigorous methodological design (Table 5). This approach would hopefully allow the true prevalence of post-traumatic stress disorder, its etiology and association s, to be accurately and confidently determined in survivors of critical illness. Only then should the emphas is turn to examine whether recognized pharmacological and psychological treatments and interventions used in other trauma populations are effective for an ICU population or require alteration to meet the needs of this group. References 1. Broomh ead LR, Brett SJ (2002) Clinical review: Intensive care follow-up - what has it told us? Crit Care 6:411-417 2. Cuthbertson BH, Hull A, Strachan M, Scott J (2004) Post-tr aumat ic stress disorder after critical illness requiring general intensive care. Intensive Care Med 30:450-455 3. Kapfhammer HP, Rothenhausler HB, Krauseneck T, Stoll C, Schelling G (2004) Posttraumatic

stress disorder and health-related quality of life in long-term survivors of acute respirator y distr ess syndrome. Am J Psychiatry 161:45- 52 4. Jones C, Griffiths RD, Humphris G, Skirrow PM (2001) Memor y, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. Crit Care Med 29:573 - 580

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J. Griffiths, A.M. Hull, and B.H. Cuthbertson 5. American Psychiatric Association (1980) Diagnostic & Statistical Manual of Mental Disorders, 3rd edn. American Psychiatric Association, Washington, DC 6. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th edn, Text Revision. American Psychiatric Association, Washington, DC 7. Tedstone JE, Tarrier N (2003) Posttraumatic stress disorder following medical illness and treatment. Clin Psychol Rev 23:409-448 8. Spitzer RL, Williams JB, Gibbon M, First MB (1992) The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 49:624-629 9. Blake DD, Weathers FW, Nagy LM, et al (1995) The development of a Clinician-Administered post-traumatic stress disorder Scale. J Trauma Stress 8:75-90 10. Davidson JR, Book SW, Colket JT, et al (1997) Assessment of a new self-rating scale for posttraumatic stress disorder. Psychol Med 27:153- 160 11. Horowitz M, Wilner W, Alvarez W (1979) Impact of Event Scale: A measure of subjective stress. Psychosom Med 41:209-218 12. Weiss D, Marmar C (1997) The Impact of Event Scale - Revised. In: Wilson J, Keane T (eds) Assessing PsychologicalTrauma and Post-TraumaticStress Disorder.Guilford,NewYork, pp 399- 411 13. Stoll C, Kapfhammer HP, Rothenhausler HB, et al (1999) Sensitivity and specificity of a screening test to document traumatic experiences and to diagnose post-traumatic stress disorder in ARDS patients after intensive care treatment. Intensive Care Med 25:697- 704 14. Schelling G, Kilger E, Roozendaal B, et al (2004) Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Bioi Psychiatry 55:627-633 15. Creamer M, McFarland A, Burgess P (2005) Psychopathology following trauma: the role of subjective experience. J Affect Disord 86:175-182 16. Jackson J, Hart R, Gordon S, Hopkins R, Girard T, Ely E (2007) Post-traumatic stress disorder and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem. Crit Care 1l:R27 17. Griffiths J, Fortune G, Barber V, Young J (2007) The prevalence of post traumatic stress disorder in survivors of ICV treatment: a systematic review. Intensive Care Med 33:1506-1518 18. Weis F, Kilger E, Roozendaal B, et al (2006) Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk patients after cardiac surgery: a randomized study. J Thorac Cardiovasc Surg 131:277-282 19. Schelling G, Stoll C, Haller M, et al (1998) Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 26:651-659 20. Schelling G, Stoll C, Kapfhammer HP, et al (1999) The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder and health-related quality of life in survivors. Crit Care Med 27:2678-2683 21. Schelling G, Richter M, Roozendaal B, et al (2003) Exposure to high stress in the intensive care unit may have negative effects on health-related quality-of-life outcomes after cardiac surgery. Crit Care Med 31:1971-1980 22. Stoll C, Schelling G, Goetz AE, et al (2000) Health-related quality of life and post-traumatic stress disorder in patients after cardiac surgery and intensive care treatment. J Thorac Cardiovasc Surg 120:505-512 23. Schelling G, Briegel J, Roozendaal B, Stoll C, Rothenhausler HB, Kapfhammer HP (200l) The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors. Bioi Psychiatry 50:978- 985 24. Hepp V, Moergeli H, Buchi S, Wittmann L, Schnyder V (2005) Coping with serious accidental injury: a one-year follow-up study. Psychother Psychosom 74:379-386 25. Rothenhausler HB, Grieser B, Nollert G, Reichart B, Schelling G, Kapfhammer HP (2005) Psychiatric and psychosocial outcome of cardiac surgery with cardiopulmonary bypass: a prospective 12-month follow-up study. Gen Hosp Psychiatry 27:18-28 26. Schnyder V, Morgeli H, Nigg C, et al (2000) Early psychological reactions to life-threatening injuries. Crit Care Med 28:86-92 27. Schnyder V, Moergeli H, Klaghofer R, Buddeberg C (2001) Incidence and prediction of posttraumatic stress disorder symptoms in severely injured accident victims. Am J Psychiatry 158:594-599

Post·traumatic Stress Disorder in Intensive Care Unit Survivors 28. Liberzon I, Abelson JL, Amdur RL, et al (2006) Increased psychiatric morbidity after abdominal aortic surgery: risk factors for stress-related disorde rs. J Vase Surg 43:929- 934 29. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB (2003) The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care 168:1457 -1461 30. Badia-Castello M, Trujillano- Cabello J, Servia-Goixart L, March-Llanes J, Rodrigu ez-Pozo A (2006) Recall and memor y after intensive care unit stay. Development of posttraumatic stress disorder. Med Clin (Bare) 126:561 - 566 31. Scragg P, Jones A, Fauvel N (200!) Psychological problems following lCV treatment. Anaesthesia 56:9- 14 32. Rattray JE, Johnston M, Wildsmith JA (2005) Predictors of emotional outcomes of intensive care. Anaesthesia 60:1085- 1092 33. Nickel M, Leiberich P, Nickel C, et al (2004) The occurrence of postt raumatic stress disorder in patients following intens ive care treatment: a cross-sectional study in a random sample. J Intensive Care Med 19:285- 290 34. Wehler M, Stolle M, Riek A, et al (2004) Post-traumatic stress disorder after medical intensive care Crit Care 8:R343 35. Girard T, Shintan i A, Jackson J, et al (2007) Risk factors for post-traumatic stress disorder symptom s following critic al illness requiring mechanical ventilat ion: a prospective cohort study. Crit Care II :R28 36. Mahler C, Boer K, Unlu C, et al (2005 ) Prevalence of symptoms related to post-traumatic stress disorder during long-term follow-up in patients after surgical treatment for secondary peritonitis. Crit Care 9:R243 37. Capuzzo M, Valpondi V, Cingolani E, et al (2005) Post-traumatic stress disorder-related symptoms after inten sive care. Minerva AnestesioI71 :167-179 38. Bennun I (2004) A critique of the research assessing post traumatic stress disorder in critical care patients. Care Crit III 20:102- 107 39. Tedstone J, Tarrier N (1997) An investigation of the prevalence of psychological morbidity in burn injured patients. Burns 23:550- 554 40. Deja M, Denke C, Weber-Carst ens S, et al (2006) Social support during inten sive care unit stay might reduce the risk for the development of posttraumatic stress disorde r and consequently improve health related quality of life in survivors of acute respiratory distress syndrome . Crit Care 10:R147 41. Czarnocka J, Slade P (2000) Prevalence and predictors of post-traumatic stress symptoms following childbirth. Br J Clin Psychol 39 35- 51 42. Alonzo AA (2000) The experience of chron ic illness and post-traumatic stress disorder : the consequences of cumulative adversity. Soc Sci Med 50:1475-1484 43. Klein S, Alexande r DA, Hutchinson JD, Simpson JA, Simpson JM, Bell JS (2002) The Aberdeen Trauma Screening Index: an instrument to predict post-accident psychopathology. Psychol Med 32:863- 871 44. Rattray J, Johnston M, Wildsmith JA (2004) The intensive care experience : development of the ICE quest ionnaire . J Adv Nurs 47:64- 73 45. Nelson BJ, Weinert CR, Bury CL, Marinelli WA, Gross CR (2000) Intensive care unit drug use and subsequent quality of life in acute lung injury patients. Crit Care Med 28:3626-3630 46. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB (1995) Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52:1048-1060 47. Shaw RJ, Harvey JE, Nelson KL, Gunary R, Kruk H, Steiner H (200!) Linguistic analysis to assess medically related posttraumatic stress symptoms. Psychosomatics 42:35- 40 48. Griffiths J, Gager M, Alder N, Fawcett D, Waldmann C, Quinlan J (2006) A self-report-based study of the incidence and associations of sexual dysfunct ion in survivors of intensive care treatment. Intensive Care Med 32:445-451 49. Jones C, Skirrow P, Griffiths RD, et al (2003) Rehabilitation after critical illness: a randomized, controlled trial. Crit Care Med 31:2456 - 2461 50. Perrin s J, King N, Collings J (1998) Assessment of long-term psychological well-being following intensive care. Intensive Crit Care Nurs 14:108-116 51. Richter JC, Waydhas C, Pajonk FG (2006) Incidence of posttraumatic stress disorder after prolonged surgical intensive care unit treatment. Psychosom 47:223-230

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Subject Index

Abdominal aortic surgery 894 - compartment syndrome (ACS) 538, 657 - surgery 315, 661 Abscess 204 Acetic acid 175 Acetylcholine 56, 801, 817 Acidosis 271, 645, 829 Acids 174 Acquired immune deficiency syndrome (AIDS) 218, 370 Actin 47 Activated clotting time (ACT) 155 - partial thromboplastin time (aPTT) 755 - protein C (APC) 714, 721, 730, 807 Activator protein (AP)-1 215,396 Acute heart failure 657 - kidney injury (AKI) 551, 559, 568 - liver failure 785 - lung injury (ALI) 13, 193, 196,203,217, 232, 382, 395, 405, 721, 725 - myocardial infarction 27 - normovolemic hemodilution (ANH) 668 - on-chronic liver failure 780, 785 - renal failure 559, 568, 770 - respiratory distress syndrome (ARDS) 13, 88, 15I, 193, 203, 214, 235, 245, 270, 274, 283, 290, 379, 529, 854 - see also respiratory distress syndrome - - failure 193 - tubular necrosis (ATN) 569, 771 Adenosine triphosphate (ATP) 385, 423, 473, 562, 632, 673 Adrenaline - see epinephrine Adrenoceptors 6, 148 Adrenocorticotrophin hormone (ACTH) 802 Adrenomedullin 93 Adverse drug event 866, 871 Afterload 649 Air trapping 257, 261 Airway pressure release ventilation (APRV) 251, 301 Albumin 208, 544, 694 - dialysis 777, 788 Aldosterone 34, 793 Alginate 695

Alkaline reserve 172 Alkalis 173 Alpha-2 adrenoceptor agonists 107 Amiloride 284 Amino acid 573 Aminoglycosides 554 Amiodarone 7 Ammonia 481,792 Ammonium 804 Amphotericin B 365 Amyotrophic lateral sclerosis 883 Anaerobic metabolism 51, 532, 642 Analgesia 491, 494, 850 Analgo-sedation 854 Anaphylactic shock 695 Anaphylaxis 538 Anemia 642 Anesthesia 317, 523, 645, 649, 857, 830, 840, 883 Angiography 744 Angiotensin II 802 - converting enzyme (ACE) 16, 60, 206 - - - inhibitors 62, 425, 569 Annexin 20 Anti-apoptotic effect 735 Antibiotics 161, 356, 362 Anticoagulation 779 Anticonvulsive drugs 179 Antidepressant 179 - poisoning 182 Antimicrobial coating 347 - prescription 870 Antithrombin 703, 716 Anxiety 850 Aortic compliance 612 - valve 77 APACHE II score 61 - III score 198 Apoptosis 43, 47, 125, 375, 455, 458, 571, 724,803 - inducing factor (AIF) 561 Aquaporin 1 20 Arachidonic acid 458 Argatroban 239 Arginine 6

908

Subject Index Arrhythmia 181, 584, 660 Arteri al pressure 428, 591, 632, 641, 654, 765,782 Arteriovenous oxygen difference (AVDO z) 814 Artificial liver support 488, 785 Ascites 545 Aspergillus 367 Aspiration 343 - of subglottic secretions 356 - pneumonitis 151 Aspirin 107 Asthma 194, 198, 256, 275, 462 Atelectasis 204, 313 Atelectrauma 249, 302 Atrial fibrillation (AF) 148 Atrio -ventricular block 180 Atropine 183 Automated external defibrillators (AEDs) 114 Autonomy 887 Autopulse 116 Autoregula tion 815 Bacterial translocation 745 Barotrauma 258 Benzod iazepine s 851, 900 Beta-agonists 210 - adrenergic hyporesponsiveness 50 - blockers 60, 62, 104, 180 Bicarbonate 278, 532, 555, 790 Bi-level positive airway pressure (BiPAP) 197, 304 Bilirubin 787, 792 Bioimpedance 621 Biomarker 33 Bioreactance 619 Biotrauma 250 Bisoprolol 106 Bleach 175 Bleeding 751 Blood brain barrier (BBB) 802 - pressure 128 - viscosity 691 - volume 621 Body position 357 Bohr effect 283 Bone marrow 4 Borderline personality disorder 900 Bradycardia 152 Brain natriuretic peptide (see B-type natriuretic peptide) - oxygen tension (PbrO z) 815 Bronchoalveolar lavage (BAL) 209, 273, 358, 516, 725 - - fluid 215 Bronchoscop y 266, 336, 360 B-type natriuretic peptide (BNP) 34, 49, 93, 531

Burn 160, 356, 381, 536 Burst-suppression 834 Button battery 174 Calcineurin inhibitors 770 Calcium 47, 284, 492 - channel blockers 179, 181 Calibration 595, 624, 659 Candida 366 Capillaries 692 Carbon monoxide 697, 765, 802 Cardiac arrest 113, 180, 256 - autonomic dysfunction 55 - disease 35 - dysfunction 43 - failure 76 - filling pressure s 527 - function 733 - index 633 - output 71, 124, 155, 238, 270, 285, 415, 416,429,527,591,607,619,642,649,655, 788 - surgery 38,92,94, 107, 314, 354, 586, 609, 613, 651, 894 - tamponade 582 - toxicity 179 - transplantation 91 Cardiogenic shock 51,447 Cardiopulmonary arrest 199 - bypa ss (CBP) 36, 93, 128, 137, 152, 155, 185, 236 - resuscitation (CPR) 113, 121, 138, 152 Cardiover sion 182 Caspase-3 47 Caspases 376 Catecholamines 50, 183,414, 564, 801 Caustic ingestion 171 CD14 802 Cecal ligation and puncture (CLP) 379 Central venous catheter 581 - - oxygen satu ration (ScvOz) 416, 533, 654 - - pressu re (CVP) 415, 525, 536, 632, 655, 766 Cerebra l blood flow (CBF) 804, 811 - - volume (CBV) 812 - edema 786 - metabolic rate for oxygen (CMROz) 815 - oxygen requirements 148 - perfusion pressure (CPP) 811 Cerebrospinal fluid (CSF) 496, 811 Charcoal hemoperfusion 786 Chemokine 20 Chest compression 113, 126 - radiography 585 Chlorhexidine 345 Cholesterol 103 Cholinergic anti-inflammatory pathway 55 Chronic obstructive pulmonary disease (COPD) 197,199 ,256 ,275 ,285,305,310 ,450

Subject Index Cirrhosis 425, 481, 745, 754, 755 Cirrhotic card iomyopathy 765 Cisplatin 564 Citrate 779 Clinical Pulmonary Infection Score (CPIS) 358 Clonazepam 825 Clonidine 856 Clothiapine 855 Coagulation 332 Coagulopathy 742, 764 Cocaine 179 Colchicine 180 Collagen 176 Colloid 414, 634, 693, 772 - osmotic pressure (COP) 694 Colonoscopy 747 Coma 200, 484 Communication 886 Community-acquired pneumonia (CAP) 25, 218, 219 Complement 20 Compliance 76, 305, 599, 813 Computed tomography (CT) 129, 224, 337 Computerized physician order 865 Congenital diaphragmatic hern ia 276 - heart disease 130, 277 - - surgery 91, 121 Congestive heart failure (CHF) 33, 36 Continuous end -diastolic volume index (CEDVI) 527 - positive airway pressure (CPAP) 197, 253, 290,303,310 - renal replacement therapy (CRRT) 434, 544, 551, 556 - veno-venous hemodiafiltration (CVVHDF) 793 - - - hemofiltration (CVVH) 155,436, 544 Contr ast-induced nephropathy (CIN) 552, 554 Convection 291 Cooling blanket 141 Coronary arte ry bypass graft (CABG) 10,26 - blood flow 124 - perfusion pressure 94, 118 - venous blood 644 Cortactin 20 Corticosteroids 8, 215, 382 - see also glucocorticoids Cortisol 215, 514 Cost-effectiveness 870 Costs 868 C-reactive protein (CRP) 400, 516, 658 Creatinine 368, 533, 552, 660, 772, 787 Cross-correlation synchrony index (CCSI) 70 Cryoprecipitate 156 Crystalloids 537, 772 Cyclic adenosine monophosphate (cAMP) 91

- guanosine monophosphate (cGMP) 423 Cyclooxygenase (COX) 20, 724, 740, 802 Cyclosporine 165, 770 Cysteine 375 Cytochrome C 377 - oxidase 46 - P450 5 Cytokine 9,43, 56, 215, 250, 295, 398, 434, 517, 793,794 Davidson Trauma Scale (DTS) 893 Dead space 282 Death effector domain (DED) 377 Decision support 868 Defibrillat ion 130 Dehydration 628 Delirium 801, 850, 851, 901 Desflurane 827 Dexamethasone 217,276 Dexmetomidine 856 Dextran 695 Diabetes 21, 771 - insipidus 534 Diabetic ketoacidosis 533 Diaphragmatic dysfunct ion 313 Diastolic dysfunction 47, 76 Diazepam 825 Dichloroacetate 51 Diffuse alveolar damage 17 Digitalis 180 Digoxin 7 Disseminated intravascular coagulation (DIC) 148, 174, 238, 440, 703, 713, 733, 782 Diuretic s 553 Dobutamine 95, 106,187,418,531,545,626, 647, 657, 673 Do-not-resuscitate (DNR) order 885 Dopamine 95, 418, 554, 772 Dopexamine 633, 650, 658 Doppler 77 - velocity 619 Drug-elut ing stents 104 Dysoxia 668 Early goal directed therapy 18 Echocardiographic tissue Doppler imaging 67 Echocardiography 88, 187, 605 Edema 13,296 Education 872 Ejection fraction 43, 66 Electrical impedance tomography (EIT) 224, 252 Electrocardiogram (EKG) 77, 113, 121, 147, 180, 587, 629 Electroencephalogram (EEG) 129, 486, 811, 818, 822, 883, Electron transport 387

909

910

Subject Index Emergency medical services (EMS) 121 Emphysema 302 Encephalitis 883 Encephalopathy 482, 764, 773, 801 End-diastolic volume index (EDV1) 766 - of-life care 26, 885 Endonuclease G (EndoG) 376 Endopeptidases 34 Endoscopic therapy 741, 743 Endothelial activation 803 - cell protein C receptor (EPCR) 704 - damage 379 - dysfunction 27 - permeabiliuty 210 Endothelin-I 44, 440, 802 - antagonists 92 Endothelium 35, 250, 691, 721 Endotoxemia 679 Endotoxin 47,58,210,273,391,449,517, 717, 730, 795 Endotracheal intubation 259 - tube 343 End-systolic pressure/volume slope 50 Enteral feeding 539 Epidemiology 193, 313 Epinephrine 95, 127, 148, 152, 418, 633, 743, 793,893 Erythrocyte 448 Erythromycin 743 Erythropoietin (EPO) 476 Esophageal Doppler 634, 659 - motility 740 Esophagectomy 203 Etomidate 828 Exercise 661 Extracellular fluid volume (ECV) 654 Extracorporeal cardiopulmonary bypass 625 - CO2 removal (ECC0 2R) 236 - gas exchange 266 - life-support 179 - liver support systems 778 - lung assist (ECLA) 235 - membrane oxygenation (ECMO) 121,131, 147, 186,235 Extravasation 584 Extravascular lung water (EVLW) 294, 596, 610 - - - index 766 Facial mask 316 Factor V Leiden 716 Fas-associated death domain (FADD) Fatty acid 481 Fenoldopam 772 Ferroportin 474 Fever 161, 811 Fibrinogen 703, 787 Fibrinolysis inhibitor (TAFI) 704 Fibrinolytic system 717

377

Fick equation 642 Filling pressures 85 Flavin adenine dinucleotide (FADH 2) 386 Flucytosine 365 Fluid challenge 655 - resuscitation 163, 536 Fluoride 175 Fosphenytoin 826 Fractioned plasma separation and adsorption (FPSA) 778, 792 Frank-Starling curve 45, 530 - relationship 88, 655 Free radicals 273, 450 Fresh frozen plasma (FFP) 757, 768 Functional residual capacity (FRC) 256, 310 Fungal infections 365 Furosemide 544 Gas exchange 198, 252, 258 Gastric colonization 357 - pH 6 - tonometry 670, 685 Gastrointest inal bleeding 739 - injury 171 Gene expression 14 - polymorphisms 714 Genetic factors 3 - predisposition 400 - determinants 13 Glasgow coma scale (GCS) 805, 819 Global end-diastolic volume (GEDV) 542, 610 - - - index (GEDVI) 528 Glomerular filtration rate (GFR) 770 Glucagon 183 Glucocorticoid 214, 382, 801 - see also corticosteroids - response elements (GRE) 215 Glucose 502, 817 - control 128 Glue therapy 746 Glutamate 444,817 ,858, Glutamine 7, 382, 458, 482 Glutathione 174,273,444 - peroxidase 457 Glycerol 817 Glycocalyx 684 Glycolysis 391 Glycyrrhetinic acid-like factors (GALF) 515 Goal-directed hemodynamic therapy 633 Gram-negative 395 - positive 28, 395 Granulocyte colony stimulating factor (G-CSF) 209,381 - macrophage colony stimulating factor (GM-CSF) 381 Guidelines 876 Guillain-Barre syndrome 199

Subject Index Haloperidol 855 Haplot ypes 15 Hy-blockers 357, 741 Heart failur e 72, 380 Heat and moisture exchanger (HME) 841 - shock proteins (HSP) 46, 378 Helicobacter pyl ori 740 Heliox 266 Helmet 316 Hemadsorption 785 Hematocrit 657, 691, 693 Heme oxygenase-1 (HO-l) 474 Hemodialysis 436, 488, 555, 778, 785 Hemodilution 692 Hemodynamic monitor ing 602 Hemofiltr ation 9 Hemoglobin 108,646,651,665,742,81 7 - dissociation curve 814 Hemolysis 3 Hemophilia 753 Hemorrhage 757 Hemorrhagic shock 531,565,648,695,696 Hemothorax 585 Heparin 156, 187, 238, 779, 866 - induced thrombocytopenia (HIT) 7, 238 Hepatic encephalopathy 780 Hepatitis 782, 791 Hepato-pulmonary syndrome 769 Hepatorenal syndrome 782, 789 Hepcidin 474 Hibernation 50, 51, 125 High frequency oscillatory ventilation (HFOV) 251,290,303 - risk surgical pat ients 631, 654 - volume hemofiltration (HVHF) 434 Hirudin 239 Human immunodeficiency viru s (HIV) 24, 162, 197, 446, 803 Humidification 265 Hyaline memb ranes 214 Hydralazine 4 Hydrochloric acid 171 Hydrocortisone 260 Hydrofluoric acid 175 Hydrogen peroxide 456 Hydroxyethyl star ch (HES) 541, 694 Hyper ammonemia 481 Hypercapnia 239, 258, 264, 269, 282 Hyperinflation 257 Hyperkalemia 180 Hyperoncotic solutions 544 Hypertension 524 Hyper ventilation 812 Hypoalbuminemia 207 Hypoglycemia 148, 498, 503, 506, 804, 828 Hypotension 182, 730 Hypothermia 125, 128, 137, 147,563,812, 828 Hypovolemia 149, 413, 524, 568, 635, 768

Hypovolemic shock 742 Hypoxemia 258, 303 Hypoxia 46, 385, 390, 473, 475, 631, 667, 685 - inducible factor (HIF)-la 385,390,476 - response elements (HREs) 390 Ileostomy 545 Immunoglobulins 165 Immunoparalysis 434, 440 Immunosuppression 770, 773 Impact of events scale (IES) 893 Imped ance card iography 225 Incentive spirometry 315 Inducible nitric oxide synthase (iNOS) 379, 406,423,476, 571, 734 Infants 228 Infection 27, 60, 344 Inflammation 385, 473, 564, 705 Inhaled anesthetics 839 - drugs 264 - iloprost 92 - nitric oxide 90 - pro stacyclin 91 Inodilators 95 Inotropic drugs 95 - support 89 Insp iratory impedance threshold valve (lTV) 115 Insulin 183, 804 Intercellular adhes ion molecule (ICAM)-l 274, 803 Interferon response factor-3 (IRF-3) 396 Interleukin (IL)-l 204, 706 - - receptor antagonist (IL-1ra) 20 - 6 14 - 8 receptor 20 - 10 16 International normalized ratio (INR) 705 Interstitial lung diseases 199 Interventricular septum 84 Intra-abdominal hypertension (IAH) 536, 767 - - pressure (IAP) 767 Intracerebral hemorrhage 754, 755 Intracranial hypertension 793 - presssure (ICP) 277, 336, 674, 811 Intraoperative goal-directed therap y 633 Intrathoracic blood volume (ITBV) 596 - - - index (ITBVI) 528, 766 - pressure 258 Intravital microscopy 571,684 Intrinsic positive end-expiratory presssure (PEEPi) 257 Intub at ion 163, 331 Iron metabolism 473 Ischemia-reperfusion 46, 137, 272, 285, 559, 561, 686 Iseganan 345

911

912

Subject Index Isoflurane 827, 844 Isoproterenol 95, 183 Janus kinase 56 Jugular venous oxygen saturation (SjV02) 814 Keratins 695 Ketamine 260, 827, 840, 854, 858 Lactate 37,51, 152, 181,417,429,654,662, 670,731,817 Lactic acidosis 465, 532, 643 Lactulose 487 L-arginine methyl ester (L-NAME) 407 Laryngeal mask airway (LMA) 336 Left bundle branch block (LBBB) 65 - ventricular compliance 259 - - end-diastolic area (LVEDA) 530, 542 Leukocytes 684, 734 Leukopenia 357 Leukotrienes 215, 246 Levetiracetam 827 Levosimendan 96, 184,419 Lidocaine 211 Linton-Nachlas tubes 746 Lipopolysaccharide (LPS) 211, 273, 379, 392, 396, 459, 723 Lipoteichoic acid (LTA) 396 Lithium 596 Liver assist device 788 - dialysis unit 787 - disease 506 - failure 196, 237, 368, 765 - transplantation 488, 763 Locked-in syndrome 881 Lorazepam 825, 829 Low cardiac output syndrome 33, 37 - tidal volume 251 Lund University Cardiac Arrest System (LUCAS) 116 Lung injury score (LIS) 195, 220 Lymphocyte 380, 392 Macrophage 56, 398, 440, 474, 497 - inhibitory factor (MIF) 16, 802 Magnesium 491, 807, 854, 855, 866 Magnetic resonance imaging (MRI) 66, 224 Major histocompatibility complex (MHC)-I molecules 161 - surgery 650 Mannose-binding lectin-2 16 Mechanical ventilation 181, 193, 224, 236, 245, 256, 259, 295, 353, 648, 764 Medication error 865 Meningeal disease 370 Meningitis 806 Meningococcemia 717 Mesenteric artery 744

Meta-analyses 463, 553, 752 Metabolic acidosis 149, 175,273,532 - see acidosis Metabolism 4 Methemoglobinemia 91,852 Methicillin-resistant Staphylococcus aureus (MRSA) 395, 404 Methylprednisolone 210 Microcirculation 461,531,570,666,680,734 Microcirculatory changes 48 - flow 668 Microdialysis 817 Microvascular function 692 Microvideoscopy 531 Midazolam 5, 773, 826, 839 Milrinone 96, 184, 420 Minimum alveolar anesthetic concentration (MAC) 840 Mitochondria 378, 477 Mitochondrial dysfunction 46 - function 385, 562 - respiratory chain 454 Mitogen activated protein kinase (MAPK) 44,392,399 Mitral valve 65, 79 Mixed venous oxygen saturation (SV02) 181, 416, 429, 533, 619, 641, 669 Model for end-stage liver disease (MELD) score 763 Molecular Adsorbent Recycling System (MARS) 777, 790 Monocyte chemotactic protein (MCP)-1 706 Morbidity 220, 406 Morphine 8, 495, 853 Mortality 61, 62, 161, 165, 196, 220, 274, 349, 360, 378, 464, 465, 633, 656, 708, 713, 769, 780, 877 Multiple organ dysfunction syndrome 55, 380 - - failure (MOF) 14, 195, 196, 269,399, 538, 564, 654, 730 Multi-wavelength imaging (MWI) 688 Muscle 445 - relaxation 264 Myeloid differentiation factor 88 (MyD88) 397 Myocardial depression 413, 734 - dysfunction 65 - infarction 101, 133, 139, 756 - ischemia 108 - relaxation 49 Myosin 47 N-acetykysteine (NAC) 210, 554 Natriuresis 34 Natriuretic hormone system 34 - peptide 33 Near-infrared spectroscopy (NIRS) 181,669, 670

Subiect Index Necrosis 375 Neonatal respiratory distress synd rome 275 Neonates 224, 277 Nephrotoxi ns 559 Nesiritide 93 Neuroleptics 179 Neuromu scular blocking agents 264 - diseases 199 Neuro n-specific enolase (NSE) 801 Neuropsychological testing 886 Neut roph il 246, 250, 380, 440, 455, 709 - count 220 - gelatinase-associate d lipocalin (NGAL) 563 N (G)-nitro-L-methyl esther 691 Nicotin amide adenine dinucleotide 386, 560 Nitr ate 697 Nitric oxide (NO) 39, 44, 45, 128, 274, 283, 297, 404, 497, 571, 691, 684, 724, 732, 765, 802,856 - - synthase (NOS) 285 Nivaquine 179 N-methyl-d-aspart ate (NMDA) 495 Non-invas ive ventilation (NIV) 228, 265, 310, 343, 763 Non-steroidal anti- inflammatory agents 161 Norepinep hrine 95, 408, 429, 731 Nosocomial pneumonia 353 Nuclear factor kappa B (NF-KB ) 215, 392, 396, 458, 560, 706, 732, 803 Nurses 875 Nutr ition 163, 211 Obesity 329, 333 Open chest CPR 126 Opioids 844, 853 Oral hygiene 345 Organophosph ates 179 Orn ithine transcarbamylase 484 Orthogona l polari zation spect ral (OPS) imaging 531, 669, 671, 677, 734 Orthotopic liver tr ansplant ation (OLT) 777 Oxidative phosphorylation 50, 386 Oxygen consumption (V0 2 ) 416, 426, 478, 633 - delivery (00 2) 416, 541, 654, 667, 692 - extractio n 667 - saturation 688 - transport 641 Pacemaker 59, 183 Pancreati tis 196, 381 Paracetamol 866 Paralytic agents 356 Parathyroid hormone (PTH) 493 Parenteral nutrition 485 Patent ductus ar teriosus 36, 39 Pathogen associated molecula r pattern s (PAMPs) 396

Pediatric cardiop ulmonary arrest 121 - critical care 33 Pendelluft 292 Pentobarbital 812, 826 Periope rative cadioprotection 101 - fluid balance 523 - per iod 650 Perip heral vascular resistance 691 Peritonitis 369, 440, 609 Permeability transition pore (PTP) 285 Perm issive hypercapn ia 240, 269 Peroxynitrite 46, 283, 407, 455, 803 Persistent pulm onary hypert ension of the newborn (PPHN) 38, 81, 276 Pharmacist 867, 876 Phar macodynamics 9 Pharm acogenet ics 3 Pharmacogenomics 3 Phar macokinet ics 9 Phenobarbital 825 Phenylephrine 94, 734 Phenytoin 825 Phosp hodies terase (POE) 91 - inhibitors 92, 184 Phospholipids 237 Plasma exchange 788 Plasmapheresis 165 Plasminogen activator inhibitor type I (PAI-l) 440, 704, 714 Platelet 156, 705, 757 - activating factor (PAF) 204, 295, 399, 802 - derived growth factor (PDGF) 476 - transfusion 332 Pneumoc ytes 214 Pneumonia 24, 27, 28, 199, 354, 405, 765 Pneumo perito neum 539 Pneumot horax 296, 337, 585 Poison 171 Poisoning 179 Poly(ADP ribose) polymerase (PARP) 377, 391,407, 457, 559 Polyethylene glycol (PEG) 695 - - albumin 697 Polymor ph isms 3 Polyne uropa thy 502 Polyurethane 326 Polyvinyl chlor ide (PVC) 325 Pontine abscess 883 Positive end-expiratory pressure (PEEP) 187, 229, 251, 272, 290, 302, 310, 543, 648 - pressure ventilatio n 127 Positron emissio n tomography (PET) scanning 883 Postoperative goal-direct ed therapy 634 Post-traumatic stress disorder 839, 891 Potassium channel 286 - - antago nists 184 Pre-eclampsia 49 1

913

914

Subject Index Preload 527, 607, 649 Pressure-controlled ventilation (PCV) 306 Procollagen 215 Propofol 5, 260, 826, 828, 839, 851, 852 Prostac yclin 91, 239, 458, 709, 724 Prostaglandin 802 Protease-activator receptor (PAR-I) 704 Protein C 703 Proton pump inhibitor 740 Pruritus 781 Publication bias 19 Pulmonary artery catheter (PAC) 525, 602, 607, 619, 641, 656, 766 - - occlusion pressure (PAOP) 85, 415, 527, 607, 633, 655, 733 - circulation 126 - edema 139, 186, 197, 529 - embolism 583, 788 - hypertension 88, 205, 440, 770 - vascular resistance 91, 270, 277, - venou s doppler 81 Pulse contour 659 - pressure 611, 612 - - vari ation (PPV) 415, 529, 542, 655 - wave analysis 608 Pulsus paradoxus 259 Pyruvate 817 - dehydrogenase 391, 670 Quality 602 - of care 26 - -life 881, 891 Racial disparities 19, 24 Radionucl ide scanning 48 Reactive oxygen species (ROS) 246, 284, 390, 454, 455, 474, 803 Recombinant activated factor VII 156, 742, 751 Red blood cell (RBC) 677, 753 Regional wall motion abnormalities (RWMA) 65 Relaxation 78 Remifentanil 773, 859 Renal failure 782 - insufficiency 871 Renin 793 Resistance 225, 599, 619 Respiratory acidosis 258 - distress syndrome (RDS) 232 - see acute respiratory distress sydnr ome - rate 263 Resynchronization therapy 65 Rhabdomyolysis 148, 829, 839 Rheumatoid arthritis 21 Rifampicin 781 Right vent ricular dysfunction 88 - - ejection fraction (RVEF) 766 - - failure 49

- - pacing 66 Rotenon e 389 Ryanodine receptor

47

Safety 602, 755 Sclerotherapy 746 Sedation 491, 494, 545, 773, 812, 839, 850, 857,894 Sedatives 260, 805 Seizures 33, 818, 822 Selective oral decontamination 345 Selenium 454 Selenoprotein P 461 Sengstaken-Blakemore tube 746 Sepsis 24, 195, 196, 385, 404, 413, 444, 454, 473, 497, 514, 568, 646, 682, 703, 792, 801 Septicemia 782 Septic encephalopathy 497 - shock 15,43, 219, 413, 447, 514, 539, 564, 569, 647, 671, 730 Sequential organ failure assessment (SOFA) 61, 195, 196, 707, 732 Seroton in-reuptake inh ibitors 179 Serum amyloid P 807 Severe sepsis 651,672, 683 Sevoflurane 840, 843 Shear stress 692 Shivering 151 Shock 200 Short Form-36 (SF-36) questionnaire 884 Sidestream dark field imaging (SDF) 531, 678 Sildenafil 92 Silicone 157 Silver nitrate 165 Simplified acute physiology score (SAPS) II 708 Simulation 118 Single nucleotide polymorphisms (SNPs) 4 - Pass Albumin Dialysis (SPAD) 792 Smoke inhalation 408 Sodium-potassium ATPase 492 Somatosensory evoked potential 129, 806 Spectrometry 646, 647 Spine fixation 335 Splanchnic hypoperfusion 739 - perfusion 767 Standardization of care 869 Statins 60, 107 Status epileptic us 822 Staurosporine 724 Steroids 154, 165 Stevens-Johnson Syndrome 160 Strain 84 Stroke volume 524, 593, 597, 634 - - variation (SVV) 415, 542 Subarachnoid hemorrhage (SAH) 496, 883 Subglottic drainage 345, 347 - suction 328

Subject Index Sucralfate 357 Sudden infant death syndrome (SIDS) 121 Sufentan il 773 Superior vena cava 581 Superoxide 273, 455 - radical s 802 Surfactant 224, 246 - protein-B 16 Surgical patients 631 System ic vascular resistance (SVR) 423, 540, 766,788 Systolic pressure variat ion (SPV) 542

Translocation of nuclear factor-kappa B 302 Tra nsplantation 380, 563 Trauma 148, 196, 199,356,381,517,538, 539, 632, 648, 657, 703 Traumatic bra in injury (TBI) 816, 882 Tricarb oxylic acid (TCA) cycle 386 Tricuspid regurgitation 278 Tumor necrosis factor (TNF) 14, 34, 44, 55, 204, 216, 251,392,476 - - a 516, 724, 732, 793 - - - receptor 376

Tachycardia 48, 49 Tachypnea 260 Tacrolimus 8, 770 Terlipressin 419, 423, 746 Theophylline 180, 555 Thermodilution 525, 608, 612 Thermoregulation 147 Thiamine 828 Thiopental 826, 828 Third space 523 Thoracic bioimp edance 619 - surgery 310, 315 Thrombin 703, 706, 722 - activatable fibrin olysis inhibitor (TAFI) 704 - antithrombin complex 715 Thromb ocytopeni a 782 Thrombo-embolic complications 755 Thrombomodulin 704, 723 Thrombophilia 713 Tidal volume 262, 293 Tissue capn ography 685 - Doppler echocardio graphy 82 - factor-pathway inhibitor (TFPI) 705 - oxygen tensions 671 - resonance analysis (TRA) 818 - type plasminogen activator (t-PA) 717 Titratable acid 172 Toll-like receptor (TLR) 43, 396, 477, 802 - - - 4 (TLR4) 25, 302, 392 Topiramate 827 Total blood volume index (TBVI) 766 - lung capacity (ILC) 256 Toxic epidermal necrolysis 160 Tracheal stenosis 335 Tracheostomy 199, 323, 331,346 Training 872 Tramadol 6 Transcr anial Doppler 818 Transesophageal echocard iography (TEE) 525, 530, 585, 587, 767 Transforming growth factor (TGF) 44, 295 Transfusion 647, 665, 747, 768, 785 - related ALI (TRALI) 196 Transjugula r intrahepatic portosystemic shunt (TIPSS) 747

Ubiquinone 388 Upper airway dysfunction Urea cycle 481, 488 Urease 485 Urinary output 524

200

Vaccine reaction 8883 Vagal signals 58 Vagus nerve 801 - - stimulation 828 Valpro ate 826 Valproic acid 484, 488 Variceal hemorrhage 745 Vascular cell adhe sion molecule (VCAM)-1 726,803 - density 683 - endothelial growth factor (VEGF) 391, 407, 476 Vasoconstriction 151,430 Vasodilatation 7, 181 Vasopressin 94, 127, 184,408, 418,423, 533, 570, 746, 793, 802 Vasopre ssor 82, 94, 183, 655, 817 - therap y 89 Vasospasm 496 Vegetat ive state 885 Velocity 82 Ventilation 227 - perfusion ratio 313 Ventilator-associated lung injury (VALl) 14, 238, 301 - - pneumonia (VAP) 328, 343, 353, 460 - induced lung injury (VILI) 208, 245, 269, 283 Ventricular assist device 188 - fibrillation 117, 121, 138, 148, 180 - tachycardia 180 Video assisted thoracoscopic surgery (VATS) 203 Viscosity 691 Vitamin D 493 Vitro nectin 20 Volutrauma 249, 302 Von Willebrand 's factor 14

915

916

Subject Index Warfarin 6 Weaning failure 649 - time 852 Wesseling algorithm 595 Work of breathing 257

Wound infection 204 - management 164 Zinc

488