ISBN: 0-8247-0474-6 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New Y...
198 downloads
1295 Views
5MB Size
Report
This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form
ISBN: 0-8247-0474-6 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA
The editors note with sadness the passing of our teacher, colleague, and friend, Dr. Joseph Rodarte. We were grateful that this volume contains one of his last works, in which he has reviewed in his usual crystal-clear fashion the difficult topic of cardiopulmonary mechanics. His presence in the scientific community will be sorely missed.
Introduction
More than a decade ago, Drs. Steven Scharf and Sharon Cassidy produced Heart– Lung Interactions in Health and Disease as part of the Lung Biology in Health and Disease series of monographs (Volume 42). That book brought forth what had been recognized for a long time—that the heart and the lung (although different organs) are related and unavoidably interdependent. Indeed, as long ago as 1853, F. Donders published a text titled Contributions to the Mechanisms of Respiration and Circulation in Health and Disease. In the twentieth century, cardiac catheterization, blood-gas measurements, and other technologies have greatly contributed to the understanding of heart–lung interactions and it is now well recognized that a pathological aberration in one of these two organs will lead to dysfunction in the other. Advances in medicine in the last one or two decades have been quite remarkable and have led to benefits that extend far beyond what was initially envisioned. This new volume, Respiratory-Circulatory Interactions in Health and Disease, edited by Drs. Steven Scharf, Michael Pinsky, and Sheldon Magder, is much more than an update of Volume 42. It is actually the continuation of the voyage toward understanding the interactions of these marvelous organs. The terms ‘‘respiratory’’ and ‘‘circulatory’’ underscore the functionality of these interactions and how they manifest themselves in health and in disease. v
vi
Introduction
In their introductory chapter, the editors state: ‘‘Detailed knowledge of the heart–lung interactions helps clinicians better understand specific clinical situations and enables the application of novel modes of treatment when one or the other of these two important organ systems is diseased.’’ Indeed, that is what this volume is about. This is major progress in our voyage toward more effective medicine. The editors and the contributors have made an outstanding contribution and, as the executive editor of the Lung Biology in Health and Disease series of monographs, I am proud and thankful to have the opportunity to present it. Claude Lenfant, M.D. Bethesda, Maryland
Preface
The cardiovascular and respiratory systems are both concerned with the transport of oxygen and metabolic byproducts to and from peripheral tissues. Indeed, it has been known for many years that the two systems are intimately linked to each other. They are connected mechanically both serially and in parallel, and neurophysiologically by virtue of the proximity of control centers in the brainstem. This makes great teleological sense since the whole organism’s response to emergent challenges involves both systems. Indeed, research into the field has been carried out for decades along roughly parallel lines, one being the mechanical and one the neurophysiological interactions. With the advent of critical care, in which dysfunction of both systems occurs, or in which manipulation of one system leads to changes in the function of the other, understanding of heart–lung interactions took on new interest. In the first edition of this book, published over a decade ago, the emphasis was clearly on mechanical interactions of clinical significance, including effects of lung volume, intrathoracic pressure, ventricular interdependence, and respiratory muscle function. Over the last decade, many of the questions dealt with in the first edition have come into greater focus. Further, investigators into other important diseases—such as left ventricular failure, obstructive sleep apnea, and sudden infant death syndrome—have emphasized the importance of both mechanical and neurovii
viii
Preface
physiological heart–lung interactions in the pathogenesis of these clinical conditions. Finally, there have been advances in our understanding of the humoral/molecular biological basis of disease leading to cardiorespiratory failure, especially the sepsis syndrome. The importance of signaling molecules, especially nitric oxide, in this syndrome is being increasingly understood. This book, a continuation of Heart–Lung Interactions in Health and Disease, attempts to touch on all these aspects. The traditional mechanical interactions are all dealt with, and emphasis has been placed on developments over the last decade. Additionally, the reader will recognize where new topics relevant to these topics have been introduced. As such, expanded coverage of sleep-disordered breathing, left ventricular failure, and cardiopulmonary failure in sepsis has been included. As in the previous edition, each chapter gives its authors’ point of view on the state of the art of the field and, often, where they believe future research should be directed. The book is divided into three parts. Part One (Basic Physiology) includes discussion of those areas necessary for understanding the basic principles of cardiocirculatory interactions. This section includes description of pulmonary mechanics, respiratory muscle function, exercise physiology, control of venous return and cardiac output, as well as various aspects of cardiocirculatory function, and cardiopulmonary interactions. New topics include the control of tissue metabolism, the development of the sympathetic nervous system, mathematical modeling of mechanical heart–lung interactions, and image analysis as a tool for investigating cardiocirculatory function. Part Two (Pathophysiology) includes topics related to the generation of disease states. New topics include molecular/cellular mechanisms underlying acute hypoxic pulmonary vasoconstriction, neurophysiological interactions during sleep, effects of muscle reflexes on respiration and circulation, and the effects of systemic inflammatory response on cardiovascular function. Part Three (Clinical Problems) includes chapters describing a number of important clinical conditions in terms of basic physiology and pathophysiology. We have included chapters on the effects of heart failure including abnormal control of circulation and ventilation, the use of respiratory maneuvers to support the failing circulation, and the effects of chronic obstructive lung disease on cardiocirculatory function. The last subsection of Part Three deals with the application of the principles of heart–lung interactions in the critical care unit. This includes sections of the use of the balloon-tipped catheter, including the controversies surrounding this mode of diagnosis and treatment, important causes of cardiocirculatory failure in sepsis (especially as related to the production of NO), and chapters on the principles of heart–lung interactions in some specific clinical situations. Finally, the use of a respiratory treatment, inhaled NO, to treat circulatory failure has been covered. As in the first edition of this book, it is our hope that the material contained herein will provide the reader with a rational basis for understanding the ways in which the cardiovascular and respiratory systems interact in normal and abnormal
Preface
ix
situations. Hopefully, the material will be provocative and controversial, and stimulate some investigation into these important problems. In this way, we hope to continue to expand the corpus of knowledge in this area. Steven M. Scharf, M.D., Ph.D. Michael R. Pinsky, M.D. Sheldon Magder, M.D.
Contributors
Sorel Bosan, Ph.D. Postdoctoral Fellow, McDonald Research Laboratory, University of British Columbia, Vancouver, British Columbia, Canada Alfred A. Bove, M.D., Ph.D. Professor of Medicine, Section of Cardiology, Temple University School of Medicine, Philadelphia, Pennsylvania T. Douglas Bradley, M.D., F.R.C.P. (C). Professor, Department of Medicine, Division of Respirology, Toronto General Hospital, and Sleep Research Laboratory of the Toronto Rehabilitation Institute, University of Toronto, Toronto, Ontario, Canada Alain Cariou Assistant Professor, Medical Intensive Care Unit, Cochin-Port Royal University Hospital, Paris, France Bartolome R. Celli Pulmonary and Critical Care, St. Elizabeth’s Medical Center, and Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts Ling Chen, M.D., Ph.D. Research Fellow, Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada
xi
xii
Contributors
Rubin Cohen, M.D., F.A.C.P., F.C.C.P. Assistant Professor of Medicine, Pulmonary and Critical Care Division, Long Island Jewish Medical Center, New Hyde Park, New York Dennis Davidson, M.D. Associate Professor, Albert Einstein College of Medicine, Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Schneider Children’s Hospital, Long Island Jewish Medical Center, New Hyde Park, New York Louis J. Dell’Italia, M.D. Professor, Department of Medicine, Division of Cardiovascular Disease, University of Alabama, Birmingham, Alabama Christian Ole Feddersen, Priv.Doz., M.D. Co-head, Internal Medicine Department, Kreiskrankenhaus Aurich, Aurich, Germany Francois Feihl, M.D. Attending Physician, Division of Pathophysiology and Medical Teaching, Lausanne University Hospital, Lausanne, Switzerland Henry E. Fessler, M.D. Associate Professor, Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland John S. Floras, M.D., D.Phil., F.R.C.P.(C). Site Director, Division of Cardiology, Mount Sinai Hospital, and Director of Research, University Health Network, and Professor of Medicine, University of Toronto, Toronto, Ontario, Canada Regina Frants Pulmonary and Critical Care, St. Elizabeth’s Medical Center, Boston, Massachusetts Bradley D. Freeman, M.D. Assistant Professor, Department of Surgery, Section of Burn, Trauma, and Surgical Critical Care, Washington University School of Medicine, St. Louis, Missouri Peter Goldberg, M.D., F.R.C.P.(C). Associate Professor, Department of Medicine, Critical Care Division, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada Phyllis M. Gootman, Ph.D. Professor, Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York Harly Greenberg, M.D. Associate Professor of Medicine, Pulmonary and Critical Care Division, Long Island Jewish Medical Center, New Hyde Park, New York Rene´ Gust, M.D., D.E.A.A. Associate Professor, Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany Eric A. Hoffman Professor of Radiology and Biomedical Engineering, Department of Radiology, University of Iowa College of Medicine, Iowa City, Iowa
Contributors
xiii
Bruce W. Hundley, Ph.D. Postdoctoral Fellow, Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York Steven G. Kelsen, M.D. Professor of Medicine and Physiology, Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania Samuel L. Krachman, D.O. Associate Professor of Medicine, Division of Pulmonary and Critical Care, Temple University, Philadelphia, Pennsylvania Urs A. Leuenberger, M.D. Associate Professor of Medicine, Section of Cardiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Q. Liu Research Associate, Department of Medicine, Division of Pulmonary and Critical Care Medicine, John Hopkins University School of Medicine, Baltimore, Maryland Geraldo Lorenzi-Filho, M.D. Pulmonary Division, University of Sa˜o Paulo, Sa˜o Paulo, Brazil Sheldon Magder, M.D., F.R.C.P.(C). Professor, Critical Care Division, Departments of Medicine and Physiology, McGill University Health Center, Montreal, Quebec, Canada Corrado P. Marini, M.D. Director, Surgical Critical Care/Metabolism Section, Department of Surgery, Long Island Jewish Medical Center, New Hyde Park, New York Michael A. Matthay, M.D. Professor, Department of Medicine, and Department of Anesthesia and Perioperative Care, Critical Care Medicine, and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California Alan S. Multz, M.D. Director, Medical Intensive Care Unit, Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center, New Hyde Park, New York Krzysztof Narkiewicz, M.D., Ph.D. Associate Professor, Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland Charles Natanson, M.D. Senior Investigator, Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland Christopher P. O’Donnell, Ph.D. Assistant Professor, Department of Medicine, Johns Hopkins University, Baltimore, Maryland Didier Payen, M.D., Ph.D. Associate Professor, Department of Medicine, Critical Care Division, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada
xiv
Contributors
Claude Perret, M.D. Honorary Professor, and former Head of the Intensive Care Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland Michael R. Pinsky, M.D., C.M., F.C.C.P., F.C.C.M. Professor, Department of Anesthesiology and Critical Care Medicine, and Director of Research, Division of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Thomas E. Podszus Abteilung Kardiologie, Pneumologie Intensivmedizin, Medizinische Klinik, Klinikum Hof, Hof, Germany James L. Robotham, M.D., F.R.C.A. Professor, Department of Anesthesiology, Strong Memorial Hospital, University of Rochester School of Medicine and Dentistry, Rochester, New York Joseph R. Rodarte, M.D.* Professor, Department of Medicine, and Chief, Pulmonary and Critical Care Section, Baylor College of Medicine, Houston, Texas Lewis J. Rubin, M.D. Professor and Director, Department of Medicine, Division of Pulmonary and Critical Care, University of California School of Medicine, San Diego, California David A. Ruggiero, Ph.D. Professor, Department of Psychiatry and Anatomy, Columbia University College of Physicians and Surgeons, New York, New York, and Neurological Research Institute of Lubec, Lubec, Maine Sami I. Said, M.D. Professor, Department of Medicine, Pulmonary and Critical Care Division, State University of New York, Stony Brook, and Department of Veterans Affairs Medical Center, Northport, New York Tsutomu Sakuma, M.D. Associate Professor, Department of Thoracic Surgery and Pulmonary Medicine, Kanazawa Medical University, Ishikawa, Japan William P. Santamore, Ph.D. Professor of Physiology and Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania Steven M. Scharf, M.D., Ph.D Section Head, Pulmonary Research, Pulmonary and Critical Care Division, Long Island Jewish Medical Center, New Hyde Park, and Professor of Medicine, Albert Einstein College of Medicine, Bronx, New York Daniel P. Schuster, M.D. Professor of Medicine and Radiology, Department of Radiology, Washington University School of Medicine, St. Louis, Missouri James S. K. Sham, Ph.D. Associate Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
* Deceased.
Contributors
xv
Larissa A. Shimoda, Ph.D. Assistant Professor, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Anthony L. Sica, Ph.D. Professor, Department of Medicine, Pulmonary and Critical Care Division, Long Island Jewish Medical Center, New Hyde Park, New York Virend K. Somers, M.D., D.Phil. Professor of Medicine, Department of Internal Medicine, Division of Cardiology, Mayo Clinic, Rochester, Minnesota William W. Stringer, M.D. Associate Professor, Department of Medicine, Harbor-UCLA Medical Center, University of California at Los Angeles School of Medicine, Torrance, California J. T. Sylvester, M.D. Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Masao Takata, M.D., Ph.D. Senior Lecturer, Department of Anesthetics and Intensive Care, Imperial College School of Medicine, and Honorary Consultant, Chelsea and Westminster Hospital, London, England Martin J. Tobin, M.D. Professor, Department of Medicine, Loyola University of Chicago Stritch School of Medicine, and Director, Division of Pulmonary and Critical Care, Hines Veterans Administration Hospital, Maywood, Illinois Binh Q. Tran Assistant Professor, Biomedical Engineering Department, Catholic University, Washington, D.C. Keith R. Walley, M.D. Professor, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada Karlman Wasserman, M.D., Ph.D. Professor, Department of Medicine, HarborUCLA Medical Center, University of California at Los Angeles School of Medicine, Torrance, California Mikolaj Winnicki, M.D., Ph.D. Fogarty Fellow, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota Jason X.-J. Yuan, M.D., Ph.D. Associate Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California School of Medicine, San Diego, California Clifford W. Zwillich, M.D. Professor and Vice Chairman, Department of Medicine, Pulmonary Division, University of Colorado, and Department of Veterans Affairs, Denver Veterans Administration Medical Center, Denver, Colorado
Contents
Introduction Preface Contributors 1.
Claude Lenfant
Heart–Lung Interactions: An Overview Steven M. Scharf, Michael R. Pinsky, and Sheldon Magder I. Introduction II. Interaction of Respiratory and Circulatory Systems III. Clinical Situations IV. Conclusions
v vii xi 1 1 2 5 7
Part One: BASIC PHYSIOLOGY Respiratory Physiology 2.
Lung and Chest Wall Mechanics: Basic Concepts Joseph R. Rodarte I. Introduction II. Respiratory System Statics
9 9 9 xvii
xviii
Contents III. Respiratory System Dynamics IV. Heart-Lung Interactions V. Closing 3. Respiratory Muscle Function and Blood Flow Steven G. Kelsen I. Introduction II. Mechanical Action III. Respiratory Muscle Contractile Properties IV. Respiratory Muscle Blood Flow
16 20 30 33 33 34 40 57
Cardiovascular Physiology 4. Right Ventricular Function and Ventricular Interdependence William P. Santamore, Alfred A. Bove, and Louis J. Dell’Italia I. Introduction II. Right Ventricular Diastolic Function III. Diastolic Ventricular Interdependence IV. Right Ventricular Systolic Function V. Systolic Ventricular Interaction 5. Venous Return Sheldon Magder and Steven M. Scharf I. Introduction II. Components of the System III. Control of Cardiac Output IV. Concepts of Stressed and Unstressed Volume V. Guyton’s Graphical Analysis VI. Role of the Heart VII. Changes in Circuit Function (Changes in the Venous Return Curve) VIII. An Applied Physiological Approach to Hypotension 6. Models of Tissue Oxygen Uptake and Microcirculatory Blood Flow Sorel Bosan and Keith R. Walley I. Introduction II. A Global Conceptual Model III. Fick’s Law IV. Oxygen Transport in the Lung V. Oxygen Transport in Peripheral Tissues VI. The Krogh Model of Oxygen Transport in the Tissues VII. Axial Oxygen Gradient in the Capillaries VIII. Effect of Red Blood Cells IX. Extending the Krogh Model
67 67 67 69 72 77 93 93 94 95 97 98 100 103 110 113 113 114 114 115 116 117 120 121 123
Contents X. Problems with Krogh Models XI. Oxygen Delivery-Consumption Relationships XII. Mismatch of Oxygen Demand and Supply: Physiologic Arterio-Venous Shunt XIII. Microvascular Flow XIV. Heterogeneous Models XV. Network Models XVI. Fractal Network Models XVII. Conclusions
xix 126 127 129 130 133 136 137 140
Cardiopulmonary Physiology 7.
8.
9.
The Sympathetic Nervous System of the Developing Mammal Anthony L. Sica, Bruce W. Hundley, David A. Ruggiero, and Phyllis M. Gootman I. Introduction II. Early Studies of the Sympathetic Nervous System III. Periodicities in Sympathetic Discharge IV. Neuroanatomical Studies of the Brainstem Sympathetic Network V. Baroreceptor and Chemoreceptor Reflexes in Developing Animals VI. Concluding Remarks Hemodynamic Effects of Ventilation and Ventilatory Maneuvers Michael R. Pinsky I. Introduction II. Ventilation as Exercise III. Relation Between Lung Volume and Airway, Pleural, and Pericardial Pressure IV. Hemodynamic Effects of Changes in Lung Volume V. Hemodynamic Effects of Changes in Intrathoracic Pressure VI. Clinical Trials of Different Forms of Mechanical Ventilation VII. Conclusion Homeostasis of Exercise Gas Exchange: Coupling of Pulmonary and Cardiovascular Function to Cellular Respiration During Exercise Karlman Wasserman and William W. Stringer I. Introduction II. Coupling of Circulation to Muscle Metabolism III. Coupling of Ventilation to Circulatory Gas Exchange IV. Mechanism(s) of Exercise Limitation in Lung Disease V. Summary
145
145 146 147 148 155 172 183 183 184 185 189 195 202 208
219 219 221 240 245 251
xx
Contents 10. Mechanical Heart–Pericardium–Lung Interactions Masao Takata and James L. Robotham I. Introduction II. Physiology of the Pericardium III. Pericardium and Cardiorespiratory Interaction IV. Pericardial Disease and Cardiac Chamber Interactions V. Conclusions 11. Dynamic Volumetric Imaging-Based Assessment of the Intrathoracic Milieu Eric A. Hoffman and Binh Q. Tran I. Introduction II. Overview of CT and MRI III. Applications to the Study of Heart-Lung Interaction IV. Conclusions
257 257 258 263 265 275 279 279 280 294 308
Part Two: PATHOPHYSIOLOGY 12. Cellular Mechanisms of Acute Hypoxic Pulmonary Vasoconstriction J. T. Sylvester, James S. K. Sham, Larissa A. Shimoda, and Q. Liu I. Introduction II. Effects of Acute Hypoxia III. Mechanisms of Acute HPV IV. Summary and Future Directions 13. Pulmonary Edema: Formation and Reabsorption Michael A. Matthay and Tsutomu Sakuma I. Introduction II. Formation of Pulmonary Edema III. Resolution of Pulmonary Edema IV. Role of Aquaporins in Alveolar Fluid Transport V. Alveolar Fluid Transport Under Pathological Conditions VI. Summary 14. Respiratory-Circulatory Interactions in Obstructive Sleep Apnea Virend K. Somers, Krzysztof Narkiewicz, and Mikolaj Winnicki I. Introduction II. Chemoreflex Responses to Hypoxemia, Hypercapnia, and Apnea III. The Mueller Maneuver IV. Baroreflex-Chemoreflex Interactions V. Chemoreflex Responses in Hypertension VI. Neural Circulatory Control in Normal Sleep VII. Neural Circulatory Control in Sleep Apnea
315
315 317 333 338 361 361 362 371 376 378 382 389 389 390 391 391 392 392 393
Contents
xxi VIII. Effects of Treatment of Sleep Apnea IX. Conclusion
15. Effects of Respiratory Muscle Afferent on the Breathing and the Afferent Hypothesis Sheldon Magder I. Introduction II. Changes in Respiratory Mechanics During Weaning III. Mechanical Effects of High Respiratory Rate IV. Control of Breathing V. Potential Clinical Approach VI. Conclusion 16. Neurohumoral Aspects of Respiratory-Cardiovascular Interactions Sami I. Said I. Introduction: Functional Interactions II. Neurohumoral Substances Participating in Cardiovascular-Respiratory Interactions III. Physiological Interactions IV. Cardiovascular-Pulmonary Interactions in Disease V. Concluding Comments 17. Pathophysiology of Pulmonary Hypertension Jason X.-J. Yuan and Lewis J. Rubin I. Introduction II. Classification of Pulmonary Hypertension III. Cellular Mechanisms of Pulmonary Vasoconstriction and Excitation-Contraction Coupling IV. Role of Intracellular Calcium in Pulmonary Vascular Remodeling V. Pathogenic Role of Dysfunctional Potassium Channels in Pulmonary Hypertension VI. Anorexigen-Mediated Pulmonary Hypertension: Effect of Fenfluramine on Potassium Channel Expression VII. Mechanisms Involved in the Therapeutic Effects of Nitric Oxide and Prostacyclin in Patients with Pulmonary Hypertension VIII. Summary and Conclusion 18. Effect of Systemic Inflammation on Cardiovascular Function Bradley D. Freeman and Charles Natanson I. Introduction II. Descriptive Studies III. Conclusion
399 400 405 405 406 406 408 421 422 427 427 427 429 437 440 447 447 448 452 456 457
467
468 471 479 479 481 492
xxii
Contents
Part Three: CLINICAL PROBLEMS Heart Failure 19. Control of Ventilation in Congestive Heart Failure Harly Greenberg I. Ventilatory Chemosensitivity in Congestive Heart Failure II. Peripheral Chemoreceptor Sensitivity and Autonomic Tone in CHF III. Control of Ventilation During Exercise in CHF IV. Control of Ventilation During Sleep in CHF V. Potential Therapeutic Modalities 20. Ventilatory Support in the Failing Heart Steven M. Scharf I. Introduction II. Principles of Cardiocirculatory Interaction III. Ventilatory Therapy for CHF and Ischemic Heart Disease IV. Models to Explain Improved Cardiac Function with CPAP V. Conclusions and Questions
497
497 499 502 506 512 519 519 520 530 541 545
Sleep-Disordered Breathing 21. Blood Pressure Regulation and Sleep Apnea Urs A. Leuenberger and Clifford W. Zwillich I. Introduction II. Relationship Between Sleep Apnea and Hypertension III. The Sympathetic Nervous System in OSA IV. Hemodynamic Abnormalities in Hypertension V. Sympathetic Nervous System in Hypertension VI. Blood Pressure Regulation During Sleep and During Sleep and During Obstructive Apnea VII. Potential Mechanisms of Sustained Increases of Sympathetic Activity and Hypertension in Sleep Apnea VIII. Vascular Function and Humoral Abnormalities in OSA IX. Conclusions 22. Pathophysiological Interreactions Between Sleep Apnea and the Heart T. Douglas Bradley, Geraldo Lorenzi-Filho, and John S. Floras I. Introduction II. Effects of Obstructive Sleep Apnea on the Pulmonary Vessels and Right Ventricle
551 551 552 554 555 556 558 564 567 570 577 577 578
Contents
xxiii III. Effects of Obstructive Sleep Apnea on the Left Ventricle IV. Mechanisms of Central Sleep Apnea in Association with Cheyne-Stokes Respiration in Congestive Heart Failure V. Pathophysiologic Consequences of Cheyne-Stokes Respiration with Central Sleep Apnea in Congestive Heart Failure VI. Summary
23. Cardiovascular Responses to Obstructive Apneas: Lessons from Animal Models Steven M. Scharf, Ling Chen, Harly Greenberg, and Christopher P. O’Donnell I. Introduction: Obstructive Sleep Apnea II. Animal Models and the Study of OSA III. Cardiovascular Effects of Induced Sleep Apnea in Animals IV. Anesthetized Animal Models in Which Certain Features of OSA Are Simulated V. Sedated Animal Models Without Arousal During Apneas VI. Conclusions 24. Sleep Apnea and Right Ventricular Function Thomas E. Podszus, Christian Ole Feddersen, and Steven M. Scharf I. Introduction II. Right Heart Morphology in OSA III. Right Heart Function in OSA IV. Right Heart Pathophysiology in OSA
581
589
600 603 613
613 614 614 624 631 637 641
641 642 644 646
Pulmonary Failure 25. Chronic Obstructive Pulmonary Disease Samuel L. Krachman and Martin J. Tobin I. Background II. Pulmonary Gas Exchange in COPD III. Control of Breathing in COPD IV. Respiratory Muscle Pump Dysfunction V. Increased Respiratory Muscle Pump Load VI. Conclusion
651
26. Circulatory Effects of COPD Bartolome R. Celli and Regina Frants I. Introduction II. Systemic Venous Return
681
651 652 655 660 665 675
681 682
xxiv
Contents III.
Right Ventricular Function and Ventricular Interdependence IV. Pulmonary Vascular Compartment V. Left Ventricular Performance VI. Conclusions
686 690 695 699
Critical Care 27. Invasive and Noninvasive Assessment of Cardiocirculatory Function: Balloon-Tipped Catheters and Echocardiography Claude Perret, Francois Feihl, and Alain Cariou I. Introduction II. History III. Information Provided by the PAC IV. Echocardiography: A Complementary Role V. Changing Strategy 28. Heart–Lung Interactions in Sepsis Sheldon Magder I. Definition of Sepsis II. Cardiovascular and Pulmonary Responses to Sepsis III. Mechanism of High Cardiac Output IV. Summary 29. Nitric Oxide and Cardiopulmonary Failure in Sepsis Rubin Cohen I. Introduction II. Nitric Oxide Synthases III. Nitric Oxide in Septic Shock: Effects on Hemodynamics IV. Nitric Oxide in the Normal Heart V. Nitric Oxide and the Heart in Endotoxemia VI. Nitric Oxide: Not Just an Endothelial-Derived Relaxing Factor VII. Regulation of iNOS VIII. Summary 30. Databases and Outcomes in Cardiopulmonary Care Alan S. Multz and Corrado P. Marini I. Introduction II. Databases III. Outcomes Data and Scoring Systems 31. Mechanical Ventilation with PEEP Henry E. Fessler I. Introduction II. History of MV and Peep III. Basic Concepts
705 705 706 709 723 728 739 739 741 742 758 763 763 764 764 774 774 779 782 783 793 793 794 798 807 807 808 809
Contents
xxv IV. Effects of PEEP V. Clinical Issues VI. Summary
32. Cardiocirculatory Management in Acute Lung Injury and ARDS Rene´ Gust and Daniel P. Schuster I. Introduction II. Optimizing Substrate Delivery III. Theoretical Basis for Fluid Restriction in ALI/ARDS IV. Experimental Evidence Supporting Active Reduction of Pc in ALI/ARDS V. Clinical Evidence for the Value of Fluid Restriction in ALI/ARDS VI. Other Clinical Approaches to Reducing Pc VII. Summary and Management Recommendations 33. Diagnostic Information from the Respiratory Variations in Central Hemodynamics Pressures Sheldon Magder I. Introduction II. Principles of Pressure Measurements III. Diagnostic Uses of Respiratory Variations in Central Hemodynamics IV. Change in Abdominal Pressure V. Information from the Hemodynamic Waveforms VI. Summary
810 826 830 837 837 838 843 845 850 851 854 861 861 861 869 874 875 880
34. Abdominal-Circulatory Interactions Peter Goldberg I. Introduction II. Animal Data III. Human Data IV. Summary
883
35. Inhaled Nitric Oxide and Acute Lung Injury Didier Payen I. Introduction II. NO: A Gas III. NO: A ‘‘Selective’’ Pulmonary Vasodilator IV. NO Inhalation Impact on Bronchial Tree and Surfactant V. Inhaled NO in Acute Lung Injury VI. Extra-Gas Exchange Effects VII. Clinical Trials on Inhaled NO in Adult ARDS
905
36. Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: Basis for Evolving Therapeutic Guidelines Dennis Davidson
883 883 892 901
905 905 908 909 910 912 913 919
xxvi
Contents I. II. III. IV. V. VI. VII.
Index
Introduction PPHN Pathophysiology: Basic and Clinical Development of Inhaled Nitric Oxide for PPHN Clinical Trials: Efficacy Safety Considerations Disease-Related Responses to I-NO Conclusion
919 920 925 926 929 933 937 945
1 Heart–Lung Interactions An Overview
STEVEN M. SCHARF
MICHAEL R. PINSKY
Albert Einstein College of Medicine and Long Island Jewish Medical Center New Hyde Park, New York
University of Pittsburgh Medical Center Pittsburgh, Pennsylvania
SHELDON MAGDER McGill University Health Center Montreal, Quebec, Canada
I.
Introduction
The respiratory and circulatory systems act in concert to deliver oxygen to the periphery from the atmosphere and carbon dioxide from the periphery to the atmosphere. The end game is played out at both ends of the field: at the microcirculatory and cellular level during normal function, disease states, and exercise, and at the alveolar capillary membrane (Chapters 6, 9). Since the 19th century, there has been the realization that these two systems interact with each other on many levels. There are interesting evolutionary aspects to this since these systems embryologically derive from different tissues, the respiratory system from foregut and the circulatory system from the mesenchyme. Nevertheless, evolution has driven these two systems to work together and to be connected in numerous intimate ways toward a common goal. The many levels at which the respiratory and circulatory systems interact and influence each other have been the subject of intense investigation. The levels of interaction include neurological, humoral, and mechanical. There are a number of disease conditions in which the interaction of these systems is important and the clinician needs to be aware of them. The purpose of this chapter is not so much to impart specific facts about each topic (this is done in the subsequent chapters to which the reader is referred for detailed review and references) but to give an appreciation of the complexity of the coordination of respiratory and cardiovascular systems. 1
2
Scharf et al.
Figure 1 Heart-lung interactions.
II. Interaction of Respiratory and Circulatory Systems (Fig. 1) A. Neurological Interactions
The respiratory system is driven by striated muscles. Indeed, these muscles are the only striated muscles that have involuntary function (Chapter 3). The rhythmicity of the respiratory related motor neurons is controlled by a brainstem central pattern generator. Most likely the central pattern generator is made up of a network of critical neurons located throughout the brainstem. This generator is under the influence of numerous other neurological and neurohumoral factors. One example is the well-known stretch receptor feedback loop from the lungs, carried via the vagus, by which increasing lung volume decreases respiratory motor neuron output (HerringBreuer reflex). It is known that the neurons of the respiratory pattern generator (or neurons with direct influence on the pattern generator) and neurons controlling autonomic neural output (sympathetic and parasympathetic) are inter-related. Like the respiratory pattern generator, the autonomic controllers are scattered throughout the brainstem (Chapter 7). The anatomic proximity of autonomic and respiratory control neurons allows them to ‘‘talk’’ to each other and to be affected by common influences. These include perceived threat (fight or flight), sleep/wake states, and alterations in arterial blood gases. Thus, it is not surprising that the actions of the respiratory neurons can influence those of the autonomic controllers and vice versa. A good example of this is the entrainment of blood pressure swings to respiration, which is a central brainstem function.
Overview
3
Other types of interactions occur in response to respiratory stressors that lead to afferent traffic into the brainstem. A good example of this is the cardiovascular response to hypoxia (Chapters 14, 23). Hypoxia is primarily sensed in the peripheral chemoreceptors, located in the carotid and aortic bodies. Stimulation of these receptors triggers increased ventilation and both sympathetic and parasympathetic cardiovascular efferent activity. The relative balance of this activity depends on many factors. One of these is the degree of ventilatory response. When the ventilatory response to hypoxia is allowed to occur, heart rate increases. However, if the ventilatory response is blocked by paralysis, then tachycardia does not occur and indeed many studies show bradycardia. Thus, the cardiovascular response to hypoxia is influenced by mechanical feedback from the ventilatory apparatus, the lungs and/ or the chest wall (including the respiratory muscles themselves; see Chapter 15). Other factors that influence the cardiovascular response to hypoxia include maturity of the subject, degree of hypoxemia and concomitant hypercapnia (asphyxia) or hypocapnia. Another type of neurological interaction also occurs in the presence of cardiovascular stressors, such as the response to congestive heart failure (Chapter 19). For example, ventilatory responses to exercise are exaggerated in heart failure. These responses are most likely mediated via vagal afferents in the lungs. These afferents respond to increased CO2 flux through the lungs with exercise, increased dead space (other chemoreceptors) and congestion in the pulmonary interstitium. Finally, abnormal cardiac function can impede the gas exchange function of the lung by pulmonary edema formation (Chapter 13). In addition to causing abnormal gas exchange, the accumulation of edema in the interstitium and alveoli leads to reflex effects on ventilation and ventilatory control. B. Humoral Interactions
Some humoral interactions relate to the humoral response to respiratory stressors (Chapter 16). A good example is the release of epinephrine from adrenal glands and norepinephrine from sympathetic nerve endings in response to hypoxemia or hypercapnia (Chapters 22 and 23). Chronic cardiorespiratory stress also elicits the release of stress hormones that may also have chronic consequences. Gram for gram the lung is the most metabolically active organ in the body. Many substances are processed, filtered, or released by the lungs. Among the many factors elaborated by the pulmonary endothelium, immune system, and epithelium are cytokines, adhesion molecules, endothelial derived relaxing (NO; see Chapters 29, 35, 36) and constricting factors, prostaglandins, and vasoregulatory peptides. Thus, it is not surprising that lung injury could result in alterations in cardiovascular function (Chapters 16, 18, 28, 29, 32). Further, general insults, like sepsis, may influence pulmonary and systemic vascular function in different ways. This may lead to changes in the mechanical interactions between respiratory and cardiovascular systems. For example, with sepsis there may be large increases in pulmonary vascular resistance at the same time that there are decreases in systemic vascular
4
Scharf et al.
resistance. The increase in pulmonary vascular resistance may adversely affect right ventricular function and lead to decreases in cardiac output. C. Mechanical Interactions
The respiratory and cardiovascular systems are mechanically linked at a number of levels. Virtually all cardiac output from the right ventricle goes through pulmonary circulation. Pulmonary vascular resistance is heavily dependent on lung volume. As lung volume increases or decreases below functional residual capacity pulmonary vascular resistance generally increases. Lung injury of various types also increases pulmonary vascular resistance. Combining several factors that increase pulmonary vascular resistance, such as applying high levels of positive end-expiratory pressure in the presence of lung injury, can lead to large increases in pulmonary vascular resistance and compromise of right ventricular function. One well-known factor increasing pulmonary vascular resistance is hypoxia (see Chapters 12, 17). In this condition the acute increase in pulmonary vascular resistance is due to acute hypoxic pulmonary vasoconstriction, itself a function of local factors operative at the level of pulmonary vascular smooth muscle influenced by the surrounding milieu. In addition chronic hypoxia or chronic shear stress leads to the elaboration of growth factors that lead to structural alterations in pulmonary vasculature and further, poorly reversible, increases in pulmonary vascular resistance. It has been recognized for well over 100 years that inspiration, which decreases pleural pressure, both encourages influx of blood into the chest and hinders the egress of blood from the chest. This dual action leads to increases in venous return from the periphery into the right heart and impedance to ventricular ejection from the left side of the heart. Hence, to understand the degree to which normal and exaggerated inspiration affects cardiovascular function, one needs to understand the factors which control the return of blood from the periphery to the right heart, venous return (Chapter 5), and the factors that control the ejection of blood from the left heart (Chapter 8). The state of baseline cardiovascular function, both peripheral, as well as right ventricular (Chapter 4) and left ventricular function will alter the changes seen during abnormal inspiration. For example, exaggerated inspiratory effort can lead to increased venous return and predominately right-sided cardiovascular changes or increased impedance to left ventricular emptying (increased left ventricular afterload; Chapter 8), inducing pulmonary edema formation. Positive-pressure ventilation, especially when applied in tandem with high levels of positive end-expiratory pressure offer different challenges to the cardiovascular system. These challenges include the tendency to decrease venous return and, under some circumstances, to increase right ventricular afterload. Both of these effects can act to decrease cardiac output (Chapter 31). There are also changes in cardiac function that may be secondary to changes in venous return or right ventricular function. When one ventricle dilates there is a stiffening of the other. This is one manifestation of ventricular interdependence (Chapters 8, 10). For example, if there is right ventricular dilation due to increased venous return, this can decrease left ventricular preload and stroke volume. Both
Overview
5
ventricular-ventricular and atrioventricular interactions are in turn influenced by coupling due to surrounding structures such as the pericardium and overlying lungs. The mechanical interactions between the heart and surrounding lungs may influence cardiac filling and stroke volume (Chapter 10). Pulmonary hyperinflation can mechanically compress the heart and limit ventricular filling. This can even lead to increases in measured cardiac pressures that may lead to misinterpretation of the state of ventricular filling (see below). Finally, understanding of the principles of heart-lung interactions will allow for the use of and interpretation of newer modes of image analysis for increasing our knowledge in this area (Chapter 11). One of the problems with research in this area has been the necessity for invasive measurements that could potentially interfere with the phenomena being studied. Accordingly, in the field of noninvasive image based analyses, rapid imaging techniques taking advantage of recording cardiovascular data in a fashion relatively independent of changes in venous return are promising techniques for analyzing the changes in heart-lung interactions in abnormal conditions.
III. Clinical Situations Virtually any respiratory disease leads to alterations in lung and/or chest wall mechanics that can influence cardiovascular function (Chapter 2). Obstructive and restrictive lung diseases lead to greatly exaggerated inspiratory and mildly exaggerated swings in expiratory intrathoracic pressures. These changes may be directly transmitted to the heart and great vessels. By altering venous return and/or left ventricular ejection, exaggerated swings in intrathoracic pressure may also influence blood oxygen delivery to the periphery beyond any alterations caused by abnormal gas exchange across diseased lungs. In addition, a number of clinical cardiovascular signs in lung disease are due to the abnormal cardiovascular-respiratory interactions seen in lung disease. One example is the presence of an exaggerated inspiratory fall in arterial pressure (pulsus paradoxus) observed with severe airways obstruction (e.g., asthma). Another is an increase in pressure in the great veins during inspiration (Kussmaul’s sign) in the presence of obstructive lung disease and other conditions. Pulsus paradoxus occurs because of a combination of decreased left ventricular filling (interdependence effects due to increased venous return), impaired left ventricular ejection (afterload effects) and direct transmission of pleural pressure swings to the arterial system. Kussmaul’s sign occurs because of alteration of venous return patterns from the abdominal compartment. Clinicians need to be aware of the changes in respiratory mechanics when interpreting cardiovascular data in patients with abnormal respiration (Chapters 27, 28, 32, 34). One common example is in the interpretation of pressures measured from intrathoracic structures such as right and left atrium (usually measured as central venous pressure and pulmonary artery occlusion pressure, respectively). During mechanical ventilation, especially when the increase in airway pressure or lung volume is marked, the consequent increase in intrathoracic pressure may be transmitted
6
Scharf et al.
to intracardiac structures. Adjustment for this component of the measured intracardiac pressure is done by measuring intrathoracic pressure (esophageal pressure) and subtracting intrathoracic pressure from intracardiac pressure. The resulting pressure is the transmural pressure and gives a better estimate of the state of cardiac filling. The same can be said for exaggerated inspiratory negative swings in intrathoracic pressure observed during airways obstruction (asthma, sleep apnea, chronic obstructive pulmonary disease; Chapters 23–27). The transmitted pressure swings may cause intracardiac or great vessel pressure to decrease. However, if intrathoracic pressure is measured it may be found that the transmural pressure actually increases. For example, in many negative airway pressure maneuvers, such as spontaneous inspiration in the setting of increased airway resistance or elastance, the decrease in intrathoracic pressure is greater than the measured decrease in arterial pressure. In this case arterial transmural pressure increases and along with the impedance to left ventricular emptying (increased left ventricular afterload). Finally, modern understanding of the mechanisms involved in the maintenance of cardiac output by cardiopulmonary resuscitation suggests that an important factor is cardiac massage related swings in intrathoracic pressure. This thoracic pump mechanism requires optimization during resuscitation and other forms of circulatory support. Acute lung injury often necessitates the use of mechanical ventilation, sometimes with increased airway pressures (Chapters 31–33). By increasing lung volume, these maneuvers offer the chance for mechanical heart-lung interactions and possibly increased right ventricular afterload to occur. By increasing intrathoracic pressure, venous return can be affected. Both of these effects will be overlaid by reflexes that buffer the decrease in flow (Chapter 31). The degree to which reflexes (primarily sympathoadrenal) minimize decreased cardiac output with increased airway pressures depends on the factors influencing venous return such as blood volume and peripheral capacitance. Patients with increased blood volume have minimal effects of high levels of airway pressures compared to patients with initially low blood volume. Obstructive sleep apnea is a common condition in middle-aged males (Chapters 21–24) and is a major risk factor for cardiovascular morbidity and mortality due to hypertension, stroke, and myocardial infarction. In this disorder there are nightly bouts of intermittent, sometimes severe, hypoxemia, hypercarbia, and large exaggerations in intrathoracic pressure swings. These can lead to a host of mechanical (right and left ventricular loading) effects. As well, chronic episodic hypoxemia triggers a number of peripheral and brainstem reflex effects that may be even more important. Obstructive sleep apnea may be the most common clinical condition in which knowledge of respiratory cardiovascular interactions will help the clinician. Another clinical scenario that may involve abnormal heart lung interactions is sudden infant death syndrome (SIDS; Chapter 7). While the pathophysiology of this calamity is poorly understood, some form of respiratory stress is involved. This may involve asphyxia, immaturity in the ventilatory controller, alteration of upper airway cardiorespiratory reflexes, and disastrous cardiac arrhythmias. Both peripheral and brainstem interactions between cardiovascular and respiratory systems appear to be involved. In this sense SIDS shares some common properties with obstruc-
Overview
7
tive sleep apnea, although in this case the abnormalities of ventilation and oxygenation are superimposed on immature brainstem reflex centers. Specific properties of heart-lung interactions may be exploited to aid the functioning of the failing heart. Just as decreasing intrathoracic pressure may impede left ventricular ejection, so increasing intrathoracic pressure aid in ejection in the failing heart (Chapters 8, 20, 23). A number of studies have demonstrated that application of increased airway pressure can augment cardiac output in heart failure. This may be due to increasing intrathoracic pressure or to changes in sympathoadrenal tone caused by increased lung volume or improved oxygenation. Impaired cardiac function leads to impairment of oxygen delivery to the tissues. The muscles of respiration (Chapter 3) depend on peripheral oxygen delivery, especially during times of cardiorespiratory stress. Thus, it is not surprising that impairment of cardiovascular function can lead to impaired function of these muscles and even respiratory failure (Chapter 15). Knowledge of the principles of heart-lung interactions are important in perioperative and postoperative management of patients (Chapter 34) of patients with complex cardio-respiratory disease. For example, patients with ischemic heart disease have been demonstrated to have silent ischemia with attempts at weaning from ventilators. This cause of ‘‘failure to wean’’ may be suspected and diagnosed by applying the principles of heart-lung interactions, thus allowing for the institution of appropriate treatment. Finally, the end result of applying cardiopulmonary care needs to be assessed by intelligent analysis of outcomes. Tools to do this, using database management and outcomes analysis are now being applied to cardiopulmonary critical care (Chapter 30). This type of analysis goes beyond the analysis of physiologic principles but is essential for determining the efficacy of new and older modes of treatment. IV. Conclusions The cardiovascular and respiratory systems interact on several different levels: neurologic—both peripheral and central—humoral, and mechanical. These interactions influence the clinical manifestations of disease of one or both of these systems. Detailed knowledge of heart-lung interactions helps clinicians better understand specific clinical situations and enable the application of novel modes of treatment when one or the other of these two important organ systems is diseased.
2 Lung and Chest Wall Mechanics Basic Concepts
JOSEPH R. RODARTE Baylor College of Medicine Houston, Texas
I.
Introduction
Because the heart and great vessels lie within the thorax, the respiratory system is the milieu within which the heart must function. The forces on the pleural surface of the lung that produce ventilation are shared by the heart and the intrathoracic arteries and veins. Therefore, circulatory transmural pressures are influenced by respiratory events. Conversely, the heart and great vessels constitute most of the mass of the mediastinum, which not only is an important but little considered component of the thoracic cavity wall but also may have important effects on the regional lung function. This chapter addresses the basic mechanical principles of these interactions. It is intended to provide an overview although some clinical applications are considered. The reader seeking more information should proceed to other chapters in this book. Not considered in this chapter are the important central reflexes with the receptors in either the lungs or the vascular structures, which affect the function of both. II. Respiratory System Statics A. Lung Pressure-Volume Curve
During uniform inflation, the lungs of all mammalian species have a similar static pressure-volume relationship. In spite of the differences in alveolar size, pleural 9
10
Rodarte
Figure 1 Lung pressure-volume curves (air-filled, saline-filled, and submerged). Curves shown are from a canine lobe but are typical of mammalian lungs. Lobe volume is expressed as percentage total lobe volume (% TLV). (From Ref. 38.)
thickness, and pleural surface/lung volume ratio, the mammalian lung pressurevolume curves expressed as a percentage of maximal volume versus transpulmonary pressure, like those shown in Figure 1, are similar. Over most of the volume range, the curves are approximated by a single exponential relationship. That is, the elastance, the additional pressure required to achieve a constant change in volume, increases linearly with the initial pressure. At negative transpulmonary pressure, air remains in the alveoli and cannot be extracted owing to the collapse of small airways. This airway collapse may be important in vivo if some region of lung is transiently exposed to compressive pressures from the weight of abdominal or mediastinal contents. If the alveoli collapse completely, very high transpulmonary pressures are required to reopen them. Tissue Forces Versus Surface Tension
Maximal surface area and minimal tissue barrier for diffusive exchange of gas between inspired air and pulmonary capillary blood are achieved in mammals by alveoli—the small, moist air sacs. Interfacial tension between the gas phase and the liquid lining of the alveolar surface is a major determinant of the pressure required to inflate the lung. Figure 1 also shows the pressure-volume relationship of the lung submerged in and filled with saline (which abolishes the surface tension). The distance between the two curves is an approximation of the contribution of surface tension to the lung pressure-volume relationship. Surface tension provides most of the lung recoil at high volumes and becomes vanishingly small as minimal volume is approached. In the airfilled lung at equilibrium between the surface and tissue forces, the surface forces deform the tissue so that the saline pressure-volume curve is an underestimate of the contribution of tissue forces to lung recoil in the air-filled state (1). If alveolar surface tension were constant, the Laplace relationship would dictate an increasing contribution to lung recoil as volume decreases. This increased contribution does not occur because there is an inverse relationship between surface tension
Lung and Chest Wall Mechanics
11
and surface area produced by pulmonary surfactant. Therefore, at physiological lung volumes, pleural pressure would be much more subatmospheric if the surface fluid had the composition of serum without surfactant. As discussed later, pleural pressure has important effects on cardiac function, pulmonary vascular resistance, and the balance between pleural and pulmonary interstitial fluids. In clinical conditions in which alveolar surface tension is abnormal, the increased lung recoil and its effects on pleural pressure may contribute substantially to pathophysiological changes. Lung recoil increases during breathing at very low lung volumes (2). If recoil increases regionally, as well as globally, lung lobes may respond to low regional lung volumes that result from changes in the thoracic cavity configuration that are produced by changes in body posture, i.e., lateral decubitus positions by increasing the local transpulmonary pressure sufficiently to maintain airway and vascular patency. B. Chest Wall Pressure-Volume Curve
The mechanics of the chest wall are considerably more complex than those of the lung. This subject has been extensively reviewed in a volume of this series (3) and will be considered only briefly here. Figure 2 shows the relationship between esophageal pressure as an estimate of pleural pressure and lung volume under two conditions. The curve on the left (-Pel,L) shows the relationship between the pleural and the airway opening pressure during breath holding with the airway open, which is
Figure 2 Pressure-volume curves of lung and chest wall. Esophageal pressure as estimate of pleural pressure (Ppl) on horizontal axis is plotted against volume on vertical axis, expressed as percentage of vital capacity (% VC). Data were obtained from normal young man under two conditions. Left curve: -Pel,L is pressure-volume relationship when lung is held inflated by respiratory muscles with glottis open and, thus, is negative of transpulmonary pressure (alveolar minus pleural pressure). Right curve: Pel,W is pressure-volume curve during muscular relaxation against occluded airway. Curve defines transthoracic pressure (pleural minus atmospheric pressure)-volume relationship.
12
Rodarte
achieved by the coordinated action of the inspiratory muscles. This curve is the negative of the pressure-volume relationship of the lung, similar to that shown in Figure 1. The curve labeled Pel,W shows the relationship between pleural pressure and lung volume when the respiratory muscles are relaxed with the airway occluded. This curve gives the pressure-volume relationship of the chest wall. The two curves intersect at functional residual capacity, when the inward recoil of the lung is balanced by the outward recoil of the chest wall. The horizontal separation between the two curves at volumes above functional residual capacity corresponds to the airway pressure required to passively inflate the respiratory system to that volume and, thus, corresponds to the pressure-volume relationship for the entire respiratory system. Neglecting for the moment dynamic considerations, the left-hand curve shows the pleural pressure-volume relationship during normal ventilation, when airway pressure is near zero. The right-hand curve shows the pleural pressure-volume relationships during mechanical ventilation, and the distance between the curves approximates alveolar pressure during mechanical ventilation. Note that, for a fixed volume excursion, the magnitudes of these pressures increase greatly as lung volume increases. The effects of the mode of ventilation and end-expiratory lung volume on pleural pressure are considered in Section III of this chapter. Two-Degree Freedom Model of the Thorax
Over most of its potential volume excursion, the thoracic cavity can assume a wide range of shapes. As the first approximation, if flexion of the spine is constant, the cavity can be considered to be expanding with two degrees of freedom. Volume changes are the sum of changes of the rib cage and abdomen-diaphragm. The contributions of the two compartments can be assessed by surface measurements of displacements of the rib cage and abdomen (4). It is important to recognize that inspirations made by expansion of the rib cage, with no displacement of the anterior abdominal wall, do not mean that the diaphragm has not contracted and descended. This is because much of the abdominal volume below the diaphragm is also beneath the rib cage. Expansion of the rib cage increases the volume of the abdominal compartment beneath the rib cage, and if the diaphragm does not contract, the free wall of the abdomen will move inward (5). In the upright human, even though during normal breathing the rib cage compartment contributes approximately two-thirds of the volume expansion as judged by surface measurements, the diaphragm still contributes approximately two-thirds of the increase in thoracic cavity volume (6). In the supine position, the abdomendiaphragm contributes even more to thoracic cavity expansion. During normal breathing in the upright posture, the inspiratory muscles are activated in a coordinated fashion such that the thorax and abdomen are driven along their relaxation characteristics. Thus, in the upright human, there are no dramatic differences in thoracic cavity shape between spontaneous breathing and mechanical ventilation. In clinical conditions, the activation of respiratory muscles may differ, producing different contributions of rib cage and abdomen to ventilation and also producing distortions of the compartments. This activation must be associated with differences
Lung and Chest Wall Mechanics
13
in thoracic cavity and lung shapes and, therefore, different distributions of pleural pressure. However, as will be noted, the static properties of the lung suggest that these differences in thoracic cavity shape may not produce dramatic differences in the distribution of pleural pressure and, therefore, are not likely to have major effects on cardiovascular function. In a supine dog with bilateral thoracotomies, contraction of the diaphragm has minimal effects on cardiac output or pericardial compliance (7). But there may be different effects when the thorax is intact. Two Muscles of the Diaphragm
In recent years it has been determined that the diaphragm is anatomically and functionally composed of two muscles, the costal and crural components, which have separate innervations (8). The two muscles are differentially activated with increasing respiratory drive (9). From anatomical considerations, differential activation of the costal and crural muscles should alter diaphragmatic configuration and potentially alter traction on the mediastinal contents. The Mediastinum as a Component of the Chest Wall
The mediastinum can be considered as a functional component of the chest wall that separates the two lungs. Because the mediastinum contains no respiratory muscles and has no muscles inserting on it, its weight must be, in part, supported either by the lung or by attachments to the diaphragm, particularly in recumbent postures, and this support influences thoracic cavity shape. This point will be discussed in the following section. C. Coupling of Lung and Chest Wall
The lung is not attached to the thoracic wall, except at the hilum. The intimate coupling between the two is accomplished by pleural pressure. Pressure, by definition, is a force normal to the surface. Therefore, the visceral pleura is free to slide over the parietal pleura. During inspiration, the rib cage and parietal pleura are displaced cranially, whereas the visceral pleura is displaced caudally. Computation of the sliding friction, considering the thickness of the pleural fluid layer, the viscosity of the pleural fluid, the velocity of displacement, and the surface area, indicates that the frictional shear forces in the pleural space are a minor component of the work of breathing (10). As the lung expands during inspiration, hilar structures are displaced caudally relative to the apex of the lung. In the supine dog, measurements of tension in the mainstern bronchi suggest that during inspiration the tracheal carina is displaced caudally by mediastinal attachments to the diaphragm, rather than by traction from the lung (11). The displacement of the carina as measured by computed tomographic scans is similar, whether the intact lungs are passively inflated from functional residual capacity to total lung capacity or the thoracic cavity is inflated over the same volume range in the presence of complete bilateral pneumothoracies (Rodarte and Hoffman, unpublished data). These data suggest that very little traction is applied
14
Rodarte
to the lung by hilar structures. If this is true, pleural surface pressure is the only significant force acting on the lung, and the integral of the pressure over a lobe or lung surface must be a vertical force equal to its weight. Distribution of pleural pressure must meet the additional constraint that it produce a parenchymal stress distribution consistent with the regional volume expansion. Fluid in a container has a vertical pressure gradient equal to the density of the fluid. In general, solids in a rigid container of the same size and shape in the absence of gravity will, in the presence of gravity, have a vertical pressure gradient less than their density. Even though the lung is relatively fluidlike, theoretical models of the effect of gravity on the lung predict a vertical gradient of pressure less than lung density (12,13). Numerous investigators have reported vertical gradients in pleural or esophageal pressure greater than lung density. This difference suggests that additional forces acting on the lung determine the distribution of pleural pressure. Traction on the lung from the major airways does not seem to be a significant factor. The additional force probably results from the requirement that lung and thoracic cavity shapes conform. If the shape of the thoracic cavity was such that the dependent portions were smaller than the undeformed shape of the lung, when exposed to gravity, equilibrium requires that the vertical gradient in regional lung volume and pleural pressure be steeper than would result from the effect of gravity alone acting on the lung (Fig. 3). Esophageal pressure in the upright human shows a pressure gradient in the region of the heart that is larger than in the upper esophagus and is greater than lung density (14,15). This distribution of pleural pressure gradients may be determined by the support of the heart as well as the shape of the rib cage. In dead, head-up dogs, increasing the heart weight by replacing the blood with mercury increases the vertical gradient in the esophageal pressure (16) (Fig. 4), a result consistent with theoretical modeling of the effect of heart weight being entirely supported by the lung (12). In the human, in contrast to the head-up dog, the heart is in contact with the diaphragm, even at total lung capacity, so that the extent to which these animal studies are applicable to humans is now uncertain. In the lateral decubitus position in the dog, the part of the lung that is directly beneath the heart is nearly at minimal volume (17). Even though there is a large cephalad displacement of the dependent hemidiaphragm resulting from the weight of the abdominal contents, this observation and subsequent comparative studies (18) suggest that the weight of the heart is not entirely supported in a sling between the mediastinal attachments to the diaphragm and the cranial thoracic outlet. To the extent that these observations are referable to the human, clinical conditions in which heart volume and weight are greatly increased could have substantial effects on regional lung function. Nonuniform Lung Deformations
The lung pressure-volume curve describes the mechanical properties of the lung parenchyma under uniform stress. On a macroscopic scale, the lung acts as an iso-
Lung and Chest Wall Mechanics
15
Figure 3 Diagrammatic illustration of possible undistorted shapes of lung and chest wall. Because in the intact animal the lung and chest wall must have the same shape, the lung will have to expand over superior regions and deflate over inferior regions to fit within the chest wall. This will result in a pleural pressure that is more negative over superior lung regions than it is over inferior ones. This in turn will alter the shape of the relaxed chest wall, making it smaller in superior regions and larger in inferior ones. The resulting gradient in pleural pressure will depend on relative distortability of lungs and chest wall. (From Ref. 39.)
tropic elastic solid. That is, if deformation by its own weight is not considered, the lung expands uniformly, maintaining a similar shape. Linear dimensions change with the cube of the lung volume. A solid also resists changes of shape, and the pressure-volume curve does not describe that property. More work is required to simultaneously change shape and volume than to produce a uniform expansion (19). Therefore, in theory, when the lung is exposed to a gradient in transpulmonary pressure, regional volume cannot be predicted from regional transpulmonary pressure. However, the lung has relatively little resistance to changes of shape (20,21), and regional lung volume distribution, when the lung is exposed to hydrostatic gradients in transpulmonary pressure, is reasonably close to that predicted by the approximation of using the uniform pressure-volume curve to predict regional volume from regional transpulmonary pressure (22–24). Static pressure gradients ⬎ 1 cm H2O/ cm height probably do not occur in vivo. Lung lobes allow additional degrees of freedom for the lung to change its shape and achieve static equilibrium with the thoracic cavity, resulting in less parenchymal deformation and less nonuniform pleural pressure. Thus, the division of the lung into lobes may facilitate the maintenance
16
Rodarte
Figure 4 Effect of weight of the heart on pleural pressure gradient. Vertical gradient in esophageal pressure in dead, head-up dogs is plotted on vertical axis against weight of heart when blood-filled and after stepwise replacement of blood with mercury. When relationships are extrapolated to zero heart weight, the predicted gradient of four of five dogs is less than lung density. Symbols identify individual dogs. (From Ref. 16.)
of ‘‘normal’’ respiratory and cardiovascular functions with changes in body position that alter the configuration of the thoracic cavity because of the weight of the abdominal and mediastinal contents. III. Respiratory System Dynamics In Section IIA, static pleural pressure-volume relationships were considered. Figure 5 shows (in addition to the data in Fig. 2) the maximal static and dynamic pleural pressures that can be achieved by voluntary activation of the respiratory muscles when the airway is closed and opened, respectively. Dynamic pressures during maneuvers that are begun from the extremes of lung volume differ from static pressures because of the time required to achieve maximal force development, the force-velocity relationship of the respiratory muscles, and the chest wall flow resistance. The region between the static-Pel,L curve and the maximal inspiratory dynamic curve defines a maximal performance envelope of the inspiratory muscles. At any volume, it represents the maximal inspiratory pressure that can be applied to the lungs to produce inspiratory airflow. During normal breathing, only a small fraction of this force is utilized. However, during maximal exercise, in normal persons or during clinical conditions with very high inspiratory resistance, inspiratory pleural pressures may approach the maximum achievable. Pleural pressures that are very negative relative to body surface pressures have substantial effects on cardiovascular function by mechanisms discussed in the next section.
Lung and Chest Wall Mechanics
17
Figure 5 Dynamic and static pleural pressure-volume relationships. Data from Figure 2 are replotted with an expanded pressure scale. Also shown are esophageal pressures generated by maximal expiratory and inspiratory efforts with the airway occluded and the pressures during maximal dynamic efforts begun from the extremes of volume with the airway open. Area between the dynamic curves defines a maximal performance envelope for the respiratory muscles. (From Ref. 40.)
The right side of Figure 5 shows maximal static and dynamic expiratory pressures. High positive values of pleural pressure do not occur during normal ventilation. However, during paroxysms of cough or expulsive maneuvers, high pleural pressures adversely affect circulatory function. For example, cough syncopy is relatively common in patients with chronic obstructive lung disease. During mechanical ventilation, pleural pressures greater than the static pressure-volume curve of the chest wall in Figure 5 are required to expand the chest wall. However, because chest wall flow resistance in normal subjects and in patients with lung disease is relatively low, dynamic pleural pressures during mechanical ventilation are only slightly to the right of the static chest wall curve. However, airway pressures much greater than the separation between the static lung and chest wall pressure-volume curves are required to overcome the flow resistance of the lung. Maximal Flow
A characteristic of the lungs of all terrestrial mammals is the phenomenon of maximal expiratory flow. In a rigid pipe, the relationship between pressure and flow is nonlinear. At low flows the fluid moves smoothly in what can be thought of as concentric rings or lamina sliding over each other such that the fluid velocity at the wall is zero and is maximal in the center of the pipe. In this regime, pressure drop is linearly related to the flow and gas viscosity. Once a steady flow is established
18
Rodarte
the pressure drop is independent of density. At bifurcations this parabolic velocity profile is disrupted and additional pressure is required to restore it. The magnitude of this pressure is dependent on gas density. At higher flows, this pattern is disrupted and flow becomes chaotic. Fluid particles collide with each other and rebound at angles different from the axis of the pipe, pressure loss is proportional to the flow squared and the gas density and is independent of the viscosity. When the cross sectional area of the tube downstream of an intersection is smaller than total cross section of the two converging branches, fluid velocity must increase. This increase in velocity is inversely proportional to the ratio of the areas and requires an additional pressure proportional to the density and the flow squared. This phenomenon is convective acceleration. The pressure losses in all three situations above are inversely proportional to the fourth power of the radius. However, the airways are elastic and not rigid pipes. Their diameter increases and thus their resistance decreases with increasing lung volume. During inspiration, pressure in the airways is higher than alveolar pressure so that the transmural pressure of the airways is larger than it would be during no flow at that volume and the airways are larger. Nevertheless, with increasing inspiratory flow rate, the pressure drop increases rather than decreases because increasing frictional losses dominate over the increase in airway diameter. In contrast, during expiration the pressures decrease from the alveoli to the airway openings so that airway transmural pressure at a given volume is less than it was during zero flow. Expiratory pressure flow curves are more curvilinear than during inspiration because the increases in turbulence, convective acceleration, and airway narrowing are additive during expiration (Fig. 6). In contrast to inspiration, during expiration there is a maximal flow at relatively low pleural pressures which range from near atmospheric at very low lung volumes to, in normals, about 20 cm H2O at the highest lung volume. With further increases in pleural pressure, flow remains constant (25). For many years physiologists thought of this phenomenon as analogous to a waterfall. That is, the flow of a waterfall is determined totally by the conditions upstream of the waterfall, and are independent of the height of the fall or conditions downstream. In similar fashion, in the lung there are critical points in the airway which determine maximal flow. Once maximal flow is achieved, further increases in effort have no effect on the pressure drop down to this point, but there is increased turbulence and pressure losses in the airways downstream. In the airway, this phenomenon is caused by the wave speed of elastic tubes. In elastic tubes that have compliance greater than the compressibility or compliance of the gas within it, a pressure disturbance is propagated through the tube by the wave speed which is proportional to the area to the three-halves (3/2) power and inversely proportional to the square root of the gas density and tube compliance. During expiratory flow, a decrease in pressure at the airway opening relative to pleural pressure progresses from the airway opening upstream at the wave speed minus the downstream gas velocity. If the velocity at some point in the airway is equal to the wave speed, the decreased pressure can not progress beyond that point so that the flow upstream from this critical point can not increase. The physiologist’s
Lung and Chest Wall Mechanics
19
Figure 6 Relationships between lung elastic recoil, maximal expiratory flow, and lung volume in normals in airway obstruction. (Left panel) Maximal expiratory flow is plotted on the left of the vertical axis which is absolute lung volume determined in the volume displacement body plethysmograph contained during a forced vital capacity maneuver. On the right, static lung elastic recoil determined from a static interrupted deflation maneuver from TLC. Solid lines and solid figures are of an age matched normal. Patients A and B are alpha-1antitrypsin-deficient patients, chosen to have the same degree of airway obstruction as judged by the flow volume curve. Both subject A and B have hyper-inflation and reduced static lung elastic recoil. Subject A is a never-smoker with no clinical symptoms of airway disease and has more reduction of recoil than subject B, who is an ex-smoker with symptoms of chronic bronchitis. (Right panel) Maximal expiratory flow from selected volumes during the forced vital capacity maneuver is plotted against static lung elastic recoil from the deflation volume curve. Patient A with reductions in both recoil and flow is superimposed on the bottom third of the normal relationship, suggesting that all of reduction in flow is due to reduction in recoil. Subject B, who has equal flow reduction, but less reduction of recoil has flows well below the normal relationship suggesting that flow is reduced due to airway disease as well as loss of lung elasticity. (From Ref. 26.)
analogy that this critical point which determines maximal flow is like a waterfall was quite apt. The airway with the lowest wave speed determines maximal flow for the whole system. At high lung elastic recoil pressure (high lung volume) the lowest wave speed occurs in the central airways and most of the pressure drop between the alveoli and the critical point is due to convective acceleration. At low lung volumes, the peripheral airways which are more compliant have the lowest wave speed. Even though the wave speed itself is inversely proportional to the square root of density, at low lung volume the pressure drop between the alveoli and the critical point is mostly viscosity dependent so maximal flow becomes dependent on gas viscosity. The important point is that it is lung elastic recoil that determines the location of a critical point and maximum flow. If the pressure volume curve of the lung is known, then the flow volume curve can be determined from the maximal flow as
20
Rodarte
a function of recoil pressure. In alpha-1-antytrypsin deficiency in the absence of airway disease (26), and in experimental emphysema in animals caused by proteolytic enzymes, maximal flow and airway resistance at low flow rates are normal as a function of lung recoil even though they are quite abnormal as a function of volume. Therefore, low flows at a given volume can occur from abnormalities of the airway with a normal lung elastic recoil or decreased lung elastic recoil with anatomically normal airways. IV. Heart-Lung Interactions Previous sections in this chapter have considered the determinants of overall and regional pleural pressures. Those sections provided insight into the mechanisms by which the mechanics of the respiratory system determine the distribution of pleural pressure. This section addresses how pleural pressure affects circulatory function. These topics are detailed elsewhere in this volume and, therefore, will be treated only briefly here. Also considered will be the effects of the beating heart on the lung. A. Global Effects of Pleural Pressure
Venous Return
For blood to flow into the intrathoracic veins and right atrium from regions lower than the heart, there must be a gradient in pressure greater than a hydrostatic gradient. Averaged over the respiratory cycle and referenced to atmospheric pressure, such a pressure gradient exists in the venous system. Inspiratory negative swings of pleural pressure distend the compliant intrathoracic veins and right atrium and facilitate forward flow. This mechanism depends on the relatively high compliance of these vessels. Although blood drains into the right side of the heart from above by its own weight, swings in inspiratory pleural pressure increase the transmural pressure of intrathoracic vessels, increasing their caliber and facilitating forward flow. When pleural pressure becomes greater than atmospheric pressure, venous return is impeded. The extrathoracic capacitance vessels must expand until sufficient pressure is generated to restore venous return. Effects on Left Ventricle
Changes in pleural pressure, as a first approximation, have no direct effect on the right ventricle and pulmonary vasculature because there is no net effect on transmural pressure, except as mediated through increased venous return or changes of left ventricular function. It is customary in cardiology to relate left ventricular chamber pressure to body surface pressure in assessing left ventricular performance. Because left ventricular systolic pressure is large relative to the difference between mean pleural and body surface pressures under most physiological conditions, this assessment results in little error. But to the extent that the pressure on the outer surface of the left ventricle approximates mean pleural pressure, the true transmural pressure
Lung and Chest Wall Mechanics
21
against which the left ventricle must work is the difference between the chamber pressure and the pleural pressure. Large decreases in pleural pressure produce a substantial afterload on the left ventricle, which impedes the ejection of blood. Transient decreases in pleural pressure produce effects that tend to both increase and decrease cardiac output. Factors increasing output include (1) increased systemic venous return, which increases right ventricular output, which in turn increases pulmonary venous return and thus left ventricular output, and (2) increased lung volume with decreased pulmonary vascular resistance. However, increased right ventricular volume may impede left ventricular filling because of interventricular interdependence mediated by shifting the septum, and decreased pleural pressure is a direct afterload on the left ventricle. Transient increases in pleural pressure reduce the afterload on the heart, and if the increases are in phase with systole, ejection would be enhanced. Which effect dominates depends on the state of the cardiovascular system (e.g., systemic vascular pressures, myocardial contractility). The interactions of these various factors are discussed extensively elsewhere in this volume. B. Effects of Lung Inflation on Pulmonary Vasculature and Fluid Balance
Vascular Resistance
Conceptually, the pulmonary vasculature can be considered as lying outside the lung parenchyma. The visceral pleura at the hilum enters the parenchyma as a sheath around the veins and the bronchial arterial complex. If the distal ramifications of the bronchi and the blood vessels could be blocked and removed, leaving the sheath intact, and if the lung were inflated by injecting air into the distal air spaces, these conduits would expand and contract symmetrically with the lung. That is, the lengths and diameters would change with the cube root of lung volume. The pressure within these channels would be pleural pressure. Therefore, the pressure-volume relationship of these channels would be the same as that of the overall lung. However, these channels are coupled to the bronchi and blood vessels, which are also elastic structures with pressure-diameter relationships. If the diameter of an airway at a transmural pressure equal to transpulmonary pressure is smaller than the channel in which it must fit, the airway diameter has to increase and the diameter of the parenchymal channel decrease for them to match. Here, the effective stress at the junction would be greater than the transpulmonary pressure (27). The effective pressure at the junction would be more negative than the pleural pressure. This seems to be the situation under most physiological conditions for both the airways (27) and the pulmonary vasculature (28). Nevertheless, as the first approximation, perivascular pressure can be considered to be nearly equal to pleural pressure. When pleural pressure is decreased and lung volume is increased, the perivascular pressure decreases concomitantly and the transmural pressure of the arteries and veins increases. Because resistance is much more sensitive to changes in diameter than to changes in length, a symmetric expansion of the vasculature with lung inflation causes a net decrease in resistance of the
22
Rodarte
large vessels. This reasoning applies to the so-called extra-alveolar vessels. The alveolar capillary network is exposed to a pressure closer to alveolar pressure. Therefore, for a constant difference between pulmonary arterial pressure and pleural pressure, the transmural pressure of the alveolar vessels is reduced and the alveolar vessels are compressed when the difference between pleural and alveolar pressure is increased by lung inflation. Lung Fluid Balance
In Section IIC, it was stated that the determinant of regional pleural pressure is the regional parenchymal lung expansion required to match lung and thoracic cavity shapes. In the past, the stress required to inflate the lung (the pleural surface pressure) was considered to be different from the liquid pressure in the pleural space. This distinction was supported by the finding of discrepancies between various techniques for measuring parenchymal surface stress and measurements of liquid pressure with fluid-filled catheters. At that time, techniques were not available for measuring the liquid pressure without producing a local deformation in the space, which altered the pressure. Improved measurement techniques (20,29,30) and supporting theory (29) provide strong evidence that pleural surface pressure and liquid pressure are identical and that the gradient in pleural pressure is less than hydrostatic because of large viscous pressure losses in an infinitesimal pleural fluid flow. In the absence of flow, there would be a hydrostatic gradient in the continuous sheet of pleural fluid. This hydrostatic gradient drives flow in the dependent direction. However, the separation between the two pleural surfaces is so small that extremely small volumes of fluid flow are required for the viscous losses to reduce the pressure gradient to that established by the distribution of lung volume. At every location, the hydraulic pressure in the pleural fluid is the pleural surface pressure. This explanation of pleural fluid dynamics requires some mechanism for the preferential reabsorption of fluid from dependent regions, presumably by lymphatic vessels, although this has not been unequivocally demonstrated. Fluid exchange with the vasculature is governed by the Starling equilibrium equation. Because the pleural surface is relatively permeable to water, there cannot be a large hydrostatic gradient between the pleural fluid and the pulmonary parenchymal interstitium. Therefore, the parenchymal interstitial space should have a pressure nearly equal to pleural pressure. As previously noted, the compartment surrounding the extra alveolar vessels and bronchi is a separate interstitial space that has a stress or effective pressure less than pleural pressure. This interstitial space serves as a sump to remove fluid from the pleural space and the alveolar interstitial space. Ultimately, clearance of this fluid is facilitated by the pumping action of the lymphatic vessels. Thus, given an alveolar pressure nearly equal to atmospheric, lung recoil pressure and pleural pressure relative to atmospheric pressure have an important role in the balance between lung fluid and pleural fluid. C. Effects of Lung on Beating Heart
The heart can be considered to sit in a pocket formed by the surrounding lung. If the lung were to expand isotropically, the space for the heart would expand with
Lung and Chest Wall Mechanics
23
lung inflation and its dimensions would increase with the cube root of lung volume. To the extent that this is true when the lung is inflated by the action of the inspiratory muscles, juxtacardiac pressures would decrease by the same amount as pleural pressure on the costal and diaphragmatic surfaces of the lung. In contrast, when the respiratory system is inflated by positive airway pressure and pleural pressure must increase to inflate the rib cage and displace the diaphragm, then juxtacardiac pressures would increase and the heart would be compressed. If the heart were less compliant than the rib cage and abdomen, juxtacardiac pressure would increase more than pleural pressure elsewhere. Left ventricular diastolic filling curves relating chamber pressure to esophageal pressure show decreased ventricular filling when airway pressure is increased (31). This decreased filling suggests that the effective juxtacardiac pressure has increased more than the estimate derived from an esophageal balloon. If ventricular ejection changes the volume of intrathoracic blood, then either the lung must expand or the thoracic cavity must contract by an equal volume. Which process dominates depends on the relative impedances. Right ventricular ejection transfers blood from the right ventricle to the pulmonary artery and has no net effect on intrathoracic volume. Similarly, blood ejected from the left ventricle into the thoracic aorta has no net effect on thoracic cavity volume. Only the difference between blood leaving the thorax through the systemic arteries and blood entering the thorax from the systemic veins produces a net change in the thoracic contents that has to be made up by displacement of the chest wall or by a change in lung volume. In a relaxed normal person with an open glottis, the heartbeat produces a displacement of the anterior abdominal wall, the rib cage over the apex of the heart, and a small to-and-fro flow of air from the lung, the pneumocardiogram. The volume and timing of these displacements are not defined. Nor is there any information about the relative impedance of the lung, rib cage, and abdomen-diaphragm to such a nonuniform application of force. Data on the relative impedances of these structures derived from pressure oscillations applied at the mouth probably would not have much predictive value. Constant-Volume Heart
Even if ventricular ejection caused no net change in intrathoracic blood volume, if end-systolic heart volume were smaller than end-diastolic heart volume, a local deformation of the lung would be required to fill the space created by the heartbeat. Although the lung has relatively little static resistance to shape change, little is known about its resistance to such a dynamic shape change. As a first approximation, this resistance may be similar to the impedance to gas flow into or out of the vicinity of the local deformation from distant regions. This resistance to dynamic deformation could be increased in disease states in which large increases in airway resistance occur in the lung periphery and in conditions in which lung compliance is greatly reduced. However, there may be little if any difference in volume contained within the pericardial sac during ventricular systole (32). When the ventricles eject blood, the
24
Rodarte
space must be filled by expansion of the adjacent lung or an equal influx of blood. Which process dominates is determined by the relative impedances of venous return and local lung deformation. The data indicate that there is little motion of the apex of the heart and that the plane of the atrioventricular valves is depressed during ventricular systole, suggesting that the atria becomes charged with blood from the systemic and pulmonary veins. Even though myocardial blood flow is reduced during systole, the vessels on the epicardial surface of the heart may increase their volume, thus contributing to this effect (32). A constant heart volume should reduce the change in juxtacardiac pressures associated with systole and increase the transmission of transmural pressure to the chambers. In spite of the preceding data, ventricular systole obviously deforms the adjacent lung because motion of lung parenchyma near the heart can be readily visualized fluoroscopically. This displacement of the lung parenchyma decreases as distance from the heart increases (33). The displacement is associated with a redistribution of alveolar gas, which facilitates intrapulmonary gas mixing and reduces the inhomogeneity of ventilation that might otherwise occur. Cardiac Momentum
During ventricular systole, blood is accelerated to pass through the aortic and pulmonary valves at high velocity. Force must be applied to tether the heart and eject the blood, rather than to have the heart propelled toward its apex. If one assumes a blunt velocity profile and representative peak left and right ventricular outflow tract velocities of 10 and 8 m/sec: and diameters of 2 and 2.3 cm, a force of ⬎5 kg would be required to tether the heart. It is not clear how much tethering is supplied by the arteries and veins and how much by the lung, which envelopes the ventricular surface in the dog and the lung and the diaphragm in the human. Traction on the pulmonary arteries and veins would transmit this force to the lung, whereas the systemic arteries, veins, and pericardial sac are ultimately connected to nonpulmonary mediastinal structures. It is even less clear what provides this force in the artificial hearts now being tested. D. Clinical Applications in Patients with Lung Disease
Airway Disease
In normal individuals, functional residual capacity (FRC) is a volume that occurs during muscular relaxation when the inward recoil of the lung is balanced by the outer recoil of the chest wall, in normal individuals, usually ⬍5 cm H2O. The pleural pressure volume loop during quiet breathing is a rather narrow loop around the lung pressure volume curve from about ⫺5 to ⫺10 cm H2O. With moderately severe bronchoconstriction maximal expiratory flow at normal FRC can fall to zero. In order to achieve the mean expiratory flow rate required to produce an adequate alveolar ventilation FRC becomes dynamically determined and patients may have to breathe with an FRC above their normal end inspiratory volume and an end inspi-
Lung and Chest Wall Mechanics
25
Figure 7 Isovolume pleural pressure-flow curves. During a series of vital capacity maneuvers with gradually increasing efforts, simultaneous measurement of esophageal pressure as an estimate of pleural pressure, inspiratory and expiratory flow rates, and lung volume were obtained. At fixed lung volumes of 25%, 50%, and 75% VC expired from TLC, simultaneous measurements of pressure and flow from each VC maneuver were obtained and smooth curves passed through them. At zero flow there is a decrease in pleural pressure with increasing volume due to the static lung pressure-volume curve. The slope of the pressure-flow relationship is steeper at higher volumes because of the increased airway diameter. During inspiration there is a monotonic, but nonlinear increase in flow with decreasing pleural pressure until a maximal effort is reached. In contrast, during expiration below 25% VC, flow reaches a maximum value at relatively low pleural pressures and is constant thereafter with increasing pressure until maximum effort is achieved.
˙ relationships, the ˙ /Q ratory volume near TLC (Fig. 7). Because of the abnormal V patient requires a greater than normal ventilation to achieve normal oxygen uptake. The airway resistance may also be increased to five or six times normal even at the increased lung volume. With the reduced maximal expiratory flow, prolonged expiratory time is required even at these high lung volumes and so the inspiratory portion of the respiratory cycle may be reduced from the normal 45% to 15% or 20%. This requires a high inspiratory flow rate which, when coupled with a high airway resistance, produces pleural pressures of ⫺25 to ⫺30 cm H2O. During expiration, even if the patient is merely relaxed and uses no expiratory effort, the very
26
Rodarte
low expiratory flow rates and high lung volumes mean that the chest wall is pushing on the obstructed lung. Pleural pressure follows the passive pressure-volume characteristic of the chest wall which can produce on the order of 10 cm H2O positive pleural pressure. If the patient is utilizing expiratory muscles, pleural pressures are even more positive during expiration. A positive alveolar pressure at end expiration was originally described during mechanical ventilation and termed auto or intrinsic PEEP (34), but it also occurs during spontaneous breathing. Therefore, with each breath pleural pressure may oscillate by 30 to 40 cm H2O, drastically changing the venus return and afterload on the left ventricle. This explains why pulsus paradoxicus occurs during asthma attacks. In young people with normal cardiovascular systems this is probably not a significant health risk, but in older asthmatics with existing cardiac disease, it may produce left ventricular failure. Severe obstructive bronchitis associated with cigarette smoking can also produce the scenario described above. Emphysema has a slightly different pathophysiology (Fig. 8). The loss of lung elastic recoil occurring with emphysema will produce an increase in FRC. This also produces a decrease in lung elastic recoil at TLC. Even in the absence of airway diseases decreased elastic recoil reduces maximum expiratory flow near the relaxation point so that FRC becomes dynamically determined and FRC is increased even more than would be predicted from the shift of the lung pressure-volume curve. Since total lung capacity is determined by the balance of forces between the expiratory recoil of the lung and chest wall and the force generating capacity of inspiratory muscles, a decrease in lung recoil would produce an increase in TLC. The chronic breathing at high lung volumes causes remodeling of the thoracic cavity, specifically dropping out of sarcomere units in the diaphragm, which shifts the chest wall pressure-volume curve upward which then further increases the relaxation volume of the respiratory system, but may not further increase FRC if it was already dynamically determined. However, it increases the force generating capacity of the inspiratory muscles at high lung volume and permits an even greater increase in TLC. The ability to increase TLC is a little understood but extremely important adaptive mechanism in COPD due to emphysema. Patients with severe disease may have TLC’s approaching 150% of predicted and FRC’s greater than their normal TLC. Had they not been able to increase their TLC, they would not have survived this degree of airway obstruction. Patients with severe emphysema (Fig. 9) may have pleural pressure of only ⫺10 cm H2O at TLC and only slightly increased inspiratory resistance but because of the long expiratory time and the need for high levels of ventilation to achieve a ˙ mismatch, they may generate ⫺20 cm H2O ˙ /Q normal oxygen uptake because of V of pleural pressure with every breath and plus 10 cm H2O pleural pressure during expiration. So they, like the asthmatics, will have 30 cm H2O pleural pressure swings with each breath. The vena cava traverses the right diaphragm at the junction of the costal diaphragm muscle and the central tendon. At the very high lung volume achieved by emphysema patients, a dynamic obstruction of the vena cava can occur limiting venus return to the right heart during inspiration (35). This, combined with a positive pleural pressure during the prolonged expiratory phase of the breathing
Lung and Chest Wall Mechanics
27
Figure 8 Schematic depiction of pressure-volume (A) and flow-volume (B) relationships in patients with airway obstruction and increased ventilatory demands. (A) Normal lung and chest wall curves from Figure 2 are reproduced. Lung pressure-volume curve is shifted upward in presence of chronic obstructive pulmonary disease (COPD). For clarity, it is assumed that vital capacity is unchanged. Relaxation volume at which the -Pel,L and Pel,W curves intersect occurs at a higher volume. (B) Maximal flow-volume curve of patient with COPD is shown with expiratory flow to right of axis and inspiratory flow to left of axis. For reference, normal peak expiratory flow is greater than 8 L/sec and flow at 50% vital capacity is about 4 L/sec. Tidal volume loops of pressure (A) and flow (B) are shown. See text for details.
cycle, produces an increased systemic venus pressure promoting peripheral edema even in the absence of right heart failure. Recently lung volume reduction surgery has been shown to provide dramatic improvement in lung function in some emphysema patients (5). The appropriate indications for this surgery, if any, are currently the subject of a multi-center national trial. It is not clear that the theoretical results below will readily translate
(A)
(B)
Lung and Chest Wall Mechanics
29
into clinical criteria for patient selection. When airway obstruction is caused by diffuse small airway disease causing dynamic hyperinflation so that quiet breathing is near TLC, inspiratory muscle function will be greatly compromised and patients will be unable to increase ventilation to perform exercise. Resection of lung tissue will of necessity contain these peripheral airways. One could estimate, that resection of some percent of the lung tissue would reduce maximum flow at that recoil by the same amount. However, using a linear approximation, surgery would increase lung recoil at constant volume above RV by the same amount, and therefore, there would be little or no improvement of maximal flow. That is, the flow volume curve would have the same slope starting from a lower RV. This would occur at the cost of reduction of the pulmonary vascular bed and gas exchanging surface area. The other extreme occurs in patients with bullus emphysema in areas accessible to resection who have less disease elsewhere. Patients with end stage disease have quiet breathing near TLC with every breath. Bullae are poorly ventilated. On high-resolution CAT scan they do not change volume between TLC and RV and do not accumulate xenon during a ventilation scan. Therefore, if such areas can be resected, it would be almost equivalent to removing a pneumothorax. Flow at constant recoil would be the same, and recoil at constant volume above RV would be the same. Patients could achieve tidal respiration at a much lower volume, increasing the mechanical advantage of the inspiratory muscles. Because lung elastance is not increased, TLC would not be decreased as much as in the previous case so vital capacity and the ability to increase ventilation above the resting level for exercise would be greater. There would be no resection of functional pulmonary bed. In patients with a combination of homogeneous diffuse emphysema and airway disease, the results are harder to predict. If the lung recoil is so low that the flow-limiting airways are included in the resection, one might predict that they would behave like the diffuse airway disease. However, if lung recoil is increased enough after the resection so that the critical point occurs in more central airways then the remaining regions could increase their flow restoring flow at that recoil to the previous value. These patients would experience benefit.
Figure 9 Pressure flow and volume in emphysema. (A) Tidal flow and maximal expiratory flow vs. absolute lung volume expressed as % of predicted TLC in a normal 60- to 65-yearold man and a patient with severe emphysema. (B) Pleural pressure vs. volume during tidal breathing and static deflation from TLC. In the normal, mean inspiratory and expiratory flows are similar and the flow-resistive work, given by the area of the tidal pressure-volume loop, is relatively small. There is a substantial difference between tidal and mechanical expiratory flow. In contrast, in the emphysema patient tidal expiratory flow is maximal even though he is breathing near TLC, which is greatly increased. Inspiratory flow is much higher than expiratory flow in order to achieve the minute ventilation required at rest. Flow-resistive work is high because of the high inspiratory flow rate even though inspiratory resistance is normal and the relaxed chest wall drives the pleural pressure positive in excess of the pressure required to achieve maximal expiratory flow, intrinsic PEEP.
30
Rodarte Mechanical Ventilation
In patients with airway obstruction who during exacerbation of their obstruction develop hypercarbic respiratory failure requiring intubation and mechanical ventilation, the consequences of dynamic hyperinflation becomes more critical. During mechanical ventilation, pleural pressure is more positive during inspiration than during expiration and patients may be inflated to higher volumes than they could achieve spontaneously. This produces continuous high positive pleural pressures which while reducing afterload on the left ventricle can severely compromise the venus return to the heart and diminish cardiac output to dangerous or even lethal levels. Cardiopulmonary Resuscitation
Initially, it was believed that manual chest compression during cardiopulmonary resuscitation (CPR) squeezed the heart between the depressed sternum and the spinal column, ejecting blood from the ventricles. This is not the major mechanism of CPR. The major forces driving the circulation are the changes in pleural pressure generated by chest compression, with the heart acting largely as a passive valved conduit (36,37). This area is of great current clinical interest, and new and more effective strategies, which combine positive airway pressure with chest compression, may greatly enhance the efficacy of CPR. V.
Closing
The following paragraph is from the first edition of this volume. Although our understanding has matured in many areas, it is as true today as a decade ago. Some extremely complex mechanical interactions have been identified in this chapter. Much is known about some and virtually nothing is known about others. In almost no instance is there sufficient information to permit a rigorous quantitative analysis. Some interactions are likely to be of trivial interest and others, such as the effects of pleural pressure during CPR, are of immense clinical importance. Although some farsighted investigators have been addressing these questions for many years, major interest in this field is relatively recent. There is much to be done.
References 1. 2. 3. 4. 5.
Wilson TA. Surface tension-surface area curves calculated from pressure-volume loops. J Appl Physiol 1982; 53:1512–1520. Klineberg PL, Rehder K, Hyatt RE. Pulmonary mechanics and gas exchange in seated normal men with chest restriction. J Appl Physiol 1981; 51:26–32. Roussos C, Macklem PT (eds). The Thorax. Part A and B. Lung Biology in Health and Disease., Vol. 29. New York, Marcel Dekker, 1985. Konno K, Mead J. Measurement of the separate volume changes of rib cage and abdomen during breathing. J Appl Physiol 1967; 22:407–422. Mead J, Loring SH. Analysis of volume displacement and length changes of the diaphragm during breathing. J Appl Physiol 1982; 53:750–755.
Lung and Chest Wall Mechanics 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
31
Loring SH, Mead J. Action of the diaphragm on the rib cage inferred from a force-balance analysis. J Appl Physiol 1982; 53:756–760. Lloyd TC Jr, Cooper JA. Effect of diaphragm contraction on canine heart and pericardium. J Appl Physiol 1983; 54:1261–1268. De Troyer A, Sampson M, Sigrist S, Macklem PT. Action of costal and crural parts of the diaphragm on the rib cage in dog. J Appl Physiol 1982; 53:30–39. Van Lunteren E, Haxhiu MA, Deal EC Jr, Perkins D, Cherniack NS. Effect of CO2 and bronchoconstriction on costal and crural diaphragm electromyograms. J Appl Physiol 1984; 57:1347–1353. Lai-Fook SJ, Kaplowitz MR. Pleural space thickness in situ by light microscopy in five mammalian species. J Appl Physiol 1995; 59(2):603–610. Miserocchi G, Agostoni E. Longitudinal forces acting on the trachea. Respir Physiol 1973; 17:62–71. Bar-Yishay E, Hyatt RE, Rodarte JR. Effect of heart weight on distribution of lung surface pressures in vertical dogs. J Appl Physiol 1986; 61:712–718. West JB, Matthews FL. Stresses, strains and surface pressures in the lung caused by its weight. J Appl Physiol 1972; 32:332–345. Milic-Emili J, Mead J, Turner JM. Topography of esophageal pressure as a function of posture in man. J Appl Physiol 1964; 19:212–216. Rehder K, Abboud N, Rodarte JR, Hyatt RE. Positive airway pressure and vertical transpulmonary pressure gradient in man. J Appl Physiol 1975; 38:896–899. Hyatt RE, Bar-Yishay E, Abel MD. Influence of the heart on the vertical gradient of transpulmonary pressure in dogs. J Appl Physiol 1985; 58:52–57. Hoffman EA. Effect of body orientation on regional lung expansion: A computed tomographic approach. J Appl Physiol 1985; 59:468–480. Hoffman EA, Ritman EL. Effect of body orientation on regional lung expansion in dog and sloth. J Appl Physiol 1985; 59:481–491. Wilson TA. Solid mechanics. In: Fishman AP, Macklem PT, Mead J. eds. Handbook of Physiology. Sect. 3. The Respiratory System. Vol. 3, Part 1. Bethesda, MD: American Physiological Society, 1986:35–40. Lai-Fook SJ, Wilson TA, Hyatt RE, Rodarte JR. Elastic constants of inflated lobes of dog lungs. J Appl Physiol 1976; 40:508–513. Rodarte JR, Fung YC. Distribution of stresses within the lung. In: Fishman AP, Macklem PT, Mead J. eds. Handbook of Physiology. Sect. 3. The Respiratory System. Vol. 3, Part 1. Bethesda, MD: American Physiological Society, 1986:233–245. Gillett D, Ford GT, Anthonisen NR. Shape and regional volume in immersed lung lobes. J Appl Physiol 1981; 51:1457–1462. Murphy BG, Plante F, Engel LA. Effect of a hydrostatic pleural pressure gradient on mechanical behavior of lung lobes. J Appl Physiol 1983; 55:453–461. Olson LE, Wilson TA, Rodarte JR. Distortion of submerged dog lung lobes. J Appl Physiol 1985; 59:521–527. Fry DL, Hyatt RE. A unified analysis of the relationship between pressure, volume and gas flow in the lungs of normal and diseased human subjects. Am J Med 1960; 29:672– 689. Black LF, Hyatt RE, Stubbs SE. Mechanism of expiratory airflow limitation in chronic obstructive pulmonary disease associated with 1-antitrypsin deficiency. Am J Respir Dis 1972; 105(6):891–899. Lai-Fook SJ, Hyatt RE, Rodarte JR. Effect of parenchymal shear modulus and lung volume on bronchial pressure diameter behavior. J Appl Physiol 1978; 44:859–868. Lai-Fook SJ. A continuum mechanics analysis of pulmonary vascular interdependence in isolated dog lobes. J Appl Physiol 1979; 46:419–429. Lai-Fook SJ, Beck KC, Southorn PA. Pleural liquid pressure measured by micropipettes in rabbits. J Appl Physiol 1984; 56:1633–1639. Wiener-Kronish JP, Gropper MA, Lai-Fook SF. Pleural liquid pressure in dogs measured using a rib capsule. J Appl Physiol 1985; 59:597–602. Prewitt RM, Wood LDH. Effects of positive endexpiratory pressure on ventricular function in dogs. J Appl Physiol 1979; 236:H534–H544.
32
Rodarte
32.
Hoffman EA, Ritman EL. Invariant total heart volume in the intact thorax. Am J Physiol 1985; 249:H883–H890. Wei J, Hoffman EA, Ritman EL, Wood EH. Cardiogenic motion of right lung parenchyma in anesthetized intact dogs. J Appl Physiol 1985; 58:384–391. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: the auto-PEEP effect. Am Rev Respir Dis 1982; 126:166– 170. Nakhjavan FK, Palmer WH, McGregor M. Influence of respiration on venous return in pulmonary emphysema. Circulation 1966; 33(1):8–16. Babbs CF. New versus old theories of blood flow during CPR. Crit Care Med 1980; 8:191– 195. Rudikoff MT, Maughan WL, Effron M, Freund P, Weisfeldt ML. Mechanisms of blood flow during cardiopulmonary resuscitation. Circulation 1980; 61:345–352. Kallok MJ, Lai-Fook, SJ. Lung deformations at minimal volume. J Appl Physiol 1980; 48: 487–494. Macklem PT, Murphy B. The forces applied to the lung in health and disease. Am J Med 1974; 57:371–377. Rodarte JR, Rehder K. Dynamics of respiration. In: Fishman AP, Macklem PT, Mead J. eds. Handbook of Physiology. Sect. 3. The Respiratory System. Vol. 3, Part 1. Bethesda, MD: American Physiological Society, 1986:131–144.
33. 34. 35. 36. 37. 38. 39. 40.
3 Respiratory Muscle Function and Blood Flow
STEVEN G. KELSEN Temple University School of Medicine Philadelphia, Pennsylvania
I.
Introduction
The respiratory skeletal muscles, like the heart, are a vital pump on which life depends. The forces applied by their contraction to the bony structures of the rib cage, spine, shoulder, and pelvic girdle distort and displace the chest wall away from its relaxed configuration and allow tidal exchange of gas between the lung and the environment. The magnitude of the resultant negative and positive swings in intrathoracic pressure generated by these muscles determine the rate of inspiratory and expiratory airflow and the size of the tidal volume. In addition, episodic powerful contractions of these muscles are required to maintain the normal elastic and flow resistive properties of the lungs and conducting airways. For example, sighing produced by the contraction of the inspiratory muscles (i.e., inflation to total lung capacity) preserves lung compliance by redistributing alveolar surfactant. Conversely, coughing produced by the coordinated cocontraction of the expiratory and inspiratory muscles clears secretions and minimizes airflow resistance. Finally, the respiratory muscles may be required to generate heightened intensities of contraction continously for prolonged periods (i.e., months to years) when respiratory system impedance is increased by lung disease. Often these extraordinary efforts must be made despite lung volume-related changes in muscle precontraction 33
34
Kelsen
length and alignment which place the muscles at a mechanical disadvantage and impair muscle force generation and the translation of force into changes in intrathoracic pressure. Intense investigation within the past decade indicates that the respiratory skeletal muscles are highly plastic and capable of adaptive changes in structure, biochemical properties and contractile function in response to altered patterns of use and changes in muscle length and alignment (1). However, recent studies also indicate that respiratory muscle function deteriorates in disease, with aging, with repeated intense contractions (i.e., fatigue) and when muscle blood flow or blood chemistry are abnormal (2–4). Under the latter conditions impairment in the pressure generating ability of the inspiratory and expiratory muscles, if sufficiently severe, may lead to deterioration in lung mechanics and even hypercapnic respiratory failure. II. Mechanical Action Conceptually, the ventilatory pump may be viewed as consisting of two compartments: the rib cage and abdomen, separated by the diaphragm (5). The rib cage is composed of the sternum, ribs, thoracic vertebrae, and costal cartilage. Contraction of the inspiratory or expiratory muscles which displace the ribs in an anterior (pump handle) and lateral (bucket handle) direction change intrathoracic and abdominal pressure. Moreover, because the costal and crural regions of the diaphragm are in apposition to the inner aspect of the lower rib cage, the lower four to six ribs (laterally and posteriorly) function as part of the abdominal wall. The portion of the diaphragm that abuts the inside of the rib cage occupies slightly more than one fourth of the internal surface of the thorax. Accordingly, changes in abdominal pressure are transmitted to the lower rib cage via the zone of apposition; conversely, expansion or compression of the lower rib cage alters abdominal pressure. The abdominal contents are essentially incompressible and most of the structures surrounding the abdominal cavity are rigid (i.e., pelvis, dorsal spine, iliac crests, rib cage). Therefore, an increase in abdominal pressure generated by descent of the diaphragm can only be dissipated by moving the ventral abdominal wall outward. Conversely, an increase in abdominal pressure generated by contraction of the abdominal or rib cage expiratory muscles can only be dissipated by displacing the diaphragm cranially. This relationship allows the diaphragm and lower rib cage muscles to affect abdominal pressure and the abdominal muscles to affect intrathoracic pressure. The mechanical action of the respiratory muscles is reflected in the volume changes of the rib cage and abdomen during breathing and their pattern of movement relative to each other. Rib cage and abdominal volume changes (expansion and deflation) have been assessed from their anterior-posterior or transverse dimensions. The temporal relationship of their change relative to one another is generally assessed by displaying rib cage and abdominal dimensions on an X-Y plot which has been termed a Konno-Mead diagram after the investigators who originated it (Figs. 1,2).
Respiratory Muscle Function
35
Figure 1 Konno-Mead diagram of relationship between abdomen and rib cage during isolated contraction of the costal and crural diaphragm. Without contribution from the chest wall and neck muscles the diaphragm primarily produces a paradoxical expiratory action on the upper rib cage during inspiration. The crural diaphragm has little effect on the lower rib cage during inspiration while the costal diaphragm expands this part of the thorax.
A. Muscles of Inspiration
Diaphragm
In normal subjects, contraction of the diaphragm, the primary muscle of ventilation, accounts for the largest portion of the change in intrathoracic pressure. Normally, the diaphragm has an elliptical and cylindrical shape. The normal diaphragm has several hiatal openings and triangular spaces (foramina of Morgagni and Bochdalek) which may transmit gas or fluid thereby affecting the pressure difference between the abdomen and rib cage. The diaphragm anatomically and functionally may be considered as two distinct muscles (5,6). Costosternal fibers (costal diaphragm) originating from the xiphoid process of the sternum and the upper margins of the lower six ribs insert on
36
Kelsen
Figure 2 Konno-Mead diagram of relationship between abdomen and rib cage in patients with neurologic injury. The C7-8 quadriplegic selectively uses the diaphragm and the sternocleidomastoid muscles for respiration. The patient with phrenic nerve injury (i.e., phrenic nerve frostbite post-CABG) primarily uses the chest wall and neck muscles to generate negative intrathoracic pressure.
the central tendon. Vertebral muscle fibers (crural diaphragm) arising from the ventro-lateral aspect of the first three lumbar vertebrae and the aponeurotic ligaments also insert on the central tendon. Normally, at end expiration the costal and crural diaphragm muscle fibers are oriented in a direction parallel to and abutting the inner surface of the rib cage. This zone of apposition allows the lower ribs (laterally and posteriorly) to function as part of the abdominal wall since it is acted on by abdominal pressure.
Respiratory Muscle Function
37
Contraction of the costal diaphragm applies an inspiratory action on the lower rib cage in two ways. Abdominal pressure generated by caudal movement of the diaphragm is transmitted across the zone of apposition and expands the lower rib cage (7). This positive pressure in the lower pleural space during inspiration is known as the appositional force and is proportional to the area of the zone of apposition and the total abdominal pressure. Second, the contraction force applied directly by the costal diaphragm fibers on insertional sites on the lower six ribs generates an inspiratory pump and bucket handle motion. The inspiratory action of the costal diaphragm is the sum of the appositional and insertional forces. In contrast, the inspiratory action of the crural diaphragm is based solely on the appositional force. There is no insertion of the crural diaphragm on the ribs and hence no direct insertional action. The crural diaphragm thus contributes to a lesser degree to the inspiratory action of the diaphragm (Fig. 1). Injury or dysfunction of the costal diaphragm, therefore, causes more impairment than that of the crural diaphragm (Fig. 1). In contrast to their effects on the lower rib cage, contraction of the costal and crural diaphragm produces an expiratory action on the upper rib cage by decreasing pleural pressure. This is illustrated by collapse of the upper rib cage during inspiration in patients with lower cervical cord transection in whom the diaphragm contracts in isolation (Fig. 2) (8,9). Expansion of the upper rib cage during inspiration, therefore, requires contraction of the scalene and parasternal intercostal muscles. Lung volume has important mechanical effects on the diaphragm. As lung volume increases, caudal movement of the diaphragm, which appears to descend in pistonlike fashion, decreases the area of the zone of apposition and the appositional force (10,11). Moreover, hyperinflation, induced by obstructive lung diseases such as COPD and asthma, alters diaphragm shape. As lung volume approaches total lung capacity, the diaphragm becomes flattened and the insertional force may be directed medially causing a decrease in lower rib cage volume during inspiration. Accordingly, with marked hyperinflation as in patients with emphysema, the costal and crural diaphragm may exert an expiratory action on the lower rib cage. The clinical sign of inward (expiratory) movement of the lower rib cage during inspiration is called Hoover’s sign and is frequently seen in patients with marked hyperinflation. On the other hand, as lung volume decreases, the area of the zone of apposition and the appositional force increases. Reductions in lung volume augment the mechanical advantage of the costal and crural diaphragm. The inspiratory action of the diaphragm is also dependent on the compliance of the abdominal cavity (12).The lower the abdominal compliance (i.e., the stiffer the abdominal wall), the greater the increase in abdominal pressure for a given diaphragmatic descent. Decreases in the abdominal compliance also facilitate lower rib cage expansion by allowing greater force to be applied insertionally. Conditions associated with decreased abdominal compliance include ascites, obesity, abdominal bandages, ileus, supine posture, and hyperinflation. Increases in abdominal compliance (i.e., open abdominal wounds or evisceration) produce the opposite effect and impair diaphragmatic efficiency. In man, the costal diaphragm is innervated by branches of the phrenic nerve which arise from the third and fourth cervical nerves. The crural diaphragm is innervated by branches of the fourth and fifth cervical nerves. Injury of the cervical cord
38
Kelsen
in the C3–5 region therefore, denervates the diaphragm. However, the topographic innervation of the diaphragm in a rostral-caudal direction allows function of the costal diaphragm to be preserved in subjects injured below C3, C4. In the thorax, the phrenic nerves travel between the parietal pleura and the pericardium until they enter the diaphragm lateral to the heart and anterior to the central tendon. This position of the phrenic nerves makes them extremely vulnerable to surgical procedures which involve the pericardium (i.e., cardiac cooling). Phrenic nerve injury is associated with a paradoxical inward movement of the anterior abdominal wall during inspiration as abdominal wall becomes subatmospheric and the flaccid diaphragm moves cranially into the thorax in response to the negative intra-thoracic pressure swing (Fig. 2). Intercostal Muscles
Three groups of intercostal muscles show phasic inspiratory electrical activity during eupneic breathing in man and hence may be considered primary inspiratory muscles: the parasternal intercostals, the upper external intercostals, and the levator costae. Contraction of these muscles causes cranial (inspiratory) displacement of the upper and lower ribs and offsets the deflationary action of negative pleural pressure on the upper rib cage. These muscles receive their sensory and motor innervation from the first to 12th thoracic nerves. The parasternal muscles are located ventrally between the costochondral junctions and the sternum. The parasternal muscles arise from the inner portion of the superior rib and insert on the rostral portion of the next lower rib. The fibers run in a caudal and lateral direction. During eupnic breathing, inspiratory activity is more concentrated in the rostal interspaces. When the scalenes are voluntarily inhibited, parasternal muscle activity increases. The external intercostals arise from the tubercles of the superior ribs and insert on the the inferior costal cartilage medially. Contraction of the external intercostals causes a pump handle, cranial elevation of the ribs about the dorsal spinal articulation. During eupnic breathing, the external intercostals are primarily active in the rostral interspaces posteriorly where they have greatest inspiratory mechanical advantage. They appear to be less active and involve fewer motor units than the parasternal muscles during inspiration (13). The levator costae arise from the transverse processes of the seventh cervical and 11 upper dorsal thoracic vertebrae and insert on the inferior rib caudally and laterally. The levator costae contribute to the pump handle and bucket handle motion of the ribs. Scalene Muscles
The scalene muscles (anterior, medial, and posterior) originate from the transverse processes of all the cervical vertebrae and insert on the superior surface of the first and second ribs. The scalenes elevate the first and second ribs during inspiration. A significant contribution to inspiration during normal breathing is suggested for the scalenes since there are electrically active during eupneic breathing. The scalenes
Respiratory Muscle Function
39
are innervated by branches of the fourth to seventh cervical nerves and so may be denervated in high cervical cord injury. Sternocleidomastoid Muscle
The sternocleidomastoid has two heads which arise from the manubrium of the sternum and the medial clavicle and insert on the ipsilateral mastoid process of the temporal bone. This muscle is inactive during eupneic breathing but can be recruited during forceful, large inspirations. The sternocleidomastoid muscle displaces the sternum cranially and enlarges the upper rib cage in an anterior-posterior direction (14). In normal humans, the sternocleidomastoid is recruited during hyperventilation, increased ventilatory load (i.e., increased airway resistance, decreased lung compliance etc.), or inspiration to total lung capacity. This muscle is innervated by cranial nerve 11and the second cervical nerve. Accordingly, sternocleidomastoid function is preserved in patients with high cervical cord injury. B. Muscles of Expiration
Intercostal Muscles
The interosseous, internal intercostal muscles (excludes parasternal intercostal muscles) produce a deflationary, pump handle motion of the ribs. During eupneic breathing, activity of the internal intercostals is confined to the caudal interspaces, where they have the greatest mechanical advantage. Abdominal Muscles
The abdominal muscles include the external and internal oblique, rectus abdominus and transversus abdominus. The abdominal muscles are innervated by the seventh to the 11th intercostal, iliohypogastric, and ilioinguinal nerves. The abdominal muscles are inactive during normal breathing in the supine position. However, they are recruited under conditions of increased ventilatory demand caused by exercise, hypercapnia or increased ventilatory loads and in assuming the upright posture. Their tonic activity in the upright position may improve the mechanical action of the diaphragm by minimizing diaphragm descent on assuming the upright posture and during inspiration. The transverse abdominus is usually recruited before the rectus abdominus or external oblique (15). When active, these muscles decrease abdominal AP and lateral diameter and abdominal compliance and increase intra-abdominal pressure (16). By virtue of their insertions on the ribs, they pull the lower ribs caudally and decrease rib cage volume and increase pleural pressure. Pleural pressure is also increased by displacing the diaphragm cranially. In part the deflationary action of the abdominal muscles on the lower rib cage is offset by the insertional forces of the diaphragm which is increased as the diaphragm is displaced cranially. The abdominal muscles contracting against a closed glottis create forces required for a normal cough. Impairment of abdominal muscle function by laparotomy or neuromuscular disease, therefore, impairs the clearance of airway secretions. Ab-
40
Kelsen
dominal muscle contraction is also necessary for phonation, micturition and parturition. Triangularis Sterni
The trianglularis sterni is a thin muscle located on the inner side of the anterior chest wall, deep to the sternum and parasternal muscles. Its fibers arise from the lower part of the posterior sternum and course superiorly and laterally to insert on the lower inner borders of ribs 3 through 7. It is innervated by the intercostal nerves. When active, it decreases rib cage volume by displacing the ribs caudally and the sternum cranially. The triangularis sterni, therefore, has a opposite effect to that of the parasternal intercostal muscles on the rib cage but may have an agonistic effect by increasing parasternal intercostal precontractile length (17). This muscle is not electrically active in normal humans in the supine position but is recruited during hyperventilation. III. Respiratory Muscle Contractile Properties Respiratory muscle force depends on fiber composition and fiber mass; the intensity of central nervous system motor outflow as reflected in the force-frequency relationship and pattern of motor unit recruitment; fiber length; velocity of fiber shortening; and fatiguability. A. Muscle Fiber Composition
The respiratory skeletal musculature represents a mix of slow and fast twitch fiber types (18,19). The precise mix varies considerably from muscle to muscle and even regionally, within a given muscle. Differences in muscle fiber type account, in a large part, for the considerable differences which exist between the several respiratory muscles in force generation, velocity of shortening and susceptibility to fatigue. Slow oxidative (type I) and fast oxidative (type IIa) fibers are highly fatigue resistant. In contrast, fast glycolytic fibers (type IIb) are highly susceptible to fatigue. Fast fibers have larger cross sectional and hence, generate greater force as well as shorten considerably faster than slow fibers. In addition, the size of fast motor units, i.e., the number of muscle fibers innervated by a single alpha motor neuron, is five to 20 times greater than the size of slow motor units (20). Accordingly, activation of fast motor units represents a ‘‘force reserve’’ which permits strenuous respiratory efforts but only for brief periods before fatigue ensues. Fiber composition is dynamic and changes throughout neonatal and adult life (21–23). The respiratory muscles of adults tend to have a higher percentage of slow fatigue resistant fibers than the same muscles in the newborn. The adult human diaphragm consists of approximately 50% slow oxidative fibers, 25% fast oxidative fibers, and 25% fast glycolytic fibers (24,25). However, considerable inter-individual differences in diaphragm muscle fiber composition contribute to important differences in muscle strength and endurance (26). Moreover, fiber cross-sectional area
Respiratory Muscle Function
41
is highly plastic and affected by activity, nutritional status, and hormonal milieu. For example, inspiratory resistive load training increase diaphragm fiber size and aerobic capacity (18). Conversely, chronic protein calorie undernutrition (27), cachexia secondary to uncontrolled infection and carcinoma (28,29), and chronic corticosteroid excess (30, 31) cause diaphragm fiber atrophy with greater effects on fast than slow twitch fibers. Muscle mass is the product of average muscle fiber diameter and the number of fibers present. Normative data for respiratory muscle mass is largely unavailable. However, it is clear that diaphragm mass varies considerably among individuals (29). Differences in diaphragm mass probably reflect differences in body habitus, hormonal and nutritional factors, and perhaps most importantly, differences in the level of muscle activity. For example, diaphragm thickness and weight are greater in men than women and greater in manual laborers than sedentary adults. B. Central Nervous System Output
Force-Frequency Relationship
Application of a single supramaximal threshold depolarizing stimulus (i.e., 1.2 to 1.5 times the voltage which generates a maximum compound action potential) to an axon innervating a respiratory muscle motor unit (or muscle sarcolemma) initiates the bell shaped tension wave form shown in Figure 3 (i.e., a twitch). The time from tension development to its peak (i.e., the contraction time) is generally shorter than the time from peak back to baseline (i.e., the relaxation time). In contrast to a twitch, the force-frequency curve is generated by applying a train of stimuli for approximately one to two seconds (Fig. 3). At stimulus frequen-
Figure 3 The twitch-tension wave form (left upper panel), the length-tension relationship (left lower panel), the force-frequency relationship (right upper panel), and the isotonic forcevelocity relationship (right lower panel). Responses of fatigued muscle are indicated by lower tracing in each panel.
42
Kelsen
cies in excess of 50 Hz, a fully fused tetanic contraction is developed and motor unit force output is maximum. For the diaphragm, axonal firing rates of 50 to 75 depolarizations/sec develop maximal force output. Accordingly, the force output of individual respiratory muscles can be increased by moving each motor unit up its force-frequency relationship toward the plateau. It is estimated that during eupneic breathing the firing rate of phrenic motor neurons is approximately 15/sec (32). During high levels of activation as during a cough or sneeze, phrenic firing rates may exceed 200/sec. The shape of the force-frequency relationship varies for slow and fast twitch fibers. Slow fibers that generate and dissipate tension more slowly achieve maximum force at lower stimulus frequencies than fast twitch muscle fibers. As a result, the axonal firing frequency required to fully activate a fast motor unit is greater than that required to maximally activate a slow twitch motor unit. In man, quasi-isometric contractions have been accomplished for the diaphragm by occluding the airway at end expiration while the cervical phrenic nerves are stimulated electrically using transcutaneous or percutaneous electrodes (33,34). In this method, a single supramaximal pulse of 0.1 msec is applied to the phrenic nerves bilaterally during breath holding at end expiration. The force output of the diaphragm is assessed from the transdiaphragmatic pressure (Pdi) (Fig. 4). Transdiaphragmatic pressure is measured as the difference in abdominal and esophageal pressure (Pdi ⫽ Pabd ⫺ [⫺Pes]). Since esophageal pressure is opposite in sign to abdominal pressure, Pdi during inspiration may be taken as the sum of the absolute values of Pabd and Pes. The evoked diaphragmatic muscle compound action potential is recorded from surface electrodes on the anterior rib cage at the sixth or seventh intercostal space in the mid clavicular line or endoesophageally to ensure that supramaximal conditions of current or voltage are achieved. The diaphragm may shorten considerably despite airway occlusion because of collapse of the rib cage. To counteract this effect the abdomen may be casted at functional residual capacity to prevent outward movement of the anterior abdominal wall and hence descent of the diaphragm. In the case of the sternomastoid muscle, the head and neck are immobilized in a rigid frame and the airway remains open. Motor Unit Recruitment
When the respiratory muscles are activated endogenously during volitional or reflexly driven contractions, motor unit recruitment follows a stereotypic hierarchy (20). During eupneic breathing, only motor units made up of slow twitch, fatigue resistant (i.e., type l) muscle fibers are activated. As efforts of greater magnitude are made as occurs during hypercapnea, hypoxia, bronchoconstriction, etc., populations of fast twitch, oxidative (i.e., type IIa) fibers are recruited followed ultimately by recruitment of fast twitch, glycolytic fibers (i.e., type IIb) fibers. As mentioned, the susceptibility to fatigue of the three fiber types demonstrates the following rank order: IIb⬎IIa⬎I (22). Accordingly, eupneic breathing is accomplished by highly fatigue-resistant type l fibers while strenuous efforts approaching maximum involve more easily fatiguable types IIa and IIb fibers.
Respiratory Muscle Function
43
Figure 4 Schematic representation of the experimental approach used to assess diaphragm strength and endurance in man. Transdiaphragmatic pressure (Pdi) is measured by catheters in the esophagus (Pes) and stomach (Pg) and displayed on an oscilloscope for visual feedback to the subject. Diaphragm EMG is recorded with surface electrode on the lower rib cage. Phrenic nerves may be stimulated in the neck transcutaneously. Constancy of lung volume and thoracoabdominal configuration is achieved by monitoring end expiratory transpulmonary pressure (Ptp) and by placing a cast around the abdomen and bottom one-fourth of the rib cage. To assess diaphragm endurance, subjects inspire against ventilatory loads of varying severity to produce target levels of Pdi.
The force output of a contracting skeletal muscle can be increased, therefore, by recruitment of inactive motor units. Since motor unit size is smallest for slow oxidative fibers, intermediate for fast oxidative fibers and greatest for fast glycolytic motor units, recruitment of progressively larger fast twitch motor units allows disproportionate increases in force to be generated. The rank order of motor unit recruitment likely accounts for the fact that the diaphragm contracts rhythmically, 24 hours a day for a lifetime and does not fatigue. In contrast, progressively more strenuous inspiratory efforts approaching the maximum may be required when ventilatory drive is high (e.g., severe hypoxia, acidosis, hypercapnia, etc.) or the mechanics of breathing are markedly deranged (as with pulmonary edema or asthma). However, such intense efforts are difficult to maintain for prolonged periods and predispose to muscle fatigue (see below).
44
Kelsen C. The Length-Tension Relationship
Active isometric force of the repiratory muscles is a function of the extent of actinmyosin contractile filament overlap as reflected in muscle fiber length (i.e., the active length-tension relationship). For any given motor unit firing rate, active tension increases progressively as fiber length is increased. However, at some muscle fiber length overlap of actin and myosin filaments is optimal and active tension is maximal L0. On the other hand, passive tension depends on muscle elasticity and increases progressively in curvilinear fashion as length increases. The total force output of a respiratory muscle at any length is the sum of the active and passive tension. In the body, respiratory muscle fiber length depends primarily upon lung volume, and to a lesser extent thoraco abdominal configuration (35,36). Progressive increases in lung volume shorten the inspiratory muscles and lengthen the expiratory muscles. At FRC, the diaphragm is close to L0 while the parasternal intercostals, sternomastoid, and scalene muscles are shorter than L0 (37). Increases in lung volume, therefore, decrease the mechanical advantage of the diaphragm but increase that of the parasternal and neck inspiratory muscles. In contrast, the expiratory muscles of the abdominal wall appear to be below L0 and approach L0 as lung volume increases. The fact that individual respiratory muscles ‘‘sit’’ at different positions on the length-tension curve at any given lung volume allows the aggregate pressure generating ability of the respiratory muscles to be well maintained over a wide range of lung volume. The effect of lung volume on the force output of the human inspiratory and expiratory muscles in aggregate is reflected in the maximal active pressure-volume diagram of the respiratory system (Fig. 5). To construct this relationship, subjects make maximal inspiratory or expiratory efforts against an occluded airway while muscle mechanical output is assesssed from the maximum static pressure generated at the mouth. However, the recoil pressure of the relaxed respiratory system contributes to airway pressure at all lung volumes except functional residual capacity (where it is zero). The pressure generated by the actively contracting muscles, Pmus, is calculated by subtracting recoil pressure from maximum static inspiratory and expiratory pressure. As can be seen, Pmus for the inspiratory muscles is greatest at lung volumes ranging from residual volume (RV) to FRC and progressively decreases thereafter. Pmus for the inspiratory muscles reaches minimum values (⬃30 cm H2O) at full lung inflation, i.e., total lung capacity (TLC). In fact, the lung volume at TLC is that lung volume at which Pmus is equal and opposite to respiratory system recoil pressure. In contrast, Pmus for the expiratory muscles is greatest at TLC and least at RV. In fact, RV is the lung volume at which expiratory Pmus is equal and opposite to respiratory system recoil. Note also that the expiratory muscles (e.g., ⬃250 cm H2O) are considerably stronger than the inspiratory muscles (e.g., ⬃150 cm H2O). The important nonrespiratory tasks performed by these muscles which require marked increases in intraabdominal pressure (e.g., defecation, micturition, parturition, and weight bearing). In normal subjects, Pmus generated by the inspiratory muscles even during strenuous
Respiratory Muscle Function
45
Figure 5 The active pressure-volume relationship of the respiratory system. Maximum static inspiratory (PImax) and expiratory (PEmax ) pressures are measured at the airway opening during a maximum voluntary effort. The pressure generated by the actively contracting muscles (Pmus) represents the difference between PImax or PEmax and respiratory system passive recoil pressure (Prs —represented by the solid line). Note that Pmus of the inspiratory muscles decreases with increasing lung volume while expiratory Pmus increases.
hyperventilation rarely exceeds 30 to 40 cm H2O. Therefore, both the inspiratory and expiratory muscles have a vast reserve of pressure over that required to maintain ventilation. This considerable reserve of the respiratory muscles is essential in patients with lung or chest wall diseases in whom the mechanics of breathing are markedly deranged. PImax is lower in women than men and in men PImax and Pdi decrease with aging (2,38) (Fig. 6).
Figure 6 The effect of aging on maximum static transdiaphragmatic pressure (Pdimax) in normal young and elderly men. Pdimax measured during the performance of an expulsive Mueller maneuver with visual feedback of the Pdi signal. Note that Pdimax is ⬃25% lower in the healthy elderly group. (From Ref. 2.)
46
Kelsen
It is apparent from the above that hyperinflation in the setting of obstructive lung disease represents a marked mechanical disadvantage to the inspiratory muscles but a mechanical advantage to the action of the expiratory muscles. Maximum static inspiratory pressure in subjects with COPD may be reduced to as little as one-third of the values obtained in age-matched normal adults (Fig. 7) (39). Changes in thoracoabdominal configuration achieved by changes in body posture also alter fiber length and configuration of the respiratory muscles at a given lung volume (35,36). For example, at a given lung volume, Pdi is greater when ab-
Figure 7 Maximum static inspiratory pressure (PImax) measured in stable outpatients with COPD and age-matched normal subjects. COPD subjects demonstrate significantly lower PImax than normals because of hyperinflation and muscle wasting. Hypercapnic COPD subjects (solid symbols) generated lower PImax than eucapnic subjects (open symbols). (From Ref. 39.)
Respiratory Muscle Function
47
dominal volume is decreased and rib cage volume is increased. Presumably, this chest wall configuration diminishes the radius curvature of the diaphragm (R) and results in greater pressure for the same tension (T) in accordance with the LaPlace relationship [i.e., Pdi ⫽ 2 T/R]. The supine posture, typical of bedridden, critically ill patients reduces abdominal volume and increases rib cage volume and, everything else being equal, augments the mechanical action of the diaphragm. Conversely, the flattened diaphragm in hyperinflated patients with severe COPD or asthma has a greater radius of curvature, and hence converts tension into pressure less effectively than when the curvature is normal. Of interest, severely ill patients with chronic obstructive lung disease, spontaneously adopt body postures which favorably affect the mechanical action of the inspiratory muscles. For example, patients with severe obstructive lung disease flex the trunk, compress the abdomen, and hyperextend the head. This posture improves the mechanical advantage of the diaphragm and neck inspiratory muscles (40). It is important to note, however, that chronic alterations in lung volume and thoraco-abdominal configuration induce adaptative changes in the length-tension characteristics of the diaphragm. For example, in experimental animals, chronic hyperinflation causes a leftward shift of the length-tension characteristic of the costal regimen of the diaphragm (Fig. 8) (41,42). In patients with chronic hyperinflation, this alteration could help to restore the mechanical advantage of the diaphragm toward normal (43,44). Length-tension adaptations, however, do not overcome the deleterious effects of diaphragm flattening which act through the LaPlace relationship. D. Force-Velocity Relationship
The respiratory muscles do not contract isometrically but rather shorten against a load. Application of loads, diminishes the velocity of shortening and converts the energy of crossbridge cycling into force (i.e., the isotonic force-velocity relationship) (Fig. 3). The force developed by contracting respiratory muscles is inversely related to the velocity of shortening. In vivo, the inspiratory muscles contract against a load (i.e., the inspiratory impedance) which increases throughout inspiration as the muscle shortens. Inspiratory impedance is a function of respiratory resistance and compliance. (The resistive load progressively decreases while the elastic load increases.) The analogue of the isotonic force-velocity relationship in intact man is the maximum inspiratory pressure-flow curve. This relationship is nearly linear rather than hyperbolic (Fig. 9) (45,46). An important consequence of the force-velocity relationship is that it provides an intrinsic muscle mechanism to augment force output when the load on the contracting respiratory muscles is increased. Derangements in the mechanical properties of the lungs and airways which increase inspiratory impedance reduce muscle shortening velocity and, hence, increase force generation. Another implication of the force-velocity relationship is that assessment of inspiratory muscle strength in patients must be performed when the airway is occluded so as to minimize muscle shortening. (Some degree of inspiratory muscle shortening occurs despite airway occlusion because of thoracic gas decompression and paradoxical movement of the abdomen and rib cage.)
48
Kelsen
Figure 8 Active (upper trace) and passive (lower trace) length-tension relationship of costal diaphragm of emphysematous (open circles) and normal hamsters (solid circles). The apex of the active length-tension curve represents L0. Note that in emphysematous animals, the LT curve is displaced toward shorter fiber lengths. This adaptive change allows the diaphragm to generate maximal tension (force) at shorter fiber lengths and helps preserve the contractile performance in the face of considerable hyperinflation. (From Ref. 41.)
E.
Fatiguability
Respiratory muscle fatigue has been defined as a loss in the capacity to develop force and/or shorten resulting from muscle fiber activity under load and which was reversible by rest (47). The important operational components of the definition of fatigue involve impaired mechanical output of the muscle and its reversibility with rest. In addition, fatigue-induced mechanical impairment of muscle function is viewed as developing when the muscle is highly active and generating appreciable levels of force. Recovery from fatigue is generally observed over a short time scale,
Respiratory Muscle Function
49
Figure 9 Pressure-flow relationship of the respiratory system.
e.g., minutes to hours. A commonly accepted classification of fatigue based on presumed sites of impaired function within the neuromuscular system is given in Table 1. In contrast to fatigue, respiratory muscle weakness has been defined as impairment in the capacity of a fully rested muscle to generate force. Muscle weakness is commonly caused by muscle fiber atrophy, metabolic derangement which impair the ability of crossbridges to generate force (e.g., acidosis or electrolyte abnormalities which affect intracellular calcium flux), or chronic reductions in muscle precontraction length which impose a mechanical disadvantage (e.g., hyperinflation of the thorax and its effects on the inspiratory muscles). Implied in the definition of weakness is the idea that alterations in muscle function are secondary to alterations in muscle structure or lung volume and hence induce changes which are more slowly reversible than fatigue, e.g., days to weeks. In the clinical setting, the distinction between muscle weakness and fatigue is difficult and not easily accomplished. Moreover, as will become apparent in the remainder of this chapter, a close association exists between respiratory muscle
Table 1
Classification of Respiratory Muscle Fatigue
Class Central Peripheral Transmission Contractile
Definition Decreases in phrenic motor output mediated by spinal or supraspinal mechanisms Fatigue occurring at the level of the muscle itself Failure of mechanisms involved in muscle excitation (i.e., highfrequency fatigue) Failure of mechanisms involved in excitation-contraction coupling or contractile protein function (i.e., low-frequency fatigue).
50
Kelsen
weakness and respiratory muscle fatigue. In fact, weak muscles are predisposed to fatigue (see below). The changes in muscle contractile properties produced when the respiratory muscles fatigue are shown in Figure 3 and have been studied extensively (33,48– 50). Fatigue prolongs contraction and relaxation time. Slowing of the tension wave form is thought to result from impaired calcium release from storage sites in the sarcoplasmic reticulum and in its rate of reuptake (51). Fatigue also depresses the force generated at a given frequency and displaces the isometric, length-tension relationship downward so that at a given fiber length, tension is diminished. Fatigue also diminishes the velocity of muscle fiber shortening against a given load. These changes indicate that fatigue not only diminishes the load bearing capacity of the respiratory muscles (i.e., maximum force output) but also slows the velocity of shortening at a given force or load. Depending on the nature of the fatigue inducing regimen, depression of force output can occur at primarily subtetanizing frequencies (e.g., ⬍15 to 20 Hz), a condition called low-frequency fatigue, or at frequencies ⬎50 Hz, a condition called highfrequency fatigue (Table 1) (33). The biochemical and biophysical processes that underlie low-frequency and high-frequency fatigue differ. Muscle force responses to tetanizing frequencies of stimulation (i.e., ⬎50 Hz) are primarily determined by the processes of neuromuscular transmission (52). High-frequency fatigue reflects impairment in muscle excitation at the level of neurotransmitter release at the neuromuscular junction, sarcolemma propagation of an action potential, or charge transfer within the T tubular system. At subtetanizing frequencies (i.e., generally ⬍15 to 20 Hz) muscle mechanical output is primarily determined by the processes of excitation-contraction coupling (e.g., calcium release from the sarcoplasmic reticulum, calcium-troponin interactions). Low-frequency fatigue appears to reflect impairments in the dihydropyridine sensitive charge sensor in the T tubular system, the ryanodine sensitive calcium channel in the sarcoplasmic reticulum, or the binding affinity of activator calcium to tropomyosin. Low-frequency fatigue may be caused in part by oxygen free radical– induced injury (53,54). Low- and high-frequency fatigue reflect impairments occurring at the level of the muscle and hence have been termed peripheral fatigue. Of interest, recovery from high-frequency fatigue is more rapid (i.e., minutes) than recovery from lowfrequency fatigue (i.e., hours) (55). Moreover, the two forms of fatigue have different physiological consequences. High-frequency fatigue impairs muscle force output under conditions in which the muscle is maximally driven by the CNS, i.e., when muscle strength is being evaluated. Low-frequency fatigue, on the other hand, impairs force generation during eupnic breathing when phrenic motor unit discharge rates are typically ⬃15 Hz (32). Low-frequency fatigue may preferentially affect the tension developed at shorter fiber lengths when the activation process in general appears to be submaximal. Slowing of the twitch contraction wave form in the fatigued muscle, especially
Respiratory Muscle Function
51
the prolonged rate of muscle relaxation, may displace the force-frequency curve leftward. That is, the stimulation frequency required to achieve a fully fused contraction may be lower following fatigue if relaxation time is markedly prolonged. Changes in the rate of relaxation of fatigued muscle seem to be sensed by the CNS and elicit a slowing in neuronal firing rates in limb muscles during maximal isometric voluntary contractions. Fatigue during performance of ventilatory tasks requiring intense efforts may also be associated with a reduction in central motor output and failure of the CNS to fully activate the respiratory muscles (56,57). That is, conditions in which the mechanics of breathing are markedly abnormal may be associated with a reduction in diaphragm EMG or phrenic neural activity. This failure of CNS mechanisms to fully activate the muscle has been termed ‘‘central fatigue.’’ The mechanism(s) underlying central fatigue are poorly understood. It is not clear whether central fatigue represents a behavioral response elicited by the unpleasant sensations present during ventilatory loading (see dyspnea below) or is mediated reflexly. Of interest, afferent information arising in diaphragm Golgi tendon organs and type III and type IV endings and spindle organs in the intercostal muscles reflexly modify the intensity and timing of phrenic motor activity in deeply anesthetized animals (58). Central fatigue may be mediated by changes in brain endorphin levels it can be partially reversed by intravenous administration of the opiate antagonist naloxone (57). Fatigue also alters the power spectral content of the raw electromyogram of the respiratory muscles (59,60). The EMG power spectral content can be analyzed by fast Fourier transform to generate the curvilinear relationship shown in Figure 10. In the fresh diaphragm, the power (or voltage) contained in the EMG wave form reaches a maximum between approximately 85 to 105 Hz, and thereafter declines. Maximum power in the electromyogram of the diaphragm, parasternal intercostal, and sternocleidomastoid occurs at somewhat different frequencies, however. Fatigue inducing contractions cause a leftward shift of the power spectral density of respiratory muscle such that more of the power in the electromyogram is contained in a lower frequency domain. Of note, the power spectral density of the contracting diaphragm changes almost immediately in the setting of fatiguing contractions and considerably before the mechanical output of the muscle fails (61). The EMG power spectrum has been taken as a useful indicator of the presence of muscle fatigue because it is minimally invasive and requires no cooperation from the subject. Accordingly, the EMG power spectrum has proven to be a useful tool to study the pathophysiological mechanisms of human respiratory muscle fatigue. The physiologic basis for shifts in the power spectral density of the muscle is not well understood (60). Possibilities include: slowing in action potential conduction velocity along the sarcolemma membrane; reduction in the activity of upper and/or lower respiratory motor neurons with consequent reductions in motor unit firing rate; and greater synchronization of firing of activated motor units. There is strong evidence that the EMG power spectrum depends primarily on the firing pattern of the bulbospinal respiratory motor neurons in the medulla which project to the spinal phrenic motor neuron pool. In fact, the power spectrum may change when central respiratory motor output is heightened even in the absence of fatigue (e.g.,
Figure 10 Schematic representation of the power spectral density of a respiratory muscle electromyogram determined by fast Fourier transform. Note the concave appearance of the relationship. Note that fatigue decreases and increases power in the high- and low-frequency domains, respectively, thereby shifting the relationship toward the left.
Figure 11 Force-frequency relationship of the human diaphragm showing rate of recovery from high and low frequency fatigue. Data obtained in a single subject before and after a period of inspiratory resistive loading to Tlim (time to fatigue). Note the presence of both highand low-frequency fatigue immediately postloading. Note also that high-frequency fatigue disappears within 10 to 14 min but low-frequency fatigue persists for the duration of the study. (From Ref. 33.)
Respiratory Muscle Function
53
hypercapnia in the absence of load) (62). Moreover, the power spectrum of the diaphragm may increase in response to centrally acting drugs (e.g., the endogenous opiate antagonist naloxone) even when the muscle is fatigued by severe inspiratory ventilatory loads (57). In humans, studies examining the pathogenesis of respiratory muscle fatigue have largely been performed in a laboratory setting on highly motivated subjects performing intense volitional contractions (61,63). Experiments have involved severe ventilatory loads to the point of exhaustion and have focused on the diaphragm because of its importance in respiration and its accessibility to measurement. The endpoint of these fatigue trials has been taken as the point at which target Pdi could not be maintained (Figs. 11–13) exercise, and in mechanically ventilated patients with severe cardiopulmonary disease (64–67). Laboratory studies have demonstrated that susceptibility of the diaphragm to fatigue depends on the pattern of muscle use, muscle strength, and muscle blood flow. However, the most important determinant of fatigue is the intensity and timing of diaphragm contractile activity. The fatiguability of the diaphragm can be quantitated in terms of the ratio between peak Pdi generated during contraction to the maximum possible Pdi(Pdi /Pdimax). Figure 14 demonstrates the effect of increasing Pdi /
Figure 12 Effect of increasing Pdi /Pdimax, i.e., the ratio of peak inspiratory Pdi during resistance breathing over maximum static Pdi (ordinate) on the time of onset of mechanical failure of the diaphragm, tlim (abscissa). Data from three normal subjects (shown as separate symbols). Note that progressive increases in Pdi /Pdimax are associated with more rapid onset of diaphragm fatigue. Note also the curvilinear nature of the relationship with apparent asymptote of 40% to 50% Pdi /Pdimax which represents a fatigue threshold. (From Ref. 63.)
54
Kelsen
Figure 13 Polygraph record of a fatigue run at 75% Pdimax and a Ti /Ttot of 60% produced during inspiratory resistive ventilatory loading. Total integrated diaphragm EMG signal in bandwidth of 20 to 1000 Hz; high integrated EMG signal in bandwidth 150 to 350 Hz; low integrated EMG signal in the bandwidth 20 to 46.7 Hz. Time markers on the x axis are 1 sec. Tlim indicates the time that the breathing effort could be sustained. Note that the EMG power in the high- and low-frequency domain change on the first several breaths well before Tlim occurs. (From Ref. 61.)
Pdimax on the time to fatigue (Tlim). With very high values of Pdi /Pdimax, time to fatigue is short, but increases rapidly as Pdi /Pdimax decreases. Since the diaphragm contracts rhythmically, its activity is reflected not only in the peak inspiratory Pdi, but the duration of inspiration (Ti) and can be quantitated as the area under a curve of tension versus time. This parameter has been termed the tension-time index (TTI) and is the product of peak Pdi /Pdimax multiplied by Ti over the duration of the total respiratory cycle (i.e., Ti /Ttot). Mathematically, the TTI ⫽ Pdi /Pdimax ⫻ Ti /Ttot. (The Ti /Ttot ratio has been termed the duty cycle of breathing and represents the portion of the respiratory cycle during which the diaphragm is active.) When the diaphragm TTI exceeds approximately 15% to 20% of maximum, fatigue occurs (Figs. 14 and 15) (61,67). Thus, the fatigue threshold can be reached by increasing Pdi or Ti /Ttot or decreasing Pdimax. Increases in Pdi occur when minute ventilation increases (i. e., inspiratory airflow or the tidal volume increase); when airway resistance is increased by bronchoconstriction or retained secretions; or when lung or chest wall compliance is decreased by lung edema, atelectasis, or pneumonia. In addition, tachypnea decreases the duration of expiration (Te) out of proportion to the duration of inspiration (Ti) thereby increasing the Ti /Ttot ratio and the tension-time index. Diaphragm contractions ⬎ ⬃50% to 60% of maximum predispose to fatigue since the Ti /Ttot usually ranges between 33 to 40%.
Respiratory Muscle Function
55
Figure 14 Polygraph record effect of the breathing duty cycle, TiTtot, on the time of mechanical failure of the diaphragm, Tlim. Subject is generating the same level of peak Pdi (75%) but two different values of Ti /Ttot. Note that the continuous effort, a Ti /Ttot of 100%, is associated with more rapid onset of diaphragm fatigue. (From Ref. 61.)
Figure 15 Relationship of the time of mechanical failure of the diaphragm, Tlim, and TTdi, the diaphragm pressure-time index, i.e., the product of Pdi /Pdimax ⫻ Ti /Ttot. Data obtained in normal subjects during strenuous volitional contractions performed in the setting of inspiratory resistive ventilatory loading. The two scales are logarithmic. Note that ⬎ ⬃15% TTdi, Tlim decreases progressively with increasing TTdi. These data indicate that the effects of the magnitude and timing of diaphragm contractions on diaphragm endurance collapse into the primary factor, the TTdi. (From Ref. 61.)
56
Kelsen
Table 2 Clinical Conditions Predisposing to Respiratory Muscle Fatigue Condition Abnormal lung or chest wall mechanics
Increased ventilatory drive
Low cardiac output state Metabolic abnormalities Nutritional depletion Aging
Mechanism Hyperinflation, increased airway resistance, decreased compliance (e.g., COPD, asthma, interstitial pulmonary fibrosis, kyphoscoliosis, ARDS) Hypoxemia, hypercapnia, fever, acidosis, lung injury inflammation (e.g., sepsis, ARDS, pneumonia, pulmonary embolus, post thoractomy) Cardiogenic, hypovolemic or septic shock, congestive heart failure Hypercapnia, metabolic acidosis, hypoxemia, electrolyte disturbances Chronic protein calorie malnutrition, hypoglycemia, starvation Decreased muscle strength
Alternatively, the TTI can be increased by factors which impair diaphragm strength (i.e., decrease Pdimax ). Decreases in Pdimax increase the TTI for a given set of lung mechanical properties and minute ventilation. Reductions in Pdimax occur with aging hyperinflation, muscle atrophy (e.g., prolonged undernutrition or cachexia), or derangements in blood chemistry (e.g., hypercapnia, profound hypoxia, hypocalcemia, hypokalemia, hypomagnesemia). The clinical conditions which predispose to inspiratory muscle fatigue are listed in Table 2. The principles underlying the therapy of this condition are listed in Table 3. An overview of therapeutic approaches to the treatment of respiratory muscle fatigue is presented in Table 4.
Table 3 Principles of Therapy of Respiratory Muscle Fatigue Decrease inspiratory swings in transdiaphragmatic pressure (Pdi) Improve the mechanics of breathing; i.e., decrease airway resistance, improve thoracic compliance and static lung volume Decrease ventilatory drive; i.e., relieve hypoxemia, hypercapnia, metabolic acidosis, fever, pulmonary congestion/inflammation, ARDS Increase Pdimax Correct hyperinflation Correct muscle atrophy induced by protein calorie deficiency Correct electrolyte and blood gas abnormalities (i.e., hypoxemia, hypercapnia, hyposphatemia, hypokalemia, hypocalcemia, hypomagnesemia) Optimize muscle blood flow and substrate availability Correct low cardiac output state (e.g., cardiogenic shock, hypovolemic shock) Correct hypoxemia, anemia, hypoglycemia
Respiratory Muscle Function
57
IV. Respiratory Muscle Blood Flow The long-term maintenance of respiratory muscle function depends on the balance between the rate which ATP supplies are generated and broken down. Removal of toxic substances which impair muscle metabolism and reduce cell pH (e.g., hydrogen ions, lactate, phosphate, etc.) must also be accomplished continuously (68). Respiratory muscle blood flow is the major mechanism by which these processes are maintained in equilibrium and fatigue prevented. Impairments in respiratory muscle blood flow as occurs in the setting of hypovolemic or endotoxic shock or cardiac dysfunction lead to respiratory muscle fatigue and hypercapnic respiratory failure (69–72). In turn, respiratory muscle blood flow, like blood flow in other skeletal muscles, depends on neural, humoral, mechanical (intramuscular pressure), and circulatory factors (e.g., arterial profusion pressure, blood volume, and cardiac output). A. Anatomy
Most information on respiratory muscle blood flow has been accumulated from studies on the diaphragmatic vascular bed since this is the largest and functionally most important of the respiratory muscles. The diaphragm circulation has several sources of inflow and extensive collateralization from the intercostal, ipsolateral inferior phrenic and internal mammary arteries (73) (Fig. 16). In the human diaphragm, these vessels anastomose head-to-head to form costophrenic arcades. The crural and sternal regions and most of the costal regions are likely perfused by the inferior phrenic arteries whereas the peripheral costal areas adjacent to the ribs are supplied by the costal arteries while the anterior sternal region of the costal diaphragm is perfused by the internal mammary arteries. The venous drainage exhibits a similar configuration. Most of the venous drainage of the diaphragm is routed through the inferior phrenic veins which anastomose with the inferior vena cava immediately distal to the hepatic veins. The high degree of collateral flow through these several arterial inputs allows diaphragm contractile activity to be unaffected by ligation of the inferior phrenic arteries even in the face of highly intense contractions. In contrast to the gross anatomy of the arterial and venous supply, the microcirculatory anatomy of the diaphragm resembles that of other skeletal muscles. The
Table 4 Fatigue
Overview of Therapeutic Approaches to the Treatment of Respiratory Muscle
Well accepted Decrease pressure-time index Optimize muscle blood flow Training
Experimental Vasoactive drugs (e.g., dopamine) Antioxidants (e.g., glutathione, vitamin E, n-acetylcysteine) Muscle ionotropic agents (e.g., digitalis, methylxanthines, beta-adrenergic agonists)
58
Kelsen
Figure 16 Anatomy of the arterial supply of the dog diaphragm. (From Ref. 73.)
branching pattern of capillaries and arterioles in the diaphragm is similar to that of the intercostal and triceps muscles. Moreover, the distribution and configuration of capillaries is similar in the costal and crural regions. B. Mechanical Factors
The level of respiratory muscle contractile activity is the most important determinant of respiratory muscle blood flow. Respiratory muscle blood flow increases with increases in minute ventilation achieved by either physical exertion, hypercapnia, or hypoxia. Nonetheless, the largest increases in diaphragm blood flow occur during inspiratory resistive loaded breathing or phrenic nerve pacing, with values approximating 300 mL/min/100 g tissue. Cardiac muscle is the only organ with higher blood flow (approximately 600 mL/min 100 g tissue). It seems likely that the substantial increase in respiratory muscle blood flow in response to heightened muscle metabolic demand is achieved by release of endothelium-derived relaxing factor which has been identified pharmacologically as nitric oxide (74,75). For example, infusions of nitric oxide synthase inhibitors into the phrenic artery results in dosedependent increases in phrenic artery resistance during basal and enhanced activity of the muscle. It has been estimated that nitric oxide release accounts for 25% to 41% of the active hyperemic response of the canine diaphragm (74). Other known
Respiratory Muscle Function
59
mediators of exercise-induced hyperemia (e.g., adenosine, ATP, lactate, inorganic phosphate and potassium) may also play a role (76). Although increasing contractile activity increases muscle blood flow, sufficiently intense contractions can actually interrupt blood flow (Fig. 17) (77,78). The effect of contraction on diaphragm blood flow is achieved by increases in intramuscular pressure compressing the intramuscular blood vessels. Diaphragm blood flow in the dog is completely abolished when Pdi is equal to or greater than 80% of maximum. In fact, contractions above 30% to 40% of Pdimax impede blood flow and blood flow largely occurs during the period of muscle relaxation (i.e., expiration). Progressive reductions in the period of muscle relaxation produced by increases in Ti /Ttot, above this level of Pdi /Pdimax, therefore, further compromise blood flow. Accordingly, diaphragm blood flow is a function of the tension-time index. In this regard, diaphragmatic perfusion, therefore, is similar to that of perfusion through the myocardium. Diaphragmatic blood flow is reduced or interrupted during inspiration (systole), and is reestablished during expiration (diastole). The relationship between tension-time index and blood flow in the dog diaphragm is shown in Figures 17 and 18 (77,78). Blood flow increases as TTI increases to ⬃20%. At TTI above 20%, diaphragm blood flow falls, however. Therefore, increases in muscle contractile activity up to a TTI of ⬃20% are associated with increases in muscle energy supply. Contractions above TTI of 20%, redispose to
Figure 17 Effect of a single sustained contraction (30 sec) on diaphragm muscle blood flow in the anesthetized dog. Blood flow (Qdi) to the perfused costal diaphragm muscle strip preparation was measured by collecting the phrenic venous effluent. Muscle contraction was induced by electrical stimulation of the phrenic nerve. Contraction period is followed by 4 min of rest. Open squares: tension ⫽ 10% maximum; closed squares: tension ⫽ 80% of maximum. Note that 80% contraction mechanically impedes blood flow during the period of contraction and elicits a postcontraction hyperemia lasting several minutes. (From Ref. 78.)
60
Kelsen
Figure 18 The relationship of diaphragm blood flow to diaphragm contractile activity as reflected in the tension time index of the electrically stimulated, rhythmically contracting dog diaphragm. Same preparation as in Figure 16. Note the curvilinear relationship of blood flow and contractile activity during 30 sec of contraction. Closed circles: Ti /Ttot of 100%; open circles: tension 100% of maximum. Blood flow reaches a maximum at a tension time index of ⬃20% of maximum and thereafter falls progressively with increasing activity. Note, however, that above the critical tension time index of 20%, duty cycle of 100% produces greater reductions in blood flow than tension 100%. These data indicate that the level of diaphragm activity reflected in the TTI determines its blood flow and that the pattern of contractions has important effects. (From Ref. 78.)
fatigue by decreasing blood supply while at the same time, increasing muscle energy consumption. The pattern of pleural and abdominal pressure changes also influences diaphragm blood flow at a given TTI. High positive abdominal pressures tend to decrease diaphragm blood flow presumably by reducing venous return to the right heart or compressing the inferior phrenic vessels. Moreover, increases in diaphragm length beyond the optimum for force development decrease muscle blood flow at rest and during intermittent contractions. This effect is mediated by passive, lengthrelated tension with resultant increases in intramuscular pressure which apply stress along the longitudinal axis of intramuscular blood vessels. Hyperinflation may also decrease diaphragmatic blood. Hyperinflation may affect diaphragm blood flow indirectly by increasing intra-abdominal pressure and directly by increasing downstream vascular pressure by increasing intra-thoracic pressure. For example, in the anesthetized dog, hyperinflation produced by intrinsic PEEP reduces diaphragm blood flow at a given TTI (79). C. Arterial Pressure
A salient feature of diaphragmatic blood flow is its ability to autoregulate in response to changes in arterial pressure, a feature of blood flow regulation in many organs
Respiratory Muscle Function
61
(80). For example, in the dog, blood flow appears to be largely unchanged over a range of mean arterial pressure from ⬃70 to 120 mm Hg (Fig. 19). Below this range, diaphragm blood flow decreases in proportion to reductions in arterial pressure. Therefore, the dog diaphragm compensates effectively for sudden changes in arterial pressure or cardiac output over a modest range. Assuming that a similar operating range applies to the human diaphragm, reduction in mean arterial pressure to less than ⬃60 mm Hg will reduce diaphragm blood flow and predispose to fatigue. Autoregulation of blood flow appears to be an intrinsic property of the vascular smooth muscle. Vascular tone is modulated by changes in transmural pressure and perhaps by changes in flow or shear forces applied to the endothelium. Nitric oxide release likely plays a role in the autoregulation of diaphragm blood flow in response to changes in arterial blood pressure. The nitric oxide effects may be accomplished by antagonizing myogenic vasoconstriction, especially at high perfusion pressures. A consequence of the shape of the arterial pressure–diaphragm blood flow relationship is that patients with systemic arterial hypotension likely experience a reduction in diaphragm blood flow. Unfortunately, hypotension and sepsis also increase ventilatory demand, thus increasing the TTI of the diaphragm and its meta-
Figure 19 Effect of changes in arterial blood pressure on diaphragm blood flow in the dog. Note that blood flow is relatively constant over a wide range of blood pressure (autoregulation). However, below a critical level, of hypotension, blood flow falls. (From Ref. 80.)
62
Kelsen
bolic activity. Sepsis also impedes oxygen extraction and reduces the arteriovenous oxygen content difference. In animal models, sepsis increases lactate production by the diaphragm. Hypotension and sepsis, therefore, are likely to stress the relationship between diaphragm metabolic demand and the ability of the diaphragm circulation to deliver vital substrates. The development of respiratory failure in the hypotensive or septic patient may be a consequence of a reduction in diaphragm blood flow or impaired oxygen uptake. D. Humoral Factors
Hypoxia and hypercapnia exert strong effects on diaphragm blood flow. These effects are largely indirect, however, as a result of increases ventilation (i.e., increases in TTdi), and effects on blood pressure and arterial acid base status. Assessing the direct effects of these humoral factors on is complicated by the above. However, it seems likely that moderate to severe hypoxemia (i.e., phrenic venous PO2 of ⬍25 mm Hg) cause vasodilation, but the magnitude of the response varies according to vessel size (81). Small arterioles having a baseline diameter of 40 µm or less dilate more than larger vessels. In experiments in which phrenic arterial PCO 2 has been varied in the absence of changes in systemic PCO 2 using an isolated, in situ diaphragm, arterial PCO 2 caused phrenic arterial dilatation only when phrenic venous pCO 2 exceeded 80 mm Hg (76). Moreover, hypoxemia and hypercapnia interact multiplicatively in producing phrenic vasodilation. These experiments indicate that both hypoxia and hypercapnia affect the diaphragm vascular bed directly but only when rather severe disturbances are present.
References 1. 2. 3. 4. 5. 6. 7. 8. 9.
Leith DE, Bradley M. Ventilatory muscle strength and endurance training. J Appl Physiol 1976; 41(4):508–516. Tolep K, Higgins N, Muza S, et al. Comparison of diaphragm strength between healthy adult elderly and young men. Am J Crit Care Med 1995; 152:677–682. Aubier M, Murciano D, Lecpocgioc U, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985; 313:420–424. Juan DA, Calverley P, Talamo C, et al. Effect of carbon dioxide on diaphragmatic function in human beings. N Engl J Med 1984; 310:874–879. Macklem PT, DeTroyer A. A model of inspiratory muscle mechanics. J Appl Physiol 1983; 55(2):547–557. De Troyer A, Sampson M, Sigrist S, et al. The diaphragm: two muscles. Science 1981; 213:237–238. Urmey WF, De Troyer A, Kelley KB, et al. Pleural pressure increases during inspiration in the zone of apposition of diaphragm to rib cage. J Appl Physiol 1988; 65(5):2207–2212. Mortola JP, Sant’ambrogio G. Motion of the rib cage and the abdomen in tetraplegic patients. Clin Sci Mol Med 1978; 54:25–32. Mead J, Banzett RB, Lehr J, et al. Effect of posture on upper and lower rib cage motion and tidal volume during diaphragm pacing. Am Rev Respir Dis 1984; 130:320–321.
Respiratory Muscle Function 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
63
Loring SH, Mead J. Action of the diaphragm on the rib cage inferred from a force-balance analysis. J Appl Physiol 1982; 53(3):756–760. Loring SH, Mead J, Griscom NT. Dependence of diaphragmatic length on lung volume and thoracoabdominal configuration. J Appl Physiol 1985; 59(6):1961–1970. Druz WS, Sharp JT. Activity of respiratory muscles in upright and recumbent humans. J Appl Physiol 1981; 51(6):1552–1561. De Troyer A. Inspiratory elevation of the ribs in the dog: primary role of the parasternals. J Appl Physiol 1991; 70(4):1447–1455. Danon J, Druz WS, Goldberg NB, et al. Function of the isolated paced diaphragm and the cervical accessory muscles in C1 quadriplegics. Am Rev Respir Dis 1979; 111:909–919. De Troyer A, Estenne M, Ninane V, et al. Tranversus abdominis muscle function in humans. J Appl Physiol 1990; 68(3):1010–1016. Mier A, Brophy C, Estenne M, et al. Action of abdominal muscles on rib cage in humans. J Appl Physiol 1985; 58(5):1438–1443. De Troyer A, Ninane V, Gilmartin JJ, et al. Triangularis sterni muscle use in supine humans. J Appl Physiol 1987; 62(3):919–925. Akabas SR, Bazzy AR, DiMaurio S, et al. Metabolic and functional adaptation of the diaphragm to training with resistive loads. J Appl Physiol 1989; 66(2):529–535. Kelsen SG, Bao S, Thomas AJ, et al. Structure of parasternal intercostal muscles in the adult hamster: topographic effects. J Appl Physiol 1993; 75(3):1150–1154. Fournier M, Sieck GC. Mechanical properties of motor units in the cat diaphragm. J Neurophysiol 1988; 59(3):1055–1065. Maxwell LC, McCarter JM, Kuehl TJ, et al. Development of histochemical and functional properties of baboon respiratory muscles. J Appl Physiol 1983; 54(2):551–561. Sieck GC, Fournier M, Blanco CE. Diaphragm muscle fatigue resistance during postnatal development. J Appl Physiol 1991; 71(2):458–464. Kelly AM, Rosser BWC, Hoffman R, et al. Metabolic and contractile protein expression in developing rat diaphragm muscle. J Neurosci 1991; 11(5):1231–1242. Lieberman DA, Faulkner JA, Craig AB, et al. Performance and histochemical composition of guinea pig and human diaphragm. J Appl Physiol 1973; 34(2):233–237. Keens TG, Bryan AC, Levison H, et al. Developmental pattern of muscle fiber types in human ventilatory muscles. J Appl Physiol 1978; 44(6):909–913. Laporta D, Grassino A. Assessment of transdiaphragmatic pressure in humans. J Appl Physiol 1985; 58(5):1469–1476. Kelsen SG, Ference M, Kapoor S. Effects of prolonged undernutrition on structure and function of the diaphragm. J Appl Physiol 1985; 58(4):1354–1359. Arora NS, Rochester DF. Respiratory muscle strength and maximal voluntary ventilation in undernourished patients. Am Rev Respir Dis 1982; 126:5–8. Arora NS, Rochester DF. Effect of body weight and muscularity on human diaphragm muscle mass, thickness, and area. J Appl Physiol 1982; 52(1):64–70. Dekhuijzen PNR, Gayan-Ramirez G, Bisschop A, et al. Corticosteroid treatment and nutritional deprivation cause a different pattern of atrophy in rat diaphragm. J Appl Physiol 1995; 78(2):629–637. Ferguson GT, Irvin CG, Cherniack RM. Effect of corticosteroids on respiratory muscle histopathology. Am Rev Respir Dis 1990; 142:1047–1052. Iscoe S, Dankoff J, Migicovsky R, et al. Recruitment and discharge frequency of phrenic motoneurones during inspiration. Respir Physiol 1976; 26:113–128. Aubier M, Farkas A, DeTroyer RM, et al. Detection of diaphragmatic fatigue in man by phrenic stimulation. J Appl Physiol 1981; 50(3):538–544. Bellemare F, Bigland-Ritchie B. Assessment of human diaphragm strength and activation using phrenic nerve stimulation. Respir Physiol 1984; 58:263–277. Grassino A, Goldman MD, Mead J, et al. Mechanics of the human diaphragm during voluntary contraction: statics. J Appl Physiol 1978; 44(6):829–839. Hubmayr RD, Litchy WJ, Gay PC, et al. Transdiaphragmatic twitch pressure. Am Rev Respir Dis 1989; 193: 547–652. Farkas GA, Decramer M, Rochester DF, et al. Contractile properties of intercostal muscles and their functional significance. J Appl Physiol 1985; 59(2):528–535.
64
Kelsen
38.
Black LF, Hyatt R. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1969; 99:696–702. Sharp JT, van Lith P, Nuchprayoon C, et al. The thorax in chronic obstructive lung disease. Am J Med 1968; 44:39–46. Druz WS, Sharp JT. Electrical and mechanical activity of the diaphragm accompaning body position in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 125: 275–280. Supinski GS, Kelsen SC. Effect of elastase-induced emphysema on the force-generating ability of the diaphragm. J Clin Invest 1982; 70:978–988. Farkas GA, Roussos C. Adaptability of the hamster diaphragm to exercise and/or emphysema. J Appl Physiol 1982; 53(5):1263–1272. Oliven A, Supinski GS, Kelsen SG. Functional adaptation of diaphragm to chronic hyperinflation in emphysematous hamsters. J Appl Physiol 1986; 60(1):225–231. Similowski T, Yan S, Gauthier AP. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med 1991; 325:917–923. Agostoni E, Fenn WO. Velocity of muscle shortening as a limiting factor in respiratory air flow. J Appl Physiol 1960; 15(3):349–353. McCool FD, McCann DR, Leith DE, et al. Pressure-flow effects on endurance of inspiratory muscles. J Appl Physiol 1986; 60(1):299–303. Respiratory Muscle Fatigue Workshop Group: Respiratory muscle fatigue. Am Rev Respir Dis 1990; 142:474–480. Kelsen SG, Nochomovitz ML. Fatigue of the mamalian diaphragm in vitro. J Appl Physiol 1982; 53(2):440–447. Aubier M, Murciano D, Lecocguic Y, et al. Bilateral phrenic stimulation: a simple technique to assess diaphragmatic fatigue in humans. J Appl Physiol 1985; 58(1):58–64. Road J, Vahi R, Rio PD, Grassino A. In vivo contractile properties of fatigued diaphragm. J Appl Physiol 1987; 63(2):471–478. Fitts RH. Cellular mechanisms of muscle fatigue. Physiol Rev 1994; 74(1):49–74. Metzger JM, Fitts RH, et al. Fatigue from high- and low-frequency muscle stimulation: role of sarcolemma action potentials. Exp Neurol 1986; 93:320–333. Nashawati E, Dimarco A, Supinski G. Effects produced by infusion of a free radical generating solution into the diaphragm. Am Rev Respir Dis 1993; 147:60–65. Anzueto A, Supinski GS, Levine SM, et al. Mechanisms of disease: are oxygen derived free radicals involved in diaphragmatic dysfunction? Am J Respir Crit Care Med 1994; 149: 1048–1052. Laghi F, D’Alfonso N, Tobin MJ. Pattern of recovery from diaphragmatic fatigue over 24 hours. J Appl Physiol 1995; 79(2):539–546. Bellemare F, Bigland-Ritchie B. Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation. J Appl Physiol 1987; 62(3):1307–1316. Petrozzino JJ, Scardella AT, Li JKJ. Effect of naloxone on spectral shifts of the diaphragm EMG during inspiratory loading. J Appl Physiol 1990; 68(4):1376–1385. Frazier DT, Revelette WR. Role of phrenic nerve afferents in the control of breathing. J Appl Physiol 1991; 70(2):491–496. Bigland-Ritchie B, Donovan EF, Roussos CS. Conduction velocity and EMG power spectrum changes in fatigue of sustained maximal efforts. J Appl Physiol 1981; 51(5):1300– 1305. Ha¨gg GM. Interpretation of EMG spectral alterations at sustained contraction. J Appl Physiol 1992; 73(4):1211–1217. Bellemare F, Grassino A. Evaluation of human diaphragm fatigue. J Appl Physiol 1982; 53(5):1196–1206. Sieck GC, Mazer A, Belman MJ. Changes in diaphragmatic EMG spectra during hyperpneic loads. Respir Physiol 1985; 61:137–152. Roussos CS, Macklem PT. Diaphragmatic fatigue in man. J Appl Physiol 1977; 43(2):189– 197. Murciano D, Boczkowski J, Lecocguic Y, et al. Tracheal occlusion pressure: a simple index to monitor respiratory muscle fatigue during acute respiratory failure in patients with chronic obstructive pulmonary disease. Ann Intern Med 1988; 108:800–805.
39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.
Respiratory Muscle Function 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81.
65
Johnson BD, Babcock MA, Suman OE. Exercise-induced diaphragmatic fatigue in healthy humans. J Physiol 1993; 460:385–405. Mador MJ, Magalang UJ, Rodis A, et al. Diaphragmatic fatigue after exercise in healthy human subjects. Am Rev Respir Dis 1993; 148:1571–1575. Bellemare F, Grassino A. Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. J Appl Physiol 1983; 55(1):8–15. Ward ME, Magder SA, Hussain SNA. Oxygen delivery independent effect of blood flow on diaphragm fatigue. Am Rev Respir Dis 1992; 145:1058–1063. Aubier M, Trippenbach T, Roussos C. Respiratory muscle fatigue during cardiogenic shock. J Appl Physiol 1981; 51(2):499–508. Madger S, Lockhat D, Luo BJ, Rousso C. Respiratory muscle and organ blood flow with inspiratory elastic loading and shock. J Appl Physiol 1985; 58(4):1148–1156. Supinski G, DiMarco A, Ketai L, Hussein F, Altose M. Reversibility of diaphragm fatigue by mechanical hyperperfusion. Am Rev Respir Dis 1988; 138:604–609. Supinski G, DiMarco A, Dibner-Dunlap M. Alterations in diaphragm strength and fatiguability in congestive heart failure. J Appl Physiol 1994; 76(6):2707–2713. Comtois A, Gorczyca W, Grassino A. Anatomy of diaphragm circulation. J Appl Physiol 1987; 62:238–244. Hussain SNA, Stewart DJ, Ludman JP, Magder S. Role of endothelium–derived relaxing factor in active hyperemia of the canine diaphragm. J Appl Physiol 1992; 72:2393–2401. Ward ME, Hussain SNA. Regulation of baseline vascular resistance in the canine diaphragm by nitric oxide. Br J Pharmacol 1994; 112:65–70. Hussain SNA. Regulation of ventilatory muscle blood flow. J Appl Physiol 1996; 81:1455– 1468. Bellemare F, Wight CM, Lavigne CM, et al. Effect of tension and timing of contraction on the blood flow of the diaphragm. J Appl Physiol 1983; 54(6):1597–1606. Bark H, Supinski G, Lamanna JC, Kelsen SG. Relationship of changes in diaphragmatic muscle blood flow to muscle contractile activity. J Appl Physiol 1987; 62(1):291–299. Kawagoe Y, Permutt S, Fessler H. Hyperinflation with intrinsic PEEP and respiratory muscle blood flow. J Appl Physiol 1994; 77:2440–2448. Hussain SNA, Roussos C, Magder S. Autoregulation of diaphragmatic blood flow in dogs. J Appl Physiol 1988; 64(1):329–336. Ward ME. Interaction between hypoxia and hypercapnia in regulating canine diaphragm arteriolar diameter. J Appl Physiol 1996; 80:802–809.
4 Right Ventricular Function and Ventricular Interdependence
WILLIAM P. SANTAMORE and ALFRED A. BOVE Temple University School of Medicine Philadelphia, Pennsylvania
I.
LOUIS J. DELL’ITALIA University of Alabama Birmingham, Alabama
Introduction
In this chapter, we will review right ventricular diastolic and systolic function and how right ventricular function is influenced by ventricular interaction. As will be pointed out, the concept of ventricular interdependence is especially important in understanding right ventricular systolic function. Lastly, we will briefly review how right ventricular function and ventricular interdependence impact on respiratory induced variations in aortic pressure and left ventricular stroke volume. II. Right Ventricular Diastolic Function Experimental studies and clinical studies and observation have clearly shown that the right ventricle is more compliant than the left ventricle. The implication relevant to this monograph is that respiratory-induced changes in intrathoracic pressure will have a large effect on right ventricular end-diastolic volume. We will discuss this at the end of this chapter and this will be covered in greater detail in Chapters 8, 10, and 12. Before discussing the diastolic characteristics, I would like to point out that while the right ventricle is more compliant than the left ventricle it should not be 67
68
Santamore et al.
considered to be a nonstressed chamber. Several investigators have proposed that the right ventricle is an unstressed structure (1–3). By definition, an unstressed ventricular chamber could have large changes in volume without any change in ventricular pressure. To assess transmural ventricular pressure, both intraventricular and external pressures needed to be measured. Since normally only a small fluid layer separates the ventricular wall and the pericardium, measuring pericardial pressure is a challenge. Tyberg and others used specially designed catheters (pericardial balloon catheters) to estimate pericardial pressure (1–3). They observed that over a wide range of right ventricular volumes that right ventricular end-diastolic pressure and pericardial pressure were nearly identical. Since transmural pressure is the cavity pressure minus the external pressure, this implies a near zero transmural right ventricular diastolic pressure. They concluded from these oberservations that the right ventricle was an unstressed structure. To examine the concept of an unstressed right ventricle, we directly measured right ventricular pressure-volume curves in vitro (4). Canine hearts were removed and perfused with cardioplegic solution. Balloons were inserted into each ventricle and filled with known volumes. To circumvent any potential problems in measuring transmural pressure, the pericardium was removed so that the intracavity and transmural pressures were identical. Figure 1 shows typical pressure-volume plots for the right and left ventricles from one experiment in vitro. In this example at every ventricular volume, right ventricular pressure was less than the left ventricular pressure. However, throughout the volume range, right ventricular (transmural) pressure was different from zero. For the six experiments, transmural pressures of 2.6 ⫾ 0.5, 3.9 ⫾ 0.9, 5.9 ⫾1.4, and 8.9 ⫾ 2.4 mm Hg were required to distend the right ventricle to 10, 20, 30, and 40 mL, respectively.
Figure 1 Plot of pressure vs. ventricular volume. (From Ref. 4.)
Right Ventricular Function
69
A transmural pressure significantly different from zero was always required to distend the right ventricle to physiologic volumes. For small dogs (10 to 15 kg) the normal right ventricular end diastolic volumes are in the range of 30 to 40 mL. We found that a substantial transmural pressure of 4 to 9 mm Hg was required to distend the right ventricle to a size of 20 to 40 mL. Thus, even in the low-volume range, we observed right ventricular transmural pressures significantly different from zero. To further investigate the concept of an unstressed ventricle, the minimal change in pressure for any given volume increment was calculated in each experiment. For the right ventricle, the minimal pressure change per volume change was 0.13 ⫾ 0.06 mm Hg/mL with a range of 0.06 to 0. 38. For the left ventricle, the minimal pressure change per volume change was 0.24 ⫾ 0.07 mm Hg/mL with a range of 0.19 to 0. 37. These pressure increment per volume increments were significantly different between the right and left ventricles. Thus the right ventricle did not behave as unstressed ventricle. These results are in agreement with those of other experimental studies (5–8) that directly examined ventricular interdependence and indirectly assessed right ventricular pressurevolume relationship. The findings showed a positive transmural pressure and increasing transmural pressure with increasing ventricular volume. The direct measurement of right ventricular compliance in patients has shown results consistent with these ideas (9). Dell’Italia et al. (9) combined high-fidelity pressure measurements with biplane cineventriculographic volumes to derive the dynamic chamber stiffness constant (0.003 ⫾ 0.001 mm Hg/mL) for the right ventricle. Although more compliant than the left ventricle, the right ventricle should not be viewed as an unstress chamber. III. Diastolic Ventricular Interdependence Bernheim is often credited with being the first to hypothesize ventricular interdependence: the concept that alterations of one ventricle could affect the other through the myocardium (10). In 1910 he postulated that left ventricular hypertrophy and dilatation could compress the right ventricle resulting in diminished right ventricular function, venous congestion, and cardiac failure. Subsequently in 1914, Henderson and Prince, using an isolated cat heart preparation, demonstrated that volume and pressure loading of one ventricle decreased the output and function of the contralateral ventricle (11). In 1956, Dexter described deterioration of left ventricular function in patients with atrial septal defects who developed right ventricular pressure and volume overload. He called this the ‘‘reverse Bernheim effect,’’ postulating leftward septal shift with resultant impaired left ventricular filling and function (12). Ventricular interdependence is defined herein as the forces that are transmitted from one ventricle to the other ventricle through the myocardium and pericardium, independent of neural, humoral, or circulatory effects (13). These ventricular independent effects are immediate as compared with circulatory changes, which require several beats. Ventricular interdependence is a consequence of the close anatomic association between the ventricles: the ventricles are encircled by common muscle fibers, share a septal wall, and are enclosed within the pericardium.
70
Santamore et al.
The evidence for diastolic ventricular interaction is indisputable, and has been the source of in-depth reviews (13–15). In the postmortem isolated heart preparation, Taylor (6), Laks (7), and their colleagues demonstrated that increasing right ventricular volume shifts the left ventricular diastolic pressure-volume relationship upward. In a reciprocal manner, as left ventricular volume and pressure increase, the right ventricular pressure-volume curve shifts to the left and becomes steeper. Bemis (16), Elzinga (17), Santamore (18), and their colleagues used isolated beating hearts in which the right and left heart volumes and loads could be controlled independently. These investigators demonstrated that independent loading of one ventricle shifted the diastolic pressure-volume relationship of the contralateral ventricle upward and to the left. These effects were observed in the absence of the pericardium, underscoring the importance of the anatomic continuity brought about by the interventricular septum and muscle fiber arrangement of the two ventricles (6,7,16–18). Figure 2, taken from a study by Weber and Janicki (19), shows the effects of ventricular interdependence on the diastolic ventricular pressure-volume relationships and the associated changes in ventricular shape. In this canine study, they
Figure 2 Acute distension of one chamber directly affects the opposite chamber. Note that both the pressure-volume curve and compliance of the opposite chamber are altered when either ventricle is distended. (From Ref. 19.)
Right Ventricular Function
71
measured the pressure-volume relationships and then fixed the hearts at normal, elevated right, or elevated left ventricular volumes. The fixed hearts were sliced and the cross sections were traced and digitized into a computer. The computer reconstructed the shape of the ventricles. As right ventricular volume and pressure increased, the left ventricular pressure-volume curve shifted to the left and became steeper. These changes in ventricular compliance were associated with a shift in the diastolic position of the septum toward the left ventricle (see Fig. 2, top panel). Conversely, increasing left ventricular volume shifted the right ventricular pressurevolume curve upward and to the left, displaced the interventricular septum toward the right ventricle, and decreased the chamber dimensions of the right ventricle (Fig. 2, bottom panel). Diastolic ventricular interdependence occurs even with the pericardium open, although the coupling is stronger with it closed (19–30). Spadaro et al. (24) used an intraventricular balloon to record left ventricular volume during progressive increases in right ventricular filling pressure with the pericardium widely unopposed, partially closed, or completely closed. The left ventricular diastolic pressure-volume relationship was, in a leftward and parallel manner, shifted upward under each condition, but the effect was greatly augmented with the pericardium closed. Janicki and Weber (5) demonstrated a parallel upward shift of the right ventricular diastolic pressure-volume relationship with the pericardium closed during progressive increases in left ventricular volume using a similar preparation. Moreover, Maruyama and coworkers (8) demonstrated that independent increases in the volume of each of the four cardiac chambers shifted the pressure-volume relationship of the other three chambers upward and to the left in the postmortem isolated heart. This effect was observed with or without the pericardium, but was greatly accentuated by the closed pericardium. In an eloquent study, Slinker and Glantz (26) analyzed transient changes in hemodynamics in an attempt to unravel the contributions of direct (i.e., ventricular interdependence) and series (circulatory) interactions. In their open-chest animal model, they concluded that direct interaction is approximately one-half as important as series interaction with the pericardium intact, and is one-fifth as important when the pericardium is removed. However, they went on to qualify that direct interaction is large enough that it cannot be ignored when analyzing left ventricular diastolic function in response to hemodynamic interventions that also change the volume of the right ventricle in the intact circulation. Diastolic ventricular interdependence is present on a moment-to-moment, beat-to-beat basis (part of the measured diastolic ventricular pressure is caused by the opposite ventricle). In other words, if we measure a left ventricular end-diastolic pressure of 12 mm Hg, part of this pressure is due to the volume in the left ventricle and the left ventricular wall characteristics. However, part of this measured left ventricular pressure is due to right ventricular volume and to pericardial constraints. Although always present, ventricular interdependence is most apparent with sudden changes in ventricular volume. For instance, changes in posture evoke a wide range of cardiovascular responses to maintain an adequate cardiac output. When changing from a recumbent to a standing position, right ventricular volume
72
Santamore et al.
decreases due to a reduced venous return. This decrease in right ventricular volume increases left ventricular diastolic compliance, in effect making it easier to fill the left ventricle. Despite the decrease in right ventricular stroke volume and pulmonary arterial pressure, left ventricular filling and stroke volume initially are maintained. After several heart beats, left ventricular end-diastolic volume decreases. In turn, this left ventricular volume decrease further increases right ventricular compliance, thereby assisting venous return to the right ventricle. Thus, diastolic ventricular interdependence helps to buffer the sudden changes in right ventricular output, maintain cardiac output, and assist venous return to the heart. Another example is the ventricular volume changes that occur with respiration and which can be observed readily with echocardiography (31–49). During spontaneous inspiration, right ventricular dimensions and volume increase (31–35). Concomitant with these changes, left atrial transmural pressure increases and the septum moves towards the left ventricle in diastole (35). Left ventricular end-diastolic volume either remains unaltered or decreases. This increase in left ventricular filling pressure with a decrease in its volume is consistent with a change in left ventricular distensibility. As mentioned before, the pericardium augments ventricular interdependence. Thus, as might be expected, conditions involving the pericardium, such as cardiac tamponade and constrictive pericarditis, accentuate ventricular interdependence and the associated respiratory changes in ventricular volume (50–52). Diastolic ventricular interdependence is always present and the interactions are large enough to be of physiological and pathophysiological importance. This phenomenon, diastolic ventricular interdependence, is well recognized and can be used to assist in clinical diagnosis. For example, Hurrell et al. (53) and Oh et al. (54) used echocardiography to observe the dynamic respiratory changes in the right and left ventricles. Hurrell compared 15 patients with surgically proven constrictive pericarditis to 21 patients with other causes of heart failure. Conventional cardiac catheterization variables used to establish the diagnosis of constrictive pericarditis lacked the sensitivity and specificity to distinguish between the two groups. However, the finding of discordance between right and left ventricular pressures during inspiration, a sign of increased ventricular interdependence, accurately distinguished between the patient groups.
IV. Right Ventricular Systolic Function A. Mechanism of Ejection
The mechanism of ejection of blood from the right ventricular chamber is also complex because contributions to shortening and stroke volume emanate from an interaction of three different sources: free wall, interventricular septum, and conus. The conus region is anatomically and embryologically different from the free wall. The conus arises from the bulbus cordis which is present as a separate chamber distal to the common ventricle in all developing vertebrate embryos. The conus, with its circumorally arranged muscle fibers (55), contracts 30 to 50 msec after the base and apex of the free wall (56–61). This temporal disparity of contraction can be exager-
Right Ventricular Function
73
ated by vagal stimulation or abolished by sympathetic stimulation (58–60). The free wall contracts in a peristalsis wave-like fashion starting at the base and progressing to the apex (55–57). The decrease in surface area of the free wall shortens the base to apex dimension and decreases the septal to free wall dimension in conjunction with thickening of the interventricular septum. The correlation of this complex pattern of contracton with the pressure and flow recordings has been studied in animals models where implanted sonomicrometer crystals measure shortening patterns in the right ventricular free wall, conus, and septum to free wall. B. Pressure-Volume Relationship
The right ventricular pressure-volume relationship provides insight into ejection dynamics by describing the coupling between the ventricle and the vasculature. Dell’Italia and coworkers used (62) simultaneous high-fidelity pressure and biplane cineventriculographic volumes to construct right ventricular pressure-volume loops in normal subjects. Figure 3 demonstrates representative right ventricular pressurevolume loops at low, medium, and high loading conditions during progressive infusions of phenylephrine. These patterns are compared to left ventricular pressurevolume loops at low load (nitroprusside) and during progressive increases in afterload (methoxamine). Comparison of right and left ventricular pressure-volume loops at low load demonstrate a decreased isovolumic contraction period for both the left (nitroprusside) and right (baseline) ventricles. In addition, at end-systole (upper left corner) blood is ejected as pressure is declining in both ventricles but to a much greater extent in the right ventricle at its normal operating pressure when compared to the left ventricle under the influence of nitroprusside infusion. Inspection of the loops at high load demonstrates nearly similar patterns with a greater isovolumic contraction phase, a rising pressure as volume decreases, and very little volume decrease at end systole as pressure declines. Therefore, the pressure-volume relationship of both the right and left ventricles depict each ventricle ejecting into its respective arterial load at baseline and during alterations in afterload. One method of defining ventricular performance relates instantaneous ventricular pressure, P(t), to instantaneous volume, V(t), during systole according to the equation: P(t) ⫽ E(t) [V(t) ⫺ V0] where E(t) represents the time varying volume elastance of the ventricle and V0 the unstressed ventricular volume. This construct of ventricular performance, frequently referred to as the end-systolic pressure-volume relationship, was first described by Suga and Sagawa for the left ventricle (63,64). The equation predicts that ventricular pressure is at all instances (t) proportional to actual volume, the slope of the line increasing from a low value at diastole to its highest value (Emax) at end systole. The slope of this relationship was highly linear for the left ventricle and increased in response to positive inotropic therapy. However, there are limitations of this relationship including nonlinearity (65), variability in slope values (66,67), and afterload dependency (68). Despite these problems that are currently well appreciated, the
74
Santamore et al.
Figure 3 (a) Left ventricular pressure-volume loops at low (nitro prusside), medium (control), and high (methoxamine) loading conditions. (b) Right ventricular pressure-volume loops at low, medium, and high loading conditions. (From Refs. 9, 70.)
Right Ventricular Function
75
end-systolic pressure volume relationship is frequently used to define changes in contractility. Maughan and coworkers (69) were the first to demonstrate that right ventricular performance may be described by a time-varying elastance in the isolated canine heart (69). Ventricular volume was measured using a water-filled latex balloon within the right ventricle and high-fidelity pressure using a micromanometer mounted within the balloon. Little work had been performed in the intact circulation because the complex geometric shape of the right ventricle made accurate volume determinations difficult. Dell’Italia and Walsh (62) studied right ventricular chamber mechanics in normal human subjects using cast-validated biplane cineventriculographic volumes and high-fidelity pressure measurements. The results of this study demonstrated that right ventricular systolic function could be approximated using a time-varying elastance model (see Fig. 4). However, the right ventricle exhibited important quantitative differences compared to the left ventricle manifested by lower slope values and higher V0 values (70). These findings are most likely explained by the lower operating pressures, larger volumes, and reduced mass of the right ventricle. Work in human subjects by Brown and coworkers (71) demonstrated similar findings using simultaneous high-fidelity right ventricular pressure and radionuclide ventriculographic-derived volume. In addition, studies in the isolated heart (69) and in humans
Figure 4 Slopes of maximum time-varying elastance (Emax), maximum pressure/volume ratio (maxPV), and end-ejection pressure/volume (EEPV) are displayed for the right ventricle by lines of best fit by passing through three points of each pressure volume loop. (From Ref. 62.)
76
Santamore et al.
(71) have demonstrated that the slope of the right ventricular end-systolic pressurevolume relationship increases in response to inotropic stress. Therefore, the right ventricle also follows the construct of time-varying elastance, thereby suggesting that the right and left ventricles behave as hydraulic pumps that are optimally matched to their respective arterial loads. Peak chamber elastance [E(t)] is obtained by the maximum slope of the linear regression applied to multiple isochronal, simultaneous pressure-volume points derived during altered loading conditions. In an attempt to simplify the quantification of chamber elastance for clinical use, time-independent pressure-volume relations near end systole, such as the maximum pressure/volume ratio, end ejection (dicrotic notch) pressure/volume, or peak pressure/minimum volume, have been used to construct end-systolic pressure-volume relations. In the left ventricle, the slopes obtained from these measures of end-systole correlate with E max (70) because end ejection has a close temporal relation to the point of peak systolic elastance (72). However, Maughan and coworkers (69) demonstrated that in contrast to the left ventricle, right ventricular ejection proceeds far beyond the points of peak pressure and peak systolic elastance because of greater pulmonary arterial compliance. Dell’Italia (62) and Brown (72) demonstrated that right ventricular end systolic pressure-volume relations near end ejection (dicrotic notch/minimum volume) and peak pressure/minimum volume underestimate E(t) because of the wide temporal separation between peak systolic elastance and end ejection in the right ventricle. However, the slopes derived from the maximum pressure/volume ratio correlated with Emax both at rest and after positive inotropic stimulation. Therefore, this marker of end systole could be used in clinical studies where the end-systolic pressure-volume relationship is used as a means to describe pump performance of the right ventricle. In addition to the end-systolic pressure-volume (ESPV) relationship, Feneley and coworkers (73) studied two other indices commonly used to evaluate the left ventricle. In dogs the relation between stroke work and end-diastolic volume (termed the preload recruitable stroke work relation) and the maximum dP/dt (dP/dtmax) versus end-diastolic volume relation were examined (73). The slope and volume-axis intercept of the preload recruitable stroke work relation were more reproducible than the slope and volume-axis intercept of the end-systolic pressure-volume relation or the slope and volume-axis intercept of the dP/dtmax –end-diastolic volume relation. The slope of the preload recruitable stroke work relation increased after calcium infusion, but the volume-axis intercept did not change significantly. In contrast, the slopes of the end-systolic pressure-volume and dP/dtmax –end-diastolic volume relations did not change significantly after calcium infusion, but the volume-axis intercepts decreased significantly. Probably, the measurement most commonly used to assess right ventricular function is ejection fraction. The ejection fraction can be derived from a number of techniques. However, this measurement is load dependent. This is probably a greater problem for the right ventricle than the left ventricle (74). As will be pointed out in the next section, right ventricular function is highly dependent on left ventricular function. Thus, these indices of right ventricular function should not be viewed independently of left ventricular function.
Right Ventricular Function V.
77
Systolic Ventricular Interaction
In recent years, evidence for systolic ventricular interaction has been substantiated. The sections that follow review the studies demonstrating the existence, magnitude, and mechanisms of systolic ventricular interdependence. A. Existence
Figures 5A and 5B show a very simple way to demonstrate systolic ventricular interdependence (75). Left and right ventricular pressures are recorded, while suddenly in diastole a partial constriction of the pulmonary artery is released (Fig. 5, top panels). On the subsequent systole, not only does right ventricular systolic pressure decrease, but left ventricular systolic pressure also decreases slightly. Because preload was not altered, only systolic ventricular interdependence can explain this decrease in left ventricular pressure. Figure 5 also shows the complementary study for the right ventricle. An aortic constriction is released in diastole, leading on the subsequent systolic contraction to a decrease in left ventricular systolic pressure and also, through ventricular interdependence, to a decrease in right ventricular systolic pressure. Several studies have revealed similar observations (16–19,76–83). Initially, isolated heart preparations were employed to break the circulatory connections and thus demonstrate ventricular interdependence. These studies showed that increasing the pressure or volume in one ventricle leads to an increase in both diastolic and systolic pressure in the other ventricle. Because circulatory connections were disrupted, only a direct mechanical effect can explain these results. Further evidence of systolic ventricular interdependence has been presented experimentally by Oboler (84) and clinically by Feneley et al. (85). These studies demonstrated the influence of left ventricular isovolumic pressure on right ventricular pressure. With normal ventricular conduction, the right ventricular rate of pressure change (dP/dt) curve is broad or double-peaked, with one of the peaks corresponding in time to the maximum left ventricular dP/dt. This relationship between right and left ventricular dP/dt was accentuated during right and left ventricular endocardial pacing. Experimental studies have also shown that this systolic interaction is an immediate effect: Rapid withdrawal from or injections into the left ventricle caused immediate changes in right ventricular pressure and volume outflow (13,78,86). In an isolated rabbit heart preparation, Bove and Santamore (13) used a high-speed injector to rapidly infuse 1.5 mL water into the left ventricular balloon. This rapid left ventricular volume increase caused an immediate increase in right ventricular pressure. Likewise, a rapid withdrawal of fluid from the left ventricular balloon caused an immediate decrease in right ventricular pressure (13). Langille and Jones (78) demonstrated similar results in an open-chest rabbit heart preparation in which the aorta was rapidly occluded and fluid rapidly infused into the left ventricle. Sudden aortic constriction in diastole increased right ventricular systolic pressure and dP/ dt during the subsequent systolic contraction. Small, rapid oscillations in left ventric-
78 Santamore et al.
Figure 5 From an acute canine study. (A) Plot of left and right ventricular pressure. A partial constriction of the pulmonary artery was released in diastole. On the subsequent systolic contraction, both left and right ventricular systolic decrease. (B) Left ventricular pressure plotted before (solid line) and after (dashed line) pulmonary artery release. (C and D) A partial constriction of the aorta was released during diastole, leading to a decrease in both left (C) and right (D) ventricular systolic. (From Ref. 75.)
Right Ventricular Function
79
ular volume produced left ventricular pressure oscillations with coincident oscillations in right ventricular pressure. In whole animal studies, Woodard et al. (86) used a ventricular assist device to rapidly withdraw blood from the left ventricle. This withdrawal occurred in systole during a single cardiac cycle. The withdrawal of blood from the left ventricle caused a rapid decrease in left ventricular pressure. Right ventricular pressure and volume outflow also decreased, resulting in a large change in developed pressure and outflow. The above studies show that systolic ventricular interdependence can have a purely systolic component. B. Magnitude
Although the aforementioned studies proved the existence of systolic ventricular interdependence, they did not quantify the magnitude of systolic interdependence. Are these observations just interesting phenomena or are they physiologically important with significant clinical implications? Two studies addressed this question and quantified the magnitude of this left ventricular assistance using a unique electrically isolated right-heart preparation (87,88). The electrically isolated right heart-preparation allowed for wide variations in the timing interval between right and left ventricular contractions. Double-peaked waveforms for right ventricular pressure and pulmonary artery blood flow occurred over a wide range (0 to 300 msec) of pacing intervals between the left and right ventricles (see Fig. 6). Numerical analysis indicated that these pressures and volume waveforms were due to two components (87). One component could be directly related to right ventricular contraction, while the other component was directly related to left ventricular contraction (see Fig. 7). Left ventricular systolic pressure was due primarily to left ventricular contraction. For left ventricular pressure, the left ventricular component was significantly larger than the right ventricular component (92.7% versus 7.3% peak-to-peak value). Right ven-
Figure 6 LV pressure, RV pressure, and volume outflow are presented at 60-, 120-, 180-, and 240-msec delay between RA and RV pacing. At 60-msec delay, RV pressure and volume outflow are double-peaked waveforms with one peak occurring before LV pressure. At 240msec delay, RV pressure and volume outflow are again double-peaked waveforms but with one peak occurring after LV pressure. (From Ref. 87.)
80
Santamore et al.
Figure 7 Computer analysis of the data in Figure 4. With the use of numerical analysis, pressure and volume outflow waveforms were separated into left and right components. (A) Left and right components for LV pressure. As is apparent, the vast majority of LV pressure can be associated with left component. (B and C) Left and right components for RV pressure and volume outflow, respectively. Both RV pressure and volume outflow have a significant left and right components. (From Ref. 87.)
Right Ventricular Function
81
tricular systolic pressure and pulmonary artery blood flow were composed of both right ventricular and left ventricular components, with the left ventricular component dominating. For right ventricular pressure, the left ventricular component was significantly greater than the right ventricular component (63.5% vs. 36 5% peak-topeak value). Similarly, for pulmonary artery blood flow, the left ventricular component was significantly greater than the right ventricular component (67.5% vs. 32.5% peakto-peak value). This study shows that left ventricular contraction is very important and may be the primary source for right ventricular developed pressure and volume outflow (87). With the same type of experimental preparation, Goldstein et al. (88) examined the mechanism for right ventricular contraction when the right ventricular free wall was electrically silent. Ultrasound demonstrated that right ventricular free wall dyskinesis increased right ventricular end-diastolic size (155% of control), but decreased left ventricular size (69% of control). The septum demonstrated reverse curvature in diastole and bulged paradoxically into the right ventricle in early systole, generating the initial peak in right ventricular pressure and reducing its volume. Later, posterior septal motion coincided with maximal left ventricular pressure and the second peak of the right ventricular pressure waveform. Therefore, when contractility of the right ventricular free wall is acutely depressed, right ventricular performance is dependent on left ventricle-septal contraction. Using an electrically isolated right heart preparation may have exaggerated the left ventricular contribution to right ventricular pressure development and volume outflow (87,88). Thus, in a canine study, we estimated the magnitude of ventricular interdependence. We measured the changes in right and left ventricular pressures (dPr, dPl) caused by sudden changes in left ventricular pressure (dPl′) with release of an aortic constriction and by sudden changes in right ventricular pressure (dPr′) with release of a pulmonary artery constriction, respectively (similar to Fig. 5). The instantaneous cross talk gain (dPr/dPl′ or dPl/dPr ′) was calculated during the ejection phase. The potential systolic pressure generated by the contralateral ventricle was evaluated as the cross talk gain multiplied by the contralateral systolic developed pressure. The pressure coupling was greater in right-to-left (0.25) than in left-to-right (0.09) ventricular interaction. The left-to-right ventricular interdependence gain (0.09) is similar to the values reported by Yaku et al. (90). The potential right ventricular pressures developed by the left ventricle (maximum 10.3, mean 4.8 mm Hg) were not significantly different from the potential left ventricular pressures developed by the right ventricle (maximum 8.8, mean 3.4 mm Hg). However, because left ventricular systolic pressure was greater than right ventricular pressure, the ratio between the potential transmitted pressure and the measured developed pressure was greater for the right ventricle (maximum 39.0, mean 17.8%) than in the left ventricle (maximum 11.1%, mean 3.9%). This suggests that about 20% to 40% of the right ventricular systolic pressure may result from left ventricular contraction and about 4% to 10% of the left ventricular systolic pressure may result from right ventricular contraction.
82
Santamore et al. C. Mechanism
The above studies have clearly shown that ventricular interdependence exists, and that a significant portion of right ventricular developed pressure and volume outflow depends on left ventricular function. Further, these studies have shown that this systolic interaction is immediate: Rapid withdrawal or injection of fluid into the left ventricle causes immediate changes in right ventricular pressure and volume outflow (13,78,86). Because of its position between the two ventricles, the septum has been identified as a key element for ventricular interaction. Several studies have demonstrated alterations in the normal end-systolic septal shape and position with alterations in systolic loading conditions. For instance, right ventricular hypertension caused a progressive leftward shift in septal position during systole (91). Pulmonary artery constriction caused a leftward septal shift (92–94). In human subjects, increased right ventricular loading, by the Mueller maneuver (35,37) or by pulmonary embolism (95), caused end-systolic septal flattening and leftward shift. It has been inferred from such studies that the end-systolic septal shape and position depend on the transseptal pressure gradient. Such a view is also supported by the tight linear relationship between the transseptal pressure gradient and the end-systolic septum to right ventricular free wall distance (96). The fact that systolic flattening and leftward shift exist at end systole, however, even though the left ventricular end-systolic pressure exceeds the right ventricular end-systolic pressure (91), suggests that additional factors are involved. One such factor is the end-diastolic position of the septum, which has been shown to determine both the magnitude and direction of septal motion during systole (97–99). In addition, right ventricular volume loading, which shifts the septum leftward in diastole, causes passive stretching of the septal muscle fibers, which, in turn, induces an increased active systolic shortening (100). Such an alteration in contraction can alter the end-systolic septal position, regardless of the transseptal pressure. Based on the concept that ventricular interdependence occurs primarily through the septum, several models have been developed to explan interaction. Elzinga et al. (17) described the shape of both ventricles by a combination of ellipsoids, and showed that right ventricular volume was inversely related to left ventricular volume. Mirsky et al. (101,102) proposed a model in which the effective left ventricular external pressure was expressed as a weighted average of the right ventricular and pericardial pressures. Maughan (81), Little (103), and Santamore et al. (104,105) developed models based on simple definitions for volume and regional elastances. Chung and colleagues (106) expanded this approach to simulate ventricular interdependence throughout the cardiac cycle. The above models imply that all interactions occur throughout the septum, and that no direct transfer of forces between the left and right ventricular free walls occurs. However, this view is not consistent with experimental results. Yamaguchi et al. (107) observed that increasing left ventricular volume altered the diastolic dimension of the right ventricular free wall and that increasing right ventricular volume not only alters septal position and dimensions but also caused regional defor-
Right Ventricular Function
83
mation in the left ventricular free wall. Goto et al. (108) showed that increasing right ventricular pressure by pulmonary artery constriction caused non-uniform regional changes in systolic shortening in the anterior, posterior, and lateral walls of the left ventricle and the septum. In an isolated rabbit heart preparation, Santamore et al. (77) produced left ventricular free wall ischemia by ligating the anterior ventricular branches of the left coronary artery. This ligation caused a rapid decrease in right ventricular developed pressure. In an isolated rabbit heart preparation, the left ventricle was vented, and thus, left ventricular cavity pressure was zero (109). Cutting the left ventricular free wall from the atrioventricular orifice to the apex prevented the left ventricle from generating wall stress during systole and thereby eliminated left ventricular free wall contributions to right ventricular developed pressure. After cutting the left ventricular free wall, right ventricular developed pressure fell dramatically. Suturing the left ventricular free wall reestablished right ventricular developed pressure. These findings imply that interaction causes overall ventricular deformation. Thus, although we agree that the septum is important in systolic interaction, we think that ventricular interdependence affects the whole heart: the right ventricular free wall, the left ventricular free wall, and the septum. In 1977, Seki et al. (110) proposed the first model that attempted to explain ventricular interdependence by considering wall stress. Seki et al. (110) modeled the biventricular cross section as a circular left ventricle with the right ventricular free wall as a portion of a circle overlapping part of the left ventricle. Forces at the interventricular sulcus were computed. However, the analysis did not allow deformation. To model ventricular interdependence, Beyar et al. (111) and Taher (112) expanded Seki’s ideas and developed an analytical model based on the balance of forces at the sulcus (Fig. 8). This configuration highlights forces at the sulci, and is useful in analyzing the mechanical interplay of forces at these junctions. Beyar et al. (111) compared model with data from animal experiments subjected to aortic and pulmonary constriction. The model predicted the observed shift in the pressurearea relationship of each ventricle by a change in loading of the opposite ventricle and predicted that large transmural gradients in stress and strain are associated with septal inversion. Thus, the model and the experimental data agree and describe the important factors that modulate diastolic septal mechanics during acute differential ventricular loading. The model shows that interaction is sensitive to the material properties of the heart wall as well as to cardiac dimensions. A conclusion also reached by Moulton et al. (113), who used a finite element approach. For example, diastolic interaction, similar to that measured experimentally, appears to be possible only if the material nonlinearities of the three walls are different. Taher applied this model to study systolic ventricular interdependence and was able to simulate most of the important aspects of this interaction (112). Before reviewing ventricular interdependence in pathological conditions, the insights from the theoretical models might be helpful. Conditions that increase the relative compliance of the septum (or decrease the septal elastance) increase ventricular interdependence. The most notable examples are volume overload
84
Santamore et al.
Figure 8 Balance of forces at the interventricular sulcus. Top panel shows cross section of heart. The summation of the forces at the sulcus is zero. The bottom panel shows how the stress or tension (Tl) in the left ventricular free wall is balanced by the tension in both the septum (Ts) and right ventricular free wall (Tr). (From Ref. 14.)
states, where experimental studies have shown an increased coupling between the ventricles (114,115). Farrar et al. (114) produced in pigs dilated cardiomyopahty by rapid ventricular pacing. The systolic gain between the right and left ventricles was significantly greater in the dilated cardiomyopathy pigs compared with normal pigs. Conversely, conditions that decrease the septal compliance (or increase the septal elastance) decrease the coupling between the ventricles. For example, Slinker
Right Ventricular Function
85
and coworkers (116) induced moderate left ventricular concentric hypertrophy in dogs. At end diastole, they found that direct interaction was one-half as important as series interaction in normal animal, but only about one-tenth as important as series interaction in determining left ventricular size in animals with concentric hypertrophy. At end systole, they found that direct interaction was about one-fifth as important as the end-systolic pressure-volume relationship in determining left ventricular size. Direct interaction is less important in hearts with concentric hypertrophy than in normal hearts, probably because the septum is thicker and, hence, less distensible. Lastly, conditions that alter the relative compliances of the walls, alter coupling between the ventricles. In dogs, Yamaguchi and colleagues (117) altered right ventricular elastance by occluding the right coronary artery and by injecting glutaraldehyde into the right coronary artery. Decreasing the right ventricular free elastance resulted in a decreased coupling between the ventricles, while stiffening the right ventricular free elastance increased the coupling. In an excellent study, Hoffman et al. (118) created a variable-volume, neoright ventricle by excision and replacement of the right ventricular free wall with a xenograft pericardial patch. Even without a contracting right ventricular free wall, cardiac output was maintained and increased with increases in left ventricular end-diastolic pressure: The stiff right ventricular free wall enabled the force transmitted from the left ventricle to be converted into right ventricular pressure development and volume outflow. However, increasing neoright ventricular size decreased this efficiency and led to decreases in cardiac output, maximal neoright ventricular pressure, and stroke work. The relationship between neo-right ventricular stroke work and left ventricular stroke work at different neoright ventricular sizes was linear both in control conditions and during pulmonary artery occlusion. Left ventricular contraction contributes 24% of left ventricular stroke work to the generation of right ventricular stroke work via the septum in the absence of a contracting right ventricle; this increases to 35% in the face of increased pulmonary afterload. Lastly, systolic ventricular interdependence may help to explain long observed phenomenon. It has been known for years that the right ventricle begins and ends ejection after the left (119). Unlike the left ventricle, the right ventricle begins to eject almost without an isovolumetric systolic contraction and continues to eject after end systole (120). This difference in contraction pattern is probably not due to intrinsic differences between right and left ventricular mechanical properties (121, 122). In an isolated heart preparation, Burkhoff et al. (121) showed that the time course of right and left ventricular pressure generation (or elastance change) was identical throughout the cardiac cycle for both ventricles. This near identity implies similarities in right and left ventricular chamber properties, despite marked anatomical and geometric differences. This discrepancy between the intrinsic right ventricular mechanical properties and its performance as a pump ejecting blood has been attributed to the fact that the right ventricle ejects against lower vascular impedance. However, ventricular interdependence may also help to explain this long observed phenomenon. During isovolumetric contraction, the pressure in the left ventricle is increasing rapidly.
86
Santamore et al.
Through ventricular interdependence, this increase in left ventricular pressure also contributes to rapid increase in right ventricular pressure. In other words, the right ventricular pressure is composed of the intrinsically generated right ventricular pressure plus the left ventricular component. For the right ventricle, this left ventricular component is large. Thus, although the left ventricle has not generated sufficient pressure to initiate its ejection, it has contributed sufficient pressure to help the right ventricle to start ejecting. During isovolumic relaxation, the opposite would occur. In an experimental study, Yamaguchi et al. (123) observed that the duration of right ventricular ejection was decreased by a sudden decrease in left ventricular afterload and was significantly related to the length of left ventricular systole. Similarly, Brown et al. (124) observed that left ventricular systolic unloading decreases the rate of right ventricular relaxation. While the pericardium accentuates diastolic ventricular interdependence, it may not be as important for systolic ventricular interdependence (114,125). Farrar and colleagues (114) produced a dilated cardiomyopathy in pigs by rapid ventricular pacing. Blood was rapidly withdrawn from the left ventricular apex into a prosthetic ventricle, and the instantaneous effects on the right ventricle were studied during volume loading and before and after pericardiectomy. When the pericardium was opened, diastolic interaction gain between the right and left ventricles was significantly reduced in both normal and congestive heart failure pigs, but systolic interaction gain showed no significant change. Schertz and Pinsky (125) observed the changes in right ventricular stroke volume and peak systolic pressure during a single left ventricular isovolumic contraction under conditions of normal or increased (1.3 ⫻ normal) right ventricular end-diastolic volume with and without an intact pericardium. Left ventricular isovolumic contraction increased right ventricular stroke volume and peak systolic pressure during all conditions. However, peak right ventricular systolic pressure increased more when the pericardium was intact. These data suggest that left ventricular ejection can enhance right ventricular stroke volume and that this interaction is not appreciably altered by the presence of an intact pericardium. D. Hemodynamic Consequences of Ventricular Interdependence
Respiratory variations in afterload (126) and left ventricular compliance via diastolic ventricular interdependence (13,14, 127) are considered the primary causes for the respiratory variations in left ventricular stroke volume and systemic arterial pressure. However, respiratory variations in intrathoracic and abdominal pressures alter the pressure gradients for blood flow into the thoracic cavity and thus vary the systemic venous return (128,129). Indeed, respiration causes significantly larger changes in systemic venous return than in left ventricular stroke volume (130,131). This theory implicitly assumes that the lungs provide an almost infinite buffer, dampening the large variations in venous return and providing a near constant filling pressure for the left ventricle. However, Appleyard and Glantz (132) reported a mean transit time of only one heartbeat through the pulmonary circulation. This is obviously in conflict with the infinite buffer idea.
Right Ventricular Function
87
Using a computer model of the cardiovascular system, we examined the role of the right ventricle (RV) in buffering systemic venous return, thereby dampening respiratory-induced variations, left ventricular (LV) stroke volume, and systemic arterial pressure variations (133). Respiration was simulated by cyclical variations in intrathoracic and abdominal pressures (cycle time five heartbeats), causing a 43mL fluctuation in venous return per heartbeat (mean 71 mL) compared with fluctuations of 19 mL in RV stroke volume, 6 mL in pulmonary venous flow, and 3 mL in LV stroke volume. On a percentage basis, the RV provided 56% of the total buffering of systemic venous return, the lungs another 30%, whereas the LV only 7%. A 10-fold increase in RV diastolic compliance increased the RV stroke volume variations from 26% to 57% of the venous return variations; a 10-fold increase in RV elastance increased them from 24% to 60%, whereas decreasing pulmonary arterial pressure from 28 to 10 mm Hg increased them from 28% to 56%. The results also suggest that an underrecognized function of the RV is to buffer systemic venous return and thereby keep LV stroke volume relatively constant. References 1. Smiseth OA, Frias MA, Kingma I, Smith ER, Tyberg JV. Assessment of pericardial constraint in dogs. Circulation 1985; 71:158–164. 2. Smiseth OA, Refsum H, Tyberg JV. Pericardial pressure assessed by right atrial pressure: a basis for calculation of left ventricular transmural pressure. Am Heart J 1984; 108:603– 605. 3. Tyberg JV, Taichman GC, Smith ER, Douglas NWS, Smiseth OA, Keon WJ. The relationships between pericardial pressure and right atrial pressure: an intraoperative study. Circulation 1986; 73:428–432. 4. Santamore WP, Constantinescu M, Little WC. Direct assessment of right ventricular transmural pressure. Circulation 1987; 75:744–747. 5. Janicki JS, Weber KT. The pericardium and ventricular interaction, distensibility and function. Am J Physiol 1980; 238:H494–H503. 6. Laks MM, Garner D, Swan HJC. Volumes and compliances measured simultaneously in the right and left ventricles of the dog. Circ Res 1967; 20:565–569. 7. Taylor RR, Covell JW, Sonnenblick EH, Ross J Jr. Dependence eof ventricular distensibility on filling of the opposite ventricle. Am J Physiol 1967; 213:711–718. 8. Maruyama Y, Ashikawa K, Isoyama S, Kanatsuka H, Ino-Oka E, Takishima T. Mechanical interactions between four heart chambers with and without the pericardium in canine hearts. Circ Res 1982; 50:86–100. 9. Dell’Italia LJ, Walsh RA. Right ventricular diastolic pressure-volume relations and regional dimensions during acute alterations in loading conditions. Circulation 1988; 77: 1276–1282. 10. Bernheim D. De l’asystolie veineuse dans l’hyper trophie due coer gauche par stenose concomitante du ventricule droit. Rev Med 1910; 39:785. 11. Henderson Y, Prince AL. The relative systolic discharges of the right and left ventricles and their bearing on pulmonary congestion and depletion. Heart 1914; 5:217–226. 12. Dexter L. Atrial septal defect. Br Heart J 1956; 18:209. 13. Bove AA, Santamore WP. Ventricular interdependence. Prog Cardiovasc Dis 1981; 23: 365–388. 14. Santamore WP, Dell’Italia LJ. Significant left ventricular contributions to right ventricular systolic function. Prog in Cardiovas Dis 1998; 40:289–308. 15. Clyne CA, Alpert JS, Benotti JR. Interdependence of the left and right ventricles in health and disease. Am Heart J 1989; 117:1366–1373.
88
Santamore et al.
16. Bemis CE, Serus JR, Borkenhagem D, Sonnenblick EH, Urschel CW. Influence of right ventricular filling pressure on left ventricular pressure and dimension. Circ Res 1974; 34: 498–504. 17. Elzinga G, Van Grondelle R, Westerhof N, Van Den Bos GC. Ventricular interference. Am J Physiol 1974; 226:941–947. 18. Santamore WP, Lynch PR, Meier G, Heckman J, Bove AA. Myocardial interaction between the ventricles. J Appl Physiol 1976; 41:362–368. 19. Weber KT, Janicki JS, Shroff S, Fishman AP. Contractile mechanics and interaction of the right and left ventricles. Am J Cardiol 1981; 47:686–695. 20. Tyson GS Jr, Maier GW, Olson CO, Davis JW, and Rankin JS. Pericardial influences on ventricular filling in the conscious dog. An analysis based on pericardial pressure. Circ Res 1984; 54:173–184. 21. Robotham JL, Mitzner W. A model of the effects of respiration on left ventricular performance. J Appl Physiol Respir Environ Exercise Physiol 1979; 46:411–418. 22. Glantz SA, Misbach GA, Moores WY, Mathey DG, Lekven J, Stone DF, Parmley WM, Tyberg JV. The pericardium substantially affects the left ventricular diastolic pressurevolume relationship in the dog. Circ Res 1978; 42:433–441. 23. Hess OM, Bhargava V, Ross J Jr, Shabetal R. The role of the pericardium in interactions between the cardiac chambers. Am Heart J 1983; 6:1377–1383. 24. Spadaro J, Bing OHL, Gaasch WH, Weintraub RM. Pericardial modulation of right and left ventricular diastolic interaction. Circ Res 1981; 48:233–238. 25. Lorell BH, Palacios I, Daggett WM, Jacobs ML, Fowler BN, Newell JB. Right ventricular distension and left ventricular compliance. Am J Physiol 1981; 240:H87–H98. 26. Slinker BK, Glantz SA. End-systolic and end-diastolic ventricular interaction. Am J Physiol 1986; 251:H1062. 27. Slinker BK, Goto Y, LeWinter MM. Direct diastolic ventricular interaction gain measured with sudden hemodynamic transients. Am J Physiol 1989; 256:H567–H573. 28. Santamore WP, Shaffer T, Papa L. Theoretical model of ventricular interdependence: pericardial effects. Am J Physiol 1990; 259:H181–H189. 29. Minczak BM, Wolfson MR, Santamore WP, Shaffer TH. Pericardial effects on ventricular interaction in preterm neonatal lambs. Pediatr Res 1990; 22:547–591. 30. Santamore WP, Li KS, Nakamoto T, Johnston WE. Effects of increased pericardial pressure on the coupling between the ventricles. Cardiovasc Res 1990; 24:768–776. 31. Scharf SM, Brown R, Sauders N, Green LH. Effects of normal and loaded spontaneous inspiration of cardiovascular function. J Appl Physiol Respir Environ Exercise Physiol 1979; 47:582–590. 32. Summer WR, Permutt S, Sagawa K, Shoukas AA, Bromberger-Barnea B. Effects of spontaneous respiration in canine left ventricular function. Circ Res 1979; 45:719–728. 33. Santamore WP, Heckman JL, Bove AA. Right and left ventricular pressure-volume response to respiratory maneuvers. J Appl Physiol Respir Environ Exercise Physiol 1984; 57:1520–1527. 34. Santamore WP, Heckman JL, Bove AA. Cardiovascular changes from expiration to inspiration during intermittent positive pressure ventilation. Am J Physiol 1983; 245:H303–H312. 35. Brinker JA, Weiss JL, Lappe DL, Rabson JL, Summer WR, Permutt S, Weisfeldt ML. Leftward septal displacement during right ventricular loading in man. Circulation 1980; 61:626–633. 36. Riggs TW, Snider R. Respiratory influence on right and left ventricular diastolic function in normal children. Am J Cardiol 1989; 63:858–861. 37. Guzman PA, Maughan WL, Yin FCP, Eaton LW, Brinker JA, Weisfeldt ML, Weiss JL. Transseptal pressure gradient with leftward septal displacement during the Mueller manoeuvre in man. Br Heart J 1981; 46:657–662. 38. Shiomi T, Guilleminault C, Stoohs R, Schnittger I. Obstructed breathing in children during sleep monitored by echocardiography. Acta Paediatr 1993; 82:863–871. 39. Shiomi T, Guilleminault C, Stoohs R, Schnittger I. Leftward shift of the interventricular septum and pulsus paradoxus in obstructed sleep apnea syndrome. Chest 1991; 100:894– 902. 40. Schulman DS, Biondi JW, Zohgbi S, Cecchetti A, Zaret BL, Soufer R. Left ventricular
Right Ventricular Function
41. 42.
43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
53. 54. 55. 56. 57. 58. 59. 60. 61. 62.
89
diastolic function during positive end-expiratory pressure: impact of right ventricular ischemia and ventricular interaction. Am Rev Respir Dis 1992; 145:515–521. Aebischer N, Malhotra R, Connors L, Kappenberger L, Parisi AF. Ventricular interdependence during Valsalva maneuver as seen by two-dimensional echocardiography: new insights about an old method. J Am Soc Echocardiogr 1995; 8:536–542. Kim BH, Ishida Y, Tsuneoka Y, Matsubara N, Hiraoka T, Takeda H, Inoue M, Kamada T, Kimura K, Kozuka T. Effects of spontaneous respiration on right and left ventricular function: evaluation by respiratory and ECG gated radionuclide ventriculography. J Nucl Med 1987; 28:173–177. Robotham JL, Stuart RS, Borkon AM, Doherty K, Baumgartner W. Effects of changes in left ventricular loading and pleural pressure on mitral flow. J Appl Physiol 1988; 65:1662– 1675. Peters J, Fraser C, Stuart RS, Baumgartner W, Robotham JL. Negative intrathoracic pressure decreases independently left ventricular filling and emptying. Am J Physiol 1989; 257:H120–H131. Pinsky MR. The effects of mechanical ventilation on the cardiovascular system. [Review.] Crit Care Clin 1990; 6:663–678. Scharf SM. Cardiovascular effects of airways obstruction. [Review.] Lung 1991; 169:1– 23. Rubal BJ, Moody JM. Effects of respiration on size and function of the athletic heart. J Sports Med Phys Fitness 1991; 31:257–264. Amoore JN, Santamore WP. Model studies of the contribution of ventricular interdependence to the transient changes in ventricular function with respiratory efforts. Cardiovasc Res 1989; 23:683–694. Amoore JN. Ventricular interdependence and the transient response of the left ventricle to inspiration: a model study. Cardiovasc Res 1987; 21:407–415. Santamore WP, Bove AA, Heckman JL. Right and left ventricular response to elevated pericardial pressure. Am Rev Respir Dis 1986; 134:101–107. Santamore WP, Bartlett R, Van Buren SJ, Dowd MK, Kutcher MA. Ventricular coupling in constrictive pericarditis. Circulation 1986; 74:597–602. Gonzalez MS, Basnight MA, Appleton CP, Carucci M, Henry C, Olajos M. Experimental cardiac tamponade: a hemodynamic and Doppler echocardiographic reexamination of the relation of right and left heart ejection dynamics to the phase of respiration. J Am Coll Cardiol 1991; 18:243–252. Hurrell DG, Nishimura RA, Higano ST, Appleton CP, Danielson GK, Holmes DR Jr, Tajik AJ. Value of dynamic respiratory changes in left and right ventricular pressures for the diagnosis of constrictive pericarditis. Circulation 1996; 93:2007–2013. Oh JK, Hatle LK, Seward JB, Danialson GK, Schaff HV, Reeder GS, Tajik AJ. Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 1994; 23: 154–162. Armour JA, Randall WC. Structural basis for cardiac function. Am J Physiol 1970; 218: 1517–1523. Santamore WP, Meier GD, Bove AA. Effects of hemodynamic alterations on wall motion in the canine right ventricle. Am J Physiol 1979; 236:H254–H262. Meier GD, Bove AA, Santamore WP, Lynch PR. Contractile function in canine right ventricle. Am J Physiol 1980; 239:H794–H804. Raines RA, LeWinter MM, Covell JW. Regional shortening patterns in canine right ventricle. Am J Physiol 1976; 231:1395–1400. Armour JA, Pace JB, Randall WC. Interrelationship of architecture and function of the right ventricle. Am J Physiol 1970; 218:174–182. Pace JB, Keefe WF, Armour JA, Randall WC. Influence of sympathetic nerve stimulation on right ventricular outflow-tract pressures in anesthetized dogs. Circ Res 1969; 24:397– 407. Pouleur H, Lefe`vre J, Mechelen HV, Charlier AA. Free-wall shortening and relaxation during ejection in the canine right ventricle. Am J Physiol 1980; 239:H601–H613. Dell’Italia LJ, Walsh RA. Application of a time varying elastance model to right ventricular performance in man. Cardiovasc Res 1988; 22:864–874.
90
Santamore et al.
63. Suga H, Sawgawa K, Shoukas AA. Load independence of the instantaneous pressurevolume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973; 32:314–322. 64. Suga H, Sagawa KP. Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 1974; 35:117–126. 65. Burkhoff D, Sugiura S, Yue DT, Sagawa K. Contractility-dependent curvilinearity of endsystolic pressure-volume relations. Am J Physiol 1987; 252:H1218–H1227. 66. Crottogini AJ, Wilshaw P, Barra JG, Aramentano R, Fischer EIC, Pichel RH. Inconsistency of the slope and the volume intercept of the end-systolic pressure-volume relationship as individual indexes of inotropic state in conscious dogs: presentation of an index combining both variables. Circulation 1987; 76:1115–1126. 67. Spratt JA, Tyson GS, Glower DD, Davis JW, Muhlbaier LH, Olsen GO, Rankin JS. The end-systolic pressure-volume relationship in conscious dogs. Circulation 1987; 75:1295– 1309. 68. Maughan WL, Sunagawa K, Burkhoff D, Sagawa K. Effect of arterial impedance changes on the end-systolic pressure-volume relation. Circ Res 1984; 54:595–602. 69. Maughan WL, Shoukas AA, Sagawa K, Weisfeldt ML. Instantaneous pressure-volume relationship of the canine right ventricle. Circ Res 1979; 44:309–315. 70. Starling MR, Walsh RA, Dell’Italia LJ, Mancini GBJ, Lasher JC, Lancaster JL. The relationship of various measures of end-systole to left ventricular maximum time-varying elastance in man. Circulation 1987; 76:32–43. 71. Brown KA, Ditchey RV. Human right ventricular end-systolic pressure-volume relation defined by maximal elastance. Circulation 1988; 78:81–91. 72. Kono A, Maughan WL, Sunagawa K, Hamilton K, Sagawa K, Weisfeldt ML. The use of left ventricular end-ejection pressure and peak pressure in the estimation of the end-systolic pressure-volume relationship. Circulation 1984; 70:1057–1065. 73. Karunanithi MK, Michniewicz J, Copeland SE, Feneley MP. Right ventricular preload recruitable stroke work, end-systolic pressure-volume, and dP/dtmax-end-diastolic volume relations compared as indexes of right ventricular contractile performance in conscious dogs. Circ Res 1992; 70:1169–1179 74. Ghignone M, Girling L, Prewitt RM. Effect of increased pulmonary vascular resistance on right ventricular performance in dogs. Am J Physiol 1984; 246:H339–H343. 75. Santamore WP, Damiano RJ Jr, Yamaguchi S, Taher M. Dynamic biventricular interaction during systole. Coron Artery Dis 1990; 1:298–306. 76. Moulopoulos SD, Sarcas A, Stametelopoulos S, Arealis E. Left ventricular performance during by-pass or distension of the right ventricle. Circ Res 1965; 17:484–491. 77. Santamore WP, Lynch PR, Heckman J, Bove AA, Meier GD. Left ventricular effects on right ventricular developed pressure. J Appl Physiol 1976; 41:925–930. 78. Langille BL, Jones DR. Mechanical interaction between the ventricles during systole. Can J Physiol Pharmacol 1977; 55:373–382. 79. Elzinga G, Piene H, DeJong JP. Left and right ventricular pump function and consequences of having two pumps in one heart. Circ Res 1980; 46:564–574. 80. Maughan WL, Kallman CH, Shoukas A. The effect of right ventricular filling on the pressure-volume relationship of the ejecting canine left ventricle. Circ Res 1981; 49:382–388. 81. Maughan WI, Sunagawa K, Sagawa K. Ventricular systolic interdependence: volume elastance model in isolated hearts. Am J Physiol 1987; 253:H1381–H1390. 82. Ullrich KJ, Riecker G, Kramer KL: Das Druckvolumendiagramm des Warmbluterherzens. Isometrische Gleichgewichtskurven. Pflugers Arch 1954; 259:481–498. 83. Slinker BK, Goto Y, LeWinter MM. Systolic direct ventricular interaction affects left ventricular contraction and relaxation in the intact dog circulation. Circ Res 1989; 65:307– 315. 84. Oboler AA, Keefe JR, Gaasch WH, Bana JS Jr, Levine HJ. Influence of left ventricular isovolumic pressure upon right ventricular pressure transients. Cardiology 1973; 58:32– 44. 85. Feneley MP, Gavaghan TP, Baron DW, Branson JA, Roy PR, Morgan JJ: Contribution of left ventricular contraction to the generation of right ventricular systolic pressure in the human heart. Circulation 1985; 71:473–480.
Right Ventricular Function
91
86. Woodard JC, Chow E, Farrar DJ. Isolated ventricular systolic interaction during transient reductions in left ventricular pressure. Circ Res 1992; 70:944–951. 87. Damiano RJ Jr, La Follette P Jr, Cox JL, Lowe JE, Santamore WP. Significant left ventricular contribution to right ventricular systolic function. Am J Physiol 1991; 261:H1514–H1524. 88. Goldstein JA, Harada A, Yagi Y, Barzilai B, Cox J. Hemodynamic consequences of electrically silent right ventricle. J Am Coll Cardiol 1988; 11:94a. 89. Yamaguchi S, Harasawa H, Li KS, Zhu D, Santamore WP. Comparative significance in systolic ventricular interaction. Cardiovascu Res 1991; 25:774–783. 90. Yaku H, Slinker BK, Bell SP, LeWinter MM. Effects of free wall ischemia and bundle branch block on systolic ventricular interaction in dog hearts. Am J Physiol 1994; 266: H1087–H1094. 91. King ME, Braun H, Goldblatt A, Liberthson R, Weyman AE. Interventricular septal configuration as a predicator of right ventricular systolic hypertension in children: a crosssectional echocardiographic study. Circulation 1983; 68:68–75. 92. Visner MS, Arentzen CE, O’Connor MJ, Larson EV, Anderson RW. Alterations in left ventricular three-dimensional dynamic geometry and systolic function during acute right ventricular hypertension in the conscious dog. Circulation 1983; 67:353–365. 93. Stool EW, Mullins CB, Leshin SJ, Mitchell JH. Dimensional changes of the left ventricle during acute pulmonary arterial hypertension in dogs. Am J Cardiol 1974; 34:868–875. 94. Olsen CO, Tyson GS, Maier GW, Spratt JA, Davis JW, Rankin JS. Dynamic ventricular interaction in the conscious dog. Circ Res 1983; 52:85–104. 95. Jardin F, Dubourg O, Gueret P, Delorme G, Bourdarias JP. Quantitative two-dimensional echocardiography in massive pulmonary embolism; emphasis on ventricular interdependence and leftward septal displacement. J Am Coll Cardiol 1987; 10:1201–1206. 96. Smith ER, Tyberg JV. Mechanisms of the ventricular septum. In: Ter Keurs HEDJ, Tyberg JV, eds. Mechanisms of the Circulation. Norwell, MA: Kluwer Academic Publishers. 1987: 171–188 97. Pearlman AS, Clark CE, Henry WL, Morganroth J, Itscoitz SB, Epstein SE. Determinants of ventricular septal motion. Circulation 1976; 54:83–91. 98. Kingma I, Tyberg JV, Smith ER. Effects of diastolic transseptal pressure gradient on ventricular septal position and motion. Circulation 1983; 68:1304–1314. 99. Weyman AE, Wann S, Feigenbaum H, Dillon JC. Mechanism of abnormal septal motion in patients with right ventricular volume overload. A cross-sectional echocardiographic study. Circulation 1976; 54:179–186. 100. Ilebekk A. Mechanics of the interventricular septum. In: Ter Keurs HEDJ, Tyberg JV, eds. Mechanics of the Circulation. Norwell, MA: Kluwer Academic Publishers, 1987. 101. Mirsky I, Laks MM. A geometric model for the myocardium: biventricular wall stresses in normal and hypertrophied states. Bull Math Biol 1980; 42:807–828. 102. Mirsky I, Laks MM. Time course of changes in the mechanical properties of the canine right and left ventricles during hypertrophy caused by pressure overload. Circ Res 1980; 46:530–542. 103. Little WC, Badke FR, O’Rourke RA. Effect of right ventricular pressure on the end diastolic left ventricular pressure-volume relationship before and after chronic right ventricular pressure overload in dogs without pericardia. Circ Res 1984; 54:719–730. 104. Santamore WP, Shaffer T, Hughes D. A theoretical and experimental model of ventricular interdependence. Basic Res Cardiol 1986; 81:529–537. 105. Santamore WP, Constantinescu M, Shaffer T. Predictive changes in ventricular interdependence. Ann Biomed Eng 1988; 16:215–234. 106. Chung DC, Niranjan SC, Clark JW Jr, Bidani A, Johnston WE, Zwischenberger JB, Traber DL. Dynamic model of ventricular interaction and pericardial influence. Am J Physiol 1997; 272:H2942–H2962. 107. Yamaguchi S, Tsuiki K. Miyawaki H, Tamada Y, Ohta I, Sukekawa H, Watanabe M, Kobayashi T, Yasui S. Effect of left ventricular volume on right ventricular end-systolic pressure-volume relation: resetting of regional preload in right ventricular free wall. Circ Res 1989; 65:623–631. 108. Goto Y, Slinker BK, LeWinter MM. Nonhomogeneous left ventricular regional shortening during acute right ventricular pressure overload. Circ Res 1989; 65:43–54.
92
Santamore et al.
109. Li KS, Santamore WP. Contribution of each wall to biventricular function. Cardiovasc Res 1993; 27:792–800. 110. Seki S, Itano T, Motohiro K, Teramoto S, Sunada T, Ohsaki K. Mechanodynamics at the interventricular sulcus: reciprocal effect of the ventricles on the ventrocular function. Jpn Circ J 1977; 41:967–974. 111. Beyar R, Dong SJ, Smith ER, Belenkie I, Tyberg JV. Ventricular interaction and septal deformation: a model compared with experimental data. Am J Physiol 1993; 265 (Heart Circ Physiol 34):H2044–H2056. 112. Taher M. Mechanical analysis of ventricular interaction. Thesis, University of Pennsylvania, 1989. 113. Moulton MJ, Creswell LL, Downing SW, Actis RL, Myers KW, Szabo BA, Vannier MW, Pasque MK. Ventricular interaction in the pathologic heart. A model based study. ASAIO J 1994; 40:M773–M783. 114. Farrar DJ, Chow E, Brown CD. Isolated systolic and diastolic ventricular interactions in pacing-induced dilated cardiomyopathy and effects of volume loading and pericardium. Circulation 1995; 92:1284–1290. 115. Farrar DJ, Woodard JC, Chow E. Pacing-induced dilated cardiomyopathy increases leftto-right ventricular systolic interaction. Circulation 1993; 88:720–725. 116. Slinker BK, Chagas AC, Glantz SA. Chronic pressure overload hypertrophy decreases direct ventricular interaction. Am J Physiol 1987; 253:H347–H357. 117. Yamaguchi S, Li KS, Harasawa H, Santamore WP. Acute alterations in systolic ventricular interdependence–mechanical dependence of right ventricle on left ventricle following acute alteration of right ventricular free wall. Basic Res Cardiol 1993; 88:350–361. 118. Hoffman D, Sisto D, Frater RW, Nikolic SD. Left-to-right ventricular interaction with a noncontracting right ventricle. J Thorac Cardiovasc Surg 1994; 107:1496–1502. 119. Wiggers CJ. Physiology in health and disease. Philadelphia: Lea and Febiger, 1954. 120. Raizada V, Sahn DJ, Covell JW. Factors influencing late right ventricular ejection. Cardiovasc Res 1988; 22:244–248. 121. Burkhoff D, Kronenberg MW, Yue DT, Maughan WL, Hunter WC, Sagawa K. Quantitative comparison of canine right and left ventricular isovolumic pressure waves. Am J Physiol 1987; 253:H475–H479. 122. Burkhoff D, Yue DT, Hunter WC, Sunagawa K, Maughan WL, Sagawa K. Quantitative comparison of force-interval relationships of the canine right and left ventricles. Circ Res 1984; 54:468–473. 123. Yamaguchi S, Li KS, Harasawa H, Zhu D, Santamore WP. The left ventricle affects the duration of right ventricular ejection. Cardiovasc Res 1993; 27:211–215. 124. Brown CD, Chow E, Farrar DJ. Left ventricular unloading decreases rate of isovolumic right ventricular pressure decline. Am J Physiol 1993; 265:H1663–H1669. 125. Schertz C, Pinsky MR. Effect of the pericardium on systolic ventricular interdependence in the dog. J Crit Care 1993; 8:17–23. 126. Buda AJ, Pinsky MR, Ingels NB, Daughters GJ, Stinson EB, Alderman EL. Efect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 301:453–459. 127. McGregor M. Pulsus paradoxus. N Engl J Med 1972; 249:480–482. 128. Brecher GA, Hubay CA. Pulmonary blood flow and venous return during spontaneous respiration. Circ Res 1955; 3:210–214. 129. Wexler L, Bergel DH, Gabe IT, Makin GS, Mills CJ. Velocity of blood flow in normal human vena cavae. Circ Res 1969; 23:349–359. 130. Hoffman JE, Guz A, Charlier AA, Wilcken DEL. Stroke volume in conscious dogs; effect of respiration, posture, and vascular occlusion. J Appl Physiol 1965; 20:865–877. 131. Leeman DE, Levine MJ, Come PC. Doppler echocardiography in cardiac tamponade: exaggerated respiratory variation in transvalvular blood flow velocity integrals. J Am Coll Cardiol 1988; 11:572–578. 132. Appleyard RF, Glantz SA. Pulmonary model to predict the effects of series ventricular interaction. Circ Res 1990; 67:1225–1237. 133. Santamore WP, Amoore JN. Buffering of respiratory variations in venous return by right ventricle: a theoretical analysis. Am J Physiol 1994; 267:H2163–H2170.
5 Venous Return
SHELDON MAGDER
STEVEN M. SCHARF
McGill University Health Center Montreal, Quebec, Canada
Albert Einstein College of Medicine Long Island Jewish Medical Center New Hyde Park, New York
I.
Introduction
Once organisms progressed beyond the level of single cells, it became essential to have a transport system to distribute nutrients and clear wastes. With the evolution of mammals and the development of means to regulate body temperature, the regulation of cardiac output became a major factor in the maintenance of homeostasis and the body heat of the organism. Blood flow delivers oxygen and nutrients and removes carbon dioxide and other wastes. Blood flow is tightly regulated by aerobic metabolic activity so that there is a linear relationship between cardiac output and oxygen consumption, both at the level of the whole body and in the regions of the body such as the heart and skeletal muscle (1). In a normal 70-kg male, cardiac output can increase more than fivefold, from 5 L/min to ⬎25 L/min (1). Since the heart can only put out what it gets, under steady-state conditions, it is obvious that cardiac output must equal the return of blood to the heart. Thus, a fivefold increase in cardiac output implies a fivefold increase in venous return. The regulation of venous return, and thus cardiac output, is the subject of this chapter. The regulation of cardiac output is often considered in terms of what regulates heart rate and stroke volume, but since the heart can only pump out what it gets, the determinants of return of blood to the heart are essential. It might seem at first 93
94
Magder and Scharf
that the heart should be able to regulate what it gets by putting more into the systemic circulation and this will then result in more blood coming back to the heart. However, this blood has to come from somewhere, and when there is a large compliant region in the circuit, as exists in the systemic circulation, the output from the heart does not determine the return of blood to the heart. The major theme of this chapter is that the heart regulates cardiac output by controlling right atrial pressure and neither arterial pressure nor the flow of blood from the heart determines the total blood flow, although they do determine regional flows. To illustrate this point, consider what happens when an individual performs isometric exercise. The blood pressure markedly increases but there is a minimal change in cardiac output (2). On the other hand, during dynamic exercise, mean blood pressure changes relatively little in the face of a relatively large change in cardiac output. As another example, septic patients have low blood pressures, yet very high cardiac outputs. Thus, under many clinically relevant conditions, there is little direct relationship between blood pressure and cardiac output, and blood pressure is a poor indicator of cardiac output. This becomes very obvious when observing patients who are continuously monitored in intensive care units. As will also be seen in this chapter, not only does the heart regulate cardiac output by regulating right atrial pressure, but the best the heart can do is to lower the right atrial pressure to zero, for this produces maximal venous return and cardiac output. In the upright posture, right atrial pressure in normal subjects is less than zero (3). Thus, in normal individuals in the upright posture, increasing cardiac function alone does not increase cardiac output unless accompanied by peripheral circulatory changes which increase venous return. Changes in pulmonary artery pressure have important effects on right atrial pressure, both in terms of the absolute right atrial pressure relative to atmosphere and in terms of the transmural right atrial pressure (4–7). Since from the point of view of regulating cardiac output, the role of the heart is to regulate right atrial pressure, changes in pleural pressure have a major effect on venous return and cardiac output through their effects on right atrial pressure. Thus, understanding the principles of venous return is essential for understanding heart-lung interactions.
II. Components of the System The normal blood volume of a 70-kg man is approximately 5.5 L. About 70% of this volume resides in small venules and veins (8,9). These vessels store a large volume at low pressures and are therefore very compliant. The inflow to this region is from the arterial vessels through the arterial resistance and capillaries. The arterial vessels have a small volume at a high pressure and their total compliance is ⬍1/ 30 of that of the venous system. The capillaries, too, have a very low compliance. When there is no flow in the system, the pressure is the same everywhere in the vasculature. When flow is present, there is some decrease in the volume in the large veins and an increase in volume in the arterial vessels. Because arterial compliance is so much smaller than the venous compliance, the increase in arterial pressure is
Venous Return
95
much larger than the fall in venous pressure. The output from each beat of the heart can only add the equivalent of a stroke volume to the volume in the venous compliant region, and, in the steady state, the same volume flows out of the compliant region on each beat. Thus, the pressure and volume in the compliant region do not change. This is also intuitive if one considers that the pressure starts the same everywhere. With flow, there is a rise in arterial pressure and a fall in the pressure in the large veins. Thus, some region must maintain the same pressure and that will be the most compliant region. The total compliance of the vasculature is equal to the sum of the parts. Because the venous compliance is so much larger than the arterial and capillary compliances, total vascular compliance is largely dependent on the venous compliance. It also needs to be appreciated that the venous vessels in the splanchnic region are much more compliant than those in the extremities, and as will be seen later, this has implications for cardiac output when the distribution of blood flow changes from the splanchnic to non splanchnic vascular beds. The blood volume in the venous compliant region drains back to the heart through a series of veins which provide a resistance to flow. This resistance is small and accounts for ⬍10% of the total pressure drop from the aorta back to the heart. It is thus often ignored (10), but this resistance to venous return is crucial, for it is an important determinant of the rate of flow out of the large upstream compliant vessels which have a low pressure but very large volume. Further, as will be discussed below, the distribution of blood flow between venous compartments of different drainage characteristics contributes to the resistance to venous return (11). In the model used in this chapter, the heart and lungs are considered as one unit with an inflow at the right atrium and an outflow at the aortic valve (8). However, the pulmonary compartment could be subdivided in a similar way as the systemic circulation with a pulmonary venous compliant region and pulmonary venous resistance (12). For the purposes of this chapter and an understanding of the interaction of the heart and circuit, it is sufficient to treat the heart and lungs as one unit, and changes in the resistance and compliances within the thoracic structures can be considered as either increasing or decreasing cardiac function.
III. Control of Cardiac Output As stated in the introduction, in the steady state, cardiac output must equal the return of blood to the heart. This in turn is determined by the mechanical characteristics of the circuit which can be called circuit function. This includes stressed vascular volume, venous compliance, resistance to venous return and the outflow pressure for the circuit, which is right atrial pressure. The right atrial pressure is controlled by cardiac function and the interaction of cardiac function and circuit function determine cardiac output. When the right atrial transmural pressure is less than zero, cardiac output is solely determined by the circuit factors (9). In the resting state and in the upright posture, right atrial pressure is, in fact, often less than zero. To understand the role of the circuit, an analogy is helpful (13,14) . The large compliance of the venules and veins is equivalent to having a large bathtub in the
96
Magder and Scharf
Figure 1 Bathtub concept of vascular capacitance. The height of the volume in the tub is the equivalent of the mean circulatory filling pressure (MCFP). When the opening is on the side of the tub, only the level of water above the hole contributes to the MCFP. The volume below this is unstressed volume.
middle of a hydraulic system (Fig. 1). The inflow tap is the equivalent of the arterial system. When the bathtub is filled and the plug removed, the rate of emptying of the tub changes little over the short run, whether or not the inflow tap is open. The outflow from the tub is determined by the height of the water above the hole at the bottom, the resistance in the pipe draining the tub and the downstream pressure at the end of the pipe, but it is not affected by the inflow over the short run. By ‘‘short run,’’ we mean approximately 60 sec, which may not seem long, but this is the time it takes for the total blood volume to circulate through the body. In the body, the lack of effect of inflow is even more significant, for in contrast to the bathtub, the source of volume for the arterial inflow is the volume draining out of the tub. If this flow decreases, there is very little volume in the heart and arteries that can be transferred to the tub to raise the height of the volume in the equivalent region of the tub and change its outflow. When the pressure in the outflow end of the tub equals the hydrostatic pressure in the tub, there is no flow from the tub. Similarly, when right atrial pressure equals the pressure in the compliant veins and venules, blood flow is zero. The equivalent pressure in the veins and venules to the hydrostatic pressure filling the tub is called the mean circulatory filling pressure (MCFP). It is determined by the volume filling the veins and the compliance of the veins. In animals, the value of MCFP is ⬃7 to 10 mm Hg under resting conditions. When the pressure at the outflow end of the tub is lowered, the tub empties. Similarly, when the right atrial pressure is lowered relative to MCFP, a pressure gradient develops and blood flows out of the veins and venules back to the heart. The lower the right atrial pressure relative to MCFP, the greater the gradient and the greater the flow. Thus, as argued above, the heart works by lowering right atrial pressure and the equation for venous return can be given by (15): MCFP ⫺ Pra Rv
(Eq. 1)
Venous Return
97
where MCFP is mean circulatory filling pressure, Pra is right atrial pressure, and Rv is the resistance to venous return. As will be seen below, this equation hold in vivo only when Pra is greater than zero. This analysis ignores the arterial compliance and lumps all the stressed volume in one compliant region which is considered to be in the veins. As arterial pressure rises, more volume is transferred from the compliant veins to the arteries, which modifies the results. However, because the arterial compliance is so small compared to the venous compliance, there is only a small error introduced in the overall analysis by leaving out the arterial compliance and the mathematics and conceptual understanding is much simpler. Therefore, arterial compliance is excluded in this analysis. Furthermore, arterial compliance is curvilinear, so that the compliance decreases at high pressures, reducing the impact of arterial compliance even further. Hence. It should be appreciated that the effects of arterial compliance on cardiac output are felt not through effects on volume transfer from venous reservoirs, but though effects on cardiac function which in turn affect right atrial pressure. Ernest Starling (16) appreciated the significance of MCFP at the turn of the last century in his investigations into the mechanisms of peripheral edema. He realized that even if the heart stopped completely, the pressure in the veins would only rise to that of the compliant region. Because the capillaries are upstream from this region, their pressure falls and approaches MCFP as flow decreases. Thus, the fall in output from a failing heart cannot elevate capillary pressures above MCFP by the decrease in output and, therefore, the heart itself does not directly cause edema. Edema occurs because of retention of fluid by the kidneys, which raises MCFP, which then raises the capillary pressures and increase filtration. In open chest anesthetized dogs, MCFP is ⬃8 mm Hg (15,17) and right atrial pressure is ⬃2 to 3 mm Hg. In closed-chest anesthetized animals values somewhat higher are measured for MCFP, in the range of 10 to 12 mm Hg (17–19). Thus, the gradient for venous return is usually small, in the range of 5 to 10 mm Hg. This means that changes in right atrial pressure of only a few mm Hg have very large effects on venous return and cardiac output (20). This is why cardiac output is so sensitive to changes in pleural pressure (6,18). Similarly, although the resistance to venous return is small, changes in this resistance also have large effect on venous return and cardiac output.
IV. Concepts of Stressed and Unstressed Volume An important concept for the understanding of venous return is that of stressed and unstressed volume. Returning to the analogy of the tub, consider the effects of putting the opening on the side of the tub (Fig. 1B). Once the water level falls to the level of the opening, no further flow will occur. In this tub, it is necessary to have sufficient volume to reach the level of the hole, but only the volume above the hole drives fluid out of the tub. Thus, only the hydrostatic column above the hole contributes to the flow, i.e., is stressed or creates a pressure. Similarly, a volume is necessary to fill out the round shape of the venules and veins. It is only the volume above this
98
Magder and Scharf
resting length that stretches the vessel walls and creates the pressure that drives the fluid out of the vessels, and thus only stressed volume is important for blood flow. The volume that just fills out the shape of the vessel is called the unstressed volume, for it does not ‘‘stress’’ the walls, and the volume above this level is called stressed volume for it stretches the vessel walls. The term that is used for describing the relationship of the total volume for a given pressure is capacitance and takes into account both unstressed and stressed volume (21). This is not to be confused with the term compliance which is the change in volume for change in pressure and represents the inverse of the slope of the pressure-volume relationship. We recently estimated stressed vascular volume in humans by examining patients undergoing an anesthetic technique called ‘‘clinical death’’ (14). This technique is used for patients who are undergoing surgery on the thoracic arch or vena cava and there is a potential for a large loss of blood. The patient is put on a cardiopulmonary bypass circuit and cooled down to 19°C which results in a flat electroencephalogram. The pump is then turned off and the blood is allowed to drain from the patient to the reservoir in the circuit. We simply measured the volume that came out when the pump was turned off. This was ⬃1.3 l and represented 25% to 30% of their predicted blood volume. This was probably the maximal capacitance for these patients who were anesthetized and cold and therefore had minimal vascular tone. As will be seen later, unstressed volume can be recruited into stressed volume and provides an internal volume reservoir. Thus, the amount of unstressed volume is important, for it determines the homeostatic reserves which are available when there is a loss of blood volume or a need for an increase in MCFP (22).
V.
Guyton’s Graphical Analysis
Based on his realization that the role of the heart in the regulation of cardiac output is through the regulation of right atrial pressure, Arthur Guyton developed a very useful graphical approach for analyzing heart and circuit interactions (8,15) which has been the basis for many subsequent analyses of the control of cardiac output. He reasoned that right atrial pressure is the variable regulated by the heart and therefore put it on the abscissa as the independent variable. He then plotted venous return on the y-axis. When venous return is zero, right atrial pressure (i.e., the x-intercept) equals MCFP (Fig. 2). That is, when right atrial pressure equals MCFP, the gradient for venous return is zero and flow is stopped (Eq. 1). When right atrial pressure is decreased by the action of the heart, venous return, and therefore cardiac output occurs (Fig. 2B). The venous return increases as the right atrial pressure is lowered further, until the right atrial pressure falls below the surrounding pleural pressure (Fig. 2C). During spontaneous breaths, this occurs at a right atrial pressure of approximately zero relative to atmosphere. Lowering right atrial pressure below this value does not result in a further change in cardiac output because the great veins collapse as they enter the thorax, and venous return (and cardiac output) is maximal. This is because the pressure inside the veins is less than the pressure outside the veins and their transmural pressure is a negative value. It is important to appreciate
Venous Return
99
Figure 2 The top of the figure shows the equivalent of the bathtub emptying into the heart under three different conditions. In (A), right atrial pressure (Pra) equals mean circulatory filling pressure (MCFP) and the flow (Q) is zero. In (B), Pra is less than MCFP and there is flow. In (C), Pra is less than atmosphere (zero surrounding pressure), and there is venous collapse and flow limitation. The corresponding positions on the venous return curve are shown on the bottom part of the figure.
that venous return and cardiac output do not stop when right atrial pressure is less than zero, it is just that they do not increase with further decreases in right atrial pressure. An analogy that is useful for the understanding of this phenomenon is that of a vascular waterfall (23). The amount of water flowing over a waterfall is determined by height of the lake upstream from the falls, the width of the river, the rocks in the river, etc., between the lake and the falls. It is not, however, determined by the height of the falls. Niagra Falls could be 1 m high or 30 m high, but the volume per minute flowing over the falls would not be affected. The power loss would be different, but not the flow. Thus, when a vascular waterfall is present, downstream characteristics of the river no longer affect the flow. Similarly, once the right atrial pressure is less than the surrounding pleural pressure, the great veins collapse as they enter the thorax and lowering right atrial pressure further does not increase flow more. This means that if the heart is taken out and the veins are allowed to drain to atmospheric pressure, venous return will be maximal. Thus, the heart only gets in the way of the venous return! Obviously, however, the heart is essential for returning the blood back to the compliant veins, i.e., the equivalent of the bathtub; this maintains MCFP which drives the blood back to the heart. We would only last for brief seconds if the circuit is disrupted, especially considering that the flow per minute is about the same as the total blood volume. Since the venous return is maximal when right atrial pressure ⱕ0, the equation for maximal venous return is: VRmax ⫽
MCFP Rv
(Eq. 2)
100
Magder and Scharf
where Rv ⫽ resistance to venous return. Since MCFP equals stressed volume (Vs) divided by venous compliance (Cv): VRmax ⫽
Vs Cv ⫻ Rv
(Eq. 3)
A resistance times a compliance gives the time constant for a monoexponential function. Therefore, VRmax ⫽
VS τv
(Eq. 4)
where τv is the time constant for drainage from the venous compartment and is the product of Rv and Cv. The time constant is an index of the drainage characteristics of a compliant reservoir draining through a resistance and is equal to the time it takes for the volume to 1/e of the total volume drained. The less the time constant the faster the drainage. If arterial compliance had been included, one would add a τ, for arterial drainage. In summary, the determinants of venous return are the stressed volume (i.e., total volume minus unstressed volume), venous compliance, resistance to venous return, and right atrial pressure, and venous return is maximal when right atrial pressure equals zero. An increase in venous return comes from an increase in stressed volume, decrease in venous compliance, decrease in resistance to venous return and a decrease in right atrial pressure. VI. Role of the Heart As we have already stated, the role of the heart in the determination of cardiac output is to regulate right atrial pressure. On the other hand, through the Frank Starling mechanism, right atrial pressure is an important determinant of stroke volume and thus cardiac output. The Frank Starling principle is based on the lengthtension properties of muscle and says that the greater the initial length of the cardiac muscle, the greater the force generated and the greater the degree of shortening, if shortening occurs (16). This is analyzed at a given level of contractility, afterload, and heart rate. The relationship can be graphically shown with a plot of the right atrial pressure as an indicator of the passive force that stretches the sarcomeres, i.e., preload, on the x-axis, and cardiac output, i.e., the total output of the heart, on the y-axis. Since these are the same coordinates that are used for the venous return plot, cardiac function and the venous return curve can both be plotted on the same graph (15). This analysis shows that cardiac output and right atrial pressure are the result of the intersection of pump function, which is made up of a set of cardiac outputs and right atrial pressures for a given contractility, heart rate and afterload, and circuit function, which is made up of a set of venous returns for a given stressed volume, venous compliance, and resistance to venous return. This plot allows an analysis of the interaction of changes in pump function and changes in circuit function on the final cardiac output and right atrial pressure. One modification, however, is neces-
Venous Return
101
sary. Because the heart is surrounded by the pleural pressure, and at end-expiration pleural pressure is slightly negative relative to atmosphere, the pressure surrounding the circuit, the cardiac function curve at end expiration must be placed slightly negative to the circuit function curve, i.e., shifted to the left of the venous return curve (Fig. 2). We can now examine the effects of changes in cardiac and circuit factors on cardiac output and right atrial pressure. A semantic issue must, however, first be addressed. One must distinguish a change in cardiac output from a change in cardiac function. Further, the term ‘‘cardiac function’’ is not equivalent to contractility. Rather, this term refers to the overall pump function of the heart which can be affected by the classical parameters of heart rate, afterload, and contractility. Overall cardiac pump function is also affected by changes in the pulmonary circulation, valvular heart disease, and pericardium. Similarly, a change in circuit function, or change of the venous return curve, is to be distinguished from a change in the actual venous return. The actual cardiac output and venous return are determined by the interaction of circuit and cardiac function, which are sets of cardiac outputs and venous returns respectively. An increase in contractility, decrease in afterload, or increase in heart rate all rotate the cardiac function curve upward. If there is no change in circuit function (venous return curve), this will result in a fall in right atrial pressure and an increase in cardiac output (Fig. 3). A decrease in pump function will result in an increase in right atrial pressure and a decrease in cardiac output (as well as venous return) even though the venous return curve or circuit function does not change. As noted above, the best the heart can do is lower right atrial pressure to zero and in the upright position, the right atrial pressure is often less than zero (3). Under this condi-
Figure 3 On the left-hand side of the figure, the venous return curve and cardiac function curves are shown. An increase in contractility shifts the cardiac function curve upward so that there is a rise in output with a fall in right atrial pressure. On the right-hand side of the figure, this is schematically shown as effectively lowering the right atrial pressure relative to the top of the volume in the venous capacitant region. This increases the gradient for venous return.
102
Magder and Scharf
Figure 4 The venous return curve and cardiac function curve with increasing degrees of cardiac function. When the cardiac function curve intersects near the plateau of the venous return curve, increases in cardiac function have only a small change in cardiac output, and once the plateau of the venous curve is reached, there is no further change in cardiac output. The dashed and dotted lines indicate increases in cardiac function. The increase represented by the dotted line did not result in a further increase in cardiac output because the curve intersects the flat part of the venous return curve.
tion, increases in cardiac function, for example, from an increase in heart rate, do not affect flow (Fig. 4). The effect on cardiac output of an increase in cardiac function thus depends on the magnitude of the initial right atrial pressure. The right atrial pressure, in turn, depends on the interactions of cardiac function and circuit function. Cardiac function is often assessed by examining the pulmonary arterial occlusion (wedge) pressure (Pw) as an index of the preload of the left heart and cardiac output.
Figure 5 The left side of the figure shows the pressure-volume relationship of the left heart. The dotted lines represent what happens with a decrease in contractility. This results in a rise in left ventricular end-diastolic pressure. However, this only decreases cardiac output when rise in left-sided pressure results in a rise in right atrial pressure as shown on the venous return curve and cardiac function curve on the right-hand side of the figure. This shows a fall in cardiac output and a rise in right atrial pressure.
Venous Return
103
It is argued that the right atrial pressure does not give an indication of adequacy of filling of the left heart. However, for the purpose of analyzing cardiac output, it is the right atrial pressure that is important, for it indicates the interaction of the heart and circuit, and even with pure failure of the left heart, cardiac output only decreases because of the rise in right atrial pressure decreases the gradient for venous return (Fig. 5). It should be clear that the best possible indicator of ‘‘volume’’ status in clinical situations would be direct measurements of MCFP. Unfortunately, this would require stopping the circulation. Measures of Pra (central venous pressure) depend on the interaction of venous return (MCFP and resistance to venous return) and cardiac function and are less good an indicator. Nevertheless, intelligent assessment of the patient can aid in interpretation of the data (see below). The worst indicator of ‘‘volume status’’ is the Pw, which is far removed from the ‘‘action’’ at MCFP. Thus, while Pw is important in assessing left ventricular function in many clinical situations both diagnostically and therapeutically, it is certainly no dipstick into the peripheral circulatory reservoirs and cannot be directly translated into ‘‘volume status.’’
VII. Changes in Circuit Function (Changes in the Venous Return Curve) One of the commonest clinical manipulations in critically ill patients is the infusion of volume. This expands stressed volume and thereby increases MCFP (Fig. 6). The venous return curve is shifted to the right and intersects the cardiac function curve at a higher right atrial pressure and cardiac output increases without any change in cardiac function. This results in a higher cardiac output for any given right atrial pressure and, importantly, a higher maximal venous return and maximal cardiac output. This is because collapse of the great veins occurs at a higher value of venous return. The increase in cardiac output without a change in cardiac function occurs because only the heart’s preload mechanism has been used. A loss of intravascular volume lowers MCFP, shifts the venous return curve to the left, which decreases cardiac output at any right atrial pressure, and, importantly, decreases maximal venous return. When this results in a cardiac output which is less than that required for normal homeostatic function, further stimulation of cardiac function will not increase cardiac output, and it is necessary to add volume to restore cardiac output. Another way that MCFP can be altered is by a change in vascular capacitance (21). Vascular capacitance is determined by the tone in the walls of the small venules and veins. Contraction of smooth muscles in these vessels results in a decrease in the cross-sectional area of the vessels, but does not seem to change the elastic properties of the walls of the vessels. Thus, the slope of the pressure-volume relationship is unchanged but the position of the curve is shifted (Fig. 6) (17,24,25). The same total blood volume is now at a higher pressure. In other words, unstressed volume is converted into stressed volume. In the bathtub analogy, this is the equivalent of lowering the opening of the tub so that less volume is needed to get to the opening and more of the volume in the tub can empty. The tone of the capacitant vessels is under sympathetic control and therefore affected by neurosympathetic activation and
104
Magder and Scharf
Figure 6 The top graph shows the pressure-volume relationship of the vasculature and the bottom part shows the cardiac function and venous return curves. The left upper figure shows that an increase in volume raises MCFP by moving up the pressure-volume relationship of the vasculature. This shifts the venous return curve to the right and increases Pra and cardiac output. In the upper right side of the figure, the change in capacitance is shown. The pressurevolume curve is shifted to the left so that, for the same volume, there is higher MCFP. It has exactly the same effect on the venous return cardiac function relationship as an increase in volume and, thus, acts effectively as an autotransfusion.
exogenous catecholamines such as norepinephrine. Activation of neurosympathetic pathways can decrease venous capacitance by recruiting unstressed volume and raising MCFP (21,26). This shifts the venous return curve to the right and is indistinguishable from an infusion of volume (Fig. 6). It also appears that a change in capacitance can occur in the veins and venules without a change in resistance to venous return (21,25). From animal studies, it appears that 10 to 18 mL/kg can be ‘‘recruited’’ from unstressed volume. This mechanism can thus provide a rapid autotransfusion. For example, a decrease in capacitance of 10 mL/kg in a 70-kg man is equivalent to an immediate infusion of 2.1 L of normal saline (assuming a distribution of 1/3 intravascular and 2/3 extravascular distribution of the normal saline) and this change occurs in only a few seconds. This provides an important compensatory mechanism for losses of intravascular volume in situations where MCFP needs to be increased to maintain blood flow. For example, when intrathoracic pressure is increased, transmission of increased intrathoracic pressure to the right atrium would increase Pra and decrease the gradient for venous return. To preserve venous return, MCFP increases and maintains the gradient for venous return (18). Further, MCFP increases with sympathoadrenal stimulation (see below) in a variety of situations important clinically. For example with hypoxia
Venous Return
105
(19), MCFP increases to allow increased venous return and cardiac output, thus maintaining oxygen delivery in the face of decreased arterial oxygen content. There are a number of important clinical and physiological implications to these concepts. There is a limit to the amount of unstressed volume which can be recruited by increasing venous tone and, once this limit is reached, a further loss of vascular volume results in an uncontrolled decrease in MCFP (Fig. 7). This shifts the venous return curve to the left and results in a decrease in the maximum venous return and cardiac output. This explains why patients with gastrointestinal bleeds often have a stable cardiac output and blood pressure even with large bleeds and then suddenly deteriorate. They were most likely compensating for the loss of volume by decreasing venous capacitance to maintain MCFP, venous return, and cardiac output. However, the limit of their ability to adapt by decreasing capacitance is reached, and a further loss of volume results in a fall in MCFP which cannot be compensated. The venous return curve is shifted to the left and there is a precipitous fall in cardiac output and blood pressure. A difficult clinical problem is that capacitance cannot be measured in an intact person and is even difficult to measure in animals (17,26,27). Thus, at the bedside, capacitance must be predicted from the volume history of the patient, such as whether there has been a loss of volume by hemorrhage, gastrointestinal losses, or excessive diuresis. Failure to consider the vascular capacitance can have significant consequences. For example, the loss of volume in a patient who has a gastrointestinal bleed can be compensated by a decrease in vascular capacitance which will maintain MCFP, venous return, and cardiac output. If, however, this patient is given a nar-
Figure 7 This figure illustrates the limits to defense of cardiac output by recruiting unstressed volume. If the patient has a steady loss of volume, as for example with a severe hemorrhage, MCFP can still be maintained by a reduction in capacitance, i.e., a shift to the left of the pressure-volume relationship as shown from 1 to 3. This can maintain the Pra and cardiac output. However, when the limit of the reduction in capacitance is reached, a further decrease in volume results in a decrease in MCFP. This results in a fall in cardiac output, a fall in Pra, and, importantly, a fall in the maximum cardiac output, i.e., the plateau of the venous return curve.
106
Magder and Scharf
cotic, nitrate, or a sympathetic blocker, all of which decrease venous tone, the compensatory increase in venous tone is removed, MCFP falls, and cardiac output falls. This point also needs to be considered when analyzing cardiovascular responses to drugs and respiratory maneuvers. The hemodynamic responses to various maneuvers will be greatly affected by the capacitant reserves of the patient, and these reserves are dependent on the total blood volume (stressed and unstressed) and the sympathetic tone. Circuit function can also be improved by a decrease in resistance to venous return (8). This effectively lets the bathtub drain more easily as, for example, would occur if the plumber put a wider drain at the bottom of the tub. An important component of the resistance to venous return from the abdomen may be located at an effective sphincterlike mechanism in the hepatic veins (28). The tone in these vessels is decreased by beta-adrenergic agents (28) and increased by alpha-adrenergic agents (29). Venous tone and thus resistance can change in the opposite direction from changes in arterial tone. For example, we found that a decrease in carotid sinus pressure provoked an increase in neurosympathetic activity which resulted in arterial vasoconstriction and increased arterial resistance. But at the same time, it resulted in a decrease in resistance to venous return draining the splanchnic bed (26). Resistance to venous return is also decreased by nitrites (30) and other vasodilating drugs and is most likely decreased in sepsis, which would account for the marked increase in cardiac output in sepsis patients (see Chapter 28). Resistance to venous return is increased by alpha-adrenergic drugs (29), nitric oxide synthase inhibitors (30), and possibly endothelin (31). The relative effect of a drug on capacitance vessels versus its effects on the resistance to venous return has an important impact on the change produced in cardiac output that occurs with a drug. Thus, a drug that is primarily an alpha constrictor will increase MCFP, but also increase resistance to venous return. It will thus decrease venous return and cardiac output. On the other hand, a drug with alpha and beta properties, such as norepinephrine, can decrease vascular capacitance with either no change or even a decrease in resistance to venous return because, as discussed above, β agonists seem to decrease resistance to venous return in the splanchnic bed. This will further increase cardiac output (32). An effective decrease in resistance to venous return occurs when there is a redistribution of blood flow from the splanchnic bed, which has a large venous compliance, to the nonsplanchnic beds, which have much smaller venous compliances (Fig. 8) (33). This can be considered to be analogous to a bathtub and sink in parallel. If more of the flow is shifted to the sink, the water level rises and the output increases. On the other hand, the bathtub outflow does not change much because it has a very large surface and the loss of volume has only a small effect on the height of the water in the tub. This produces a decrease in the slope of the venous return curve without a change in MCFP, the hydrostatic pressure in the capacitance reservoirs. For this mechanism to be effective, the differences in time constants and/or the shift in blood flow between the reservoirs needs to be large. Shifting of blood flow between regions of different time constants may be an important mechanism whereby cardiac output increases in exercise (34) as blood flow shifts to the short time constant drainage beds of the muscles.
Venous Return
107
Figure 8 This figure illustrates the principle behind the two parallel compartment model of the vasculature. The splanchnic bed has a large capacitant region whereas the peripheral muscle has a smaller capacitance. When there is a shift of the fraction of flow to the muscle bed, the pressure rises in the muscle bed, which increases flow from this region. The upper part of the curve shows the venous return curves in the two models. With a shift to the muscle bed, there is a decrease in the resistance to venous return. In exercise, this is usually met by a rise in cardiac function so that Pra may not change and the cardiac output is significantly increased. Ra-s ⫽ splanchnic arterial resistance; Ra-p ⫽ peripheral arterial resistance; Rv-s ⫽ resistance to venous return draining the splanchnic bed; Rv-v ⫽ resistance to venous return draining the peripheral bed.
When any of the above mechanisms increase circuit function, there is an increase in cardiac output with an increase in right atrial pressure. This is in contrast to what happens when there is an increase in cardiac function, which produces an increase in cardiac output with a fall in right atrial pressure. A common observation in patients is that there is a rise or fall in cardiac output with no change in right atrial pressure. For this to occur, there has to be a change in both cardiac output and circuit function (Fig. 9). An example where there is an increase in cardiac output with no change in the right atrial pressure, is the response to norepinephrine. Administration of norepinephrine increases cardiac function and also decreases capacitance and thereby increases MCFP. The latter shifts the venous return curve to the right at the same time as the cardiac function curve is shifted upward so that there is no change in right atrial pressure (32). We saw that there was a limit to the ability of the heart to increase cardiac output, because of collapse of the great veins as they enter the thorax. Thus, when right atrial pressure is less than pleural pressure, cardiac output is maximal (18).
108
Magder and Scharf
Figure 9 This figure illustrates how there can be a rise in cardiac output without a change in Pra. This occurs when there is an increase in cardiac function and circuit function (shown in dotted lines).
There is also a limit to the potential benefit of increasing venous return. This occurs because there is a plateau to the cardiac function curve which is produced under normal conditions by the pericardium, but the cardiac cytoskeleton and the even the mediastinal structures can also limit filling (35). Once this plateau is reached, further increases in right atrial pressure, i.e., preload, will not produce a further increase in cardiac output because there is no further stretch of the sarcomeres (Fig. 10). The heart can then be considered to be volume limited. Failure to appreciate this point can result in the misuse of volume in patients. Based on this reasoning, right atrial pressure is the value which should be used to determine the optimal volume for cardiac output and not the wedge pressure. This
Figure 10 This figure shows the principle behind the limit to the potential to increase cardiac output by increases in preload. When the venous return curve intersects the flat part of the cardiac function curve, further shifts to the right of the venous return curve and increases in Pra do not change cardiac output. The dotted and dashed lines represent increases in circuit function.
Venous Return
109
is especially true when right ventricular dysfunction is present, for the limit on the system occurs in the right heart, and even if the left heart is underfilled, further volume loading will not be of help. There can be no left-sided success without rightsided success. Furthermore, when cardiac output is limited by right heart function, only the cardiac function curve of the right heart is of important for the control of cardiac output. Thus, in this condition, decreases in left ventricular afterload or increases in contractility do not affect cardiac output. Even in a patient with a pure left heart problem, it is still the right atrial pressure which determines the interaction of cardiac function and circuit function and thus cardiac output (8). Cardiac output can only fall with left heart dysfunction when the left ventricular end-diastolic pressure increases, which increases left atrial pressure, which increases pulmonary venous pressure, which increases pulmonary arterial pressure, which increases the load on the right heart and increases right ventricular pressure, which increases right ventricular end-diastolic pressure, which increases right atrial pressure. Thus, the cardiac function curve intersects the venous return curve at a lower flow value and cardiac output is decreased. As indicated above, the cardiac function curve starts at a negative right atrial pressure relative to atmosphere because the heart is surrounded by subatmospheric pleural pressure at end expiration, the usual time point for hemodynamic measurements. Since pleural pressure changes during the ventilatory cycle, the position of the cardiac function curve relative to the venous return curve changes during the ventilatory cycle (6,18). The fall in pleural pressure with a spontaneous breath, shifts the cardiac function curve to the left, which results in a fall in right atrial pressure and an increase in cardiac output as long as the venous return curve does not intersect the flat part of the cardiac function curve (Fig. 11). When the venous return curve intersects the flat part of the cardiac function curve, there is no change in right atrial pressure or cardiac output with a spontaneous breath. This point can be used to determine if a patient’s heart is volume limited (see Chapter 33). On the other hand, an increase in pleural pressure shifts the cardiac function curve to the right, which
Figure 11 This figure illustrates the effects of changes in intrathoracic pressure on the interaction of cardiac function and circuit function. With a decrease in pleural pressure (i.e., spontaneous breath), the cardiac function shifts to the left relative to the venous return curve (dashed line). There is a small rise in output with a fall in Pra. With an increase in intrathoracic pressure, the cardiac function curve is shifted to the right (dotted line) and there is a fall in output with a rise in Pra.
110
Magder and Scharf
decreases cardiac output and increases right atrial pressure unless the venous return curve intersects the flat part of the cardiac function curve in which case there is no fall in cardiac output until the ascending part of the cardiac function curve intersects the venous return curve. The increase in pleural pressure also changes the collapse pressure in the great veins which, as noted above, occurs when right atrial pressure is less than pleural pressure. VIII. An Applied Physiological Approach to Hypotension Consideration of the interaction of the heart and circuit can be useful for diagnosing the cause of hypotension and determining the appropriate therapeutic response (36). We find it helpful to start with a statement of Poiseulle’s Law which says that blood pressure equals cardiac output times systemic vascular resistance. To be precise, there really should be the addition of a small downstream pressure but this is small and relatively constant. Thus: BP ⫽ Q ⫻ SVR (⫹C)
(Eq. 5)
where BP ⫽ blood pressure, Q ⫽ cardiac output, SVR ⫽ systemic vascular resistance, and C is the downstream pressure which is essentially a constant and can be ignored. A low blood pressure is thus due to either a decrease in systemic vascular resistance or a decrease in cardiac output. Since systemic vascular resistance is a derived variable from the measured cardiac output and blood pressure, the question is really whether the blood pressure is decreased (1) with a normal or elevated cardiac output, in which case the problem is the decrease in systemic vascular resistance, or (2) with a decrease in cardiac output, in which case the cardiac output is the problem. If a systemic vascular resistance problem is identified, the diagnostic possibilities include sepsis, spinal injury, epidural drugs, vasodilating drugs, anemia, liver disease, beri-beri, thyrotoxicosis, or anaphylaxis. All these should be evident clinically. Early management should then include therapy which raises the systemic vascular resistance such as norepinephrine. If, on the other hand, cardiac output is decreased, then one must consider whether this is due to a decrease in cardiac function or a decrease in circuit function. This can be determined by examining the right atrial pressure (see comments above regarding Pw). If it is elevated, then the primary problem is the heart and therapy should be directed to improving cardiac function. If right atrial pressure is low, then the primary problem is the circuit and inadequate vascular volume is the commonest problem and volume infusion is the therapy of choice. Thus, appreciation of the basic principles of circuit function (i.e., venous return) and cardiac function can lead to a rapid assessment of the cause of hypotension and the correct therapeutic approach. References 1.
Clausen JP. Circulatory adjustments to dynamic exercise and effect of physical training in normal subjects and in patients with coronary artery disease. Prog Cardiovasc Dis 1976; 18:459–495.
Venous Return 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
111
Asmussen E. Similarities and dissimilarities between static and dynamic exercise. Circ Res (Suppl) 1981; 48:I3–I10. Notarius CF, Levy RD, Tully A, Fitchett D, Magder S. Cardiac vs. non-cardiac limits to exercise following heart transplantation. Am Heart J 1998; 135:339–348. Scharf SM, Brown R, Saunders N, Green LH, Ingram R. Changes in canine, left ventricular size and configuration with positive end-expiratory pressure. Circ Res 1979; 44:672–678. Scharf SM, Brown R, Saunders N, Green LH. Hemodynamic effects of positive-pressure inflation. J Appl Physiol: Respir Environ Exercise Physiol 1980; 49(1):124–131. Scharf SM, Brown R, Tow DE, Parisi AF. Cardiac effects of increased lung volume and decreased pleural pressure. J Appl Physiol 1979; 47:257–262. Scharf SM, Caldini P, Ingram RH. Cardiovascular effects of increasing airway pressure in the dog. Am J Physiol 1977; 232(1):H35–H43. Guyton AC, Jones CE, Coleman TG. Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: W.B. Saunders, 1973. Guyton AC, Lindsey AW, Kaufman BN. Effect of mean circulatory filling pressure and other peripheral circulatory factors on cardiac output. Am J Physiol 1955; 180:463–468. Berne RM, Levy MN. The cardiovascular system. In: Berne RM, Levy MN. eds. Physiology. St. Louis: C.V. Mosby, 1983:439–638. Caldini P, Permutt S, Wadell JP, Riley R. Effect of epinephrine on pressure, flow and volume relationships in the systemic circulation of dogs. Circ Res 1974; 34:606–623. Permutt S, Wise RA, Sylvester JT. Interaction between the circulation and ventilatory pumps. In: Lenfant C, Roussos CH, eds. The Thorax. New York: Marcel Dekker, 1988. Magder S. Heart-lung interactions in sepsis. In: Dantzker DR, Scharf SM, eds. Cardiopulmonary Critical Care, Philadelphia: W.B. Saunders, 1998:435–448. Magder S, De Varennes B. Clinical death and the measurement of stressed vascular volume. Crit Care Med 1998; 26:1061–1064. Guyton AC. Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev 1955; 35:123–129. Starling EH. The Linacre Lecture of the Law of the Heart. London: Longmans, Green & Co., 1918. Nanas S, Magder S. Adaptations of the peripheral circulation to PEEP. Am Rev Respir Dis 1992; 146:688–693. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of positive end-expiratory pressure on the gradient for venous return. Am Rev Respir Dis 1992; 146:4–10. Tarasiuk A, Scharf SM. Effects of periodic obstructive apneas on venous return in closedchest dogs. Am Rev Respir Dis 1993; 148: 323–329. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of positive end-expiratory pressure on the gradient for venous return. Am Rev Respir Dis 1991; 143:19–24. Rothe CF. Venous system: physiology of the capacitance vessels. In: Shepherd JT, Abboud FM, eds. Handbook of Physiology, Bethesda, MD: American Physiological Society, 1983: 397–452. Rothe CF. Reflex control of veins and vascular capacitance. Physiol Rev 1983; 63(4):1281– 1295. Permutt S, Riley R. Hemodynamics of collapsible vessels with tone: the vascular waterfall. J Appl Physiol 1963; 18(5):924–932. Deschamps A, Fournier A, Magder S. The influence of neuropeptide Y on regional vascular capacitance in dogs. Am J Physiol 1994; 266:H165. Deschamps A, Magder, S. Effects of heat stress on vascular capacitance. Am J Physiol 1994; 266: H2122–H2129. Deschamps A, Magder S. Baroreflex control of regional capacitance and blood flow distribution with or without alpha adrenergic blockade. J Appl Physiol 1992; 263:H1755–H1763. Magder S, Vanelli G. Circuit factors in the high cardiac output of sepsis. J Crit Care 1996; 111:155–166. Green JF. Mechanism of action of isoproterenol on venous return. Am J Physiol 1977; 232(2):H152–H156. Appleton C, Olajos M, Morkin E, Goldman S. Alpha-1 adrenergic control of the venous circulation in intact dogs. J Pharmacol Exp Ther 1985; 233:729–734.
112 30. 31. 32. 33. 34. 35. 36.
Magder and Scharf Magder S. Kabsele K. Evidence for constitutive release of nitric oxide in the venous circuit of pigs. J Cardiovasc Pharmacol 1998; 32:366–372. Rastegarpanah M, Magder, S. Role of sympathetic pathways in the vascular response to sepsis. J Crit Care 1998; 13:169–176. Datta P, Magder S. Hemodynamic response to norepinephrine with and without inhibition of nitric oxide synthase in porcine endotoxemia. Am J Respir Crit Care Med 1999; 160: 1987–1993. Permutt S, Caldini P. Regulation of cardiac output by the circuit: venous return. In: Boan J, Noordergraaf A, Raines J, eds. Cardiovascular System Dynamics, Cambridge, MA: MIT Press, 1978: 465–479. Magder S, Vanelli G. Cardiac and circuit interactions and high output sepsis in pigs. Intensive Care Med 1994; 20(S1): S17 (Abstract). Bishop VS, Stone HL, and Guyton AC. Cardiac function curves in conscious dogs. Am J Physiol 1964; 207(3):677–682. Magder S. Shock Physiology. In: Pinsky MR, Dhainault JF. eds. Physiological Foundations of Critical Care Medicine. Philadephia: Williams and Wilkins, 1992:140–160.
6 Models of Tissue Oxygen Uptake and Microcirculatory Blood Flow
SOREL BOSAN and KEITH R. WALLEY University of British Columbia Vancouver, British Columbia, Canada
I.
Introduction
Maintaining an adequate supply of oxygen to metabolically active tissues is crucial. Failure to do so will slow aerobic metabolism, induce ATP production from alternative anaerobic pathways, and lead to tissue damage. Since the critical metabolite for most organs is oxygen, circulation physiology for these organs is designed to maintain a tissue oxygen supply that matches tissue oxygen demand. To understand the complex steps involved in flow of oxygen from the atmosphere to tissues, investigators have developed conceptual models and test these models with experimental measurement. Unfortunately, many of the key features of oxygen transport can not be easily measured. Accordingly, mathematical models of these processes have been developed to help test and refine our conceptual models, and so increase our understanding of oxygen transport. In this chapter we review models of oxygen transport and closely associated models of microcirculatory blood flow. We first review, in broad strokes, the transport of oxygen from the atmosphere to the mitochondria in order to make the problem of understanding oxygen uptake tractable. Diffusion is a key component of oxygen transport so we briefly review Fick’s law—an early and simple model of one step in the oxygen transport pathway. Next we consider oxygen uptake by the lungs. While the lungs are not a focus of this chapter, many key issues relevant to models of tissue oxygen uptake are found 113
114
Bosan and Walley
in the lungs and have been more completely studied in this organ. We move to Krogh cylinder models of tissue oxygen uptake—really the first fully developed mathematical models. Recent extensions of these models are considered. While these models enhance our understanding, they leave many features unexplained and highlight the observation that features of oxygen transport, such as microregional tissue Po2, cannot easily be measured. Since this can not be done directly, an alternative approach is to measure the onset of anaerobic metabolism, which occurs at very low mitochondial Po2 (even though it can not easily be measured). Therefore we review models of the relationship between oxygen consumption and delivery. This leads to a discussion of the importance of heterogeneity of blood flow and oxygen delivery. Thus, we finish with a review of models that incorporate heterogeneity in one way or another. II. A Global Conceptual Model It is useful to consider the pathway of oxygen transport from the air we breath to the final step of the electron transport chain as a global conceptual model linking individual steps in oxygen transport. First, lung ventilation transports oxygen by bulk flow to the alveolar-capillary membrane. Next, diffusion down an oxygen partial pressure (Po2) gradient transports oxygen onto hemoglobin molecules in the blood. The next step in oxygen transport is bulk flow of oxygenated blood from the lungs to the tissues. One of the most important features of oxygen transport is close matching of the rate of individual capillary oxygen delivery to the rate of oxygen consumption by cells surrounding individual capillaries—hence the central role of microcirculatory blood flow and the importance of corresponding models. Then, diffusion down an oxygen partial pressure gradient carries oxygen from hemoglobin in the capillaries into the surrounding tissue. In the surrounding tissue different carriers for oxygen, such as myoglobin, are available to facilitate oxygen transport (1). Diffusion plays an important role over the small distances encountered within cells. Finally, mitochondrial oxygen accepts low energy electrons at the end of the ATPproducing electron transport chain. Note that diffusion is critically important at several steps and unimportant at others. III. Fick’s Law Fick’s law (1) is one of the earliest mathematical models of oxygen transport and states ˙ gas) depends on the area of tissue (A), that diffusion of a gas through a sheet of tissue (V on the diffusivity of the gas (Dgas), on the gas partial pressure difference (P1 ⫺ P2) across the tissue, and inversely on tissue thickness (T). Thus, Fick’s law is: ˙ gas ⫽ A ⋅ Dgas ⋅ (P1 ⫺ P2)/T V Diffusivity of a gas is a physical constant that is proportional to the solubility of the gas in the tissue sheet divided by the square root of the molecular weight of the gas. The area for diffusion and thickness depend on anatomy. Thus, oxygen partial pressure is crucial in limiting diffusion-dependent steps in oxygen transport.
Microcirculatory Blood Flow
115
IV. Oxygen Transport in the Lung The main function of the lungs is to move the oxygen from the air into the circulation. To this effect, the lung contains roughly 5 ⫻ 108 alveoli (2), which are the main sites of oxygen uptake. The net effect of subdividing the lung into so many small sacs is an enormous increase in surface area that can be exposed to the inspired air and, by Fick’s law, aid diffusion. To complement this, the microcirculation of the lung has also evolved into a unique structure, forming effective sheets of flowing blood around each alveolus (3). The sheet flow allows full utilization of the increased surface area offered by the alveolus, lowering the resistance to oxygen flux thus reducing the oxygen pressure gradient needed to drive oxygen transport. Moreover, this sheet is located extremely close to the alveolar wall, resulting in a diffusion distance of less than 0.5 µm for gaseous exchange between air and blood. Finally, pulmonary arterioles are also unique compared to other organs in that morphologically they are more similar to systemic venules than systemic arterioles, serving to minimize the resistance to flow into the lungs. Thus, the design of the lungs greatly facilitates the diffusion of oxygen from inspired gas into the blood. This design is so efficient that even in disease states that result in arterial hypoxemia oxygen transport across the lungs is rarely limited by diffusion but can be limited by alveolar hypoventilation, shunt, and ventilation-perfusion (VA /Q) mismatch in the lungs. A. Diffusion limitation
Diffusion limitation of oxygen transport from alveoli to arterial blood in the lungs only becomes the limiting step to overall oxygen transport in exceptional circumstances. In athletes exercising maximally at high altitude the transit time of blood through the pulmonary capillaries can become shorter than the loading time of oxygen onto hemoglobin (4), resulting in diffusion limitation of gas transport. However, in almost all other circumstances diffusion does not limit gas transport (5). B. Hypoventilation
Even with the highly specialized design of the lungs for gas exchange, there is still a drop of 55 torr between the inspired air and the alveolar oxygen pressure (6). Much of this large drop is due to the dilution of oxygen with water vapor and carbon dioxide. These ideas are expressed by the alveolar gas equation as follows: PAo2 ⫽ (PB ⫺ PH2O ) ⫻ FI o2 ⫺ (Paco2 /R) where PAo2 is the partial pressure of oxygen in the alveolus, PB is the barometric pressure, PH2O is the partial pressure of water vapor, FI o2 is the fraction of inspired oxygen, Paco2 is the partial pressure of arterial carbon dioxide, and R is the respira˙ co /V ˙ o . The alveolar gas equation indicates that PAo2 must decrease tory quotient, V 2 2 as Paco2 rises. A decrease in alveolar Po2 then results in a decrease in arterial Po2. Paco2 is proportional to CO2 production and inversely proportional to alveolar ventilation. Thus, hypoventilation, specifically alveolar hypoventilation, results in an ele-
116
Bosan and Walley
vated alveolar Paco2 and, according to the alveolar gas equation, a decrease in alveolar and arterial Po2. Alveolar ventilation is an important determinant of oxygen pressure in the alveoli and, hence, in arterial blood. Sophisticated regulation mechanisms exist to maintain the oxygen flux into the pulmonary capillaries at the optimum level (7,8). The main regulator is a chemoreceptor system detecting the oxygen pressure in the pulmonary venules and adjusting the alveolar ventilation through such mechanisms as increased breathing frequency. Indeed, alveolar ventilation can be increased more than 20 times the resting value and is not a limiting factor for oxygen uptake in health (9). C. Shunt
Shunting of mixed venous blood past gas exchanging alveoli directly into the pulmonary veins can be an important contributor to arterial hypoxemia. Shunt can occur outside the lungs, for example in some congenital heart diseases, and within the lungs, for example, in ARDS where pulmonary arterial blood shunts past flooded alveoli (10). Shunt has a particularly dramatic effect on arterial Po2 due to the nonlinear oxygen-hemoglobin dissociation curve. D. VA /Q Mismatch
The most important cause of clinically significant arterial hypoxemia is VA /Q mismatch. That is, oxygen ventilation of alveoli is not adequately matched to blood perfusing the alveolar capillaries. As a result some regions have ventilation in excess of perfusion while other regions have perfusion in excess of ventilation. The regions with excess ventilation contribute to dead space while the regions with excess perfusion contribute to a ‘‘physiologic shunt.’’ Physiologic shunt contributes to arterial hypoxemia just as anatomic shunt does. How should the distribution of blood perfusion and airflow be arranged to maximize oxygen flux into the circulation? Evans et al. (11), through a simple theoretical study showed that in order to achieve optimal gas transport the ratio of ventilation (VA) to perfusion (Q) must be constant throughout the lungs. Note that the individual distribution values are not important as long as the distributions are matched in the sense that their ratio is constant (12). We know from experimental measurements that this is not true. Indeed, the VA /Q ratio in a normal lung varies from about 0.6 to 3, with 0.8 being the average (13). As pulmonary blood flow is increased, for example during exercise, heterogeneity decreases through capillary recruitment and regulation, increasing the efficiency of gas transport. Consideration of oxygen transport in the lungs introduces several concept that are fundamental in understanding gas exchange in peripheral tissues. V.
Oxygen Transport in Peripheral Tissues
This chapter reviews models of oxygen transport in the periphery. The first models focused on the final stage in oxygen transport-carrying oxygen from the circulation
Microcirculatory Blood Flow
117
into the tissues where it is consumed. The two basic forces governing the movement of oxygen at this stage are convection and diffusion. Hydrodynamic forces such as osmolarity play an insignificant role in the transport of water and lipid soluble substances, since the diffusion of these substances across the capillary wall is extremely rapid. Indeed, about a thousand times more glucose crosses the muscle capillaries into the extravascular space through diffusion than move across by hydrodynamic forces. The main driving force for convection within the microcirculation is blood flow. Though lymphatic flow is also at work within the interstitium, this plays an insignificant role in the transport of small molecules such as oxygen. The driving forces for diffusion, on the other hand, are the concentration gradients existing both within the capillary blood and the extravascular space. Although water-soluble substances such as urea can only cross the capillaries through aqueous pores, lipid-soluble substances such as oxygen diffuse freely across at any point. This effectively increases the surface area available for diffusion by at least a thousand times since the aggregate area of aqueous pores represents less than one thousandth of the total capillary surface area. Hence, the diffusion rates of lipid-soluble substances such as oxygen, are many orders of magnitude larger than the hydrophilic ones. Once within the extravascular space, small molecules readily permeate the extracellular and intracellular space. Thus, under normal conditions, metabolism is not limited by diffusion rates. Finally, it should be noted that although most substances are delivered to the tissues as freely dissolved solutes in the blood, the transport of oxygen, as well as carbon dioxide, is facilitated by red blood cells, greatly enhancing the blood’s ability to carry oxygen. Quantification of the diffusion process is achieved through Fick’s law which states that the rate of diffusion for a gas is directly proportional to the concentration gradient of the gas. When considering the diffusion of oxygen in the microcirculation there are two concentration gradients that must be taken into account. One is along the capillary radius, the other along the length of the capillary. The former sets the gradient for the movement of oxygen across the capillaries and into the tissue. The latter determines the initial oxygen concentrations for the former. Indeed, this line of formulation serves as the basis of all theoretical studies of oxygen diffusion in tissues.
VI. The Krogh Model of Oxygen Transport in the Tissues The natural next step from Fick’s law was the construction of a comprehensive model for describing the movement of oxygen in tissues. The earliest effort for a comprehensive oxygen transport model in the microcirculation is credited to the Danish physiologist August Krogh (14). By today’s standards this model was a relatively modest attempt. Indeed, Krogh made numerous simplifying assumptions in order to derive a model that could be solved with relative ease. Kreuzer (15) provided a comprehensive review of these assumptions, some of which are still used in the most complicated models of today. At the heart of the Krogh model are straight cylinders representing capillaries running in parallel. This geometry was inspired by his study of skeletal muscles, which provide some of the most regularly organized capillary structures in the body. Surrounding each capillary is a cylindrical region
118
Bosan and Walley
of tissue that the capillary supplies with oxygen (Fig. 1). The combined capillary/ tissue cylinder is commonly referred to as the Krogh tissue cylinder. Within the Krogh tissue cylinders, oxygen is driven by axial convection in the capillaries and radial diffusion in the tissues. The movement of oxygen originating from a given capillary is limited to the tissue-cylinder surrounding that particular capillary. Namely, there is no communication between parallel cylinders. Additional assumptions include: 1. Oxygen exchange occurs only in the capillaries and not in the arterioles and venules. 2. Cells are represented as homogeneously mixed minute sinks of oxygen. 3. The whole model is in steady state (i.e., independent of time). 4. There is no stirring. 5. Transport of oxygen within the blood is ignored.
Figure 1 (A) Krogh tissue-cylinder. Rc, capillary radius; Rt, tissue radius. The KroghEhrlang equation can be derived by applying steady-state mass balance to an infinitesimally small region (∆x) at any point along the cylinder’s length. (B) Cross section of a tissue slab showing how Krogh tissue cylinders cover the tissue.
Microcirculatory Blood Flow
119
6. Oxygen concentration is the same throughout the capillary and there is chemical equilibrium between oxygen and hemoglobin. 7. There is no resistance to the movement of oxygen at the capillary boundary. 8. Oxygen consumption does not depend on the local oxygen pressure (zeroorder reaction with no facilitated diffusion). Moreover, the tissue cylinders are assumed to be homogeneously distributed within the tissue (Fig. 1). These simplifications combined with the assumption that the transit times are constant for a constant flow (i.e., all cylinders have the same length and diameter) allowed Krogh to represent the entire capillary network of an organ using just one tissue cylinder. With all these assumptions, Krogh, along with the mathematician Erlang finally presented the following model (Fig. 1):
冢
0⫽D
冣
d 2c 1 dc ⫹ ⫺ go dr 2 r dr
Where c is the oxygen concentration, r radial distance, and go the rate of oxygen consumption in the tissue. The solution is: C ⫺ Cc ⫽
冢
冣
go r 2 ⫺ r 2c R2 r ⫺ ln D 4 2 rc
where R is the tissue cylinder radius, rc capillary radius, and Cc the oxygen concentration in the capillary. The radial oxygen profile predicted by this equation is shown in Figure 2. Note that for this version of the model, the profile is exactly the same anywhere along the capillary length. It can be seen that the tissue cylinder radius
Figure 2 Hypothetical plot showing the effects of blood transport on tissue Po2 (solid line). Notice that for the classic Krogh-Erlang model (dashed line), large bulk of the Po2 drop occurs in the tissue, whereas including blood transport causes a large drop in the capillary.
120
Bosan and Walley
is a primary resistance to oxygen movement. If the radius is too large compared to the Po2 gradient, available oxygen will be depleted before reaching the outermost portions of the cylinder. The only way to counteract this effect, according to the model, is to reduce the tissue cylinder radii by increasing the capillary density (16). It should be noted though that significant experimental evidence to the contrary exists (17,18). VII. Axial Oxygen Gradient in the Capillaries One of the most glaring problems that immediately jumps out from studying the solution of the Krogh-Erlang model is the lack of flow anywhere in the equation. Indeed, since Krogh ignored oxygen transport within the capillaries and assumed them to have constant oxygen content, flow plays no role in the delivery of oxygen to tissues. Thus, early attempts at extending the Krogh model centered on the inclusion of a longitudinal oxygen gradient (19,20). It was noticed early on that the concentration of the blood oxygen content along the capillary length could be calculated from the initial oxygen concentration at the arteriolar inlet to the capillary, as well as the amount that is lost as the blood moves along the capillary. Kety proceeded to extend the Krogh-Erlang model by using an equation where the capillary loses as much oxygen as is consumed along the capillary length z (19): d[O2] ⫺M ⫽ π(R2 ⫺ r 2c) dz F Where M is the total consumption rate in the tissue at a given location along the capillary length, F is blood flow, R is the radius of the tissue cylinder, and r c is the radius of the capillary. [O2] is the total oxygen concentration of the blood expressed by: [O2] ⫽ α Po2 ⫹ CHm ⋅ S In this latter equation, the dissolved oxygen is proportional to the partial oxygen pressure according to Henry’s law (with α as the constant of proportionality) and CHm is the blood oxygen carrying capacity, and S is the oxygen saturation, representing the fraction of hemoglobin bound to oxygen. Substituting the latter equation into the former one and integrating over the length of the capillary yields the solution describing the capillary oxygen pressure at axial distance. One concept introduced by this extension is known as the ‘‘lethal corners.’’ Lethal corners refers to the fact that as the blood is moving through the capillaries, its oxygen content is depleted according to the rate of consumption in the tissues. Thus, in the case of reduced oxygen supply at the capillary inlet, the tissues located at the outermost edge of the cylinder, closest to the venular end of the capillaries are most susceptible to hypoxia. Once again, there is experimental evidence against the importance of this phenomenon (17,18). A point to highlight in this extended version of the Krogh model is that although blood flow is an important variable in determining the capillary oxygen con-
Microcirculatory Blood Flow
121
tent, it does not appear on its own. Rather it is a part of the model parameter M/F as given in the above equation. More commonly, as a result of the inclusion of the latter equation, this parameter is expressed as (M/F ⋅ CHm). This indicates that the physiological factors in this ratio affect the capillary oxygen pressure jointly, rather than individually. Thus, an increase in oxygen consumption countered by either a corresponding increase in flow or hematocrit results in no change in the capillary oxygen pressure. If we now notice that F ⋅ CHm is a close approximation of oxygen supply, the main determinant of the vascular oxygen levels in the microcirculation turns out to be the ratio of oxygen demand to supply.
VIII. Effect of Red Blood Cells There are numerous factors that affect tissue Po2. These include metabolic demand, blood flow, and capillary spacing. The Krogh-Kety model successfully incorporates a number of these factors. One important prediction of these models, however, is inconsistent with experimental observations. The Krogh-Kety model predicts that the dominant radial-transport parameter is the distance oxygen must diffuse. For example, for a given Krogh tissue cylinder, the capillary radius, in comparison to the tissue radius, is relatively small. Since the radial Po2 drop is approximately linear, the bulk of the radial Po2 drop is predicted to occur in the tissues. Thus the predicted site of primary resistance to oxygen transport is the extravascular space (Fig. 2). Experimental observations carried out in the mid-eighties by Honig and colleagues, however, showed that tissue Po2 gradients are much less than those predicted by the models (21,22). One such experiment, as an example, measured intracellular Po2 distribution by myoglobin cryospectrophotometry. Volumes roughly 30 µm3, containing one or two mitochondria, were sampled around a capillary using a photometer which measured myoglobin saturation. On average for a capillary having a Po2 of 30 torr, the observed tissue Po2 roughly 3 µm away was below 5 torr—much lower than predicted by Krogh-Kety models (Fig. 2). Indeed, the only way to bring the model observations to a level consistent with experimental observations was to lower the capillary oxygen content for the models very significantly. This strongly suggested that that the primary site of resistance to oxygen movement was the capillary. Thus, it was deduced that the transcapillary oxygen gradient must depend not only on diffusion but also on the kinetic reactions involving oxygen within the blood. Whole-organ multiple indicator dilution experiments carried out by Rose and Goresky (23) lent further support to the idea that blood provides a significant resistance to the movement of oxygen in capillaries. In these experiments a bolus of tracers (18O2 as oxygen tracer, and 51Cr-labelled red cells as the reference tracer) were injected into the arterial circulation and sampled in downstream veins. By curve-fitting the predictions of distributed models to tracer curves, they measured a significant resistance to oxygen movement in the coronary circulation. They hypothesized that this resistance provided for a more even distribution of oxygen in the tissues by preventing the entire oxygen content of the blood from diffusing out into the tissues at the arteriolar end of the capillaries.
122
Bosan and Walley
Oxygen, unlike most solutes, is not homogeneously distributed throughout the blood (or in some of the tissues), but is rather transported reversibly bound to hemoglobin. Hemoglobin, in turn, travels in pulses contained within red blood cells. Indeed, ⬍2% of the total blood oxygen content is available in the dissolved form. Although small in amount, the oxygen in solution is still extremely important since it is one of the primary determinants of the affinity of hemoglobin to oxygen. Hemoglobin molecules are tetramers of heme groups, each of which contained in a peptide chain. The reversible binding of oxygen takes place at the Fe atom of each heme group. Thus each hemoglobin molecule can bind four oxygen molecules. Oxygen saturation is the fraction of oxygen-binding sites occupied by oxygen and is expressed as a fraction or percent. The reversible binding of oxygen to hemoglobin is cooperative in nature. Thus, attachment of one oxygen molecule triggers conformational changes within hemoglobin, altering its affinity towards other oxygen molecules. Under normal conditions, values of oxygen saturation plotted against Po2 result in a sigmoid curve, referred to as the oxyhemoglobin dissociation curve (Fig. 3). The oxygen affinity of hemoglobin is defined as the oxygen pressure at which hemoglobin is 50% saturated (P50). The affinity of hemoglobin to oxygen is affected by numerous factors. Indeed, hemoglobin provides an excellent example of allosterism. Carbon dioxide is an important variable through the Bohr effect. CO2 binds with hemoglobin, forming carbaminohemoglobin. This molecule, in turn has less affinity for oxygen. Carbon dioxide can also generate H⫹ from dissociation of H2CO3. Binding of H⫹ to oxyhemoglobin causes the release of the bound oxygen and lowering of the oxygen affinity. Other allosteric factors are temperature, pH of the blood and 2,3-diphospho-
Figure 3 A typical oxyhemoglobin dissociation curve.
Microcirculatory Blood Flow
123
glycerate (DPG); detailed theoretical analysis of these allosteric effects are explored elsewhere (24–26). The oxyhemoglobin dissociation curve plays an important role in the delivery of oxygen from the blood to the tissues. For example, affinity changes are particularly adaptive in heavy exercise, causing an increase in oxygen flux to the muscles, with relatively little change in capillary Po2. The flat portion of the dissociation curve at high Po2 (A in figure 3) is a major safety factor against hypoxemia. Indeed, the blood saturation remains at 90% for a Po2 decline of up to 30% from normal conditions. As the blood oxygen pressure drops, the steep-slope portion of the dissociation curve (B in figure 3) allows the release of large amounts of oxygen to meet high demand, without lowering the blood Po2 too rapidly. This may be particularly important since sufficiently high blood Po2 must be maintained in the capillaries to provide enough of an oxygen gradient to allow adequate diffusion into the extravascular space. Thus, when the capillary Po2 does fall there must be a corresponding drop in the cell Po2, to ensure that proper oxygen flux is maintained. For example, to counter the drop in capillary Po2 during light exercise which is a result of increased oxygen extraction, tissue Po2 falls by as much as 25 torr to a value of 5 torr (13). Since the intracellular Po2 needed to maintain oxidative metabolism is approximately 0.5 torr, such a drop has no effect on tissue function. In fact, the whole purpose of an intracellular Po2 ⬎ 0.5 is to permit diffusion into the cell interior. Thus there is a large tissue Po2 reserve to help regulate appropriate oxygen flux. Indeed, tissues with higher metabolism, such as the heart, normally have lower reserves (i.e., their resting tissue Po2 is significantly lower than other tissues). IX. Extending the Krogh Model The Krogh model as presented thus far does not allow for transport within the capillaries. However, the oxygen source and the basis of oxygen supply are the red blood cells that arrive in the form of discrete units. Thus oxygen must be unloaded from hemoglobin, diffuse through the erythrocytes, and cross the cell membrane and the blood plasma before reaching the capillary rim. Although initially it was thought that this did not play an important role, as mentioned above, the work of Honig and others presented evidence to the contrary. Thus the next step in the evolution of Krogh style models was the inclusion of oxygen transport in the blood. The first stage of modeling oxygen transport within blood was studying the complicated issue of release of oxygen from hemoglobin (27–29). To simplify understanding it is generally assumed that the oxygen-hemoglobin reaction is in equilibrium (30). This, in turn, allows the use of the dissociation curve for the purposes of extending the Krogh model. There are two distinct approaches for studying oxyhemoglobin dissociation. The first is based on kinetic models (31,32), the other is to construct the dissociation curves empirically (33,34). To better understand the resistance offered by the blood to oxygen transport, rapid-mixing experiments were used. In these experiments either red blood cells or hemoglobin is quickly added into a chamber and mixed with a solution containing
124
Bosan and Walley
known concentrations of O2. After the mixing, the hemoglobin saturation is monitored continuously using spectrophotometry (35,36). This way, the rate of uptake of oxygen can be accurately measured. It was found that 50% saturation point (halftime) for hemoglobin was reached in roughly 5 to 10 msec, whereas the halftime for red blood cells was 50 to 100 msec. Indeed, on average, the rate of oxygen uptake by erythrocytes was measured to be about 40 times slower than freely dissolved hemoglobin. Theoretical calculations which accounted for diffusion in the cytosol explained part of the discrepancy. Eliminating the effect of the predicted cytosol resistance from red blood cell halftimes reduced the halftime difference to roughly fivefold. In addition, Kreuzer and Yahr showed that stagnant layers of packed red blood cells oxygenate almost as quickly as hemoglobin (43), pointing to the incompletely stirred diffusion boundary layer as a significant source of resistance to oxygen movement out of the erythrocytes (36). Sophisticated mathematical analysis provided additional support for this theory. Since these two factors combined (cytosol and the incompletely stirred layer) more than account for the difference observed between the red blood cell and hemoglobin oxygen uptakes, it is unlikely that erythrocyte membrane is a significant source of resistance to oxygen movement. To include the effects of oxygen transport in the capillaries, discrete cell models were developed by Hellums and others (42,44–48). In these models red blood cells are represented as cylinders passing through the capillary like the cars of a train (Fig. 4). Oxygen transport between the red blood cells is allowed by diffusion. The model results revealed that periodic variations of oxygen concentration as the
Figure 4 ‘‘Train’’ model of red blood cell movement through a capillary. The plot at the bottom shows the oxygen pressure at the capillary rim, as detected by the sensor A.
Microcirculatory Blood Flow
125
red blood cells passed through the capillaries is not particularly important under most conditions and that a mean level of constant oxygen concentration could be used instead (48). This mean level lowers the oxygen concentrations at the capillary rim by up to 28% in comparison to Krogh-style models, which do not take blood oxygen transport into account. The drop observed in the capillaries due to red blood cells is generally known as the ‘‘extraction pressure’’ (EP) or ‘‘capillary barrier’’ and successfully accounts for the drop in Po2 at the capillaries as observed by Honig (see the previous section). It should be noted that according to these models, the extraction pressure is a gradient driven phenomenon. Thus, it is linearly proportional to the oxygen flux. The oxygen flux in turn is proportional to consumption and Krogh cylinder radii. Hence, for new levels of consumption M′, and radii R′, new extraction pressures can be calculated from the current one according to the following equation: EP′ ⫽ EP{M′(R′2 ⫺ r 2c)}/{M(R2 ⫺ r 2c)} One of the most important results of these models is that the oxygen flux and thus the extraction pressure is critically dependent on the red blood cell spacing. Indeed, theoretical studies done found that a relationship similar to the following was needed in order to maintain a constant flux at the capillary wall (49–51): Lⱕ
2α √F
where L is the distance between two red blood cells, F is the blood flow, and alpha is a function of red blood cell size and capillary diameter. As long as the red blood cell spacing is smaller than the above ratio, then it is possible to maintain constant oxygen flux across the capillaries. If red blood cell spacing increases above the ratio, then flux across the capillaries decreases, even if all other conditions are held constant. Thus, at this point the plasma separating the red blood cells effectively behaves like an oxygen sink since a portion of the oxygen flux is now directed towards maintaining the plasma Po2. It should be noted that this phenomenon comes into play only under highly abnormal conditions such as very high blood flows and very low hematocrit. The inclusion of the effects of red blood cells successfully explained the low tissue Po2 observations. There still remained the question of how to maintain a large tissue oxygen flux, particularly in the face of high consumption, given such low tissue Po2 gradients. The answer to this is facilitated diffusion involving myoglobin. Theoretical work done toward inclusion of facilitated diffusion in Krogh-type models showed that myoglobin plays no role in tissues with relatively low consumption (6). Only when the consumption increases to levels which would require a significant drop in the tissue Po2 does myoglobin become effective. At these levels, myoglobin provides the tissues with the ability to move oxygen almost free of diffusional resistances. Indeed, myoglobin can be thought of as serving as a reserve tissue oxygendiffusional capacity, which becomes activated during low tissue Po2. Hence, the presence of myoglobin does not significantly affect tissue Po2 but rather presents the
126
Bosan and Walley
tissue with the means of maintaining sufficient oxygen flux at Po2 levels that would otherwise lead to anoxia. Finally, the effect of the distribution of consumption on tissue Po2 levels was also studied, and was found to have negligible impact (6). Encouraged by the advancements made in theoretical explanations of facilitated diffusion of oxygen, additional limiting assumptions of the original Kroghtype models were also tested around the same time. As previously mentioned, one shortcoming of the Krogh-type models is its prediction that capillary separation could act as a limit to oxygen transport (52). This prediction is a result of the combined assumptions that there is no intercommunication between tissue cylinders, as well as zero-order consumption in the tissues. It has been shown that using firstorder or Michaleis-Menton consumption largely eliminates the dependence on radius seen in the Krogh-Erlang equation (42). Furthermore, Krogh models could not account for the measured lack of relative correlation between the Po2 at a given point and the Po2 of the proximal capillary (17). In these cases, even when the Po2 level of the capillary closest to the tissue point was significantly reduced, the tissue point Po2 remained fairly constant. This clearly contradicted the behavior of Krogh tissue cylinders, which would predict a significant drop in the tissue Po2 in correlation with the drop in the capillary, since the only source of oxygen for that tissue-point would be the nearest capillary. Allowing oxygen diffusion between tissue cylinders solved this problem (17). Indeed, significant exchange between tissue cylinders was predicted leading to a more homogeneous distribution of Po2, lessening the importance of ‘‘lethal corners’’ predicted by the original Krogh models. Additional relaxation, in the assumptions made by Krogh, further enhances the degree of homogeneity seen in the microvasculature. For example, it had long been suspected that the capillaries might not be the only sites of oxygen exchange. Indeed, both experimental and theoretical work designed to test this idea strongly support that diffusion out of the small arterioles tends to even out the Po2 distribution in the microcirculation (16).
X.
Problems with Krogh Models
Though the extended versions of the Krogh model are useful, when they are applied to situations involving networks or whole organs they fall short. For example, the Po2 distributions predicted by homogeneous Krogh models tend to be clustered around a mean with standard deviations too narrow to be realistic (Fig. 5). Furthermore, experimental testing of many model predictions requires measurements of tissue Po2 and other variables at a resolution that is not yet easily attainable. Thus, an alternative approach to test oxygen transport models was to measure oxygen delivery, oxygen consumption, and the oxygen extraction ratio at the onset of anaerobic metabolism during progressive reduction in oxygen flux to a tissue. When Schumacker et al. applied Krogh-Kety-type models toward predicting whole organ oxygen extraction using this experimental approach, the Krogh model did not predict experimentally observed values (53). Revision of simpler oxygen transport models was required.
Microcirculatory Blood Flow
127
Figure 5 Predicted Po2 histogram from the Krogh model calculated in a tissue block of 177µm ⫻ 140µm ⫻ 250µm. Bars represent class frequencies (left axis) and * and connecting lines represent the cumulative histogram (right axis). (From Ref. 48.)
XI. Oxygen Delivery-Consumption Relationships Important features of oxygen extraction capacity of tissues can usefully be illustrated using the relationship between oxygen delivery and oxygen consumption (Fig. 6). In the whole body and in other organs, a biphasic relationship is found (53,54). At high oxygen deliveries sufficient to maintain aerobic metabolism, oxygen consumption is relatively constant and independent of oxygen delivery. If oxygen delivery is decreased then, at some low value, oxygen consumption must fall because it is not possible to extract more oxygen than is delivered. Decreasing oxygen consumption, dependent upon decreasing oxygen delivery, is associated with evidence of anerobic metabolism including mounting lactic acidosis and decreased organ function (55). It should be noted that in order to maintain proper cell function the mean tissue Po2 must be maintained above 0.5 torr (13). Thus, presumably, as the oxygen reserve of the organ is depleted and thus in certain regions of the organ tissue demands for oxygen cannot be met, the tissue oxygen pressure falls below 0.5 torr. Under these conditions tissue hypoxia starts to sets in. Notice that even in this situation the tissue extraction ratio still continues to increase as oxygen delivery falls below the critical point. The critical oxygen extraction ratio (oxygen consumption divided by oxygen delivery) at the transition from plateau (aerobic metabolism) to downslope (anaerobic, supply-dependent metabolism) is a key measure of the oxygen extraction ability of a tissue or organ (Fig. 6). This ratio has been found to be remarkably constant at approximately 60% to 70% in different animal models (56–59) and between a
128
Bosan and Walley
Figure 6 Plot showing the biphasic relationship between oxygen supply (DO2) and oxygen consumption (VO2).
variety of isolated organs (56,57,59). However, the critical oxygen extraction ratio is decreased (to ⬃50%) in animal models of sepsis (56–60). This suggests that sepsis induces a tissue oxygen extraction defect. At least two important mechanisms may account for a ‘‘critical oxygen extraction ratio.’’ One possibility is that diffusion becomes limited at the critical oxygen extraction ratio because a critical capillary Po2 is reached at the critical oxygen delivery-consumption point (53). A second important potential mechanism is that, similar to the lungs, a physiologic arteriovenous shunt may be present. Because the oxygen in the shunt fraction of blood is not available for tissue uptake, the critical oxygen extraction ratio is, at most, 1 minus shunt fraction. Any form of arteriovenous oxygen shunt could conceivably contribute to this including anatomic shunt (53), oxygen diffusion shunt from adjacent arterioles to venules (61), and mismatching of oxygen demand and supply in the tissues (62). In the whole body the importance of diffusion limitation has been tested by left-shift of the oxygen-hemoglobin dissociation curve (54). When this is done there is no substantial change in the whole body critical oxygen extraction ratio. At the same oxygen saturation, left-shift of the oxygen hemoglobin dissociation curve would greatly decrease capillary Po2. If diffusion limitation were the explanation for the onset of anaerobic metabolism the critical oxygen extraction ratio should have decreased. Since the critical oxygen extraction ratio did not change Schumacker and colleagues conclude that ‘‘diffusion limitation does not initiate the early fall in oxygen consumption below the critical oxygen delivery’’ (54). These results suggest that, in many organ systems, physiologic arterio-venous shunt may be the most
Microcirculatory Blood Flow
129
important mechanism accounting for the critical oxygen extraction ratio. To the extent this is true, Krogh-type models would require significant revision. In contrast to the whole body and some organs, the heart (63) and working skeletal muscle (64) appear to be characterized by a critical capillary Po2 rather than by a critical oxygen extraction ratio. Left-shifting the oxygen-hemoglobin dissociation curve significantly decreases the critical myocardial oxygen extraction ratio but has no effect on the coronary venous Po2 (63). This suggests that maximal oxygen uptake by the myocardium is diffusion limited rather than limited by a physiologic arteriovenous shunt fraction. Interestingly, working skeletal muscle is also characterized by a critical venous Po2, rather than by a critical oxygen extraction ratio (64). Working heart and skeletal muscle, with high oxygen consumption, may have developed mechanisms to avoid the limitation of physiologic shunt that is crucial in other tissues. In most organs, and on average in the whole body, diffusion is not the limiting step in transport of oxygen from the atmosphere to the mitochondria as oxygen supply becomes limited (54). The heart and working muscle are therefore exceptions. To understand these observation which appear to contradict many of the prediction of Krogh-type models, the role of heterogeneity of blood flow and oxygen demand in tissues has been modeled (62). XII. Mismatch of Oxygen Demand and Supply: Physiologic Arterio-Venous Shunt Just as V/Q mismatch appears to be the most clinically important mechanism for limiting oxygen transport by the lungs, it has been postulated that mismatch between oxygen demand and supply is an important limiting factor for oxygen extraction by the tissues (60,62,65). This suggestion is attractive, in part because impaired microvascular function occurs in sepsis (66,67), is an important component in matching oxygen supply to demand, and could account for decreased critical oxygen extraction ratios observed in models of sepsis. In a theoretical assessment of the effect of mismatching of oxygen demand to supply within tissue beds it was found that biphasic oxygen consumption-oxygen delivery relationships, with many features of those measured in humans and in animal models, were predicted (62). Small regions of tissue can be characterized by their oxygen demand to oxygen supply ratios. Regions with limited oxygen supply in relation to demand result in relatively hypoxic areas of tissue while regions with excess oxygen supply in relation to demand contribute to physiologic shunting of arterial blood past the capillary bed into the venous drainage. When the distribution of microvascular oxygen demand/supply is closely regulated with little variation, at a value near the average extraction ratio, then oxygen extraction is efficient with relatively few hypoxic regions and little shunt of oxygenated blood past the tissues. The critical oxygen extraction ratio is high in this setting. Increasing the dispersion of the distribution of demand/supply decreases the critical oxygen extraction ratio (Fig. 7). That is, mismatching between oxygen demand and oxygen supply impairs oxygen transport much as it does in the lungs.
130
Bosan and Walley
Figure 7 Effect of increasing relative dispersion (heterogeneity) on the ratio of microregional oxygen supply to demand. In theory, increased relative dispersion limits the ability of tissues to extract oxygen so that the critical oxygen extraction ratio decreases (From Ref. 62.)
The theoretical analysis suggested that for relative dispersion ⬍20% the critical oxygen extraction ratio is optimized (Fig. 7). However, when relative dispersion is increased beyond 30% the critical oxygen extraction ratio decreases sharply (62). Because of the difficulty of measuring variation in microregional oxygen consumption this hypothesis has not been tested directly. However capillary transit time distributions may be reasonable surrogate measurements reflecting distributions of oxygen demand/supply (60,65). Humer and colleagues (60) found that following endotoxin infusion the relative dispersion of capillary transit times increased by ⬃15% compared to nonendotoxin controls. This was associated with a reduction in the critical oxygen extraction ratio to approximately 60% from 74% in controls. The theoretically predicted reduction in critical oxygen extraction ratio due to increased supply/demand mismatching corresponded closely to the experimentally measured reduction in critical oxygen extraction ratio (60). Similar observations were made in the heart, where increased heterogeneity of blood flow after endotoxin infusion was associated with a decrease in myocardial oxygen extraction ratio (68). Thus, these data (60,62) and other observations (65) are consistent with the hypothesis that microregional mismatching of oxygen supply to demand may contribute substantially to physiologic arteriovenous shunt and therefore may account for the critical oxygen extraction ratio and the limit to oxygen transport in many tissues. XIII. Microvascular Flow Matching microvascular blood flow (and oxygen delivery) to local oxygen demand is therefore a critical issue in oxygen transport to tissues (69). In general, the greater the degree of metabolic activity in an organ, the larger the blood flow it receives.
Microcirculatory Blood Flow
131
For example, the heart, while constituting only 0.5% of the total body weight, accounts for roughly 12% of the whole body energy use under resting conditions. Consequently, coronary flow to the heart is roughly 80 mL/min/100 g. In contrast, blood flow under resting conditions to the muscles is only 4 mL/min/100 g, even though the muscles make up approximately 30% to 40% of the total body weight. Under heavy exercise, however, muscle blood flow can increase up to 20-fold in response to metabolic rate increases up to 50-fold (13,69,70). It should be noted that supply of metabolites may not be the only reason for flow regulation. Kidneys, for example, receive 360 mL/min/100 g in order to ensure the proper regulation of extracellular fluid composition. Numerous in vivo and in vitro studies have pointed to the arterioles, feeding local flow networks as the site at which organ flow regulation takes place (71,72). A variety of theories have been proposed for explaining the flow regulation mechanism. One of the earliest is the vasodilator theory (72,73). According to this theory, numerous vasoactive substances are produced in response to increased metabolism or insufficient metabolite delivery. For example, ADP, as described earlier, is a product of increased metabolism. If enough oxygen is not supplied to stimulate synthesis of ATP from this ADP, it will accumulate in the cells. Adenosine is a powerful vasodilator potentially able to affect local arterioles. Other vasoactive substances proposed include carbon dioxide, lactic acid, histamine, and potassium and hydrogen ions (74,75). The main problem with this theory is the large distances the vasoactive substances must travel in order to reach the arterioles supplying the tissue. Indeed, in some tissues, such as the skeletal muscle, this distance can exceed 1 mm (71). A recently proposed idea that these substances are communicated to the arterioles through diffusion from the venules (76–78) which are coupled with the arterioles is attractive but also has possible problems. For example, the distances separating the venules from the arterioles can be quite large as well. In addition, not all venules are directly coupled with the arterioles feeding them but are sometimes matched with arterioles supplying other networks (79). A second theory for local blood flow regulation is the myogenic theory (80,81). According to this, an increase in blood pressure will cause the vessel walls to stretch. A sudden stretch in the vessel walls leads to an increase in their tone, causing them to constrict. This constriction in turn reduces blood flow to proper levels. The converse would be true for reduced blood flow. It is doubtful that myogenic responses play a dominant role in blood flow regulation since a strong myogenic response would lead to a feedback loop effectively shutting down the circulation. It is well known, however, that hemodynamic factors, such as increased shear stress do cause the release of numerous vasoactive substances such as nitric oxide (NO) (81,82). It is believed that there exist mechanisms for the amplification and propagation of local vasoactive signals back to the arterioles, be they metabolic or hemodynamic in origin (83–86). Endothelial cells may function as conductors and amplifiers of the signal, carrying it back to the precapillary sphincters that close or open based on the signal fed to them. That is, downstream capillaries, in response
132
Bosan and Walley
to vasoactive stimuli, can integrate and transmit signals along the microvascular endothelium to affect upstream arteriolar flow control (85). A recent theory put forward by Groebe (71), based on original ideas by Burton (87), postulates that the sensors for flow regulation are located at the capillary level, but this time placed close to the venules, since the most likely place for oxygen shortage to appear is farthest away from the arterioles. The effectors, however, are not located at the arterioles but at the venules, thus providing a short distance for communication between the sensors and the effectors. The arterioles in this theory are entrusted to maintain the capillary pressure constant, and adjust it to maintain the flow preset by the venules. Although this mechanism would be effective further experimental work is needed for its verification. Understanding the mechanisms regulating local flow is incomplete. It is probable that not just one but a combination of mechanisms are actually at work. A question arises as to how the local regulation and the cardiac output are matched. Observations suggest that under basal conditions, with ample supply of oxygen, local regulators of flow are probably not active (88). Thus, changes in the capillary flow are induced by changes in the arterial flow and pressure. As the tissue Po2 falls below a certain level, local regulators take over, redirecting flow to the areas where it is needed most, and become the dominant regulator of flow through the organ. The resulting flow pattern is significantly more homogeneous than under basal conditions (88, 89). This suggests that heterogeneity in local tissue perfusion is a consequence of one of two things—excess oxygen reserves even in the most poorly perfused areas, or failing local flow regulation mechanism under increased metabolic activity. Thus, under high metabolic activity, properly working local flow regulators seek to reduce the flow heterogeneity, thus increasing oxygen extraction efficiency, as previously described. It should be noted that at present it is not clearly understood as to whether flow heterogenity exists in response to heterogeneous nature of oxygen consumption in tissues or as a result of hemodynamic variables (90). Understanding the nature of flow heterogeneity, and thus oxygen delivery heterogeneity, is of utmost importance for studies looking at the delivery side of oxygen transport. As blood flows from the aorta into arteries and arterioles, its path is continually bifurcated into more and more branches. Conditions that effect pressure are different in each branch. For example, the interstitial pressures may be greater down one path than the other, resulting in higher resistance to flow in one path than in the other. Alternatively, the shape and the length of one branch may facilitate a faster passage through that branch than the other. Such differences repeated over and over at each bifurcation, down the arterial, arteriolar, and capillary generations, result in a blood flow that is highly varied by the time it reaches the site of oxygen release. The importance of these heterogeneities is highly tissue and substance dependent. For example, Caruthers et al. (91), have shown that pulmonary flow heterogeneity contributes little towards the measurement of transport characteristics for small solutes such as urea and butane-diol. On the other hand, flow heterogeneity seems to have a large impact for transport of solutes in the heart (92). Thus, quantifying flow heterogeneity through models is of utmost importance in order to be able to evaluate its impact on oxygen delivery.
Microcirculatory Blood Flow
133
XIV. Heterogeneous Models It is clear that heterogeneity of flow in relation to demand is fundamental in determining oxygen extraction capacity. Heterogeneous oxygen transport models seek to combine flow and tissue heterogeneity with Krogh-style capillary diffusion. One of the simplest ways to do this is to assume that the tissue consists of numerous, parallel Krogh cylinders with varying characteristics. This can be accomplished by keeping the inputs to all these cylinders the same, but now permitting different variables to be chosen to represent each capillary. These variations, in turn, allow different tissue-cylinder sizes, capillary radii, and flow rates, etc. Due to the difficulty involved in simulating large numbers of cylinders with completely different characteristics, the literature has been mostly limited to studying heterogeneity in capillary spacing (i.e., tissue cylinder radius) and the flow (i.e., consumption-tosupply ratio) (48). The first question to arise from these models is also an important requirement: how to develop a set of conclusive descriptors for quantifying tissue and flow heterogeneity. Some progress has been made is the development of descriptors for capillary-geometry heterogeneity. Simple counts of capillaries such as the capillary density are adequate for most qualitative studies even though, if not carefully used, capillary density in itself may be a misleading measure. For example, it is often taken to be in correlation with the level of metabolism. Thus, a higher capillary density is assumed to represent a higher metabolic activity in that tissue. This is generally true. However, alternatively, in some tissues, particularly those with irregular capillary geometries, low capillary density may imply higher oxygen extraction efficiency (18,52,93). Given that capillary beds have heterogeneous spacing (even red muscles—such as the heart—have capillaries with numerous branches with complicated shapes [94]), capillary density (CD) is inadequate for complex models. Linear analysis may be used instead to determine the degree of variability in intercapillary distances. These indeed ended up being extremely popular with the multicylinder Krogh models, since intercapillary distances are a direct measurement of the Krogh tissue cylinders. Unfortunately, intercapillary distances once again only make sense in tissues with highly regular capillary arrangement such as red muscle (95). In addition, the mean distance and the distribution of intercapillary distances were often calculated from capillary density measurements. This severely limited the accuracy of intercapillary distance as a measure of capillary distribution heterogeneity, since the actual distribution may greatly differ from one tissue sample to the next. Indeed, it was shown that these distributions did, in fact, have a significant impact on Po2 distribution in the tissue (96,97). To answer the above-mentioned problems, the idea of capillary domain of influence was developed (95). This is similar to the idea of intercapillary distance, however, it is a three-dimensional concept. In a given tissue, each capillary is assigned a region of dominance based on the fact that this capillary is the closest one of all the capillaries to the tissue in its domain (Fig. 8). The assignment is done by a two-dimensional Voronoi tessellation algorithm (98) for regularly arranged capillaries. This algorithm simply states that a hypothetical line should be drawn
134
Bosan and Walley
Figure 8 A sample of capillaries (circles) and their associated domains as calculated by Voronoi tessellation.
connecting each and every capillary with all other capillaries. Then bisecting lines must be drawn on these hypothetical lines. The polygons that result from the intersection of these bisecting lines are the areas of domain assigned to each capillary. This method has the additional advantage of accommodating irregularly arranged capillaries through the use of three-dimensional algorithms, although they tend to be highly computing intensive. The inclusion of hemodynamic heterogeneity in these models has been far more problematic than static geometric heterogeneity (99). It is difficult to combine data collected from different species of the same genus or class (99). For some parameters, even using values obtained from different individuals of the same species may lead to diverging results. As a result, the development of a satisfactory measure of hemodynamic heterogeneity has been slow in coming. Van Beek et al. have assessed the importance of flow heterogeneity by combining the fractal models of flow heterogeneity with models of oxygen diffusion (100). Relying on the recursive nature of fractals, they calculated oxygen distribution profiles by using smaller and smaller tissue cubes (i.e., using larger and larger orders of branching for flow), as shown in Figure 9. Their results showed that the Po2 distributions predicted from these models agreed with data obtained from the heart by Loiselle (101). Furthermore, the standard deviations of these distributions are predicted to be in error by less than 1% when the tissue size used decreased below 100 µm, suggesting that below this size there was little additional Po2 heterogeneity. This result agreed closely with Bassingthwaighte’s prediction of 50 to 75 µm (102,103) for the size below which Po2 heterogeneity disappears, who arrived at this number through an alternative approach. This agreement is especially true when considering that the numbers reported by Van Beek are slightly overestimated due to the fact that onedimensional analysis was used for a three-dimensional tissue. These results suggest that in tissue sizes smaller than 100 µm cubes, there is little Po2 heterogeneity to be found (probably due to the countering effects of diffusion), even though flow contin-
Microcirculatory Blood Flow
135
Figure 9 (Bottom) Profile of a heterogeneous flow distribution (solid line) of a section of tissue representing the left ventricular wall of saline-perfused arrested guinea pig heart. The flow distribution was generated by a fractal vascular network to a spatial resolution of 50 µm (i.e., heterogeneity below this resolution was ignored). The dashed line shows the homogeneous flow distribution for comparison. (Top) Distribution of the oxygen tension as generated by the fractal Krogh model. (From Ref. 119.)
ues to be highly heterogeneous. Thus, 100-µm can be chosen as the spatial resolution for studying tissue Po2 heterogeneity in normal hearts. A final, and perhaps currently the most interesting, area of heterogeneous model construction involves determining the effect of local flow regulation on oxygen distribution. Given that the use of accurate hemodynamic data in heterogeneous models is currently problematic, regulation models concentrate on purely theoretical studies. For example, although we have evidence that local flow regulation probably directs oxygen where it is most needed (104), a detailed understanding of the implications of this regulation on Po2 distribution in the microvasculature is still poorly understood. Combining oxygen models with models of flow regulation, therefore, can provide a greater insight into this matter. Dinnar, for example, constructed a model based on vasomotion to study the effects of ‘‘blinking capillary’’ model on the oxygen distribution (105). In this model the capillary bed geometry was designed
136
Bosan and Walley
like a ladder with three rungs. One side of the ladder represented the arteriolar input, the other side venular output, and the three rungs represented capillaries. For baseline oxygen consumption, a single rung remaining open was enough to supply enough oxygen. When the oxygen consumption was increased fivefold, the single rung could not deliver enough oxygen and thus hypoxia resulted. Two rungs now alternately open for durations of 0.5 sec did supply sufficient oxygen, however. For a sevenfold increase in consumption, the flow needed to be alternated between all three rungs in order to supply enough oxygen. Notice that since the two or three capillaries involved in each simulation alternated in providing flow (effectively simulating vasomotion) the total flow remained constant. Thus, these models predict that capillary beds that employ vasomotion are able to support much higher levels of oxygen consumption with no increase in arteriolar flow or capillary pressure (i.e., oxygen delivery), than capillary beds that do not use this regulation. Experimental verification of this finding has not been carried out, however.
XV. Network Models Quantification of the flow heterogeneity can be approached in two distinct manners. The first involves quantitative replication of microvascular topology, architecture, and rheology as a first step toward a complete hemodynamic description of microvasculature. Such models, referred to as network models, have been constructed with varying degrees of ambition and functionality (106–108). The main thrust of the network concept is to emphasize the concept that the microvasculature is an internally organized functional unit as opposed to a collection of loosely interrelated elements. Currently, construction of network models aims to predict two distinct but related measures. The first one is the prediction of segment flows and their direction in each of the segments within the network. The second prediction is the hematocrit of each segment. Calculation of flows (called linear analysis) involves computation of the flow in each segment as well as the pressures at each node from initial estimates of rheological parameters such as viscosity. The second calculation (called rheological analysis) involves the computation of the hematocrit and apparent viscosity in each segment using the results of the linear analysis. Then, the results of the rheological analysis are used in carrying out the next linear analysis. This recursive procedure is repeated until a converging solution is found to the equations describing the network. Experimental data for the verification of network models are gathered using high precision video microscopy. Flows are generally measured by tracking individual red blood cells (109). Hematocrits are determined using microphotometric methods (110,111). Pries et al. (106), for example, constructed an anatomically accurate model with nearly 1,000 capillary segments. His anatomic data was obtained from 50–80 to mm2 sections of the rat mesentery. Hemodynamic and structural parameters important to the network model were obtained from 40 min of video and still photographs of the mesenteric networks. Unfortunately, the model failed to predict precisely various physiological parameters measured in individual vessels, such as hematocrit and even flow direction. Indeed, the inability to
Microcirculatory Blood Flow
137
make precise predictions is the main shortcoming of network models based on accurate geometric and hemodynamic data. This is, in part, due to the difficulty of constructing complex models ruled by nonlinear behavior. However, as our computational skills have improved, the difficulty of obtaining experimental measurements with the appropriate level of precision necessary to base these models on has also become an important limitation (99,112). XVI. Fractal Network Models An alternative approach to modeling flow heterogeneity (at least for organ level models and observations) is based on fractals (103). According to this theory, if we were to take a cube of tissue and measure flow based on the tracer-labeled microsphere technique, we would observe a distribution of microspheres representing flow heterogeneity (113,114). If we now proceed to cut the cube into smaller cubes, similar heterogeneity will also be found in each of the smaller cubes. This process of cutting smaller and smaller cubes from the original one and observing similar heterogeneity in the smaller pieces is called self-similarity. Self-similarity of flow heterogeneity is the basis for the observation that flow heterogeneity is fractal in nature. Indeed, self-similarity has been found for at least 2 orders of magnitude of change in the heart-muscle flow studies (115) (Fig. 10). The attempt to model flow distribution in a fractal network based on vessel length and radii was pioneered by Bassingthwaighte (103). The fractal vascular networks, unlike their morphological equivalents, are based on simple geometric assumptions which, in turn, are based on recursion and are not anatomically accurate. The recursive assumption simply states that at each bifurcation, the two daughter branches of a vessel are of different diameters and length, and thus have different flow. In deterministic models (models which do not incorporate any randomly fluctuating components), the ratio of flow between the two daughters (γ) is precisely fixed (Fig. 11) (116). In stochastic models (models which do incorporate randomly varying components), the ratio of flow is randomly distributed throughout the vascular network with a given mean (γ) and distribution (σ) (116). The rational behind stochastic models is to replicate the observation that flow in the capillaries is done in a blinking fashion—or vasomotion (85,117). It should be noted that the branching distribution characteristics in the network encapsulate the vasoregulatory state of the vessels and are not just a replication of the passive geometry. Even so, these models are highly simplified and abstract in comparison to the real microvasculature. Verification of the fractal models has been based on the relative dispersion of flow, representing the relative spread of the flow normalized to its mean (103,118). More precisely, relative dispersion at a certain branching level is defined as the standard deviation of flow, at that level, divided by the mean flow at the same level. The relative dispersion (RD) of the fractal model of n generations of bifurcations can be calculated using the following equation (119):
冤
RD ⫽ N(γ 2 ⫹ (1 ⫺ γ))
冥
log N ⫺1 log 2
1/2
138
Bosan and Walley
Figure 10 Sample distribution of flows obtained from microspheres. Percent distribution of each flow range was computed by dividing the tissue into 28 sections and counting the radiactivity in each section. Since the amount of radioactivity is directly related to flow, the counts can be converted to flows. For fractal tissues, each section could then be divided into smaller pieces and the flow distribution calculated for that section would look the same as the overall distribution. (From Ref. 119.)
Where N ⫽ 2n. Since after several generations the same total flow goes through many more vessels, the average flow per vessel decreases. By the same token, the standard deviation of the flow decreases as the branch generation increases. Contrary to standard deviation, however, the RD increases. This increase, observed through experimental data obtained from the heart, was matched very closely by the fractal models (Fig. 12). Based on these fits, γ for the branches was calculated to be 0.45 to 0.47 for the deterministic models and 0.43 to 0.47 for the stochastic ones (119). The first thing to note about these findings is how well such a geometrically simple model describes the data. Secondly, considering that a γ of 0.5 corresponds to homogeneous flow, it was surprising to discover how small a perturbation from homogeneity was needed to produce a highly heterogeneous flow in the microvasculature. Indeed these values were close to observations made by Tyml and Ellis (117) who measured the ratio of the lowest to highest red blood cell velocity in the rat mescentary to be 0.74 during hyperemia, which corresponds to a γ of 0.425 (notice that 0.425/(1 ⫺ 0.425) ⫽ 0.74). It should be noted that the γ for the resting frog muscle
Microcirculatory Blood Flow
139
Figure 11 Fractal vascular network showing two generations of bifurcations. γ is the ratio of flow between two daughters of a branch and F is the inflow into the network. Thus, if the inflow F ⫽ 5 and γ ⫽ 0.25, then the flows at the two daughter branches of the first bifurcation would be 1.25 and 3.75, respectively. (From Ref. 119.)
Figure 12 A graph showing relative dispersion (RD) of flow as a function of the number of pieces, N. Triangles represent RD of flow measured from baboon myocardium (average of 10 baboons). The dashed line shows the fit of predicted RDs as calculated using the deterministic fractal flow model. (From Ref. 119.)
140
Bosan and Walley
was found to be 0.37 by the same authors. Thus more work needs to be done in order to apply the fractal models to a variety of situations.
XVII.
Conclusions
The ultimate goal of oxygen transport research would be to construct a comprehensive model that accurately describes the transport of oxygen at all scales, from the microvasculature to the whole organ. Unfortunately, the current state of knowledge and experimental techniques do not yet permit us to construct precise models even at the capillary network level. Thus, this final goal is some time away. Meanwhile, improvements are being made both at the experimental and mathematical front. For example, significant advancements have been reported in the quality, reproducibility, and resolution of oxygen content and hemodynamic parameter measurements at the capillary network level. In particular, video microscopy holds a lot of promise in this direction as higher-powered image processing and new fluorescent techniques are quickly becoming available. These advancements in experimental technique combined with further refinements in theory should soon yield highly complex and useful models, enabling research in this area to move to the next stage of inquiry involving questions of function and therapy rather than mechanism.
References 1. Kreuzer F, Hoofd LJ. Facilitated diffusion of CO and oxygen in the presence of hemoglobin or myoglobin. Adv Exp Med Biol 1976; 75:207–215. 2. Weibel ER. Morphometry of the Human Lung. New York: Academic Press, 1963:xi, 151. 3. Fung YC. Biomechanics: Circulation. New York: Springer, 1997:xvii, 571. 4. Torre-Bueno JR, Wagner PD, Saltzman HA, Gale GE, Moon RE. Diffusion limitation in normal humans during exercise at sea level and simulated altitude. J Appl Physiol 1985; 58:989–995. 5. Wagner PD, West JB. Effects of diffusion impairment on O2 and CO2 time courses in pulmonary capillaries. J Appl Physiol 1972; 33:62–71. 6. Shelton G. Model applications in respiratory physiology. In: Egginton S, Ross HF, eds. Oxygen Transport in Biological Systems: Modelling of Pathways from Environment to Cell. Cambridge: Cambridge University Press, 1992:135–163. 7. Levitzky MG. Pulmonary Physiology. New York: McGraw-Hill, 1995:xvi, 299. 8. Braun HA, Loehnen CP, Beall CE, Cheney FW. Introduction to Respiratory Physiology. Boston: Little Brown, 1980:vii, 159. 9. Hodgkin JE, Petty TL. Chronic Obstructive Pulmonary Disease: Current Concepts. Philadelphia: Saunders, 1987:xv, 316. 10. Rossaint R, Hahn SM, Pappert D, Falke KJ, Radermacher P. Influence of mixed venous PO2 and inspired O2 fraction on intrapulmonary shunt in patients with severe ARDS. J Appl Physiol 1995; 78:1531–1536. 11. Evans JW, Wagner PD, West JB. Conditions for reduction of pulmonary gas transfer by ventilation-perfusion inequality. J Appl Physiol 1974; 36:533–537. 12. Hoppensteadt FC, Peskin CS. Mathematics in Medicine and the Life Sciences. New York: Springer-Verlag, 1992:xii, 252. 13. Honig CR. Modern cardiovascular physiology. Boston: Little, Brown, 1988:xviii, 317. 14. Krogh A. The number and distribution of capillaries in muscle with calculations of the
Microcirculatory Blood Flow
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.
141
oxygen pressure head necessary for supplying the tissue. J Physiol (Lond) 1919; 52:409– 415. Kreuzer F. Oxygen supply to tissues: the Krogh model and its assumptions. Experientia 1982; 38:1415–1426. Ellsworth ML, Ellis CG, Popel AS, Pittman RN. Role of microvessels in oxygen supply to tissue. News Physiol Sci 1994; 9:119–123. Clark PA, Kennedy SP, Clark A, Jr. Buffering of muscle tissue PO2 levels by the superposition of the oxygen field from many capillaries. Adv Exp Med Biol 1989; 248:165– 174. Hudlicka O, Egginton S, Brown MD. Capillary diffusion distances—their importance for cardiac and skeletal muscle performance. News Physiol Sci 1988; 3:119–123. Kety SS. Determinants of tissue oxygen tension. Fed Proc 1957; 16:666–670. Blum JJ. Concentration profiles in and around capillaries. Am J Physiol 1960; 198:991. Gayeski TE, Honig CR. O2 gradients from sarcolemma to cell interior in red muscle at maximal VO2. Am J Physiol 1986; 251:H789–H799. Gayeski TE, Honig CR. Intracellular PO2 in long axis of individual fibers in working dog gracilis muscle. Am J Physiol 1988; 254:H1179–H1186. Rose CP, Goresky CA. Limitations of tracer oxygen uptake in the canine coronary circulation. Circ Res 1985; 56:57–71. Bidani A, Flumerfelt RW. Transient response of muscle and nonbrain tissue to adjustments in O2 and CO2 balance. Ann Biomed Eng 1981; 9:89–144. Salathe EP, Fayad R, Schaffer SW. Mathematical analysis of carbon dioxide transport by blood. Math Biosci 1981; 57:109. Ulanowicz RE, Frazier GCJ. The transport of oxygen and carbon dioxide in hemoglobin systems. Math Biosci 1970; 7:111. Buerk DG, Goldstick TK. Arterial wall oxygen consumption rate varies spatially. Am J Physiol 1982; 243:H948–H958. Gibson QH, Kreuzer F, Meda E, Roughton FJW. The kinetics of human hemoglobin in solution and in the red blood cell at 37 C. J Physiol (Lond) 1955; 129:65. Moll W. The influence of hemoglobin diffusion on oxygen uptake and release by red cells. Respiration Physiology 1968; 6:1–15. Bouwer ST. Facilitated Oxygen Diffusion Through Hemoglobin Solutions. Measurement of Diffusion and Reaction Parameters. Nijmegen, Netherlands: University of Nijmegen, 1987. Adair GS. The hemoglobin system. IV. The oxygen dissociation curve of hemoglobin. J Biol Chem 1925; 63:529. Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curve. J Physiol (Lond) 1910; 41. Buerk DG. An evaluation of Easton’s paradigm for the oxyhemoglobin equilibrium curve. Adv Exp Med Biol 1984; 180:333–344. Buerk DG, Bridges EW. A simplified algorithm for computing the variation in oxyhemoglobin saturation with pH, PCO2, T, and DPG. Chem Eng Commun 1986; 47:113. Hartridge H, Roughton FJW. The rate of distribution of dissolved gasses between the red blood corpuscle and its fluid environment. J Physiol (Lond) 1927; 62:232. Meldon JH. Blood-gas equilibria, kinetics and transport. Chem Eng Sci 1987; 42:199. Kreuzer F, Hoofd L. Facilitated diffusion of oxygen and carbon dioxide. In: Fahri LE, Tenney SM, eds. Handbook of Physiology—The Respiratory System, Sect. 3, Vol. 4. Baltimore: Williams & Wilkins, 1987:89–111. Coin JT, Olson JS. The rate of oxygen uptake by human red blood cells. J Biol Chem 1979; 254:1178–1190. Huxley VH, Kutchai H. The effect of the red cell membrane and a diffusion boundary layer on the rate of oxygen uptake by human erythrocytes. J Physiol 1981; 316:75–83. Huxley VH, Kutchai H. Effect of diffusion boundary layers on the initial uptake of O2 by red cells. Theory versus experiment. Microvasc Res 1983; 26:89–107. Weingarden M, Mizukami H, Rice SA. Transient effects on the initial rate of oxygenation of red blood cells. Bull Math Biol 1982; 44:119–34. Popel AS. Theory of oxygen transport to tissue. Crit Rev Biomed Eng 1989; 17:257–321.
142
Bosan and Walley
43. Kreuzer F, Yahr WZ. Influence of red cell membrane on diffusion of oxygen. J Appl Physiol 1960; 15:1117–1122. 44. Hellums JD. The resistance to oxygen transport in the capillaries relative to that in the surrounding tissue. Microvasc Res 1977; 13:131–136. 45. Sheth BV, Hellums JD. Transient oxygen transport in hemoglobin layers under conditions of the microcirculation. Ann Biomed Eng 1980; 8:183–196. 46. Baxley PT, Hellums JD. A simple model for simulation of oxygen transport in the microcirculation. Ann Biomed Eng 1983; 11:401–416. 47. Clark A Jr, Federspiel WJ, Clark PA, Cokelet GR. Oxygen delivery from red cells. Biophys J 1985; 47:171–181. 48. Hoofd L. Updating the Krogh Model—Assumptions and Extensions. In: Egginton S, Ross HF, eds. Oxygen Transport in Biological Systems: Modelling of Pathways from Environment to Cell. Cambridge: Cambridge University Press, 1992:135–163. 49. Homer LD, Weathersby PK, Kiesow LA. Oxygen gradients between red blood cells in the microcirculation. Microvasc Res 1981; 22:308–323. 50. Federspiel WJ, Sarelius IH. An examination of the contribution of red cell spacing to the uniformity of oxygen flux at the capillary wall. Microvasc Res 1984; 27:273–285. 51. Aroesty J, Gross JF. Convection and diffusion in the microcirculation. Microvasc Res 1970; 2:247-67. 52. Hudlicka O, Hoppeler H, Uhlmann E. Relationship between the size of the capillary bed and oxidative capacity in various cat skeletal muscles. Pflugers Arch 1987; 410:369–375. 53. Schumacker PT, Samsel RW. Analysis of oxygen delivery and uptake relationships in the Krogh tissue model. J App Physiol 1989; 67:1234–1244. 54. Schumacker PT, Long GR, Wood LD. Tissue oxygen extraction during hypovolemia: role of hemoglobin P50. J App Physiol 1987; 62:1801–1807. 55. Walley KR, Becker CJ, Hogan RA, Teplinsky K, Wood LD. Progressive hypoxemia limits left ventricular oxygen consumption and contractility. Circ Res 1988; 63:849–859. 56. Nelson DP, Beyer C, Samsel RW, Wood LD, Schumacker PT. Pathological supply dependence of O2 uptake during bacteremia in dogs. J Applied Physiol 1987; 63:1487– 1492. 57. Nelson DP, King CE, Dodd SL, Schumacker PT, Cain SM. Systemic and intestinal limits of O2 extraction in the dog. J App Physiol 1987; 63:387–394. 58. Nelson DP, Samsel RW, Wood LD, Schumacker PT. Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia. J Appl Physiol 1988; 64:2410– 2419. 59. Segal JM, Phang PT, Walley KR. Low-dose dopamine hastens onset of gut ischemia in a porcine model of hemorrhagic shock [see comments]. J App Physiol 1992; 73:1159– 1164. 60. Humer MF, Phang PT, Friesen BP, Allard MF, Goddard CM, Walley KR. Heterogeneity of gut capillary transit times and impaired gut oxygen extraction in endotoxemic pigs. J Appl Physiol 1996; 81:895–904. 61. Piiper J, Meyer M, Scheid P. Dual role of diffusion in tissue gas exchange: blood-tissue equilibration and diffusion shunt. Adv Exp Med Biol 1984; 180:85–94. 62. Walley KR. Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory. J Appl Physiol 1996; 81:885–894. 63. Walley KR, Collins RM, Cooper DJ, Warriner CB. Myocardial anaerobic metabolism occurs at a critical coronary venous PO2 in pigs. Am J Resp Crit Care Med 1997; 155:222– 228. 64. King CE, Dodd SL, Cain SM. O2 delivery to contracting muscle during hypoxic or CO hypoxia. J Appl Physiol 1987; 63:726–32. 65. Honig CR, Odoroff CL. Calculated dispersion of capillary transit times: significance for oxygen exchange. Am J Physiol 1981; 240:H199–H208. 66. Drazenovic R, Samsel RW, Wylam ME, Doerschuk CM, Schumacker PT. Regulation of perfused capillary density in canine intestinal mucosa during endotoxemia. J Appl Physiol 1992; 72:259–265. 67. Lam C, Tyml K, Martin C, Sibbald W. Microvasc perfusion is impaired in a rat model of normotensive sepsis. J Clin Invest 1994; 94:2077–2083.
Microcirculatory Blood Flow
143
68. Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR. Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol 1995; 79:479–486. 69. Guyton AC, Hall JE. Textbook of Medical Physiology. Philadelphia: W.B. Saunders, 1996: xliii, 1148. 70. Guyton AC, Jones CE, Coleman TT. Circulatory Physiology: Cardiac Output and its Regulation. Philadelphia: Saunders, 1973:vii, 556. 71. Groebe K. Precapillary servo control of blood pressure and postcapillary adjustment of flow to tissue metabolic status. A new paradigm for local perfusion regulation. Circulation 1996; 94:1876–1885. 72. Renkin EM. Control of microcirculation and blood-tissue exchange. In: Renkin EM, Michel CC, eds. Handbook of Physiology—The Cardiovascular System, Sect. 2. Vol. 4. Baltimore: Williams & Wilkins, 1984:627–687. 73. Shepherd JT. Circulation to skeletal muscle. In: Shepherd JT, Abboud FM, eds. Handbook of Physiology—The Cardiovascular System, Sect. 2. Vol. 3. Baltimore: Williams & Wilkins, 1983:319–370. 74. Haddy FJ. The role of a humoral Na⫹, K⫹-ATPase inhibitor in regulating precapillary vessel tone. J Cardiovasc Pharmacol 1984; 6:S439–S456. 75. Pearson JD. Endothelial cell control of vascular tone and permeability. In: Halliday A, Hunt BJ, Poston L, Schachter M, eds. An Introduction to Vascular Biology: from Physiology to Pathophysiology. Cambridge: Cambridge University Press, 1998:32–49. 76. Falcone JC, Bohlen HG. EDRF from rat intestine and skeletal muscle venules causes dilation of arterioles. Am J Physiol 1990; 258:H1515–H1523. 77. Hester RL. Uptake of metabolites by postcapillary venules: mechanism for the control of arteriolar diameter. Microvasc Res 1993; 46:254–261. 78. Saito Y, Eraslan A, Hester RL. Importance of venular flow in control of arteriolar diameter in hamster cremaster muscle. Am J Physiol 1993; 265:H1294–H1300. 79. Myrhage R, Eriksson E. Vascular arrangements in hind limb muscles of the cat. J Anat 1980; 131:1–17. 80. Johnson PC. The myogenic response. In: Renkin EM, Michel CC, eds. Handbook of Physiology-The Cardiovascular System, Sect. 2. Vol. 4. Baltimore: Williams & Wilkins, 1984: 409–442. 81. Cockell AD, Poston L. Flow-mediated responses in the circulation. In: Halliday A, Hunt BJ, Poston L, Schachter M, eds. An Introduction to Vascular Biology: from Physiology to Pathophysiology. Cambridge: Cambridge University Press, 1998:32–49. 82. Davies PF. How do vascular endothelial cells repond to flow? News Physiol Sci 1989; 4: 22. 83. Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol 1991; 260:H862–H868. 84. Segal SS, Duling BR. Flow control among microvessels coordinated by intercellular conduction. Science 1986; 234:868–870. 85. Song H, Tyml K. Evidence for sensing and integration of biological signals by the capillary network. Am J Physiol 1993; 265:H1235–H1242. 86. Kessler M, Hoper J, Harrison DK, et al. Tissue O2 supply under normal and pathological conditions. Adv Exp Med Biol 1984; 169:69–80. 87. Burton AC. Physiol and Biophysics of the Circulation; An Introductory Text. Chicago: Year Book Medical Publishers, 1972:xiv, 226. 88. Harrison DK, Kessler M, Knauf SK. Regulation of capillary blood flow and oxygen supply in skeletal muscle in dogs during hypoxaemia. J Physiol 1990; 420:431–446. 89. Tyml K. Heterogeneity of microvascular flow in rat skeletal muscle is reduced by contraction and by hemodilution. Int J Microcirc Clin Exp 1991; 10:75–86. 90. Van Beek JH. Is local metabolism the basis of the fractal vascular structure in the heart? Int J Microcirc Clin Exp 1997; 17:337–345. 91. Caruthers SD, Harris TR, Overholser KA, Pou NA, Parker RE. Effects of flow heterogeneity on the measurement of capillary exchange in the lung. J Appl Physiol 1995; 79:1449– 1460. 92. King RB, Raymond GM, Bassingthwaighte JB. Modeling blood flow heterogeneity. Ann Biomed Eng 1996; 24:352–372.
144
Bosan and Walley
93. Egginton S, Johnston IA. An estimate of capillary anisotropy and determination of surface and volume densities of capillaries in skeletal muscles of the conger eel (Conger conger L.). Q J Exp Physiol 1983; 68:603–617. 94. Kassab GS, Fung YC. Topology and dimensions of pig coronary capillary network. Am J Physiol 1994; 267:H319–H325. 95. Egginton S, Ross HF. Planar analysis of tissue capillary supply. In: Egginton S, Ross HF, eds. Oxygen Transport in Biological Systems: Modelling of Pathways from Environment to Cell. Cambridge: Cambridge University Press, 1992:135–163. 96. Turek Z, Olders J, Hoofd L, Egginton S, Kreuzer F, Rakusan K. PO2 histograms in various models of tissue oxygenation in skeletal muscle. Adv Exp Med Biol 1989; 248:227–237. 97. Turek Z, Hoofd L, Rakusan K. A comparison of the methods for assessment of the heterogeneity of myocardial capillary spacing. Adv Exp Med Biol 1987; 215:13–19. 98. Egginton S, Ross HF. Influence of muscle phenotype on local capillary supply. Adv Exp Med Biol 1989; 248:281–291. 99. Groebe K. Practical applications of models of oxygen supply, diffusion, and consumption: past, perspectives, and problems. Adv Exp Med Biol 1996; 388:161–175. 100. Van Beek JH, Barends JP, Westerhof N. The microvascular unit size for fractal flow heterogeneity relevant for oxygen transport. Adv Exp Med Biol 1994; 345:901–908. 101. Loiselle DS. Exchange of oxygen across the epicardial surface distorts estimates of myocardial oxygen consumption. J Gen Physiol 1989; 94:567–590. 102. Bassingthwaighte JB, Van Beek JH, King RB. Fractal branchings: the basis of myocardial flow heterogeneities? Ann the NY Acad Sci 1990; 591:392–401. 103. Bassingthwaighte JB, Liebovitch LS, West BJ. Fractal Physiology. The American Physiological Society Methods in Physiology Series. New York: Oxford University Press, 1994: xi, 364. 104. Harrison DK, Birkenhake S, Hagen N, Knauf S, Kessler M. Regulation of capillary blood flow: a new concept. Adv Exp Med Biol 1989; 248:583–589. 105. Dinnar U. The relations between microvascular structure and oxygen supply. Adv Exp Med Biol 1997; 430:139–151. 106. Pries AR, Secomb TW, Gaehtgens P, Gross JF. Blood flow in microvascular networks. Experiments and simulation. Circ Res 1990; 67:826–834. 107. Popel AS, Gross JF. Analysis of oxygen diffusion from arteriolar networks. Am J Physiol 1979; 237:H681–H689. 108. Gaehtgens P. Why networks? Intl J Microcirc Clin Exp 1992; 11:123–132. 109. Schmid-Schonbein GW, Skalak R, Usami S, Chien S. Cell distribution in capillary networks. Microvasc Res 1980; 19:18–44. 110. Pries AR, Ley K, Gaehtgens P. Generalization of the Fahraeus principle for microvessel networks. American J Physiol 1986; 251:H1324–H1332. 111. Pries AR, Kanzow G, Gaehtgens P. Microphotometric determination of hematocrit in small vessels. Am J Physiol 1983; 245:H167–H177. 112. Pries AR, Secomb TW, Gaehtgens P. Structure and hemodynamics of microvascular networks: heterogeneity and correlations. Am J Physiol 1995; 269:H1713–H1722. 113. Heymann MA, Payne BD, Hoffman JI, Rudolph AM. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis 1977; 20:55–79. 114. Bassingthwaighte JB, Malone MA, Moffett TC, et al. Molecular and particulate depositions for regional myocardial flows in sheep. Circ Res 1990; 66:1328–1344. 115. Bassingthwaighte JB, King RB, Roger SA. Fractal nature of regional myocardial blood flow heterogeneity. Circ Res 1989; 65:578–590. 116. Van Beek JH, Bassingthwaighte JB, Roger SA. Fractal networks explain regional myocardial flow heterogeneity. Adv Exp Med Biol 1989; 248:249–257. 117. Tyml K, Ellis CG. Localized heterogeneity of red cell velocity in skeletal muscle at rest and after contraction. Adv Exp Med Biol 1989; 248:735–743. 118. Bassingthwaighte JB, Van Beek JHGM. Lightning and the heart: fractal behavior in cardiac function. Proc IEEE 1988; 76:693–699. 119. Van Beek JHGM. Fractal models of heteogeneity in organ blood flow. In: Egginton S, Ross HF, eds. Oxygen Transport in Biological Systems: Modelling of Pathways from Environment to Cell. Cambridge: Cambridge University Press, 1992:135–163.
7 The Sympathetic Nervous System of the Developing Mammal
ANTHONY L. SICA Long Island Jewish Medical Center New Hyde Park, New York
BRUCE W. HUNDLEY and PHYLLIS M. GOOTMAN State University of New York Health Science Center at Brooklyn Brooklyn, New York
DAVID A. RUGGIERO Columbia University College of Physicians and Surgeons New York, New York and Neurological Research Institute of Lubec Lubec, Maine
I.
Introduction
Perhaps no component of the nervous system has been studied so extensively as the sympathetic division of the autonomic nervous system. Studies of the sympathetic nervous system have been carried out for over a century, although most of the research effort focused on mature mammals (over 22,000 papers were found in a recent Medline search). In contrast, interest in the sympathetic nervous system of immature mammals has been a relatively recent development, especially in the relationship of autonomic pathophysiology and sudden infant death syndrome (SIDS) (1–6). However, this review will not focus primarily on the possible involvement of the autonomic nervous system in the etiology of SIDS. Rather, after giving a historical review of the early literature about the sympathetic system, we will present anatomical and physiological findings obtained from studies of adult animals to provide a contemporary view of the neural circuits and transmitter phenotypes participating in the generation of central sympathetic activity. Studies of central mechanisms involved in the autonomic nervous system of the immature animal will be presented when possible; however, it should be noted that there are far fewer studies of developing animals than mature ones. In contrast, as much more is known about the autonomic responses of developing animals to baroreceptor and chemoreceptor 145
146
Sica et al.
afferent inputs, modulation of sympathetic activity by such inputs will be examined in this chapter. II. Early Studies of the Sympathetic Nervous System Despite the absence of sophisticated techniques, investigators of the 19th century were able to obtain a good deal of knowledge about the sympathetic system using the relatively simple technique of surgical transection. For example, Claude Bernard (7) and Brown-Sequard (8) discovered that sectioning the cervical sympathetic nerve or removal of the superior cervical ganglion caused the blood vessels of the rabbit’s ear to dilate. Electrical stimulation of the peripheral end of the cut cervical sympathetic nerve constricted the blood vessels of the ear. These studies provided evidence for an important function of the sympathetic nervous system, i.e., the dependence of vascular tone on innervation by sympathetic efferent fibers. Bernard (9) was probably the first to focus attention on the role of supraspinal regions in generating sympathetic nerve activity by demonstrating that a surgical transection near the medullospinal junction was followed by an immediate and profound fall in blood pressure. Bernard’s experiments were seminal in that they established a role for supraspinal neuronal circuits in the maintenance of basal tone of sympathetic vasoconstrictor nerves. The necessity of supraspinal structures for the maintenance of vascular tone was reinforced by Sherrington’s (10) experiments showing the hypotension and depression of somatomotor reflexes induced by a surgical transection at the medullospinal junction could not be evoked again by a second transection made caudal to the level of the first transection. The search for specific regions of the brain responsible for sympathetic nerve activity began in the laboratory of Carl Ludwig. One of his students, Oswjannikow (11), found that serial transections of the rabbit or cat brainstem did not noticeably affect blood pressure until a cut was made through the pons, 1 to 2 mm behind the caudal border of the inferior cerebellar peduncle. Serial transections between this level and one somewhat rostral to the obex of the medulla progressively lowered blood pressure to a value near that evoked after transection of the cervical spinal cord. Dittmar (12), also working in Ludwig’s laboratory, confirmed those results. More recently, Schlaefke and Loeschcke (13) found that local cooling of the rostral ventrolateral medulla (RVLM) caused a pronounced fall in blood pressure. Such a manipulation, however, could have affected cell bodies as well as axons en passant, i.e., fibers passing through this region, but which originate elsewhere. That this region contained the cell bodies of neurons involved in controlling sympathetic outflow was established by Feldberg et al. (14). Structures involved in cardiovascular regulation were also identified using electrical stimulation of the dorsal medullary surface. Ranson and Billingsley (15) found that stimulation of a region rostral and lateral to the obex of the medulla evoked pressor responses, whereas depressor responses were evoked by stimulation in the vicinity of the nucleus of the solitary tract (NTS). Ranson and Billingsley recognized a major interpretative problem associated with electrical stimulation, whether cell bodies or axons en passant were activated, and were cautious not to
Sympathetic Nervous System
147
attribute their results to the activation of functionally discrete and anatomically circumscribed centers for cardiovascular control. Nevertheless, their findings reinforced the view that a ‘‘vasomotor center,’’ located in the dorsal medulla, was the source of basal sympathetic nerve discharge. The search for a ‘‘vasomotor center’’ reflected the concept that specific functions were compartmentalized within the central nervous system, i.e., associated with fairly discrete regions of the brain. The hypothesis that basal sympathetic discharge could be localized to relatively discrete anatomical loci conflicted with the subsequent discovery that a number of sites responsive to electrical stimulation, extending through the reticular formation to the ventral surface of the brainstem, were associated with pressor and depressor responses (16). Thus, the finding of a large number of vasoactive sites in the brainstem supported an alternative hypothesis, that basal sympathetic discharge represented the coordinated activity of a diffuse network of neurons. That different regulatory systems located in the lower brainstem contributed to sympathetic discharge was first shown by Adrian et al. (17) by demonstrating sympathetic nerve activity with bursts related to both the cardiac and respiratory cycles. Later, Alexander (18) provided the crucial link between nerve activity and the maintenance blood pressure by showing that decreases of blood pressure were a consequence of decreased activity in postganglionic sympathetic nerve traffic. The concept of a diffuse network of neurons shaping basal central sympathetic discharge resonates well with the findings of contemporary anatomical studies of adult animals. Furthermore, examination of sympathetic nerve activity, pre- and postganglionic, and the spike trains of central sympathetic-related neurons revealed common periodicities/rhythms that represented common modulatory influences. III. Periodicities in Sympathetic Discharge It has long been known that the discharges of sympathetic nerves were comprised of bursts of activity related to both the cardiac and the respiratory cycles (17,19). Later, these bursts were shown to contain rhythms restricted to relatively specific spectral bands. Two well-known rhythms in sympathetic discharges, the 2- to 6-Hz (related to the cardiac rhythm) and 10-Hz (range 8 to 13 Hz) rhythms have been reported in mature animals (20–26), and have been reviewed recently by Malpas (27). The 2- to 6-Hz periodicity in sympathetic discharge was shown to be an endogenous brainstem rhythm, entrained by phasic baroreceptor afferent inputs, and was prominent in the activities of caudal and rostral ventrolateral medullary neurons (21,24,28–30). Recent studies have shown that neurons of the caudal and RVLM, caudal medullary raphe, the para-ambiguual area as well as caudal ventrolateral pons had activities in the 2- to 6-Hz and 10-Hz frequency bands, and that a subpopulation of neurons in each structure had axonal projections to sites in the thoracic spinal cord, containing sympathetic preganglionic neurons (31–33). These findings provide additional support for the concept that the sympathetic controller system is diffusely organized, with a number of different regions with access to the site of final common output, thereby modulating postganglionic neurons and target organs. One could argue that such widespread loci of rhythmic activity could repre-
148
Sica et al.
sent some degree of redundancy in the design of the sympathetic system, thereby allowing cardiovascular regulation when one component of the system sustains damage, or when physiological conditions change—for example, during sleep or anesthesia. Unlike the mature animal, brainstem regions involved in rhythm generation have not been examined extensively in immature animals. However, we have shown that both the 2- to 6-Hz and 10-Hz rhythms were present in the discharges of preand postganglionic nerves of developing animals (34–39). While both rhythms appeared early in development, only the 2- to 6-Hz rhythm appeared in very young newborns; the 10-Hz rhythm appeared later in development (35,39,40). As the 2to 6-Hz rhythm was also highly correlated with blood pressure, it may be reasonably concluded that central sympathetic-related neurons of newborns have the capacity to integrate baroreceptor afferent information, and that such integration is reflected in the discharges of pre- and postganglionic nerves. The significance of the lag in the appearance of the 10-Hz rhythm remains to be explored; however, it could represent a delay in the establishment of synaptic relationships among neurons involved in generating such activity. The functional relationship of the 10-Hz rhythm to cardiovascular function in immature animals remains an unanswered question. However, in a recent study of adult rabbits, Kishi et al. (41) compared the efficacy of electrical stimulation of the renal sympathetic nerve at 5 Hz and 10 Hz, and showed that the latter frequency elicited shorter latency and larger amplitude changes in renal vascular conductance than the former. Thus, endogenous 10 Hz in the sympathetic system could represent the optimal frequency of action potentials required to evoke maximally effective transmitter release, thereby providing for efficient interneuronal communication.
IV. Neuroanatomical Studies of the Brainstem Sympathetic Network A. First-Order Barosensory Neurons
Baroreceptors transmit over the carotid sinus and aortic depressor branches of cranial nerves IX and X. First order or primary barosensory neurons with cell bodies located in the petrosal and nodose ganglia synapse on neurons within dorsal, medial, and commissural subnuclei of the NTS at levels caudal to obex. Physiological activation of baroreceptors using an elegant, vascularly isolated carotid sinus preparation, suggest that these populations are functionally differentiated by different pressure thresholds (42). Baroreceptor afferents and with other viscerosensory cells may use an excitatory amino acid, l-glutamate (GLU), as a neurotransmitter. Partly in support are bradycardic responses to excitation of GLU receptor sites within NTS and baroreceptor-stimulated release of endogenous amino acids (43–45), buttressed by GLU immunoreactivity in vagal afferents by electron microscopy (46). Vagal (nodosal) afferents to NTS, capable of synthesizing nitric oxide (47) have yet to be characterized physiologically, although brainstem changes in NO synthase levels are strongly implicated in the ontogenetic development of the gasping reflex (48).
Sympathetic Nervous System
149
Perinatal maturation of cardiorespiratory control circuits critically depend on coordinated changes in transmitter phenotypes and receptor binding sites. In support are striking biphasic, ‘‘up/down’’ regulatory patterns of GLU-receptor densities within cardiorespiratory divisions of the rats’ NTS and reticular formation and spinal cord (49). In neonatal swine-a model for SIDS (50), GLU-R1, an AMPA receptor subtype distinguished by high affinity for ligand and unique developmental and adaptive plasticity is encoded by brainstem neurons subserving sensory and autonomic processing and projection fields, such as the thoracic sympathetic column (51). If detected in pigs, age-related expression of GLU by cardiorespiratory circuits would be relevant to an as yet unproved developmental defect of chemoreceptor circuits underlying SIDS (52). B. Baroreceptor Reflex
The development of cardiorespiratory circuits is still poorly understood as most studies have focused on adult models. Visceral reflexes are mediated differentially by topographic connections among sensory ganglia, the NTS, and columns in medullary reticular formation and raphe which innervate cardiorespiratory motoneurons monosynaptically or through as yet ill-defined polysynaptic networks (53,54). Involved in these reflexes are cells which synthesize catecholamines, GLU, γaminobutyric acid (GABA), serotonin, and neuropeptides such as stress hormones, vasopressin, and corticotrophic-releasing hormone and that are activated or suppressed by homeostatic challenges (55–61). The NTS connects with cardiorespiratory control regions, providing monosynaptic innervation of sympathetic column (62) and parasympathetic motoneurons of cranial nerves IX and X (63) (Fig. 1A). A central, unresolved question is the identity of the tonic vasomotor neuron and transmitter(s) responsible for maintaining sympathetic nerve discharges. Vasomotor centers are thought to reside in two contiguous regions of the lateral tegmental field (LTF): the dorsal intermediate reticular zone and rostral ventrolateral tegmentum. Vasopressor cells in dorsal LTF with firing rates coupled to baroreceptors may aid in maintaining basal sympathetic nerve discharges (25,64,65) possibly by local interneuronal innervation of RVLM (53). Major NTS projection targets in brainstem reticular formation relevant to baro- and chemo receptor reflexes are the RVLM and adjoining paragigantocellular region (66) and interneurons distributed dorsally and caudally (53,54). Within the RVLM (67) longitudinally organized columns of adrenergic and nonadrenergic barosenitive and pulse-synchronous neurons, lie a rostral pool of neurons critically involved in the tonic and reflex control of sympathetic nerve discharges, coregulating blood pressure, cardiac rate, and output (56). A subambiguual region, referred to as the C1 area, synthesizes adrenaline in rats (58) and other mammals, including neonatal swine (59). An unresolved question is the role of the central adrenergic neuron in vasomotor regulation. Proposed sympathetic control circuits include parallel neurochemically distinct sympathospinal pathways, and a single premotor pathway cosynthesizing GLU and adrenaline. Alternatively, adrenaline may inhibit sympathetic discharge via a glycinergic spinal sympathetic interneuron (Fig. 1B). Sympathoexci-
Figure 1 (A) Proposed baroreceptor reflex circuits regulating parasympathetic motoneurons in nucleus ambiguus (n. Ambig.) and sympathetic premotor neurons in rostral ventrolateral medulla (RVLM) and transmitters. GABA-ergic interneurons in the caudal ventrolateral medulla (CVLM) are interposed between the baroreceptor division of nucleus tractus solitarii (NTS) and sympathetic bulbospinal cells in RVLM. Excitatory amino acids (EAAs) act on receptors at each limb of the baroreceptor reflex arc. Maturational changes in EAA receptors and nitric oxide in brainstem and spinal cord play important coordinated roles in cardiorespiratory reflex development in neonates (this figure is reproduced with permission from Ref. 60). (B) Proposed circuits regulating sympathetic activity and transmitters. (a) Direct parallel sympathetic pathways. (b) Local interneurons in RVLM and/or spinal gray synapsing, respectively, on sympathetic premotor and preganglionic motor neurons. (c) Direct vasomotor pathways colocalizing adrenaline and L-Glu or other candidate transmitters. The same concept applies to other putative sympathetic control centers (this figure is reproduced with permission from Ref. 56).
Sympathetic Nervous System
151
tatory locus in RVLM maintains resting levels of blood pressure, theoretically via pacemaker cells distinguished by rapid conduction velocities: 3.5 m/sec, and which project exclusively to spinal preganglionic neurons (SPGNs) and synthesize an excitatory amino acid transmitter. Slow conducting cells, 0.7 m/sec, synthesize adrenaline, are barosensitive and project bidirectionally (68,69). Differential regulation of vascular beds is likely subserved by distinct cell groups, theoretically providing descending topographic innervation of segmental sympathetic motoneurons (56). Among the groups adjoining the sympathetic premotor cells is the Botzinger complex, local interneurons, and a cardiomotor column in nucleus ambiguus (53,63,70). Such a configuration was also described for cardiomotor neurons of the nucleus ambiguus in the developing pig (71,72). Ascending projections largely arise from levels caudal to the sympathoexcitatory area and terminate in limbic thalamus (73), amygdala (74), and hypothalamic-preoptic regions (75) regulating release of neurohypophyseal and adrenocorticotrophic stress hormones. C1 adrenergic neurons in RVLM and ambiguual motoneurons extend caudally as far as the spinocervical junction and receive input from NTS axon trajectories, directly and, likely, polysynaptically via interneurons interposed between NTS and chemosensory regions proximal to the ventral medullary surface (53). Collectively, NTS projections form circuits involved in behavioral, endocrine, and reflex responses to visceral stimulation (76–79). The critical importance of the NTS- RVLM reflex arc in mediating sympathetic and cardiomotor components of the baroreceptor reflex was demonstrated in rats (80) and extended by findings implicating pools of inhibitory interneurons intercalated between the NTS and RVLM (81). Excitotoxic lesions, restricted to RVLM, or electrolytic destruction of their descending axon pathway to sympathetic column blocked or attenuated the reflex response to baroreceptor activation (80). A trisynaptic brainstem pathway leading from the NTS to sympathetic preganglionic neurons was subsequently proposed (81), although polysynaptic circuits cannot be excluded (Fig. 1A). Barosensory signals are conveyed to the NTS which in turn, relays, via intermediary neurons, to a sympathoexcitatory region of medullary reticular formation (67), which projects to sympathetic preganglionic neurons including adrenomedullary motoneurons (62). NTS projection fibers run diagonally across the lateral tegmentum and issue branches en passant, synapsing onto interneurons which, in turn, ascend to synapse on sympathetic premotor cells concentrated in the RVLM (54). Direct pathways to sympathetic premotor cells in RVLM also exist (53,54) and, as described below, have been implicated in the arterial chemoreceptor reflex (61). NTS neurons also descend to terminate sympathetic cell column and phrenic motor nucleus (77). The source of baroreceptor inhibition of sympathoexcitatory neurons remains an open question (82). GABAA receptors exert tonic inhibitory influence on RVLM cells generating sympathetic nerve discharge-based on respective rise and fall in blood pressure following injections of the GABAA receptor antagonist bicuculline or GABA into RVLM or their application onto the subjacent ventral surface (55,61,83). A likely source of inhibition are cells in LTF which were found to project locally to RVLM via short intrareticular projection pathways (53,63) and synthesize GABA (58). Intrareticular inputs to RVLM, in fact, partly
152
Sica et al.
arise from GABAergic neurons from loci in caudal tegmentum (84), activated by baroreceptor stimulation, at latencies consistent with an intermediary position in the reflex arc (85,86). Barosensory cells in one region designated the caudal ventrolateral medulla (CVLM) form symmetric, presumptive inhibitory synapses on bulbospinal neurons in RVLM (81)—a circuit supporting our hypothesis. That sympathoinhibitory cells may be distributed and not localized to a solitary column is suggested by parallel intrareticular inputs to RVLM (53,87) and electrophysiologically identified neurons with baroreceptor activities that project monosynaptically to RVLM, originating from areas outside of the purported vasodepressor region of CVLM (88). In support of a more complex intramedullary network are the multiple pools of GABA-ergic neurons distributed along baroreflex pathways, within the NTS (89) and across a broad span of reticular formation and raphe (58,90), encompassing medial paragigantocellular vasodepressor (66) and lateral vasopressor regions (67, 83) as well. The role of the classical medial gigantocellular vasodepressor region in baroreceptor reflex function requires further study although it is tentatively supported by vasodepressor responses to excitatory amino acid stimulation (66). A medial NTS fiber trajectory terminates in the vasodepressor region within the nucleus gigantocellularis (ventral portion) which, in turn, synapses monosynaptically on sympathetic preganglionic cells, paralleling the lateral vasopressor pathway. SPGNs receive parallel inputs from serotonergic neurons in the rostral ventromedial medulla (91), among other coneurotransmitters involved in sympathetic control (53,56). C. Third Messenger as Metabolic Marker of Cardiovascular Reflexes
Basal and stimulated expression by the c-fos proto-oncogene may not be a passive marker of functional activities, but rather is essential for central cardiovascular control. Immediate early gene (IEG) transcripts are thought to act as third messengers in signal transduction, by coupling cell surface events to (late) genes encoding transmitter/receptor complexes (92). Second- and higher-order cells within the baroreceptor reflex arc were identified in neonates (93) by monitoring expression of IEG proteins which are induced rapidly and transiently by synaptic activity and voltagegated Ca⫹ entry. The importance of this gene to circulatory mechanisms is illustrated by lowered resting levels of arterial blood pressure and suppression of RVLM disinhibition by prior administration of a 15-Mer antisense oligonucleotide to c-fos mRNA (94). D. Supramedullary Circuits: Relevance to Behavior and Endocrine Function
Baroreceptor relays to higher brain segments account for the full expression of stress adaptation responses to cardiorespiratory challenges as occur in exercise or incurred by injury. Behaviors such as arousal responses to blood pressure perturbations (95,96) are likely to involve the locus ceruleus and hypothalamic cells, which are activated by hypotension (76,97). Subcortical sites activated by hypertension include cells in the amygdala and distributed along its output pathways: stria terminalis and
Sympathetic Nervous System
153
ventral amygdalofugal systems, relaying to the lower brainstem directly (98) or via the hypothalamus (47,54). E. Circuits Regulating Secretion of Hypothalamic Stress Hormones
The importance of vasopressin and oxytocin hypothalamic neurons in the development of stress adaptation responses is suggested by ontogenetic studies in swine (99). The critical importance of stress hormones in the newborn, in response to asphyxia (100), is demonstrated by appreciable numbers of hypothalamic neurons at birth (101). From our work in piglets, the A1 noradrenergic column exists in neonates (59) and is functionally activated by hypotension as depicted in Figure 2 (93). A1 projections have not been traced in neonatal human or swine although in adult species ascend to terminate on vasopressinergic neurons in the paraventricular hypothalamic nucleus (PVH) (102); both components are potently activated by isovolemic hypotension and to a greater degree by hemorrhage (97,103–105). Descending hypothalamic projections to the NTS and reticular formation (106) are activated by hypotension (76) and, via a vasopressin receptor (V1 subtype) mechanism in RVLM, maintain blood pressure during moderate isovolemic hemorrhage (107). Nitric oxide, which acts centrally, stimulating release of vasopressin into the circulation (108), is synthesized by vagal and hypothalamic afferents to NTS (47), including cells in PVH activated by hypotension (76). Their roles in neonates are unknown though pertinent to postnatal maturation of physiological responses to homeostatic challenges, such as hypotension. Whether baroreceptors activate vasopressinergic cells in piglet hypothalamus or those containing corticotrophic-releasing hormone is another key unanswered question. Area postrema (AP) responses to hypotension in the neonatal pig (93) and adult rabbit (97) are likely related to its receptivity to increased circulating levels of angiotensin and vasopressin, given its fenestrated vasculature and position outside of the blood brain barrier. Most cells in AP are excited by baroreceptors (109). A major effort in our lab is to study in neonatal swine the postnatal ontogeny of chemoreceptor reflexes which may be defective in SIDS (52). The role of the locus ceruleus in the rats’ stress/arousal is complemented by circuits regulating chemosensory transmission at the level of the first-order synapse. Descending noradrenergic projections to NTS inhibit, via an alpha-adrenoreceptor mechanism, cyanideevoked chemosensory responses (110). The postnatal development of peripheral and central chemoreceptor circuit neurons is still poorly understood as most studies have focused on adult models. In brief, chemoreceptor reflexes in adult rats are mediated by primary chemoreceptor afferents to NTS, originating in the petrosal ganglion. Chemoreceptor branches of the carotid sinus nerve are spatially segregated (ventrolateral subnucleus) though partially overlapping (caudomedial subnucleus) with baroreceptor fields (41,111-113). Arterial reflex responses to hypoxia are mediated by a direct NTS projection to sympathoexcitatory premotor neurons in RVLM (63), a circuit partially dependent on GLU (44,61). Pressor responses to GLU stimulation of chemoreceptor fields in NTS of anesthetized (61) and awake (114) rats are attenuated by GLU receptor blockade of RVLM. Whereas the cardiovagal component is
154
Sica et al.
Figure 2 Hypotension-induced expression of the c-fos gene in neonatal swine. Baroreceptor withdrawal by nitroprusside activates neurons in the porcine reticular formation of rostral and caudal ventrolateral medulla. Asterisks indicate neurons co-expressing the c-fos gene product, FOS, and tyrosine hydroxylase (TH)—the rate-limiting catecholaminergic enzyme. Rostrally these catecholaminergic cells synthesize adrenaline (a) and at caudal levels, noradrenaline (b). Abbreviations: cvlm, caudal ventrolateral medulla; lrn, lateral reticular nucleus; ltf, lateral tegmental field; vms, ventral medullary surface; VII, facial nucleus (this figure is reproduced with permission from Ref. 93).
Sympathetic Nervous System
155
mediated by NMDA receptors, non-NMDA receptors mediate the sympathoexcitatory component of the arterial chemoreceptor reflex (44). Central responses to hypoxia in awake rats, based on c-fos expression are complicated by secondary effects due to behavioral struggling/arousal responses and hormone actions on cells lying within chemoreceptor reflex pathways. An example is the vasopressin receptor mechanism in RVLM that protects arterial blood pressure in the face of moderate nonhypotensive hemorrhage (107). The AP which connects monosynaptically to NTS and RVLM (53,54,63) and other visceral processors (115) is activated by hypoxemia in rabbits (97) and hypercapnia in piglets (116–118). Part of an essential inhibitory ‘‘neuroprotective’’ mechanism, the AP mediates circulatory adaptation responses to cold stress (119) and emesis (120), and has been implicated in the chemoreceptor hypothesis of SIDS (116). Excited by hypercapnia and less robustly after hypoxia are predominantly nonadrenergic cells in the caudal NTS and C1 vasomotor area and A1 noradrenergic column in caudal reticular formation regulating release of vasopressin (121). Surprisingly, hypoxia failed to activate the locus ceruleus, implicating a parallel visceral pathway to forebrain, possibly via the amygdala, mediating bradycardia and struggling/anxiety defense responses designed to conserve oxygen while maintaining upper airway patency. Other cell groups responding to hypercapnia were refractory to hypoxic stimulation, such as the ventral retrotrapezoid nucleus: a purported CO2 chemosensor (122), paragigantocellular region and the periaqueductal gray which, theoretically, coordinates behaviorally generated responses to hypercapnic stress (123). The pontine parabrachial complex is involved given a hypercapnic response to GLU stimulation of the external lateral subnucleus (124,125)—a subnucleus receiving input from the chemoreceptor division of NTS (126) and activated by hypercapnia (127). Since that subnucleus ascends to terminate in the amygdala and hypothalamus (128), these circuits are implicated in airway defense/arousal responses to hypercapnic stress that, as mentioned, may be compromised in SIDS (116,129).
V.
Baroreceptor and Chemoreceptor Reflexes in Developing Animals
A. Baroreceptors
The carotid sinus and aortic arch are the principal sites of baroreceptor terminals that form the afferent arm of the baroreceptor reflex and serve to maintain mean arterial pressure and heart rate within normal ranges via innervation of target organs by efferent sympathetic fibers. The presence of anatomical connections, however, should not imply that functional activity is also present. Also, activity may be present in preganglionic nerves, but developmental lags in the establishment of pre- and postganglionic neuronal connections may delay the innervation of target organs. This reflex undergoes postnatal maturation which proceeds at markedly different rates depending upon the species studied. The term fetal lamb, for example, exhibited renal sympathetic nerve activity that had greater sensitivity to baroreceptor stim-
156
Sica et al.
ulation than either the newborn or neonatal lamb. The postnatal development of this reflex was marked by a resetting of baroreceptor sensitivity, i.e., less sensitive, that paralleled the postnatal increase of mean arterial pressure (130). The development of the baroreceptor reflex has been the subject of a number of excellent reviews. Gootman (2) has described the maturation of the baroreceptor reflex in a number of different species; and Table 1 has been adapted from that source with the addition of more recent references where appropriate. For a description of more recent work in the fetal and postnatal lamb, the reader should consult the reviews by Segar (131) and Wood (132). We shall review patterns of IEG induction by baroreceptor withdrawal in neonatal swine (93). Hypotension was sustained by systemic administration of the vaso-
Table 1 Baroreceptor Reflexes Species Lamb
Age Fetus: immature, mature Fetus: immature, mature Fetus: immature, mature; neonate Fetus: immature Fetus: immature Fetus: mature, Immature Fetus: immature Mature Fetus: immature
Fetus: premature, mature
Fetus: immature Mature Mature
Response elicited by a. Balloon in descending aorta → ↑ BP Exogenous NE Exogenous Ach PE and aortic balloon a. Exogenous E- ↑BP; b. Stimulate vagus N; Exogenous E, NE → ↑ BP Exogenous E, NE → ↑ BP Hemorrhage (8–28% of blood volume) Hemorrhage (9–33% of blood volume) Hemorrhage (5% of blood volume); 15% Hemmorhage (15% of blood volume)
DA → ↑ BP atrophine PE NE, E
Response ↓HR (age dependent) ↑HR, ↑ BP ↓HR, ↓ BP ↓HR (fetal response ⬍ that of neonate) ↓HR; ↓HR; ↓HR; ↓HR for large ↑ in BP ↓HR (for large ↑ BP); ↑HR (no reflex), ↑ BP (0) HR, ↓BP, ↑renin, aldosterone ↑HR, ↑ aldosterone, ↑Ang II, ↓BP Transient ↑ HR ↓HR ↓HR, ↓ BP, ↓ Body F, ↓ GI F, ↓ Ren F, ↓ Lung F, ↑ RenR, ↓ LiverR, ↑ Lung R, ↑ PVR ↓HR ↑HR ↓HR ↓HR fetus ⬍ adult
Sympathetic Nervous System
157
Table 1 Continued Species
Response elicited by
Age Fetus: mature
Fetus: Fetus: Fetus: Fetus:
mature mature mature mature
Fetus: premature– mature Fetus: premature– mature Fetus: mature Fetus: mature
a. Exogenous E; b. Clamp abdominal aorta → ↑ BP CS pouch (50% ↑ BP) ↓CS pressure BSI PR–baroreflex slope: pulse interval vs. arterial pressure BSI cord occlusion Inferior vena cava cuff Moderate hypotension Severe hypotension Ang I, Ang II, NE → ↑ BP Hemorrhage (17% blood volume) ⫹ ganglionic block
Fetus to 6 wks
BSI
Fetus to adult
AVP, NP, E
Neonate: 1–22 d
Inferior vena cava cuff: Moderate and severe hypotension Ang I, Ang II, NE Exogenous NE BCCO NE, E Cut CSN BSI Methoxamine, NE Severe hemorrhage Volume expansion
Neonate 3–14 d Neonate Neonate Neonate: 6–12, 96 hr Neonate: 1–11d Neonate: 1–5 d Neonate: 1–15 d Neonate: 6–14 d Neonate: 3–7 d, 6–8 wks Neonate: 2–7 d
Graded hemorrhage to 20% blood volume
Response ↑ Vagal Discharge; ↑ CSN activity (0) HR, (0) BP ↑ BP, ↑ PP ↓ with ↑ arterial PO2 ↓ HR ↓ BSI ↑ HR ↓ HR ↓ HR fetus ⬎⬎ adult ↓ HR then (0), ↓blood volume, ↓ Ven P, prolonged effects, ⬎ ↓ blood volume RSNA, HR of fetus ⬎ neonate (130,131, 178) ↑ BP, ↓ HR, ↓RSNA ↓ BP, ↑ HR, AVP—no effect on fetus and newborn (179) ↑ HR, neonate ⬍ adult ↓ HR (⫽ fetus) ↑ BP, ↓ HR (⬍ adults) ↑ BP ↓ HR neonate ⬍ adult ↑ HR, ↑BP Adult ⬎ neonate Adult ⬎⬎ neonate ↓ HR, ↓CO, (0) SVR ↓ RSNA, ↓ HR, (3–7 d blocked by SAD; 6– 8 wks no block) (180) ↑ HR, ↓BP, (0) RSNA (203)
158
Sica et al.
Table 1 Continued Species Rabbit
Age Fetus: mature Fetus: mature Neonate ⬎ 1-d-old 0–17 d 4–10 wks Neonate: 0–14 d, 3 wks
Neonate: 11–17 d 10–14 d
Response elicited by Exogenous E Exogenous E to mother Exogenous E Record from CSN
Response (0) HR, ↑BP ↓HR, ↑ BP
c. cut CSN
↓HR, ↑ BP no age-related differences in threshold (0) HR, change BP; less effective; 1 d vs. 15 d; ↑BP
PE, BSI PE, BSI
HR neonate ⬍⬍ adult; HR neonate ⬍ adult
a. CS pouch; b. Valsalva maneuver;
Guinea pig
Fetus: mature
Exogenous NE → ↑ BP
(0) HR
Dog
Fetus: mature to neonate
Left CCO
(0) HR (age-dependent response), ↑ BP ↑ HR (by 6 d)
0–11 d Neonate: 1–56 d
Bilateral vagotomy BCCO
Neonate: 2–24 d
a. BCCO b. Bilateral vagotomy BCCO Record from vagus nerve with occlusion of main pulmonary artery Nitroglycerin, PE
Neonate: 1–35 d Neonate: 4 wks
Neonate: 6–10 wks
↑BP (1 d small ↑, by 10 d ⫽ to adult) ↑HR (⫽ adult) ↑HR (⬍ adult) ↑BP, ↑ RenR No activity until 11 d old, discharge ↑during occlusion Change in HR in neonate ⬍ adult
Rat
Neonate: 2 wks Neonate: 1–4 wks Neonate: 5–6 d, ⬎ 42 d
Aortic constriction PE, hydralazine PE
↓HR (0) until 2 wks BSI present @ 5 d, ↓ @ 10–20 d, ↑ @ 42d (181)
Cat
Fetus to neonate: 0–10 d Neonate
Stimulation of vagus N
No response until 11 d
CSN activity
Neonate
BCCO
Weaker in young animals ↑HR (age-related), ↑ BP;
Sympathetic Nervous System
159
Table 1 Continued Species
Age 1–46 d
Neonate: 2–67 d Newborn: ⬍ 1 wk, adult ⬎ 6 mo Swine
Response elicited by a. Exogenous E → ↑ BP b. Valsalva maneuver Hemorrhage, tilt, Valsalva maneuver PE
Neonate
CSN activity
Neonate
BCCO
Neonate: 2 h–23 d
CS stimulation by pressure
Neonate: 4–8 wks
a. Aortic depressor nerve stimulation b. C-fiber stimulation PE increases MesF, FemF, CarR, FemR → ↑ BP Maintained lung inflation (fictive Valsalva maneuver)
Neonate: 1–60 d
Neonate: 1–49 d
⬍1 d–2 wks
Response ↓HR (age-related); ↓HR (response only @ 4 wks) BP (age-related responses) ↓ HR (p ⫽ NS, newborn vs. adult) (182) Weaker in young animals (0) HR (no response until 2 wks), ↑ BP, RenR ⬎ 1 wk, ↑FemF (by 3rd d) ↓ HR, ↓BP, ↓RenF, ↓MesF, ↓ FemF (1 wk or older) (183) ↓ Hr, ↓ BP ↑ HR, ↑BP ↓ HR (age-related), ↓SNA (34,184) ↓ BP (no overshoot ⱕ2 wks), (0) HR (⬍ 2 wks), SNA (no overshoot ⬍ 2 wks) (183) ↑ HR, ↓BP, ↓Fs
birth to 6 wks
Hemorrhage (sequential to 20 mL/kg) PE → ↑ BP; NP → ↓BP NP (prolonged hypotension) PE, NP, BSI
Opossum
50–65 d
BCCO
Neonate ↑BP (12 mm Hg), adult ↑BP (36 mm Hg); ↑HR adult, (0) HR neonate
Primate
Neonate
CSN activity
9d
BCCO
Weaker in younger animals (0) HR, ↑ BP
5–59 d 11–57 d
↓ BSI (age-related) ↑ c-fos expression in NTS (93) ↑ with age, increase greater from 2 wks on (185)
160
Sica et al.
Table 1 Continued Species
Age
Human
Premature (⬍ 1500 g)
Response elicited by
Newborn: 1–6 d
Saline infusion, ligation DA Exogenous NE
Newborn: 4 h to 12 d
Tilt
Newborn: 1–6 d
Tilt
Newborn: 1–77 h Newborn/neonate: 1– 10 d
Tilt Tilt, crying
Newborn: 35 h
Exogenous NE
26–38 wks
a. Tilt 45° head-up, non-stressed infants; b. respiratory distress
Newborn: 2 & 24 h
Tilt
Newborn: term
35–42 wks
Tilt a. head-up b. head-down BSI during ECMO
39 wks
PE, NP (isoflurane)
Response (0) HR ↓HR (transient and reflex), ↑ BP ↑HR, ↓ BP, ↓ forearm blood flow, HR ⫽ adult but no change of adult BP CA urinary excretion ⫽ that of adult ↑HR, ↓ BP ↑HR, (0) BP (no change until 3rd day) ↓HR (brief ⬍ min), ↑ BP ↑PVR, (0)HR, ↓limb F (32%), ↓ BP (0) HR, ↑BP, ↑limb F (74%), ↓ PVR ↑HR, ↓ BP, 2 h ⬍ 24 h (186) ↑HR, ↓ BP ↓HR, ↑ BP (187) BSI sensitivity increased during ECMO (188) ↑BP → ↓ HR; ↓BP → ↑ HR; ↓ responses with isoflurane (82)
Definitions: Immature—early gestational age, e.g., from lambs ⬍100 days gestational age; premature— middle gestational age, e.g., from lambs 100–124 days gestational age; mature—late gestational age, e.g., from lambs ⬎125 days gestational age. Primate: mature 159–162 days gestational age (term is 168 days). Human mature: last trimester (28–36 weeks); dogs: mature 7–9 weeks gestational age (term is 9 weeks). Abbreviations: (0), No significant change in parameter. (↑) Increase in parameter. (↓), Decrease in parameter. (→), Leads to a ↑, ↓, or (0) in parameter. Ach ⫽ acetylcholine; Ang I ⫽ angiotensin I; Ang II ⫽ angiotensin II; AVP ⫽ arginine vasopressin; BCCO ⫽ bilateral common carotid occlusion; BP ⫽ arterial blood pressure; BSI ⫽ baroreflex sensitivity index; CA ⫽ catecholamines; CO ⫽ cardiac output; CS ⫽ carotid sinus; CSN ⫽ carotid sinus nerve; DA ⫽ ductus arteriosus; E ⫽ epinephrine; F ⫽ arterial blood flow; Fem ⫽ femoral; GI ⫽ gastrointestinal; HR ⫽ heart rate; Mes ⫽ mesenteric; N ⫽ nerve; NE ⫽ norepinephrine; NP ⫽ nitroprusside; P ⫽ pressure; PE⫽ phenylephrine; PP ⫽ pulse pressure; PVR ⫽ peripheral vascular resistance; R ⫽ resistance; Ren ⫽ renal; RSNA ⫽ renal sympathetic nerve activity; SAD ⫽ sino aortic denervation; SNA ⫽ sympathetic nerve activity; SVR ⫽ systemic vascular resistance; ven ⫽ venous; vol ⫽ volume. Source: Ref. 2.
Sympathetic Nervous System
161
dilator nitroprusside to 2-week-old piglets and older, 1- and 2-month-old neonates. Baroreceptor withdrawal induced expression of c-fos proto-oncogene in the dorsolateral NTS—a recipient of baroreceptor afferents and along established cardiovascular reflex pathways including the RVLM (Fig. 2). Within the RVLM of adult rat, most adrenergic neurons containing the norepinephrine-methylating enzyme, PNMT, including bulbospinal cells projecting to upper thoracic segments, were activated by hydralazine-induced hypotension (60). Replicating findings in adult mammals, catecholaminergic neurons within the porcine homologue of the RVLM were activated by hypotension in the neonate (93) presumably by disinhibition of RVLM bulbospinal neurons (133). By contrast, few were activated in RVLM following phenylephrine-induced hypertension, which presumably were reflexively inhibited. As seen in neonates (93), RVLM neurons in adults demonstrate robust expression following sustained hypotension in rabbit (97) and rat (60). Studies in conscious rabbits suggest that catecholaminergic neurons activated by hypotension are vasodepressor in function and spatially segregated from the predominantly noncatecholaminergic cells activated by hypertension (97). Following hypotension many cells at caudal and intermediate levels of porcine ventral reticular formation express Fos, as observed in the adult conscious rabbit (97). In swine the dorsolateral tegmental field was also activated, supporting the theory of at least two regions involved in generating sympathetic nerve discharge and circulatory control (64,65). B. Chemoreceptors
Arterial chemoreceptors are located near the carotid bifurcation (carotid body) and at the root of the main thoracic arteries (aortic bodies) The carotid body is innervated by fibers of the glossopharyngeal nerve (nerve of Herring) that travel as part of the carotid sinus nerve. The aortic bodies are innervated by afferent vagal fibers. The blood supply to these organs is quite large and the receptors are thought to monitor the chemical environment of arterial blood. Chemoreceptor discharge increases with a decrease in arterial PO2, an increase in arterial PCO2, or a decrease in pH (129). Both the hypoxic response and the postnatal resetting of chemoreceptor discharge have been extensively described elsewhere (134–138). A comprehensive review of chemoreceptor-mediated reflexes in developing animals of different species is presented in Table 2, which has been adapted from Gootman (2) and updated where appropriate. A more extensive treatment of fetal chemoreceptor function is available in the review by Teitel (139), while the effect of chronic hypoxia is found in the review by Hanson (140). The tonic influences of the carotid body chemoreceptors on cardiorespiratory control mechanisms have been shown to be extremely important for the viability of the developing neonate. In both neonatal rat and piglet models, carotid body denervation was associated with central apnea and heart rate slowing as well as with an alarming rate of mortality (141–144). The cascade of events initiated by such denervations was remarkably similar to the agonal events of infants on memoryequipped monitors, who were later diagnosed as SIDS cases (145). In the piglet model, one study was able to demonstrate a critical period for mortality; i.e., death
162
Sica et al.
Table 2 Chemoreceptors Species Lamb
Age
Method eliciting response
Fetus: Immature Mature Mature
Cord occlusion Cord occlusion Cord occlusion
Mature
Cord occlusion
Mature
Mature
Cord occlusion Only umbilical vein occluded Cord occlusion
Mature Mature
Cord occlusion Cord occlusion
Mature
Repeated cord occlusion
Mature
After 10 min Hypoxia and SAD
Mature Mature
Hypoxia and hypercapnia Hypoxia CSN denervation
Mature
Occlusion of hypogastric artery ewe: N2 / O2
Mature
Response No response ↑ BP, ↓HR ↑ BP, ↑HR, pulmonary VC ↑ BP, ↓HR, ↓ Fem F, Fem VC ↑ BP, ↓HR ↓ BP, ↓HR ↑ BP, ↓HR, ↓ Fem F, ↑ Ren F ↑ BP, ↑Cerebr F ↑ HR, ↑ BP, ↑ CBF, SAD → ↑ HR OBP, ↓CarR (189) ↓ HR, ↑ FemR; 2nd : ↓ HR, (0) FemR (190) ↓ BP ↓ HR, ↑ BP; ↑ HR, delayed ↑ BP (191) ↑ BP, ↓HR (132) ↓ HR, ↑ FemR, (0) CarR (0) HR, (0) FemR, ↑ CarF (192) ↓ HR (193) ↓ HR(blocked by CSN denervation; aortic denervation had no effect) (194)
Llama
Fetus
Hypoxia CSN denervation
↓ HR, ↑ BP, ↑ vasc R; (0) HR, ↑ plasma VP, ↑ vascR (195)
Goat
Mature
Cord occlusion After 4.5 min
↑ BP, ↓HR ↓ BP, ↑HR
Rabbit
Mature
Cord occlusion
Mature Mature
Cord occlusion Cord occlusion
↓ HR (with or without vagi) ↓ BP, ↓HR ↓ BP, ↓HR
Mature
Cord occlusion
↑ BP, ↓HR
Calf
Sympathetic Nervous System Table 2 Species
163
Continued Age
Method eliciting response
Response
Mature
Cord occlusion After 6 min Cord occlusion
↑ BP ↓ BP ↑ BP, ↑ HR
Human
Mature
Cord occlusion
No consistent BP change, ↓ HR
Guinea pig
Mature Fetus:
Cord occlusion Maternal blood gas changes producing fetal hypoxia
↓ BP, ↓ HR
Lamb
Mature Mature Mature
Hypoxia Hypercapnia, nicotine Hypoxia, nicotine
Mature
Asphyxia
Mature
Hypoxia Severe hypoxia Hypoxia Hypoxia Hypoxia Hypoxia with ↓ pH Hypoxia Hypoxia
CSN discharge No discharge Aortic chemoreceptor Discharge ↑ BP, HR variable, ↓ Ren F, ↓ Brain, ↓ Car F ↑ BP, ↓ HR, ↓ Fem F ⬎ ↑BP, ↓ HR ↑ BP, ↓ HR ↓ BP, ↓ HR ↑ BP, ↓ HR (not significant) ↑ BP, ↓ HR, ↓ F ↑ BP, ↓ HR ↑ BP, ↓ HR, ↓ Fem F, ↓ Car F, ↑ Cor F ↑ HR ↑ BP, ↓ HR ↑ BP, ↑ HR, ↑ Cerebr F ↑ BP, ↑ HR, ↓ CO ↓ BP, ↓ HR, ↓ CO ↑ BP, ↑ HR, ↓ CO
Primate
Mature
Mature Immature Mature Mature Mature Immature Mature Immature Mature
Immature Immature Mature Immature Mature
Cat
Mature
Hypoxia Hypoxia Hypoxia Hypoxia Severe hypoxia Hypoxia ⫹ hypercapnia, ↓ pH Hypoxia Hypoxia Hypoxia Acidosis with HC1 Hypoxia With vagi cooled Moderate hypoxia Severe hypoxia Moderate hypoxia Severe hypoxia Vagotomy
↑ Cerebr F ↓ BP ↑ BP, ↓ HR BP, HR (little change) ↑ BP, ↑ HR ↓ BP, ↓ HR ↓ BP, ↑ HR ↓ BP, ↓ HR ↓ BP, ↓ HR ↓ BP, ↓ HR No effect
164
Sica et al.
Table 2 Continued Species
Age
Method eliciting response
Response
Guinea pig
Mature
Moderate hypoxia Severe hypoxia Vagotomy
↓ BP, ↓HR ↓ BP, ↓HR No effect on responses
Rat
Immature Mature
Hypoxia Hypercapnia Hyperoxia
↓ HR ↓ HR ↓ HR
Goat
Mature
Hypoxia
↑ BP, ↓HR (late), ↓ AoF, ↓ Car F
Swine
Mature
Hypoxia Severe hypoxia
↓ BP (variable), ⫹ HR ↓ BP, ↓HR
Rabbit
Mature
Asphyxia
Mature
Asphyxia
↑ BP, ↓HR (variable), ↓ Ren F, ↓Brain F No responses
Dog
Mature
Asphyxia
↑ BP, ↓HR (variable), ↓ Ren F, ↓Brain, ↓Car F
Primate
Mature
Hypoxia
Mature
Hypoxia
↓ Umbilical F, ↓ CO, adrenal F, Cor F maintained ↓ BP, ↓HR
Human
Mature
Hypoxia
Normal ↓ HR Distressed ↓HR
Lamb
Neonates: 10–60 d
Anoxia
Neonate
Alkalosis (0.6 M NaHCO3)
Birth-8 d 6 hr to 10 d
Hypoxia, hypercapnia Hypoxia Severe hypoxia Hypoxia Hypoxia Hyperoxia
↑ BP(⬍5%), ⫹ HR, ↓O2 consumption ↑ Pulmon F, ↓ Pulmon Vas R, ↓ systemic Vas R, ↑ CO ↑ BP, ↓HR No consistent changes ↑ BP, ↑HR ↓ BP, ↑Pulmon P, ↑ Pulmon R ↑ BP, ↑HR ↓ BP, ↓HR (3–10%)
Prolonged hypoxia
↓ HR (196)
4 hr to 10 d Newborn 40 min to 10 d Neonate: birth to 12 d
Sympathetic Nervous System Table 2
165
Continued
Species
Age
Method eliciting response
Response
Dog
3–4 d
Anoxia (N2)
↓ BP, ↓ HR, ↓ Ren R
Cow
5–48 hr
Asphyxia
↑ BP, ↓ Iliac F
Rabbit
Neonate
Anoxia, asphyxia
Newborn 11–50 d
Asphyxia Asphyxia
↑ BP (small and age dependent) No responses ↑ BP (no responses until 30 d), ↓HR (to 11 d), ↑ HR (12–36 d) HR (36 d to adult)
Cat
1–4 d
Asphyxia
↑ BP (age dependent)
Swine
6–96 hr 1–22 d
Asphyxia Hypercapnia
⬍ 1 day to 3 wk 2–4 d, 2 wk, 2 mo
Hypercapnia
3d
5 levels of hypoxia
5–7 d
Hypoxia and hypercapnia
⬍20 d
Hypoxia
3 wks 14–20 d
Hypoxia and hypercapnia Hypoxia and isoproterenol
↑ BP, ↑ HR, ↑ Resp ↑ BP, ↑ HR, ↑ Ren R, ↑ Car R, ↑ Fem R, ↑ Car F, ↑ Ren F ↑ BP, ↑ HR, ↑ Cat F, ↑ Ren F Age-related responses: 2 d to 2 wk: (0) HR; 2 mo ↑ HR; ↓BP; 2 mo (0) BP; ↓ Mes R @ 2 wks in severe hypoxia, ↑ @ 2 mo in severe hypoxia; ↓ Fem R @ 2 d to 2 wk in moderate hyopoxia; ↓ @ 2 wks in severe hypoxia (1,97) @ moderate hypoxia, ↑ BP; @ severe hypoxia, biphasic change of BP (173) ↑ BP, ↑ HR, ↑ E, NE, D; ↑ Foreb BV (198) ↑ Resp; modulation of postganglionic SNA (39) ↑ BP, ↑ (199) ↓ BP, ↓ HR (prolonged hypoxia) (200)
Neonate
Hypoxia Hypercapnia Hyperoxia
Rat
Hypoxia (20 min) moderate and severe
↑ HR ↓ HR ↓ HR
166
Sica et al.
Table 2 Continued Species
Age
Method eliciting response
Response
Primate
1–10 d 1–8 d
Hypoxia Asphyxia
↑ BP then ↓, HR (deficient) ↓ CO, kidney, liver, GI ⬍ % CO; heart, brain, adrenal ⬎ % CO
Human
Preterm
Hypoxia Hypercapnia Asphyxia
↓ HR ↑ HR CA release Preterm ⬍ term ↑ HR ↑ BP, ↑HR variable, ↑ Pulmon P ↑ HR (10%) ↓ HR (⬍5%), ↑ Resp (not maintained) ↑ HR small (3–5%), ↑ Resp poorly sustained (0) HR (no response) ↓ HR (201) ↑ HR (202)
Preterm Term Preterm 2–27 hr
Rabbits
Hypoxia Hypoxia
5 hr to l5 d
Hypoxia (3 min) 12% O2 15–18% O2
6 hr to 11 d
Hypoxia and hypercapnia
3 mo 9 wks
Hypercapnia Hypoxia Hypoxia and hypercapnia
⬍24 h to 1 wk
Central chemoreceptors artifical CSF perfusion → change pH
↓ HR, ↓ BP
See legend to Table 1 for explanations of symbols. VC ⫽ vasoconstriction; Cerebr F ⫽ cerebral blood flow; Car F ⫽ carotid flow; Cor F ⫽ coronary artery flow; CO ⫽ cardiac output; Pulmon ⫽ pulmonary; Pulmon F ⫽ pulmonary artery flow; Vas R ⫽ vascular resistance; Pulmon P ⫽ pulmonary pressure; Resp ⫽ respiration; Ao F ⫽ aortic flow. Source: Ref. 2.
occurred only when denervation was carried out in the second week of life, whereas denervation carried out later in the neonatal period was associated with apnea and heart rate slowing (142). In a second recent study, mortality was not an outcome, rather a critical period for the development of prolonged apnea was noted (during quiet sleep) in piglets denervated in the second week of life (141). These findings are somewhat surprising as relatively little activity is present in carotid sinus nerve recordings in early development (134,135,138). However, neither the threshold level of carotid sinus nerve activity required to maintain homeostatic mechanisms or the effect of carotid body ablation on central structures involved in cardiorespiratory regulation is known. Perhaps carotid body afferents exert a trophic influence on neurons in the NTS, where these afferents terminate (54,112,113), such that cardiorespiratory function is unperturbed. Deafferentation of these cells may also provoke
Sympathetic Nervous System
167
an excitotoxic release of GLU since this transmitter is thought to be released by chemoreceptor terminals in the NTS (146,147). The ability to respond appropriately to hypoxic stimulation is important for the organism’s survival, and different response patterns emerge during an organism’s development. Unlike adults, neonates, both human and animal, are unable to maintain a sustained increase in ventilation when challenged by hypoxia; rather, ventilatory responses have a biphasic pattern which consists of a transient increase of ventilation, then decrease toward or below control levels, and sometimes apnea (148–151). This response may seem paradoxical given the fact that neonates are known to survive longer in anoxia than adults (152,153). However, the biphasic pattern may be a variant of the defense strategy adopted for survival under anoxic conditions (154). Nevertheless, the persistence of a biphasic response pattern beyond the first few weeks of life may compromise infant survival since neurons may have lost their intrinsic ability to sustain relatively prolonged periods of hypoxia/anoxia. Whereas the excitatory component of the biphasic response is likely mediated by GLU (155), depression due to inhibition depends upon release of GABA during prolonged hypoxia (156–158). Indeed, bicuculline, a GABAA receptor antagonist, has been shown to reverse the depressive component of the biphasic response to hypoxia (159). Thus, tonic release of GABA may underlie the continued manifestation of the immature biphasic response (159). Until recently, anatomical studies of SIDS cases and neurobehavioral studies of near-miss sudden death infants supported a strong role for hypoxia in the etiology of SIDS (2,40,160,161). However, recent findings have implicated central chemosensory structures in the pathology of SIDS (123). Kinney et al. (162) described SIDS cases with developmental abnormalities of the arcuate nucleus, a putative chemosensory region of the human ventral medullary surface (163). While arcuate hypoplasia was demonstrated in two SIDS cases (162), a more subtle defect, i.e., markedly diminished numbers of muscarinic cholinergic and kainate glutamatergic receptors, was observed in the arcuate of a larger number of SIDS cases (162). As both receptor types are involved in shaping cardiorespiratory responses to hypercapnic stimulation, arcuate anomalies may underlie a subset of SIDS cases who are unable to express functionally appropriate responses to chemoreceptor activation. That chemosensitive regions may be located beyond the traditionally accepted chemosensory areas of the ventral medulla (163) is suggested by animal experiments (122,164–166). Thus, one possibility for the pathogenesis of SIDS may be an infant with either absent or diminished capacity to respond to increasing levels of CO2. Accordingly, excitation of NTS neurons would not be sufficient to evoke compensatory reflex changes in respiratory motor output. In addition, the failure to develop sufficient activity in the NTS would also lead to a loss of reflex changes in sympathetic activity, and therefore, functionally appropriate changes in cardiovascular function would not occur. Such an inability to respond appropriately to hypercapnic stimulation would also affect other regions with putative chemoreceptor properties. The AP is synpatically related to the NTS and is involved in respiratory and cardiovascular regulation, especially under stressful conditions (109,116,119,167–170). The NTS and AP have been implicated in cardiorespiratory regulation during condi-
168
Sica et al.
tions of increased chemical drive by anatomical studies monitoring the expression of Fos, the protein product of the IEG and proto-oncogene c-fos (171). While both NTS and AP neurons expressed Fos-like immunoreactivity (FLI) following prolonged hypoxia, only NTS neurons were reliably activated after prolonged hypercapnia (95,121,172,173). Because little is known about the response to prolonged hypercapnia in developing animals, we recently performed a study using the piglet to determine whether prolonged hypercapnic stimulation elicited age-related changes in numbers of NTS and AP neurons excited by such stimulation. Prolonged hypercapnic stimulation evoked expression of Fos in both the NTS and the AP. The number of neurons with FLI in both structures far outnumbered those of unstimulated, age-matched control animals (see Figs. 3 and 4). While the AP exhibited no age-related changes in number of neurons with FLI (Fig. 4), neurons of the NTS showed age-related increases in FLI expression. However, this increase followed a biphasic pattern: NTS neurons with FLI increased in number over the first two postnatal weeks but decreased in number during the fourth and fifth weeks, to levels noted during the first week (see Figs. 3 and 5). Hence, the marked increase of neurons with FLI in the second postnatal week may represent a period of hyperexcitability when chemoreceptor activation may lead to inappropriate changes in cardiorespiratory responses. The overall topographic organization of NTS neurons with FLI in the piglet was similar to that of mature animals of other species (95,96,172,173). While hypercapnic-induced expression of Fos is not selective for neurons subserving any particular function, the overall pattern of such expression suggests some neurons with FLI are involved in processing peripheral chemoreceptor and baroreceptor information, and possibly in shaping central respiration- and sympathetic-related activities. For example, that neurons with FLI in the dorsal strip and medial subnucleus of the NTS in the piglet might participate in processing peripheral chemo- and baroreceptor information is supported by studies in the rat and cat showing that these afferent inputs terminated in those regions (57,173,174). Furthermore, peripheral chemoreceptors have been shown to increase impulse activity during hyperoxic-hypercapnic stimulation, but not to the high discharge rates observed during hypoxic or asphyxic hypercapnia (137). Also, postnatal increases of peripheral chemoreceptor discharge in the lamb were reported during steady-state hypercapnic stimulation, but level of activity was also dependent upon PO2 (175). Chemoreceptor activity in the piglet, however, responded to hypercapnic stimulation and was only minimally affected by level of PO2 (134). Thus, because the relationship between alterations of impulse activity along afferent pathways and FLI in recipient neurons is unknown, a contribution of peripheral chemoreceptors to the pattern of Fos expression could not be discounted. However, there is evidence that the pattern of Fos expression in the NTS of piglets might represent more the contribution of central CO2 chemoreceptors than peripheral chemoreceptors because similar patterns were noted in the NTS of peripherally chemodenervated adult animals of other species (173). The expression of Fos in response to stimulation of afferent pathways provides a useful monitor of neuronal populations involved in some manner in the shaping of central responses to activation. However, expression of Fos alone does not give
Sympathetic Nervous System
169
Figure 3 Camera lucida drawings of the porcine medulla oblongata demonstrate c-fos gene induction in the nucleus of the solitary tract (NTS) at equivalent anteroposterior levels just rostrally to calamus scriptorius in 7- (A), 14- (B), and 33- (C) d-old stimulated piglets. Nuclear labeling occurs primarily in the dorsal region subjacent to nucleus gracilis (ng) and within medial subnuclei. The NTS of the postnatal day (PD) 14 neonate (B) demonstrates a higher density of immunolabeled nuclei than on other postnatal days (A, C). Abbreviations: apc, area postrema, caudal pole; ng, nucleus gracilis; tr, solitary tract; X, vagal motor nucleus; XII, hypoglossal nucleus. Each symbol (filled circle) represents one immunolabeled nucleus. (This figure is reproduced with permission from Ref. 118.)
170
Sica et al.
Figure 4 Camera lucida drawings of transverse sections of porcine medulla oblongata rostral to obex compare FOS-like immunoreactivity (FLI) in the area postrema (ap) and subjacent subpostremal zone at postnatal day (PD) 26. A. Markedly larger number of neurons contain FLI in the ap and subjacent zone of this CO2 -stimulated piglet as compared to B, the control. Each symbol (filled circle) represents one immunolabeled nucleus. (This figure is reproduced with permission from Ref. 116.)
Figure 5 (A) Total number of neurons (⫾ SE) expressing FOS in the nucleus of the solitary tract (NTS) and area postrema (AP) of experimental and control animals. Asterisks indicate significant difference between groups. (B) Adjusted number of counts (⫾ SE), i.e., total count of AP and NTS neurons with FLI in each experimental animal minus total count of pairedcontrol animal. Left panel, adjusted number of neurons expressing FOS in the NTS of experimental animals in each of three age groups. The asterisk indicates a significant increase of FLI in age group 2. Right panel, adjusted number of counts for AP neurons expressing FOS in each of three age groups. (This figure is reproduced with permission from Ref. 118.)
172
Sica et al.
much information about the functional status of neurons activated by stimulation. For example, it is not possible to determine whether neurons in our study of the NTS that had FLI were respiration related, sympathetic related, or interneurons. However, the identification of shared neurotransmitter phenotypes strengthens the argument for a common function. For example, whether adrenergic and/or noradrenergic neurons are prolonged hypercapnia could be answered using a dual immunolabeling method identifying IEG products and catecholaminergic enzymes on the same section (93). The presence of double-labeling would provide additional evidence that a neuron was involved in cardiovascular regulation. However, one must also be cognizant of the possibility that catecholaminergic enzymatic activity might be downregulated by prolonged exposures to hypercapnia as has been recently described for TH and PNMT mRNA in rat pups exposed to hypoxia in utero (176). Such downregulation may itself interfere with normal functioning of catecholaminesynthesizing neurons (177) and form the basis for pathophysiological changes leading to SIDS.
VI. Concluding Remarks As can be readily discerned from this review, the database describing the central neural components involved in the regulation of the sympathetic nervous system in immature animals is far less developed than that of mature animals. On the other hand, there is a substantial body of knowledge describing stimulus-induced changes in peripheral indices of sympathetic activity in fetal, newborn, and neonatal animals of different species (cf. Tables 1 and 2). However, relatively few of those experiments were carried out using the most powerful experimental design wherein each animals serves as its own control. Rather, most experiments either focused on a single developmental stage, or studied different animals of the same species at different developmental stages. Nevertheless, it must be recognized that such studies provided important, although somewhat limited information due to a restricted focus in the former case, or increased variability in the latter case. However, the ability to study the same animal during development presents substantial challenges for those species with neonates too small to allow for chronic instrumentation. In animals of sufficient size at birth, we may measure maturational changes in peripheral and/or central indices of sympathetic activity, e.g., telemetric monitoring of biological activity ranging from relatively simple signals (ECG) to the extracellular activity of central neurons. With such instrumentation on board, we may monitor the same animal during its development, in its natural environment, and in different physiological states (awake/asleep). This animal preparation would also allow us to answer important physiological and behavioral questions related to the maturation of the central neurons in the sympathetic system because these cells could be perturbed by lesions, by ablation of peripheral afferent inputs, or by neurotransmitter agonists, antagonists, or antisense oligodeoxynucleotides delivered, directly or indirectly, using implantable devices such as miniature osmotic pumps. Such studies, when combined with anatomical studies of immediate/ intermediate gene transcripts and neu-
Sympathetic Nervous System
173
rotransmitter phenotypes, would provide a superb approach to the study of developmental-related issues in the sympathetic system. A better understanding of the normal processes involved in the maturation of the sympathetic system would provide a stronger theoretical base, thereby enabling more systematic approaches to the studies of pathophysiological changes in the sympathetic system such as those thought to be involved in the etiology of SIDS.
Acknowledgments This work was supported by National Institutes of Health grants HL-20864 (P.M.G., A.L.S., D.A.R.) and HD-28931(P.M.G., A.L.S.).
References 1. Gootman PM, Gootman N, Buckley BJ, Peterson BJ, Steele AM, Sica AL, Gandhi MR. Effects of hypoxia in developing swine. In: Acker H, Trebski A, O’Regan RG, eds. Chemoreceptors and Chemoreceptor Reflexes. New York: Plenum Press, 1990:155–163. 2. Gootman PM. Developmental aspects of reflex control of the circulation. In: , Gilmore JP, Zucker IH, eds. Reflex Control of the Circulation. Boca Raton, FL: CRC Press, 1991:965– 1027. 3. Harper RM, Bandler, R. Finding the failure mechanism in sudden infant death syndrome. Nature Med 1998; 4:757–758. 4. Schwartz PJ. The autonomic nervous system and sudden death. Eur Heart J 1998; 19(suppl F):F72–F80. 5. Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, Bosi G, Giorgetti F, Marni ED, Perticone F, Rosti D, Salice P. Prolongation of the QT interval and the sudden death syndrome. N Engl J Med 1998; 338:1709–1714. 6. Slotkin TA. Fetal nicotine or cocaine exposure: which one is worse? J Pharmacol Exp Ther 1998; 285:931–945. 7. Bernard C. Influence de grand sympathetique sur la sensibilite et sur la calorification. C R Soc Biol Paris 1851; 3:163–164. 8. Brown-Sequard CE. Recherches sur l’influence du systeme nerveux sur les fonctions de la vie organique. Med Exam Philad 1852; 486. 9. Bernard C. Lecons sur la Physiologie et la Pathologie du Systeme Nerveux, Vol. l. Paris: Bailliere, 1863. 10. Sherrington C. The Integrative Action of the Nervous System. New Haven, CT: Yale University Press, 1906. 11. Oswjannikow P. Die tonischen und reflectorischen Centren der Gefassnerven. Ber Verh Saechs Wiss Leipzig Math Phys Kl 1871; 23:135–143. 12. Dittmar C. Uber die Lage des sogenannten Gefas-scentrums in der Medulla oblongata. Ber Verh Saechs Wiss Leipzig Math Phys Kl 1873; 25:449–469. 13. Schlaefke ME, Loeschcke HH. Lokalisation eines an der Regulation von Atmung und Kreislauf bewilligen Gebietes an der ventralen Oberfiache der Medulla oblongata durch Kalteblockade. Pflugers Arch 1967; 297:201–220. 14. Feldberg W. The ventral surface of the brain stem: A scarcely explored region of pharmacological sensitivity. Neurosci 1976; 1:427–441. 15. Ranson SW, Billingsley PR. Vasomotor reactions from stimulation of the floor of the fourth ventricle. Am J Physiol 1916; 41:85–90. 16. Wang SC, Ranson SW. Autonomic responses to electrical stimulation of the lower brain stem. J Comp Neurol 1939; 71:437–455.
174
Sica et al.
17. Adrian ED, Bronk DW, Phillips G. Discharges in mammalian sympathetic nerves. J Physiol (Lond) 1932; 74:115–133. 18. Alexander RS. Tonic and reflex functions of medullary sympathetic cardiovascular centers. J Neurophysiol 1946; 53:1551–1566. 19. Bronk DW, Ferguson LK, Margaria R, Solant DY. The activity of the cardiac sympathetic systems. Am J Physiol 1936; 117:237–249. 20. Barman SM, Gebber GL. Basis for synchronization of sympathetic and phrenic nerve discharges. Am J Physiol 1976; 231:1601–1607. 21. Barman SM, Gebber GL. Brain stem neuronal types with activity patterns related to sympathetic nerve discharge. Am J Physiol 1981; 240:R335–R347. 22. Cohen MI, Gootman PM. Spontaneous and evoked oscillations in respiratory and sympathetic discharge. Brain Res 1969; 16:265–268. 23. Cohen MI, Gootman PM. Periodicities in efferent discharge of splanchnic nerve of the cat. Am J Physiol 1970; 218:1092–1101. 24. Gebber GL, Barman S.M. Basis for 2–6 cycles rhythm in sympathetic nerve discharge. Am J Physiol 1980; 239:R48–R56. 25. Gootman PM, Cohen MI. Efferent splanchnic activity and systemic arterial pressure. Am J Physiol 1970; 219:897–903. 26. Gootman PM, Cohen MI. Periodic modulation (cardiac and respiratory) of spontaneous and evoked sympathetic discharge. Acta Physiol Pol 1973; 24:99–109. 27. Malpas SC. The rhythmicity of sympathetic nerve activity. Prog Neurobiol 1998; 56:65– 96. 28. Barman SM, Gebber, GL. Sympathetic nerve rhythm of brainstem origin. Am J Physiol 1980; 239:R42–R47. 29. Gebber GL. Central oscillators responsible for sympathetic nerve discharge. Am J Physiol 1980; 239: H143–H155. 30. McCall RB, Gebber GL. Brainstem and spinal synchronization of sympathetic nervous discharge. Brain Res 1975; 89:139–143. 31. Barman SM, Gebber GL. Subgroups of rostral ventrolateral medullary and caudal medullary raphe neurons based on patterns of relationship to sympathetic nerve discharge and axonal projections. J Neurophysiol 1997; 77:65–75. 32. Barman SM, Gebber GL. Classification of caudal ventrolateral pontine neurons with sympathetic nerve-related activity. J Neurophysiol 1998; 80:2433–2445. 33. Dempsey CW, Richardson DE, Kocsis B, Fontana CJ, Song JH.Neurons of the rostral para-ambiguual field have activity correlated to the 10-Hz rhythm in sympathetic nerve discharge of urethane-anesthetized cat. Brain Res 1997; 768:102–110. 34. Gootman PM, Sica AL. Spectral analysis: a tool for study of neonatal sympathetic systems. News Physiol Sci 1994; 9:233–236. 35. Gootman PM, Hundley BW, Sica AL. The presence of coherence in sympathetic and phrenic activities in a developing mammal. Acta Neurobiol Exp 1996; 56:137–145. 36. Sica AL, Siddiqi ZA, Gandhi MR, Condemi G. Evidence for central patterning of sympathetic discharge in kittens. Brain Res 1990; 530:349–352. 37. Sica AL, Siddiqi ZA. Respiration-related features of symapthetic discharges in the developing kitten. J Auton Nerv Syst 1993; 44:77–84. 38. Sica AL, Siddiqi ZA. Reduction of baroreceptor-related sympathetic discharge during NMDA receptor antagonism. Brain Res 1994; 665:323–326. 39. Sica AL, Hundley BW, Gootman PM. Postganglionic sympathetic discharge in neonatal swine. Pediatr Res 1996; 39:85–89. 40. Gootman PM, Gootman N, Sica AL. A neuro-cardiac theory for Sudden Infant Death Syndrome: Role of the autonomic nervous system. J SIDS Inf Mort 1996; 1:169–182. 41. Kishi E, Ootsuka Y, Rong W, Terui N. Functional significance of the 10 Hz rhythmic discharges in sympathetic nerves. Clin Exp Pharm Physiol 1998; 25:464–467. 42. Dean C, Seagard JL. Expression of c-fos protein in the nucleus tractus solitarius in response to physiological activation of carotid baroreceptors. Neuroscience 1995; 69:249–257. 43. Gordon FJ, Talman W. Role of excitatory amino acids and their receptors in bulbospinal control of cardiovascular function. In: Kkunos G, Ciriello J eds. Central Neural Mechanisms in Cardiovascular Regulation. Boston: Birkhauser, 1992:209–225.
Sympathetic Nervous System
175
44. Machado BH, Mauad H, Chianca DA Jr, Haibara AS, Colomban E. Autonomic processing of the cardiovascular reflexes in the nucleus tractus solitarii. Braz J Med Biol Res 1997; 30:533–543. 45. Talman WT, Perrone MH, Reis DJ. Evidence for L-glutamate as the neurotransmitter of baroreceptor afferent nerve fibers. Science 1980; 209:813–814. 46. Sykes RM, Spyer KM, Izzo PN. Demonstration of glutamate immunoreactivity in vagal sensory afferents in the nucleus tractus solitarius of the rat. Brain Res 1997; 762:1–11. 47. Ruggiero DA, Mtui EP, Otake K, Anwar M. Central and primary visceral afferents to nucleus tractus solitarii may generate nitric oxide as a membrane permeant neuronal messenger. J Comp Neurol 1996; 364:51–67. 48. Gozal D, Torres J E , Gozal ET, Nockton J, Dixon MK, Gozal YM, Hornsby PJ. Nitric oxide modulates anoxia-induced gasping in the developing rat. Biol Neonate 1998; 73: 264–274. 49. Rao H, Jean A, Kessler JP. Postnatal ontogeny of glutamate receptors in the rat nucleus tractus solitarii and ventrolateral medulla. J Auton Nerv Syst 1997; 65:25–32. 50. Tong SW, Ingenito S, Anderson JE, Gootman N, Sica AL, Gootman PM. Development of a swine animal model for the study of sudden infant death syndrome (SIDS). Lab Anim Sci 1995; 45:398–403. 51. Ruggiero DA, Anwar, S, Kim J, Glickstein S. Visceral afferent pathways to the thalamus and olfactory tubercle: behavioral implications. Brain Res 1998; 799:159–171. 52. Richerson GB. Sudden infant death syndrome: the role of central chemosensitivity. Neuroscientist 1997; 3:3–7. 53. Ruggiero DA, Cravo SL, Arango V. Central control of the circulation by the rostral ventrolateral reticular nucleus: anatomical substrates. Prog Brain Res 1989; 81:49–79. 54. Ruggiero DA, Pickel VM, Milner TA, Anwar M, Otake K, Mtui ET, Park D. Viscerosensory processing in nucleus tractus solitarii: Structural and neurochemical substrates. In: Barraco RA, ed. Nucleus of the Solitary Tract. Boca Raton, FL: CRC Press, 1994: 3– 34. 55. Benarroch EE, Granata AR, Ruggiero DA, Park DH, Reis DJ. Neurons of C1 area mediate cardiovascular responses initiated from ventral medullary surface. Am J Physiol 1986; 250: R932–R945. 56. Chalmers J, Pilowsky P. Brainstem and bulbospinal neurotransmitter systems in the control of blood pressure. J Hypertens 1991; 9:675–694. 57. Maqbool A, McWilliam PN, Batten TF. Co-localization of c-Fos and neurotransmitter immunoreactivities in the cat brain stem after carotid sinus nerve stimulation. J Chem Neuroanat 1997; 13:189–200. 58. Ruggiero DA, Meeley MP, Anwar M, Reis DJ. Newly identified GABA-ergic neurons in regions of the ventrolateral medulla which regulate blood pressure. Brain Res 1985; 339: 171–177. 59. Ruggiero DA, Anwar M. Gootman PM. Presumptive adrenergic neurons containing phenylethanolamine N-methyltransferase immunoreactivity in the medulla oblongata of neonatal swine. Brain Res 1992; 583:105–119. 60. Sved AF, Gordon, FJ. Amino acids as central neurotransmitters in the baroreflex pathway. News in Physiological Sciences 1994; 9:243–246. 61. Urbanski R, Sapru H. Putative neurotransmitters involved in medullary cardiovascular regulation. J Auton Nerv Syst 1988; 25:181–193. 62. Ross CA, Ruggiero DA, Joh,TH, Park DH, Reis DJ. Rostral ventrolateral medulla: selective projections to the thoracic autonomic cell column from the region containing C1 adrenaline neurons. J Comp Neurol 1984; 228:168–184. 63. Ross CA, Ruggiero DA, Reis DJ. Connections between the nucleus of the tractus solitarii and the rostral ventrolateral medulla: a possible anatomical substrate of baroreceptor and other visceral reflexes. J Comp Neurol 1986; 242:511–534. 64. Barman SM, Gebber GL. Sequence of activation of ventrolateral and dorsal medullary sympathetic neurons. Am J Physiol 1983; 245:R438–R447. 65. Gootman PM, Cohen Ml, Piercey MP, Wolotsky PA. search for medullary neurons with activity patterns similar to those in sympathetic nerves. Brain Res 1975; 87:395–406. 66. Aicher SA, Reis DJ, Ruggiero DA, Milner TA. Anatomical characterization of a novel
176
67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.
84. 85. 86. 87.
Sica et al. reticulospinal vasodepressor area in the rat medulla oblongata. Neuroscience 1994; 60: 761–779. Ruggiero DA, Cravo SL, Golanov EV, Gomez R, Anwar M, Reis DJ. Adrenergic and nonadrenergic spinal projections of a cardiovascular-active pressor area of medulla oblongata: quantitative topographic analysis. Brain Res 1994; 663:107–120. Haselton JR, Guyenet PG. Central respiratory modulation of medullary sympathoexcitatory neurons in the rat. Am J Physiol 1989; 30:199–214. Haselton JR, Guynet PG. Electrophysiological characterisization of putative C1 adrenergic neurons in the rat. Neuroscience 1989; 30:199–214. Ruggiero DA, Giuliano R, Anwar M, Reis DJ. Anatomical substrates of cholinergic-autonomic regulation in the rat. J Comp Neurol 1990; 292:1–53. Hopkins DA, Gootman, PM, Gootman N, DiRusso SM, Zeballos ME. Brainstem cells of origin of the cervical vagus and cardiopulmonary nerves in the neonatal pig (Sus scrofa). Brain Res 1984; 306:63–72. Hopkins DA, Gootman PM, Gootman N, Armour JA. Anatomy of medullary and peripheral autonomic neurons innervating the neonatal porcine heart. J Auton Nerv Syst 1997; 64: 74–84. Otake K, Ruggiero DA. Monoamines and nitric oxide are employed by afferents engaged in midline thalamic regulation. J Neurosci 1995; 15:1891–1911. Zardetto-Smith AM, Gray TS. Organization of peptidergic and catecholaminergic efferents from the nucleus of the solitary tract to the rat amygdala. Brain Res Bull 1990; 25:875– 887. Tucker DC, Saper CB, Ruggiero DA, Reis DJ. Organization of central adrenergic pathways: I. relationships of ventrolateral medullary projections to the hypothalamus and spinal cord. J Comp Neurol 1987; 259:591–603. Krukoff TL, Mactavish D, Jhamandas JH. Activation by hypotension of neurons in the hypothalamic paraventricular nucleus that project to the brainstem. J Comp Neurol 1997; 385:285–296. Mtui EP, Anwar M, Gomez R, Reis DJ, Ruggiero DA. Projections from the nucleus tractus solitarii to the spinal cord. J Comp Neurol 1993; 337:231–252. Mtui EP, Anwar M, Reis DJ, Ruggiero DA. Medullary visceral reflex circuits: local afferents to nucleus tractus solitarii synthesize catecholamines and project to thoracic spinal cord. J Comp Neurol 1995; 351:5–26. Zardetto-Smith AM, Gray TS. Catecholamine and NPY efferents from the ventrolateral medulla to the amydala in the rat. Brain Res Bull 1995: 38:253–260. Granata AR, Ruggiero DA, Park DH, Joh TH, Reis DJ. Brain stem area with C1 epinephrine neurons mediates baroreflex vasodepressor responses. Am J Physiol 1985; 248:H547– H567. Jeske I, Reis DJ, Milner TA. Neurons in the barosensory area of the caudal ventrolateral medulla project monosynaptically on to sympathoexcitatory bulbospinal neurons in the rostral ventrolateral medulla. Neuroscience 1995; 65:343–353. Murat I, Lapeyre G, Saint-Maurice C. Isoflurane attenuates baroreflex control of heart rate in human neonates. Anesthesiology 1989; 70:395–400. Ross CA, Ruggiero DA, Park DH, Joh TH, Sved AF, Fernandez-Pardal J, Saavedra JM, Reis DJ. Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J Neurosci 1984; 4:474– 494. Blessing WW. Depressor neurons in rabbit caudal medulla act via GABA receptors in rostral medulla. Am J Physiol 1988; 254:H686–H692. Agarwal SK, Calaresu FR. Monosynaptic connection from caudal to rostral ventrolateral medulla in the baroreceptor reflex pathway. Brain Res 1991; 555:70–74. Terui N, Masuda N, Saeki Y, Kumada M. Activity of barosensitive neurons in the caudal ventrolateral medulla that send axonal projections to the rostral ventrolateral medulla in rabbits. Neurosci Lett 1990; 118:211–214. Zagon A. Internal connections in the rostral ventromedial medulla of the rat. J Auton Nerv Syst 1995; 53:43–56.
Sympathetic Nervous System
177
88. Jeske I, McKenna KE. Quantitative analysis of bulbospinal projections from the rostral ventrolateral medulla: contribution of C1-adrenergic and noradrenergic and noradrenergic neurons. J Comp Neurol 1992; 324:1–13. 89. Meeley MP, Ruggiero DA, Ishitsuka T, Reis DJ. Intrinsic GABA neurons in the nucleus of the tractus solitarius and the rostral ventrolateral medulla of the rat: an immunocytochemical and biochemical study. Neurosci Lett 1985; 58:83–89. 90. Kihara M, Kubo T. Immunocytochemical localization of GABA containing neurons in the ventrolateral medulla oblongata of the rat. Histochemistry 1989; 91:309–314. 91. Bacon SJ, Zagon A, Smith AD. Electron microscopic evidence of a monosynaptic pathway between cells in the caudal raphe nuclei and sympathetic preganglionic neurons in the rat spinal cord. Exp Brain Res 1990; 79:589–602. 92. Greenberg HE, Sica AL, Scharf SM, Ruggiero DA. Expression of c-fos in the rat brainstem after chronic intermittent hypoxia. Brain Res 1999; 816:638–645. 93. Ruggiero DA, Tong SH, Gootman N, Gootman PM. Hypotension-induced expression of the c-fos gene in the medulla oblongata of piglets. Brain Res 1996; 706:199–209. 94. Suzuki S, Pilowsky P, Minson J, Arnolda L, Llewellyn-Smith IJ, Chalmers J. c-fos Antisense in the rostral ventral medulla reduces arterial blood pressure. Am J Physiol 1994; 266:R1418–R1422. 95. Horne RSC, Berger PJ, Bowes G, Walker AM. Effect of sinoaortic denervation on arousal responses to hypotension in newborn lambs. Am J Physiol 1989; 256:H434–H440. 96. Horne RSC, De Preu ND, Berger PJ, Walker AM. Arousal responses to hypertension in lambs: effect of sinoaortic denervation. Am J Physiol 1991; 260:H1283–H1289. 97. Li Y-W, Dampney RAL. Expression of fos-like protein in brain following sustained hypertension and hypotension in conscious rabbits. Neuroscience 1994; 61:613–634. 98. Ross CA, Ruggiero DA, Reis DJ. Afferent projections to cardiovascular portions of the nucleus of the tractus solitarius in the rat. Brain Res 1981; 223:402–408. 99. Stebbins CL, Symons JD. Vasopressin contributes to the cardiovascular response to dynamic exercise. Am J Physiol 1993; 264:H1701–H1707. 100. Leffler CW, Busija DW, Brooks P, Croft JT, Share L, Beasley DG, Fletcher AM. Vasopressin responses to asphyxia and hemorrhage in newborn pigs. Am J Physiol 1987; 252:R122– R126. 101. Van Eerdenburg FJCM, Swaab DF. Increasing neuron numbers in the vasopressin and oxytocin containing nucleus of the adult female pig hypothalamus. Neurosci Lett 1991; 132:85–88. 102. Blessing WW, Jaeger CB, Ruggiero DA, Reis DJ. Hypothalamic projections of medullary catecholamine neurons in the rabbit: A combined catecholamine fluorescence and HRP transport study. Brain Res Bull 1982; 9:279–286. 103. Chan RKW, Sawchenkko PE. Spatially and temporally differentiated patterns of c-fos expression in brainstem catecholaminergic cell groups induced by cardiovascular challenges in the rat. J Comp Neurol 1994; 348:433–460. 104. Shen E, Dun SL, Ren C, Dun NJ. Hypovolemia induces Foslike immunoreactivity in neurons of the rat supraoptic and paraventricular nuclei. J Auton Nerv Syst 1992; 37:227– 230. 105. Shen E, Dun SL, Ren C, Dun NJ. Hypotension preferentially induces c-fos immunoreactivity in supraoptic vasopressin neurons. Brain Res 1992; 593:136–139. 106. Swanson LW, Sawchenko PE. Hypothalamic integration: Organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 1983; 6:269–324. 107. Gomez RE, Cannata MA, Milner TA, Anwar M, Reis, DJ, Ruggiero, DA. Vasopressinergic mechanisms in the nucleus reticularis lateralis in blood pressure control. Brain Res 1993; 604:90–105. 108. Ota M, Crofton JT, Festavan GT, Share L. Evidence that nitric oxide can act centrally to stimulate vasopressin release. Neuroendocrinology 1993; 57:955–959. 109. Papas S, Ferguson AV. Electrophysiological evidence of baroreceptor input to the area postrema. Am J Physiol 1991; 261:R9–R13. 110. Perez H, Ruiz S. Medullary responses to chemoreceptor activation are inhibited by locus coeruleus and nucleus raphe magnus. Neuroreport 1995; 6:1245–1248. 111. Ciriello J, Hochstenbach SL, Roder, S. Central projections of baroreceptor and chemore-
178
112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123.
124. 125. 126. 127. 128. 129. 130. 131. 132. 133.
Sica et al. ceptor afferent fibers in the rat. In: Barraco RA, ed. Nucleus of the Solitary Tract. Boca Raton, FL: CRC Press, 1994:35–50. Donoghue S, Felder RB, Jordan D, Spyer KM. The central projections of carotid baroreceptors and chemoreceptors in the cat: A neurophysiological study. J Physiol (Lond) 1984; 347:397–409. Jordan D, Spyer KM. Studies on the termination of sinus nerve afferents. Pflugers Arch 1977; 369:65–73. Machado BH, Bonagamba LGH. Microinjection of L-glutamate into the nucleus tractus solitarri increases arterial pressure in conscious rats. Brain Res 1992; 576:131–138. Leslie RA, Gwyn DG. Neuronal connections of the area postrema. Federation Proc 1984; 43:2941–2943. Ruggiero DA, Gootman PM, Gootman N, Ingenito S, Chang,C, Sica, AL. The area postrema of newborn swine is activated by hypercapnia: relevance to sudden infant death syndrome. J Auton Nerv Syst 1999; 76:167–175. Sica AL, Gootman PM, Ingenito S, Anwar M, Ruggiero DA. Age-related expression of c-fos in the solitary tract nucleus (NTS) after CO2 stimulation. Neurosci Abstr 1998; 24: 627. Sica AL, Gootman PM, Ruggiero DA. CO2-induced expression of c-fos in the nucleus of the solitary tract and the area postrema of developing swine. Brain Res 1999; 837:106–116. Qian ZM, Koon HW. Area postrema is essential for the maintenance of normal blood pressure under cold stress in rats. Exp Brain Res 1997; 121:186–190. Borison HL, Borison R, McCarthy LE. Role of the area postrema in vomiting and related functions. Fed Proc 1984; 43:2955–2958. Teppema LJ, Veening JG, Kranenburg A, Dahan A, Berkenbosch A, Olievier CN. Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia. J Comp Neurol 1997; 388:169–190. Coates EL, Li A, Nattie EE. Widespread sites of brainstem ventilatory chemoreceptors. J Appl Physiol 1993; 75:5–14. Harper RM, Ni H, Zhang J. Discharge relationships of periaqueductal gray neurons to cardiac and respiratory patterning during sleep and waking states. In: Depaulis A, Bandler R, eds. The Midbrain Periaqueductal Gray Matter. New York: Plenum Press, 1991:41– 55. Chamberlin NL, Saper CB. Topographic organization of cardiovascular responses to electrical and glutamate microstimulation of the parabrachial nucleus in the rat. J Comp Neurol 1992; 326:245–262. Chamberlin NL, Saper CB. Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat. J Comp Neurosci 1994; 14:6500– 6510. Herbert H, Moga MM, Saper CB. Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J Comp Neurol 1990; 293:540–580. Teppema LJ, Veening JG, Berkenbosch A. Expression of c-fos in the brainstem of rats during hypercapnia. Adv Exp Med Biol 1995; 393:47–51. Fulwiler CE, Saper CB. Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res Rev 1984; 7:229–259 Herbst JJ, Book LS, Minton SD. Gastroesophageal reflux causing respiratory distress and apnea in newborn infants. J Pediatr 1979; 104:763–768. Segar, JL, Hajduczok G, Smith BA, Merrill DC, Robillard JE. Ontogeny of the baroreflex control of renal sympathetic nerve activity and heart rate. Am J Physiol 1992; 263:H1819– 1826. Segar JL. Ontogeny of the arterial and cardiopulmonary baroreflex during fetal and postnatal life. Am J Physiol 1997; 273:R457–R471. Wood CE. Baroreflex and chemoreflex control of fetal hormone secretion. Reprod Fertil Dev 1995; 7:479–489. Minson, JB, Llewellyn-Smith IJ, Arnolda LF, Pilowsky PM, Oliver JR, Chalmers JP. Disinhibition of the rostral ventral medulla increases blood pressure and Fos expression in bulbospinal neurons. Brain Res 1994; 646:44–52.
Sympathetic Nervous System
179
134. Mulligan EM. Discharge properties of carotid bodies, In: Haddad GG, Farber JP, eds. Developmental Neurobiology of Breathing, Lung Biology in Health and Diseases, Vol. 53. New York: Marcel Dekker, 1991:321–340. 135. Blanco CE, Dawes GS, Hanson MA, McCooke HB. The response to hypoxia of arterial chemoreceptors in fetal sheep and new-born lambs. J Physiol (Lond) 1984; 351:25–37. 136. Kumar P, Hanson MA. Re-setting of the hypoxic sensitivity of aortic chemoreceptors in the newborn lamb. J Dev Physiol 1988; 11:199–206. 137. Carroll JL, Bamford OS, Fitzgerald RS. Postnatal maturation of carotid chemoreceptor responses to O2 and CO2 in the cat. J Appl Physiol 1993; 75:2383–2391. 138. Marchal F, Bairam A, Haouzi P, Crance JP, Di Giulio C, Vert P, Lahiri S. Carotid chemoreceptor response to natural stimuli in the newborn kitten. Respir Physiol 1992; 87:183– 193. 139. Teitel DF. Fetal chemoreception: a developing story. Reprod Fertil Dev 1996; 8:471–482. 140. Hanson MA. Role of chemoreceptors in effects of chronic hypoxia. Comp Biochem Physiol 1997; 119A:695–703. 141. Cote, A, Porras H, Meehan B. Age-dependent vulnerability to carotid chemodenervation in piglets. 1996; J Appl Physiol 80:323–331. 142. Donnelly DF, Haddad GG. Prolonged apnea and impaired survival in piglets after sinus and aortic nerve section. J Appl Physiol 1990; 68:1048–1052. 143. Hofer M. Role of the carotid sinus and aortic nerves in respiratory control of infant rats. Am J Physiol 1986; 251:R811–R817. 144. Shair HN, Myers MM. Effects of combined carotid sinus and aortic depressor nerve denervations in neonatal rat pups. Biol Neonate 1997; 71:251–264. 145. Meny RG, Carroll JG, Carbone MT, Kelly DH. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 1994; 93:44–49. 146. Mizusawa A, Ogawa H, Kikuchi Y, Hida W, Kurosawa S, Okabe S, Takashima T, Shirato K. In vivo release of glutamate in nucleus tractus solitarius o fthe rat during hypoxia. J Physiol (Lond) 1994; 478:55–66. 147. Pastuszko A. Metabolic responses of the dopaminergic system during hypoxia in newborn brain. Biochem Med Metab Biol 1994; 51:1–15. 148. Cross, KW, Oppe TE. The effect of inhalation of high and low concentrations of oxygen on the respiration of the premature infant. J Physiol (Lond) 1952; 117:38–55. 149. Cross KW, Hooper JMD, Lord JM. Anoxic depression of the medulla in the newborn infant. J Physiol (Lond) 1954; 125:628–640. 150. Haddad GG, Mellins RB. Hypoxia and respiratory control in early life. Annu Rev Physiol 1984; 46:629–643. 151. Lawson EE, Long WA. Central origin of biphasic breathing pattern during hypoxia in newborns. J Appl Physiol 1983; 55:483–488. 152. Glass HG, Snyder FF, Webster E. The rate of decline in resistance to anoxia of rabbits, dogs and guinea pigs from the onset of viability to adult life. Am J Physiol 1944; 140: 609–615. 153. Lutz PL. Mechanisms for anoxic survival in the vertebrate brain. Annu Rev Physiol 1992; 54:601–618. 154. Hochachka PW. Defense strategies against hypoxia and hypothermia. Science 1986; 231: 243–241. 155. Ang RC, Hoop B, Kazemi H. Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response. J Appl Physiol 1992; 72:1480–1487. 156. Hedner T, Hedner J, Bergman B, Iversen K. Jonason J. Effects of GABA and GABA analogues on respiratory regulation in the preterm rabbit. Biol Neonate 1983; 43:134–145. 157. Hedner J, Hedner T, Wessberg P, Jonason J. An analysis of the mechanism by which γaminobutyric acid depresses ventilation in the rat. J Appl Physiol 1984; 56:849–856. 158. Kazemi H, Hoop B. Glutamic acid and gamma-aminobutyric acid neurotransmitters in central control of breathing. J Appl Physiol 1991; 70:1–7. 159. Sica AL, Siddiqi ZA, Hundley BW, Gootman PM, Steele AM. Effects of GABAA receptor antagonism on inspiratory activities in kittens. Neurosci Lett 1993; 160:149–152. 160. Hunt CE, McCulloch K, Brouillette RT. Diminished hypoxic ventilatory responses in nearmiss sudden infant death syndrome. J Appl Physiol 1981; 50:1313–1317.
180
Sica et al.
161. Quattrochi JJ, McBride PT, Yates AJ. Brainstem immaturity in sudden infant death syndrome: a quantitative rapid Golgi study of dendritic spines in 95 infants, Brain Res 1985; 325:39–48. 162. Kinney HC, Filiano JJ, White WF. Abnormalities in the arcuate nucleus in the sudden infant death syndrome: a review. J SIDS Inf Mort 1996; 1:113–130. 163. Filiano JJ, Choi JC Kinney HC. Candidate cell populations for respiratory chemosensitive fields in the human infant medulla. J Comp Neurol 1990; 293:448–465. 164. Dean JB, Lawing WL, Millhorn DE. CO2 decreases membrane conductance and de-polarizes neurons in the nucleus tractus solitarii. Exp Brain Res 1989; 76:656–661. 165. Huang R-Q, Erlichman JS, Dean JB. Cell-cell coupling between CO2 excited neurons in the dorsal medulla oblongata. Neuroscience 1997; 80:41–57. 166. Li A, Nattie EE. Focal central chemosensitivity in the RTN studied with a CO2 diffusion pipette in vivo. J Appl Physiol 1997; 83:420–428. 167. Bongianni F, Mutolo D, Carfi M, Pantaleo T. Area postrema receptors mediate respiratory and gastric responses in the rabbit. Neuroreport 1998; 9:2057–2062. 168. Cai Y, Hay M, Bishop VS. Synaptic connections and interactions between area postrema and nucleus tractus solitarius. Brain Res 1996; 724:121–124. 169. Chen C-Y, Bonham AC. Non-NMDA and NMDA receptors transmit area postrema input to aortic baroreceptor neurons in NTS. Am J Physiol 1998; 275:H1695–H1706. 170. Frugiere A, Nunez E, Pasaro R, Gaytan S, Barillot JC. Efferent projections from the rostral ventrolateral medulla to the area postrema in rats. J Auton Nerv Syst 1998; 72:34–45. 171. Morgan J. Proto-oncogene expression in the nervous system. Disc Neurosci 1991; 7:1– 50. 172. Haxhiu MA, Yung K, Erokwu B, Cherniack NS. CO2-induced c-fos expression in the CNS catecholaminergic neurons. Respir Physiol 1996; 105:35–45. 173. Jansen AH, Nance DM, Liu P, Weisman H, Chernick V. Effect of sinus denervation and vagotomy on c-fos expression in the nucleus tractus solitarius after exposure to CO2. Pflugers Arch 1996; 431:876–881. 174. Finley JCW, Katz DM. The central organization of carotid body afferent projections to the brainstem in the rat. Brain Res 1992; 572:108–116. 175. Calder NA, Kumar P, Hanson MA. Development of carotid chemoreceptor dynamic and steady-state sensitivity to CO2 in the newborn lamb. J Physiol (Lond) 1997; 503:187–194. 176. White LD, Lawson EE. Effects of chronic prenatal hypoxia on tyrosine hydroxylase and phenylethanolamine N-methyltransferase messenger RNA and protein levels in medulla oblongata of postnatal rat. Pediatr Res 1997; 42:455–462. 177. Obonai T, Yasuhara M, Nakamura T, Takashima S. Catecholamine neurons alteration in the brainstem of sudden infant death syndrome victims. Pediatrics 1998; 101:285–288. 178. Segar JL, Mazursky JE, Robillard JE. Changes in ovine renal sympathetic nerve activity and baroreflex function at birth. Am J Physiol 1994; 267:H1824–H1832. 179. Nuyt AM, Segar JL, Holley AT, O’Mara MS, Chapleau MW, Robillard JE. Arginine vasopressin modulation of arterial baroreflex responses in fetal and newborn sheep. Am J Physiol 1996; 271:R1643–R1653. 180. Merrill DC, McWeeny OJ, Segar JL, Robillard JE. Impairment of cardiopulmonary baroreflexes during the newborn period. Am J Physiol 1995; 268:H1343–1351. 181. Kasparov S, Paton JF. Changes in baroreceptor vagal reflex performance in the developing rat. Pflugers Arch 1997; 434:438–444. 182. Parrish MD, Hill JM, Kaufman MP. Cardiovascular and respiratory response to static exercise in the newborn kitten. Pediatr Res 1991; 30:95–99. 183. Gootman PM, Gandhi MR, Steele AM, Hundley BW, Cohen HL, Eberle LP, Sica AL. Respiratory modulation of sympathetic activity in neonatal swine. Am J Physiol 1991; 261:R1147–R1154. 184. Cohen HL, Gootman PM, Hundley BW, Condemi G, Eberle LP. Power spectral analysis of the baroreflex in neonatal swine. Brain Res 1991; 558:131–135. 185. Patton DJ, Hanna BD. Postnatal maturation of baroreflex heart rate control in neonatal swine. Can J Cardiol 1994; 10:233–238. 186. Chen CM, Tsai TC, Lan MC. Effect of body tilting on physiological functions in healthy term neonates. Acta Pediatr 1995; 84:474–477.
Sympathetic Nervous System
181
187. Thoresen M, Cowan F, Wallow L. Cardiovascular responses to tilting in healthy newborn babies. Early Hum Dev 1991; 26:213–222. 188. Buckner PS, Maidens JM, Finer NN. Characterization of the neonatal heart rate baroreflex during and after ECMO. Early Hum Dev 1993; 32:49–61. 189. Stein P, White SE, Homan J, Hanson MA, Bocking AD. Altered fetal cardiovascular responses to prolonged hypoxia after sinoaortic denervation. Am J Physiol 1999; 275:R340– R346. 190. Giussani DA, Unno N, Jenkins SL, Wentworth RA, Derks JB, Collins JH, Nathanielsz PW. Dynamics of cardiovascular responses to repeated partial umbilical cord compression in late-gestation sheep fetus. Am J Physiol 1997; 273:H2351-H2360. 191. Itskovitz J, LaGamma E, Bristow J, Rudolph AM. Cardiovascular responses to hypoxemia in sinoaortic-denervated fetal sheep. Pediatr Res 1991; 30:381–385. 192. Giussani DA, Spencer JAD, Moore PJ, Bennet,L, Hanson MA. Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. J Physiol (Lond) 1993; 461:431–449. 193. Baan J Jr, Boekkooi, PF, Teitel DF, Rudolph AM. Heart rate fall during acute hypoxemia: a measure of chemoreceptor response in fetal sheep. J Develop Physiol 1993; 19:105– 111. 194. Bartelds B, van Bel F, Teitel, DF, Rudolph, AM. Carotid, not aortic, chemoreceptors mediate the fetal cardiovascular response to acute hypoxemia in lambs. Pediatr Res 1993; 34: 51–55. 195. Giussani DA, Riquelme RA, Moraga FA, McGarrigle HHG, Gaete CR, Sanhueza EM, Hanson MA, Llanos AJ. Chemoreflex and endocrine components of the cardiovascular responses to acute hypoxemia in the llama fetus. Am J Physiol 1996; 271:R73–R83. 196. Sladek M, Grogaard JB, Parker RA, Sundell HW. Prolonged hypoxemia attenuates laryngeal reflex apnea in young lambs. Pediatr Res 1993; 34:813–820. 197. Gootman PM, Gootman N. Cardiovascular responses to hypoxia in developing swine. Adv Exp Med Biol 1994; 360:333–335. 198. Bauer R, Bergmann R, Walter B, Brust P, Zwiener U, Johannsen B. Regional distribution of cerebral blood volume and cerebral blood flow in newborn piglets—effects of hypoxia/ hypercapnia. Dev Brain Res 1999; 112:89–98. 199. Meadow W, Rudinsky B, Raju T, John E, Fornell L, Shankararao R. Correlation of flow probe determination of common carotid artery blood flow and internal carotid artery blood flow with microsphere determinations of cerebral blood flow in piglets. Pediatr Res 1999; 45:324–330. 200. Woodson GE, Brauel G. Arterial chemoreceptor influences on the laryngeal chemoreflex. Otolaryngol Head Neck Surg 1992; 107:775–782. 201. Poets CF, Samuels MP, Noyes JP, Hewertson J, Hartmann H, Holder A, Southall DP. Home event recordings of oxygenation, breathing movements and heart rate and rhythm in infants with recurrent life-threatening events. J Pediatr 1993; 123:693–701. 202. Ward SL, Bautista DB, Woo MS, Chang M, Schuetz S, Wachsman L, Sehgal S, Bean X. Responses to hypoxia and hypercapnia in infants of substance-abusing mothers. J Pediatr 1992; 121:704–709. 203. Smith FG, Abu-Amarah I. Systemic and renal hemodynamic effects of hemorrhage in conscious lambs. Am J Physiol 1997; 273:H339–H346.
8 Hemodynamic Effects of Ventilation and Ventilatory Maneuvers
MICHAEL R. PINSKY University of Pittsburgh Medical Center Pittsburgh, Pennsylvania
I.
Introduction
The cardiocirculatory-respiratory system is a complex and highly integrated system that balances the ever changing and often conflicting metabolic demands of the body in a smooth fashion over a remarkably wide range of metabolic demands and constraints that life creates. The system includes such varied functional structures as the left and right atria (LA and RA, respectively) and ventricles (LV and RV, respectively) and the pulmonary and systemic vasculature. It works in an environment of differential extravascular pressures that reflect the tissue surface pressures of the major body compartments, thorax, abdomen, cranium, and muscular tissue spaces. The system’s response to the varying demands and field conditions are profoundly influenced by myocardial reserve, vascular resistance, circulating blood volume, blood flow distribution, autonomic tone, and endocrinological processes, as well as by baseline lung volume and its change, intrathoracic pressure (ITP), and the surrounding pressures for the remainder of the circulation, as induced by the mechanical and spontaneous breath. It should not be surprising, therefore, that dramatically different hemodynamic responses to similar ventilatory maneuvers can occur among subjects. These concepts have been previously described by our group (1–13) and others (14–18). The reader is referred to these prior reviews for greater in-depth discussions of the specific physiologic details discussed below. This chapter will focus primarily on the clinical application of these principals in common condi183
184
Pinsky
tions and as a physiological paradigm for the reader to understand better the subsequent chapters in Section IV for specific disease states. Clearly, the ultimate cardiovascular response to any ventilatory stress, from spontaneous ventilation to positive-pressure ventilation, is dependent on the basal cardiovascular state of the subject. For example, maximal aerobic metabolism in young healthy subjects is limited by muscle strength, endurance, and coordination, not by minute ventilation or cardiac output. However, that this same subject suffers a serious systemic illness, such as trauma or acute respiratory distress syndrome, if it leads to severe compromise of cardiovascular or respiratory reserve, then even simple ventilatory maneuvers such as positive-pressure breathing can profoundly alter cardiovascular status while the goal of spontaneous ventilation may be unreachable. Finally, complex cardiopulmonary responses can occur in critically ill patients, limiting the overall effectiveness of advanced resuscitative therapies to treat cardiopulmonary insufficiency. Thus, it is not surprising that hemodynamic responses to specific ventilatory interventions or spontaneous ventilatory efforts are often unpredictable, varying from one subject to the next despite outwardly similar therapies or ventilatory patterns. Numerous studies have been published over the preceding decades regarding the pathophysiologic basis of heart-lung interactions. These data can be grouped by those that explore basic mechanisms of cardiopulmonary interaction and those that compare different modes of ventilation or similar modes of ventilation during differing cardiovascular states. Although cardiopulmonary interactions can be quite complex, if considered within the limited context of single major interactions, reasonably accurate predictions can be made as to the overall cardiopulmonary effect of a specific intervention, ventilatory pattern, or cardiopulmonary disease state. This review will address these issues in two successive steps. First, we will describe the basic mechanisms underlying the cardiopulmonary interactions. Second, recent clinical trials of established and novel ventilatory therapies will be examined for their observed hemodynamic effects. The goal of this development is to illustrate that by using the constructs developed in the first section, reasonable predications can be made regarding the hemodynamic effects of ventilation in a wide variety of clinical situations. Furthermore, as will be seen, specific responses to ventilatory maneuvers suggest specific underlying cardiovascular conditions and accordingly may alert the physician to alter cardiovascular support. Heart-lung interactions can be broadly grouped into interactions that involve four basic concepts. Although addressed separately, these processes often coexist. The four basic concepts are: (1) ventilation is exercise, it consumes O2 and produces CO2 and thus may stress normal adaptive circulatory mechanisms; (2) inspiration increases lung volume above end-expiratory volume; (3) spontaneous inspiration decreases ITP; and (4) positive-pressure ventilation increases ITP. II. Ventilation as Exercise Spontaneous ventilatory efforts are induced by contraction of the respiratory muscles, of which the diaphragm and intercostal muscles comprise the bulk of the tissue.
Hemodynamics of Ventilation
185
However, with marked hyperpenea, abdominal wall muscles and muscles of the shoulder girdle also function as accessory respiratory muscles. Blood flow to these muscles is derived from several arterial circuits whose absolute flow is believed to exceed the highest metabolic demand of maximally exercising skeletal muscle under normal conditions (19). Thus, under conditions of normal cardiovascular function, blood flow is not the limiting factor determining maximal ventilatory effort. Although ventilation normally requires ⬍ 5% of total O2 delivery to meet its demand (19), in lung disease states where the work of breathing is increased, such as pulmonary edema or bronchospasm, the requirements for O2 may increase to 25% or 30% of total O2 delivery (19–22). Furthermore, if cardiac output is limited, blood flow to other organs and to the respiratory muscles may be compromised, inducing both tissue hypoperfusion and lactic acidosis (23). The institution of mechanical ventilation for ventilatory and hypoxemic respiratory failure may reduce metabolic demand on the stressed cardiovascular system increasing SvO2 for a constant cardiac output and CaO2. Intubation and mechanical ventilation, when adjusted to the metabolic demands of the patient, may dramatically decrease the work of breathing, resulting in increased O2 delivery to other vital organs and decreased serum lactic acid levels. Under conditions in which fixed right-to-left shunts exist, the obligatory increase in SvO2 will result in an increase in the PaO2, despite no change in the ratio of shunt blood flow to cardiac output. Numerous studies in the clinical literature have documented increased myocardial stress associated with spontaneous ventilation in patients with coronary artery disease or in whom the work cost of breathing is markedly increased. For example, Breach and Grenvik (24) reported that patients with cardiovascular insufficiency but normal pulmonary mechanics could not be weaned from mechanical ventilatory support without the use of supplemental inotropic support (24). Lemaire et al. (25) demonstrated that patients with severe chronic obstructive lung disease developed acute LV dysfunction during the first minutes of weaning from mechanical ventilatory support. This could be mitigated by diuresis and inotropic support. Similarly, Richard et al. (26) demonstrated that LV dysfunction was a common occurrence during weaning in COPD patients. Myocardial ischemia or worsening of myocardial ischemia in patients with acute coronary syndromes have also been reported when patients with cardiogenic pulmonary edema are made to breathe spontaneously, and these syndromes are reversed by the institution of mechanical ventilatory support. However, this hemodynamic improvement only occurs once the negative swings in intrathoracic pressure are also abolished (27–29).
III. Relation Between Lung Volume and Airway, Pleural, and Pericardial Pressure General confusion exists both in the literature and at the bedside in understanding and applying different forms of ventilation and their effects on cardiovascular response. This confusion is heightened by the common practice of equating changes in airway pressure (Paw) with changes in both pleural pressure (Ppl) and lung volume.
186
Pinsky
Although positive-pressure ventilation increases lung volume only by increasing Paw, the degree to which both Ppl and lung volume increase will also be a function of airway resistance as well as lung and thoracic cage compliance. Lateral chest wall Ppl and pericardial pressure (Ppc) increase similarly in normal and acute lung injury (ALI) states for a constant tidal volume despite widely varying lung compliance and a greater mean and plateau Paw during the acute lung injury condition (30). The primary determinant of the increase in Ppl and Ppc during positive-pressure ventilation is lung volume change (31). Importantly, the increase in Ppl during sustained increases in lung volume is greater than the increase in Ppc. Thus, estimating Ppc by measuring Ppl on any surface within the thorax may still underestimate actual Ppc, which is LV surrounding pressure. Furthermore, if tidal volume is reduced to maintain the same end-inspiratory airway pressure during ALI as during normal control conditions, both Ppl and Ppc will increase less than when tidal volume is maintained constant and airway pressure allowed to increase (30,32). Changes in Ppl induced by positive-pressure ventilation are not similar in all regions of the thorax; pleural pressure at the diaphragm increases least, and juxtacardiac Ppl increases most (33). These differences are in addition to the normally described hydrostatic pressure gradient in the pleural space from posterior to anterior surface. Because ALI is often nonhomogeneous, with aerated areas of the lung displaying normal specific compliance, large increases in Paw are often seen during mechanical ventilation in such patients even when the absolute tidal volume of ventilation is low. This increased Paw should overdistend these aerated lung units (34). Vascular structures that are distended may have a greater increase in their surrounding pressure than collapsible structures (35). However, two separate studies have demonstrated that, despite this nonhomogeneous alveolar distention, if tidal volume is kept constant, then Ppl will increase equally, independent of the mechanical properties of the lung (30,36). Thus, if tidal volume is kept constant, changes in peak and mean Paw will reflect changes in the mechanical properties of the lungs and patient cooperation and may, if elevated, increase lung injury and increase mortality, but will not reflect changes in Ppl nor alter global dynamics of the cardiovascular system. Unfortunately, we demonstrated, in postoperative patients, that the percentage of Paw that will be transmitted to the pericardial surface is not constant from one subject to the next as PEEP is increased (37) (Fig. 1). In summary, it is extremely difficult to predict with any degree of accuracy the amount to which increases in Paw, either induced by PEEP or positive-pressure breaths, will increase in Ppc or Ppl. Furthermore, the degree to which Ppc will increase relative to Ppl is a function of prior pericardial restraint. Thus, the clinical practice of assuming some constant fraction of Paw transmission to the pleural surface as a means of calculating the effect of increasing Paw on Ppl is not only inaccurate but potentially dangerous to patient management. Although one cannot know the actual Ppl or Ppc, the functional impact of increasing Paw on LV filling pressure (defined as LV end-diastolic pressure minus Ppc) can be measured. The influence of the artifactual elevation of ITP and its effect on measures of LV filling pressure by extrinsic PEEP can be ascertained if the subject is instrumented with a balloon floatation pulmonary artery catheter. One
Hemodynamics of Ventilation
187
Figure 1 Sequential trend recordings of right ventricular stroke volume (SVrv), left ventricular stroke volume (SVlv), aortic pressure (PAo), transmural left atrial pressure (Platm ), pulmonary arterial pressure (Ppatm ), right atrial pressure (Pratm ), airway pressure (Paw), and pleural pressure (Ppl) as ventilator driving pressure is increased in a stepwise fashion. Time between each level shown is ⬃ 60 sec. High-frequency jet ventilation is both preceded and followed by 5 sec of apnea for comparison. See text for explanation. (From Ref. 147.)
merely observes the behavior of the pulmonary artery occlusion pressure waveform during a transient period of airway disconnection at end expiration. This technique is referred to as the ‘‘nadir wedge method.’’ The immediate pressure drop seen following airway disconnection results in a value similar to the on-PEEP transmural LV filling pressure. Importantly, if this measurement is made too late following airway disconnection (⬎ 5 sec), it will reflect a higher pulmonary artery occlusion pressure than actually exists on PEEP because the airway disconnection-associated increase in venous return finally makes its way to the left ventricle (37).
188
Pinsky
However, if dynamic hyperinflation or air trapping exists, then using the nadir pulmonary artery occlusion pressure to estimate transmural LV filling pressure becomes inaccurate. Recently, a novel method was suggested by Teboul (personal communication) to estimate LV filling pressure during PEEP without the need to transiently remove the patient from positive-pressure ventilation and without the limitation of hyperinflation-induced inaccuracies. This method is based on the following hypothesis: If respiratory swings of pulmonary artery occlusion pressure (∆Ppao) are compared with the simultaneous changes of alveolar pressure (∆Palv), an index of transmission (IT) of pressures from the alveolar compartment to the pulmonary veins would then be obtained (IT ⫽ ∆Ppao/∆Palv). The difference between stop-flow end-inspiratory and end-expiratory airway pressure is assumed to reflect ∆Palv. In a patient mechanically ventilated with an optimal applied PEEP, LV filling pressure could then be estimated from a calculated transmural pulmonary artery occlusion pressure by subtracting from the end-expiratory pulmonary artery occlusion pressure the product of total PEEP (PEEP) by IT [i.e., transmural Ppao ⫽ end-expiratory Ppao–(PEEPtot ⫻ ∆Ppao/∆Palv)]. Although this technique gives estimated values of transmural pulmonary artery occlusion pressure equal to nadir wedge measures when no intrinsic PEEP is present, it gives values lower than nadir wedge pressure when intrinsic PEEP is present. Although it remains to be validated by direct measures of pericardial pressure for its validation, operationally this construct appears to be valid. Although one may not know the actual Ppl of a given patient with any degree of accuracy, it is possible to accurately estimate the pressure swing in Ppl during a positive-pressure breath. Thus, allowing the operator some insight into the transmission of airway pressure to the pleural surface, so as to calculate lung compliance. Since intrathoracic vascular structures sense intrathoracic pressure (ITP) as their surrounding pressure, dynamic and rapid swings in ITP, as may occur during ventilation, will be reflected in these intrathoracic vascular pressure swings. Review of data from several published studies reveals that both right atrial pressure and pulmonary artery diastolic pressure swings tend to closely follow Ppl swings during ventilation, such that transmural right atrial and transmural pulmonary artery pressures remain fairly constant during normal tidal volume breathing. This relationship falls down in hypovolemic states and when increasing lung volume markedly increases pulmonary vascular resistance. However, these conditions are usually apparent for other clinical signs. Regrettably, one needs to measure these intrathoracic vascular pressures invasively to acquire the data, and the recent trend in medicine is to avoid such monitoring. Potentially, swings in systolic arterial pressure can be used to assess swings in Ppl, assuming no LV outflow obstruction exists. Still, the use of such hemodynamic surrogates to monitor Ppl is of yet unproven value. An important limitation to the use of intrathoracic vascular pressures to estimate Ppl or Ppc exists, independent of measurement errors. Ppc may not increase as much as juxtacardiac Ppl during positive-pressure ventilation, especially in heart failure states. Presumably, as the total cardiac volume (blood and muscle mass) decreases with the application of positive airway pressure (vide infra) its venous
Hemodynamics of Ventilation
189
return decreases and/or LV ejection increases. Under these common conditions, if pericardial restraint was limiting cardiac filling (i.e., Ppc exceeds juxtacardiac Ppl), then the pericardium will become less of a limiting membrane (38,39). Pericardial pressure is the surrounding pressure for ventricular distention. Thus, estimates of Ppc made by using Ppl measures may overestimate actual surrounding pressure as Ppl is increasing. Second, esophageal pressure is often used clinically to estimate swings in both Ppl and Ppc. Although esophageal pressure is accurate at reflecting negative swings in Ppl during spontaneous inspiration in upright seated individuals (40) and in recumbent dogs in the left lateral position (41), it underestimates both the positive swings in Ppl and the mean increase in Ppl seen with increases in lung volume during positive-pressure ventilation. During Mueller and Valsalva maneuvers, however, because lung volume does not change, swings in esophageal pressure will accurately reflect swings in Ppl (40). Thus, for rapid changes in lung volume and airway pressure, Ppl and Ppc may behave similarly, but this assumption needs to be validated in individual studies. Furthermore, esophageal pressure may serve as a reasonable surrogate for Ppl or Ppc, but is one step removed from these values and may underestimate increases in either Ppl or Ppc when lung volumes also increase. Since Ppl is not uniform throughout the thoracic cavity and does not vary by equal magnitudes with changes in lung volume from one site to another, and since Ppc and Ppl may not vary equally, there is no one specific pressure that can represent all surface pressures and their change. To simplify the discussion, however, we shall refer to a global intrathoracic pressure (ITP) that the reader may assume will represent the appropriate Ppl, Ppc, or esophageal pressure measured or needed for that example. Thus, one can correctly say that ITP decreases with spontaneous inspiration and increases with positive-pressure inspiration although lung volume increases with both forms of inspiration. Accordingly, changes in ITP represent one of the primary differences between spontaneous and positive-pressure ventilation (42,43) and explain more of the observed differences in the hemodynamic response to ventilation seen between these two modes. The other primary difference between spontaneous and positive-pressure ventilation is the work of breathing, which tends to be lower during positive-pressure ventilation. Based on the above limitations in the measure of ITP and the role of metabolic demand on determining work of breathing, we will consider first the metabolic demands of breathing, followed by the hemodynamic effects of changes in lung volume and ITP on cardiovascular performance.
IV. Hemodynamic Effects of Changes in Lung Volume Lung inflation alters autonomic tone and pulmonary vascular resistance and, at high lung volumes, mechanically interacts with the heart in the cardiac fossa to limit absolute cardiac volumes. Each of these processes is important under specific conditions in determining the hemodynamic response to mechanical ventilation.
190
Pinsky A. Autonomic Tone
The lungs are richly enervated with autonomic fibers that mediate multiple homeostatic processes. These processes include baroreceptor control on blood pressure, inflation-induced chronotropic responses, and neuro-endocrine control of salt and water metabolism. In the acute setting only baroreceptor and heart rate control mechanisms appear to be operative, whereas under chronic conditions of prolonged mechanical ventilation, chronic obstructive lung disease or the use of prolonged noninvasive ventilatory support, neuro-endocrine effects dominate these processes. The most commonly observable example of autonomic control is the inflationchronotropic response, which acts through vagally mediated reflex arcs (44,45). Lung inflation at normal tidal volumes (⬍ 10 mL/kg) increases heart rate. Inspiration-associated cardioacceleration is referred to as respiratory sinus arrhythmia (46) and denotes normal autonomic tone (47). Loss of respiratory sinus arrhythmia denotes dysautonomia and its reappearance precedes return of peripheral autonomic control in diabetics with peripheral neuropathy (48). However, some degree of respiratory-associated heart rate change is intrinsic to the heart itself. For example, even following cardiac transplantation when the heart demonstrates no chronotropic response to the intravenous infusion of atropine, a small degree of ventilation-associated heart rate changes persists (49), suggesting that mechanoreceptors in the right atrium can alter sinoatrial tone. Pulmonary vasoconstriction also may occur through vagal reflex arcs (50), but does not appear to induce significant hemodynamic effects. Reflex arterial vasodilatation and bradycardia (the opposite heart rate response to normal tidal volume inspiration) can also occur with lung hyperinflation (44, 51–55). This inflationvasodilatation response appears to be mediated by afferent vagal fibers, because it is abolished by selective vagotomy. Blocking sympathetic afferent fibers also blocks this reflex (53,56), presumably by withdrawing central sympathetic tone. However, the inflation-vasodilatation response does not appear to result in significant cardiovascular depression, except during either high-frequency ventilation, when the autonomic stimulus is heightened, and with marked lung hyperinflation (44,53). Importantly, although increases in heart rate may occur with the application of PEEP and the associated decreases in cardiac output, the increases are less than those seen when cardiac output is reduced to similar degrees by hemorrhage (50). The reasons for this difference are not known but may reflect PEEP-induced sympatholytic actions and PEEP-induced increases in arterial pressure minimizing baroreceptor stimulation. Humoral factors, including compounds blocked by cyclo-oxygenase inhibition (57), released from pulmonary endothelial cells during lung inflation may also induce this depressor response (58–60) on a breath-by-breath basis. However, these interactions do not appear to grossly alter cardiovascular status (61). For example, unilateral lung hyperinflation (unilateral PEEP) does not appear to influence systemic hemodynamics (62), although it does induce the release of prostacyclinlike compounds into the systemic circulation. The role of nitric oxide in these interactions is still poorly understood. Increased levels of nitric oxide are seen in the exhaled
Hemodynamics of Ventilation
191
gas of rabbits ventilated at increasing tidal volumes (50). The significance of this finding remains to be defined, primarily because nitric oxide can come form several sources in the lungs. For example, nitric oxide could be released by nonadrenergic, noncholinergic autonomic nerve endings in the airways, as seen in subjects with asthma, or be released from alveolar inflammatory cells, if lung hyperinflation induces alveolar damage. Independent of these phasic reflex arcs that function over a more immediate time frame, ventilation may alter global salt and water metabolism by right atrial receptor release of atrial naturetic factor and antidiuretic hormone. Both positivepressure ventilation and sustained hyperinflation induced by PEEP stimulate a variety of endocrinological responses that induce fluid retention. The combination of lung distention compressing the right atrium and increased intrathoracic pressure decreasing venous return induces a sympathetic response that functions to retain fluid and electrolytes by the kidneys. Plasma norepinepherine, plasma rennin activity (63,64), and atrial naturetic peptide (65) increase when otherwise healthy subjects are given positive-pressure ventilation with or without PEEP. Interestingly, when subjects with congestive heart failure are exposed to positive airway pressure in the from of nasal continuous positive airway pressure (CPAP), plasma atrial naturetic peptide activity decreases in parallel with improvements in blood flow (66,67), suggesting that when hemodynamics are improved, rather than challenged by positive airway pressure ventilation, the body responds by reducing this stress response. These points will be described later in this book in the chapter ‘‘Neurohumoral and Mechanical Effects of Sleep Apnea on LV Function,’’ by Bradley and Floras. Importantly, one may measure circulating levels of catecholamines to predict the hemodynamic response of ventilatory maneuvers as either stressors or support of cardiovascular function. B. Pulmonary Vascular Resistance
The major hemodynamic effects of increases in lung volume are purely mechanical (42,68–72). Lung inflation affects cardiac function and ultimately cardiac output by altering both RV afterload and biventricular filling (73). The exact interaction among RV ejection pressure, pulmonary input impedance, and RV systolic function has not been defined, although it is probably different from that for LV ejection for a variety of reasons. For example, RV contraction is more peristaltic in nature than LV contraction, it uses LV contractile force to develop a majority of its intralumenal pressure, and it ejects into a vascular system with a highly variable but usually low impedance pulmonary vascular circuit. These issues are described in detail in another chapter in this book, ‘‘Right Ventricular Function,’’ by Santamore. The reader is referred to that chapter for specific aspects of this complex and unique ventricle. Right ventricular afterload is difficult to define owing to the above considerations, but in a simplified manner can be estimated as maximal RV systolic wall stress (74). Thus, RV afterload, by the LaPlace equation, is a function of the product of RV end-diastolic volume and systolic RV pressure (75). Since both the RV
192
Pinsky
and pulmonary arteries exist within the intrathoracic compartment, changes in ITP will not alter the pressure gradients between the RV and pulmonary artery. When referenced to ITP, transmural pulmonary arterial pressure (pulmonary artery pressure minus ITP) is the actual RV ejection pressure. Transmural pulmonary artery pressure can increase by one of four mechanisms. First, with increased pulmonary arterial flow; as occurs with exercise, pulmonary arterial pressure will increase, even as calculated pulmonary vascular resistance decreases, owing to distention and recruitment of the pulmonary vasculature. These recruitment and distention responses tend to minimize the increased RV afterload allowing cardiac output to increase in response to increasing metabolic demand. However, as listed below, this normal adaptive response may be profoundly inhibited by cardiopulmonary disease and ventilation. Furthermore, transmural pulmonary artery pressure can increase due to increases in pulmonary outflow pressure as may occur with either left-sided cardiac dysfunction or veno-occlusive disease. Relevant to this chapter, however, pulmonary vascular resistance can increase either by active changes in vasomotor tone or passive increases in pulmonary vasomotor tone, both induced by lung inflation. Increases in transmural pulmonary artery pressure increase the RV afterload, thus impeding RV ejection (76). If the RV does not empty as much as before, RV stroke volume will decrease (77) and RV end-systolic volume will increase (74), increasing RV wall stress and thus RV afterload further. This viscous cycle is the process by which acute cor pulmonale rapidly spirals toward total cardiovascular collapse. In the setting of reduced RV coronary perfusion, due to either systemic hypotension or increased RV wall stress, such increases in RV afterload can induce ischemia and infarction of the RV free wall (78). Since right atrial pressure is also the back-pressure for systemic venous return, increases in right atrial pressure due to RV overdistension will decrease systemic venous return (79). The pericardium plays an important role in minimizing these potential detrimental right-sided interactions, markedly limiting RV overdistension. In fact, the primary physiologic role of the pericardium appears to be to limit RV overdistension and prevent rotational dysfunction of the heart within the thorax. When increases in transmural pulmonary artery pressure are less severe, however, as may occur during end inspiration, mild hypoxemia, and PEEP at ⱕ 7.5 cm H2O, RV end-diastolic volume must increase slightly if cardiac output is to be maintained (75,80). In a chronic state, this is accomplished by both humorally mediated fluid retention and increases in peripheral vasomotor tone. However, acutely one must perform active therapeutic interventions, such as intravenous volume infusion and infusion of vasoactive pharmacological agents to maintain cardiac output in these conditions (81). Under almost all conditions, the increase in transmural pulmonary artery pressure during positive-pressure ventilation is due to an increase in pulmonary vascular resistance, because neither instantaneous cardiac output (79) nor LV filling (82) usually increases. Mechanical ventilation can modify pulmonary vascular resistance by any of several mechanisms. It may reduce pulmonary vascular resistance by reducing elevated pulmonary vasomotor tone. If regional PAO2 decreases below 60 mm Hg, local
Hemodynamics of Ventilation
193
pulmonary vasomotor tone will increase, reducing local blood flow (83). This process is called hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction is an important process to optimize matching of ventilation to perfusion when regional impairments in ventilation exist. However, if alveolar hypoxia occurs throughout the lungs, then overall pulmonary vasomotor tone increases, increasing pulmonary vascular resistance and impeding RV ejection (74). At low lung volumes, alveoli spontaneously collapse as a result of loss of interstitial traction. Lung volume is reduced in acute hypoxemic respiratory failure (84,85). Therefore, pulmonary vascular resistance is often increased in these patients owing to alveolar collapse and the resultant hypoxic pulmonary vasoconstriction. Thus, if PEEP opens collapsed lung units and replenishes alveolar gas with O2, then hypoxic pulmonary vasoconstriction will be reduced, pulmonary vascular resistance will decrease, and RV ejection will improve, thus increasing alveolar O2 pressure (PaO2) (86–89), reexpanding collapsed alveolar units (84,90–93), reversing acute respiratory acidosis (89), or decreasing the central sympathetic tone (62,94); these are all mechanisms by which PEEP may reduce vascular resistance. Changes in lung volume affect pulmonary vascular resistance, independent of those changes ascribed above to active changes in vasomotor tone (84,90–92). If mechanical ventilation overdistends aerated lung units, then pulmonary vascular resistance will also increase. To understand this better, one must consider the pulmonary vasculature to comprise two different types of vessels depending on what extravascular pressure surrounds them (91). The large pulmonary arteries and veins sense interstitial pressure as their surrounding pressure, which is similar to ITP at rest. Thus, they can be referred to as extra-alveolar vessels. Extra-alveolar vessels are acted upon by the interstitial forces of the lung that keep them patent (90,95,96). As lung volume increases, the radial interstitial forces increase, and, like airways, the diameter of the extra-alveolar vessels increases. Similarly, as lung volume decreases, the radial interstitial traction decreases, and extra-alveolar vessels decrease their cross-sectional diameter. The decrease in airway caliber is associated with an increasing number of small-airway closures. The alveoli downstream from collapsed airways then become hypoxic, increasing pulmonary vascular resistance by the process of hypoxic pulmonary vasoconstriction (87,90). The small pulmonary arterioles, capillaries, and pulmonary venules sense alveolar pressure as their surrounding pressure and are referred to as alveolar vessels. Increases in lung volume above functional residual capacity (FRC) increase alveolar vessel vascular resistance (87,96). The causes of this increase in alveolar vessel resistance are more complex than for extra-alveolar vessels but have significant importance in the setting of hyperinflation. Since transpulmonary pressure (alveolar pressure minus ITP) is the distending pressure of the lung, it increases as lung volume increases. Transpulmonary pressure is also the extravascular pressure difference between alveolar and extra-alveolar vessels, with the higher pressure being outside the alveolar vessels. If transpulmonary pressure exceeds transmural pulmonary artery pressure, the pulmonary vasculature will collapse where extra-alveolar vessels pass into alveolar loci within the pulmonary arteriolar segment. As the vasculature is compressed, its cross-sectional area is reduced, increasing pulmonary vascular
194
Pinsky
resistance. Another mechanism purported to increase pulmonary vascular resistance during hyperinflation is increased alveolar septal stretching, although this mechanism has not been validated. Increasing lung volume during mechanical ventilation also increases extraalveolar vascular compliance (97) by stretching open the extra-alveolar vessels, thus increasing their capacitance (98), while at the same time decreasing alveolar vessel capacitance. If the cross-sectional area of the pulmonary capillaries is already reduced, as is the case with chronic obstructive lung disease, then hyperinflation can create significant pulmonary hypertension and may precipitate acute RV failure (acute cor pulmonale) (99) and RV ischemia (78), whereas if normal pulmonary vascular resistance exists, then lung hyperinflation will reduce pulmonary venous outflow. Putting all these concepts together into a common experiment, Canada et al. (100) demonstrated that PEEP decreased pulmonary vascular resistance in the injured lung, while it increased pulmonary vascular resistance in the spared lung. Thus, PEEP may increase pulmonary vascular resistance if it induces overdistension of the lung above its normal resting lung volume, but reduce pulmonary vascular resistance if it recruits collapsed lung units and increases lung volume back to FRC. C. Ventricular Interdependence
Clearly, changes in LV preload can occur by changes in RV output because the two ventricles pump in series. However, LV preload can also be altered by changes in RV end-diastolic volume in a less direct flow manner. Since the two ventricles share a common intraventricular septum, are housed in a common pericardial space, and are surrounded by a fixed cardiac fossal volume, increases in RV volume must limit LV filling. Increases in RV volumes decrease LV diastolic compliance by the mechanism of ventricular interdependence (101,102). Thus, for the same LV filling pressure, RV dilation will decrease LV end-diastolic volume and cardiac output. This is the cause of pulsus paradoxus as seen in both normal subjects and those with acute bronchospasm during spontaneous respiration. However, this mechanism is less often seen during positive-pressure ventilation because RV volumes usually decrease. Importantly, if RV volumes are markedly increased, as may occur with chronic cor pulmonale, then positive-pressure inspiration may increase LV stroke volume and arterial pulse pressure by decreased RV volume-induced increased LV diastolic compliance. Nevertheless, inspiration-associated RV dilation can occur during positive-pressure inspiration if venous return is not impaired. This inspiration-associated increase in RV end-diastolic volume decreasing LV end-diastolic volume can be partially mitigated by volume resuscitation (103) or vasopressor infusion (104), although it is a sign of both fluid overload and/or increased intra-abdominal pressure. Accordingly, in the fluid-resuscitated patient, RV volumes often increase during positive-pressure inspiration with pulmonary hypertension (80) and will decrease with LV diastolic compliance. Importantly, fluid resuscitation in this setting is only minimally useful in restoring cardiac output since it will improve cardiac output only by increasing RV volumes further. This is manifest clinically
Hemodynamics of Ventilation
195
as the poor cardiovascular responsive to fluid resuscitation commonly seen in subjects with acute pulmonary hypertension. D. Mechanical Heart-Lung Interactions
As lung volume greatly increases, the chest wall expands outward and the diaphragm descends, but the heart is trapped in the cardiac fossa (105). Thus, juxtacardiac ITP may increase more than lateral chest wall or diaphragmatic ITP (33,39,106). Since this compressive effect is due to the inflating lungs and not the cause of lung inflation, it can be seen with either spontaneous hyperinflation (107) or positive-pressureinduced hyperinflation with PEEP (108,109). This decrease in ‘‘apparent’’ LV diastolic compliance (103), as referenced to atmospheric pressure alone, was previously misinterpreted as impaired LV contractility, because LV stroke work for a given LV end-diastolic pressure or pulmonary artery occlusion pressure is decreased (110,111). However, since LV preload is defined as LV end-diastolic volume, when LV end-diastolic volume is kept constant, cardiac output also remains constant as lung expansion is increased by the addition of larger and larger levels of PEEP (70,103,112). V.
Hemodynamic Effects of Changes in Intrathoracic Pressure
The heart exists within the thorax and can be considered from a purely mechanical viewpoint as being a pressure chamber within a pressure chamber. Therefore, changes in ITP will affect the pressure gradients for both systemic venous return to the RV and systemic outflow from the LV, independent of the heart itself. Using this construct, increases in ITP, by increasing right atrial pressure and decreasing transmural LV systolic pressure, will reduce these pressure gradients and thereby decrease intrathoracic blood volume, whereas decreases in ITP will augment venous return and impede LV ejection, thereby increasing intrathoracic blood volume. Let us separately examine the effects of ITP on venous return and LV ejection. A. Systemic Venous Return
Blood flows back to the heart from the body along low-pressure/low-resistance conduits. Right atrial pressure is the downstream pressure for this venous blood flow (113). Swings in ITP will induce similar swings in right atrial pressure, thus phasically altering the pressure gradient for venous return. The pressure gradient for venous return can be defined as the difference between the pressure in the upstream venous reservoirs, referred to as mean systemic pressure relative to right atrial pressure. As downstream right atrial pressure varies, as occurs during ventilation, the rate of venous return changes inversely with its pressure changes. Mean systemic pressure, on the other hand, is a function of blood volume, peripheral vasomotor tone, and the distribution of blood within the vasculature (18). Mean systemic pressure may not change rapidly during the ventilatory cycle, whereas right atrial pressure usually does owing to concomitant changes in ITP.
196
Pinsky
Accordingly, variations in right atrial pressure represent the major factor determining the fluctuation in pressure gradient for systemic venous return during ventilation (79,114). With increases in ITP, as seen with positive-pressure ventilation or hyperinflation during mechanical ventilation, right atrial pressure relative to atmosphere increases. As a result, the pressure gradient for systemic venous return decreases decelerating venous blood flow (77), decreasing RV filling, and consequently, decreasing RV stroke volume (77,79,115–122). The opposite movement of blood volume occurs during spontaneous inspiration (43,77,104,117,120,123). However, this simple construct ignores the fact that a significant proportion of the systemic venous blood flow traverses the abdominal compartment. Importantly, as the diaphragm descends, intra-abdominal pressure also increases, increasing mean systemic pressure as well, thus minimizing any decrease in venous return seen during positive-pressure ventilation (124–125). Accordingly, the pressure gradient for venous return may not be reduced by PEEP, especially in patients with hypervolemia. In fact, abdominal pressurization by diaphragmatic descent may be the major mechanism by which the decrease in venous return is minimized during positive-pressure ventilation (126–130) and explains the same effects seen during spontaneous inspiration (131–134). Furthermore, ventilation also alters hepatic performance in a most unpredictable fashion. Although PEEP decreases liver blood flow in proportion to the induced decrease in cardiac output, the liver’s ability to clear hepatocytic-specific compounds, such as indocyanine green, is unaltered, presumably because hepatic compression redistributes blood flow within the liver to a larger surface area of hepatocytes. In support of this hypothesis, when cardiac output is restored to pre-PEEP levels by fluid resuscitation (130,135) while PEEP is maintained, liver clearance mechanisms increase above pre-PEEP levels (135–137). These data are consistent with a PEEP-induced alteration in intrahepatic blood flow distribution. B. Right Ventricular Filling
RV filling pressure (defined as right atrial pressure minus Ppc) is insignificantly altered by acute volume loading in patients undergoing open-chest operations (138). This suggests that under normal conditions RV diastolic compliance is greater than pericardial compliance. Although right atrial pressure increases with volume loading, so does Ppc, and the two increase at a similar rate, such that RV filling pressure remains unchanged. This constancy of RV filling pressure as ITP increases, also occurs in patients given increasing levels of PEEP in the ICU following open-chest operations (139). Presumably, conformational changes in the RV more than wall stretch are responsible for RV enlargement (38). The clinical implication of these data is that with changes in ITP, changes in right atrial pressure do not follow changes in RV end-diastolic volume. RV end-diastolic volume can become very large when cardiac contractility is reduced and intravascular volume is expanded. Under these conditions, RV filling pressure increases as a result of either decreased RV diastolic compliance, increased pericardial compliance, increased end-diastolic volume, or a combination of all three. The relation between RV filling pressure and
Hemodynamics of Ventilation
197
volume is curvilinear (101). Thus, as RV end-diastolic volume increased above a threshold level, RV filling pressure increases more rapidly. Furthermore, in both humans and dogs with acute ventricular failure, volume loading increases Ppc more than ITP, consistent with pericardial restraint limiting biventricular filling (32,37). However, with the application of PEEP in this setting, the lessor ITP increases until it approximates Ppc, then both ITP and Ppc increase similarly as PEEP increases. These data demonstrate that lung expansion exerts a hemodynamic effect on the heart during diastole that is similar to pericardial tamponade, with the expanding lungs rather than the pericardial sac limiting biventricular filling (39,140). The observation that RV filling occurs with little change in its unstressed volume under normal conditions may be of clinical relevance to differences in the hemodynamic responses seen during spontaneous and positive-pressure ventilation. Small changes in either heart rate or LV afterload, as may occur during ventilation, will not significantly alter cardiac output under normal conditions (53,122,123). Thus, the primary determinant of cardiac output is venous return (18). Maximum venous return for a constant blood volume and peripheral vasomotor tone is realized at a right atrial pressure at or below zero relative to atmospheric pressure because this will maximize the pressure gradient for venous return (113,118). If the RV were filling below its unstressed volume, then transient increases in venous blood flow into the RV (RV filling) could occur without increasing right atrial pressure (140). Two aspects of ventilation and the pulmonary circulation work to keep this process running smoothly. First, ventilation is cyclical. Inspiration is always followed by expiration. Thus, any increase in venous return (spontaneous inspiration or positive-pressure expiration) is always followed by a reciprocal change minimizing any sustained RV load. Second, the RV normally ejects a stroke volume proportional to its instantaneous venous blood flow, independent of either the amount of that flow or the phase of the respiratory cycle (79). This venous return-induced accommodation to changes in venous outflow occurs primarily because the pulmonary circulation has a very low input impedance and can decrease its resistance to marked increases in blood flow by both distension and recruitment of pulmonary vessels (77,141). If either RV diastolic compliance decreased or right atrial pressure increased independent of changes in RV end-diastolic volume, then this adaptive system would not work. Thus, positive-pressure ventilation, by dissociating right atrial pressure from RV filling pressure, removes a major adaptive processes operative in RV hemodynamics during spontaneous ventilation. Importantly, even if normal cardiopulmonary interactions are restored by instituting spontaneous ventilatory efforts, cardiac output will only increase if the RV can transfer the increased venous return into the pulmonary circulation. Thus, one sign of acute cor pulmonale is the failure to increase cardiac output when transiting from positive-pressure to spontaneous ventilation. The primary effect of changes in lung volume and ITP on cardiovascular status in subjects with normal baseline cardiovascular function is to alter RV preload via altering venous blood flow. To the extent that both mean ITP and swings in lung volume are maintained as low as possible, these detrimental hemodynamic effects can be avoided. Interestingly, pressure-limited ventilation strategies have this as an
198
Pinsky
added benefit. This construct is supported by the clinical observation that prolonging expiratory time, decreasing tidal volume, and avoiding PEEP minimize any decrease in cardiac output in ventilator-dependent patients (20,79,117–121,142,143). Similarly, intravascular fluid infusion or increased autonomic tone, by increasing upstream venous pressure (113,131,132), will also maintain venous blood flow despite the addition of increased ITP (104). Clinically, patients placed on positive-pressure ventilation often display a decrease in cardiac output that is presumed to reflect a functional hypovolemia. However, if positive-pressure ventilation induced profound hyperinflation (e.g., acute severe bronchospasm) or if ITP is increased for a sustained interval of time (thoracic crush injury), then the pressure gradient for venous return would dissipate rapidly leading to cardiovascular collapse and death. Spontaneous inspiratory efforts by decreasing ITP decrease right atrial pressure. The reduction in right atrial pressure removes the pressure dam to venous return, accelerating blood flow into the RV (43,68,118–120). This bolus-increased venous return is transmitted to the pulmonary artery on the subsequent beats. Thus, normal spontaneous inspiration is associated with a matched increase in both pulmonary blood flow and alveolar ventilation augmenting alveolar gas exchange. This inspiration-associated increase in venous return is referred to as the ‘‘thoracic pump’’ and is the primary reason why cardiac output is usually higher during spontaneous ventilation than during apnea. However, increases in venous return as ITP decreases are limited because at negative transmural pressures seen with marked negative swings in intrathoracic pressure (54), the large systemic vena cavae collapse as they enter the thorax, limiting maximal venous flow (113,133,134). If this were not the case, then the RV could become overdistended with volume with every vigorous spontaneous inspiratory effort and fail (144). C. Left Ventricular Preload and Ventricular Interdependence
Since the right and left heart function in series, a reduction of inflow to the right heart must eventually lead to a reduction in outflow from the left heart, and vice versa. This concept is modified by changes in intrathoracic pressure as exemplified by the Valsalva maneuver. Sustained increases in ITP during a Valsalva maneuver will initially reduce RV filling but do not alter LV preload (82). However, after two to three beats, the decreased RV output is reflected by a decrease in both LV preload and output (105,145). Positive-pressure ventilation and its phase relation to the ventilatory cycle has been modeled as a form of repetitive Valsalva maneuvers (20,71, 72,96,103,110,111,122,142,146–150). However, more direct mechanical coupling between the LV and the RV exists through ventricular interdependence, as described above. The heart is a collection of muscular pumps sharing common walls and an external housing. Changes in absolute volume of either ventricle alter the diastolic compliance of the other ventricle by the process referred to as ventricular interdependence. Classically, ventricular interdependence is thought to occur as increases in RV volume decrease LV diastolic compliance, LV preload, and LV output. Right ventricular end-diastolic volume increases during spontaneous inspiration, transiently shifting the intraventricular
Hemodynamics of Ventilation
199
septum from its neutral position into the LV (102). As the RV dilates, LV diastolic compliance is reduced (101,151,152), reducing LV end-diastolic volume. This is the primary mechanism thought to be operative in pulsus paradoxus (43). However, equally as such, RV volumes can decrease during positive-pressure, reducing ventricular interdependence and allowing LV volumes to increase for the same filling pressure (101,151,152). Thus, the LV is not deformed by positive-pressure ventilation or the use of PEEP (70,71,148,149). If anything, positive-pressure inspiration decreases the size of both ventricles toward their common intraventricular septum by an amount predicted by the differential compliances of each ventricle (103,153). Indeed, Qvist et al. (154) demonstrated that if LV end-diastolic volume was kept constant, cardiac output would also remain constant even with the application of high levels of PEEP. Finally, although positive-pressure ventilation could markedly alter both end-diastolic and end-systolic volumes, it did not change the LV pressurevolume relation in humans (155). D. Left Ventricular Afterload
Left ventricular afterload can be defined as maximal systolic wall tension, which, by the LaPlace equation, is proportional to the product of transmural LV pressure and the radius of curvature of the LV. Maximal LV wall tension usually occurs at the end of isometric contraction, reflecting both maximal (end-diastolic) LV volume and aortic diastolic pressure. Thus, under conditions of normal LV dimensions, during systole, even though LV intracavitary pressure increases, the radius of curvature of the LV decreases much more. Accordingly, the LV unloads itself during ejection. When no aortic outflow obstruction exists, transmural LV systolic pressure can be approximated as transmural arterial pressure. This is important, because it explains the dominant role of diastolic pressure hypertension in altering LV afterload and the ability of arterial pressure to be an excellent surrogate marker of change in LV output. In congestive heart failure states, when the LV is dilated and does not greatly reduce its volume during systole (reduced ejection fraction and increased end-systolic volume), then maximal LV afterload occurs during ejection and is impacted greatly by systolic arterial pressure. If arterial pressure were to remain constant as ITP increased, then transmural LV pressure would decrease and LV wall tension would decrease as well. Similarly, if transmural arterial pressure were to remain constant as ITP increased but LV enddiastolic volume were to decrease because of the associated decrease in systemic venous return usually seen with increases in ITP (see above), then LV wall tension would decrease. This mechanism has been evoked to explain the improved LV performance in subjects during chronic continuous positive airway pressure (CPAP) therapy. Finally, decreases in ITP with a constant arterial pressure will increase LV transmural pressure and thus increase LV afterload, impeding LV ejection (82), the increase in afterload being directly proportional to the decrease in ITP. This mechanism has been evoked to explain the induction of acute LV failure during weaning from mechanical ventilation or the induction of acute pulmonary edema in subjects with severe inspiratory airflow obstruction (upper airway obstruction, severe bron-
200
Pinsky
chospasm). Thus, increases in ITP unload the LV, whereas decreases in ITP increase LV afterload (156,157). The actual cause of loaded spontaneous ventilatory effort-induced decreased LV stroke volume (pulsus paradoxus) is complex (158–162) and worthy of additional comment. Spontaneous inspiratory efforts can be considered to have both transient (initiation of the breath) and steady-state effects on LV systolic function. Initially, there is a transient intraventricular septal shift from right to left and the RV expands with blood. This results in an immediate though transient reduction in LV end-diastolic volume as LV diastolic compliance decreases. However, with sustained inspiratory efforts the septum shifts back to its neutral position after two to three beats. At the same time and throughout all of spontaneous inspiration, decreases in ITP increase in LV afterload (LV pressure minus ITP) increase LV endsystolic volume (82). Importantly, as ITP progressively decreases during the inspiratory effort, the increased afterload effect also becomes more pronounced. Thus, in certain heart failure conditions, echocardiographic analysis of LV systolic function demonstrate LV systolic dysfunction (regional wall motion abnormalities and mitral regurgitation) only at end inspiration. Three separate mechanisms have been proposed to explain the impaired systolic function of the LV during loaded spontaneous inspiration. These include (1) increases in LV transmural pressure increasing LV ejection pressure; (2) increases in aortic input impedance (163), and (3) altered series contraction of the LV myocardium (164). Furthermore, if airway obstruction is prolonged, then arterial desaturation can occur (165), which may directly reduce both LV diastolic compliance and systolic function (166). In fact, arterial desaturation is thought to be the primary factor determining impaired LV function in obstructive sleep apnea. These points are discussed in greater detail in the chapter later in this volume by Scharf. The hemodynamic effect of increasing ITP is not as straightforward as is decreasing ITP for a variety of reasons. First, sudden increases in ITP may alter arterial pressure but usually do not alter arterial pressure relative to ITP (transmural arterial pressure) (82). In fact, it is the increase in ITP that increases arterial pressure without changing aortic blood flow that gives rise to reverse pulsus paradoxus (no change in arterial pulse pressure but an inspiration-associated increase in systolic pressure) seen during positive-pressure ventilation in patients with congestive heart failure (105). If the increase in ITP is sustained, however, then the ITP-induced decrease in systemic venous return will eventually decrease LV output, thus decreasing arterial pressure (82). In this manner, it can be seen that LV preload and afterload are invariably linked. In the steady state, changes in ITP that result in altered cardiac output also alter peripheral vasomotor tone through baroreceptor mechanisms (53). Baroreceptor reflexes tend to keep systemic pressure (arterial pressure) and flow (cardiac output) constant. Since the primary baroreceptors are extrathoracic in location, living at the bifurcation of the common carotid artery into the internal and external carotid arteries, any ITP-induced increase in arterial pressure will be sensed as an increase in organ perfusion pressure. Thus, if increasing ITP increased arterial pressure without changing transmural arterial pressure, then the periphery would reflexively vasodilate to maintain a constant extrathoracic arterial pressure-flow relation (147). Re-
Hemodynamics of Ventilation
201
duced sympathetic tone is a cardinal marker of cardiovascular improvement in subjects with congestive heart failure treated with chronic CPAP therapy. Since coronary perfusion pressure is not increased by ITP-induced increases in arterial pressure, whereas mechanical constraint from the expanding lungs may obstruct coronary blood flow, coronary hypoperfusion from a combined coronary compression and a decrease in coronary perfusion pressure is a potential complication of increased ITP (167–169). Potentially, increases in ITP should augment LV ejection by decreasing LV afterload. This effect should have limited therapeutic potential, just as all afterload reducing therapies are limited by both the minimal end-systolic volume and the obligatory decrease in venous return. Thus, the potential augmentation of LV ejection by increasing ITP is limited under most conditions except marked cardiomyopathy, because increasing ITP by reducing LV ejection pressure can only decrease end-systolic volume, which is usually already small and cannot decrease much more. Importantly, the decrease in venous return associated with the increase in ITP can easily progress to a total cessation of venous blood flow. These combined effects of reduced venous return and improved LV ejection are shown in Figure 1, which describes the effects of progressive increases in ITP on arterial pressure and cardiac output in a canine model of acute ventricular failure from our laboratory (147). As ITP increases, all intrathoracic vascular pressures (measured as absolute vascular pressure minus ITP) decrease as blood leaves the thoracic compartment, whereas stroke volume initially increases associated with an increase in arterial pressure equal to that in ITP. This cardiac augmentation becomes preload-limited after LV filling pressure decreases to some minimal threshold value, such that stroke volumes do not increase further as ITP increases although filling pressures continue to decrease and arterial pressure continues to increase. These hypotheses have subsequently been reduplicated by others (21,170–173). The dissociation between cardiac output and arterial pressure induced by increases in ITP makes assumptions about changes in cardiac output by changes in arterial pressure during positive-pressure ventilation questionable at best. Mechanistically speaking, not only do increases in ITP unload the LV, but abolishing negative swings in ITP will also reduce LV afterload. That is, if one focuses only on transmural LV ejection pressure, one can see that identical amounts of LV ejection pressure decrease will occur if ITP were to increase either from zero to 15 mm Hg or from a ⫺15 mm Hg to zero. The process of abolishing negative swings in ITP is potentially more clinically relevant than increasing ITP for many reasons. First, many pulmonary disease states are associated with exaggerated decreases in ITP during inspiration. For example, increased elastic or resistive loads will induce marked negative swings in ITP during spontaneous inspiration. In restrictive lung disease states, such as interstitial fibrosis or acute hypoxemic respiratory failure (lung collapse), for the same increase in lung volume, ITP must decrease much more than under normal conditions. Similarly, in obstructive diseases, such as vocal cord paralysis, laryngeal edema, or severe bronchospasm (asthma), similarly large decreases in ITP must occur to overcome the increased resistance to inspiratory airflow (42,54). Second, exaggerated decreases in ITP require increased
202
Pinsky
respiratory efforts that increase the work of breathing, taxing a potentially stressed heart and circulation. This is the proposed reason why respiratory distress is often associated with lactic acidosis in the absence of arterial hypoxemia. Finally, negative swings in ITP can only slightly increase venous blood flow because venous return rapidly becomes flow limited as the large veins collapse as they enter a markedly negative intrathoracic compartment from zero atmospheric pressure. The point at which negative swings in ITP induce venous flow limitation depends on the intravascular volume status, RV performance, and the rate of decrease in ITP. For most patients, however, flow limitation exists at ITP below ⫺10 cm H2O (113). Accordingly, further decreases in ITP, as commonly seen during forceful inspiratory efforts, will not increase venous blood flow further, but will continuously and progressively increase LV afterload. It follows therefore, that selectively abolishing markedly negative swings in ITP, without concomitantly increasing ITP above atmosphere, should disproportionally reduce LV afterload more than venous return (LV preload). This concept finds purchase in many clinical scenarios. For example, merely removing large upper airway obstruction by endotracheal intubation, without the addition of mechanical ventilation, will selectively reduce LV afterload. Similarly, by providing positive airway pressure to overcome the resistive pressure load of moving air into the lungs during severe bronchospasm in pressure-assisted modes of mechanical ventilation, one will also selectively abolish negative swings in ITP without inducing increases in ITP, which would otherwise impair venous return. Importantly, if hyperinflation were to also develop during this form of mechanical ventilatory support, then venous return would decrease owing to both the increase in ITP and the lung volume-related increase in pulmonary vascular resistance. In support of these complex but synergistic constructs, several clinical studies have demonstrated improved LV performance after the institution of positivepressure ventilation in patients with combined cardiovascular insufficiency and respiratory distress (104,146,173–175). Using similar logic, weaning patients from positive-pressure ventilation, by allowing the return of decreases in ITP, may precipitate acute LV failure and pulmonary edema in patients with borderline LV function (24,176), as described above in the section of this chapter on ‘‘Ventilation as Exercise.’’ Clearly, weaning is a form of cardiac stress testing, because LV loading invariably occurs in the transition from positive pressure to spontaneous ventilation. Following this logic to its conclusion, the institution of either CPAP or PEEP in patients with heart failure may further augment LV output by reducing LV afterload, despite the obligatory decrease in LV preload if the prior inspiratory decreases in ITP could be abolished (104,146,173–175,177).
VI. Clinical Trials of Different Forms of Mechanical Ventilation Based on the above discussion, it should be clear that depending on the baseline cardiovascular and respiratory state, markedly different hemodynamic effects can occur for the same type of ventilation, be that spontaneous or positive-pressure ventilation. Accordingly, no firm rules apply as to the specific response that will be seen
Hemodynamics of Ventilation
203
in all patients and under all conditions. However, some generalities are reasonable, and more importantly, the hemodynamic response to specific forms of ventilation and ventilatory maneuvers reflects baseline hemodynamic status. Thus, the physician can proceed with some degree of confidence in initiating specific forms of ventilatory support and can also use the response to such interventions to ascertain the hemodynamic state of the patient. Different modes of ventilatory support may be associated with differing degrees of patient comfort despite similar levels of external work (178). Accordingly, some differences reported between modes of ventilation during both maintenance ventilatory support and weaning reflect differences in patient effort and matching of patient effort with ventilatory support. To the extent that this matching is poor, the metabolic demand of that ventilatory support will be greater. Clearly, in patients with markedly increased work of breathing, hypervolemia, or impaired LV pump function, the institution of mechanical ventilatory support can be lifesaving because of its ability to decrease global O2 consumption, independent of any beneficial effects that mechanical ventilation may have on gas exchange. In contrast, in patients with decreased pulmonary elastic recoil (emphysema), increased pulmonary vascular resistance (pulmonary embolism or essential pulmonary hypertension), hypovolemia, or airflow obstruction (asthma and chronic bronchitis), the institution of mechanical ventilatory support may induce cardiovascular instability by markedly impairing both venous return and RV ejection. If not rapidly identified and corrected, such ventilatory strategies can lead to total cardiovascular collapse. Similarly, as stated above in the initial section of this chapter, withdrawal of ventilatory support invariably increases intrathoracic blood volume and LV afterload and can be used as a cardiovascular stress test. Patients who pass this test easily usually wean successfully from mechanical ventilatory support, whereas those who fail often are not ready to be weaned (176) or require supplemental inotropic support to sustain spontaneous ventilation (24). Although it is not known what percentage of patients fail weaning trials because of cardiovascular insufficiency, rather than gas exchange abnormalities, cardiovascular insufficiency must play a role in most patients who fail weaning trials because of the interaction between work of breathing and cardiac output. Identification of such patients early in the course of care may improve their outcome by directing supportive therapies toward cardiovascular as well as ventilatory endpoints. Realistically, multiple hemodynamic, pulmonary, and psychological factors are compounded to create any given cardiovascular situation, and the patient’s response to the initiation of ventilatory support or to weaning may vary. Thus, it is often difficult to single out the primary process determining cardiovascular instability. The caregiver is usually left with a series of diagnostic and therapeutic options. Viewed in this perspective, alterations in ventilatory support can be seen as a ‘‘ventilatory probe’’ of the patient’s cardiovascular status. A. Acute Lung Injury
As described above, spontaneous ventilation by decreasing ITP increases intrathoracic blood volume whereas positive-pressure ventilation by increasing ITP
204
Pinsky
decreases it (118). If PEEP increases lung volume, then it will also decrease intrathoracic blood volume further (139,143). However, unless marked contractile dysfunction exists, PEEP will not alter LV contractility (112). However, since the effect of positive-pressure ventilation is more a function of the increase in lung volume, not airway pressure, to the degree that tidal volume is maintained constant along with the percent inspiratory time, the two modes of ventilation will have similar cardiovascular effects. Likewise, to the degree that hyperinflation occurs, the hemodynamic effects of increased ITP, and potentially increased pulmonary vascular resistance will be exaggerated. In support of this concept Singer et al. (179) found that the degree of hyperinflation, not the airway pressure, determined the decrease in cardiac output in ventilator-dependent but hemodynamically stable patients. In preload-dependent patients such increases in ITP will also decrease cardiac output proportional to the decrease in LV end-diastolic volume (129,180). Thus, therapies aimed at restoring LV preload, such as fluid resuscitation (181–184) or lower-body compression (185), will return cardiac output to its baseline value even though the increased ITP and lung volume are maintained. If cardiac output does not return to basal levels following restoration of LV preload, then another diagnosis must be entertained as the cause of hemodynamic insufficiency. Common related processes that limit cardiac output in patients with acute lung injury include pulmonary hypertension, due to increased pulmonary vascular resistance, or cardiac tamponade, due to extrinsic cardiac compression from the hyperinflated lungs (186). While, if mechanical ventilation is associated with an increase in cardiac output, not only is venous return not the limiting factor in defining total blood flow in this patient, but processes such as increased pulmonary vascular resistance or LV afterload (impaired LV contractility) have been minimized (175,187). Several studies have examined the hemodynamic effects of different modes of mechanical ventilatory support in critically ill patients with acute lung injury. Since both forms of ventilatory support were used on each subject, differences in the determinants of the hemodynamic responses among subjects was minimized allowing one to truly compare ventilator modes. Most of the hemodynamic differences between different modes of mechanical ventilation can be explained by their effects on mean ITP. Thus, if two totally different modes of ventilation result in similar changes in ITP and ventilatory effort, then their hemodynamic effects are also similar. Some specific examples follow to illustrate this point. Lessard et al. (188) compared volume-controlled conventional ventilation with pressure-controlled and pressure-controlled inverse ratio ventilation (PCIRV) in nine patients with ARDS. Ventilator settings were adjusted to keep total PEEP and tidal volume consistent between treatment arms, thus minimizing changes in ITP among the three therapies. Although arterial pressure was slightly lower with PCIRV compared to the other treatments, no significant hemodynamic effects were seen. Similarly, when 10 patients with ARDS had their tidal volumes and total PEEP matched, PCIRV and volume-controlled ventilation had similar hemodynamic effects (189). However, when pressure-controlled with a smaller tidal volume was compared to volumecontrolled both Abraham and Yoshihara (190) and Poelaert et al. (191) found that
Hemodynamics of Ventilation
205
pressure-controlled ventilation was associated with higher cardiac outputs. This is a very important finding because it documents the superiority of pressure-limited ventilatory strategies that are associated with permissive hypercapnia over volumecontrolled ventilation aimed at sustaining normocapnia to maximize cardiac output in patients with acute lung injury. Furthermore, partial ventilatory support either using intermittent mandatory ventilation (IMV) or pressure-support ventilation gave similar hemodynamic responses (192) and levels of tissue oxygenation (193) when matched for similar tidal volumes. Finally, when very small tidal volumes are used, as in high-frequency jet ventilation as compared to volume-controlled ventilation, if mean airway pressure is matched, cardiac output is unchanged (194). B. Heart Failure
Patients in congestive heart failure demonstrate a marked reduction in their preload responsiveness and an increased impact of afterload in determining cardiac output. Thus, the observation that cardiac output does not decrease and often increases in response to increasing ITP by the application of positive-pressure ventilation and PEEP in patients with congestive heart failure should not be surprising. Indeed, several studies have shown just that. In patients with cardiogenic pulmonary edema, the addition of PEEP to improve oxygenation did not decrease cardiac output (177). Similarly, the addition of PEEP to patients with heart failure did not decrease cardiac output in another study, and in the subgroup of subjects with a pulmonary artery occlusion pressure in excess of 18 mm Hg, demonstrating volume overload, cardiac output actually increased (173). Rasanen et al. (175,195) carried this analysis even further, demonstrating that myocardial ischemia worsened in patients with acute myocardial infarction and cardiogenic pulmonary edema when levels of ventilatory support were progressively decreased and that this beneficial cardiac effect corresponded to abolishing the negative swings in ITP induced by spontaneous ventilatory efforts by CPAP therapy even if the spontaneous efforts were sustained (174). These data demonstrate that, although spontaneous ventilation is exercise and places increased metabolic load on the heart, it is the increased afterload induced by the negative swings in ITP that primarily increases myocardial O2 demand. These findings have been duplicated by several other groups since then. For example, DeHoyos et al. (196) applied CPAP to patients with either normal cardiac function or heart failure. Both 5 and 10 cm H2O CPAP progressively increased cardiac output and stroke volume in heart failure patients in whom baseline pulmonary artery occlusion pressure ⬎ 12 mm Hg, while cardiac output decreased in patients with normal cardiac function and those with heart failure but without an elevated pulmonary artery occlusion pressure. Again, the beneficial effects of CPAP on cardiac output was associated with a decrease in negative swings in esophageal pressure (as a surrogate marker of ITP) during spontaneous inspiration and a proportional increase in arterial systolic pressure (197). Finally, Lin et al. (198) studied 100 patients admitted for the diagnosis of acute cardiogenic pulmonary edema randomized to receive nasal O2 or CPAP during the initial 6 hours of treatment. They observed a significant reduction in shunt fraction and need for subsequent intubation, and an increase in cardiac output and SvO2 in the CPAP group.
206
Pinsky
Beach et al. (24) demonstrated that patients on mechanical ventilatory support with stable but limited cardiac reserve could not be weaned from the ventilator unless supplemental cardiovascular support was applied by the infusion of positive inotropes. Lemaire et al. (176) then demonstrated that withdrawal of ventilatory support could induce severe cardiac decompensation in otherwise stable patients with combined heart failure and acute respiratory failure secondary to chronic airway obstructions. These patients developed immediate and dramatic increases in pulmonary artery occlusion pressure not attributable to increased venous return alone, documenting that acute LV failure was the primary mechanism for the cardiovascular collapse seen during weaning in these patients. C. Chronic Obstructive Pulmonary Disease
Patients with chronic airflow obstruction may be even more compromised than other subjects because of their propensity to develop dynamic hyperinflation when they decompensate. This tendency to hyperinflation, owing to expiratory airflow limitation, makes apparently similar ventilatory modes markedly different in their tendency to destabilization despite minimal differences in tidal volume. This is because of either differences in expiratory time or patient-related variables related to comfort and breathing patterns. Although dynamic hyperinflation increases lung volume asymmetrically because different regions of the lung express different time constants, surprisingly dynamic hyperinflation alters hemodynamic function in a fashion similar to extrinsic PEEP. In support of this statement, matching extrinsic PEEP with intrinsic PEEP induces no measurable hemodynamic effects (199,200). However, once extrinsic PEEP levels exceed intrinsic PEEP, predictable reductions in RV end-diastolic volume and ejection fraction occur (201). There is little hemodynamic difference between increasing airway pressure to generate a breath by positive-pressure ventilation, and decreasing extrathoracic pressure (iron lung) by negative extrathoracic pressure ventilation (202). Thus, the following discussion is equally valid with all forms of mechanical ventilatory support including those not associated with endotracheal intubation. Since the level of intrinsic PEEP can vary from one breath to the next and by very large amounts over a few breaths, the application of this principal in the clinic is less clear (203). If the physician knew at a given point in time that the level of intrinsic PEEP in a patient was 15 cm H2O, for example, and based on this information he or she increased the level of extrinsic PEEP to this level to minimize the work-cost of spontaneous breathing, assuming that such an increase in extrinsic PEEP would not impair venous return, the subsequent hemodynamic effect may not be what is expected and its interpretation may be subject to error. If by altering the level of extrinsic PEEP the patient’s ventilatory pattern also changed, then the level of intrinsic PEEP might very well change and by a large amount. If that patient senses discomfort or increased resistance to spontaneous inspiration due to a poorly functioning PEEP value, then respiratory rate would probably increase, increasing intrinsic PEEP further. Similarly, if the patient had increased respiratory drive and
Hemodynamics of Ventilation
207
the extrinsic PEEP allowed for a more efficient respiratory effort, then tidal volume could increase markedly, also increasing intrinsic PEEP. Under either of these two scenarios, the physician would incorrectly conclude that this level of extrinsic PEEP exceeded the intrinsic PEEP level and would decrease extrinsic PEEP. Although in the latter example this would decrease tidal volume and reduce intrinsic PEEP, it would do so at a cost of alveolar ventilation and in the initial scenario, it would be inappropriate because it would only make ventilatory efforts less effective. On the other side, changes in ventilatory pattern can reduce intrinsic PEEP if a longer time is allowed for exhalation or if tidal volume decreases. For example, if the matching of extrinsic PEEP to intrinsic PEEP reduced patient effort during breathing, then the patient may very well decrease his or her tidal volume or respiratory rate, both of which would decrease intrinsic PEEP. However, since extrinsic PEEP was not changed, no hemodynamic benefit would be realized by this reduction in dynamic hyperinflation, unless the physician simultaneously decreased the level of extrinsic PEEP in parallel. However, if the application of increasing amounts of extrinsic PEEP in patients with chronic airflow obstruction does not alter any measured variable, including respiratory rate and tidal volume, then that level of extrinsic PEEP is probably below the intrinsic PEEP level at that moment. D. Cardiac Cycle-Specific Increases in ITP
Since LV filling and ejection do not occur at the same point in time, if the increases in ITP induced by positive-pressure ventilation were synchronized to occur at a specific point within the cardiac cycle and then delivered with each heartbeat, then the effects of increased ITP on venous return and LV ejection can be isolated (204). Briefly, when LV contractility is normal, although increases in ITP decreased venous return, these effects are minimized by synchronizing the increase in ITP to occur immediately before the aortic pressure upstroke once LV filling had occurred (204,205). Not surprisingly, this preload-sparing effect is accentuated in hypovolemic states (205). Furthermore, in heart failure, the augmentation of cardiac output appears to be optimal with increases in ITP synchronized with LV ejection (204). This systolic augmentation in heart failure is also seen when the impaired LV ejection is due to selective acute mitral regurgitation (206), endotoxemia (207), and in patients with congestive cardiomyopathy (208–213). The application of cardiaccycle-specific (synchronous) ventilation requires the use of a high-frequency ventilator and can be most easily accomplished using a jet ventilator. The beneficial effects of synchronous jet ventilation have even been seen in complex cardiovascular states, such as in a subject with end-stage liver failure, ARDS, and cardiovascular insufficiency. The improvement in cardiac output during systolic synchronous jet ventilation in that patient averaged 30% as compared to a nearly similar mean airway pressure and ventilatory frequency not in synchrony with the cardiac cycle (214). It follows, therefore, that if a patient is to be ventilated with a high-frequency jet ventilator, then the ventilator should be synchronized with early systole to optimize cardiovascular status and maintain adequate ventilation.
208
Pinsky E.
CPAP and Obstructive Sleep Apnea
As opposed to the immediate effects of ventilatory maneuvers on cardiac function in acutely ill patients, chronic CPAP therapy as applied in the treatment of patients with sleep apnea syndrome alters cardiac function primarily by changing humoral factors over a longer period of time. The humoral changes favor reduced reactive sympathetic tone and lessening salt and water retention, promoting improved LV ejection and diuresis, respectively. However, the relation between CPAP and obstructive sleep apnea is not simple, as discussed later in the volume, by Somers and O’Donnell. For example, Buckle et al. (215) studied the effects of nighttime nasal CPAP in eight patients with Cheyne-Stokes respiration and congestive heart failure using polysomonography, and they failed to see any hemodynamic benefit or change in breathing pattern. But Granton et al. (216) studied the effect of 3 months of nightly nasal CPAP on inspiratory muscle strength and LV ejection fraction in nine patients with heart failure and obstructive apnea compared to a control group of eight patients without nocturnal nasal CPAP. Both maximum inspiratory force and LV ejection fraction increased in the CPAP group but not the control group given oxygen. Similarly, patients receiving nocturnal nasal CPAP had reductions in serum and urinary norepinephrine levels, consistent with reduced cardiovascular stress (217). F. Use of Heart-Lung Interactions to Diagnose Cardiovascular Insufficiency
Studies by Perel et al. (218–220) suggest that the relation between ventilatory efforts and systolic arterial pressure may identify which patients may benefit from cardiac assist by increases in ITP and which patients may not. Patients who increase their systolic arterial pressure during ventilation in proportion to an apneic baseline tend to have a greater degree of volume overload (219) and heart failure (218) than subjects in whom systolic arterial pressure decreases. In parallel dog studies, these investigators have shown that normal and hypovolemic dogs decrease their systolic arterial pressure during positive-pressure ventilation, as compared to apneic values, whereas the same animals increase their systolic arterial pressure once volume resuscitated and placed in heart failure (220). It is not clear by what mechanism positive pressure produces these phasic changes in arterial pressure. However, recent data using echocardiographic signals to measure dynamic LV volume changes during ventilation show that these pressure changes are a direct manifestation of ITP transmission to the arterial circuit rather than proportional changes in LV stroke volume (221). VII. Conclusion The clinical application of heart-lung interactions is fraught with many uncertainties owing to the complex interactions that exist and the different baseline cardiac and respiratory status present in each patient. However, for an individual patient, most of these vagaries can by surpassed by breaking down those factors that alter venous
Hemodynamics of Ventilation
209
return, LV afterload, work of breathing, and hyperinflation. To the extent that these processes can be considered separately, reasonable predictions of the hemodynamic response to any form of ventilation is possible. In the future, using the hemodynamic response to specific forms of ventilation will become an accepted method for probing the cardiovascular status of a given patient.
References 1. Pinsky MR. The influence of positive-pressure ventilation on cardiovascular function in the critically ill. Crit Care Clin 1985; 1:699–717. 2. Pinsky MR. Hemodynamic effects of artificial ventilation. In: Snyder JV, ed. Oxygen Transport in the Critically Ill, Chicago: Year Book, 1986:319–332. 3. Pinsky MR. Effects of mechanical ventilation on the cardiovascular system. In: Tobin MJ, ed. Mechanical Ventilation. Orlando, FL: W.B. Saunders, 1990:663–678. 4. Miro A, Pinsky MR. Hemodynamic effects of mechanical ventilation. In: Grenvik A, Downs J, Rasanen J, Snow ND, eds. Contemporary Management in Critical Care; Mechanical Ventilation and Assisted Respiration: Past, Present, and Future. New York: Churchill Livingstone, 1991:73–90. 5. Pinsky, MR. Cardiopulmonary interactions: the effects of negative and positive pleural pressure changes on cardiac output. In: Dantzker D, ed. Cardiopulmonary Medicine and Critical Care. Philadelphia: W.B. Saunders, 1991:87–120. 6. Pinsky MR, Kramer D. The effects of intrathoracic pressure in cardiovascular performance. In: Tinker J, Zapol W, eds. Care of the Critically Ill. Berlin: Springer-Verlag, 1991:41– 58. 7. Miro A, Pinsky MR. Cardiopulmonary interactions. In: Fuhrman BP, Zimmerman JJ, eds. Pediatric Critical Care. St. Louis: Mosby Year Book, 1992:249–258. 8. Pinsky MR. Cardiopulmonary interactions. In: Abrams JH, Cerra FB, eds. Essentials of Surgical Critical Care. St. Louis: Quality Medical Publishing, 1993:276–283. 9. Pinsky MR. Heart-lung interactions. In: Pinsky MR, Dhainaut JF, eds. Pathophysiologic Foundations of Critical Care. Baltimore: Williams and Wilkins, 1993:472–490. 10. Pinsky MR. Heart-lung ventilator interactions, In: Marini JJ, Slutsky AS, eds. Physiological Basis of Ventilatory Support. New York: Marcel Dekker, 1998:491–531. 11. Miro AM, Pinsky MR. Heart-lung interactions. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. New York: McGraw-Hill, 1994:647–671. 12. Pinsky MR. Hemodynamic effects of artificial ventilation. In: Shoemaker WC, Ayres SM, Grenvik A, et al., eds. Textbook of Critical Care. Philadelphia: W.B. Saunders, 1995:911– 922. 13. Pinsky MR. Cardiovascular effects of ventilator support and withdrawal. Anesth Analg 1994; 79:567–576. 14. Permutt S, Wise RA, Brower RG. How changes in pleural and alveolar pressure cause changes in afterload and preload. In: Cassidy SS, Scharf SM, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:243–250. 15. Robotham JL, Peters J. Mechanical effects of intrathoracic pressure on left ventricular performance. In: Cassidy SS, Scharf SM, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:251–284. 16. Kaufman MP, Cassidy SS. Reflex effects of lung inflation and other stimuli on the heart and circulation. In: Cassidy SS, Scharf SM, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:339–364. 17. Scharf SM. Cardiovascular effects of positive pressure ventilation. J Crit Care 1992; 7: 268–279. 18. Goldberg HS, Rabson J. Control of cardiac output by systemic vessels. Circulatory adjustments of acute and chronic respiratory failure and the effects of therapeutic interventions. Am J Cardiol 1981; 47:696–702.
210
Pinsky
19. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982; 307:786–797. 20. Grenvik A. Respiratory, circulatory and metabolic effects of respiratory treatment. A clinical study in postoperative thoracic surgical patients. Acta Anaesthesiol 1966; suppl 122. 21. Shuey CBJ, Pierce AK, Johnson RLJ. An evaluation of exercise tests in chronic obstructive lung disease. J Appl Physiol 1969; 27:256–261. 22. Stock MC, David DW, Manning JW, Ryan ML. Lung mechanics and oxygen consumption during spontaneous ventilation and severe heart failure. Chest 1992; 102:279–283. 23. Kawagoe Y, Permutt S, Fessler HE. Hyperinflation with intrinsic PEEP and respiratory muscle blood flow. J Appl Physiol 1994; 77:2440–2448. 24. Beach T, Millen E, Grenvik. Hemodynamic response to discontinuance of mechanical ventilation. Crit Care Med 1973; 1:85–90. 25. Mitzner W, Gioia F, Weinmann GG, Robotham JL, Ehrlich W. Interaction between high frequency jet ventilation and cardiovascular function. Ann Biomed Eng 1987; 15:319– 329. 26. Richard C, Teboul JL, Archambaud F, Hebert JL, Michaut P, Auzepy P. Left ventricular function during weaning of patients with chronic obstructive pulmonary disease. Intensive Care Med 1994; 20:181–186. 27. Hurford WE, Lynch KE, Strauss HW, Lowenstein E, Zapol WM. Myocardial perfusion as assessed by thallium-201 scintigraphy during the discontinuation of mechanical ventilation in ventilator-dependent patients. Anesthesiology 1991; 74:1007–1016. 28. Hurford WE, Favorito F. Association of myocardial ischemia with failure to wean from mechanical ventilation. Crit Care Med 1995; 23:1475–1480. 29. Chatila W, Ani S, Guaglianone D, Jacob B, Amoateng-Adjepong Y, Manthous CA. Cardiac ischemia during weaning from mechanical ventilation. Chest 1996; 109:1577–1583. 30. Romand JA, Shi W, Pinsky MR. Cardiopulmonary effects of positive pressure ventilation during acute lung injury. Chest 1995; 108:1041–1048. 31. O’Quin RJ, Marini JJ, Culver BH, Butler J. Transmission of airway pressure to pleural space during lung edema and chest wall restriction. J Appl Physiol 1985; 59:1171–1177. 32. Pinsky MR, Guimond JG. The effects of positive end-expiratory pressure on heart-lung interactions. J Crit Care 1991; 6:1–11. 33. Novak RA, Matuschak GM, Pinsky MR. Effect of ventilatory frequency on regional pleural pressure. J Appl Physiol 1988; 65:1314–1323. 34. Gattinoni L, Mascheroni D, Torresin A, et al. Morphological response to positive end expiratory pressure in acute respiratory failure. Computerized tomography study. Intensive Care Med 1986; 12:137–142. 35. Globits S, Burghuber OC, Koller J, et al. Effect of lung transplantation on right and left ventricular volumes and function measured by magnetic resonance imaging. Am J Respir Crit Care Med 1994; 149:1000–1004. 36. Scharf SM, Ingram RHJ. Effects of decreasing lung compliance with oleic acid on the cardiovascular response to PEEP. Am J Physiol 1977; 233:H635–H641. 37. Pinsky MR, Vincent JL, De Smet JM. Estimating left ventricular filling pressure during positive end-expiratory pressure in humans. Am Rev Respir Dis 1991; 143:25–31. 38. Kingma I, Smiseth OA, Frais MA, Smith ER, Tyberg JV. Left ventricular external constraint: relationship between pericardial, pleural and esophageal pressures during positive end-expiratory pressure and volume loading in dogs. Ann Biomed Eng 1987; 15:331–346. 39. Tsitlik JE, Halperin HR, Guerci AD, et al. Augmentation of pressure in a vessel indenting the surface of the lung. Ann Biomed Eng 1987; 15:259–284. 40. Milic-Emili J, Mead J, Turner JM. Improved method for assessing the validity of the esophageal balloon technique. J Appl Physiol 1964; 19:207–211. 41. Marini JJ, Rodriguez RM, Lamb V. The inspiratory workload of patient-initiated mechanical ventilation. Am Rev Respir Dis 1986; 134:902–909. 42. Bromberger-Barnea B. Mechanical effects of inspiration on heart functions: a review. Fed Proc 1981; 40:2172–2177. 43. Wise RA, Robotham JL, Summer WR. Effects of spontaneous ventilation on the circulation. Lung 1981; 159:175–186. 44. Glick G, Wechsler AS, Epstein SE. Reflex cardiovascular depression produced by stimulation of pulmonary stretch receptors in the dog. J Clin Invest 1969; 48:467–473.
Hemodynamics of Ventilation
211
45. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev 1973; 53:159– 227. 46. Anrep GV, Pascual W, Rossler R. Respiratory variations in the heart rate. I. The reflex mechanism of the respiratory arrhythmia. Proc R Soc Lond B Biol Sci 1936; 119:191– 217. 47. Taha BH, Simon PM, Dempsey JA, Skatrud JB, Iber C. Respiratory sinus arrhythmia in humans: an obligatory role for vagal feedback from the lungs. J Appl Physiol 1995; 78: 638–645. 48. Bernardi L, Calciati A, Gratarola A, Battistin I, Fratino P, Finardi G. Heart rate–respiration relationship: computerized method for early assessment of cardiac autonomic damage in diabetic patients. Acta Cardiol 1986; 41:197–206. 49. Bernardi L, Keller F, Sanders M, et al. Respiratory sinus arrhythmia in the denervated human heart. J Appl Physiol 1989; 67:1447–1455. 50. Persson MG, Lonnqvist PA, Gustafsson LE. Positive end-expiratory pressure ventilation elicits increases in endogenously formed nitric oxide as detected in air exhaled by rabbits. Anesthesiology 1995; 82:969–974. 51. Cassidy SS, Eschenbacher WL, Johnson RLJ. Reflex cardiovascular depression during unilateral lung hyperinflation in the dog. J Clin Invest 1979; 64:620–626. 52. De Burgh D, Hazzledine JL, Ungar A. The reflex effects of alterations in lung volume on systemic vascular resistance in the dog. J Physiol (Lond) 1967; 188:331–351. 53. Shepherd JT. The lungs as receptor sites for cardiovascular regulation. Circulation 1981; 63:1–10. 54. Stalcup SA, Mellins RB. Mechanical forces producing pulmonary edema in acute asthma. N Engl J Med 1977; 297:592–596. 55. Vatner SF, Rutherford JD. Control of the myocardial contractile state by carotid chemoand baroreceptor and pulmonary inflation reflexes in conscious dogs. J Clin Invest 1978; 61:1593–1601. 56. Pick RA, Handler JB, Murata GH, Friedman AS. The cardiovascular effect of positive end-expiratory pressure. Chest 1982; 82:345–350. 57. Said SI, Kitamura S, Vreim C. Prostaglandins: Release from the lung during mechanical ventilation at large tidal ventilation. J Clin Invest 1972; 51:83a. 58. Bedetti C, Del Basso P, Argiolas L, Carpi A. Arachidonic acid and pulmonary function in heart-lung preparation of guinea-pig: modulation by PCO2. Arch Int Pharmacodyn Ther 1987; 285:98–116. 59. Berend N, Christopher KL, Voelkel NF. The effect of positive end-expiratory pressure on functional residual capacity: role of prostaglandin production. Am Rev Respir Dis 1982; 126:646–647. 60. Pattern MY, Liebman PR, Hetchman HG. Humorally mediated decreases in cardiac output associated with positive end-expiratory pressure. Microvasc Res 1977; 13:137–144. 61. Berglund JE, Halden E, Jakobson S, Svensson J. PEEP ventilation does not cause humorally mediated cardiac output depression in pigs. Intensive Care Med 1994; 20:360– 364. 62. Fuhrman BP, Everitt J, Lock JE. Cardiopulmonary effects of unilateral airway pressure changes in intact infant lambs. J Appl Physiol 1984; 56:1439–1448. 63. Payen DM, Brun-Buisson CJ, Carli PA, et al. Hemodynamic, gas exchange, and hormonal consequences of LBPP during PEEP ventilation. J Appl Physiol 1987; 62:61–70. 64. Farge D, De la Coussaye JE, Beloucif S, Fratacci MD, Payen DM. Interactions between hemodynamic and hormonal modifications during PEEP- induced antidiuresis and antinatriuresis. Chest 1995; 107:1095–1100. 65. Frass M, Watschinger B, Traindl O, et al. Atrial natriuretic peptide release in response to different positive end-expiratory pressure levels. Crit Care Med 1993; 21:343–347. 66. Wilkins MA, Su XL, Palayew MD, et al. The effects of posture change and continuous positive airway pressure on cardiac natriuretic peptides in congestive heart failure. Chest 1995; 107:909–915. 67. Shirakami G, Magaribuchi T, Shingu K, et al. Positive end-expiratory pressure ventilation decreases plasma atrial and brain natriuretic peptide levels in humans. Anesth Analg 1993; 77:1116–1121.
212
Pinsky
68. Brecher GA, Hubay CA. Pulmonary blood flow and venous return during spontaneous respiration. Circ Res 1955; 3:40–214. 69. Goldstein JA, Vlahakes GJ, Verrier ED, et al. The role of right ventricular systolic dysfunction and elevated intrapericardial pressure in the genesis of low output in experimental right ventricular infarction. Circulation 1982; 65:513–522. 70. Jardin F, Farcot JC, Boisante L, Curien N, Margairaz A, Bourdarias JP. Influence of positive end-expiratory pressure on left ventricular performance. N Engl J Med 1981; 304: 387–392. 71. Jardin F, Farcot JC, Gueret P, Prost JF, Ozier Y, Bourdarias JP. Echocardiographic evaluation of ventricles during continuous positive airway pressure breathing. J Appl Physiol 1984; 56:619–627. 72. Prec KJ, Cassels DE. Oximeter studies in newborn infants during crying. Pediatrics 1952; 9:756–761. 73. Luce JM. The cardiovascular effects of mechanical ventilation and positive end-expiratory pressure. JAMA 1984; 252:807–811. 74. Maughan WL, Shoukas AA, Sagawa K, Weisfeldt ML. Instantaneous pressure-volume relationship of the canine right ventricle. Circ Res 1979; 44:309–315. 75. Sibbald WJ, Driedger AA. Right ventricular function in acute disease states: pathophysiologic considerations. Crit Care Med 1983; 11:339–345. 76. Piene H, Sund T. Does normal pulmonary impedance constitute the optimum load for the right ventricle? Am J Physiol 1982; 242:H154–H160. 77. Pinsky MR. Determinants of pulmonary arterial flow variation during respiration. J Appl Physiol 1984; 56:1237–1245. 78. Johnston WE, Vinten-Johansen J, Shugart HE, Santamore WP. Positive end-expiratory pressure potentiates the severity of canine right ventricular ischemia-reperfusion injury. Am J Physiol 1992; 262:H168–H176. 79. Pinsky MR. Instantaneous venous return curves in an intact canine preparation. J Appl Physiol 1984; 56:765–771. 80. Sibbald WJ, Calvin J, Driedger AA. Right and left ventricular preload, and diastolic ventricular compliance: Implications of therapy in critically ill patients. In: Critical Care: State of the Art. Fullerton, CA: Society of Critical Care, 1982. 81. Sibbald WJ, Calvin JE, Holliday RL, Driedger AA. Concepts in the pharmacologic and nonpharmacologic support of cardiovascular function in critically ill surgical patients. Surg Clin North Am 1983; 63:455–482. 82. Buda AJ, Pinsky MR, Ingels NBJ, Daughters GT, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 301:453–459. 83. Madden JA, Dawson CA, Harder DR. Hypoxia-induced activation in small isolated pulmonary arteries from the cat. J Appl Physiol 1985; 59:113–118. 84. Hakim TS, Michel RP, Chang HK. Effect of lung inflation on pulmonary vascular resistance by arterial and venous occlusion. J Appl Physiol 1982; 53:1110–1115. 85. Quebbeman EJ, Dawson CA. Influence of inflation and atelectasis on the hypoxic pressor response in isolated dog lung lobes. Cardiovasc Res 1976; 10:672–677. 86. Brower RG, Gottlieb J, Wise RA, Permutt S, Sylvester JT. Locus of hypoxic vasoconstriction in isolated ferret lungs. J Appl Physiol 1987; 63:58–65. 87. Hakim TS, Michel RP, Minami H, Chang HK. Site of pulmonary hypoxic vasoconstriction studied with arterial and venous occlusion. J Appl Physiol 1983; 54:1298–1302. 88. Marshall BE, Marshall C. A model for hypoxic constriction of the pulmonary circulation. J Appl Physiol 1988; 64:68–77. 89. Marshall BE, Marshall C. Continuity of response to hypoxic pulmonary vasoconstriction. J Appl Physiol 1980; 49:189–196. 90. Dawson CA, Grimm DJ, Linehan JH. Lung inflation and longitudinal distribution of pulmonary vascular resistance during hypoxia. J Appl Physiol 1979; 47:532–536. 91. Howell JBL, Permutt S, Proctor DF, et al. Effect of inflation of the lung on different parts of the pulmonary vascular bed. J Appl Physiol 1999; 16:71–76. 92. West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 1964; 19:713–724.
Hemodynamics of Ventilation
213
93. Whittenberger JL, McGregor M, Berglung E, et al. Influence of state of inflation of the lung on pulmonary vascular resistance. J Appl Physiol 1999; 15:878–882. 94. Fuhrman BP, Smith-Wright DL, Kulik TJ, Lock JE. Effects of static and fluctuating airway pressure on intact pulmonary circulation. J Appl Physiol 1986; 60:114–122. 95. Lodato RF, Michael JR, Murray PA. Multipoint pulmonary vascular pressure–cardiac output plots in conscious dogs. Am J Physiol 1985; 249:H351–H357. 96. Lopez-Muniz R, Stephens NL, Bromberger-Barnea B, Permutt S, Riley RL. Critical closure of pulmonary vessels analyzed in terms of Starling resistor model. J Appl Physiol 1968; 24:625–635. 97. Grant BJ, Fitzpatrick JM, Lieber BB. Time-varying pulmonary arterial compliance. J Appl Physiol 1991; 70:575–583. 98. Thorvaldson J, Ilebekk A, Kiil F. Determinants of pulmonary blood volume. Effects of acute changes in airway pressure. Acta Physiol Scand 1985; 125:471–479. 99. Block AJ, Boysen PG, Wynne JW. The origins of cor pulmonale; a hypothesis. Chest 1979; 75:109–110. 100. Canada E, Benumof JL, Tousdale FR. Pulmonary vascular resistance correlates in intact normal and abnormal canine lungs. Crit Care Med 1982; 10:719–723. 101. Taylor RR, Covell JW, Sonnenblick EH, Ross JJ. Dependence of ventricular distensibility on filling of the opposite ventricle. Am J Physiol 1967; 213:711–718. 102. Brinker JA, Weiss JL, Lappe DL, et al. Leftward septal displacement during right ventricular loading in man. Circulation 1980; 61:626–633. 103. Marini JJ, Culver BH, Butler J. Mechanical effect of lung distention with positive pressure on cardiac function. Am Rev Respir Dis 1981; 124:382–386. 104. Brunwald E, Binion JT, Morgan WL, Sarnoff SJ. Alterations in central blood volume and cardiac output induced by positive pressure breathing and counteracted by metraminol (Aramine). Circ Res 1999; 5:670–675. 105. Butler J. The heart is in good hands. Circulation 1983; 67:1163–1168. 106. Novak R, Matuschak GM, Pinsky MR. Effect of positive-pressure ventilatory frequency on regional pleural pressure. J Appl Physiol 1988; 65:1314–1323. 107. Cassidy SS, Wead WB, Seibert GB, Ramanathan M. Changes in left ventricular geometry during spontaneous breathing. J Appl Physiol 1987; 63:803–811. 108. Hoffman EA, Ritman EL. Heart-lung interaction: effect on regional lung air content and total heart volume. Ann Biomed Eng 1987; 15:241–257. 109. Olson LE, Hoffman EA, Halden E, Jakobson S, Svensson J. Heart-lung interactions determined by electron beam X-ray CT in laterally recumbent rabbits. J Appl Physiol 1995; 78:417–427. 110. Cassidy SS, Robertson CHJ, Pierce AK, Johnson RLJ. Cardiovascular effects of positive end-expiratory pressure in dogs. J Appl Physiol 1978; 44:743–750. 111. Conway CM. Haemodynamic effects of pulmonary ventilation. Br J Anaesth 1975; 47: 761–766. 112. Berglund JE, Halden E, Jakobson S, Landelius J. Echocardiographic analysis of cardiac function during high PEEP ventilation. Intensive Care Med 1994; 20:174–180. 113. Guyton AC, Lindsey AW, Abernathy B, et al. Venous return at various right atrial pressures and the normal venous return curve. Am J Physiol 1999; 189:609–615. 114. Kilburn KH. Cardiorespiratory effects of large pneumothorax in conscious and anesthetized dogs. J Appl Physiol 1963; 18:279–283. 115. Chevalier PA, Weber KC, Engle JC, Gerasch DA, Fox IJ. Direct measurements of right and left heart outputs in a Valsalva-like maneuver in dogs. Proc Soc Exp Biol Med 1972; 139:1429–1437. 116. Guntheroth WC, Gould R, Butler J, et al. Pulsatile flow in pulmonary artery, capillary and vein in the dog. Cardiovasc Res 1974; 8:330–337. 117. Guntheroth WG, Morgan BC, Mullins GL. Effect of respiration on venous return and stroke volume in cardiac tamponade. Circ Res 1999; 20:381–390. 118. Guyton AC. Effect of cardiac output by respiration, opening the chest, and cardiac tamponade. In: Guyton AC, ed. Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: Saunders, 1967:378–386.
214
Pinsky
119. Holt JP. The effect of positive and negative intrathoracic pressure on cardiac output and venous return in the dog. Am J Physiol 1999; 142:594–603. 120. Morgan BC, Abel FL, Mullins GL, Guntheroth WG. Flow patterns in cavae, pulmonary artery, pulmonary vein, and aorta in intact dogs. Am J Physiol 1966; 210:903–909. 121. Morgan BC, Martin WE, Hornbein TF, Crawford EW, Guntheroth WG. Hemodynamic effects of intermittent positive pressure respiration. Anesthesiology 1966; 27:584–590. 122. Scharf SM, Brown R, Saunders N, Green LH. Hemodynamic effects of positive-pressure inflation. J Appl Physiol 1980; 49:124–131. 123. Scharf SM, Brown R, Saunders N, Green LH. Effects of normal and loaded spontaneous inspiration on cardiovascular function. J Appl Physiol 1979; 47:582–590. 124. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of positive end-expiratory pressure on the canine venous return curve. Am Rev Respir Dis 1992; 146:4–10. 125. Takata M, Robotham JL. Effects of inspiratory diaphragmatic descent on inferior vena caval venous return. J Appl Physiol 1992; 72:597–607. 126. Chihara E, Hashimoto S, Kinoshita T, Hirose M, Tanaka Y, Morimoto T. Elevated mean systemic filling pressure due to intermittent positive-pressure ventilation. Am J Physiol 1992; 262:H1116–H1121. 127. Takata M, Wise RA, Robotham JL. Effects of abdominal pressure on venous return: abdominal vascular zone conditions. J Appl Physiol 1990; 69:1961–1972. 128. Barnes GE, Laine GA, Giam PY, Smith EE, Granger HJ. Cardiovascular responses to elevation of intra-abdominal hydrostatic pressure. Am J Physiol 1985; 248:R208– R213. 129. Lichtwarck-Aschoff M, Zeravik J, Pfeiffer UJ. Intrathoracic blood volume accurately reflects circulatory volume status in critically ill patients with mechanical ventilation. Intensive Care Med 1992; 18:142–147. 130. Brienza N, Revelly JP, Ayuse T, Robotham JL. Effects of PEEP on liver arterial and venous blood flows. Am J Respir Crit Care Med 1995; 152:504–510. 131. Magder S, Georgiadis G, Cheong T. Respiratory variations in right atrial pressure predict the response to fluid challenge. J Crit Care 1992; 7:76–85. 132. Terada N, Takeuchi T. Postural changes in venous pressure gradients in anesthetized monkeys. Am J Physiol 1993; 264:H21–H25. 133. Scharf S, Tow DE, Miller MJ, Brown R, McIntyre K, Dilts C. Influence of posture and abdominal pressure on the hemodynamic effects of Mueller’s maneuver. J Crit Care 1989; 4:26–34. 134. Tarasiuk A, Scharf SM. Effects of periodic obstructive apneas on venous return in closedchest dogs. Am Rev Respir Dis 1993; 148:323–329. 135. Sha M, Saito Y, Yokoyama K, Sawa T, Amaha K. Effects of continuous positive-pressure ventilation on hepatic blood flow and intrahepatic oxygen delivery in dogs. Crit Care Med 1987; 15:1040–1043. 136. Richard C, Berdeaux A, Delion F, et al. Effect of mechanical ventilation on hepatic drug pharmacokinetics. Chest 1986; 90:837–841. 137. Dorinsky PM, Hamlin RL, Gadek JE. Alterations in regional blood flow during positive end-expiratory pressure ventilation. Crit Care Med 1987; 15:106–113. 138. Tyberg JV, Taichman GC, Smith ER, Douglas NW, Smiseth OA, Keon WJ. The relationship between pericardial pressure and right atrial pressure: an intraoperative study. Circulation 1986; 73:428–432. 139. Pinsky MR, Desmet JM, Vincent JL. Effect of positive end-expiratory pressure on right ventricular function in humans. Am Rev Respir Dis 1992; 146:681–687. 140. Jayaweera AR, Ehrlich W. Changes of phasic pleural pressure in awake dogs during exercise: potential effects on cardiac output. Ann Biomed Eng 1987; 15:311–318. 141. Grant BJ, Lieber BB. Compliance of the main pulmonary artery during the ventilatory cycle. J Appl Physiol 1992; 72:535–542. 142. Cournaud A, Motley HL, Werko L, et al. Physiologic studies of the effect of intermittent positive pressure breathing on cardiac output in man. Am J Physiol 1948; 152:162–174. 143. Harken AH, Brennan MF, Smith B, Barsamian EM. The hemodynamic response to positive end-expiratory ventilation in hypovolemic patients. Surgery 1974; 76:786–793. 144. Lores ME, Keagy BA, Vassiliades T, Henry GW, Lucas CL, Wilcox BR. Cardiovascular
Hemodynamics of Ventilation
145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169.
215
effects of positive end-expiratory pressure (PEEP) after pneumonectomy in dogs. Ann Thorac Surg 1985; 40:464–468. Sharpey-Schaffer EP. Effects of Valsalva maneuver on the normal and failing circulation. Br Med J 1955; 1:693–699. Peters J, Kindred MK, Robotham JL. Transient analysis of cardiopulmonary interactions. II. Systolic events. J Appl Physiol 1988; 64:1518–1526. Pinsky MR, Matuschak GM, Klain M. Determinants of cardiac augmentation by elevations in intrathoracic pressure. J Appl Physiol 1985; 58:1189–1198. Rankin JS, Olsen CO, Arentzen CE, et al. The effects of airway pressure on cardiac function in intact dogs and man. Circulation 1982; 66:108–120. Robotham JL, Rabson J, Permutt S, Bromberger-Barnea B. Left ventricular hemodynamics during respiration. J Appl Physiol 1979; 47:1295–1303. Ruskin J, Bache RJ, Rembert JC, Greenfield JCJ. Pressure-flow studies in man: effect of respiration on left ventricular stroke volume. Circulation 1973; 48:79–85. Janicki JS, Weber KT. The pericardium and ventricular interaction, distensibility, and function. Am J Physiol 1980; 238:H494–H503. Olsen CO, Tyson GS, Maier GW, Spratt JA, Davis JW, Rankin JS. Dynamic ventricular interaction in the conscious dog. Circ Res 1983; 52:85–104. Bell RC, Robotham JL, Badke FR, Little WC, Kindred MK. Left ventricular geometry during intermittent positive pressure ventilation in dogs. J Crit Care 1987; 2:230–244. Qvist J, Pontoppidan H, Wilson RS, Lowenstein E, Laver MB. Hemodynamic responses to mechanical ventilation with PEEP: the effect of hypervolemia. Anesthesiology 1975; 42:45–55. Denault AY, Gorcsan J III, Deneault LG, Pinsky MR. Effect of positive pressure ventilation on left ventricular pressure-volume relationship. Anesthesiology 1999; 79:A315. Pinsky MR, Summer WR, Wise RA, Permutt S, Bromberger-Barnea B. Augmentation of cardiac function by elevation of intrathoracic pressure. J Appl Physiol 1983; 54:950–955. Pinsky MR, Summer WR. Cardiac augmentation by phasic high intrathoracic pressure support in man. Chest 1983; 84:370–375. Blaustein AS, Risser TA, Weiss JW, Parker JA, Holman BL, McFadden ER. Mechanisms of pulsus paradoxus during resistive respiratory loading and asthma. J Am Coll Cardiol 1986; 8:529–536. Strohl KP, Scharf SM, Brown R, Ingram RHJ. Cardiovascular performance during bronchospasm in dogs. Respiration 1987; 51:39–48. Scharf SM, Graver LM, Balaban K. Cardiovascular effects of periodic occlusions of the upper airways in dogs. Am Rev Respir Dis 1992; 146:321–329. Viola AR, Puy RJ, Goldman E. Mechanisms of pulsus paradoxus in airway obstruction. J Appl Physiol 1990; 68:1927–1931. Scharf SM, Graver LM, Khilnani S, Balaban K. Respiratory phasic effects of inspiratory loading on left ventricular hemodynamics in vagotomized dogs. J Appl Physiol 1992; 73: 995–1003. Latham RD, Sipkema P, Westerhof N, Rubal BJ. Aortic input impedance during Mueller maneuver: an evaluation of ‘‘effective length.’’ J Appl Physiol 1988; 65:1604–1610. Virolainen J, Ventila M, Turto H, Kupari M. Effect of negative intrathoracic pressure on left ventricular pressure dynamics and relaxation. J Appl Physiol 1995; 79:455–460. Garpestad E, Parker JA, Katayama H, et al. Decrease in ventricular stroke volume at apnea termination is independent of oxygen desaturation. J Appl Physiol 1994; 77:1602–1608. Gomez A, Mink S. Interaction between effects of hypoxia and hypercapnia on altering left ventricular relaxation and chamber stiffness in dogs. Am Rev Respir Dis 1992; 146: 313–320. Abel FL, Mihailescu LS, Lader AS, Starr RG. Effects of pericardial pressure on systemic and coronary hemodynamics in dogs. Am J Physiol 1995; 268:H1593–H1605. Khilnani S, Graver LM, Balaban K, Scharf SM. Effects of inspiratory loading on left ventricular myocardial blood flow and metabolism. J Appl Physiol 1992; 72:1488–1492. Satoh S, Watanabe J, Keitoku M, Itoh N, Maruyama Y, Takishima T. Influences of pressure surrounding the heart and intracardiac pressure on the diastolic coronary pressure-flow relation in excised canine heart. Circ Res 1988; 63:788–797.
216
Pinsky
170. Beyar R, Goldstein Y. Model studies of the effects of the thoracic pressure on the circulation. Ann Biomed Eng 1987; 15:373–383. 171. Cassidy SS, Wead WB, Seibert GB, Ramanathan M. Geometric left-ventricular responses to interactions between the lung and left ventricle: positive pressure breathing. Ann Biomed Eng 1987; 15:285–295. 172. Scharf SM, Brown R, Warner KG, Khuri S. Intrathoracic pressures and left ventricular configuration with respiratory maneuvers. J Appl Physiol 1989; 66:481–491. 173. Grace MP, Greenbaum DM. Cardiac performance in response to PEEP in patients with cardiac dysfunction. Crit Care Med 1982; 10:358–360. 174. Rasanen J, Nikki P, Heikkila J. Acute myocardial infarction complicated by respiratory failure. The effects of mechanical ventilation. Chest 1984; 85:21–28. 175. Rasanen J, Vaisanen IT, Heikkila J, Nikki P. Acute myocardial infarction complicated by left ventricular dysfunction and respiratory failure. The effects of continuous positive airway pressure. Chest 1985; 87:158–162. 176. Lemaire F, Teboul JL, Cinotti L, et al. Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation. Anesthesiology 1988; 69:171–179. 177. Calvin JE, Driedger AA, Sibbald WJ. Positive end-expiratory pressure (PEEP) does not depress left ventricular function in patients with pulmonary edema. Am Rev Respir Dis 1981; 124:121–128. 178. Manning HL, Molinary EJ, Leiter JC. Effect of inspiratory flow rate on respiratory sensation and pattern of breathing. Am J Respir Crit Care Med 1995; 151:1–7. 179. Singer M, Vermaat J, Hall G, Latter G, Patel M. Hemodynamic effects of manual hyperinflation in critically ill mechanically ventilated patients. Chest 1994; 106:1182– 1187. 180. Hartmann M, Rosberg B, Jonsson K. The influence of different levels of PEEP on peripheral tissue perfusion measured by subcutaneous and transcutaneous oxygen tension. Intensive Care Med 1992; 18:474–478. 181. Dhainaut JF, Devaux JY, Monsallier JF, Brunet F, Villemant D, Huyghebaert MF. Mechanisms of decreased left ventricular preload during continuous positive pressure ventilation in ARDS. Chest 1986; 90:74–80. 182. Huemer G, Kolev N, Kurz A, Zimpfer M. Influence of positive end-expiratory pressure on right and left ventricular performance assessed by Doppler two-dimensional echocardiography. Chest 1994; 106:67–73. 183. Jardin F. PEEP and ventricular function. Intensive Care Med 1994; 20:169–170. 184. Goertz A, Heinrich H, Winter H, Deller A. Hemodynamic effects of different ventilatory patterns. A prospective clinical trial. Chest 1991; 99:1166–1171. 185. Gunter JP, deBoisblanc BP, Rust BS, Johnson WD, Summer WR. Effect of synchronized, systolic, lower body, positive pressure on hemodynamics in human septic shock. A pilot study. Am J Respir Crit Care Med 1995; 151:719–723. 186. Schuster S, Erbel R, Weilemann LS, et al. Hemodynamics during PEEP ventilation in patients with severe left ventricular failure studied by transesophageal echocardiography. Chest 1990; 97:1181–1189. 187. Abel JG, Salerno TA, Panos A, et al. Cardiovascular effects of positive pressure ventilation in humans. Ann Thorac Surg 1987; 43:198–206. 188. Lessard MR, Guerot E, Lorino H, Lemaire F, Brochard L. Effects of pressure-controlled with different I:E ratios versus volume- controlled ventilation on respiratory mechanics, gas exchange, and hemodynamics in patients with adult respiratory distress syndrome. Anesthesiology 1994; 80:983–991. 189. Chan K, Abraham E. Effects of inverse ratio ventilation on cardiorespiratory parameters in severe respiratory failure. Chest 1992; 102:1556–1561. 190. Abraham E, Yoshihara G. Cardiorespiratory effects of pressure controlled ventilation in severe respiratory failure. Chest 1990; 98:1445–1449. 191. Poelaert JI, Visser CA, Everaert JA, Koolen JJ, Colardyn FA. Acute hemodynamic changes of pressure-controlled inverse ratio ventilation in the adult respiratory distress syndrome. A transesophageal echocardiographic and Doppler study. Chest 1993; 104:214–219. 192. Dries DJ, Kumar P, Mathru M, et al. Hemodynamic effects of pressure support ventilation in cardiac surgery patients. Am Surg 1991; 57:122–125.
Hemodynamics of Ventilation
217
193. Sternberg R, Sahebjami H. Hemodynamic and oxygen transport characteristics of common ventilatory modes. Chest 1994; 105:1798–1803. 194. Bayly R, Sladen A, Guntupalli K, Klain M. Synchronous versus nonsynchronous highfrequency jet ventilation: effects on cardiorespiratory variables and airway pressures in postoperative patients. Crit Care Med 1987; 15:915–917. 195. Rasanen J. Respiratory failure in acute myocardial infarction. Appl Cardiopulm Pathophys 1999; 2:271–279. 196. De Hoyos A, Liu PP, Benard DC, Bradley TD. Haemodynamic effects of continuous positive airway pressure in humans with normal and impaired left ventricular function. Clin Sci (Colch) 1995; 88:173–178. 197. Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995; 91:1725–1731. 198. Lin M, Yang YF, Chiang HT, Chang MS, Chiang BN, Cheitlin MD. Reappraisal of continuous positive airway pressure therapy in acute cardiogenic pulmonary edema. Short-term results and long-term follow-up. Chest 1995; 107:1379–1386. 199. Ranieri VM, Giuliani R, Cinnella G, et al. Physiologic effects of positive end-expiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis 1993; 147:5–13. 200. Ambrosino N, Nava S, Torbicki A, et al. Haemodynamic effects of pressure support and PEEP ventilation by nasal route in patients with stable chronic obstructive pulmonary disease. Thorax 1993; 48:523–528. 201. Baigorri F, de Monte A, Blanch L, et al. Hemodynamic responses to external counterbalancing of auto-positive end- expiratory pressure in mechanically ventilated patients with chronic obstructive pulmonary disease. Crit Care Med 1994; 22:1782–1791. 202. Ambrosino N, Cobelli F, Torbicki A, et al. Hemodynamic effects of negative-pressure ventilation in patients with COPD. Chest 1990; 97:850–856. 203. Pinsky MR. Through the past darkly: ventilatory management of patients with chronic obstructive pulmonary disease. Crit Care Med 1994; 22:1714–1717. 204. Pinsky MR, Matuschak GM, Bernardi L, Klain M. Hemodynamic effects of cardiac cyclespecific increases in intrathoracic pressure. J Appl Physiol 1986; 60:604–612. 205. Matuschak GM, Pinsky MR, Klain M. Hemodynamic effects of synchronous high-frequency jet ventilation during acute hypovolemia. J Appl Physiol 1986; 61:44–53. 206. Stein KL, Kramer DJ, Killian A, Pinsky MR. Hemodynamic effects of synchronous high-frequency jet ventilation in mitral regurgitation. J Appl Physiol 1990; 69:2120– 2125. 207. Guimond JG, Pinsky MR, Matuschak GM. Effect of synchronous increase in intrathoracic pressure on cardiac performance during acute endotoxemia. J Appl Physiol 1990; 69:1502– 1508. 208. Pinsky MR, Marquez J, Martin D, Klain M. Ventricular assist by cardiac cycle-specific increases in intrathoracic pressure. Chest 1987; 91:709–715. 209. Robotham JL, Stuart RS, Borkon AM, Doherty K, Baumgartner W. Effects of changes in left ventricular loading and pleural pressure on mitral flow. J Appl Physiol 1988; 65:1662– 1675. 210. Beyar R, Halperin HR, Tsitlik JE, et al. Circulatory assistance by intrathoracic pressure variations: optimization and mechanisms studied by a mathematical model in relation to experimental data. Circ Res 1989; 64:703–720. 211. Beyar R, Sideman S, Dinnar U. Cardiac assist by intrathoracic and abdominal pressure variations: a mathematical study. Med Biol Eng Comput 1984; 22:507–515. 212. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of systolic and diastolic positive pleural pressure pulses with altered cardiac contractility. J Appl Physiol 1992; 73:498– 505. 213. Fessler HE, Brower RG, Wise RA, Permutt S. Mechanism of reduced LV afterload by systolic and diastolic positive pleural pressure. J Appl Physiol 1988; 65:1244–1250. 214. Angus DC, Lidsky NM, Dotterweich LM, Pinsky MR. The influence of high-frequency jet ventilation with varying cardiac-cycle specific synchronization on cardiac output in ARDS. Chest 1997; 112:1600–1606.
218
Pinsky
215. Buckle P, Millar T, Kryger M. The effect of short-term nasal CPAP on Cheyne-Stokes respiration in congestive heart failure. Chest 1992; 102:31–35. 216. Granton JT, Naughton MT, Benard DC, Liu PP, Goldstein RS, Bradley TD. CPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1996; 153:277–282. 217. Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995; 152:473–479. 218. Baeaussier M, Coriat P, Perel A, et al. Determinants of systolic pressure variation in patients ventilated after vascular surgery. J Cardiothorac Vasc Anesth 1995; 9:547–551. 219. Coriat P, Vrillon M, Perel A, et al. A comparison of systolic blood pressure variations and echocardiographic estimates of end-diastolic left ventricular size in patients after aortic surgery. Anesth Analg 1994; 78:46–53. 220. Szold A, Pizov R, Segal E, Perel A. The effect of tidal volume and intravascular volume state on systolic pressure variation in ventilated dogs. Intensive Care Med 1989; 15:368– 371. 221. Denault AY, Gasior TA, Gorcsan J, Mandarino WA, Deneault LG, Pinsky MR. Determinants of aortic pressure variation during positive-pressure ventilation in man. Chest 1999; 116:176–186.
9 Homeostasis of Exercise Gas Exchange Coupling of Pulmonary and Cardiovascular Function to Cellular Respiration During Exercise
KARLMAN WASSERMAN and WILLIAM W. STRINGER University of California at Los Angeles School of Medicine Torrance, California
I.
Introduction
The major immediate role of the cardiovascular and ventilatory systems is to support cellular respiration (O2 consumption and CO2 production). The ability of the cardiovascular and ventilatory systems to respond adequately to the exercise stress is a measure of their functional competence or ‘‘health.’’ Figure 1 shows a schematic representation of the cardiovascular and ventilatory coupling to muscle respiration. To perform exercise normally, the production of chemical energy in the form of adenosine triphosphate (ATP) depends primarily on homeostatic mechanisms that transport O2 from the lungs to the tissues. The primary stimulus for this appears to come from muscle metabolism because the cardiovascular and ventilatory responses to exercise are predictable, based on the changes in metabolic rate. Because the circulation can not respond as quickly as muscle contraction can be activated, a reserve of chemical energy in the form of phosphocreatine (Cr⬃P) exists in the muscle, making instant movements possible. In addition, there are small O2 stores in the form of oxymyoglobin in muscles that can be used for aerobic regeneration of high-energy phosphate bonds (⬃P) in the form of adenosine triphosphate (ATP). Later in exercise, if the O2 supply is inadequate to regenerate ⬃P aerobically, exercise time can be extended by producing ATP from anaerobic glycolysis with a net increase in muscle (1–4) and arterial blood lactate (1,2,5–7). 219
220
Wasserman and Stringer
Figure 1 Scheme illustrating the gas transport mechanisms for coupling pulmonary (external) to cellular (internal) respiration. The gears represent the functional interdependence of the physiological components of the system (peripheral circulation, heart, blood, pulmonary ˙ O ) and CO2 produccirculation, lungs) that couple the increase in muscle O2 consumption (Q 2 ˙ CO ) to O2 uptake (V ˙ O ) and CO2 output (V ˙ CO ) at the lungs. In the steady-state, V ˙O ⫽ tion (Q 2 2 2 2 ˙ QO2. Ventilation (tidal volume (VT ) ⫻ breathing frequency (f)) increases in relation to the ˙ CO ) arriving at the lungs and the drive to achieve arterial CO2 and newly produced CO2 (Q 2 hydrogen ion homeostasis. Creatine phosphate (Creat⬃PO4 ) and pyruvate (Pyr) to lactate (Lac) in the muscle gear represent anaerobic sources of high-energy phosphate not directly reflected by lung gas exchange. (From Ref. 33.)
The exercise energetic demands of muscle contraction provoke the greatest stimulus to the human respiratory apparatus. Since both the cardiovascular and ventilatory systems must respond to the same increase in cellular respiration, it would be desirable for the circulatory and ventilatory control mechanisms to be linked to each other as well as to cellular respiration, as illustrated in Figure 1. Lack of a coupled control of peripheral blood flow to muscle respiration would either overperfuse the tissues relative to their metabolic requirement or underperfuse them. The former would impose more than normal demands on cardiac work. The latter would impair the rate of the aerobic regeneration of high energy phosphate bonds during exercise. This will induce a lactic acidosis and shorten exercise duration (8). On the lung side of the circulation, underventilation relative to perfusion would result in arterial hypoxemia and hypercap˙ ), and shift ˙ A /Q nia with respiratory acidosis (low alveolar ventilation to perfusion, V of the oxyhemoglobin curve to the right. While overventilation would result in need˙) ˙ A /Q lessly high arterial PO2 values, hypocapnia with a respiratory alkalosis (high V and a left-shifted oxyhemoglobin (O2 Hb) dissociation curve. The ventilatory and circulatory control mechanisms do not allow these changes in acid-base balance to occur in normal subjects. However diseases of the lungs (9) or heart (10–13) may prevent normal coupling of these organs to metabolism during exercise. Despite the fact that the mechanism for coupling of the circulation and ventilation to metabolism is still poorly understood, it is difficult to deny that the circulatory
Homeostasis of Exercise Gas Exchange
221
and the ventilatory responses to exercise are closely coupled to the metabolic rate (Fig. 1). Thus the size of the cardiac output increase is consistently related to O2 consumption (14,15), but upregulated by reduced arterial O2 content. Similarly, ventilation increases in response to exercise in proportion to the increase in CO2 production (16), which is modulated further by the size of the dead space ventilation (13,17) and the need to provide ventilatory compensation if a lactic acidosis supervenes. The remarkably consistent and efficient regulation of muscle venous and arterial PO2 and PCO2 leads one to conclude that the metabolic processes in the muscles, in some way, control the cardiac output and alveolar ventilation. This chapter has both a general and specific objective. The general objective is to identify basic normal physiological responses to exercise that are so consistent that they could be incorporated into our general thought processes when interpreting the integrated cardiorespiratory responses to exercise in humans. The specific objective is to discuss the mechanism(s) of reduced exercise performance in patients with lung diseases. II. Coupling of Circulation to Muscle Metabolism A. Cellular Respiration and Muscle Bioenergetics
Splitting of the terminal phosphate bond of ATP provides the energy for the conformational change in actin and myosin that constitutes muscle contraction (18). Exercise utilizes three sources of ATP: that derived from aerobic metabolism of substrate (mitochondrial respiration), that obtained during the hydrolysis of phosphocreatine (Cr⬃P), and that resulting from anaerobic glycolysis with lactic acid as a byproduct. Each source plays a different role in enabling exercise to be performed. Mitochondrial Respiration
The majority of ⬃P regenerated in the mitochondria is related to the renewal of ATP from adenosine diphosphate (ADP), inorganic phosphate and the energy derived from substrate oxidation. This energy results from proton and electron transport down the energy levels in the electron transport chain and ultimately to atomic oxygen (Fig. 2). These reactions result in the consumption of oxygen and the formation of water. About five-sixths of the substrate for these energy generating reactions is from carbohydrate, mostly glycogen in the muscle cells (Fig. 2, pathway A) and the remainder from fatty acids. During aerobic glycolysis (Fig. 2, pathway A), 3 ATP are generated in the breakdown of a glycosyl component of glycogen to pyruvate and 2 ATP when glucose is the substrate. Because the cytosolic NADH⫹H⫹, formed during aerobic glycolysis, is oxidized by the proton shuttle in the mitochondrial membrane and eventually by mitochondrial oxidative coenzymes and oxygen, there is no change in the cytosolic redox state, lactate/pyruvate ratio, or significant net lactate accumulation. In the steady state of exercise, aerobic metabolism is the only source of ATP. Thus O2 transport by the cardiorespiratory system provides all the O2 required. The O2 stores in the blood are largely depleted by the first minute of exercise except for
222
Wasserman and Stringer
Figure 2 Pathways of aerobic and anaerobic glycolysis. During aerobic glycolysis (pathway A), cytosolic NADH⫹H⫹ is reoxidized by mitochondrial membrane shuttles, mitochondrial coenzymes, the electron transport chain and O2. During anaerobic glycolysis (pathway B), pyruvate reoxidizes cytosolic NADH⫹H⫹ to NAD⫹ with net lactate production. Since lactate does not accumulate for exercise below the lactic acidosis (anaerobic) threshold (LAT), glycolysis takes place aerobically. Above LAT work rates, lactate concentration increases relative to pyruvate, indicating a change in cytosolic redox state and an increase in NADH⫹H⫹ /NAD⫹ ratio as shown in the lower insert on the right side of the figure. FFA, free fatty acid; Lac, lactate; Pyr, pyruvate; TCA, tricarboxylic acid; k, equilibrium coefficient. (From Ref. 37.)
Homeostasis of Exercise Gas Exchange
223
that due to the Bohr effect when work is performed above the lactic acidosis (anaerobic) threshold (19). In this condition, pyruvate (Fig. 2, pathway B), rather than the proton shuttle, reoxidizes cytosolic NADH⫹H⫹ to NAD⫹, thereby sustaining glycolysis with a lowered redox state. However, there is a net increase in NADH⫹H⫹ / NAD⫹ reflected in an increase in lactate/pyruvate ratio (20,21) and net increase in lactic acid production in the muscle cell (2,22). This results in an increase in arterial ˙ o2 of the onset of tissue anaerobiosis (6). The lactate and lactate/pyruvate at the V H⫹ from anaerobic metabolism shifts the oxyhemoglobin (O2 Hb) dissociation curve to the right, allowing more O2 to unload from O2 Hb at a given PO2 (discussed below) (19,23). The delivery of sufficient atmospheric O2 for ATP regeneration in the muscle is dependent on the ability of the circulation to transport O2 from the lungs at the rate required by the active muscles (Figure 1). Phosphocreatine
At the start of exercise, the ATP consumed at the myofibril is regenerated from (Cr⬃P) (24). The latter serves to shuttle high-energy phosphate (⬃P) from mitochondrial ATP, the site of aerobic ⬃P generation, to cytosolic ATP, the site of its consumption (Fig. 3). It also serves as a source of ⬃P for the rapid regeneration of cytosolic ATP. Thus as the rate of ATP consumption increases, the ratio of Cr⬃P to creatine in the cytosol decreases. The increase in creatine concentration facilitates the translocation of ⬃P from the mitochondrion to the myofibril (24). The ⬃P stores in the form of Cr⬃P are limited in the muscle (approximately 16 to 35 mmol/L muscle water ⫽ ⬃P derived from consumption of 60 to 130 mL O2 from mitochondrial respiration) (3). Cr⬃P concentration changes very rapidly ˙ O ) (25). at the start of exercise with similar dynamics to the increasing O2 uptake (V 2 Thus, the net contribution of Cr⬃P to muscle bioenergetics is complete by the time ˙ O reaches a steady state (⬍3 min for moderate intensity exercise). The greater V 2 consumption of Cr⬃P, the larger is the O2 deficit (25,26). The alkaline reaction
Figure 3 Scheme by which creatine phosphate (Cr⬃P) shuttles high energy phosphate (⬃P) between adenosine triphosphate (ATP) in the mitochondrion and the cytosol of the myocyte. Creatine phosphate also serves as a buffer source of ⬃P for the immediate availability of cytosolic ATP for contraction of the myofibril. In the mitochondrion, the consumption of one molecule of oxygen by electron transport regenerates approximately 6 ATP. (From Ref. 83.)
224
Wasserman and Stringer
accompanying the splitting of phosphocreatine to neutral creatine and inorganic phosphate (27,28) is thought to account for a major part of the increase in tissue CO2 stores at the start of exercise (28). Anaerobic Glycolysis (Pathway B, Fig. 2)
Cr⬃P decreases to its steady-state value during the early O2 deficit period of exercise. If O2 transport and body O2 stores are inadequate to supply O2 for mitochondrial respiration to satisfy the total ATP requirement for exercise, after [Cr⬃P] stabilizes, anaerobic glycolysis can be used to supplement aerobic glycolysis to regenerate ATP. In this process, pyruvate reoxidizes cytosolic NADH⫹H⫹ to NAD⫹. As a result of this reaction, pyruvate is converted to lactate and lactate/pyruvate ratio increases (Fig. 2, pathway B). Consumption of 22.4 mL O2 begets 6 mmol of ATP during aerobic glycolysis. Because 2 mmol of lactate is generated from 1 mmol of glucose or glycosyl during anaerobic glycolysis, with production of 2 or 3 mmol ATP (depending on whether glycogen or glucose is the substrate), for a deficit of O2 transport of 22.4 mL/min during exercise, 4 or 6 mmol/min lactate will accumulate to obtain 6 mmol of ATP, anaerobically. This relatively small deficit in O2 uptake is difficult to detect by gas exchange measurements, although Koike et al. (29) have shown it to be measurable. ˙ O at the onset of lactate accumulation and HCO3⫺ buffering of the exerThe V 2 ˙ O ) at which anaerocise-induced lactic acidosis (30,31,32) identifies the work rate (V 2 bic glycolysis (pathway B, Fig. 2) begins to supplement aerobic glycolysis (pathway ˙ O at A, Fig. 2) or the anaerobic threshold (AT) (32). It can be measured as the V 2 which lactate and lactate/pyruvate systematically increase as work rate increases (6). But more easily, it could be determined, noninvasively, by a plot of simultaneous ˙ CO vs V ˙ O . When the slope of this plot changes to a value of ⬎ measurements of V 2 2 ˙ O (v-slope method of Beaver et al. (32)). This change ˙ CO is increasing faster than V 1, V 2 2 ˙ O that is consistent in repeated in slope can be seen to occur at a sharply defined V 2 tests. Its importance is that the ability to sustain exercise at a work rate above the AT is foreshortened, a true steady state is not achievable, and the physiological responses to exercise are different in many aspects, as described elsewhere (33). ˙ O at the onset of anaerobic glycolysis. Two As defined above, AT is the V 2 additional terms are used to describe the same phenomenon, the terminology de˙O pending on the method of measurement. Lactate threshold (LT) describes the V 2 at which lactate concentration increases, reflecting the onset of anaerobic glycolysis. ˙ O at which metabolic acidosis develLactic acidosis threshold (LAT ) describes the V 2 ops reflecting the increase in H⫹ concentration accompanying the lactate increase. In support of the concept that the lactic acidosis of exercise results from tissue hypoxia is the observation that the muscle lactate/pyruvate ratio (3,22,34), a measure of the cell redox state (changes in proportion to the cytosolic NADH⫹H⫹ /NAD⫹ ratio), increases at the lactate threshold. This same phenomenon has been observed to take place in the arterial blood of man (7). The cytosolic NADH⫹H⫹ /NAD⫹ ratio is regulated by the mitochondrial redox state through the mitochondrial membrane shuttles (a-glycerol phosphate and malate-aspartate). These feed electrons and pro-
Homeostasis of Exercise Gas Exchange
225
tons directly to mitochondrial coenzymes, as illustrated in Figure 2, pathway A. Only mechanisms that limit the reoxidation of mitochondrial coenzymes would result in increases in cytosolic NADH⫹H⫹ /NAD⫹ and lactate/pyruvate ratios. As would be predicted, patients with deficiencies in coenzymes that catalyze the reoxidation of mitochondrial NADH⫹H⫹ to NAD⫹, develop a lactic acidosis at inappropriately low work rates in a pattern similar to that found in patients with heart failure (35). B. V˙O2 as a Function of Increasing Work Rate
The rate of the aerobic regeneration of ATP in response to exercise is reflected by ˙ O . The number of molecules of ATP regenerated from each the rate of increase in V 2 molecule of oxygen consumed is well established, being slightly higher for carbohydrate (⬃ 6 or 6.18, the latter if glycogen rather than glucose is the substrate) than fatty acids (⬃ 5.65). The rate of O2 consumption to perform a given power output aerobically is also well-characterized, averaging approximately 10 mL/min/watt (Fig. 4) or 2.7 mmol ATP/min/watt, regardless of the degree of fitness, age, or gender of the subject (36,37). C. Effect of Exercise Above the Anaerobic Threshold on Exercise Gas Exchange
If the blood supply is inadequate to maintain the capillary PO2 needed to perform exercise totally aerobically, anaerobic glycolysis will be stimulated with the
Figure 4 Effect of progressively increasing work rate during cycle ergometer exercise on ˙ O response in normal subjects is reproducible for cycle ergome˙ O for 17 normal subjects. The V V 2 2 ter work regardless of age, gender, or training. The average regression slope and standard deviation for the 17 subjects is given in the figure. The slope is consistent among subjects but is displaced upward depending on the body weight (5.8 mL/min/kg (84,47)). (From Ref. 83.).
226
Wasserman and Stringer
accumulation of lactic acid (37). Simultaneously, anaerobic glycolysis and lactate release by the muscles will accelerate (10,28). Since lactic acid is highly dissociated (⬎99.9%) at the pH of cell water, the H⫹ must be immediately buffered in the cell as it is formed. Because HCO3⫺ is the primary buffer of the increased cellular H⫹, H2CO3 is formed at the same rate that lactate accumulates (Fig. 5). Because H2CO3 dissociates rapidly into CO2 and H2O, CO2 production by the cell increases over that predicted from the rate of aerobic metabolism (Fig. 5).
Figure 5 Gas exchange during aerobic (A) and aerobic plus anaerobic (B) exercise. The net increase in cellular lactic acid production requires buffering on its formation, predominantly by bicarbonate (HCO3⫺). The latter mechanism increases the CO2 production of the cell by approximately 22.3 mL/mmol of HCO3⫺ buffering lactic acid. The increase in cell lactate and decrease in cell HCO3⫺ results in chemical concentration gradients causing lactate to be transported out of and HCO3⫺ to be transported into the cell. (From Ref. 33.)
Homeostasis of Exercise Gas Exchange
227
Arterial blood lactate and HCO3⫺ change reciprocally and approximately stoichiometrically in response to exercise above the subject’s LAT (16,38–41). The increase in CO2 output over that predicted from aerobic metabolism has been shown to occur simultaneously with the development of lactic acidosis (32,42,43). This is the basis of the v-slope method for determining the AT as described above. An inadequate cardiovascular response to exercise resulting in a low AT is accompanied by relatively slow O2 uptake kinetics (44–46). ˙ O max is approached, a larger fraction of the regenerated ATP is derived As V 2 from anaerobic metabolism (29,37,47). By experimentally reducing the O2 supply to exercising muscles in normal subjects (increasing the carboxyhemoglobin ˙ O at submaxi˙ O , and the V (COHb) in blood), Koike et al. found that the AT, peak V 2 2 mal above AT exercise were reduced in proportion to the increase in COHb (29)and ˙ O kinetics were slowed (48). that V 2 D. Femoral Venous and Arterial pH, Standard HCO3ⴚ, Lactate, PCO2, and PO2 Changes in Response to Exercise
Figure 6 shows the simultaneous change in arterial and femoral venous, pH, standard ˙ O max) and heavy (85% V ˙ O max) HCO3⫺, lactate, PCO2, and PO2 for moderate (40% V 2 2 exercise. A vertical dashed line is drawn at 30 sec to illustrate the relative stability of femoral venous PCO2 , lactate, and increase in femoral vein pH with increase in standard HCO3⫺ during this very early period of exercise. The mechanism for the femoral venous increase in HCO3⫺ and pH during the first 30 sec of exercise was previously addressed (28), and attributed to the metabolic alkalosis resulting from the early hydrolysis of Cr⬃P. This constancy in femoral venous PCO2 takes place despite a simultaneous decrease in PO2. Particularly evident during heavy exercise, femoral venous PO2 starts to decrease soon after the beginning of exercise, reaching a constant value by 40 sec. For moderate intensity exercise, it took about 11/2 to 2 min for femoral venous PCO2 and pH to become constant, while there is stability in the arterial measurements. This contrasts with heavy work rate exercise during which femoral venous pH fell prominently during the first 2 min due to the continued release of lactate and CO2 as HCO3⫺ buffered the newly produced lactic acid. The rate of decrease in femoral venous pH slowed as PCO2 in femoral venous blood stopped increasing, and started to decrease. After 2 min, arterial and femoral venous pH decreased in parallel fashion. Particularly noteworthy is that femoral venous and arterial lactate and standard HCO3⫺ were virtually the same during moderate exercise. In contrast, femoral venous lactate started to increase before arterial lactate and maintained a higher value during the entire 6 min of heavy exercise, demonstrating continued lactate release by the exercising muscles. It is of interest that femoral venous standard HCO3⫺ slowed its rate of decrease relative to arterial at about 21/2 min. This suggests the introduction of alkali into the plasma of venous blood, possibly from the red cells secondary to the chloride shift, i.e., as HCO3⫺ increases in red cells consequent to the addition of CO2 to capillary blood, plasma chloride exchanges for red cell HCO3⫺.
Figure 6 Simultaneous change in arterial and femoral venous blood pH, standard (Std) ˙ O max) and heavy (85% V ˙ O max) exercise. HCO3⫺, lactate, PCO2 and PO2 for moderate (40% V 2 2 A vertical dashed line is drawn at 30 sec to illustrate the relative stability of femoral venous PCO2 with decrease in PO2 , slight alkalization of pH with increase in Std HCO3⫺. The metabolic alkalosis in femoral venous blood within the first 30 sec of exercise is not reflected in the arterial blood. Femoral venous PO2 measurements decrease to a constant value within 40 sec for both work rates. Femoral venous PCO2 remains constant for the first 30 s of exercise for both levels of work. For moderate work, femoral venous PCO2 and pH become constant by about 11/2 to 2 min. This contrasts with the heavy work rate exercise during which pH continues to decrease due to the continued net production of lactic acid. See text for further discussion of changes and mechanisms.
Homeostasis of Exercise Gas Exchange
229
E. Critical Capillary PO2 (ccPO2 ): Theoretical Considerations
Isolated mitochondria can respire and rephosphorylate ADP to ATP at a PO2 of 1 mm Hg or less (49). However, to sustain muscle mitochondrial respiration during exercise, the capillary PO2 must be appreciably ⬎ 1 mm Hg for O2 to diffuse from the red cell to the sarcoplasm. Wittenberg and Wittenberg (50) estimated this PO2 to be between 15 and 20 mm Hg. It was termed the ‘‘critical’’ capillary PO2 (ccPO2 ) because it represents the lowest capillary PO2 that allows the muscle mitochondria to receive the O2 required to perform exercise aerobically. In an organ such as skeletal muscle, where the metabolic rate increases faster than the blood flow, the end-capillary or femoral venous PO2 progressively decreases as the metabolic rate increases (e.g., Fig. 6). At the metabolic rate at which the capillary PO2 becomes diffusion limited (‘‘critical’’), the capillary PO2 will have fallen to a value below which it cannot overcome the diffusive resistance between the capillary and mitochondria for aerobic regeneration of ATP. The diffusive resistance is determined by the medium for diffusion and the physical distance between red cells in the muscle capillary (O2 source) and the muscle mitochondria or myoglobin (O2 sink). From the arterial Po2 , the concentration of hemoglobin, the shape of the oxyhemoglobin dissociation curve, and the Bohr effect, the fall in capillary PO2 through the muscle capillary bed can be predicted for various blood flow/metabolic rate ˙ m/V ˙ O m), as illustrated in Figure 7. This model assumes a hemoglobin ratios (Q 2 concentration of 15 g/dL, arterial PO2 ⫽ 90 mm Hg, the rate of O2 consumption along the capillary bed to be constant, and the Bohr effect limited to the CO2 produced as a result of aerobic metabolism. Given these parameters, each liter of blood ˙ m/V ˙ O m of 5 would result in complete extraction will contain 200 mL O2. Thus, a Q 2 of O2 from the blood if the ccPO2 could fall to zero. Of course this is impossible. Because not all of the O2 can be extracted from the capillary blood, the maximal extraction being about 85%, the blood flow to the legs must be at least 6 L/min to ˙ O ⫽ 1 L/min, aerobically. The blood flow requirement perform a work task with a V 2 is even higher in patients with arterial hypoxemia, anemia, carboxyhemoglobinemia, or a hemoglobinopathy with a left-shifted oxyhemoglobin dissociation curve. ˙ m/V ˙ O m needed to perform work totally aerobically is determined by The Q 2 the ccPO2 , i.e., the lowest PO2 needed to provide the diffusion pressure for overcoming the diffusive resistance to satisfy the muscle O2 requirement. Because the ccPO2 ˙ m/ must be above the mitochondrial PO2 for O2 to diffuse from capillary to cell, a Q ˙ O m ⫽ 5 must result in anaerobic metabolism and a net increase in lactic acid V 2 production in cells toward the venous end of the capillary bed. The ccPO2 can be reached any place along the capillary bed without a change in the femoral venous ˙ m/V ˙ O m ⫽ 5, 4, and 3 in Figure 7. Of course, PO2 , as illustrated by the curves for Q 2 the mean capillary PO2 would be progressively decreased despite no change in muscle venous effluent PO2. However, more of the muscle would be functioning anaero˙ m/V ˙ O m muscle units. Provided that bically with an increasing proportion of low Q 2 ˙ ˙ O m were uniform, a ratio of 6 would be required to sustain muscle aerobic the Qm/V 2 metabolism. This is the minimal ratio of blood flow to muscle O2 consumption for
230
Wasserman and Stringer
Figure 7 Model of muscle capillary O2 partial pressure (Po2) as blood travels from artery to vein. The model assumes hemoglobin concentration of 15 g/dL, arterial Po2 of 90 mm Hg, and a linear O2 consumption along the capillary. The rate of fall of capillary Po2 depends ˙ m)/muscle V ˙ O m) ratio. The curves include a Bohr effect ˙ O (V on the muscle blood flow (Q 2 2 due to a respiratory CO2 production. The capillary Po2 is heterogeneous along the capillary ˙ m/V ˙ O m. The end-capillary Po2 cannot decrease below the bed even with a homogenous Q 2 ˙ m/V ˙ O m ⬍ 6 will have increased critical capillary Po2. Any muscle unit with a theoretical Q 2 anaerobic metabolism and lactate production. See text for application of model. (From Ref. 37.)
the capillary PO2 to remain at or above the ccPO2 of 15 mm Hg estimated by Wit˙ m/V ˙ O m ratios, the closer the tenberg and Wittenberg (50). The more uniform the Q 2 femoral venous PO2 would represent the lowest capillary PO2. ˙ m/V ˙ O m ratio muscle units would result in inefficient A mix of high and low Q 2 O2 transport because some muscle units with low ratios would have to function ˙ m/V ˙ O m would be overperfused. As partially anaerobically, and some with high Q 2 ˙ m/V ˙ O increased, the femoral vein would contain more blood from the high Q ˙Om V 2 2 muscle unit. Thus the femoral venous PO2 might be expected to increase with ˙ m/V ˙ O m ratio muscle units. Because this does not appear to occur in normal uneven Q 2 ˙ m/V ˙ O m ratios in exercising muscles are quite uniform subjects, it is likely that the Q 2 with a value of about 6 for work rates below the AT. This value coincides with the observation that the cardiac output increase in response to exercise is 6 L/min/L ˙ O (14). It is also of interest to note that the lower, shallow part of the O2 Hb dissociV 2
Homeostasis of Exercise Gas Exchange
231
ation curve becomes prominent just below 15 mm Hg. Thus, decreasing the capillary PO2 to below this level would provide relatively little gain in O2 for the muscle but at a relatively large expense of decreasing diffusion-driving pressure. The capillary PO2 must be heterogeneous, even if there were a single ‘‘ideal’’ blood flow/metabolic rate ratio in the muscle. This is because the blood enters the muscle with a PO2 ⫽ 90 mm Hg (in a normal subject at sea level), and leaves the capillary bed at a PO2 which is approximately equal to that of the femoral vein. That the ccPO2 was reached should be evident experimentally, by the failure of end capillary or femoral venous PO2 to decrease further despite increasing work rate ˙O. and V 2 Measurement of Critical Capillary PO2 Normal Subjects
To determine the ccPO2 in normal subjects, 10 healthy adults were studied with femoral vein and arterial catheters, five during progressively increasing and five during two levels of constant work rate leg cycling exercise, one below and one above the lactic acidosis threshold (LAT ). During progressively increasing work rate in the normal subjects, femoral vein blood PO2 reached a ‘‘floor’’ or lowest value in the middle of the subjects’ work capacities and before lactate concentration started to increase (Fig. 8) (19).
Figure 8 Average (five normal subjects) femoral vein oxygen tension (Po2) (left panel), oxyhemoglobin saturation (O2 Hb sat’n) (middle panel), and lactate concentration (right panel) ˙ O max. Vertical dashed line indicates during increasing work rate exercise in ramp pattern to V 2 the average lactic acidosis threshold (LAT) determined by gas exchange using the v-slope method (32). Vertical bars indicate standard error of mean values at rest, the LAT, and ˙ O max , but ˙ O max . There is no significant difference between the Po2 values from the LAT to V V 2 2 the O2 Hb sat’n decreased significantly above the LAT. (From Ref. 19.)
232
Wasserman and Stringer
To investigate further the hypothesis that femoral vein PO2 reaches a ‘‘floor’’ value (ccPO2) by the time the LAT was reached, five normal subjects performed two constant work rate exercise tests for 6 min, one at a moderate work rate (40% of ˙ O ⫽ 1.76 L/min) and one at a heavy work rate (85% of ˙ O max, avg ⫽ 113 W, V V 2 2 ˙ VO2max, avg ⫽ 265 W, Vo2 ⫽ 3.36 L/min). These tests were done with a high rate of sampling of femoral vein blood (every 5 sec during the first 2 min and then every 30 sec for 4 min) in order to obtain good resolution of the kinetics of PO2 , O2 Hb, and pH change, and an accurate measure of the minimal femoral vein PO2. The results of these studies are shown in Figure 9. The femoral vein PO2 reached the same floor value at about 40 sec after the start of exercise for both moderate and heavy work intensities (Fig. 9A). The femoral venous PO2 did not change significantly for the remainder of the 6-min exercise period, despite the large difference ˙ O . In contrast to PO2 , O2 Hb saturation continued to decrease past in work rate and V 2 the time when the femoral vein (end-capillary) PO2 became constant (Fig. 9B). A striking difference can be seen in the pH changes for the moderate and heavy exercise (Fig. 9C). Hartley et al. (51) also found that femoral vein PO2 reached a nadir during moderate work and that the increased O2 extraction from the capillary blood at higher work rates could be accounted for by increased blood acidification. Heart Failure Patients
Koike et al. (52) studied the femoral vein PO2 changes during leg cycling exercise in 10 patients with stable chronic heart failure. Each patient performed three exercise protocols—a progressively increasing work rate test in ramp pattern, a moderate intensity constant work rate (CWR) exercise test (80% of LAT), and a heavy intensity CWR exercise test (the LAT plus 50% of the difference between the LAT and
Figure 9 Femoral venous Po2 , oxyhemoglobin saturation (O2 Hb Sat’n), and pH as related to time of exercise for two constant work rate tests, one below (open circles) and one above (closed circles) LAT. Data are averages of five subjects. Below- and above-LAT work rates averaged 113 and 265 W, respectively. Note that O2 Hb sat’n is lower during the higherintensity exercise despite identical PO2 values. (From Ref. 19.)
Homeostasis of Exercise Gas Exchange
233
˙ O max). In all 10 subjects, femoral vein PO2 fell to its lowest value in the middle, V 2 ˙ O of the subjects’ aerobic capacities (Fig. 10). The changes and not at the highest V 2 in femoral venous and ccPO2 were highly reproducible in each subject performing the three different protocols. In five of the subjects, the PO2 (and O2 Hb saturation) ˙ O increased Fig. 10, right column). While this finding seems actually increased as V 2 paradoxical, its reproducibility in a given subject, as seen in Figure 10, attests to the reliability of the phenomenon. The remaining five subjects decreased their femoral
Figure 10 Femoral vein oxygen partial pressure (PO2) plotted as a function of oxygen ˙ O ) during two constant work rate tests of moderate and heavy intensity and an uptake (V 2 incremental (ramp) exercise test for 10 patients with chronic heart failure. Numbers correspond to patients described in the original report. Femoral vein PO2 rapidly decreased toward ˙ O . After the femoral vein PO2 reached its nadir, it increased a minimal value with increasing V 2 ˙ O (right column), but was unchanged for the other five in five patients despite increasing V 2 patients (left column). Arrows show the lactic acidosis threshold (LAT) determined non-invasively by the v-slope method during the incremental exercise test. (From Ref. 52.)
234
Wasserman and Stringer
vein PO2 to a constant level in the mid work rate range of their work capacity (Fig. 10, left column), similar to that of the normal subjects (Figs. 8, 9). An arrow is drawn ˙ O equal to the LAT determined by the v-slope method (32). in Figure 10 at the V 2 When the LAT was reached, the femoral vein PO2 had reached its lowest value. The ˙ O , signifies failure for the femoral vein PO2 to decrease further, despite an increasing V 2 that O2 flow into the muscle cells had become diffusion limited (ccPO2 had been ˙ O is O2 transport dependent (29). reached). Thus, for work rates above this level, V 2 Change in Femoral Venous Lactate Concentration at the Critical Capillary PO2 Normal Subjects
To determine the relationship between the ccPO2 and the increase in femoral venous lactate released from the exercising muscles, we plotted the femoral venous blood lactate concentration against the simultaneous femoral venous PO2 for both the progressively increasing and constant work rate exercise tests for each subject (Fig. 11). These studies show that femoral venous lactate concentration did not increase until the femoral venous and therefore the end-capillary PO2 reached its lowest value. Thereafter femoral venous lactate increased without a further fall in femoral venous PO2. Thus lactate release takes place from exercising muscle after the ccPO2 is reached.
Figure 11 Femoral vein lactate as function of femoral vein Po2 for incremental (ramp) exercise in five normal subjects (left panel) and 10 constant work rate exercise tests (five below and five above the LAT) in five normal subjects (right panel). The highest Po2 values are where exercise starts. Different symbols represent different subjects. (From Ref. 19.)
Homeostasis of Exercise Gas Exchange
235
Heart Failure Patients
To estimate the femoral venous PO2 at which femoral venous lactate concentration started to increase, the femoral venous lactate concentration was plotted against its respective PO2 value for each exercise protocol for each patient shown in Figure 10. As for the normal subjects, lactate concentration did not increase until the lowest PO2 had been reached in the femoral vein (Fig. 12). This provides further evidence that the lactate concentration increased after the critical capillary PO2 was reached.
Figure 12 Relationship between femoral vein lactate and oxygen partial pressure (PO2) for each exercise test for each patient shown in Figure 10. Each patient performed three tests, a progressively increasing work rate test in ‘‘ramp’’ pattern, and moderate- and heavy-intensity constant work rate tests. The highest PO2 values are where exercise starts. Femoral vein lactate increased after femoral vein PO2 reached its lowest value. After reaching the minimum value, PO2 was unchanged in five and increased in five patients. (From Ref. 52.)
236
Wasserman and Stringer
˙ O in patients Figure 13 Lowest femoral vein PO2 (critical capillary PO2) versus peak V 2 with chronic heart failure (CHF) and fit normal subjects. Linear regression lines were calculated for each group. (From Ref. 85.) For the patients, r ⫽ .70 (P ⫽ .01). For the normal subjects, r ⫽ .86 (P ⫽ .06). (From Refs. 19, 52.)
ccPO2 in Normal Subjects and in Patients with Stable Chronic Heart Failure
The ccPO2 ranged between 16 and 23 mm Hg for the normal subjects and from 14 to 20 mm Hg for the CHF patient group (Fig. 13). It was positively correlated with ˙ O /kg in the patient group and negatively correlated in the normal subjects. the peak V 2 From Fick’s Law of Diffusion,a this finding suggests that those patients who reach ˙ O . It also illustrates that their ccPO2 at a lower work rate have a lower maximal V 2 the ccPO2 can be at a lower level if the mass flow of O2 is reduced, as predicted ˙ O m and the PO2 gradient in the Fick equation by the direct proportionality between V 2 for diffusion. In contrast, normal fit subjects had a lower ccPO2 , the higher the peak ˙ O . This is possible only if there is an increase in capillary diffusion area and/or V 2 shorter diffusion path for O2 with increasing fitness. Despite the few subjects (5 normals and 10 patients), the different direction of the regressions for the patients and the physically fit subjects suggests that capillary recruitment is used much more effectively in normal subjects. F. Pattern of Capillary Recruitment: Diffusion-Limited and Non-Diffusion-Limited
˙ O increase and end-capillary Applying Fick’s Law of Diffusion to the pattern of V 2 PO2 change during exercise, non-diffusion-limited and diffusion-limited musclecapillary recruitment in response to exercise can be analyzed. By definition, a non˙ O while capillary PO2 is simultaneously dediffusion-limited state is increasing V 2 creasing, assuming that myocyte and mitochondrial PO2 did not decrease faster than capillary PO2. In contrast, a diffusion-limited state is one in which end capillary
Homeostasis of Exercise Gas Exchange
237
˙ O . The only mechanism to account PO2 decreases no further despite increasing V 2 ˙ for the increase in VO2 while end-capillary PO2 decreases is an increase in muscle capillarity (increase in capillary surface area [A] and decrease in diffusion distance [L], i.e., increase in A/L). Once the ccPO2 had been reached, capillary recruitment must account for the increase in O2 transport into cells (diffusion-limited capillary recruitment). From Fick’s Law of Diffusion, the product of the diffusion coefficient (D) ˙ O and P(c-m)O2 , as shown in and A/L is the slope of the relationship between V 2 ˙ O as a function of P(c-m)O2 are shown Figure 14. Generalized plots of exercise V 2
˙ O as a function of femoral vein PO2 in a normal subject and heart failure Figure 14 V 2 patients taken from the left (HF I) and right (HF II) columns of Figure 10. Assuming that mitochondrial respiration is taking place with myocyte mitochondrial PO2 near its lowest level (⬃ 1 mm Hg), then the femoral vein PO2 describes the change in capillary mitochondrial PO2 difference P(c-m)O2. From Fick’s law of diffusion, the slopes radiating from the origin are the product of the diffusion coefficient for O2 (D) and the capillary surface area (A) for ˙ O increases while femoral vein diffusion divided by the diffusion distance (L). Initially, V 2 and end-capillary PO2 decreases showing that O2 transport to the myocyte is not diffusion limited. However, in both normal subjects and patients, the PO2 stops decreasing despite ˙ O showing that O2 movement into the myocyte has become diffusion limited. increasing V 2 The normal subjects maintain the same partial pressure over a range of work rates. Thus, ˙ O is increasing by capillary recruitment (increasing A/L). The femoral vein PO2 falls to a V 2 ˙ O . The femoral vein PO2 remains similar minimal PO2 in the patients but at a reduced V 2 ˙ O by relatively constant in heart failure patient HF-I (left column of Fig. 10), increasing V 2 recruitment (increasing A/L). In heart failure patient HF-II (right column of Fig. 10), end ˙ O , remaining on approximately the same A/L isocapillary PO2 increases with increasing V 2 pleth. Thus this type of heart failure patient appears to be unable to recruit microcirculation ˙ O . The arrowin response to exercise, having to rely on increasing capillary PO2 to increase V 2 heads indicate the direction of change.
238
Wasserman and Stringer
for normal subjects and patients with heart failure in Figure 14, based on the data ˙ O increases, PO2 decreases, changing in the shown in figures 8 to 10. Initially V 2 opposite direction to that expected if O2 were diffusion limited. When femoral ve˙ O continues to increase, O2 nous PO2 , and therefore P(c-m)O2 stops decreasing as V 2 transfer to the myocyte has become diffusion limited. The plot of the typical normal subject showed considerable non-diffusionlimited capillary recruitment (Fig. 14). In contrast, the heart failure patients showed relatively little non-diffusion-limited capillary recruitment with two different patterns of change. These are defined as HF I and HF II based on the two patterns of ˙ O increased reported in Figure 10. The HF I curve femoral venous PO2 change as V 2 describes the group whose femoral venous PO2 remained constant after reaching its lowest value. The HF II curve describes the pattern in which femoral vein PO2 ˙ O . In both patterns, femoral venous PO2 initially deincreased despite increasing V 2 ˙ O increased, showing early non-diffusion-limited capillary recruitment. creased as V 2 ˙ O by increasing D ⫻ A/L, although Above the ccPO2 , the HF I group increased V 2 this recruitment was much less than that for the normal subject. Above the ccPO2 , ˙ O in a quasi-proportional pattern to the patients in the HF II group increased their V 2 increase in femoral venous (end-capillary) PO2. Thus the relationship followed Fick’s Law of Diffusion, revealing that D ⫻ A/L or muscle capillarity is relatively ˙O. fixed despite increasing V 2 ˙ O , and lactate The finding of an increase in femoral venous PO2 as work rate, V 2 increased in 5 of the 10 heart failure patients needs explanation. If additional capil˙ O , capillary PO2 must increase to inlary bed could not be recruited to increase V 2 ˙ O . To achieve this increase in capillary PO2 , blood flow through the same crease V 2 ˙ O m ratios capillary bed must increase. Alternatively, inhomogeneity in the Qm/V 2 (Fig. 7) as work of the exercising muscles increased, could explain the paradoxical increase in femoral vein PO2. However, the latter mechanism will not result in an ˙O. increase in V 2 The observation in the normal subjects and the patients, showing that the lowest femoral venous PO2 did not occur at the peak work rate, but rather in the midrange of work capacity, should caution investigators from assuming that the lowest femoral venous PO2 (and O2 Hb saturation) occurs at the maximum work rate. Also, a single measurement of femoral venous PO2 can not predict the critical capillary PO2. G. Mechanism of Oxyhemoglobin (O2Hb) Dissociation Above the LAT
From figure 9, O2 Hb dissociation decreases rapidly for the first minute and then more slowly for the next 1 to 2 min before O2 Hb saturation reaches a constant value, for work rates below the LAT. The change after 1 min followed the decrease in pH. For the work rate above the LAT , the decrease in O2 Hb saturation was much more marked and sustained for the entire 6 min of exercise. The femoral venous desaturation that was not accounted for by the decrease in PO2 , could be completely accounted for by the pH decrease, which of course was much more marked for the work rate above the LAT (Fig. 9, right panel). To illustrate this in a more conven-
Homeostasis of Exercise Gas Exchange
239
tional way, the data shown in Figure 9 were replotted with femoral venous O2 Hb saturation against the independently measured femoral venous PO2 (Fig. 15). The lower part of the O2 Hb dissociation curves for various physiological pH values were overlaid on these data. Two very important points should be noted: (1) the decrease in O2 Hb saturation not accounted for by a decrease in PO2 could be accounted for by the decrease in measured pH (Fig. 9, right panel); (2) the decrease in O2 Hb saturation from 25% to 13% can be accounted for by the Bohr effect (acidification of the capillary blood) (right panel, Fig. 15). For exercise above the LAT, capillary blood acidification is the only mechanism for O2 Hb dissociation. The mechanism for the striking acidification of the muscle capillary blood for work rates accompanying the exercise lactic acidosis is shown by a plot of the simultaneous change in femoral venous PCO2 and HCO3⫺ as a function of femoral venous PO2 (Fig. 16). Since the increase in intracellular lactic acid concentration is buffered by intracellular HCO3⫺, both the extra CO2 generated from intracellular HCO3⫺ and the consumption of extracellular HCO3⫺ by the cells serve to acidify the capillary blood of the muscles producing lactate (Fig. 16). While arterial HCO3⫺ has been shown in a number of studies to be coupled to the lactate increase, not so clearly shown in previous studies is the striking increase in femoral venous PCO2 without a decrease in PO2 above the LAT (Fig. 16). This results from the release of CO2 from cells as intracellular HCO3⫺ buffers newly produced lactic acid (Fig. 5) after the ccPO2 had been reached.
Figure 15 Changing femoral vein oxyhemoglobin saturation (O2 Hb Sat’n; see Fig. 9B) as a function of femoral vein Po2 (Fig. 9A) for the 6-min constant work rate exercise tests shown in Figure 9. Superimposed are the lower part of oxyhemoglobin dissociation curves for pH values of 7.0–7.4. Panel A: Data for below LAT. Panel B: Data for above LAT exercise. Start of exercise is where O2 Hb Sat’n is highest. Femoral vein O2 Hb Sat’n progressively decreased as exercise continued, as shown in Figure 9. O2 Hb Sat’n fell on pH isopleths, in agreement with measured pH (Fig. 9C). This indicates that the entire decrease in O2 Hb saturation that takes place after Po2 reaches its lowest value can be accounted for by Bohr effect. (From Ref. 37.)
240
Wasserman and Stringer
Figure 16 Femoral vein (end-capillary) Pco2 and HCO3⫺ as a function of end-capillary Po2 during constant work rate heavy exercise. Values are the average for the same five normal subjects shown in Figure 15. Values at the start of exercise are at the right and move leftward ˙ O increases. (From Ref. 85.) as V 2
H. Lactic Acidosis in the Respiratory Adaptation to Heavy Work
From the dependency of normal extraction of O2 from muscle capillary bed on the lactic acidosis during heavy exercise, the lactic acidosis can be viewed as a respiratory adaptation to facilitate cellular respiration and oxidative metabolism under conditions of relatively high O2 requirement. In this respect, it is of interest that patients with muscle enzyme disorders that prevent lactate from increasing normally in re˙ O and arterial-venous sponse to exercise (53,54), have an abnormally reduced peak V 2 ˙ O2 difference (C(a-v¯)O2) at their maximally tolerated VO2. In contrast, the C(a-v¯)O2 is not abnormally low in patients with carnitine palmotoyl transferase deficiency, a muscle enzyme defect that does not impair development of an exercise lactic acidosis (54).
III. Coupling of Ventilation to Circulatory Gas Exchange Gas exchange at the airways can be used to measure gas exchange at the cells except for short periods during which transient changes in circulatory or ventilatory gas transport are dissociated from cellular respiration. This dissociation is determined by characteristics of the control mechanisms. Coupling of ventilation to circulatory gas exchange and cellular respiration is reflected in the changes seen in gas exchange kinetics at the airway in response to constant work rate exercise.
Homeostasis of Exercise Gas Exchange
241
A. Exercise Gas Exchange in Response to Constant Work Rate Exercise
Constant work rate exercise tests have been very useful for characterizing the cardiopulmonary coupling of external to cellular respiration for purposes of determining relative fitness to perform exercise and for detecting and grading disease. Because of its importance, the pattern of the gas exchange responses to a given work task, how it is quantified and the underlying physiological mechanisms are hereby described. B. V˙O2 and V˙CO2 Kinetics
The kinetics of gas exchange in response to constant work rate exercise have been identified and quantified by doing replicate constant work exercise tests in which gas exchange was measured breath by breath. In order to get relatively noise-free, time-weighted gas exchange measurements, the breath-by-breath data were interpolated second by second. These data were then time-aligned for each replicate study to the onset of exercise. The time-aligned second-by-second data were then averaged to reduce noise, allowing the reproducible changes in gas exchange to be visualized (Fig. 17). In this way, the gas exchange responses become clear. From these types of studies, three phases in exercise gas exchange have been identified. ˙ CO at the start of exercise. Since ˙ O and V Phase I is the immediate increase in V 2 2 these increases start with the first breath of exercise, it cannot be due to metabolic changes during exercise. This is supported by the fact that the respiratory exchange ratio (R) remains the same as at rest for approximately the first 15 sec of exercise (Fig. 17) (55,56). Phase I has been explained by the sudden increase in pulmonary blood flow caused by the immediate increase in heart rate and stroke volume at the start of exercise. Because the blood passing through the lungs during these early seconds of exercise was formed during resting metabolism, and already resided in veins at the time exercise was started, the immediate increases in O2 uptake and CO2 output have the same relationship as at rest. Therefore, R is the same as at rest. ˙ CO result from an increase in ˙ O and V Because these proportional increases in V 2 2 cardiac output (pulmonary blood flow) at the start of exercise, it has been termed ‘‘cardiodynamic.’’ As anticipated, the size of phase I is reduced if the exercise is performed in the supine position (57) or from unloaded exercise (58) because stroke volume is already high and similar to that found during exercise. If heart rate does not increase in response to exercise, such as in patients with heart block (59) or if pulmonary blood flow can not increase appropriately because of increased pulmonary vascular resistance (60), phase I is reduced. On the other hand, phase I is relatively high in the more fit normal subject (61). Phase II starts when muscle capillary blood at the start of exercise arrives at the lungs. This is marked by a decrease in the R (Fig. 17) starting at about 15 sec. The decrease in R at 15 sec is accounted for by CO2 , generated from aerobic metabolism, going into the CO2 stores rather than being delivered to the lungs for exhalation. ˙ CO during early exercise. The ˙ O increases without a comparable increase in V Thus V 2 2
242
Wasserman and Stringer
Figure 17 Changes in ventilation and gas exchange during cycle ergometer constant work rate exercise starting from rest (‘‘0’’ time) and ending at 4 min in a normal subject. This study is the average of six similar repetitions in which gas exchange was measured breath ˙ e, by breath. The vertical bars are the standard errors of the data. The abrupt increase in V ˙ O at the start of exercise (‘‘0’’ time) is termed phase I and thought to be related, ˙ CO and V V 2 2 mechanistically, to the abrupt increase in cardiac output at the start of exercise. R is usually unchanged from rest for about 15 sec. The start of phase II is signaled by a decrease in R ˙ O to their asymptotes (phase ˙ e, V ˙ co2 and V and is the period of exponential-like increase in V 2 II). This is the period when increasing cellular respiration is reflected in lung gas exchange. ˙ CO increases more slowly than V ˙ O due to R decreases transiently during phase II because V 2 2 aerobically generated CO2 being taken up by tissues during early exercise (see text for a more complete discussion). R usually then increases to a value higher than rest because the R.Q. of the muscle substrate, being primarily glycogen, is higher than the average for the body, which depends on the R.Q. of the diet.
Homeostasis of Exercise Gas Exchange
243
mechanism for this early retention of aerobically generated CO2 has been attributed to the alkalization of the cell (27), accompanying the splitting of Cr⬃P (an acid compound with a low pK) into creatine (a neutral compound) and inorganic phosphate. This increase in muscle HCO3⫺ is associated with an increase in muscle effluent blood HCO3⫺ and K⫹ immediately after the start of exercise (28). The 15-sec delay for R to decrease represents a circulatory delay from muscle capillaries to lung capillaries. After 30 sec, muscle venous PCO2 starts to increase (Fig. 6) adding physically dissolved CO2 to the tissue CO2 stores. Before the end of the first minute of exercise, R starts to increase (56) because the mechanisms for increasing the CO2 stores become progressively less important (Cr⬃P/Cr ratio decreasing to an asymptote) (25) and the period of decreasing venous O2 Hb saturation (Fig. 9) (Haldane effect) is largely over. At the same time, muscle ˙ CO increase toward a steady state to a level appropriate for the work rate ˙ O and V V 2 2 being performed. The steady-state R is generally higher than that at rest because muscle substrate, being primarily carbohydrate, has an RQ close to 1. Phase II reflects the period of major increase in cellular respiration. If the exercise is below ˙ O increases as a single exponential with a time constant of approximately the LAT, V 2 ˙ CO reaches a steady state shortly 30 sec (58), reaching a steady state by 3 min. V 2 thereafter (58,62,63). The kinetics are faster at a given work rate, the more fit the subject (61). The amplitude of phase II is larger, the smaller the amplitude of phase I (Fig 17) (64). Grassi et al. (65) confirmed good agreement between simultaneously ˙ O and alveolar V ˙ O kinetics in fit normal subjects for below LAT measured leg V 2 2 constant work rate exercise from unloaded cycling. If the exercise intensity is heavy or very heavy for a normal subject (above the LAT ), or if the subject is so impaired that the cardiovascular response is inade˙ O can be significantly slowed quate to supply the total oxygen need, the increase in V 2 and a steady state is not achieved by 3 min (66–69). In this metabolic condition, ˙ O reaches an asymptote (70). A true steady-state lactate continues to increase until V 2 ˙ O can be sustained only when all of the cellular energy requirements are derived in V 2 from reactions using O2 transferred from the atmosphere. ˙ O kinetics are informative with respect to determining fitness Because the V 2 and the presence of disease in the gas transfer function, there has been considerable interest in methods to quantify them. Since the actual data do not conform to a single exponential relationship, the mean response time (MRT) is most commonly ˙ O kinetics. The MRT combines the characteristics of phase used to quantify the V 2 ˙ O dynamics. It can be obtained by performing a single exponential best I and II V 2 fit through the data from zero time and expressed as the time constant of an exponential process (63% of the asymptotic response) (61). A model of an exponential rise ˙ O with a time delay provides a better fit through the data of phase II (71). This in V 2 model fits a time constant through the data after the completion of phase I. The exponential fit through these data does not go through the origin and generally has a negative time delay (71). The smaller phase I, the greater the agreement between the MRT and time constant calculated from the exponential fit with a time delay. Sietsema et al. (61) showed that the MRT is similar among subjects of differing fitness at very low work rates (e.g., unloaded cycling) since even unfit individ-
244
Wasserman and Stringer
uals can virtually achieve their steady-state response during phase I. However as work rate is increased, the MRT discriminates between the more and less fit subjects. ˙ O max, has a shorter Thus the more fit subject, defined as an individual with a higher V 2 MRT for a given submaximal work rate than the less fit subject. Phase III starts at 3 min after exercise onset. If the work rate is below the ˙ O has reached a steady state by 3 min. If the work rate is above subject’s AT, V 2 ˙ O slowly increases beyond 3 min at a rate which correlates with the subject’s AT, V 2 the magnitude of the lactate increase (44,66,67). ˙ O varies from steady state for work To quantify the magnitude by which V 2 ˙O rates above the AT , Whipp and Wasserman (67) determed the rate of rise in V 2 ˙ O (6–3)). This has been found to be a very between 3 and 6 min of exercise (∆V 2 useful measurement because several studies have shown a linear correlation between ˙ O (6–3), with the regression line of the correlation being lactate increase and ∆V 2 similar in different studies (44,48,66,67,72). For exercise above the LAT, not only is there a slow component to the increase ˙ O , but V ˙ CO increases rapidly to values above V ˙ O as a result of release of CO2 in V 2 2 2 from HCO3⫺ as it buffers lactic acid (Fig. 18). Figure 19 provides a unifying hypothe-
˙ O for seven leg cycling work rates performed on different Figure 18 Time course of V 2 days in a single subject. Each curve is second-by-second average of four to eight replicate studies. End-exercise (1 min postexercise) antecubital venous lactate concentrations are ˙ CO measurements for each work rate. The three lowest work rates were shown to right of V 2 designed to be below the subject’s anaerobic threshold (AT), and the four remaining work ˙ O continued to increase during rates were designed to be at progressively higher work levels. V 2 the four work rates above the AT, the rate of increase being more marked the higher the work rate. In contrast, the Vco2 kinetics are not appreciably different, reaching a constant level by 3 to 4 min in all seven tests. (From Ref. 86.)
Homeostasis of Exercise Gas Exchange
245
˙ O and V ˙ CO . Figure 19 Hypothesis by which lactic acid increase during exercise affects V 2 2 During exercise, lactic acidosis does not develop until a critically low PO2 is reached in the capillary bed. Accumulation of lactic acid leads to (1) buffering by HCO3⫺, releasing CO2 into the extracellular fluid, and (2) decreasing extracellular HCO3⫺ in exchange for cellular lactate. Additional CO2 from buffer adds to CO2 from aerobic respiration, leading to increase ˙ CO . Simultaneously, decrease in capillary pH, resulting from accumulating lactic acid, in V 2 dissociates oxyhemoglobin (Bohr effect). Decrease of pH also acts as a vasodilator, increasing ˙ O , the former through local blood flow. Thus lactate accumulation affects both Vco2 and V 2 the buffering mechanism and the latter through the effect of acidosis on oxyhemoglobin dissociation and vascular tone.
˙ O for work rates above the LAT sis linking the mechanism for the slow rise in V 2 and the mechanism for the high rate of CO2 production. While at three minutes, ˙ O is approximately that expected from a linear extrapolation of work rate from V 2 ˙ O slowly increases to values above these steady-state moderate work rate exercise, V 2 ˙ linearly extrapolated VO2 values for heavy exercise as the work rate is sustained for ˙ O is due a longer duration (73). It can be postulated that part of this slow rise in V 2 ˙ E (74) and heart rate with time, despite a constant to the progressive increase in V ergometer work rate. However, it might also be explained by decreased muscle efficiency (75,76). IV. Mechanism(s) of Exercise Limitation in Lung Disease The cause of exercise limitation in patients with chronic obstructive pulmonary disease (COPD) is variable among patients and may involve several mechanisms. Also the pathophysiology of exercise limitation is usually different in patients classified as obstructive (or airflow limited) in contrast to restrictive or interstitial lung disease. Appreciating the mechanism of exercise limitation in a given patient is critical to their treatment. Not well appreciated is that the pathophysiology limiting exercise in patients with lung disease can be can be determined by their gas exchange response to cardiopulmonary exercise testing. As illustrated in Figure 20, patients with lung disease(s) may be exercise limited by abnormalities in one or more of the following three central functions, resulting in (1) a decreased ability to adequately ventilate the lungs (Fig. 20, right
246
Wasserman and Stringer
Figure 20 Factors that play a role in exercise limitation in patients with lung diseases. ˙ , ventilation-perfusion ratio; Vd/Vt, ˙ /Q See text for a detailed discussion of each factor. V physiological dead space tidal volume ratio; FEV1 , forced expired volume in 1 sec.
arm); (2) an increase in the ventilation needed to support the metabolic requirements of exercise (Fig. 20, left arm); and (3) a reduced ability to increase cardiac output to meet the muscle O2 requirement (Fig. 20, center arm). Furthermore, each of these functions can be abnormal due to one or more mechanisms as described below. A. Reduced Ventilatory Capacity
Airflow Obstruction
Airflow obstruction reduces the ventilatory capacity. This limits the ability of the lungs to be adequately ventilated when the ventilatory requirement increases such as during the increased metabolic demand of exercise. Generally, the breathing reserve during exercise (maximal ventilatory capacity minus maximum ventilation reached at peak exercise) is very small (commonly zero but almost always ⬍15 L/min). Airflow obstruction is a major factor causing patients to be exercise limited. It becomes an increasingly significant factor when coupled to mechanisms that increase the ventilatory requirement (factors shown in the left or center arm of Fig. 20). Airflow obstruction is usually not a factor limiting exercise in patients with ILD. Decreased Lung Elastic Recoil
Patients with emphysema have poor elastic recoil. Therefore when they breathe more rapidly in response to exercise, the patient becomes progressively more hyperinflated. This reduces the possible size of the tidal volume. Thus increasing breathing
Homeostasis of Exercise Gas Exchange
247
rate must be employed to eliminate the metabolic CO2 . The CO2 stimulus causes tachypnea leading to the sensation of dyspnea. In addition, the hyperinflation stimulates stretch receptors in the lungs (77) and muscle spindles in the chest wall (78) possibly also playing a role in the sensation of dyspnea. Increased Lung Elastic Recoil
Patients with ILD have increased elastic recoil and limited ability to expand their lungs because of reduced lung distensibility (compliance). Thus the patient adopts a rapid and relatively shallow breathing pattern during exercise with the reduced tidal volume approaching the patients inspiratory capacity. While patients with ILD generally have a small breathing reserve, it may not be zero as commonly found in patients with COPD. Patients with ILD are generally not limited by their disturbed ventilatory mechanics, but rather to impaired ability to increase pulmonary blood flow in response to exercise (79). Chest Wall Limitation
Patients with chest wall disease, such as chest deformity (e.g., kyphoscoliosis), low flat diaphragm of emphysema, or paralyzed diaphragm will have limited ability to increase their tidal volume and therefore to satisfy their ventilatory requirement. They are usually symptomatic due to dyspnea, and CO2 retention in response to exercise is common. B. Increased Ventilatory Requirement
˙ Mismatching (Increased VD /VT) V˙A /Q
˙ mismatching increases the ventilatory requirement. ˙ a/Q In lung disease patients, V ˙ CO is a rectanThe relationship between alveolar ventilation and PaCO2 for a given V 2 ˙ lung will require more ˙ a ⫻ PaCO2 /863). Thus high V ˙ a/Q ˙ CO ⫽ V gular hyperbola (V 2 ˙ lung would ˙ a/Q ventilation to lower PaCO2 by a certain amount than the low V conserve ventilation for an equal increase in PaCO2. Consequently, despite a normal ˙ . The calculated ˙ E will be elevated in the presence of mismatching of V ˙ a/Q PaCO2 , V physiological dead space fraction (Vd/Vt) becomes larger, the greater proportion ˙ lung units. ˙ a/Q of high V ˙ lung units are prominent, arterial hypoxemia results. The ˙ a/Q When low V latter stimulates the carotid bodies to further increase ventilatory drive. Hypoxemia, increased Vd /Vt, and reduced arterial pH are primary causes of the increased ventilatory drive in both COPD and ILD patients. Hypoxemia
Hypoxemia may occur in patients with ILD or COPD, although the mechanism usually differs. In the patient with COPD, the mechanism is the presence of low ˙ lung units. In contrast, the primary mechanism in ILD appears to be the rapid ˙ a/Q V passage of desaturated blood through a smaller than normal capillary bed. This
248
Wasserman and Stringer
reduces the red cell capillary residence time for O2 to reach a diffusion equilibrium with the alveolar gas. In patients with ILD, the arterial O2 desaturation is generally progressive with increasing work rate, because red cell transit through pulmonary capillaries becomes progressively more rapid. Thus equilibration time for O2 in the pulmonary capillary is less as the work rate and pulmonary blood flow increase. In COPD, arterial O2 Hb desaturation commonly occurs during exercise but, typically, it is not progressive. However, progressive hypoxemia can take place when ˙ lung units or a right to left shunt devel˙ a/Q blood flow increases through the low V ops through a potentially patent foramen ovale. When right atrial pressure increases above left atrial pressure, as commonly occurs during exercise in patients with a significant increase in pulmonary vascular resistance, O2 Hb-poor blood could flow from right atrium into the left atrium in those patients with a potentially patent foramen ovale. The direct effect of the exercise-induced hypoxemia is to stimulate the carotid body chemoreceptors and thereby increase ventilatory drive. An indirect effect of arterial hypoxemia to ventilatory drive is the increased production of lactic acid at a relatively low work rate caused by the reduction in arterial O2 content and flow to tissues. Reduced pH
Patients with severe obstructive and, less commonly, restrictive lung disease can develop respiratory acidosis (hypercapnia) during exercise. This increases ventilatory drive, primarily by stimulating the carotid bodies. In addition, a metabolic acidosis secondary to lactate increase may develop at unusually low work rates either because of impaired cardiac output increase, arterial hypoxemia or increased carboxyhemoglobin level (cigarette smokers). C. Impaired Ability to Increase Cardiac Output
Intrathoracic Pressure Changes with Breathing
Patients with emphysema develop positive (above atmospheric) pressures in their chest during expiration because of poor elastic recoil. When breathing rate increases in these patients, as in response to exercise, hyperinflation develops and the intrathoracic pressure during expiration increases. The high intrathoracic pressure during expiration increases the pressure around and in the heart and intrathoracic blood vessels leading to the heart (80). This impedes the entry of blood from the extrathoracic blood vessels into the heart during the expiratory phase of breathing. This is functionally a partial Valsalva maneuver. Since the expiratory phase of the respiratory cycle is a considerably larger fraction of the respiratory cycle than the inspiratory phase, the increasing pressure in the chest may impede inflow of blood into the thorax and cardiac filling as respiratory rate increases during exercise. This is a likely explanation for the relatively low cardiac output response to exercise reported in emphysema patients (81) and the relatively low O2 pulse (9).
Homeostasis of Exercise Gas Exchange
249
A failure for the circulation to meet the muscle O2 demands is likely to force the patient to stop exercise prematurely from muscle fatigue because the patient can not sustain aerobic regeneration of ATP in the muscles. This is best reflected during ˙ O kinetics. Nery et al. (46) constant work rate exercise from measurements of V 2 ˙ showed that COPD patients had abnormally slow VO2 kinetics. These findings must be interpreted as a failure to produce ATP, aerobically, at a normal rate and therefore to invoke anaerobic regeneration of ATP. Because the PO2 in the venous effluent blood from the exercising muscle de˙ O kinetics could not be a defect creases normally in COPD patients (82), the slow V 2 in the ability for the skeletal muscle to extract O2. Rather the slow kinetics with normal extraction of O2 must logically be interpreted as a failure for O2 transport to increase fast enough to keep pace with the rate of muscle contraction, i.e., a circulatory delay. If the skeletal muscle had a defect in the ability to utilize O2 because of some metabolic disturbance, the muscle effluent PO2 should be increased. While it is difficult to envisage the type of muscle biochemical abnormality that ˙ O kinetics, a slow cardiovascular response to exercise would lead to a slow phase II V 2 ˙ O kinetics to be slow. Because only aerobic regeneration of ATP can be obligates V 2 sustained, muscle fatigue should be expected to contribute or be responsible for the ˙ O kinetics are abnorexercise limitation in COPD patients when O2 transport and V 2 mally slow. However, breathlessness might develop before or with the onset of fatigue if the CO2 load from aerobic metabolism and lactic acidosis stimulate the ventilatory chemoreceptors to a level that exceeds the patient’s ventilatory capacity. Maltais et al concluded that the increase in lactate seen at low work rates in COPD patients is not related to a deficit in O2 transport because the systematic ˙ O which they found did not reach statistical signifireductions in O2 transport and V 2 cance (82). However, this ignores the accuracy required to measure the small deficits in O2 transport that cause large increases in lactate as a result of anaerobiosis. It ˙ O of 50 watts work can be calculated that a 10% deficit in O2 transport for the V 2 (100 mL/min or 4.5 mmol/min), will result in a rate of lactate increase of 18 to 27 mmol/min from anaerobic glycolysis to replace the equivalent of the aerobically generated ATP. Pulmonary Vascular Disease
Pulmonary vascular occlusive disease limits the ability of the right ventricle to de˙ O would increase more slowly than liver blood to the left side of the heart. Thus, V 2 that expected if the exercise were performed totally aerobically (33,47). The failure to meet the O2 requirement for aerobic ATP regeneration results in a slowing of ˙ O increase as work rate increases and a disproportionate increase in V ˙ CO (33), V 2 2 reflecting the buffering of the lactic acid from increased anaerobic metabolism. The abnormality in the coupling of external to cellular respiration in pulmonary vascular disease is accompanied by decreased perfusion of ventilated airspace and therefore increased physiological dead space. This mechanism, along with the low work rate lactic acidosis and exercise hypoxemia, causes increased ventilatory drive leading to the symptom of dyspnea.
250
Wasserman and Stringer
Most patients with ILD have a limited ability to increase pulmonary blood flow normally in response to exercise because the disease process, inflammation and fibrosis of alveoli, affects the microvascular bed. Thus cardiac output might be adequate at rest, but be inadequate during exercise because of the failure to recruit new pulmonary blood vessels or dilate the pulmonary microcirculation in response to exercise. Thus pulmonary blood flow fails to increase appropriately for the work rate. Some patients with emphysema also lose a large part of their pulmonary vascular bed and thereby are exercise limited because pulmonary blood flow can not increase rapidly enough to allow left ventricular output to satisfy the tissues O2 demand. This is reflected by gas exchange measurements in response to constant work rate exercise tests which show that O2 kinetics are abnormally slow (46). Primary Heart Disease, Hypoxemia, Anemia and Carboxyhemoglobinemia
Patients with lung diseases might have primary heart disease that limits the ability of the heart to satisfy the increase in O2 transport needed to perform exercise. Other factors that impair O2 flow to the muscles, such as arterial hypoxemia, anemia and carboxyhemoglobinemia, might act in conjunction with pulmonary vascular or primary heart disease to reduce exercise tolerance. The reduced O2 transport caused by these factors results in a lactic acidosis at a reduced work rate. The lactic acidosis increases ventilatory drive and can be responsible for dyspnea as well as fatigue at unusually low work rates in patients with COPD. D. Exercise Lactic Acidosis and Dyspnea
Lactic acidosis from anaerobic glycolysis is a common by-product of any physiological state in which O2 transport is inadequate to satisfy the oxidative needs of cellular respiration. Because of the link between acid-base regulation and ventilatory control, ventilatory drive will be increased when cardiac output or O2 flow is inadequate to satisfy the muscle O2 requirement for the aerobic regeneration of ATP. The mediators of this additional ventilatory stimulation is the increased lactic acid (H⫹) forma˙ CO resulting from the release of CO2 when HCO3⫺ buffers the newly tion and V 2 formed lactic acid. E.
Near-Syncope with Exercise
Patients with ILD who have severe ventilatory restriction may experience syncopal symptoms during exercise. Direct arterial pressure measurements show large swings in arterial pressure during breathing which become more marked with exercise. Thus with inspiration, cardiac and therefore peripheral arterial pressure might decrease to levels that could conceivably underperfuse the brain, causing near-syncope. Patients with obstructive and restrictive lung diseases share a number of pathophysiological mechanisms that reduce exercise tolerance. However, the patients with ILD, in contrast to patients with COPD, are more commonly limited by their failure
Homeostasis of Exercise Gas Exchange
251
to increase blood or O2 flow to the muscles, rather than by their abnormal respiratory mechanics. Presumably, the reduced ability to increase blood flow in ILD is due to failure of the pulmonary circulation to recruit reserve pulmonary blood vessels in response to exercise, in addition to the failure of the right ventricle to hypertrophy sufficiently to overcome the increased pulmonary vascular resistance caused by the underlying disease.
V.
Summary
During exercise, O2 transport from capillary to myocyte is not diffusion limited until end-capillary PO2 reaches its lowest value (critical capillary PO2 ). Critical capillary ˙ O max. PO2 is reached at the mid-level of the subject’s work capacity, not at V 2 Femoral vein lactate increases during leg cycling exercise after the critical capillary PO2 is reached. The increase in lactate is essential because the increase in H⫹ that accompanies the increase in lactate becomes the mechanism for oxyhemoglobin dissociation (‘‘Bohr effect’’) above the subject’s anaerobic threshold. This is, functionally, a respiratory adaptation to anaerobiosis. Both normal subjects and patients with chronic stable heart failure have a critical capillary PO2 in the 15 to 20 range. The pattern of change in end-capillary ˙ O increases, describes the V ˙ O at which O2 becomes diffusion-limited and PO2 as V 2 2 the extent to which new muscle capillary bed is recruited. The delivery of O2 to the muscles to sustain aerobic regeneration of ATP for muscular exercise is totally dependent on the ability of the circulation to transport it at the required rate. Failure of the circulation to deliver O2 at the rate needed to sustain exercise slows the rate of aerobic regeneration of ATP and O2 consumption. This invokes anaerobic ATP regeneration and causes lactic acid to accumulate in the muscle and blood. Because lactic acid is buffered by HCO3⫺ in the cell, CO2 output increases ˙ O and V ˙ CO over that predicted from aerobic metabolism. Thus, the patterns of V 2 2 during exercise differ, depending on whether the work is or is not accompanied by ˙ O kinetics are slowed lactic acidosis. For work rates that engender a lactic acidosis, V 2 ˙ O . Thus gas exchange mea˙ CO exceeds V and may not reach a steady state, while V 2 2 surements on a breath-by-breath basis are of great value in the study of cellular respiration and the circulatory coupling to external respiration in response to exercise. Patients with chronic lung diseases can be exercise limited by three major functions, impaired ventilatory capacity, increased ventilatory requirement and/or impaired peripheral O2 delivery. The pathophysiological mechanisms underlying exercise limitation can be assessed by cardiopulmonary exercise testing. Thus it is an invaluable test to perform when attempting to identify and quantify the extent to which each physiological site in the coupling of external to cellular respiration contributes to exercise limitation and may serve as a critical guide to major therapeutic decisions in patient management.
252
Wasserman and Stringer Endnote
˙ o2 m ⫽ D ⫻ P(cap-mito)O2 ⫻ A/L, where V ˙ o2 m ⫽ the rate of O2 moleca. V ular diffusion per unit time into muscle, D ⫽ diffusion coefficient for O2 in the tissue fluid, P(cap-mito) ⫽ the partial pressure gradient of O2 between the capillary and mitochondria, A ⫽ diffusion surface area and L ⫽ the path length for O2 diffusion. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
Knuttgen HG, Saltin B. Muscle metabolites and oxygen uptake in short-term submaximal exercise in man. J Appl Physiol 1972; 32(5):690–694. Jorfeldt L, Juhlin-Dannfelt A, Karlsson J. Lactate release in relation to tissue lactate in human skeletal muscle during exercise. J Appl Physiol 1978; 44(3):350–352. Karlsson J. Pyruvate and lactate ratios in muscle tissue and blood during exercise in man. Acta Physiol Scand 1971; 81:455–458. Katz A, Sahlin K. Regulation of lactic acid production during exercise. J Appl Physiol 1988; 65(2):509–518. Wasserman K. Anaerobiosis, lactate and gas exchange during exercise: the issues. Fed Proc 1986; 45:2904–2909. Wasserman K, Beaver WL, Davis JA, Pu J-Z, Heber D, Whipp BJ. Lactate, pyruvate, and lactate-to-pyruvate ratio during exercise and recovery. J Appl Physiol 1985; 59:935– 940. Wasserman K, Beaver WL, Whipp BJ. Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation 1990; 81(suppl II):14–30. Wasserman K. The anaerobic threshold measurement to evaluate exercise performance. Am Rev Respir Dis 1984; 129(suppl):S35–S40. Nery LE, Wasserman K, French W, Oren A, Davis JA. Contrasting cardiovascular and respiratory responses to exercise in mitral valve and chronic obstructive pulmonary diseases. Chest 1983; 83:446–453. Sullivan MJ, Knight D, Higginbotham MB, Cobb FR. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation. 1989; 80:769– 781. Wasserman K, Zhang YY, Riley ML. Ventilation during exercise in chronic heart failure. Basic Res Cardiol 1996; 91:1–11. Weber KT, Janicki JS. Lactate production during maximal and submaximal exercise in patients with chronic heart failure. J Am Coll Cardiol 1985; 6:717–724. Kobayashi T, Itoh H, Kato K. The role of increased dead space in the augmented ventilation of cardiac patients. In: Wasserman K, ed. Exercise Gas Exchange in Heart Disease. Armonk, NY: Futura, 1996: 145–156. Rowell LB. Human Circulation Regulation During Physical Stress. New York: Oxford University Press, 1986:215. Weber KT, Janicki JS. Cardiopulmonary Exercise Testing: Physiological Principles and Clinical Applications. Philadelphia: W.B. Saunders, 1986. Wasserman K, Van Kessel A, Burton GB. Interaction of physiological mechanisms during exercise. J Appl Physiol 1967; 22:71–85. Wasserman K. Breathing during exercise. N Engl J Med 1978; 298:780–785. Engelhardt VA, Lyubimova MN. Myosin and adenosinetriphosphatase. Nature 1939; 144: 668. Stringer W, Wasserman K, Casaburi R, Porszasz J, Maehara K, French W. Lactic acidosis as a facilitator of oxyhemoglobin dissociation during exercise. J Appl Physiol 1994; 76: 1462–1467.
Homeostasis of Exercise Gas Exchange 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
36. 37. 38. 39. 40. 41. 42. 43. 44.
253
Henriksson J, Katz A, Sahlin K. Redox state changes in human skeletal muscle after isometric contraction. J Physiol 1986; 380:441–451. Katz A, Sahlin K. Effect of decreased oxygen availability on NADH and lactate contents in human skeletal muscle during exercise. Acta Physiol Scand 1987; 131:119–127. Sahlin K, Katz A, Henriksson J. Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem J 1987; 245:551–556. Boning D, Hollnagel C, Boecker A, Goke S. Bohr shift by lactic acid and the supply of O2 to skeletal muscle. Respir Physiol 1966; 85:231–243. Meyer RA, Sweeney HL, Kushmerick MJ. A simple analysis of the phosphocreatine shuttle. Am J Physiol 1984; 248:C365–C377. Yoshida T, Watari H. 31 P-Nuclear magnetic resonance spectroscopy study of the time course of energy metabolism during exercise and recovery. Eur J Appl Physiol 1993; 66:494– 499. Barstow TJ, Buchthal S, Zanconato S, Cooper DM. Muscle energetics and pulmonary oxygen uptake kinetics during moderate exercise. J Appl Physiol 1994; 74:1742–1749. Piiper J. Production of lactic acid in heavy exercise and acid-base balance. In: Moret PR, Weber J, Haissly J, Denolin H, eds. Lactate: Physiologic, Methodologic and Pathologic Approach. New York, Springer-Verlag, 1980:35–45. Wasserman K, Stringer W, Casaburi R, Zhang YY. Mechanism of the exercise hyperkalemia: an alternate hypothesis. J Appl Physiol 1997; 83:631–643. Koike A, Weiler-Ravell D, McKenzie DK, Zanconato S, Wasserman K. Evidence that the metabolic acidosis threshold is the anaerobic threshold. J Appl Physiol 1990; 68:2521– 2526. Wasserman K, McIlroy MB. Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 1964; 14:844–852. Wasserman K. The anaerobic threshold measurement in exercise testing. Clin Chest Med 1984; 5:77–88. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting the anaerobic threshold by gas exchange. J Appl Physiol 1986; 60:2020–2027. Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of Exercise Testing and Interpretation, 2d ed. Philadelphia: Lea & Febiger, 1994. Bylund-Fellenius AC, Walker PM, Elander A, Holm S, Holm J, Schersten T. Energy metabolism in relation to oxygen, partial pressure in human skeletal muscle during exercise. Biochem J 1981; 200:247–255. Bogaard JM, Scholte HR, Busch FM, Stam H, Versprille A. Anaerobic threshold as detected from ventilatory and metabolic exercise responses in patients with mitochondrial respiratory chain defect. In: Tavassi L, DiPrampero PE, eds. Advances in Cardiology. The Anaerobic Threshold: Physiological and Clinical Significance. Basel: Karger, 1986;135–145. Whipp BJ, Wasserman K. Efficiency of muscular work. J Appl Physiol 1969; 26:644–648. Wasserman K. Coupling of external to cellular respiration during exercise: the wisdom of the body revisited. Am J Physiol 1994; 266:E519–E539. Osnes J-B, Hermansen L. Acid-base balance after maximal exercise of short duration. J Appl Physiol 1972; 32:59–63. Bouyhus A, Pool J, Binkhorst RA, Van Leeuwen P. Metabolic acidosis of exercise in healthy males. J Appl Physiol 1966; 21(3):1040–1046. Beaver WL, Wasserman K, Whipp BJ. Bicarbonate buffering of lactic acid generated during exercise. J Appl Physiol 1986; 60:472–478. Stringer W, Casaburi R, Wasserman K. Acid-base regulation during exercise and recovery in man. J Appl Physiol. 1992; 72:954–961. Wasserman K, Whipp BJ, Koyal S, Beaver WL. Anaerobic threshold and respiratory gas exchange during exercise. J Appl Physiol 1973; 35:236–243. ˙ O relationship during heavy, constant ˙ CO /V Stringer W, Wasserman K, Casaburi R. The V 2 2 work rate exercise reflects the rate of lactate accumulation. Eur J Appl Physiol 1995; 72: 25–31. Zhang YY, Wasserman K, Sietsema KE, Barstow TJ, Mizumoto G, Sullivan CS, Ben-Dov I. O2 uptake kinetics in response to exercise: a measure of tissue anaerobiosis in heart failure. Chest 1993; 103:735–741.
254 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
Wasserman and Stringer Auchincloss JH, Ashutosh K, Rana S, Peppi D, Johnson LW, Gilbert R. Effect of cardiac, pulmonary, and vascular disease on one-minute oxygen uptake. Chest 1976; 70:486–493. Nery LE, Wasserman K, Andrews JD, Huntsman DJ, Hansen JE, Whipp BJ. Ventilatory and gas exchange kinetics during exercise in chronic airways obstruction. J Appl Physiol 1982; 53:1594–1602. Hansen JE, Sue DY, Oren A, Wasserman K. Relation of oxygen uptake in work rate in normal men and men with circulatory disorders. Am J Cardiol 1987; 59:669–674. Koike A, Wasserman K, McKenzie DK, Zanconato S, Weiler-Ravell D. Evidence that diffusion limitation determines oxygen uptake kinetics during exercise in humans. J Clin Invest 1990; 86:1698–1706. Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. J Biol Chem 1955; 217:383–393. Wittenberg BA, Wittenberg JB. Transport of oxygen in muscle. Annu Rev Physiol 1989; 51:857–878. Hartley L, Vogel J, Landowne M. Central, femoral, and brachial circulation during exercise in hypoxia. J Appl Physiol 1973; 34(1):87–90. Koike A, Wasserman K, Taniguichi K, Hiroe M, Marumo F. Critical capillary oxygen partial pressure and lactate threshold in patients with cardiovascular disease. J Am Coll Cardiol 1994; 23:1644–1650. Lewis SF, Haller RG. The pathophysiology of McArdle’s disease: clues to regulation in exercise and fatigue. J Appl Physiol 1986; 61:391–401. Lewis SF, Vora S, Haller RG. Abnormal oxidative metabolism and O2 transport in muscle phosphofructokinase deficiency. J Appl Physiol 1991; 70:391–398. Wasserman K, Whipp BJ, Casaburi R, Beaver WL. Carbon dioxide flow and exercise hyperpnea: Cause and effect? Am Rev Respir Dis 1977; 115:225–237. Wasserman K, Whipp BJ, Casaburi R. Handbook of Physiology. Bethesda, MD: American Physiological Society, 1986; 595–619. Weiler-Ravell D, Whipp BJ, Cooper DM, Wasserman K. The control of breathing at the start of exercise as influenced by posture. J Appl Physiol 1983; 55(5):1460–1466. Diamond LB, Casaburi R, Wasserman K, Whipp BJ. Kinetics of gas exchange and ventilation in transitions from rest or prior exercise. J Appl Physiol 1977; 43:704–708. Casaburi R, Spitzer S, Haskell R, Wasserman K. Effect of altering heart rate on oxygen uptake at exercise onset. Chest 1988; 95:6–12. Sietsema KE, Cooper DM, Rosove MH, Perloff JK, Child JS, Canobbio MM, Whipp BJ, Wasserman K. Dynamics of oxygen uptake during exercise in adults with cyanotic congenital heart disease. Circulation 1986; 73:1137–1144. Sietsema KE, Daly JA, Wasserman K. Early dynamics of O2 uptake and heart rate as affected by exercise work rate. J Appl Physiol 1989; 67:2535–2541. Casaburi R, Whipp BJ, Wasserman K, Beaver WL, Koyal SN. Ventilatory and gas exchange dynamics in response to sinsoidal work. J Appl Physiol 1977; 42:300–311. Wasserman K. Coupling of external to internal respiration. Am Rev Respir Dis 1984; 129: 21–24. Wasserman K. New concepts in assessing cardiovascular function. Circulation 1988; 78: 1060–1071. Grassi B, Poole DC, Richardson RS, Knight DR, Erickson BK, Wagner PD. Muscle O2 uptake kinetics in humans: implications for metabolic control. J Appl Physiol 1996; 80: 988–998. Roston WL, Whipp BJ, Davis JA, Effros RM, Wasserman K. Oxygen uptake kinetics and lactate concentration during exercise in man. Am Rev Respir Dis 1987; 135:1080–1084. Whipp BJ, Wasserman K. Oxygen uptake kinetics for various intensities of constant load work. J Appl Physiol 1972; 33:351–356. Casaburi R, Barstow T, Robinson T, Wasserman K. Dynamic and steady-state ventilatory and gas exchange responses to arm exercise. Med Sci Sports Exerc 1992; 24:1365–1374. Riley M, Nicholis P, Nugent AM, Steele IC, Bell N, Davies PM, Stanford CF, Patterson VH. Respiratory gas exchange and metabolic responses during exercise in McArdle’s disease. J Appl Physiol 1993; 75:745–754. Wasserman K, Casaburi R, Beaver WL, Roston WL, Whipp BJ. Assessing the adequacy
Homeostasis of Exercise Gas Exchange
71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86.
255
of tissue oxygenation during exercise. In: Bryan-Brown CW, Ayres SM, eds. New Horizons: Oxygen Transport and Utilization. Fullerton, CA: Society of Critical Care Medicine, 1987; 109–144. Whipp BJ. Dynamics of pulmonary gas exchange. Circulation 1987; 76(suppl VI):18–28. Casaburi R, Storer TW, Ben-Dov I, Wasserman K. Effect of endurance training on possible determinants of VO2 during heavy exercise. J Appl Physiol 1987; 62:199–207. Whipp BJ, Wasserman K. Effect of anaerobiosis on the kinetics of O2 uptake during exercise. Fed Proc 1986; 45:2942–2947. Riley M, Wasserman K, Fu PC, Cooper CB. Muscle substrate utilization from alveolar gas exchange in trained cyclist. Eur J Appl Physiol 1996; 72:341–348. Kushmerick MJ. Energetics of muscle contraction. In: Peachey LD, Adrian RH, Geiger SR, eds. Handbook of Physiology, Section 10: Skeletal Muscle. Bethesda, MD: American Physiological Society, 1983:189–236. Crow MT, Kushmerick MJ. Chemical energetics of slow- and fast-twitch muscles of the mouse. J Gen Physiol 1982; 79:147–166. Widdicombe JG. Nervous receptors in the respiratory tract and lungs. In: Hornbein TF, ed. Regulation of Breathing, Part 1. New York: Marcel Dekker, 1981:429–472. Duron B. Intercostal and diaphragmatic muscle endings and afferents. In: Hornbein T, ed. Regulation of Breathing, Part 1. New York: Marcel Dekker, 1981:473–540. Hansen JE, Wasserman K. Pathophysiology of activity limitation in patients with interstitial lung disease. Chest 1996; 109:1566–1576. Butler J, Schrijen F, Polu JM, Albert RK. Cause of the raised wedge pressure on exercise in chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138:350–354. Minh VD, Chun D, Dolan GF, Lee HM, Vasquez P. Mixed venous oxygenation, exercise, ˙ ratio in chronic obstructive pulmonary disease. Am Rev Respir Dis ˙ /Q body posture, and V 1981; 124:226–231. Maltais F, Jobin J, Sullivan MJ, Bernard S, Whittom F, Killian KJ, Desmeules M, Belanger M, LeBlanc P. Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD. J Appl Physiol 1998; 84:1573–1580. Wasserman K, Sue DY. Coupling of external to cellular respiration. In: Wasserman K, ed. Exercise Gas Exchange in Heart Disease. Armonk, NY: Futura, 1996:1–15. Wasserman K, Whipp BJ. Exercise physiology in health and disease (state of the art). Am Rev Respir Dis 1975; 112:219–249. Wasserman K, Stringer W. Critical capillary PO2 , net lactate production, and oxyhemoglobin dissociation: effects on exercise gas exchange. In: Wasserman K, ed. Exercise Gas Exchange in Heart Disease. Armonk, NY: Futura, 1998:157–181. Casaburi R, Barstow TJ, Robinson T, Wasserman K. Influence of work rate on ventilatory and gas exchange kinetics. J Appl Physiol 1989; 67:547–555.
10 Mechanical Heart–Pericardium–Lung Interactions
MASAO TAKATA
JAMES L. ROBOTHAM
Imperial College School of Medicine and Chelsea and Westminster Hospital London, England
University of Rochester School of Medicine and Dentistry Rochester, New York
I.
Introduction
Physiology and pathophysiology of the pericardium have fascinated physiologists for many years. Because patients with congenital absence of the pericardium are often asymptomatic (1,2) and pericardiectomy in animals (3) and humans after cardiac surgery (4) does not usually result in profound hemodynamic alterations, the significance of the pericardium in cardiovascular physiology tends to be overlooked in clinical practice. However, experimental studies over the past two decades demonstrated that the pericardium influences cardiac performance by constraining the heart even under normal conditions. Moreover, owing to the close relationships of the pericardium not only with the heart but also with the lungs, the pericardium significantly modifies cardiorespiratory interactions under both normal and pathological conditions. It is well known that the pericardium substantially affects hemodynamics in disease state. Characteristic respiratory-induced hemodynamic signs observed in pericardial disease, e.g., pulsus paradoxus or Kussmaul’s sign, suggest that unique hemodynamic events take place during respiration with the presence of pericardial pathology. This chapter attempts to provide a foundation to understand the role of pericardium in cardiovascular physiology and cardiorespiratory interaction in normal as well as diseased states. We shall provide an overview of the anatomy and physiology of the pericardium, the concept of pericardial surface pressure, and the role of the 257
258
Takata and Robotham
pericardium in modulating cardiac loading conditions and cardiorespiratory interactions under physiological and pathophysiological situations. Specific emphasis will be placed on understanding of pathophysiology of pericardial diseases, which leads to a more generalized concept of how the pericardium constrains the heart and affects cardiac chamber interactions. II. Physiology of the Pericardium A. Anatomy of the Normal Pericardium
The pericardium consists of two distinct anatomical layers. The visceral pericardium actually constitutes the external surface of the heart and is also called epicardium. The parietal pericardium, which the word ‘‘pericardium’’ usually refers to, is a thin, semitransparent membrane enclosing the heart. The space between the two layers is called the pericardial or intrapericardial space. Under normal conditions, the pericardial space is minimum with only a small amount of fluid present, approximately 30 to 50 mL in human adults (5). Thus, the pericardium (i.e., parietal pericardium) is virtually in direct contact with the heart surface (i.e., epicardium). The pericardium is also in intimate contact with other structures in the thorax. It is tethered by its reflection around major vessels and fibrous connection with the vertebral columns, sternum, and diaphragm. The outer surface of the pericardium is in direct contact with the pleura, and the lungs constitute a space that envelops the heart and pericardium, termed as cardiac fossa. Understanding of these close relationships of the pericardium not only with the heart but also with the lungs is essential for analyses of complex heart-pericardium-lung interactions, particularly during respiration. Pericardial tissue has a tensile strength quite similar to that of rubber. A number of experimental studies have investigated in vitro mechanical behavior of the parietal pericardium, and found that the pericardial tissue is highly extensible at low levels of stress but with an abrupt transit becomes relatively inextensible at higher levels of stress (6–9). This characteristic in pericardial material properties is considered to reflect a complex and yet incompletely understood interaction between collagen and elastic fibers and a glycosaminoglycan-rich hydrogel matrix (8,9). The pressure-volume relationship of the whole pericardium parallels the behavior that would be expected from such in vitro tissue properties: the entire pressure-volume relationship is curvilinear with a distinct bend or knee, i.e., flat at small volumes with an abrupt change to a much steeper curve at larger volumes. Thus, the pericardium exerts little constraining forces over the heart when the intrapericardial volume is small, but its restraining effects becomes substantial once the intrapericardial volume exceeds a certain limit. Importantly, the transition between a compliant and noncompliant pericardium appears to occur at an intrapericardial volume that is at the high end of the normal physiological heart volume (10). B. Pericardial Surface Pressure
Given the above elastic properties, it is apparent that the restraining effects of the pericardium over the heart, i.e., pericardial constraint, increase with an increased
Heart-Pericardium-Lung Interactions
259
heart volume or increased pericardial fluid. To assess the degree of the pericardial constraint in vivo, measurement of pericardial pressure, the pressure over the heart below the parietal pericardium, is essential. However, the technique for measurement of pericardial pressure is not very straightforward (11). Indeed, early measurements of pericardial pressure using fluid-filled catheters inserted into the pericardial space all yielded minimum values over a wide range of heart volumes, and hence questioned any significant role for pericardial constraint. This is because under normal conditions, the pericardial pressure is not a simple ‘‘liquid’’ pressure but should rather be considered as a ‘‘surface’’ pressure (12–15). The concept of liquid versus surface pressure is derived from analysis of pleural pressure in traditional pulmonary mechanics (16,17). A liquid pressure is a generalized hydrostatic pressure acting in the liquid in all directions. It can be measured with a fluid-filled cannula or transducer-tipped catheter, and hence is familiar to clinicians. A surface pressure is a force per unit acting perpendicularly over a surface or between two surfaces. It is equal to the sum of any liquid pressure and a ‘‘contact stress’’, i.e., a regional pressure due to deformation forces produced by the apposition of two surfaces. Because the pericardium is virtually in direct contact with the heart surface, the constraining forces are mainly transmitted in a form of contact stress. The pericardial surface pressure under physiological conditions is thus higher than the pericardial liquid pressure. As the pericardial fluid accumulates, the pericardium will lose its contact with the heart surface, and the pericardial surface pressure becomes equal to pericardial liquid pressure. A fluid-filled catheter inserted into the pericardial space would therefore underestimate the true pericardial pressure under normal, nontamponade conditions. In contrast, a flat, flexible balloon inserted between the heart and pericardium is more sensitive to such contact forces (16,17). Although the flat balloon technique is not totally free from errors because of distortion of the curved interface between the pericardium and heart by the inserted balloon itself (15,18), it is at present accepted by most investigators as a better, if not the best, method than a fluid-filled cannula to estimate pericardial surface pressure (12–15,19–24). Studies with flat balloon sensors have clarified several important characteristics of pericardial pressure. Pericardial pressure over the ventricles shows a phasic change within a cardiac cycle (11,12,15,20,22,24) with its maximum near end diastole and minimum near end systole. The waveform of this phasic change is indeed remarkably similar to ventricular dimensions experimentally measured by sonomicrometer crystals (15) (see Figs. 1, 2). This suggests that the pericardial pressure over the ventricles reflects instantaneous changes in ventricular volumes during a cardiac cycle. Moreover, significant regional differences were observed in pericardial pressure over various sites of the heart, e.g. between the left (LV) and right ventricles (RV) (15,20,22,23). Smiseth et al. (20) and ourselves (15) demonstrated that the pericardial pressure on either ventricle is influenced mainly by underlying ventricular volume, though the effect of opposite ventricular volume may sometimes dominate. Thus under normal physiological conditions, pericardial pressure appears to have a regional nature, being influenced mainly by local events occurred around that area.
Figure 1 Changes in pericardial (Ppe), extrapericardial pleural (Pex), and esophageal (Pes) pressures during negative intrathoracic pressure in anesthetized dogs. The animals were instrumented with flat latex balloons (to measure Ppe and Pex) over the LV, a cylindrical balloon in the esophagus (Pes), an electromagnetic flow probe around aorta (aortic blood flow, QAO), and micromanometer-tipped catheters in the LV and RV (left ventricular pressure, PLV and right ventricular pressure, PRV ) via thoracotomy, and the chest was closed airtight. Negative intrathoracic pressure was produced by phrenic nerve stimulation with the animal’s airway occluded. Pes and Pex showed a quasi-square wave decrease with an amplitude of ⬃ ⫺10 mm Hg. However, Ppe did not fall as much as Pex and Pes, particularly at end-diastole, resulting in an increased transpericardial pressure (Ppe minus Pex). QAO showed a decrease during negative intrathoracic pressure, i.e., pulsus paradoxus. Note that Ppe always exhibited a phasic change within a cardiac cycle with its maximum near end diastole and minimum near end systole, consistent with the changes in local cardiac volumes. (From Ref. 15.)
Figure 2 Changes in pericardial (Ppe) and extrapericardial pleural (Pex) pressures during PEEP in anesthetized dogs. The animals were instrumented via thoracotomy with two flat latex balloons, one placed into the pericardial space over the LV to measure Ppe, and the other placed over the pericardium beneath the lung to measure Pex. The chest was reapproximated, and changes in Ppe and Pex were recorded during application of PEEP under baseline volume conditions (panel A) and plasma volume expanded conditions (panel B). With a PEEP of 0 cm H2O, Ppe was positive with a phasic change during a cardiac cycle, consistent with
Heart-Pericardium-Lung Interactions
261
the changes in local cardiac volumes, while Pex was approximately 0 mm Hg with minimal oscillations. With a PEEP of 20 cm H2O, Ppe increased under both baseline and plasma volume-expanded conditions. Under baseline volume conditions, Pex became positive and phasic, approaching Ppe with regard to its phasic values and waveform. The component of transpericardial pressure was thus markedly reduced. Under plasma volume expanded conditions, Pex became positive and phasic but remained lower than Ppe, with a substantial component of transpericardial pressure still present. ECG, electrocardiogram; PLV, left ventricular pressure. (From Ref. 24.)
262
Takata and Robotham C. Functions of the Pericardium
Traditionally, several functions have been ascribed to the pericardium (5): 1) to protect the heart from direct invasion of microorganisms in the thorax; 2) to maintain the heart in a relatively fixed geometric position in the chest cavity; 3) to minimize friction between the heart and surrounding structures when the heart contracts and dilates; and, most importantly, 4) to influence the cardiac filling dynamics by exerting external constraining forces over the heart (pericardial constraint). With an elevated heart volume, there is little question that the pericardium limits cardiac filling and hence the ‘‘preload’’ of the heart. This notion is supported by experimental studies that evaluate changes in pressure-volume relationships of the cardiac chambers before and after pericardiectomy (25–27) or studies using the flat balloon technique (12–15,19–24). When the heart volume is markedly elevated, the pericardium would prevent the heart from overdilatation, myocardial hemorrhage, or valvular insufficiency (28). On the other hand, if the chronic dilation of the heart or slowly developing pericardial effusion occurs over a long period of time, the pericardium would grow and enlarge, with the pericardial constraint remained relatively unchanged (10,27). Controversies exist at what degree the pericardium constrains the heart under normal physiological conditions. Tyberg and colleagues (13,19,29), using liquidfilled balloons, reported that the pericardial pressure is approximately equal to, or accounts for 80%–90% of, the right atrial (RA) or RV diastolic pressures. They suggested that the RV is working with a very low transmural pressure, and the most of the right heart cardiac filling is limited by the elastic recoil of the pericardium rather than the intrinsic stiffness of the RA and RV. Since their finding implied that Frank-Starling mechanism is not actually functioning in the right heart, it produced a considerable debate (30). On the contrary, Freeman and LeWinter (14), Hoit et al. (22), Scharf et al. (23), and ourselves (15) utilized air-filled balloons, and found that the contribution of the pericardial pressure to the RV diastolic pressure would be somewhere between one-half and two-thirds. The precise point where the pericardium begins to limit cardiac filling, particularly on the right heart, remains unclear, due mainly to the lack of method that allows an accurate in vivo calibration of the balloon sensor on such an ill-defined and continually changing curved surface as the heart (15). Despite these uncertainties, most investigators agree that the pericardium has a much more constraining effect on the heart than previously considered even under normal circumstances, and that the pericardial pressure constitutes a major component of diastolic pressures of the thin-walled right heart, but a smaller component of diastolic pressures of the thicker-walled left heart. In addition to the above functions, recent experimental studies suggest a potential nonmechanical role of pericardium in cardiovascular physiology. Pericardial mesothelial cells in culture are able to release biologically active cardiovascular mediators such as endothelin and prostaglandins (31–33). Mebazaa et al. (33) found in sheep that prostaglandins, atrial natriuretic factor, and endothelins were present in pericardial fluid and their concentrations actively changed in response to physiological stimuli. Their findings suggest an interesting possibility that the pericardium
Heart-Pericardium-Lung Interactions
263
may serve as a ‘‘source’’ of humoral cardiovascular mediators, and the pericardial space and fluids may act as a ‘‘reservoir’’ for the mediators produced by the pericardium or myocardium. In vivo significance of such paracrine function of the pericardium remains to be further investigated.
III. Pericardium and Cardiorespiratory Interaction A. Influence of the Pericardium on Ventricular Loading
The effects of respiration on circulatory system require consideration of various mechanical stresses imposed over the heart, pulmonary circulation, and peripheral vascular beds during respiratory maneuvers. Changes in ventricular loading conditions produced by respiration lead to profound effects on cardiac performance, and therefore are of particular clinical significance. Experimental studies have demonstrated that the pericardium plays an important role in modulating such respiratoryinduced changes in ventricular preload and afterload. During spontaneous respiration, a decreased intrathoracic pressure and an increased abdominal pressure together enhance venous return from systemic circulation (34–36). The RV volume will increase due to the enhanced venous return (37,38), whereas the LV volume will decrease because of a mechanism known as diastolic ‘‘ventricular interdependence’’ (39–45). The increased RV volume would shift the septum leftward, producing a decrease in LV compliance and impairment of LV filling. The decrease in LV preload due to ventricular interdependence is considered to be a major mechanism causing pulsus paradoxus (46), i.e., an inspiratory decrease in arterial pressure associated with a decrease in LV stroke volume. The presence of the pericardium, by limiting the LV and RV volumes together, has been shown to be a dominant determinant of the degree of ventricular interdependence and pulsus paradoxus under many conditions (42,45). In addition to its effect on LV preload, negative intrathoracic pressure also directly increases the LV afterload (45,47,48). The decreased surrounding pressure of the LV would increase the transmural LV pressure, resulting in a decreased LV stroke volume. The increase in LV afterload is an alternative mechanism for pathogenesis of pulsus paradoxus. It would become a major factor under conditions when the LV is sensitive to small changes in afterload, e.g., heart failure, or under conditions with a marked negative pleural pressure, e.g., status asthmaticus or upper airway obstruction. Until recently, however, the role of the pericardium in modulating the effects of respiration on the LV afterload had not been well characterized. Using flat balloon sensors, we have studied changes in pericardial and extrapericardial pressures during negative intrathoracic pressure produced by phrenic nerve stimulation in dogs (15). The pericardial pressure over the LV did not fall as much as extrapericardial pleural pressure or esophageal pressure, with an increase in transpericardial pressure (pericardial pressure minus extrapericardial pressure) both at end systole and end diastole (Fig. 1). An enhanced systemic venous return would produce an increase in total ventricular volumes, resulting in an increased
264
Takata and Robotham
elastic recoil of the pericardium and hence the increased transpericardial pressure. Therefore in the presence of the pericardium, the true surrounding pressure over the LV is ‘‘less’’ negative than the applied negative intrathoracic pressure. This implies that the degree of the LV afterload produced by respiration is effectively attenuated by the pericardium. In an intuitive sense, with the presence of the pericardium around the heart, part of the imposed afterload (i.e., negative intrathoracic pressure) is not transferred to the LV surface, being consumed to expand the pericardial sac against the elastic recoil force of the pericardial tissue. The most common role ascribed to the pericardium in modulating cardiac performance is an external constraint of cardiac diastolic filling limiting ventricular preload. Our findings demonstrated that the pericardium also attenuates the effects of respiration on ventricular afterload, and would further lead to an appreciation of a more generalized role of the pericardium. The elastic recoil of the pericardium appears to ‘‘buffer’’ acute increases in both LV preload and afterload. Thus, a possible role of the pericardium is to limit acute changes in ventricular loading not only during respiration but also during any pharmacological, neural, humoral, or mechanical perturbation. For example, during exercise, there are large swings in intrathoracic and abdominal pressures, increased sympathetic tone, and increased venous pumping from muscular activity, which all result in acute changes in the total venous return and ventricular afterload. In such situations, the pericardium may prevent the overdistension of the heart, and assist ventricular ejection by attenuating increases in LV afterload. The pericardium may play an important role in maintaining hemodynamic stability under a wide variety of physiological and pathophysiologic conditions. B. Pericardial Versus Lung Constraint
Under normal closed-chest conditions, the lungs have macroscopically a direct contact with the pericardial surface, producing a focal pleural surface pressure over the heart (14,21,24,49–52). Thus, the total external constraint of the heart consists of two components, a load produced by the elastic recoil of the pericardium, i.e., pericardial constraint, and a load produced by the focal pleural surface pressure around the heart, i.e., lung constraint. Pericardial pressure relative to atmospheric pressure includes the influence of the extrapericardial pleural pressure (i.e., the lung constraint), representing the total external constraint of the heart. Pericardial pressure relative to extrapericardial pleural pressure, i.e., the transpericardial pressure, reflects only the component of pericardial constraint. With positive pressure ventilation, the effects of the lung constraint become apparent. The relative impact of pericardial versus lung constraint during positive end-expiratory pressure (PEEP) has been evaluated by several studies (14,21,24). Figure 2 illustrates typical changes in simultaneously measured pericardial and extrapericardial pressures over the LV during PEEP (24). With a PEEP of 0 cm H2O, most of the pericardial pressure was contributed by the transpericardial pressure. In contrast, with increases in PEEP, the pericardial pressure is mainly determined by the increased extrapericardial pleural pressure, as the component of transpericardial pressure decreased.
Heart-Pericardium-Lung Interactions
265
During spontaneous respiration, pleural pressure is normally negative throughout the chest cavity. Cardiac filling is usually facilitated by the negative pleural pressure, because it dominates over any focal contact stress produced by the apposition of the lung and heart. However, the presence of lung constraint may become important during spontaneous respiration, if the lung volume is abnormally elevated. For example, a ‘‘teardrop’’ heart is often observed in status asthmaticus despite a markedly negative generalized pleural pressure measured with a esophageal balloon (53). In this case, the lungs may impose a positive local surface pressure over the heart, limiting venous return. The same principle may account for some component of the exercise limitation in patients with COPD in whom air trapping markedly increases at elevated respiratory rates. It appears that the lungs act as a second pericardium as the lung volume increases, during either positive or negative pressure ventilation (24). Experimental studies looking at the relationships of maximal exercise and pericardiectomy also lend insight as to the potential role of the lung acting as a second pericardium. Michell and coworkers have shown an increase in maximal stroke volume, cardiac output, and oxygen consumption following pericardiectomy in dogs (3). It has also been observed that illicit use of pericardiectomy improves racing results in greyhound dogs (54). In both situations there appeared to be no harmful effects with the absence of the pericardium, and these experiments are often considered as direct evidence that the pericardium acts only to limit cardiac function and thus its presence is not particularly beneficial. However, it is important to appreciate that those data were taken from the normal closed-chest condition, a setting in which not just the pericardium but the lungs are present within the thorax in their normal anatomical relationships, exerting a restraining forces over the pericardium and heart, particularly as the heart volume increases. If the lung constraint were not present and the heart could expand as much as it wants, during maximal exercise with both a very large negative intrathoracic pressure and peripheral muscle ‘‘pump’’ augmenting venous return, the heart could expand too much, leading to deleterious hemodynamic effects. The presence of lung constraint might provide an explanation why animals and humans are able to survive without the pericardium.
IV. Pericardial Disease and Cardiac Chamber Interactions A. Hemodynamic Profiles of Pericardial Disease
A broad spectrum of pericardial diseases can be conceptually classified into two distinct clinical entities, i.e., cardiac tamponade and constrictive pericarditis (55). In cardiac tamponade, excessive accumulation of pericardial fluid due to any pathological process leads to an elevated pericardial constraint. The classic hemodynamic profile of tamponade includes elevation and equilibration of RV and LV diastolic pressures with pericardial pressure, reduced cardiac output and hypotension, and pulsus paradoxus (56,57). Compensatory mechanisms in response to reduced cardiac output, including baroreflex-mediated tachycardia and vasoconstriction, further modulate the clinical presentation of tamponade. The hallmark of constrictive pericarditis is a thickened, noncompliant, and adherent pericardium that restricts filling
266
Takata and Robotham
of cardiac chambers. The pericardial constraint is markedly elevated owing to pathological changes in the elastic properties of the pericardial tissue itself. The pericardial pressure in constriction should be elevated, if it can be appropriately measured in the adhesive pericardial space. Thus, the clinical manifestations of constrictive pericarditis have many similarities to that of cardiac tamponade; i.e., reduced cardiac output, hypotension, tachycardia, and elevated atrial and RV and LV diastolic pressures. This is not surprising, because the key pathophysiological problem is common between the two forms of pericardial disease, i.e., an abnormally elevated pericardial constraint and pericardial pressure. Despite these similarities, it has also been documented, and indeed has challenged physiologists and cardiologists for decades, that considerable differences are present in hemodynamic profiles between cardiac tamponade and constrictive pericarditis. There are classic observations of differences in vascular pressure waveforms in pericardial diseases. With tamponade, the systolic x descent in atrial pressure becomes prominent whereas the diastolic y descent is attenuated (55,58). With constriction, atrial pressure shows a prominent y descent with a relatively small x descent, and ventricular diastolic pressure often exhibits a ‘‘dip and plateau’’ pattern, i.e. a steep transient decrease at early diastole followed by a relatively unchanged portion during late diastole (55,59). Experimental studies further demonstrated that venous flow waveforms, normally biphasic with one peak during ventricular systole and the other during ventricular diastole (35,36,60), are also altered in pericardial diseases. With an experimental tamponade in dogs, we found that the biphasic pattern in venous flows was replaced by a predominant systolic flow with an almost absent diastolic component (61), consistent with Doppler studies in dogs and humans that measured flow velocities in superior vena cava or hepatic vein (62–65). In contrast, with constriction, an enhanced diastolic venous flow with a relatively small systolic component was observed by Doppler studies in humans (62,64–66). These observations imply that the manner in which the pericardium constrains the heart may be quite different between tamponade and constriction despite similarly increased pericardial pressure. Since atrial filling is almost limited to the time of ventricular emptying in tamponade, the degree of a vertical cardiac chamber interaction between an atrium and its ipsilateral ventricle, termed ‘‘atrio-ventricular interaction’’ (61), appears to be enhanced with tamponade pathology. The differences in venous pressure and flow waveforms may be related to the unique nature of pericardial constraint specific to each pericardial pathology, and its influence on the atrioventricular interactions. In addition to those steady-state vascular pressure and flow changes, respiratory-induced hemodynamic signs are manifested differently in cardiac tamponade and constrictive pericarditis. Pulsus paradoxus is observed more often in tamponade than constriction (67). Kussmaul’s sign, a paradoxical inspiratory increase in right atrial pressure, is occasionally associated with constriction but rarely with tamponade (58,59). As described earlier, respiration produces large changes in right heart volume due to an increase in systemic venous return, which then decrease left heart filling via ventricular interdependence leading to pulsus paradoxus. Thus, the status of ventricular interdependence, i.e., a mechanism of horizontal cardiac chamber in-
Heart-Pericardium-Lung Interactions
267
teraction, seems to be different in nature or degree between tamponade and constriction. The effects of pericardial constraint on ventricular interdependence might also explain the differences in incidence of Kussmaul’s sign in the two forms of pericardial diseases. B. Coupled Versus Uncoupled Pericardial Constraint
In an attempt to understand pathogenesis for the hemodynamic differences between tamponade and constriction, we have developed a conceptual framework characterizing the influence of the pericardial constraint on cardiac chamber interactions, based on a novel concept of ‘‘coupled versus uncoupled’’ pericardial constraint (68). We hypothesized that the nature of the pericardial constraint can be classified as one of two types: (1) a coupled constraint exerted by uniform pericardial liquid pressure over all four cardiac chambers, and (2) an uncoupled constraint produced by independent and different local pericardial surface pressures over each cardiac chamber. The essence of this theory is that a coupled constraint restricts the volumes of four cardiac chambers together, while an uncoupled constraint independently restricts the volume of each cardiac chamber. As described earlier, under normal conditions the pericardial pressure is essentially a regional surface pressure. With cardiac tamponade, the regional differences in pericardial pressure are abolished and replaced by a uniform liquid pressure due to a liquid column in the pericardial space. On the contrary, with constrictive pericarditis, most of the pericardium would still maintain its macroscopic contact with the heart surface, and the pericardial pressure should be of regional nature (i.e., related to the underlying chamber volume) unless a large amount of effusion is present in addition to constrictive pathology. It is thus reasonable to apply the coupled vs. uncoupled constraint concept to the interpretation of hemodynamic events with cardiac tamponade and constrictive pericarditis. Based on this reasoning, the effects of pericardial constraint on cardiac chamber interactions, on both vertical and horizontal chamber interactions, were studied by use of mathematical model analyses (68). As will be described below, the coupled versus uncoupled constraint concept offers a useful unifying theory to understand the pericardial constraint of the heart in normal and disease states, and provides insights to develop better diagnostic and therapeutic strategies in pericardial disease. C. Pericardial Constraint and Atrioventricular Interaction
To study the effects of coupled versus uncoupled pericardial constraint on flowmediated atrioventricular interaction; an open-loop mathematical model of right heart circulation was constructed (68). As illustrated in Figure 3, the RA and RV were modeled by time-varying elastances (Era and Erv) connected with systemic venous and pulmonary arterial impedances, and a ‘‘coupled’’ constraint was modeled by adding a single pericardial elastance (Epe) over both Era and Erv while an ‘‘uncoupled’’ constraint was modeled by adding two different pericardial elastances (Epera and Eperv) on Era and Erv . Differential equations defining the behavior of the model were numerically solved on a computer, and the effects of increases in pericardial
268
Takata and Robotham
Figure 3 An electrical analog of the mathematical model of atrioventricular interaction with pericardial constraint. The model is a lumped, linear parameter, open-loop model including all elements of the right heart circulation. The RA and RV were characterized as timevarying elastances (Era and Erv). The systemic venous system was modeled by an upstream pressure source (Pu) and a four-element venous impedance network including a capacitance (Cv), an inertance (Lv), and two resistances (Rvd and Rvp). The pulmonary arterial system consists of a three-element Windkessel impedance network including a capacitance (Cp) and two resistances (Rpp and Rpd), and a downstream pressure source (Pd ). Two one-way valves, represented by diodes, were interposed between Era and Erv (tricuspid valve) and between Erv and the pulmonary arteries (pulmonic valve). A resistance placed between Era and Erv represents transtricuspid valve resistance (Rt). The driving force for flow in the model is provided by a pressure gradient between Pu and Pd , and periodic increases in Era and Erv with the two competent valves. A coupled pericardial constraint was modeled by adding a ‘‘single’’ external elastance (Epe) over both the right atrial and ventricular elastances (Era and Erv), while an uncoupled pericardial constraint was modeled by adding two ‘‘separate’’ external elastances (Epera and Eperv) on Era and Erv respectively. Pp, pressure at the pulmonary arterial capacitance; Ppe , pericardial pressure over both RA and RV for coupled constraint; Ppera, pericardial pressure over RA for uncoupled constraint; Ppera, pericardial pressure over RV for uncoupled constraint; Pra , RA pressure; Prv, RV pressure; Pv, pressure at the systemic venous capacitance; Qp, pulmonary arterial flow; Qt , tricuspid flow; Qv, combined vena caval flow. (From Ref. 68.)
Heart-Pericardium-Lung Interactions
269
elastances were simulated (Fig. 4). With increases in Epe (coupled constraint), the venous flow became a predominantly systolic flow and the RA pressure showed a prominent x descent. With increases in Epera and Eperv (uncoupled constraint), the venous flow became a predominantly diastolic flow, with a markedly attenuated A wave in tricuspid flow. The RA pressure showed a prominent y decent, with a ‘‘dip and plateau’’ pattern in RV pressure. The model therefore well approximated the characteristic steady-state venous flow and pressure changes observed in pericardial diseases; increased coupled constraint accounted for the patterns in tamponade, and increased uncoupled constraint accounted for those in constriction. Why do such characteristic flow and pressure patterns take place with the increased coupled or uncoupled constraint? An intuitive explanation could be made when appreciating that the RA pressure, the downstream pressure for systemic venous return, is determined almost entirely by the pericardial pressure in severe forms of both pericardial diseases (55,58,59). With tamponade (coupled), ‘‘elevated’’ and ‘‘uniform’’ pericardial pressure restricts the heart as a whole, coupling changes in all cardiac chamber volumes. During systole, ventricular ejection reduces the intrap-
Figure 4 Simulation traces in the mathematical model of atrioventricular interaction, showing changes in combined vena caval flow (Qv), tricuspid flow (Qt), RA pressure (Pra), and RV pressure (Prv) with increases in pericardial constraint. Panel A: control condition with no pericardial elastance; panel B: increased coupled constraint (Epe⫽2.5); panel C: increased uncoupled constraint (Epera ⫽ Eperv ⫽ 5.0). S, ventricular systole; D, ventricular diastole; E, rapid filling wave in tricuspid flow; A, atrial contraction component in tricuspid flow; x, x descent in RA pressure; y, y descent in RA pressure. See text for further explanation. (From Ref. 68.)
270
Takata and Robotham
ericardial volume and pericardial pressure, resulting in an decrease in RA pressure (x descent) and a systolic antegrade venous flow. If sufficient volume can move into the RA to replace the ejected stroke volume, the decreased pericardial and RA pressure will return to baseline with the venous flow approaching zero at end systole. During diastole, the atrial emptying and ventricular filling, i.e., intrapericardial volume transfer, do not affect the pericardial pressure. Thus the RA pressure should be minimally changed (diminished y descent), leading to an almost absent diastolic venous flow. With constriction (uncoupled), ‘‘elevated’’ and ‘‘regional’’ pericardial pressures individually restrict the atrial and ventricular volumes. During systole, ventricular ejection decreases the pericardial pressure over the ventricle but not over the atrium. Thus, the RA pressure shows little change during systole (diminished x descent) with a small systolic venous flow. During diastole, the atrial emptying into the ventricle produces a decrease in pericardial pressure over the atrium. The resultant decrease in RA pressure ( y descent) will enhance venous return, producing a diastolic antegrade venous flow. The model also allows analyses of atrial function in relation to ventricular filling in pericardial diseases (68). In tamponade, the predominant diastolic venous flow implies that the RA fills with a volume nearly equal to stroke volume during systole and empties it into the RV during the succeeding diastole. Direct filling of RV from the venous system is minimum during diastole. Thus, the atrium does not function well as a passive ‘‘conduit’’ for venous return during diastole, while it serves as an efficient ‘‘reservoir’’ for ventricular filling. On the other hand, in constrictive pericarditis, the predominant diastolic venous flow means that the atrium serves effectively as a passive ‘‘conduit’’ but not as a ‘‘reservoir,’’ and the decreased A wave in tricuspid flow suggest that contribution of atrial contraction to ventricular filling, a ‘‘booster’’ function, is diminished. Our findings, together with previous experimental studies in the literature (61– 66), suggest that echocardiographic observation of changes in atrioventricular volumes within a cardiac cycle may provide an useful alternative strategy for early diagnosis of tamponade or constrictive physiology. Marked coupling between atrial and ventricular volume changes (i.e., reciprocal changes during a cardiac cycle) with a dominant systolic venous flow patterns should be useful signs of cardiac tamponade, while minimal changes in atrial volume and predominant diastolic venous flow should suggest a constrictive pericarditis. D. Pericardial Constraint and Ventricular Interdependence
To study the effects of coupled versus uncoupled pericardial constraint on pressuremediated ventricular interdependence, we have developed a simple analytical model of interdependence (68) based on the volume elastance model by Sunagawa and colleagues (69) (see Fig. 5). The LV and RV were assumed to consist of three volume elastances—LV free wall (Elvf ), RV free wall (Ervf ) and septum (Es )—with all myocardium-mediated interactions being conceptually integrated into the interaction via the septal elastance. Coupled versus uncoupled pericardial constraints were modeled as additional volume elastances (Epe in coupled constraint; Epeiv and Epervin
Heart-Pericardium-Lung Interactions
271
Figure 5 Schematic illustration of the analytical model of ventricular interdependence with pericardial constraint. The LV and RV were assumed to consist of three volume elastances, i.e., LV free wall (Elvf ), RV free wall (Ervf ) and septum (Es). Vlvf and Vrvf were defined as the volumes of the LV and RV when the transseptal pressure is zero, i.e., LV pressure (Plv) and RV pressure (Prv) are equal. Vs was defined as the volume contribution of the septal shift to either ventricle when the transseptal pressure is not zero. In this model, all myocardium-mediated interactions, including transseptal as well as transcommon fiber interactions, are conceptually integrated into the interaction through the septal elastance. Coupled and uncoupled pericardial constraints were modeled as additional volume elastances. With a coupled pericardial constraint, both ventricles were assumed to share a single external elastance (Epe) and a uniform pericardial liquid pressure (Ppe). With an uncoupled constraint, two separate external elastances (Epelv and Eperv and regional pericardial surface pressures (Ppelvand Pperv) were added over each ventricle independently. (From Ref. 68.)
uncoupled constraint) in a similar fashion to the model of atrioventricular interaction. In this model, three parameters which directly characterize the ‘‘status’’ of ventricular interdependence were defined. Right-to-left volume interdependence gain: GV ⫽
∂Plv ∂Vrv
Right-to-left pressure interdependence gain: GP ⫽
∂Plv ∂Plv ⫽ ∂Prv ∂Vrv
冫 ∂P ∂V
rv
rv
272
Takata and Robotham
Effective RV elastance with interdependence: Erveff ⫽
∂Prv ∂Vrv
where GV and GP represent the degree of ventricular interdependence or ‘‘cross-talk gains,’’ and Erveff reflects an effective elastance of the combined RV and LV seen from the systemic venous port, under conditions when interdependence is present. Analytical solution of the model enables us to express these interdependence parameters as functions of the pericardial elastances. With no pericardial constraint: GV ⫽
Elvf ⋅ Ervf Es ⫹ Elvf ⫹ Ervf
GP ⫽
Elvf Es ⫹ Elvf
Erveff ⫽
(Es ⫹ Elvf )Ervf Es ⫹ Elvf ⫹ Ervf
With the coupled constraint: GV ⫽
Elvf ⋅ Ervf ⫹ Epe Es ⫹ Elvf ⫹ Ervf
GP ⫽
冢
Erveff ⫽
Elvf ⋅ Ervf ⫹ Epe Es ⫹ Elvf ⫹ Ervf
冣冫冢
(Es ⫹ Elvf ) Ervf ⫹ Epe Es ⫹ Elvf ⫹ Ervf
冣
(Es ⫹ Elvf) Ervf ⫹ Epe Es ⫹ Elvf ⫹ Ervf
With the uncoupled constraint: GV ⫽ GP ⫽
(Elvf ⫹ Epelv )(Ervf ⫹ Eperv ) Es ⫹ (Elvf ⫹ Epelv ) ⫹ (Ervf ⫹ Eperv ) Elvf ⫹ Epelv Es ⫹ (Elvf ⫹ Epelv)
Erveff ⫽
{Es ⫹ (Elvf ⫹ Epelv )}(Ervf ⫹ Eperv ) Es ⫹ (Elvf ⫹ Epelv ) ⫹ (Ervf ⫹ Eperv )
These equations, although they look complex at first glance, actually clarify important aspects of how the pericardial constraint affects the ventricular interdependence. Both the coupled and uncoupled constraints enhanced the interdependence gains as well as the effective RV elastance, but the way of enhancement was ‘‘qualitatively’’ different between the two constraint conditions. As shown clearly in the
Heart-Pericardium-Lung Interactions
273
formulae, a coupled constraint (Epe) increases these parameters in a totally different fashion from ventricular elastances, while uncoupled constraints (Epelv and Eperv) increase them essentially in a similar manner to the free-wall elastances. In other words, the coupled pericardium would provide a unique interdependence mechanism in addition to the already present myocardium-mediated interactions, whereas the uncoupled pericardium would behave as additional free walls, increasing the effective stiffness of the LV and RV free walls and augmenting the myocardium-mediated transseptal interactions. The model also demonstrated that the degree of enhancement of ventricular interdependence is ‘‘quantitatively’’ different between the coupled versus uncoupled constraint conditions (68) (see Fig. 6). At a given level of the total pericardial elastance, the interdependence gains (GV and GP) were higher with the coupled than the uncoupled constraint. On the other hand, the effective RV elastance (Erveff) was higher with the uncoupled than the coupled constraint. A question follows as to why such quantitative differences in the degree of interdependence are observed between the two constraint conditions. Appreciation of the difference in enhancement mechanisms may give us a clue for an explanation. As the degree of the pericardial constraint increases, the coupled pericardium produces a complete intrapericardial volume coupling between the two ventricles, whereas the uncoupled pericardium only provides a partial volume coupling by enhancing the already present transseptal interaction. GV and GP should therefore be larger with the coupled than the uncoupled constraint. With the coupled constraint, the RV is connected to the elastance of the total pericardium, while with the uncoupled constraint the RV is connected only to the elastance of the right-sided pericardium, and its connection to the left-sided pericardium is mediated by the transseptal interaction. Since the elastance of a regional portion of the pericardium should be larger than the total pericardial elastance, it is likely that the Erveff increases more with the uncoupled than the coupled constraint at a given level of pericardial stiffness. The differences between the two constraint conditions should increase as the influence of trans-septal interaction is attenuated by increases in Es (Fig. 6). E. Pulsus Paradoxus and Kussmaul’s Sign in Pericardial Disease
The interdependence parameters defined in the analytical model are also useful to predict the likelihood that the respiratory-induced hemodynamic signs will be manifest under the coupled or uncoupled constraint conditions. As the interdependence gains (GV and GP) increase, the inspiratory increase in RV volume or pressure would produce a greater rise in transmural LV diastolic pressure (relative to pleural pressure) at a given LV volume. The inspiratory rise in effective LV diastolic elastance would therefore be greater with higher values of GV and GP. This results in larger decreases in LV filling from the pulmonary circulation, thereby increasing the degree or likelihood of pulsus paradoxus (40,45). Analyses based on the quantitative changes in interdependence gains thus provide a reasoning why a pulsus paradoxus is manifest not only in cardiac tamponade but also in constrictive pericarditis, and
274
Takata and Robotham
Figure 6 Quantitative assessment of changes in the interdependence parameters with increases in the total pericardial elastance (Epetotal). Epe for the coupled constraint and Epelv and Eperv for the uncoupled constraint were increased to achieve the same value of Epetotal. Panel A: changes in right-to-left volume interdependence gain (GV ); panel B: changes in right-toleft pressure interdependence gain (GP); panel C: changes in effective RV elastance with interdependence (Erveff). At a given level of Epetotal , GV and GP were higher with the coupled (solid line) than the uncoupled (dashed line) constraint. This implies that a pulsus paradoxus should be manifest more frequently in the coupled (tamponade) than the uncoupled constraint (constriction). In contrast, Erveff were higher with the uncoupled than the coupled constraint, suggesting that the likelihood of Kussmaul’s sign is more with the uncoupled (constriction) than the coupled constraint (tamponade). Note that the differences in GV, GP, and Erveff between the coupled and uncoupled constraint conditions became larger as the septal elastance (Es) increased from 2.5, 5 to 10 and the myocardium-mediated interaction decreased. (From Ref. 68.)
why it should be observed to a greater extent or more frequently with tamponade (coupled) than constriction (uncoupled). Kussmaul’s sign has long been accepted as an useful clinical sign for constrictive pericardial pathology in the cardiology textbooks (58,59), yet its pathogenesis had not been well understood. It was controversial whether a normally observed inspiratory increase in systemic venous return is associated with a Kussmaul’s sign, or the rise in RA pressure implies a decrease in venous return. If the Kussmaul’s
Heart-Pericardium-Lung Interactions
275
sign is associated with an increase in venous return, there must be a greater increase in the upstream extrathoracic venous pressure than the increase in RA pressure. We have demonstrated in canine experiments that a Kussmaul’s sign should only occur during inspiration with an active diaphragmatic descent (36). When an inspiratory increase in systemic venous return is mainly attributed to a large increase in abdominal pressure, the rise in transmural RA pressure may exceed the fall in pleural pressure, leading to manifestation of a Kussmaul’s sign. Indeed, in Kussmaul’s original description, the sign was elicited better by a large inspiration, presumably involving a greater degree of diaphragmatic descent in a supine position, thus raising abdominal pressure (46). Under conditions of uncoupled pericardial constraint, a greater effective RV elastance (Erveff ) is more likely to be achieved, and in this situation the inspiratory increase in right heart volume would produce greater increases in transmural RV diastolic or RA pressure relative to pleural pressure. This is consistent with the classic observation that a Kussmaul’s sign is observed relatively frequently in constrictive pericarditis (uncoupled) but rarely in cardiac tamponade (coupled). In an intuitive sense, with constriction only the elastances of the right heart and right sided pericardium accept the enhanced venous return, whereas with tamponade the left sided pericardium would also participate in buffering the effects of the increased right heart volume, resulting in a decreased likelihood of a Kussmaul’s sign at a similar level of total pericardial constraint.
V.
Conclusions
The pericardium plays a substantial role in modulating cardiovascular hemodynamics and interactions between the heart and lungs. To analyze the constraining effects of the pericardium, the concept of pericardial liquid versus surface pressures is essential. The pericardium under normal conditions not only limits cardiac preload but also attenuates changes in LV afterload during respiration. The presence of the pericardium, and to a lesser degree the presence of the lungs, may contribute to maintaining hemodynamic stability under a variety of physiological and pathological conditions. Analyses of the differences in hemodynamic profiles between cardiac tamponade and constrictive pericarditis lead to insights as to how the pericardium constrains the heart. Based on a novel concept of ‘‘coupled versus uncoupled’’ pericardial constraint, the effects of pericardial constraint on cardiac chamber interactions can be mathematically characterized. The model analyses indicated that coupled versus uncoupled constraint can explain the differences in venous flows and right atrial/ventricular pressures observed in tamponade and constriction. Coupled constraint (tamponade) should produce greater interdependence gains, increasing the occurrence of pulsus paradoxus, whereas uncoupled constraint (constriction) is associated with a greater effective right ventricular elastance, increasing the likelihood of Kussmaul’s sign. Understanding of pathophysiology of pericardial diseases and a theoretical framework based on the coupled versus uncoupled constraint concept are useful to interpret complex heart-pericardium-lung interactions in various clinically relevant conditions.
276
Takata and Robotham Acknowledgments
The authors thank Mosby–Year Book Inc. for permission to extensively adapt and modify the following book chapter: Takata M, Robotham JL: Pericardial effusion and tamponade. In: Critical Heart Disease in Infants and Children. Nichols DG, Cameron DE, Greeley WJ, Lappe DG, Ungerleider RM, Wetzel RC, eds. St. Louis, Mosby–Year Book, 1995:255–273. We also express our appreciation to Drs. W. Mitzner, S. Beloucif, and Y. Harasawa for their critical contributions during the development of our experimental studies, and Miss J. Woods for her secretarial assistance. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
Moore RL. Congenital deficiency of the pericardium. Arch Surg 1925; 11:765. Beppu S, Naito H, Matsuhisa M, Miyatake K, Nimura Y. The effects of lying position on ventricular volume in congenital absence of the pericardium. Am Heart J 1990; 120:1159– 1166. Stray-Gundersen J, Musch TI, Haidet GC, Swain DP, Ordway GA, Mitchell JH. The effect of pericardiectomy on maximal oxygen consumption and maximal cardiac output in untrained dogs. Circ Res 1986; 58:523–530. Ebert PA, Najafi H. The pericardium. In: Sabiston DCJ, Spencer FC, eds. Surgery of the Chest. Philadelphia: W.B. Saunders, 1990:1230–1249. Rhode EA. Physiology of the normal pericardium. In: Reddy PS, Leon DF, Shaver JA, eds. Pericardial Disease. New York: Raven Press, 1982:31–47. Rabkin SW, Berghaus DG, Bauer HF. Mechanical properties of the isolated canine pericardium. J Appl Physiol 1974; 36:69–73. Wiegner AW, Bing OHL, Borg TK, Caulfield JB. Mechanical and structural correlates of canine pericardium. Circ Res 1981; 49:807–814. Lee MC, Fung YC, Shabetai R, LeWinter MM. Biaxial mechanical properties of human pericardium and canine comparisons. Am J Physiol 1987; 253:H75–H82. Naimark WA, Lee JM, Limeback H, Cheung DT. Correlation of structure and viscoelastic properties in the pericardia of four mammalian species. Am J Physiol 1992; 263:H1095– H1106. Freeman GL, LeWinter MM. Pericardial adaptations during chronic cardiac dilation in dogs. Circ Res 1984; 54:294–300. Shabetai R. Pericardial and cardiac pressure. Circulation 1988; 77:1–5. Holt JP, Rhode EA, Kines H. Pericardial and ventricular pressure. Circ Res 1966; 8:1171– 1181. Smiseth OA, Frais MA, Kingma I, Smith ER, Tyberg. JV. Assessment of pericardial constraint in dogs. Circulation 1985; 71:158–164. Freeman GL, LeWinter MM. Determinants of intrapericardial pressure in dogs. J Appl Physiol 1986; 60:758–764. Takata M, Mitzner W, Robotham JL. Influence of the pericardium on ventricular loading during respiration. J Appl Physiol 1990; 68:1640–1650. Agostoni E. Mechanics of the pleural space. Physiol Rev 1972; 52:57–128. Permutt S, Caldini P. Tissue pressures and fluid dynamics of the lungs. Fed Proc 1976; 35: 1876–1880. Tsitlik JE, Halperin HR, Guerci AD, Dvorine LS, Popel AS, Siu CO, Yin FCP, Weisfeldt ML. Augmentation of pressure in a vessel indenting the surface of the lung. Ann Biomed Eng 1987; 15:259–284. Tyberg JV, Taichman ER, E.R.Smith, Douglas NWS, Smiseth OA, Keon WJ. The relationship between pericardial pressure and right atrial pressure: an intraoperative study. Circulation 1986; 73:428–432.
Heart-Pericardium-Lung Interactions 20. 21.
22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.
277
Smiseth OA, Douglas NWS, Thompson CR, Smith ER, Tyberg JV. Nonuniformity of pericardial surface pressure in dogs. Circulation 1987; 75:1229–1236. Kingma I, Smiseth OA, Frais MA, Smith ER, Tyberg JV. Left ventricular external constraint: relationship between pericardial, pleural and esophageal pressures during positive end-expiratory pressure and volume loading in dogs. Ann Biomed Eng 1987; 15:331– 346. Hoit BD, Lew WYW, LeWinter M. Regional variation in pericardial contact pressure in the canine ventricle. Am J Physiol 1988; 255:H1370–H1377. Scharf SM, Brown R, Warner KG, Khuri S. Intrathoracic pressures and left ventricular configuration with respiratory maneuvers. J Appl Physiol 1989; 66:481–491. Takata M, Robotham JL. Ventricular external constraint by the lung and pericardium during positive end-expiratory pressure. Am Rev Respir Dis 1991; 143:872–875. Bartle SH, Hermann HJ, Cavo JW, Moore RA, Costenbader JM. Effect of the percardium on left ventricular volume and function in acute hypervolemia. Cardiovasc Res 1968; 3: 284–289. Spotnitz HM, Kaiser GA. The effect of the pericardium on pressure-volume relations in the canine left ventricle. J Surg Res 1971; 11:375–380. LeWinter MM, Pavelec R. Influence of the pericardium on left ventricular end-diastolic pressure-segment relations during early and later stages of experimental chronic volume overload in dogs. Circ Res 1982; 540:501–509. Kuno Y. The significance of the pericardium. J Physiol 1915; 50:1–36. Hamilton DR, Dani RS, Semlacher RA, Smith ER, Kieser TM, Tyberg JV. Right atrial and right ventricular transmural pressures in dogs and humans. Effects of the pericardium. Circulation 1994; 90:2492–2500. Slinker BK, Ditchey RV, Bell SP, LeWinter MM. Right heart pressure does not equal pericardial pressure in the potassium chloride-arrested canine heart in situ. Circulation 1987; 76:357–362. Miyazaki T, Pride HP, Zipes DP. Prostaglandins in the pericardial fluid modulate neural regulation of cardiac electrophysiological properties. Circ Res 1990; 66:163–75. Miyazaki T, Zipes DP. Pericardial prostaglandin biosynthesis prevents the increased incidence of reperfusion-induced ventricular fibrillation produced by efferent sympathetic stimulation in dogs. Circulation 1990; 82:1008–1019. Mebazaa A, Wetzel RC, Dodd-o JM, Redmond EM, Shah AM, Maeda K, Maistre G, Lakatta EG, Robotham JL. Potential paracrine role of the pericardium in the regulation of cardiac function. Cardiovasc Res 1998; 40:332–342. Takata M, Wise R, Robotham JL. Effects of abdominal pressure on venous return: abdominal vascular zone conditions. J Appl Physiol 1990; 69:1961–1972. Takata M, Robotham JL. Effects of inspiratory diaphragmatic descent on inferior vena caval venous return. J Appl Physiol 1992; 72:597–607. Takata M, Beloucif S, Shimada M, Robotham JL. Superior and inferior vena caval flows during respiration: pathogenesis of Kussmaul’s sign. Am J Physiol 1992; 262:H763– H770. Olsen CO, Tyson GS, Maier GW, Davis JW, Rankin JS. Diminished stroke volume during inspiration: a reverse thoracic pump. Circulation 1985; 72:668–679. Robotham JL. Hemodynamic consequences of mechanical ventilation. Acta Anaesthesiol Scand 1987; 36:7–52. Scharf SM, Brown R, Saunders N, Green LH. Effects of normal and loaded spontaneous inspiration on cardiovascular function. J Appl Physiol 1979; 47:582–590. Brinker JA, Weiss JL, Lappe DL, Rabson JL, Summer WR, Permutt S, Weisfeldt ML. Leftward septal displacement during right ventricular loading in man. Circulation 1980; 61: 623–633. Wead WB, Norton JF. Effects of intrapleural pressure changes on canine left ventricualr function. J Appl Physiol 1981; 50:1027–1035. Bove AA, Santamore WP. Ventricular interdependence. Prog Cardiovasc Dis 1981; 23:365– 388. Cassidy SS, Wead WB, Seibert GB, Ramanathan M. Changes in left ventricular geometry during spontaneous breathing. J Appl Physiol 1987; 63:803–811.
278 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69.
Takata and Robotham Peters J, Kindred MK, Robotham JL. Transient analysis of cardiopulmonary interactions. I. Diastolic events. J Appl Physiol 1988; 64:1506–1517. Peters J, Fraser C, Stuart RS, Baumgartner W, Robotham JL. Negative intrathoracic pressure independently decreases both left ventricular inflow and outflow. Am J Physiol 1989; 257: H120–H131. Kussmaul A. Ueber schwielige Mediastino-Pericarditis und den paradoxen Puls. Klin Wschr 1873; 10:443. Hausknecht MJ, Brin KP, Weisfeldt ML, Permutt S, Yin FCP. Effects of left ventricular loading by negative intrathoracic pressure in dogs. Circ Res 1988; 62:620–631. Peters J, Kindred MK, Robotham. JL. Transient analysis of cardiopulmonary interactions. II. Systolic events. J Appl Physiol 1988; 64:1518–1526. Fewell JE, Abendschein DR, Carlson CJ, Rapaport E, Murray JF. Mechanism of decreased right and left ventricular end-diastolic volumes during continuous positive-pressure ventilation in the dog. Circ Res 1980; 47:467–472. Marini JJ, Culver BH, Butler J. Mechanical effect of lung distention with positive pressure on cardiac function. Am Rev Respir Dis 1981; 124:382–386. Lloyd TC Jr. Respiratory system compliance as seen from the cardiac fossa. J Appl Physiol 1982; 53:57–62. Wallis T, Robotham JL, Compean R, Kindred MK. Mechanical heart-lung interaction with positive end-expiratory pressure. J Appl Physiol 1983; 54:1039–1047. Stalcup SA, Mellins RB. Mechanical forces producing pulmonary edema in acute asthma. N Engl J Med 1977; 297:592–596. Shabetai R. The Pericardium. New York: Grune & Stratton, 1981:101. Shabetai R, Fowler NO, Guntheroth WG. The hemodynamics of cardiac tamponade and constrictive pericarditis. Am J Cardiol 1970; 26:480–489. Reddy PS, Curtiss EI, O’Toole JD, Shaver JA. Cardiac tamponade: hemodynamic observations in man. Circulation 1978; 58:265–272. Reddy PS, Curtiss EI, Uretsky BF. Spectrum of hemodynamic changes in cardiac tamponade. Am J Cardiol 1990; 66:1487–1491. Reddy PS. Hemodynamics of cardiac tamponade in man. In: Reddy PS, Leon DF, Shaver JA, eds. Pericardial Disease. New York: Raven Press, 1982:161–185. Reddy PS. Hemodynamics of constrictive pericarditis. In: Reddy PS, Leon DF, Shaver JA, eds. Pericardial Disease. New York: Raven Press, 1982:275–297. Appleton CP, Hatle LK, Popp RL. Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 1987; 10:1032–1039. Beloucif S, Takata M, Shimada M, Robotham JL. Influence of pericardial constraint on atrio-ventricular interactions. Am J Physiol 1992; 263:H125–H134. Linden R, Byrd BF. Superior vena cava Doppler: a non-invasive method for the diagnosis of pericardial disease. Int J Cardiol 1987; 16:145–153. Appleton CP, Hatle LK, Popp RL. Cardiac tamponade and pericardial effusion: respiratory variation in transvalvular flow velocities studied by Doppler echocardiography. J Am Coll Cardiol 1988; 11:1020–1030. Byrd BF, Linden RW. Superior vena cava doppler flow velocity patterns in pericardial disease. Am J Cardiol 1990; 65:1464–1470. Borganelli M, Byrd BF. Doppler echocardiography in pericardial disease. In: Schiller NB, ed. Cardiology Clinics: Doppler Echocardiography. Philadelphia: W.B. Saunders, 1990: 333–348. Hatle LK, Appleton CP, Popp RL. Differentiation of constrictive pericarditis and restrictive cardiomyopathy by doppler echocardiography. Circulation 1989; 79:357–370. Shabetai R. The pathophysiology of pulsus paradoxus in cardiac tamponade. In: Reddy PS, Leon DF, Shaver JA, eds. Pericardial Disease. New York: Raven Press, 1982:215– 230. Takata M, Harasawa Y, Beloucif S, Robotham JL. Coupled vs. uncoupled pericardial constraint: effects on cardiac chamber interactions. J Appl Physiol 1997; 83:1799–813. Maughan WL, Sunagawa K, Sagawa K. Ventricular systolic interdependence: volume elastance model in isolated canine hearts. Am J Physiol 1987; 253:H1381–H1390.
11 Dynamic Volumetric Imaging-Based Assessment of the Intrathoracic Milieu
ERIC A. HOFFMAN
BINH Q. TRAN
University of Iowa College of Medicine Iowa City, Iowa
Catholic University Washington, D.C.
I.
Introduction
The effect of breathing on cardiac performance has long been suspected. As early as 1853, Donders (1) made observations that spontaneous inspiration has the dual effect of increasing the return of venous blood to the heart while decreasing the ejection of blood into the systemic circulation. Since Donders, many others have investigated the effects of breathing on right and left heart dynamics. Most studies have required invasive surgical techniques to open the chest and insert instrumentation (i.e., ultrasonic flowmeters, pressure-tip or liquid-filled catheters, implanted metallic markers) (2–4) to facilitate measurement of hemodynamic and cardiac dimensional changes in response to various breathing protocols. Similarly difficult instrumentation challenges have been faced by those studies interested in evaluating the role of the intrathoracic environment on pulmonary function. Because of the complex interplay between the heart and lungs within the thorax, these invasive procedures most certainly alter the normal interaction between the two physiologic systems. The heart and lungs are dynamic organ systems functioning within the unique negative pressure environment of the intact thorax. Noninvasive imaging has afforded the opportunity to study the interdependence of these organ structures with evaluation focused both on intra and inter organ relationships. It is through recognition of these interdependence phenomena that one begins to appreciate their importance to the prediction of the total mechanical response of the cardiopulmonary 279
280
Hoffman and Tran
system. This can be achieved in part by piecing together individual response characteristics determined while other components of the system are held in isolation. In this chapter, we take the opportunity to present observations made from what has been termed dynamic (5) and electron beam (6) X-ray computed tomography (CT) as well as observations obtained utilizing magnetic resonance imaging (MRI). We will discuss the notion of the heart as a constant volume pump, minimizing energy expenditure as blood is pumped through the pulmonary and systemic vascular beds. In discussing the interactions between the heart and lungs, we note that there are both heart-lung and lung-heart interactions as they effect both cardiac and pulmonary function. A discussion regarding the effect of the heart on the lung and the use of X-ray CT to study pulmonary blood flow and ventilation is presented elsewhere in this series (7). The overall theme of the research presented in this chapter is systems integration serving to dictate function and to promote functional efficiency. The advent of medical imaging modalities, such as diagnostic X-ray, ultrasound, positron emission tomography (PET), single-photon emission computed tomography (SPECT), X-ray CT, MRI, etc., has provided the opportunity to non-invasively study cardiac and pulmonary structure and function without disturbing the cardiac milieu. While each of the above imaging modalities is currently being used to study cardiac and/or pulmonary function, only MRI (echo-planar, EPI discussed below) and dynamic X-ray CT are capable of providing both structural and functional information of the cardiac and pulmonary systems together, detailing the interaction between the two organ systems. Single or biplane projection X-ray has been used to estimate threedimensional (3D) ventricular size, but accuracy has been limited due to the inadequacies of the necessary geometric assumptions needed to translate one or two projections into a volumetric measure as discussed below. Ultrasound has been used extensively to study cardiac function but is not useful for studying lung function. PET and SPECT have been used in pulmonary ventilation and perfusion studies, but inherently low spatial and temporal resolutions make them unsuitable for studying pulmonary structure. Numerous studies by our laboratory and others have demonstrated the utility of high-resolution CT for studying lung and cardiac structure and function. To date, while MRI has been used to study cardiac function, it has shown limited success until recently in imaging of the lung. Developments in the production and use of hyperpolarized helium and hyperpolarized xenon as well as the use of high-concentration oxygen as contrast enhancing agents (8) offer exciting potential applications of MRI to study pulmonary ventilation and function. As we discuss heart-lung interactions in this chapter, we will explore the use of dynamic X-ray CT and MR imaging techniques for evaluating these interactions in the never-invaded thorax. We will describe past, present, and future research activities pertaining to these two imaging modalities that we believe make them the de facto standards for imaging of the cardiac and pulmonary systems. II. Overview of CT and MRI True assessment of heart-lung interaction requires high-speed, volumetric imaging protocols due to cardiac and pulmonary rhythmogenic motion. Modern CT and MR
Imaging-Based Assessment
281
scanners offer capabilities to trigger image acquisition timed to specific events in the cardiac cycle. Coupled with specialized devices developed by several laboratories to measure air flow at the mouth and to standardize the lung volume at which the subject remains apneic during scanning (9,10), it is possible to minimize imaging artifacts caused by cardiac and respiratory motion. A. High-Speed X-ray CT
The 1895 discovery of X-rays by Roentgen, who received the Nobel Prize for his work in 1901, rapidly opened the door to the noninvasive exploration of the body’s innermost realms, and immediately found use in select clinical applications related to surgery, dentistry, and battlefield medicine. With the development of X-ray contrast agents and heart catheterization in the early 1950s, imaging began to reveal the inner dynamics of the living breathing being. Utilizing direct observation of fluoroscopic screens to confirm the placement of intracardiac catheters (see Fig. 1), Earl Wood
Figure 1 Precursors to current dynamic multidimensional imaging methods used to study cardiopulmonary structure and function. Lower right: Complex catheterization and associated monitoring used for the simultaneous recording of vascular pressures and indicator-dilution curves. Included is a twin-beam oscilloscope (O) providing continuous display of patient’s electrocardiogram and the pressure; an ear oximeter (E) used to monitor arterial oxygen saturation; and cuvette oximeters (H,V,Y) for recording dilution curves. Upper left: Video tape recording and data-processing room as it existed in 1963 and used to analyze videodensitometric dilution curves during exposures to acceleration. (Modified from Refs. 82 and 83.)
282
Hoffman and Tran
and colleagues developed methodologies for direct measurement of cardiac pressures coupled with indirect measures of cardiac output and vascular volumes utilizing dye dilution methods (11). As also depicted in Figure 1, Wood and colleagues developed a multitude of biplane fluoroscopic and video recording methods for determining cardiac function including the use of contrast agents coupled with automated border recognition of the chambers, implantation of metallic markers to allow tracking of regional myocardial function, and other techniques. In the early 1970s, it was felt that if only the true shape of the cardiac borders could be determined volumetrically, then engineering methods such as finite element analysis could be applied to the heart to help understand the structure versus function relationships. As shown in Figure 2, elaborate methods were developed by numerous investigators to estimate the volume of the left ventricle (assessing the volume and shape of the right ventricle was hopeless). As discussed by Wood and colleagues (12), and as demonstrated in Figure 2, which is a composite of images from the Wood paper,
Figure 2 Upper panel: Three Plexiglas ‘‘eggs’’ and a silastic ventricular cast used to examine methods for estimating cross-sectional shape from projection images. Cross-sectional shape and volume could be accurately calculated from the first two models, but failed for the twisted ellipsoid. Because the true LV cavity does not have a true ellipsoidal cross section, this study added power to the argument for the need for a move to true dynamic volumetric imaging of the heart. Lower panel: left ventricular case, angiographic silhouettes of a left ventricular cast along with videometry outline, and a computer-based ‘‘surface’’ display of the estimated chamber shape based upon the biplane image data. (Modified from Ref. 84.)
Imaging-Based Assessment
283
the models used to estimate ventricular volumes from biplane angiography were inadequate and true shape description was not possible. When EMI Corporation released their first X-ray CT scanners developed by Godfrey Hounsfield in the mid1970s (13), medicine was again catapulted into a new era long before the imaging method began to change our understanding of the integrated functioning of the human form with its vast number of simultaneous dynamic processes. Image resolution has improved significantly over the past two decades to the point where so-called high-resolution CT (HRCT) provides detail of lung anatomy at submillimeter resolution. High-resolution CT generally utilizes 1- to 1.5-mmthick slices and a high-frequency reconstruction algorithm that serves to enhance edges. However, there is growing appreciation regarding the need for volumetric imaging to evaluate anatomic information, while simultaneously satisfying the need for very high-speed scanning in order for one to evaluate the heart and lungs dynamically. Simultaneous to Hounsfield’s research which lead to the development of EMI’s first brain CT scanner, the group at the Mayo Clinic led by Earl Wood, and eventually Erik Ritman, developed what became known as the Dynamic Spatial Reconstructor, or DSR, discussed below (5). Dynamic Spatial Reconstructor (DSR)
The DSR was designed over the mid-1970s and installed at the Mayo Clinic in 1979 (5). The DSR, as depicted in Figure 3, has a continuously rotating gantry equipped with 14 X-ray guns and 14 image detection systems gathering data from a hemicylindrical fluorescent screen. Up to 240 contiguous 0.9-mm-thick sections can be obtained in a period as short as 1/60 sec and the acquisition can be repeated 60 times per second. To achieve these data acquisition times, compromises were made in image detection and gray-scale resolution was sacrificed. Although the DSR has remained a one-of-a-kind system, it is a true tour de force. The image manipulation and display techniques developed for handling the massive datasets generated by the DSR were the vanguard for techniques now used to process and manipulate images obtained from the now available commercial volumetric scanners. In addition, as discussed below, much of the work establishing the accuracy and precision of volumetric imaging was performed on the DSR (5). As shown in Figure 4, through the simultaneous reconstruction of a stacked set of 0.9-mm-thick sections of the heart with a scan aperture of as short as 1/60 sec, it was now possible to extract a 3D image of the stop-action imaged cardiac myocardium. Of particular interest was the fact that now all four chambers of the heart could be imaged with an accuracy of ⫾ 5% volumetrically (14), and the lung volumes were shown to be imaged and measured with an accuracy of ⫾ 3% (15). Figure 5 demonstrates that it was now possible to image the elusive shape of the right ventricular chambers, made difficult by its thin walls. Furthermore, the alteration of the cardiac chambers could be followed at multiple time points throughout the cardiac cycle. With the simultaneous assessment of the geometry of all four cardiac chambers, new insights were made possible regarding the integrated functioning of the heart within the noninvaded thorax. The primary lesson learned from the DSR was that organ systems in general,
284
Hoffman and Tran
Figure 3 Artist sketch of the Dynamic Spatial Reconstructor, built in 1979 and capable of gathering projection images allowing for the reconstruction of up to 240 contiguous crosssectional images within a 1/60-sec scan aperture. (Modified from Ref. 5.)
and the heart and lungs in particular, must be studied dynamically and volumetrically if one is to gain insights into the true nature of their physiology. Electron Beam CT (EBCT)
One solution to the problem of collecting many angles of view, and scanning a number of contiguous slices in a short time, is provided by electron beam CT (EBCT, shown in Fig. 6) produced by the Imatron Corporation of South San Francisco (6). In this system, the X-ray source and detection devices are stationary. The X-ray generator consists of four fixed parallel pairs of semicircular tungsten target rings spanning 210° about the patient which are electromagnetically swept by a highintensity electron beam. This creates a rotating fan beam of X-ray. Opposite the four X-ray source targets, two side-by-side scintillation crystal detectors record the focused incident X-ray intensity. The combination of target and detector rings result in eight transaxial slices (7-mm-thick pairs with 4-mm gaps between pairs) obtained by sweeping the electron beam sequentially over each of the target rings and recording X-ray intensity via the two fixed solid-state detector rings. Each sweep of the target ring by the electromagnetically steered electron beam produces a pair of transaxial slices. Temporal resolution for acquisition of each image are on the order
Imaging-Based Assessment
285
Figure 4 Clockwise from upper left are shown contiguous cross-sectional images of the contrast-enhanced heart of an anesthetized dog imaged via the DSR using 2/60 sec of image data for the reconstruction process. In the center is shown a shaded surface display of the reconstructed, opened myocardium demonstrating the anatomic details of the inner surfaces of the heart at end diastole using no simplifying mathematical assumptions.
of 50 msec per slice pair (plus an 8-msec reset interval); hence, eight parallel slices (scanned two per sweep) requires approximately 224 msec to complete. Dynamic physiologic events such as the heart beat, pulmonary blood flow, or respiratory gas turnover can be followed by gating the 50 msec/sweep of the four target rings appropriately. A single target ring can be swept repeatedly to capture one cycle of the event of interest, such as the heart beat, and then the next ring can be similarly swept, timed to the same physiologic event such as the QRS complex of the ECG. In this manor, one would, for example, be able to acquire a set of slices through the heart with each heart level scanned at multiple points through a single cardiac cycle. Such a scanning algorithm requires that sequential cycles of a physiologic event be repeatable so that when a dynamic volumetric dataset is compiled from the multiple scanning sequences, the dataset represents a reasonably accurate sampling of the true 4D physiologic process. To reduce the complexity of the system such that one can hope to match the limits of the scanning modality, one must, at times, resort to holding portions of the system constant such as scanning during a breath hold while watching blood flowing or the heart beating. It is possible, however, to increase the complexity of the interactions by appropriately timing the car-
286
Hoffman and Tran
Figure 5 Four angles of view of a shaded surface display of the right ventricle, right atrium, main pulmonary arteries with associated early branches, and superior vena cava. Data are from an anesthetized dog scanned via the DSR and imaged at end diastole.
Figure 6 Schematic of the electron beam CT (EBCT) scanner produced by Imatron Corporation of South San Francisco. The EBCT scanner has no moving parts and allows for the acquisition of a pair of cross-sectional images in 50 msec. See text for a detailed description.
Imaging-Based Assessment
287
diac and respiratory cycles to each other so as to allow for scanning algorithms to be developed which evaluate cross system interactions such as the effect of the heart on the lung or lung on the heart. Imatron has added several additional modes of scanning which allow for scanning of single thin slices (as thin as 1.5 mm) in 100 msec with table motion occurring either continuously or stepwise between slice acquisitions. Here, an additional collimator is moved into place under computer control to appropriately narrow the beam emanating from the central target ring. One of the two detector rings is doublepopulated such that the single thin slice can be reconstructed with high spatial resolution. To date the scanner has allowed for up to 120 contiguous slices to be scanned in as little as 12 to 15 sec. These large numbers of contiguous images are highly useful for imaging relatively large volumetric structures such as the lung with high levels of image resolution. One can gate each slice acquisition to the ECG, slowing total scanning time to a multiple of the time for completion of an R-R interval of the ECG. Gating is often performed to minimize the slice-to-slice variability caused by heart motion and the resulting derived variability of parenchymal spatial location. In the ‘‘continuous volume’’ mode of scanning the table motion is continuously passed through the imaging plane as the beam is repeatedly swept along the central target ring. The beam sweep is so rapid relative to the motion occurring during the beam sweep that the result is only a slight image blurring, while allowing for very rapid acquisition of volumetric, anatomically aligned image information. In this mode, ECG gating is not possible. These rapid volumetric image acquisition modes allow for very flexible scanning algorithm development tailored to physiologically meaningful respiratory interventions. Examples include assessment of regional ventilation obtained by repeated volumetric scanning with intervening breaths to observe washin/washout of a radio-dense gas, examination of lung inflation on cardiac size by scanning at multiple volumes of a static lung inflation or deflation maneuvers, or scanning the lung gated to multiple points within a cardiac cycle, to name just a few. The primary limitation to scanning is eventually the total radiation exposure and the amount of contrast agent which is considered safe relative to the benefits to be gained by the individual and/or the scientific investigation. When applying CT methodology to the study of human physiology, the fact that ionizing radiation is involved places limitations to the protocol design. The EBCT scanner generates approximately the same per-second dose of radiation as a conventional CT scanner. Thus, because of the shorter scan apertures, the radiation exposure is reduced. With the ability to alter the current (milliamps, mA) and voltage (kilovolts, kV) of the electron beam, it would be possible to provide for lower doses of radiation. Additionally, the radiation risk is not simply proportional to the total number of slices scanned, but is more closely related to the total number of slices scanned at a fixed level of the body (i.e., per-cell exposure). Helical/Spiral CT
With the growing understanding of the value of volumetric visualization, new-generation CT machines have emerged which have become known as helical (or spiral)
288
Hoffman and Tran
CT scanners (16). These scanners are similar to conventional CT scanners in that they most often have a single X-ray source-detector pair. However, helical CT has adopted a slip ring assembly that allows the X-ray gun and detectors to continually rotate without having to stop to unwind cabling. During this continuous revolution, the patient table is also continuously moved through the imaging field such that a helical set of X-ray-based projection images is obtained. To reconstruct individual cross-sectional images, the helical projection data are interpolated so as to obtain a consistent, co-planar set of projections that can be used in the reconstruction process. Recently, systems have been built that are capable of spinning the X-ray source at a rate of 500 msec per revolution. With slightly more than 180° of rotation required to reconstruct a high-quality cross-sectional image, it is now possible with the newer helical scanners to acquire images in a fast as 300 msec. Recently, helical CT began a transition from fan-beam to cone-beam geometry with the introduction of multislice systems (17). These narrow-angle cone-beam spiral CT scanners will eventually be refined with wide cone-beam apertures. Conebeam spiral CT uses a 2D detector array, allows larger scanning range in shorter time with higher image resolution, and has important medical and other applications (18,19). As the name implies, multislice scanner technology involves using multiple detector rings to acquire multiple cross-sectional slices of patient data for each gantry rotation. Acquiring multiple image slices per rotation allows for a significant reduction in the time necessary to acquire a particular volume of patient data. Among other substantial improvements, faster scan times are expected to significantly impact functional imaging protocols where the rate of contrast agent to a tissue can be imaged over time, allowing for regional assessment of tissue perfusion. In a period of less than 10 years, the progression from CT scanners employing axial configurations to those with spiral and now quad-spiral modes has allowed scan times to be reduced by up to 10 to 20 times for many standard imaging protocols. With the anticipated introduction of larger detector arrays, faster gantry rotation speeds, and more efficient reconstruction algorithms among other improvements, these trends in reduction of acquisition times can be expected to continue (alongside significant improvements in in-plane spatial resolution and patient dose). It is not unrealistic to expect the next generation of scanners to be able to acquire a volumetric dataset of an entire organ in a single subsecond acquisition. Every major CT manufacturer is intent on developing multislice technology as the future of the industry. To take full advantage of the benefits of this progression toward nearly instantaneous full volumetric acquisition, it is imperative that research intended to develop the next generation of clinical applications be conducted using the most advanced forms of this technology available. B. Magnetic Resonance Imaging
The principle that all protons possess a magnetic moment is the foundation of magnetic resonance imaging (MRI; also referred to as nuclear magnetic resonance, NMR). This notion was first proposed by Otto Stern (who in 1943 received a Nobel
Imaging-Based Assessment
289
Prize for this discovery) and Walter Gerlach in 1924 (20). In 1946, Felix Bloch (21) and Edward Purcell (22), independently of each other, were able to measure NMR signals in a solid, for which they were awarded the Nobel Prize in 1952. Since the 1950s, NMR has found extensive use in the field of analytical chemistry. However, its applications to medical imaging were limited until the first 2D images were reported by Lauterbur in 1973 (23). In a relatively short period of time, approximately only 25 years since it was first used to acquire medical images, usage and availability of MR (the term ‘‘nuclear’’ was dropped because of the incorrect connotation that somehow radiation was involved) facilities have grown dramatically, along with the diagnostic capabilities of MR imaging for medical applications. The application of MRI to the study of the heart and lungs requires a more detailed examination than did X-ray CT because of the tremendous flexibility made available by the methodology. The nonionizing nature of MR imaging, as compared to CT, cannot be understated and is a large factor in its rapid growth, expansion, and acceptance for medical applications. Spin-Echo Imaging
In order to obtain a conventional MR image, several steps are involved. First, a ‘‘slice’’ select (Gz) gradient is applied (i.e., in the craniocaudal direction) creating a head-to-foot gradient in the magnetic field. A narrow-bandwidth RF signal excites protons with a specified resonance frequency at the desired imaging slice location. For each image slice, a 2D image is obtained by phase (Gy) and frequency (Gx) encoding magnetic gradient fields in the slice plane of interest as an RF signal is applied (i.e., spin-echo sequence). The detected signal from the AC coil receiver is an amplitude versus time signal for specific phase, frequency, and slice gradients. This signal is converted into the frequency domain, or k-space, by taking the Fourier transform of the signal and represents one line in k-space. This process is then repeated with multiple different phase encoding gradients to obtain multiple lines in k-space at subsequent TR (repetition time) intervals. Once acquisition is completed, the image is then obtained by computing the inverse Fourier transform of the 2D k-space information. With a conventional spin-echo MR sequence, to obtain a 256 ⫻ 256 image (frequency points and phases) with a TR of 2 sec requires approximately 8.5 min (256 phases * 2 sec/TR/60 sec/min). Figure 7 shows how k-space is acquired using conventional methods. Echo-Planar Imaging (EPI)
Owing to lengthy image acquisition times (on the order of several seconds to minutes), initial MR scans of biologic tissue were restricted to imaging of only stationary systems. Motion artifacts produced unbearable blurring in the image. To adequately image heart-lung interactions, consideration must be given to the fact that there exists simultaneous, cyclic motion of both the heart (⬃ 1 Hz) and lungs (⬃0.25 Hz). Thus, the study of heart-lung interactions requires an imaging system with fast scan aperture times in order to capture the dynamic information involved and to reduce image motion blur.
290
Hoffman and Tran
Figure 7 Formation of an image in k-space. Point A: Initial center of k-space before phase and frequency-encoding gradients are applied. Point B: Simultaneous excitation of gradients relocates spatial frequency in both Kx and Ky to point B. Point C: 180° inversion pulse flips spatial encoding point to C. Phase and frequency gradients are turned off. Point D: Frequency gradient is applied which generates a line in k-space (i.e., 256 frequency points). Each line is completed in one TR interval. The process is then repeated at the next phase-encoding level until the number of phases (i.e., 256) is obtained. The acquisition time for one image is TR times number of phases.
Mansfield first proposed echo-planar imaging (EPI), an ultrafast imaging sequence, in 1977 (24,25). This technique combined an oscillating frequency-encoding magnetic gradient (Gy) with a small constant phase-encoding gradient (Gx) within a single RF pulse. By doing so, it was believed that this MR imaging sequence could drastically reduce the acquisition times compared to traditional spin-echo sequences. A decade later, in 1987, Rzedzian and Pykett refined the technique to obtain biomedical images with scan aperture times on the order of 20 to 100 msec, as opposed to several minutes with previous methodologies (26,27). This drastic reduction in image acquisition times permitted, for the first time, cine-mode cardiac volumetric and functional imaging using MRI. EPI utilizes the same RF pulse sequences as conventional MR (i.e., spin-echo, gradient echo, etc.). The improvement in scan times is mainly due to the acquisition of information in k-space. Rather than obtaining information line by line by incrementally changing the phase-encoding gradient at each TR interval and filling kspace over numerous RF pulse cycles, EPI permits acquisition of all frequencyencoding and phase-encoding information in one single pulse cycle. This is done by oscillating the frequency-encoding gradient and pulsing the phase-encoding gradient on and off at each zero-crossing point of the frequency-encoding gradient. In this manner, all the lines of k-space may be acquired in one TR interval. Figure 8 shows a plot of how k-space is filled using EPI.
Imaging-Based Assessment
291
Figure 8 EPI formation of image in k-space. Point A: Initial center of k-space prior to application of preencoding pulses. Point B: preencoding pulses applied moves spatial frequency to point B. Point C: The 180° inversion RF pulse relocates the spatial-frequency point to C. Point D: The activation of the oscillating frequency-encoding gradient generates the line from C–D. Point E: When the oscillating frequency-encoding gradient intersects the zerocrossing point, a phase-encoding gradient is applied steps the trajectory to point E, where the negative portion of the oscillating frequency-encoding gradient moves the k-space trajectory from E–F. At F, another phase-encoding gradient is applied. This process is repeated until the entire k-space is filled. The entire duration for this acquisition is one TR interval (⬃20–100 msec).
The trade-off between EPI and conventional MR is that the fast acquisition times of EPI has a detrimental effect on image resolution. The signal-to-noise (SNR) ratio of EPI images is about one-third that of conventional MR protocols (28) caused by the drastically reduced image acquisition times. EPI acquires each point in kspace in approximately 4 µsec compared to 31 µsec per pixel of spin-echo MR methods. Fortunately, the degradation in image resolution with EPI is not enough to detract from using it for evaluation of cardiac structure and function. Myocardial MRI Tagging Methods
Advanced MRI scanning techniques have been used to study regional myocardial function in normal and abnormal left ventricles and may be used to study changes in myocardial wall motion during various breathing maneuvers. Using a technique called spatial modulation of magnetization (SPAMM), a grid of orthogonal presaturation ‘‘tagged’’ lines can be superimposed on an image of the ventricles always at a predetermined point of the cardiac cycle (i.e., delay from R-wave detection) (29– 31). To study motion of the myocardium throughout the cardiac cycle, images are obtained from the onset of the QRS peak until end diastole is reached, with one slice acquisition occurring in each heart beat while progressively increasing delay times from the QRS peak from beat to beat (to eliminate image artifacts, one often skips a beat between image acquisition cycles). From these image sequences, the
292
Hoffman and Tran
points where orthogonal tagged lines intersect, i.e., node points, can be followed throughout the cardiac cycle for analysis of regional wall motion or regional strain measurements. Many investigators have shown a correlation between abnormalities in regional myocardial motion or strain with occurrences of regional myocardial ischemia (32,33). Applications of SPAMM to noninvasively tag myocardial tissue for studying regional wall motion was first described by Zerhouni and colleagues (29). Axel and Dougherty subsequently described improved, efficient techniques for generating a spatial pattern of parallel magnetization specifically for studying myocardial motion (31). Using this technique, myocardial SPAMM tags are generated from a set of corresponding RF and gradient pulse sequences (see Fig. 9). To improve the quality of the tagging stripes, the amplitudes of the pulse sequences (RF and gradient sequences) are distributed based upon a binomial distribution sequence (i.e., 1-2-1, 1-3-3-1, 1-4-6-4-1, etc.). The gradient pulses are arranged in a direction perpendicular to the desired direction of the stripe orientation. To produce a grid pattern superimposed upon the myocardium, the procedure described can be repeated with a second gradient pulse oriented orthogonal to the original. A 2D grid of stripes using this sequence can be produced in 9 msec and easily integrated into an EPI imaging sequence or any other standard MR imaging sequence to study heart-lung interaction. SPAMM magnetization tags are made visible by modulation of the transverse magnetization during the imaging pulse.sequence. Spacing between tagging stripes is inversely related to the gyromagnetic ratio and the integral of the gradient G over time (i.e., ∫ G ∗ dt) (29). The duration of the spatially modulated tagged stripes range between 60 and 450 msec and is determined by the finite T1 relaxation time of cardiac tissue. An example of cardiac images acquired using a SPAMM sequence is shown in Figure 10. Other various methods of superimposing saturation patterns upon the myocardium have been reported in the literature. Parallel line tagging patterns have been used to study myocardial wall motion and deformation during cardiac contraction
Figure 9 Binomial SPAMM pulse sequence for obtaining 2D spatial grid tag pattern. The binomial distribution of RF pulse amplitudes improves the quality of the tagged grid pattern. To generate the grid pattern, the RF and gradient (G) pulse sequences must be performed twice (A and B), the first gradient, GA , orthogonal to the second, GB . This SPAMM pulse sequence is performed prior to the imaging pulse sequence.
Imaging-Based Assessment
293
Figure 10 Short-axis MRIs of the human heart. Spatial modulation of magnetization was used here to noninvasively tag the myocardium such that the tags are a local property of the protons and thus move with myocardial motion. This allows one to follow the local contraction patterns of the myocardium and thus follow regional distribution of myocardial strain throughout the cardiac cycle.
(31). McVeigh, Zerhouni, and colleagues have developed imaging techniques for depositing magnetization tags using a starburst pattern (34,35) and also using a combined starburst SPAMM methodology which deposits magnetization tagging points based upon a polar coordinate system rather than a rectilinear coordinate system (36). This alternative coordinate system for deposition of myocardial magnetization tags may in fact be more appropriate for the geometry of the left ventricle. Using these various types of magnetization tags, both qualitative and quantitative measurements of regional myocardial wall motion can be evaluated. Numerous laboratories using principles of continuum mechanics have reported quantitative techniques for estimation of myocardial wall motion and deformation (37–39). Studies have been conducted to evaluate the accuracy of these noninvasive imaging-based techniques for studying in vivo deformation, both static and dynamic (40–42). Using a deformable silicon gel phantom model, validation of MR measured axial and longitudinal shearing motion using SPAMM were compared to those obtained using optical techniques (40). These studies reported that interobserver differences in point localization resulted in larger motion errors when homogeneous strain was assumed. Nonhomogeneous strain analysis resulted in better accuracy compared to optical methods. Noninvasive myocardial magnetization tagging using SPAMM techniques has been used extensively to study myocardial function. These techniques, first developed by Zerhouni et al. (29) and further improved by Axel (30,31,38–40), McVeigh (34,36,37), and others have been shown to be effective tools for quantifying regional myocardial strain throughout the cardiac cycle. Imaging techniques using noninvasive MRI have been developed to measure blood flow in large vessel cross sections (i.e., aorta (43–45), pulmonary artery (43–
294
Hoffman and Tran
46), carotid artery, vena cava (43), etc.) at multiple time points throughout the cardiac cycle. Analysis of velocity and flow profiles of these large vessels can provide valuable physiologic information relating to heart-lung interaction. Whereas analysis of cardiac structure, motion, and deformation requires quantitation of information obtained from the magnitude of the MR signal, velocity and flow quantitation is obtained by subtraction of velocity-encoded phase information contained in the MR signal. In vivo validation of cine-phase contrast flow imaging techniques have been reported in the literature for the vena cava, aorta, pulmonary artery, and coronary blood flows (43–48). MRbased measurements showed strong correlation to those made using implanted ultrasound blood flow probes and Doppler ultrasound imaging. (44,49). Additional studies have compared stroke volume and cardiac output measurements using MR methods with values obtained by the Fick principle and thermodilution (50). As blood flow measurements are sensitive to accurate, reliable identification of vessel boundaries, efforts are under way to develop algorithms for automatic segmentation of vessel contours (51–53). Additional key factors that influence measurement results are background selection, size and shape of the vessel, maximum velocity encoded in diastole, and temporal resolution (54). Measurements are highly sensitive to patterns of turbulent flow due to a decrease in SNR. Thus, regions exhibiting complex flow patterns should be avoided. Urchuk and colleagues have reported development of noninvasive MR-based techniques for estimation of aortic pressure profiles (55). Estimation of blood pressure and blood flow profiles throughout the cardiac cycle may in the near future present opportunities for noninvasive estimation of vessel wall elastic properties. In turn, changes with these properties may serve as a highly sensitive indicator of formation of arterial disease.
III. Applications to the Study of Heart-Lung Interaction A. ‘‘Constant’’ Total Heart Volume Relationship
The fetus develops within the fluid environment of the uterus and the fetal heart develops within the environment of the fluid-filled lungs. In the presence of this noncompressible, high-inertia environment, the fetal heart manages to pump blood. Given this milieu, the tiny heart is either expending a large amount of energy shifting fluid volumes as it works to eject blood from the ventricles or is able to pump blood without changing volume. This fetal environment was unwittingly recreated in a series of studies reported by Sass and colleagues (56). In response to concern over oxygen desaturation during exposure to high gravitational forces, such as were expected during the takeoff and reentry phases of space flight, Sass et al. showed that when dogs were placed in a rigid water-filled cylinder and ventilated with liquid fluorocarbon, the oxygen desaturation was avoided (alveolar collapse in the dependent lung region was prevented). It is interesting to note that Sass’s dogs maintained a normal cardiac output. From these observations, one might hypothesize that the fibers of the heart orient themselves either by environmentally imposed factors or by a genetically
Imaging-Based Assessment
295
defined pattern such that the heart is able to function as a constant volume pump. In the early 1930s Hamilton and Rompf (57) observed, via the aid of monoplane fluoroscopy and percutaneously placed fish hooks in the apex and base of dog hearts, that the apical hooks moved very little as compared to the hooks at the base of the ventricles. These authors also observed that when smoke was placed in the mouth of the dog during apnea, little smoke was expelled with each heartbeat. Other studies, in which a ‘‘cardiometer’’ was placed around the heart in an open-chest preparation, added additional support to the authors’ hypothesis that the total volume of the heart remains fairly constant throughout the cardiac cycle. Hamilton also presented evidence suggesting that the concept of an invariant heart volume explains the failure (58) of the pneumocardiogram as a quantitative index of cardiac function. Hamilton and Rompf argued that it made teleologic sense that the heart should minimize the energy expended in moving extracardiac structures while maximizing the energy devoted to its primary task—that of moving blood through the pulmonary and systemic circulations. Gauer (59), who was one, if not the first, to use fluoroscopy in conjunction with contrast enhancement of the blood to study cardiac function, concluded from his early studies of ventriculograms in humans that total heart volume does change. Gauer hypothesized that large hearts showed a contractile pattern oriented toward lateral wall motion, while the faster, smaller hearts of animals such as the dog managed to eject blood by an ‘‘internal contraction pattern with no change in the epicardial contour.’’ The minimal impact on concepts of cardiac mechanics of both Hamilton’s and Gauer’s work may relate to the uncertainty of their measurement methods. Assuming that cardiac muscle is incompressible, maintenance of a constant total heart volume can occur by a reciprocal emptying and filling of the cardiac chambers and/or change in myocardial blood volume. Interactions necessary for maintenance of a constant heart volume have been observed in their various forms with various degrees of invasiveness, and are briefly reviewed below. Atria and ventricles do show volume reciprocity, and myocardial blood volume can vary—in fact, can vary according to interdependence mechanisms. The Total Heart Volume
In seeking to understand heart lung interactions, Hoffman and colleagues came to realize that a first approach should be to simply understand how the heart functions within the negative-pressure, closed-chest environment, and they sought to understand how the total heart volume varies as a function of the cardiac cycle. It was felt that an understanding of this baseline variability in the total heart volume would then serve to help in understanding the variability in heart geometry which might occur as a function of lung volume changes. The ‘‘total heart volume’’ has been defined as the contents of the pericardial sac. Using anesthetized dogs scanned in the Dynamic Spatial Reconstructor, Hoffman and Ritman (60) demonstrated that the total heart volume throughout the cardiac cycle remains within 5% of the enddiastolic value. This relationship can be seen in graphic form in Figure 11, whereby a volume drop between end diastole and end systole is consistently limited to 5% or less of the total end-diastolic volume of the heart. Although our measurements
296
Hoffman and Tran
Figure 11 Upper tracing shows that the total volume of the heart (contents of the pericardial sac) measured via dynamic volumetric CT imaging throughout a cardiac cycle. Lower trace shows the corresponding left ventricular pressure curve for the same cardiac cycle. Note that the total volume of the heart remains within 5% of the end-diastolic value throughout the cardiac cycle. (Modified from Ref. 60.)
have been validated to be accurate to ⫾5%, the repeatability of the volume drop across animals and between species in addition to the observed smooth volume transition between diastole-to-systole-to-diastole has led us to believe that this small variation is real and not simply noise in the measurement. As demonstrated in Figure 12, the ‘‘constant’’ heart volume relationship was associated with the epicardial apex of the heart remaining fixed in space as the atrial-ventricluar valve plane descends toward the apex in systole and returns toward the cardiac base in diastole. This relationship was also found in awake normal human volunteers scanned via MRI (61). Here, 3-mm-thick contiguous (interleaved acquisition) spin-echo images were gathered to measure the total heart volume. The gated scan sequence took approximately 2.5 to 5.0 hours total scanning time as the individuals remained absolutely still, breathing quietly during scanning. As in the dogs, there was a consistent drop in total heart volume through systole, but the total volume stayed within 4% of the end-diastolic heart volume throughout the cycle. The constant heart volume relationship is maintained in large part through a reciprocal emptying and filling of the atria and ventricles with the epicardial apex remaining fixed in space as the atrioventricular valve planed moves in as a piston, descending toward the apex in systole. To understand the regional wall motion associated with the maintenance of heart volume constancy, a magnetic resonance tagging technique referred to as SPAMM (30), discussed earlier in this chapter, was employed. By tracking the SPAMM-based stripe intersections, we are able to map myocardial motion (62). Through this process, as demonstrated in Figure 13, Hoffman and colleagues have found that the basal myocardium twists, untwists, and then moves inwards in systole. Contrarily, apical myocardium shows a twisting and inward motion throughout sys-
Imaging-Based Assessment
297
Figure 12 Midsagittal sections of the heart selected from dynamic volumetric CT image datasets of two cardiac cycles of an anesthetized dog imaged via the Dynamic Spatial Reconstructor. Upper panel is from an imaging sequence gathered with lung volume held at 0 cmH2 O, and lower panel is from a sequence with lung volume held at 15 cmH2 O. Lines are drawn in the left panel representing the atrioventricular valve plane (black line) and epicardial apex (white line) at end diastole. These lines are held fixed in space and transferred to the end-systolic time point (right panels). Note that the epicardial apex in the right panel has not moved from its end-diastolic location while the atrioventricular valve plane has moved in a pistonlike motion toward the apex during systole. It is this fixed positioning of the epicardial apex and pistonlike motion of the atrioventricular valve plane that provide the basic mechanics for maintaining a near constant total heart volume relationship throughout the cardiac cycle. (Modified from Ref. 60.)
tole. It is the untwisting at the base of the heart in systole without a concomitant untwisting at the apex that presumably contributes to the pulling down of the valve plane (63). Greenbaum et al. (64) have demonstrated three distinct layers of fibers, based upon orientation angle, at the base of the heart and two at the apex. This may or may not be coincident to the three versus two phases of motion that we find at the base and apex respectively. Atrial Stiffness and Ventricular Afterload
In a further series of dog studies, Hoffman et al. (65) found that when anesthetized with inovar and nitrous oxide, the dogs were in atrial fibrillation for the first hour or so of anesthesia and then either spontaneously converted to sinus rhythm or were
298
Hoffman and Tran
Figure 13 Via use of spatial modulation of magnetization (myocardial tagging) protocols associated with magnetic resonance imaging, we have tracked the centroids of triangles formed by the intersection points of the tag lines in the region of the left ventricular myocardium. Images demonstrate that in early systole the basal regions of the myocardium twist and then move endocardially. At the equatorial plane, the myocardium moves almost exclusively endocardially. At the apical regions, the myocardium twists, untwists, and then moves endocardially. It is this differential twist and untwist of the apex and the twist without the untwist of the base during systole that serve to ‘‘wring’’ the myocardium such that the atrioventricular valve plane functions as a piston serving to maintain a reciprocal emptying and filling of the atria and ventricles.
convertible, surprisingly, via xylocain. In sinus rhythm with lungs held at 0 cmH2O airway pressure during DSR scanning, the mean change in total heart volume between end diastole and end systole was 3% while in atrial fibrillation, the mean change was 9%.We have previously shown that a feature of the normal functioning of the heart in sinus rhythm in both dogs (60) and humans (63) is the phenomenon of the epicardial apex remaining fixed in space while the atrioventricular (A-V) valve plane moves in a pistonlike motion toward the apex during systole. In Figure 14, we demonstrate how the A-V valve plane motion is altered in atrial fibrillation. Midlong axis sections through the left ventricle are depicted at end diastole (left column) and end systole (right column) in sinus rhythm (upper row) and atrial fibrillation (bottom row). In the left column we have drawn a line in space at the level of the A-V valve plane. In the right column we have drawn the same line at the same point in space and than have added a second line at the new location of the valve plane. Note that in the case of sinus rhythm, the valve plane moved 20 mm while in the same dog in AF the valve plane moves only 8.5 mm. Suga and
Imaging-Based Assessment
299
Figure 14 Midsagittal sections of the heart selected from dynamic volumetric CT image datasets of two cardiac cycles of an anesthetized dog imaged via the Dynamic Spatial Reconstructor. Upper panel is from an imaging sequence gathered with the heart in sinus rhythm and lower panel is from a sequence with the heart in atrial fibrillation. In both conditions, the heart was paced via bipolar leads in the coronary sinus and heart rate was kept constant between the two conditions. Lines are drawn in the left panel representing the atrioventricular valve plane. These lines are held fixed in space and transferred to the end-systolic time point (right panels), and a new line is then drawn in the right panel representing the new location of the atrioventricular valve plane. Note that the motion of the valve plane in sinus rhythm was 20 mm and reduced to 8.5 mm under conditions of atrial fibrillation, suggesting the tethering of the valve by a stiffened atrium.
colleagues (66,67) have shown, using an isolated LV preparation as a model of LV contraction, that the P-V relationship along with an estimate of ventricular volume at zero pressure can be used to calculate the total work of the left ventricle. They have described this work as the time-varying elastance model. Later work (68) has shown that a strong linear correlation exists between total work and MVO2 as well as myocardial blood flow (MBF). The model has been useful in studying cardiac performance under a number of conditions and is well validated through a number of techniques including dynamic CT (69). If circumstances occur (i.e., increased atrial stiffness) such that the P-V-derived relationships no longer serve to reflect total work of the heart, this will be reflected in an alteration of the slope of the total work versus MBF (or MVO2 ) relationship. To test this hypothesis, seven dogs were studied (70) with the goal being to measure myocardial blood flow using a contrast dilution technique (71) and total work estimated using the pressure-
300
Hoffman and Tran
volume relationship derived from the volumetric images. These dogs were scanned in the DSR while in atrial fibrillation and after conversion, with heart rate maintained constant across conditions via pacing with a bipolar pacing catheter placed in the coronary sinus. The goal was not to study true sinus rhythm, but rather to understand the potential role atrial stiffness might play in ventricular afterload. As Murphy’s Law would have it, three out of the four dogs reverted to sinus rhythm before we could begin scanning and never converted back into atrial fibrillation. Of the four that were in atrial fibrillation during scanning, one dog had a significantly different filling pressure in sinus rhythm versus atrial fibrillation. Of the remaining three dogs, we were able to make a very interesting, albeit small, set of observations which beg to be studied further. From the predicted total work using the pressure volume loops in atrial fibrillation as compared with sinus rhythm for volumetric measurements of both the left and right ventricles, total work was consistently less (on the order of 20%) in atrial fibrillation than in paced sinus rhythm. This relationship is shown for the left ventricle of an example dog in Figure 15. On the other hand, as total work was found to be less in atrial fibrillation, myocardial blood flow estimated from left ventricular free-wall time intensity curves shown in Figure 16 was found to be greater in atrial fibrillation as compared to paced sinus rhythm by an average of 16%. This suggests a dissociation between calculated total work and myocardial blood flow. These data serve to highlight the importance of considering atrial-
Figure 15 Pressure-volume curves for the left ventricle from the same study depicted in Figure 14, where the anesthetized dog was studied via dynamic volumetric CT scanning under conditions of paced atrial fibrillation and sinus rhythm. Note that the apparent work of the left ventricle was reduced under conditions of atrial fibrillation. Our notion is that this apparent reduction in work is a misconception if there is a tethering of the valve plane through increased stiffness of the atria during atrial fibrillation, and atrial stiffness should be considered to be an added after load to the left ventricle (in addition to aortic pressure), and this becomes particularly important under conditions of increased atrial stiffness.
Imaging-Based Assessment
301
Figure 16 Aortic and myocardial time intensity curves following bolus contrast injection into the aortic root while imaging via the Dynamic Spatial Reconstructor. Top curve of each pair represents uncorrected curves with intensity variations due to varying position of limited angles of view used in the reconstruction of each imaged time points. (DSR rotates at 15 rpm, and each time point used in the curve reconstruction represents 4/60 sec of scanning.) Lower curve of each pair represents a correction for the limited angle of view artifact by subtracting off the image intensity of a matched scan without contrast injection. By comparing the area of the time-intensity curve in the aorta with the time-intensity curve in the myocardium, we calculate the blood flow and blood volume values recorded in the bottom panels. Note that while the pressure-volume curve (Fig. 17) for atrial fibrillation indicated a reduction of work compared with sinus rhythm, blood flow in this dog appeared to increase, suggesting that work may have increased despite the estimates made from the pressure-volume curve, indicating work not represented by pressure-volume relationship.
ventricular interactions when evaluating ventricular afterload. Under pathologic states, atrial stiffness in addition to aortic pressure may serve to impede ventricular emptying and to contribute to ventricular myocardial work of contraction. Atrial Baffles: An Added Ventricular Afterload?
With the notion that a constant total heart volume (⫾5%) is an index of the normal, integrated functioning of the heart in the intact thorax, coupled with the findings that in dogs atrial fibrillation disrupts the constant THV relationship, Hoffman and colleagues turned their attention to congenital heart disease where repairs entail placement of a noncompliant baffle into the atria. They selected hypoplastic left heart syndrome (HLHS) with staged repair leading to the Fontan procedure and transposition of the great arteries with a Mustard or Senning procedure. These two abnormalities complement each other in that the final surgical repairs result in either a single ventricle (post-Fontan) or a ventricular pair (post-mustard or Senning) connected to an atrial system tethered by the presence of interposed baffling. The state of the art in the field of imaging has clearly developed to a point whereby not only can we now begin to assess the ‘‘plumbing,’’ but we can begin to evaluate the
302
Hoffman and Tran
mechanical functioning of the heart. Perhaps the disruption of the constant THV relationship is an index of inefficiency; it is certainly an index of an abnormal integration of the cardiac components. Fogel et al. (72) have prospectively studied single-ventricle patients with morphologic functional single right ventricles and morphologic functional single left ventricles. Subjects were studied to evaluate changes in cardiac mechanics as assessed via SPAMM tagging of three short axis levels spanning base to apex to test the hypothesis that mechanics will significantly change through the steps of a staged Fontan procedure. Findings have lead to the demonstration that indeed significant changes in regional wall mechanics take place throughout the staged repair (73,74). With increased attention to the mechanical properties of the heart throughout staged surgical procedures, we now have the tools to better understand the mechanisms behind our successes and failures, and we may be able to influence the long-term viability of the single ventricle. B. Effects of the Lung on the Heart
X-Ray CT Studies in Dogs
Early studies of the DSR were designed to show the effect of lung inflation on the heart, and we showed that lung inflation served to decrease the total heart volume at all phases of the cardiac cycle. Both the RV and the LV end-diastolic volumes were reduced. The effect of lung inflation on the left ventricular chamber is shown in Figure 17. Although LV stroke volume was reduced with lung inflation, ejection fraction was preserved. It was concluded that the drop in cardiac output, in the case of static lung inflation maneuvers, was due to decreased end-diastolic volume. As lung inflation resulted in smaller heart volume, the percent change in total heart volume through the cardiac cycle was also observed to decrease. In theory, cardiaccycle-specific changes in intrathoracic pressure should have effects on both ventricular preload and afterload, and potentially improve cardiac performance. Some current theories of the mechanism of closed-chest ‘‘cardiac massage’’ rely on such an explanation. Such changes have in fact been studied and documented by Pinsky and his colleagues (75,76). They studied the effect of cardiac-cycle-specific jet ventilation in a dog model of acute ventricular failure. Success of cardiac gated respiration was not obtainable in the normal heart in Pinsky’s studies. To study this phenomenon using a noninvasive imaging technique, we have developed a respirator whereby a single board computer is programmed by macros to control a bank of high-frequency needle valves and gated to external signals allowing for the creation of any respiratory waveform desired. We were able, again, to use EBCT to evaluate the ventricular stroke volume and cardiac mechanics. Through physical slewing of the animal in the scanner, we were able to scan with the imaging plane along the true left ventricular short axis and thus we were able to accurately identify the division of the atria and ventrcles for ventricular volume measurements. We measured stroke volumes, ejection fraction, wall motion, and myocardial blood flow with the EBCT scanner (77).
Imaging-Based Assessment
303
Figure 17 Computer-derived shaded surface representations of the contrast-enhanced blood inside the left ventricle of an anesthetized dog imaged at end diastole and end systole via the Dynamic Spatial Reconstructor. Upper panels were with lungs held at 0 cmH2 O airway pressure and lower panels were with the lungs held at 16 cmH2 O during scanning. Note that with lung inflation, chamber volume in diastole was reduced from 40.5 to 33.2 cc (or mL) and systolic chamber volume was reduced from 26.3 to 21.1 cc (or mL). While stroke volume was reduced with lung inflation, ejection fraction remained preserved. These data demonstrated that static lung inflation served to reduce chamber volume throughout the cardiac cycle. Thus, it was reasoned that with appropriate timing of positive-pressure lung inflation, positive-pressure respiration might be used as a cardiac assist device.
As depicted in Figure 18, in six mongrel dogs, inspiration gated to cardiac contraction significantly increased ejection fraction (13.4% ⫾ 6.5%, P ⬍ .001), stroke volume (3.7 ⫾ 2.7 cc/stroke, P ⬍.001), and cardiac output (37% ⫾ 28%, P ⬍.001) over standard ventilation. In this particular example, an understanding of the interactions of heart and lung brought about through noninvasive detection techniques such as ultrafast volumetric imaging may yield important new patient management approaches. A recurrent problem in the medical and surgical intensive care population is the patient with coexistent respiratory and cardiac failure. These patients are supported with positive pressure ventilation (usually standard volume cycled ventilation), inotropic infusions, and not infrequently with mechanical cardiac assist devices such as the intra-aortic balloon pump or the ventricular assist
304
Hoffman and Tran
Figure 18 Average (six dogs) cardiac output (gray bars) and ejection fraction (black bars) during standard positive-pressure ventilation (left) and cardiac-triggered (right) ventilation. Cardiac-triggered ventilation was triggered such that the complete inspiratory/expiratory cycle of the tidal breath occurred within the systolic phase of the cardiac cycle. Measurements were obtained via use of volumetric, dynamic CT imaging and thus did not require thoracotomy for instrument placement.
device. Inotropic infusions have inherent risks and benefits. While they may improve perfusion to the cardiac and cerebral circulation, there may be detrimental effects in the pulmonary or splanchnic circulations. Devices such as the IABP or VAD necessitate intravascular placement of a foreign body with the attendant risk of infection or vascular injury. An alternative may be the naturally occurring interaction between the lungs and the heart. Heart-Lung Interactions in Humans Studied via MR-EPI
EPI’s fast scan aperture time is ideal for reducing motion artifacts associated with cardiac and respiratory motion and to follow changes in cardiac geometry when the respiratory cycle is entrained to the cardiac cycle (78). As an example of the effect of the cardiac cycle and respiratory cycle effects on a single slice image of the heart, refer to Figures 19 through 21. In Figure 19, a single slice of the heart is shown at 10 progressively delayed (relative to the R-wave of the ECG) time points of 10 heartbeats imaged via MR-EPI where the subjects was instructed to remain apneic during scanning. The plot at the lower portion of Figure 19 demonstrates the progressive left ventricular chamber area throughout systole and a return to the original area throughout diastole when imaged at a fixed scanner table location. When the same scanner table location is imaged at each point over multiple cardiac cycles during apnea (Fig. 20), the left ventricular chamber area is remarkably constant. This indicates that mechanical and geometric properties of the heart from cycle to cycle and MR-based methodologies developed for measuring chamber area are highly reproducible. As shown in Figure 21, when the subject is instructed to breathe
Imaging-Based Assessment
305
Figure 19 Cross-sectional images of a single cardiac slice of the beating heart with lung volume held constant. Slice location was held constant relative to the scanner table coordinate system. Peak-to-peak changes in LV chamber area were approximately 33%. The x-axis represents the image number. Each image was acquired relative to the QRS complex, with each acquisition delayed by an additional 50 msec relative to the previous-acquisition timepoint.
during a scan sequence designed to repeat that used in to gather data shown in Figure 20, one can see that the act of respiration during scanning caused significant changes in chamber area. This can be interpreted as being due to the fact that varying portions of the heart are seen within the imaged location due to descent of the heart associated with descent of the diaphragm. Another explanation is that the observed changes could be due to the fact that the chamber of the heart is geometrically altered throughout the respiratory cycle. The only way to truly separate the two possibilities is to image the heart volumetrically. Thus, a high-speed, volumetric imaging protocol, in which the heart is imaged from apex to base, is required to study the effects of breathing on cardiac function. Figure 22 shows an example of acquisitions gathered from such an imaging protocol. Images were acquired as shown by the schematic in Figure 22 (bottom left). Scans were obtained with image acquisition occurring always at the same cardiac phase, while the subject was trained to synchronize breathing depth and frequency to audible sounds emitted from the MR scanner. The subject inspired continuously over four heartbeats, then exhaled for the duration four heartbeats, and then paused for two beats. Single-slice scans acquired accounting for both cardiogenic
306
Hoffman and Tran
Figure 20 Cross-sectional images of a single cardiac slice with imaging synchronized to 200 msec post-QRS and with the subject apneic. Variation in LV chamber area were negligible across scan acquisitions occurring over 20 heart cycles.
and respiratory motions were then repeated from apex to base until the extent of the ventricle had been imaged. Using this information, gathered for scanning at near end systole and near end diastole, 3D volumetric reconstructions of the entire left ventricle could be retrospectively generated for further examination. Analysis using volumetric techniques, rather than single-slice methods, enables us to account for 3D displacements (x, y, z) as well as deformation caused by heart-lung interactions during various breathing maneuvers. C. Effects of Spontaneous Breathing Maneuvers on Cardiac Performance Studied via MRI
Using EPI and a 3D imaging protocol described above to study heart-lung interaction, we were able to investigate the effects of spontaneous breathing (78–80) and other breathing maneuvers (79–81) (i.e., Mueller and Valasalva) on LV size and function. With imaging occurring at fixed cardiac phases (i.e., systole and diastole) while patient breathing maneuvers were entrained to audible cardiac-cycle-based cues from the MR scanner, we were able to make several observations. First, we observed that end-systolic volume (ESV) did not change significantly (P ⬍ .05) across phases of a spontaneous breathing cycle in normal, healthy volunteers. However, with scan-
Imaging-Based Assessment
307
Figure 21 Cross-sectional images of a fixed cardiac slice with imaging synchronized to a fixed cardiac phase (200 msec post-QRS) while the subject was breathing. Peak-to-peak LV chamber area variation was approximately 66%.
ning occurring during late diastole, end-diastolic volume (EDV) increased by up to 15% ⫾ 3.5% (normalized to initial diastolic volume obtained at functional residual capacity [FRC]). There was a noticeable increase in EDV during spontaneous inspiration, reaching a peak slightly delayed from transition between inspiration to expiration. During mid to late expiration, we observed a rapid decrease in EDV to premaneuver levels. These results indicate a strong correlation between changes in pleural pressure and lung volume during spontaneous breathing and cardiac size. Additional studies were performed to isolate the effects of pleural pressure from lung volume changes during breathing. Here, deep Mueller and Valsalva maneuvers were performed by healthy volunteers while scanning was performed synchronized to systolic and diastolic cardiac phases. As with the breathing protocols, no significant changes in ESV were observed with either Mueller or Valsalva maneuvers. However, examination of EDV revealed interesting results. The Mueller maneuver produced a significant initial decrease in LV volumes (16.7% ⫾ 7.8%, P ⬍ .05) within two heartbeats after performing the maneuver. This was presumably due to interaction between the ventricles subsequent to engorgement of the right ventricle caused by increased venous return initially. However, within the next two heart cycles (four heartbeats after initiation of the maneuver), EDV returned to premaneu-
308
Hoffman and Tran
Figure 22 Representative images from apex to base shown for inspiratory phase 3 with imaging gated to late systole. Transverse slices of the heart from apex to base are shown.
ver levels and remained unchanged for the next 16 heart cycles despite maintenance of the maneuver for the duration of the imaging sequence. Repeating the same study while volunteers performed the Valsalva maneuver resulted in a slow, continuous decrease in LV chamber volumes until reaching a plateau at 14 heartbeats after initiation of the maneuver. This continuous decrease in LV volume is likely due to a decreased venous return during a Valsalva maneuver. IV. Conclusions The nature of interactions between the heart and lungs affecting both ventilation and circulation within the intact environment of the thorax is quite complex, as has been alluded to in other chapters. While others have attempted to study these interactions ex vivo or within the open chest, we believe that these interventions may in fact greatly alter the delicate balance of the actual physiology. As compared to previous, more invasive techniques for studying cardiopulmonary interactions, we have discussed here more recent imaging methodologies for observing these interactions in the never-disturbed thorax. Compared to other imaging modalities, CT and MRI permit detailed study of both the geometry and the functional characteristics of each organ system. Herein, we have demonstrated the need for both dynamic and volumetric imaging methodologies in order to properly and adequately represent the structure and function of the heart and lungs due to the dynamic nature exhibited by each system. The fast imaging capabilities of dynamic X-ray CT and echo-planar
Imaging-Based Assessment
309
imaging make these imaging options particularly suitable for use in studying heartlung interactions. Using both CT and EPI, we have developed extensive imaging protocols for studying both the pulmonary and circulatory systems in detail. Ongoing efforts by our laboratory have developed and refined image analysis methodologies for characterizing heart and lung function. To this extent, these techniques have been applied to the study of both normal and abnormal physiology as it pertains to the study of heart-lung interactions. These volumetric imaging techniques have been used to demonstrate that total heart volume remains essentially constant throughout the cardiac cycle (⫾5%). This finding may provide valuable clues to the working efficiencies of the heart during normal sinus rhythm and abnormal function (i.e., atrial fibrillation, ventricular afterload). Further studies have indicated a strong inverse relationship between increasing intrathoracic pressures and decreased total heart volume (i.e., volume of all four cardiac chambers) during static lung inflation maneuvers. Increases and decreases in total heart volume concomitant to decreases and increases in intrathoracic pressures lend credence to the notion put forth by others that positive end-expiratory pressure (PEEP) has a negative effect on cardiac function. Further studies by us have shown a strong correlation between changes in lung volume during spontaneous breathing and cardiac diastolic geometry, with minimal effects on systolic ventricular volume. Manipulations in pleural pressure independent of lung volume changes (i.e., Mueller and Valsalva maneuvers) have exhibited less pronounced effects on cardiac volumes. Observing the direct fluctuations in cardiac chamber volumes with swings in intrathoracic pressure and lung inflation, we further hypothesized that strategic timing of lung inflation and deflation synchronized to cardiac events may have the benefit of augmenting cardiac performance. In conjunction with computational models of heart-lung interactions, We have shown experimentally that timing mechanical ventilation to specific cardiac events can increase cardiac output and stroke volume by up to 30%. These examples serve to illustrate the potential benefits of noninvasive volumetric imaging protocols such as these for the study of heart-lung interactions. With advances in clinically viable and commercially available imaging methods to study the heart and lungs both dynamically and volumetrically, and with advancing methods for handling the large datasets which emerge from such scanning methodologies, it is our expectation that an understanding of heart-lung mechanics will continue to advance. The methods will provide critically important tools for the development and evaluation of interventions to pathologic states of both the heart and lungs. It is clear that the cardiopulmonary system is tightly integrated, and one can only fully understand its function by studying it in its integrated state. References 1.
Donders FC. Contribution to the mechanism of respiration and circulation in health and disease. In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, PA: Dowden, Hutchinson, and Ross, Inc., 1975:298–318.
310 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
Hoffman and Tran Buda AJ, Pinsky MR, Ingles NB, et al. Effect of intrathoracic pressure on LV performance. N Engl J Med 1979; 301:453–459. Summer WR, Permutt S, Sagawa K, Shoukas AA, Bromberger-Barnea B. Effects of spontaneous respiration on canine left ventricular function. Circ Res 1979; 45:719–728. Karam M, Wise RA, Natarajan TK, Permutt S, Wagner HN. Mechanism of decreased left ventricular stroke volume during inspiration in man. Circ Res 1984; 45:719–728. Ritman EL, Robb RA, Harris LD. Imaging Physiological Functions: Experience with the DSR. Philadelphia: Praeger, 1985. Boyd DP, Lipton MJ. Cardiac computed tomography. Proc IEEE 1983; 71:298–307. Hoffman E, Olson L. Characterizing lung structure/function with X-ray CT. In: Hlastalla M, Robertson T, eds. Complexities of Structure and Function of the Lunged. New York: Marcel Dekker, 1998. Chen Q, Jakob PM, Griswold MA, Levin DL, Hatabu H, Edelman RR. Oxygen enhanced MR ventilation imaging of the lung. Magma 1998; 7:153–161. Kalender WA, Reinmuller R, Fichte H, Behr J, Beinert T, Seissler W. Spirometrically gated CT measurement of lung density and structure. Radiology 1992; 185:354. Tran BQ, Tajik JK, Chiplunkar RA, Hoffman EA. Lung volume control for quantitative Xray CT. Ann Biomed Eng 1996; 24:S-66. Fox I, Wood E. Circulatory system: methods; indicator-dilution technics in study of normal and abnormal circulation. In: Glasser, ed. Medical Physics. Chicago: The Year Book Publishers, 1960; 3:163–178. Wood E, Ritman E, Sturm R, Johnson S, Spivak P, Gilbert BK, Smith HC. The problem of determination of the roentgen density, dimensions and shape of homogeneous objects from biplane roentgenographic data with particular reference to angiocardiography. San Diego Biomedical Symposium, San Diego, 1972:3–43. Hounsfield GN. Computerized transverse axial scanning (tomography). 1. Description of system. Br J Radiol 1973; 46:1016–1022. Hoffman EA, Ritman EL. Shape and dimensions of cardiac chambers: importance of CT section thickness and orientation. Radiology 1985; 155:739–744. Hoffman EA, Sinak LJ, Robb RA, Ritman EL. Noninvasive quantitative imaging of shape and volume of lungs. J Appl Physiol Respir Environ Exercise Physiol 1983; 54:1414–1421. Kalender WA, Fichte H, Bautz W, Skalej M. Semiautomatic evaluation procedures for quantitative CT of the lung. J Comput Assist Tomogr 1991; 15:248–255. Saito T, Misaki M, Shirato K, Takishima T. Three-dimensional quantitative coronary angiography. IEEE Trans Biomed Eng 1990; 37:768–777. Saito Y. Multislice X-ray CT scanner. Med Rev 1998; Nov: 1–8. Wang G, Lin TH, Cheng PC, Shinozaki DM. A general cone-beam reconstruction algorithm. IEEE Trans Med Imaging 1993; 12:486–496. Gerlach W, Stern O. On the position of the quantum lines in a magnetic field. Ann Physik 1924; 74:675–699. Bloch F. Nuclear induction. Physiol Rev 1946; 70:460–474. Purcell EM, Torrey HC, Pound RV. Resonance absorption by nuclear magnetic moments in a solid. Physiol Rev 1946; 69:37–38. Lauterbur PC. Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature 1973; 242:190–191. Mansfield P. Multiplanar image formation using NMR spin echoes. J Phys Chem 1977; 10: L55. Mansfield P, Pykett I. Biological and medical imaging by NMR. J Magn Reson 1978; 29: 355–373. Pykett I, Rzedzian R. Instant images of the body by magnetic resonance. Magn Reson Med 1987; 5(6):563–571. Rzedzian R, Pykett I. Instant images of the human heart using a new, whole-body MR imaging system. Am J Roentgenol 1987; 149(2):245–250. De la Paz RL. Echo-planar imaging. Radiographics 1994; 14:1045–1058. Zerhouni EA, Parish DM, Rogers WJ, Yang A, Shapiro EP. Human heart: tagging with MR imaging—a method for noninvasive assessment of myocardial motion. Radiology 1988; 169:59–63.
Imaging-Based Assessment 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.
46. 47. 48. 49.
50. 51.
311
Axel L, Dougherty L. MR imaging of motion with spatial modulation of magnetization. Ragiology 1989; 171:841–845. Axel L, Dougherty L. Heart wall motion: improved method of spatial modulation of magnetization for MR imaging. Radiology 1989; 172:349–350. Herman MV, Gorlin R. Implications of left ventricular asynergy. Am J Cardiol 1969; 23(4): 538–547. Baxley WA, Reeves TJ. Abnormal regional myocardial performance in coronary artery disease. Prog Cardiovasc Dis 1971; 13(5):405–421. McVeigh ER, Zerhouni EA. A rapid starburst sequence for cardiac tagging. Presented at Eighth Annual Meeting of Society of Magnetic Resonance in Medicine. Berkeley, CA: SMRM, 1989:23. Bouton S, Yang A, McCrindle BW, Kidd L, McVeigh ER, Zerhouni EA. Differentiation of tumor from viable myocardium using cardiac tagging with MR imaging. J Comput Assist Tomogr 1991; 15(4):676–678. Bolster BD, McVeigh ER, Zerhouni EA. Myocardial tagging in polar coordinates with use of striped tags. Radiology 1990; 177:769–772. McVeigh ER, Zerhouni EA. Noninvasive measurement of transmural gradients in myocardial strain with MR imaging. Radiology 1991; 180:677–683. Axel L, Goncalves RC, Bloomgarden D. Regional heart wall motion: two-dimensional analysis and functional imaging with MR imaging. Radiology 1992; 183:745–750. Young AA, Axel L. Three-dimensional motion and deformation of the heart wall: estimation with spatial modulation of magnetization—a model-based approach. Radiology 1992; 185: 241–247. Young AA, Axel A, Dougherty L, Bogen DK, Parenteau CS. Validation of tagging with MR imaging to estimate material deformation. Radiology 1993; 188:101–108. Constable RT, Rath KM, Sinusas AJ, Gore JC. Development and evaluation of tracking algorithms for cardiac wall motion analysis using phase velocity MR imaging. Magn Reson Med 1994; 32(1):33–42. Drangova M, Shu Y, Bowman B, Pelc NJ. In Vitro Validation of Phase Contrast Measurements of Myocardial Wall Motion. Berkeley, CA: Society of Magnetic Resonance, 1994:1476. Firmin DN, Nayler GL, Klipstein RH, Underwood SR, Rees RS, Longmore DB. In vivo validation of MR velocity imaging. J Comput Assist Tomogr 1987; 11(5):751–756. Evans AJ, Iwai F, Grist TA, Sostman HD, Hedlund LW, Spritzer CE, Negro-Vilar R, Beam CA, Pelc NJ. Magnetic resonance imaging of blood flow with a phase subtraction technique. In vitro and in vivo validation. Invest Radiol 1993; 28(2):109–115. Lee VS, Spritzer CE, Carroll BA, Pool LG, Bernstein MA, Heinke SK, MacFall JR. Flow quantification using fast cine phase-contrast MR imaging, conventional cine phase-contrast MR imaging and doppler sonography: in vitro and in vivo validation. Am J Roentgenol 1997; 169(4):1125–1131. Pelc LR, Pelc NJ, Rayhill SC, Castro LJ, Glover GH, Herfkens RJ, Miller DC, Jeffery RB. Arterial and venous blood flow: noninvasive quantitation with MR imaging. Radiology 1992; 185(3):809–812. Pelc NJ, Shimakawa A, Glover GH. Phase contrast cine MRI. Presented at Eighth Annual Meeting of Society of Magnetic Resonance in Medicine, Amsterdam, 1989:101. Chang JM, Friese K, Caputo GR, Kondo C, Higgins CB. MR measurement of blood flow in the true and false channel in chronic aortic dissection. J Comput Assist Tomogr 1991; 15(3):418–423. Hartiala JJ, Mostbeck GH, Foster E, Fujita N, Dulce MC, Chazouilleres AF, Higgins CB. Velocity-encoded cine-MRI in the evaluation of left ventricular diastolic function: measurement of mitral valve and pulmonary vein flow velocities and flow volume across the mitral valve. Am Heart J 1993; 125(4):1054–1066. Hundley WG, Li HF, Meshack BM, Lange RA, Willard JE, Landau C, Peshock RM. Quantitation of cardiac output with velocity-encoded, phase difference magnetic resonance imaging. Am J Cardiol 1995; 75(17):1250–1255. Burkart DJ, Felmlee JP, Johnson CD, Wolf RL, Weaver AL, Ehman RL. Cine phase-contrast MR flow measurements: improved precision using an automated method of vessel detection. J Comput Assist Tomogr 1994; 18(3):469–475.
312 52.
53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75.
Hoffman and Tran Van der Geest RJ, Niezen RA, Van der Wall EE, de Roos A, Reiber JHC. Automated measurement of volume flow in the ascending aorta using MR velocity maps: evaluation of inter- and intraobserver variability in healthy volunteers. J Comput Assist Tomogr 1998; 22(6):904–911. Kozerke S, Botnar R, Oyre S, Scheidegger MB, Pederson EM, Boesiger P. Automatic vessel segmentation using active contours in cine phase contrast flow measurements. J Magn Reson Imag 1999; 10(1):41–51. Buoncore MH, Bogren H. Factors influencing the accuracy and precision of velocity-encoded phase imaging. Magn Reson Med 1992; 26(1):141–154. Urchuk SN, Fremes SE, Plewes DB. In vivo validation of MR pulse pressure measurement in an aortic flow model: preliminary results. Magn Reson Med 1997; 38:215–223. Sass DJ, Ritman EL, Caskey PE, Banchero N, Wood EH. Liquid breathing: prevention of pulmonary arterial-venous shunting during acceleration. J Appl Physiol 1972; 32:451–455. Hamilton W, Rompf J. Movement of the base of the ventricle and the relative constancy of the cardiac volume. Am J Physiol 1932; 102:559–565. Guilio L. Recerche sul cardiopneumogramma (oscillazioni cardiopneumatche) nell’uomo. Arch Fisiol 1955; 55:121–134. Gauer O. Volume changes of the left ventricle during blood pooling and exercise in the intact animal. Their effects on left ventricle performance. Physiol Rev 1955; 35:143– 155. Hoffman EA, Ritman EL. Invariant total heart volume in the intact thorax. Am J Physiol Heart Circ Physiol 1985; 249:H883–H890. Hoffman E, Ehman R, Sinak L, Felmlee J, Chandrasckaran K, Julsrud P, Ritman EL. Law of constant heart volume in humans: a noninvasive assessment via X-ray CT, MRI, and ECHO. J Am Coll Cardiol 1987; 9:38A. Chung N, Wu X, Bailey KR, Ritman EL. LV pressure-volume area and oxygen consumption: evaluation in intact dog by fast CT. Am J Physiol 1990; 258:H1208–H1215. Hoffman E, Rumberger J, Dougherty L, Reichek N, Axel L. A geometric view of cardiac efficiency. J Am Coll of Cardiol 1989; 13:86A. Greenbaum R, Ho S, Gibson D, Becker AE, Anderson RH. Left ventricular fibre architecture in man. Br Heart J 1981; 45:248–263. Hoffman E, Ritman E. Law of constant heart volume disrupted by atrial fibrillation. Fed Proc 1986; 45:776. Khalafbegui F, Suga H, Sagawa K. Left ventricular systolic pressure-volume area correlates with oxygen consumption. Am J Physiol 1979; 237:H566–H569. Suga H. Total mechanical energy of ventricle model and cardiac oxygen consumption. Am J Physiol 1979; 236:H498–H505. Nozawa T, Yasumara Y, Futaki S, Tanaka N, Igarashi Y, Goto Y, Suga H. Relation between oxygen consumption and pressure-volume area of in situ dog heart. Am J Physiol 1987; 253:H31–H40. Chung N, Wu X, Bailey K, Ritman EL. LV pressure-volume area and oxygen consumption: evaluation in intact dog by fast CT. Am J Physiol 1990; 27:H1208–H1215. Cristescu MG, Ritman E, Hoffman E. Mechanics, energetics and constant heart volume: atrial fibrillation vs. sinus rhythm. FASEB J 1990; 4:A433. Wong T, Wu L, Chung N, Ritman EL. Myocardial blood flow estimated by synchronous, multislice, high speed tomography. IEEE Trans on Med Imag 1989; 8:70–77. Fogel M, Gupta K, Weinberg PM, Hoffman EA. Strain and wall motion analysis of single ventricles throughout staged Fontan reconstruction using magnetic resonance tagging. J Am Coll Cardiol 1993; 21:2A. Fogel MA, Gupta KB, Weinberg PM, Hoffman EA. Regional wall motion and strain analysis across stages of Fontan reconstruction by magnetic resonance tagging. Am J Physiol 1995; 269:H1132–H1152. Fogel MA, Weinberg PM, Chin AJ, Fellows KE, Hoffman EA. Late ventricular geometry and performance changes of functional single ventricle throughout staged Fontan reconstruction assessed by magnetic resonance imaging. J Am Coll Cardiol 1996; 28:212–221. Pinsky MR, Matuschak GM, Klain M. Determinants of cardiac augmentation by elevations in intrathoracic pressure. J App Physiol 1985; 58:1189–1198.
Imaging-Based Assessment 76. 77. 78. 79. 80. 81. 82. 83. 84.
313
Pinsky MR, Matuschak GM, Bernardi L, Klain M. Hemodynamic effects of cardiac cycle– specific increases in intrathoracic pressure. J Appl Physiol 1986; 60:604–612. Hanson III C, Haywood M, Hoffman E. Cardiopulmonary dynamics with EKG gated ventilation. J Am Coll Cardiol 1992; 19:189A. Tran BQ, Pattekar MA, Hoffman EA. Heart-lung interaction studied by echo-planar MR imaging with respiration synchronized to the cardiac cycle. Am J Respir Crit Care Med 1995; 151(4)pt 2:708. Tran BQ. Cardio-pulmonary interaction during cardiac-gated ventilation: combined imaging and model-based study, Ph.D. Thesis Iowa City: University of Iowa, 1998. Tran BQ, Hoffman EA. Role of breathing on cardiac performance: experimental and mathematical models. SPIE Med Imag 1999; 3660:150–158. Tran BQ, Hoffman EA. Role of pleural pressure on LV volume assessed via high-speed MR imaging. Circulation 1997; 96(8) suppl:I514. Johnson SA, Robb RA, Greenleaf JF, Ritman EL, Lee SL, Herman GT, Sturm RE, Wood EH. The problem of accurate measurement of left ventricular shape and dimensions from multiplane roentgenographic data. European Journal of Cardiology 1974; 1:241–258. Wood EH, Sturm RE, Sanders JJ. Mayo Clinic Proceedings 1964; 39:849–865. Wood EH, Ritman EL, Sturm S, Johnson P, Spivak BK, Gilbert BK, Smith HC. The problem of determination of the roentgen density, dimensions and shape of homogeneous objects from biplane roentgenographic data with particular reference to angiocardiography. Proceedings of the San Diego Biomedical Symposium 1972; 11:3–43.
12 Cellular Mechanisms of Acute Hypoxic Pulmonary Vasoconstriction
J. T. SYLVESTER, JAMES S. K. SHAM, LARISSA A. SHIMODA, and Q. LIU Johns Hopkins University School of Medicine Baltimore, Maryland
I.
Introduction
Although acute hypoxic pulmonary vasoconstriction (HPV; see Table 1) has been studied intensively for over 50 years, its mechanisms remain unclear. Understanding these mechanisms is important because HPV plays significant roles in both normal and diseased lungs. In normal lungs, HPV maximizes systemic arterial oxygen tension by diverting pulmonary blood flow from poorly ventilated hypoxic lung regions to well ventilated normoxic lung regions. In diseased lungs, where hypoxia is diffuse, HPV occurs throughout the pulmonary vasculature, resulting in pulmonary hypertension, right ventricular failure, and increased morbidity and mortality. Much of the early work on HPV was performed in intact animals or isolated lungs, preparations which provide consistent and physiologically relevant responses, but place significant limitations on mechanistic investigation. Over the last decade, investigators have added pulmonary vascular tissue and cells and the powerful techniques of cellular and molecular biology to their experimental armentarium, and produced an explosion of new information. In this review, we summarize and synthesize this new information. First, we describe the effects of acute hypoxia in isolated vascular tissues and cells. Next, we present current mechanistic hypotheses and discuss the evidence for and against them. Finally, we present a mechanistic schema based on current data which provides a framework for future investigation. 315
316
Sylvester et al.
Table 1 Abbreviations Used in the Text 4-AP [Ca2⫹ ] i cAMP, cGMP ChTx Cl Ca , ClC-3 channels DIDS DPI EDCF EDRF EGTA ER ET FCCP GMP, GDP, GTP HPV ICRAC IκB IP3 KATP , KCa , KIR , KV channels MAP kinase MLC kinase mRNA NADH NADP⫹, NADPH NBT NF-κB NO NOS •O2⫺ PAEC PASMC PCr pHi PI PI-3 kinase PIP kinase PKA, PKC, PKG pS ROS RT-PCR SERCA sGC SOD SR STOC TEA
4-Aminopyridine Intracellular calcium concentration Cyclic adenosine and guanosine monophosphates Charybdotoxin Calcium-activated and volume-regulated chlorine channels 4,4′-Diisothiocyanostilbene-2,2′-disulfonic acid Diphenyleneiodonium Endothelium-derived contracting factor Endothelium-derived relaxing factor Ethylene glycol bis (β-aminoethyl ether) N,N,N′,N′-tetraacetic acid Endoplasmic reticulum Endothelin Carbonyl cyanide p-trifluoromethoxyphenyl hydrazone Guanosine mono-, di, and triphosphates Hypoxic pulmonary vasoconstriction Calcium release activated calcium current Inhibitor of nuclear factor κB Inositol triphosphate ATP-dependent, calcium-activated, inward rectifier, and voltageactivated potassium channels Mitogen-activated protein kinase Myosin light chain kinase Messenger ribonucleic acid Nicotiamide adenine dinucleotide (reduced form) Nicotiamide adenine dinucleotide phosphate (oxidized and reduced forms) Nitroblue tetrazolium Nuclear factor κB Nitric oxide Nitric oxide synthase Superoxide anion Pulmonary artery endothelial cell Pulmonary artery smooth muscle cell Phosphocreatine Intracellular pH Phosphatidylinositol 1-Phosphatidylinositol 3-kinase Phosphatidylinositol 4-phosphate kinase Protein kinases A, C, and G Picosiemens Reactive oxygen species Reverse transcriptase-polymerase chain reaction Sarcoplasmic (endoplasmic) reticulum calcium ATPase Soluble guanylate cyclase Superoxide dismutase Sarcoplasmic reticulum Spontaneous transient outward current Tetraethylammonium
Acute Hypoxic Pulmonary Vasoconstriction
317
II. Effects of Acute Hypoxia A. Isolated Pulmonary Arteries
Within species, hypoxic responses of isolated pulmonary arteries differed with respect to vessel locus (1,2); therefore, to discuss results obtained across species, we have categorized arteries as proximal (approximately generation 1 to 5) or distal (approximately generation 6 and greater). This categorization is preferable to one based on size, since pulmonary arteries 250 µm in diameter from rat are more proximal and respond differently to hypoxia than arteries of similar size from cat or pig (2–7). Isolated arteries of unclear origin were assigned to the most likely category. Proximal Pulmonary Arteries
Hypoxic responses of extrapulmonary and proximal intrapulmonary arteries have been studied in many laboratories. Only a few investigators, however, were able to obtain hypoxic responses large enough and reproducible enough to study without first exposing the vessels to a contractile stimulus (precontraction) (8–18). In some of these studies, special conditions may have promoted hypoxic responsiveness. For example, slowly developing hypoxic contractions were elicited in rings from guinea pig main pulmonary arteries (14) and rabbit intrapulmonary arteries (10) after exposing the vessels to glucose-free physiologic salt solutions for 75 to 120 min. Strips of porcine main pulmonary artery ‘‘adapted’’ by exposure to an O2 tension of 40 mm Hg for 4 to 6 h contracted to hypoxia, whereas nonadapted strips exhibited no response or vasorelaxation (8). Rat pulmonary arterial rings perfused with nonrecirculating physiological salt solutions containing HEPES and Tris as buffers and no CO2, conditions which could cause intracellular alkalosis and washout of tissue mediators, developed contractions slowly over 90 to 120 min upon exposure to 100% N2 (11). Rat pulmonary arterial rings exposed alternately for 2 h to phenylephrine and KCl (1 µM and 80 mM, respectively, for 5 min followed by 15-min washouts) subsequently exhibited hypoxic contractions which averaged 75% of maximum phenylephrine responses (15). Whether glucose deprivation, hypoxic adaptation, mediator washout, intracellular alkalosis, repeated contractile stimulation before hypoxic exposure, or some other condition accounted for the ability of these preparations to contract to hypoxia in the absence of precontraction is unknown. In most laboratories, precontraction was required to obtain reliable hypoxic responses (1,5,12,14,16–54). A wide variety of agonists have been used for precontraction, including phenylephrine (1,26–30,36,38,40–42,47,51–53), KCl (17,19,25, 29,32,43,46,48,51,52), norepinephrine (19,23,29,35,43,44), prostaglandin F2α (5,33, 34,37,54), 5-hydroxytryptamine (7–19,24,31), U-46619 (24,29,48), endothelin-1 (16,51), angiotensin II (29), epinephrine (50), histamine (22), phorbol esters (12), and electrical field stimulation (14). Concern that precontraction may be unphysiologic is tempered by the realization that pulmonary arteries are continuously exposed to vasoactive substances in vivo and by observations that vasoconstrictors prevented loss of hypoxic vasoconstriction in isolated lungs perfused with physiologic salt solutions (55,56). Precontraction might allow pulmonary arterial smooth muscle to
318
Sylvester et al.
achieve some threshold state of activation required for expression of contractile responses to hypoxia, or activate transduction pathways, which could then be secondarily modulated by hypoxia. In any case, it seems clear that basal tension, whether generated by intrinsic or extrinsic mechanisms, can significantly influence pulmonary arterial responses to hypoxia and other stimuli (57,58). Given possible differences due to species, agents used for precontraction, and other factors, hypoxic responses of proximal pulmonary arteries have been surprisingly consistent. Severe hypoxia for ⬎30 min usually elicited a triphasic response: (1) early transient contraction; (2) relaxation; and (3) late sustained contraction (1,5,19,24,25,30,32–34,36,37,51,54). When the duration of hypoxia was ⬍15 min, only early contraction (12,16,27–29,35) or early contraction and relaxation (17,18,26,41,42,46–48,53) were seen. Early Hypoxic Contraction
Early hypoxic contraction has received the most investigative attention. This phase of the response was partially or completely endothelium-dependent (1,5,8,16,17,19, 23–26,29,30,40–42,46,48,49,51,53); associated with decreased smooth muscle cGMP concentrations (26,27,53); and attenuated by hemoglobin (18,26,27,40) and inhibitors of nitric oxide (NO) synthase (1,23,36,40,46,48,49,51,53) or soluble guanylate cyclase (sGC) (26,27,42,46,53). These results indicate that early hypoxic contraction was at least partly due to decreased activity of the endothelium-derived relaxing factor, NO, allowing secondary expression of underlying basal or hypoxiainduced vasomotor tone. Since NO is synthesized from O2 and L-arginine, decreased NO activity during hypoxia could be due to substrate limitation of NO synthesis (26,59–62). Hypoxia might also exert an inhibitory effect at or distal to sGC, the smooth muscle enzyme activated by NO to produce cyclic GMP and vasorelaxation (29,63). Because inhibition of NO synthase (NOS) enhanced (rather than inhibited) hypoxic pressor responses in isolated lungs (60,61,64,65), it is unlikely that decreased NO activity mediates HPV in vivo. Involvement of other endothelium-derived factors in early hypoxic contraction has not been thoroughly examined; however, early hypoxic contraction was (16,18) or was not (1,18,42) blocked by antagonists of cyclooxygenase. One study suggests that neither reactive oxygen species nor peptides played a role (18). Endothelin antagonists have not affected early hypoxic contraction (30,33,35,52). In some laboratories, early hypoxic contraction was endothelium independent (5,15,20,33,41,42,66), suggesting mediation by mechanisms intrinsic to vascular smooth muscle. Because early hypoxic contraction in endothelium-denuded arteries was associated with decreased levels of cGMP and could be blocked by inhibitors of sGC, it was proposed that hypoxia inhibited a cGMP-dependent relaxation mechanism intrinsic to vascular smooth muscle (20,42). According to this hypothesis, superoxide anions (•O2⫺ ) produced in proportion to PO2 by a smooth muscle microsomal NADH oxidase were metabolized by SOD to H2 O 2, which interacted with catalase to activate sGC independently of NO, increase cGMP, and cause relaxation. Conversely, a decrease in PO2 would lead to contraction. This hypothesis is supported by observations in isolated pulmonary arteries that H2 O 2 and reoxygenation
Acute Hypoxic Pulmonary Vasoconstriction
319
after hypoxia caused relaxations which were blocked by SOD, catalase, or inhibitors of sGC (20,67–79). Furthermore, NADH increased lucigenin-enhanced chemilumenescence in pulmonary artery homogenates, indicating increased production of reactive oxygen species. This activity fractionated with microsomes, was inhibited by SOD or the •O2⫺ scavenger, nitroblue tetrazolium (NBT), and was associated with absorbtion spectra typical of cytochrome b558 (70–72). Early hypoxic contraction was accompanied by a transient increase of intracellular calcium concentration ([Ca2⫹ ] i ) (34), enhanced by increased extracellular [Ca2⫹ ] (41,42), and inhibited by Ca2⫹-free conditions or blockers of L-type calcium channels, such as verapamil, nifedipine, and amlodipine (5,12,29,44,66,73). These results suggested the early hypoxic contraction was triggered by an increase in [Ca2⫹ ] i resulting from enhanced Ca2⫹ influx through L-type Ca2⫹ channels. However, depletion of Ca2⫹ stores in sarcoplasmic reticulum (SR) with thapsigargin and cyclopiazonic acid, which block SR Ca2⫹ uptake, or ryanodine, which promotes SR Ca2⫹ release, prevented early hypoxic contraction, suggesting that the response was triggered by Ca2⫹ release from SR (15). In canine pulmonary arteries, hypoxia was thought to release Ca2⫹ from ryanodine-sensitive but not IP3-sensitive stores (38), which are thought to be functionally and structurally distinct in systemic arterial myocytes (74,75). To add to the confusion, some laboratories reported that early hypoxic contraction was not prevented by calcium-free conditions, verapamil, or depletion of intracellular calcium stores with ryanodine (16,18,24), suggesting that the response was calcium independent. Confusion also exists with respect to the role of protein kinase C (PKC). For example, the PKC inhibitor Ro-31–8222 blocked early hypoxic contraction in rat pulmonary arteries (34), whereas H-7, another PKC inhibitor, had no effect (24). In some studies, early hypoxic contraction was preceded by a small relaxation (1,40–44,54). In rat pulmonary arteries, this relaxation was blocked by endothelial denudation, inhibitors of NOS or sGC, hemoglobin, and superoxide dismutase (SOD), suggesting that it was mediated by decreased destruction of NO by oxygen radicals resulting from an hypoxia-induced decrease in ⋅O2⫺ production (40,42). In canine pulmonary arteries, early hypoxic contraction was briefly interrupted by a small relaxation, which could be blocked by indomethacin, suggesting mediation by vasodilator prostaglandins such as prostacyclin . Because early hypoxic contraction is transient and occurs in isolated systemic arteries (19,35,46,76,77), its relevance to in vivo HPV is uncertain. Hypoxic Relaxation
The relaxation phase of the response has not been well studied; however, relaxation is typical of hypoxic responses in systemic arteries (78,79), and similar mechanisms might be involved. In rabbit aorta precontracted with norepinephrine, it was concluded that hypoxic relaxation was caused by deterioration of energy state and secondary impairment of the phosphatidylinositol (PI) transduction pathway in vascular smooth muscle (80–89). This conclusion was based on several lines of evidence: (1) hypoxic relaxation was not altered by endothelial denudation (81); (2) hypoxia decreased smooth muscle concentrations of phosphocreatine (PCr) and/or ATP (83)
320
Sylvester et al.
and increased concentrations of PI cycle intermediates upstream from the ATPrequiring PIP kinase step (80,85); and (3) hypoxia did not similarly inhibit contractile responses to KCl, which result from depolarization rather than activation of the PI pathway (82). More recently, it was reported that hypoxia decreased GTP and GTP/GDP concentrations in rabbit aorta, presumably because decreased availability of ATP limited GTP synthesis (90). These findings suggested that hypoxia caused relaxation by interfering with a G protein-dependent component of receptor-linked signal transduction. Consistent with findings in systemic arteries, hypoxic relaxation in pulmonary arteries was endothelium independent (1,5,19,24), unaltered by inhibitors of NOS, cyclooxygenase, or lipoxygenase (5,19,36), and associated with deterioration of energy state and intracellular acidosis (91). In addition, glibenclamide, an antagonist of ATP-dependent potassium (KATP ) channels, inhibited hypoxic relaxation in ferret (92) and rat (47) pulmonary arteries, suggesting that decreased energy state activated myocyte KATP channels, leading to hyperpolarization, decreased Ca2⫹ influx through voltage-dependent Ca2⫹ channels (93), a fall in [Ca2⫹ ] i (34), and relaxation, as proposed for systemic vessels (94). Charybdotoxin, a specific inhibitor of calciumactivated K⫹ (KCa ) channels, had no effect on hypoxic relaxation in ferret vessels, but tetraethylammonium ions (TEA), a nonspecific K⫹ channel inhibitor, caused partial inhibition (92), and glibenclamide ⫹ TEA inhibited hypoxic relaxation more than either agent alone. These results suggested that activation of TEA-sensitive K⫹ channels, which were insensitive to glibenclamide and charybdoxin (and therefore presumably not KATP or KCa channels), also contributed to hypoxic relaxation. Other investigators, however, found that glibenclamide, charybdotoxin, and TEA had no effect on hypoxic relaxation (24,36). 4-Aminopyridine (4-AP), an inhibitor of voltage-dependent potassium (KV ) channels, augmented hypoxic relaxation, perhaps as a result of increased normoxic baseline tension (36). Hypoxic relaxation was inhibited by ouabain, low external [K⫹], or cooling, interventions designed to decrease activity of Na⫹-K⫹ ATPase (23). Usually, the Na⫹-K⫹ pump contributes to resting membrane potential, and decreased activity results in depolarization; however, since these interventions would be expected to increase (ouabain, cooling) or decrease (low external [K⫹]) membrane potential, their effects on hypoxic relaxation must have been related to other factors, such as [Na⫹] i or energy state, which should increase when pump activity slows (95). A rise in [Na⫹] i could prevent the fall in [Ca2⫹ ] i thought to occur during hypoxic relaxation (34) by enhancing Ca2⫹ influx through reversed Na⫹-Ca2⫹ exchange. A rise in energy state could prevent hypoxic activation of KATP channels and thereby block the hyperpolarization and relaxation that would otherwise occur. The positive effects of high glucose concentrations on vasomotor tone during hypoxic relaxation in isolated lungs (96,97) and pulmonary arteries (19,32,91,98) favor the latter possibility; however, improvements in energy state during severe hypoxia were not associated with improvements in vasomotor tone in endothelium-denuded pulmonary arteries (91), suggesting that other factors must be considered. The relation of hypoxic relaxation to in vivo responses to hypoxia remains uncertain; however, pulmonary vasodilation has been observed in both isolated lungs
Acute Hypoxic Pulmonary Vasoconstriction
321
and intact animals exposed to severe hypoxia (99–103), and in isolated lungs this vasodilation could be inhibited by glibenclamide (104). Possibly, similar mechanisms are involved. Late Hypoxic Contraction
Late hypoxic contraction was usually endothelium dependent (1,5,30,33,51,66), but not attenuated by inhibitors of NOS or cyclooxgenase (1,5,19,36,51), indicating it was not due to reduced release of NO or vasodilator prostaglandins from endothelium. Contributions by other endothelium-derived relaxing factors (EDRFs), such as endothelium-derived hyperpolarizing factor (105–107), have not been ruled out. It has been proposed that late hypoxic contraction is mediated by endotheliumderived contracting factors (EDCFs) (1,5,34). Since inhibitors of cyclooxygenase and lipoxygenase did not block late hypoxic contraction, vasoconstrictor prostaglandins or leukotrienes were not the EDCFs involved (1,5,19,36,51). Another possibility is endothelin-1 (ET-1), a 21-amino acid peptide produced by vascular endothelium, which activates smooth muscle ETA and (in some vessels) ETB receptors (108), resulting in marked pulmonary vasoconstriction (76,109,110). BQ123, an ETA receptor antagonist, did not alter precontraction induced by phenylephrine, but eliminated endothelium-dependent late hypoxic contraction in porcine proximal intrapulmonary arteries (52). These results were consistent with findings in proximal pulmonary arteries from sheep (111) and, as discussed below, distal pulmonary arteries from pigs (112). Moreover, ET-1 antagonists have consistently blocked HPV in humans and intact animals (111,113–117). These results suggest that ET-1 might be the EDCF responsible for late hypoxic contraction. Other investigators, however, reported that ETA receptor antagonists did not block HPV in either isolated lungs or pulmonary arteries (30,33,35,118,119). This discrepancy might be due to preparation- or species-dependent release of factors other than ET-1 which could mediate or facilitate late hypoxic contraction. After its transient increase during early hypoxic contraction, [Ca2⫹ ] i in rat pulmonary arteries remained slightly elevated but unchanging during late hypoxic contraction (34). Furthermore, late hypoxic contraction was abolished by exposure to verapamil or Ca2⫹-free media (5,24). These results suggested that late hypoxic contraction resulted from (1) a stable increase in [Ca2⫹ ] i, maintained by Ca2⫹ influx through L-type Ca2⫹ channels, and (2) an increase in myofilament sensitivity to Ca2⫹. Since endothelial denudation abolished late hypoxic contraction but did not alter the [Ca2⫹ ] i response to hypoxia (120), the increase in Ca2⫹ sensitivity was thought to be caused by an EDCF. Transduction of these or other necessary effects probably did not involve PKC, since late hypoxic contraction was not altered by an inhibitor of PKC or associated with changes in smooth muscle IP3 concentration (25,34). On the other hand, inhibitors of tyrosine kinases, which can alter Ca2⫹ sensitivity (121), selectively blocked late hypoxic contraction (31,120). Although ET-1 has been reported to increase Ca2⫹ sensitivity in systemic vessels (122–124) and activate tyrosine kinases (125–129), other mediators share these properties (126,127,130). In porcine proximal intrapulmonary arteries, late hypoxic contraction was associated with improvement of smooth muscle energy state and intracellular pH (pHi ),
322
Sylvester et al.
both of which had declined during the preceding hypoxic relaxation (91). Glucosefree conditions abolished late hypoxic contraction and recovery of energy state and pHi, but endothelial denudation abolished only late hypoxic contraction. These results suggested that recovery of energy state and pHi in hypoxic pulmonary arteries was due to accelerated glycolysis in smooth muscle and that late hypoxic contraction was mediated at least in part by endothelial factors which required hypoxic recovery of energy state and pHi for transduction or extracellular glucose for production and release. Characteristics of late hypoxic contraction have not been the same in all laboratories. Some investigators found that late hypoxic contraction was partly or completely endothelium independent (1,19,24,51,52,131). These findings may depend to some extent on the agonist used for precontraction (19,51); for example, late hypoxic contraction appeared to be independent of endothelium when the arteries were precontracted with KCl, but to require endothelium when serotonin was used (19). In addition, late hypoxic contraction was not seen after exposure to severe hypoxia in ferret pulmonary arteries (generation 3–4) or porcine pulmonary arteries (generation 4–5), or after exposure to moderate hypoxia in porcine pulmonary arteries (generation 3–4) (1,132). These results emphasize the possibly confounding influences of species, vessel locus, and oxygen tension, as well as the concentration and action of agents used for precontraction and other unknown factors (1,19,29,51). Nevertheless, because it is sustained, blocked by antagonists of L-type Ca2⫹ channels, and not observed in isolated systemic arteries (1,5,19,91), late hypoxic contraction is believed by many investigators to be the phase of the response in proximal pulmonary arteries that is most relevant to in vivo HPV. Distal Pulmonary Arteries
Fewer data are available from very small (ⱕ300 µm) very peripheral (ⱖ6th generation) pulmonary arteries (2–4,6,7,44,69,112,133), which are thought to be a major locus of HPV (134). Precontraction was sometimes unnecessary to elicit hypoxic responses in these vessels, perhaps because they developed intrinsic tone (135,136). In distal arteries from cat lungs, physiologic levels of hypoxia for ⬍15 min caused transient contractions which were potentiated by indomethacin or precontraction with KCl and inhibited by verapamil or decreased extracellular [Ca2⫹ ] (2–4,44). In addition, this response was associated with membrane depolarization, action potential generation, and reduced membrane input resistance, but not with alteration of the relation between membrane potential and extracellular [K⫹] (3,4). These results suggested that hypoxia depolarized and contracted vascular smooth muscle by increasing membrane Ca2⫹ conductance. In bovine distal pulmonary arteries, pretreatment with U46619 was necessary for contractile responses to occur during 10-min exposures to 0% O2 (69). This response was reduced by endothelial denudation or inhibitors of NOS, abolished by LY83583 (an inhibitor of sGC), but unaffected by indomethacin, suggesting that hypoxia caused contraction by decreasing (1) smooth muscle sGC activity via an L-arginine-independent pathway, and (2) endothelial
Acute Hypoxic Pulmonary Vasoconstriction
323
production of an L-arginine-dependent vasodilator. In distal arteries from rabbit lung, hypoxic contractions were absent or small, whether or not the vessels were precontracted (44). This lack of responsiveness was not improved by exposure to procaine or perivascular lung tissue. In the above studies, vasomotor tone was assessed by measuring isometric tension. Some authorities believe that measurements of vascular diameter at constant transmural pressure provide a more physiologic assessment of tone (137). When this approach was used in porcine distal pulmonary arteries, 30-min exposures to physiological levels of hypoxia caused monotonic PO2-dependent contractions which were abolished by Ca2⫹-free conditions, nifedipine, or endothelial denudation (6,7,112,133). Hypoxia had no effect on porcine bronchial arteries of similar diameter which were isolated and studied using the same techniques, suggesting that the response was specific for pulmonary vessels. Inhibitors of cyclooxygenase and NOS did not prevent hypoxic constriction, indicating that hypoxic suppression of NO or prostaglandin activities was not involved in mediation (6); however, contractile responses to hypoxia, but not KCl or U46619, were eliminated by either BQ123 or SOD (7,112). These results suggested that acute HPV in distal porcine pulmonary arterioles required endothelium and was mediated by •O2⫺ and ET-1. B. Pulmonary Arterial Smooth Muscle Cells (PASMCs)
Contractile Responses
In myocytes cultured from fetal bovine pulmonary arteries (generation 1–2), hypoxia increased phosphorylated myosin light chain (MLC) content and caused progressive wrinkling and distortion of the flexible polymerized polydimethyl siloxane surface on which the cells were grown, indicating contraction (138). These responses persisted even after multiple passages in culture. In myocytes isolated from cat pulmonary arteries ⬍600 µm in diameter (but not pulmonary arteries ⬎800 µm or cerebral arteries), hypoxia caused a 19% to 24% decrease in cell length, increased wrinkling of the flexible growth surface, and MLC phosphorylation. These contractions were comparable to maximal contractions induced by serotonin, prostaglandin F2α , indomethacin, or norepinephrine. In myocytes from rat main pulmonary artery after 3 to 4 days of culture on collagen gels, hypoxia caused reversible contractions similar in magnitude (⬇20%) to those activated by 60 mM KCl (139). In contrast, hypoxic contractions were smaller (ⱕ4%) in myocytes freshly isolated from porcine proximal and distal pulmonary arteries (140), which are known to exhibit endothelium-dependent hypoxic contraction (1,6,8,30,112); however, hypoxic contractions were markedly potentiated in these cells (25% to 30%) by exposure to a low concentration of ET-1 (10-10 M), which did not itself cause contraction (140). These results demonstrate that reductions in O2 tension were sensed by PASMCs and transduced into contractile responses which may have varied with species, vessel locus, and endothelial modulation. Hypoxic contractions appeared to be specific for PASMCs because they were not observed in systemic arterial myocytes studied under similar conditions (140,141).
324
Sylvester et al. Intracellular Calcium Concentration
Acute hypoxia elevated cytoplasmic [Ca2⫹] in PASMCs of rat, cat, dog, pig, rabbit, and fetal lamb (15,139,140,142–149). These responses were rapid in onset, maintained during hypoxia, reversible upon reoxygenation, more readily observed in cells from distal than proximal pulmonary arteries, and absent in cells from systemic arteries (139,140,142–144,146,147,149). In some studies, the magnitudes of Ca2⫹ responses to hypoxia were comparable to maximal Ca2⫹ responses induced by agonists (15,139,145,146), while in others they were smaller (142,147,148,150). Simultaneous measurement of [Ca2⫹ ] i and cell length showed that hypoxia-induced changes in these variables were positively correlated , suggesting that hypoxic contraction occurred in response to increased [Ca2⫹ ] i (138,141). Hypoxia did not appear to alter myofilament Ca2⫹ sensitivity (34,140,147). Elevation of [Ca2⫹ ] i could be due to increased influx of extracellular Ca2⫹, increased Ca2⫹ release from internal stores, decreased Ca2⫹ extrusion, or decreased SR Ca2⫹ uptake. Consistent with results in isolated lungs and pulmonary arteries (29,151–154), the Ca2⫹ response to hypoxia in PASMCs was completely abolished, partially inhibited, or reversed by removal of extracellular Ca2⫹ (143,146,147,149), attenuated by Ca2⫹ channel antagonists (142,144,149), and potentiated by the Ca2⫹ channel agonist BAY K8644 (144). These findings indicate that hypoxia increased Ca2⫹ influx through voltage-gated Ca2⫹ channels. In cultured myocytes from rat main pulmonary artery, hypoxia generated by the oxygen scavenger, sodium dithionite, elicited a biphasic Ca2⫹ response similar to that subsequently observed in rat pulmonary arteries (34). A large initial increase in [Ca2⫹ ] i was dependent on the magnitude and rate of decrease in PO2, abolished by depletion of SR Ca2⫹ stores with caffeine, and unaffected by removal of extracellular Ca2⫹. A smaller sustained increase in [Ca2⫹ ] i was dependent on extracellular Ca2⫹, but not abolished by verapamil or nifedipine (146). Depletion of Ca2⫹ stores with thapsigargin, an inhibitor of SR Ca2⫹ ATPase, caused a similar biphasic response and obliterated subsequent responses to hypoxia. The authors concluded that hypoxia caused Ca2⫹ release from intracellular stores, leading to store-operated capacitative Ca2⫹ entry (155,156). Whether the use of dithionite, which generates reactive oxygen species as it produces hypoxia (157), invalidates this conclusion is unknown; however, exposure of PASMCs from fetal lambs to authentic hypoxia also increased influx of Mn2⫹, which is thought to be an index of Ca2⫹ entry through store-operated Ca2⫹ channels (144). Hypoxia-induced release of Ca2⫹ from intracellular stores has been confirmed in PASMCs from several species (15,144,146,147). Complete or partial inhibition of the Ca2⫹ response to hypoxia by ryanodine suggested that hypoxia released Ca2⫹ from ryanodine-sensitive Ca2⫹ stores (15,144,146,147). In fetal lamb PASMCs, a transient hypoxia-induced increase in [Ca2⫹ ] i persisted after ryanodine, suggesting that Ca2⫹-induced Ca2⫹ release from SR may have contributed to the sustained elevation of [Ca2⫹ ] i seen before ryanodine (144). Pharmacological experiments in isolated pulmonary arteries suggested that hypoxia did not release Ca2⫹ from IP3-sensitive stores (38), but this has not been studied in PASMCs.
Acute Hypoxic Pulmonary Vasoconstriction
325
The effects of hypoxia on Ca2⫹ removal mechanisms have also not been investigated in PASMCs. In bovine intrapulmonary arteries, Ca2⫹ extrusion by Na⫹-Ca2⫹ exchange was impaired during hypoxia (158). In rabbit pulmonary arteries, hypoxia enhanced norepinephrine-induced contractions, suggesting increased Ca2⫹ sequestration (159). Whether these or other changes in Ca2⫹ removal altered [Ca2⫹ ] i is unknown. Membrane Depolarization
As noted above, resting membrane potential measured with microelectrodes in isolated pulmonary arteries was about ⫺50 mV during normoxia (3,4,160). Moderate hypoxia produced a sustained depolarization of about 15 mV, which was inhibited by reduction of external [Ca2⫹] or antagonists of L-type Ca2⫹ channels (2–4,160). These early findings established that hypoxia caused depolarization in pulmonary arterial smooth muscle, and suggested that this depolarization was related to Ca2⫹ entry through L-type Ca2⫹ channels. In isolated PASMCs, resting membrane potential measured using patch-clamp techniques ranged between ⫺35 and ⫺60 mV. Several laboratories demonstrated that hypoxia caused depolarization in PASMCs; however, a requirement for Ca2⫹ entry through L-type Ca2⫹ channels was not confirmed (15,145,161–166). In cultured PASMCs from rat main pulmonary artery, hypoxia generated with sodium dithionite produced sustained depolarizations and spontaneous action potentials, but removal of extracellular Ca2⫹ prevented only the action potentials (164). Other investigators found that hypoxia-induced depolarizations in freshly isolated PASMCs were abolished by ryanodine and thapsigargin, suggesting that depolarization was initiated by Ca2⫹ release from SR (15). One study of hypoxic depolarizations in rat PASMCs found that it was necessary to induce a relatively positive basal membrane potential with external K⫹, current injection, or ET-1, suggesting critical dependence of the hypoxic response on the basal activities of participating ion channels (165). Ion Channels
Since membrane impedance of PASMCs is high (2.6 to 17 GΩ) (167–169), small perturbations of ion channel activity could provoke marked changes in membrane potential. A wide variety of ion channels have been identified in PASMCs. Their activities depend on many factors, including species, size and locus of the arteries of origin, cell phenotype, stage of cellular development, cell culture history, resting membrane potential, presence of vasoactive agents, and activities of intracellular messengers and signaling pathways (161,162,164,170–172). Potassium Channels
Vascular smooth muscle contains four major types of K⫹ channels: voltage-gated (KV ), Ca2⫹-activated (KCa ), ATP-sensitive (KATP ), and inward rectifier (KIR ) (173); however, only the first three have been identified in PASMCs. Delayed rectifier KV channels are thought to be the major regulators of resting membrane potential in PASMCs (145,162,167,168,174–177) (but also see 165,166,
326
Sylvester et al.
178). They were activated at membrane potentials positive to ⫺50 mV, and their currents consisted of rapidly inactivating, slowly inactivating, and noninactivating components (167,169,177). Channel activity was independent of external Ca2⫹, blocked by 4-AP and quinine, but insensitive to TEA, charybdotoxin, iberiotoxin, and glibenclamide (167,169,173,174,177,179). In PASMCs, delayed rectifier KV channels were modulated by [Ca2⫹ ] i (145,180), [ATP] i (181); PKC-dependent phosphorylation (177); vasoactive agents such as ET-1, NO, angiotensin II, and arachidonic acid (177,182–185); cytochrome P450 inhibitors (186); reducing agents and oxidants (175,187,188); and metabolic inhibitors (174,189,190) and acidosis (191). KV channels other than the delayed rectifier have been described in PASMCs. At potentials above ⫹10 mV, fast transient outward (A-type) K⫹ currents were observed occasionally in freshly isolated cells (166,169) and more frequently in cultured cells (167,192). In rabbit and pig PASMCs, a voltage-gated, low-threshold (⫺80 to ⫺65 mV), noninactivating KV current was thought to be important regulator of resting membrane potential (166,178,193). The kinetically distinct components of KV currents reflect the presence of different KV channel subtypes, and KV channels of different conductances have been demonstrated in PASMCs (194). Immunoblotting and RT-PCR studies revealed the expression of multiple KV channel genes in PASMCs, including KV channel α-subunits of the Shaker subfamily (KV1.1, KV1.2, KV1.4, KV1.5, KV1.6), Shab subfamily (KV2.1), modulatory α-subunit (KV9.3), as well as KV β subunits (KVβ1.1, KVβ2, and Kvβ3) (148,194,195). KV1.5, and KV2.1 α-subunits may constitute the major components for the delayed rectifier KV channels responsible for resting membrane potential regulation in PASMCs, as application of specific antibodies against these subunits elevated resting membrane potential (15,148). A KV2.1/KV9.3 heteromultimer channel was found to be active at resting membrane potential in rat PASMCs (196). It is now widely accepted that hypoxia inhibits a 4-AP-sensitive, voltage-gated K⫹ current (145,161,162,164,165,171,174,190,197). In PASMCs dialysed with high [EGTA] i and [ATP] i , inhibition occurred at PO2 ⬍75 mm Hg, and was rapid in onset (⬍1 min), sustained during hypoxia, and reversible upon reoxygenation (164,174). These currents were preferentially expressed in PASMCs from small pulmonary arteries, consistent with findings that hypoxic responses were more readily observed in these vessels. The molecular identity of the oxygen-sensitive KV channel(s) in PASMCs remains controversial. Using specific KV channel antibodies, some investigators found that inhibition of KV2.1, but not KV1.5, caused significant depolarization; however, hypoxic contraction and Ca2⫹ responses to hypoxia and 4AP were blocked by anti-KV1.5, but unaffected by anti-KV2.1 (148). They hypothesized that inhibition of KV2.1 channels shifted resting membrane potential into the range for KV1.5 activation, and subsequent hypoxic inhibition of KV1.5 channels caused augmented depolarization. Other investigators showed that internal dialysis of an anti-KV1.5 antibody caused membrane depolarization, but failed to block the hypoxia-induced increase in [Ca2⫹ ] i, suggesting that KV1.5 was active at resting membrane potential but not involved in the hypoxic response (15). Since both studies
Acute Hypoxic Pulmonary Vasoconstriction
327
were performed in rat PASMCs from arteries of similar size using similar techniques, the reasons for these discrepancies are unclear. The identity of the O2-sensitive K⫹ channel is further complicated by studies in rabbit PASMCs suggesting that delayed-rectifier and A-type K⫹ currents did not contribute to resting membrane potential and were not sensitive to hypoxia (166,178). Instead, a novel 4-AP-sensitive, noninactivating KV current appeared to control resting membrane potential, and to be inhibited by acute hypoxia and downregulated by chronic hypoxia (166,198). It is not known which KV channel subtype was responsible for this current. In rat PASMCs, KV2.1/KV 9.3 heteromultimeric channels were active at resting membrane potential, tightly controlled by internal [ATP], and reversibly inhibited by hypoxia, suggesting that they could play an important role in acute HPV (196). KCa currents have been recorded extensively in myocytes from pulmonary arteries of different sizes and species (169–171,177,183,189, 193,197,199–211), and a rat homologue of the slowpoke gene (rSlo) encoding KCa channels has been detected in PASMCs (194). Whole-cell KCa currents usually exhibited large variations due to the high conductance of KCa channels (⬇250 pS in symmetrical K⫹). They were activated both by membrane potential and elevated [Ca2⫹ ] i and inhibited by TEA, charybdotoxin, and iberiotoxin, but were insensitive to 4-AP, glibenclamide, apamin, or Ba2⫹. In PASMCs from adult animals, KCa channels probably contributed little to resting membrane potential, as ChTx or low concentrations of TEA had minimal effect on resting membrane potential (52,162,176), consistent with the lack of effects of these agents on resting tension in isolated vessels (92) or baseline perfusion pressure in perfused lungs (212). During agonist stimulation, however, they might function as a negative feedback mechanism, causing repolarization or hyperpolarization to reduce Ca2⫹ entry through voltage-gated Ca2⫹ channels (176,213). In fetal PASMCs, KCa channels might play a more prominent role in regulating resting membrane potential, and evidence suggests a shift in the expression of KCa to KV channels in PASMCs during maturation (144,171,201). Activation of KCa channels by spontaneous Ca2⫹ release from SR elicited spontaneous transient outward currents (STOCs) in PASMCs (169,205,208). STOCs in systemic arterial myocytes were activated by local releases of Ca2⫹ (Ca2⫹ sparks) from ryanodine receptors located in close proximity to KCa channels, perhaps in the regions of caveolae, for fine-tuning membrane potentials while reserving global Ca2⫹ for activation of contractile machinery (214,215). It is not known whether such mechanisms are operative in PASMCs. KCa channels in PASMCs were modulated by PKA-, PKC-, and NO/cGMP/PKG-dependent phosphorylation (199,203,211,216); [ATP] i (200, 217–220); vasoactive agents (182,207,210,216); redox and metabolic states (189, 209,221); fatty acids and polyamines (185,222,223); and membrane stretch (222). A proposal that KCa channels in canine PASMCs were inhibited by hypoxia (163) was not confirmed in a subsequent study from the same laboratory (145); however, hypoxic inhibition of KCa channels, thought to be due to changes in redox and/or metabolic state, was later reported in rabbit PASMCs (187,209,217– 219,224,225). Inhibition of KCa channels is unlikely to be responsible for hypoxic
328
Sylvester et al.
depolarization, because KCa channels are closed at resting membrane potentials (161,162,176,177); however, when the cells are depolarized and [Ca2⫹ ] i is elevated during hypoxia, inhibition of KCa channels could reduce negative feedback stabilization of membrane potential (176) and thereby enhance depolarization and Ca2⫹ influx. KATP currents have been recorded in rabbit PASMCs (93,226–228). These currents were small, quasi-instantaneous, and time independent, with an estimated single channel conductance of 15 pS (227). KATP channels were activated by K⫹ channel openers (cromakalin, pinacidal, nicorandil, RP-49356, minoxidil, diazoxide); inhibited by external Ba2⫹, 4-AP, and sulfonylureas (glibenclamide, tolbutamide); but unaffected by charybdotoxin and low concentrations of TEA (173). Channel activity was completely inhibited at [ATP] i ⱖ 1 mM, and activated by submillimolar concentrations of nucleotide diphosphates (93,227,228). Activity is likely to be regulated by a variety of endogenous vasodilators and vasoconstrictors, including β-adrenergic agonists, adenosine, NO, and endothelin, as described in systemic arterial myocytes (173,229–231). The physiological roles of KATP channels in PASMCs have yet to be determined. They did not contribute to membrane potential under resting conditions, since glibenclamide did not alter membrane potential in PASMCs, basal tone in isolated pulmonary arteries, or pulmonary perfusion pressure in isolated lungs or intact animals (92,93,96,161,162,176,177,212,232). These findings also make it unlikely that KATP channels signalled HPV; however, KATP channel activation and secondary PASMC hyperpolarization may explain the pulmonary vasorelaxation elicited by severe hypoxia (96,104). Chloride Channels
Two types of Cl⫺ channels have been demonstrated in PASMCs. Ca2⫹-activated Cl (ClCa ) channels were blocked by niflumic acid, 4,4′-diisothiocyanostilbene-2,2′disulfonic acid (DIDS), or depletion of intracellular Ca2⫹ stores. They were activated by micromolar increases in [Ca2⫹ ] i due to Ca2⫹ influx through L-type Ca2⫹ channels, spontaneous SR Ca2⫹ release, or Ca2⫹ release induced by vasoactive agents, such as endothelin-1, angiotensin II, norepinephrine, histamine, ATP and caffeine, or metabolic inhibition by cyanide (182,207,210,233–239). They may be expressed more abundantly in PASMCs from large pulmonary arteries (236). Since the equilibrium potential of Cl⫺ in PASMCs is about ⫺20 mV, agonist-induced activation of ClCa channels could cause membrane depolarization and secondary vasoconstriction (210,233,235,240). Outward-rectifying, volume-regulated Cl⫺ currents were demonstrated in canine PASMCs during cell swelling induced by decreased external osmolarity (241). In addition, the gene products of volume-regulated chloride channels (ClC-3) were detected by RT-PCR. These currents were sensitive to DIDS, extracellular ATP, and the antiestrogen compound tamoxifen. Whether Cl⫺ channels contribute to HPV has not been investigated. Calcium Channels
The predominant Ca2⫹ channel in all vascular tissue is the voltage-gated L-type Ca2⫹ channel. This channel has a unitary conductance of 20 to 25 pS with 110 mM Ba2⫹
Acute Hypoxic Pulmonary Vasoconstriction
329
as the charge carrier (242) or 3.5 pS with 2 mM Ca2⫹ (243), and is active at membrane potentials between ⫺40 and ⫺10 mV (244). Because the resting membrane potential of PASMCs is positioned strategically at the threshold for channel activation, small depolarizations could cause channel activation and enhance Ca2⫹ influx, while small hyperpolarizations could deactivate these channels and reduce Ca2⫹ entry (243,245). L-type Ca2⫹ currents can be activated pharmocologically by dihydropyridine agonists (BAY K8644) and blocked by inorganic blockers (Cd2⫹, Ni2⫹ ) and three classes of organic antagonists: dihydropyridines (nifedipine), phenalkylamines (verapamil), and benzothiazepines (diltiazem). These currents were demonstrated in rabbit and rat PASMCs (167,246,247), shown to be regulated by the NO-cGMP pathway (246), and implicated in numerous studies of HPV in isolated pulmonary arteries and lungs. In rabbits, hypoxia inhibited Ca2⫹ currents (ICa) in myocytes from both large pulmonary and systemic arteries of rabbits, but caused a 10-mV shift to more negative potentials in the ICa-voltage relation of myocytes from small pulmonary arteries (247–249). A reduced threshold voltage for ICa activation could promote Ca2⫹ channel opening at resting membrane potentials, thereby increasing Ca2⫹ influx, as observed in PASMCs (142–144,149), and perhaps produce Ca2⫹-dependent depolarization, as observed in isolated pulmonary arteries (2–4,160). Transient or T-type Ca2⫹ currents have not been recorded in PASMCs; however, experiments in isolated lungs suggested that they might contribute to vasoconstriction caused by chronic hypoxia (250). Store-operated capacitative calcium entry via calcium release activated channels (ICRAC ) in PASMCs has also been suggested (146,251), but such currents have not been directly recorded; however, mRNA for a mammalian homologue of transient receptor potential (trp) proteins identified in Drosophila, thought to be the ICRAC channel (156,252–254), was detected in PASMCs during proliferation in culture (251). Other Channels
Tetrodotoxin-sensitive Na⫹ currents and nonselective cation currents were identified in cultured human and rabbit PASMCs, respectively (205,255). The regulation and physiological roles of these currents are unknown. C. Pulmonary Arterial Endothelial Cells (PAECs)
Chronic hypoxia is known to have numerous effects on pulmonary vascular endothelium, including alterations in barrier function (256,257), membrane transport (258– 260), energy metabolism (261–263), and production of growth factors (264–268) and other proteins (269–275); however, there has been little work on the effects of acute hypoxia in these cells. Signal Transduction Membrane Potential and Ion Channels
In bovine PAECs, membrane potential was thought to be determined by (1) an inwardly rectifiing K⫹ current, (2) an outwardly rectifying Cl⫺ current, and (3) a back-
330
Sylvester et al.
ground monovalent cation current (276). The high membrane impedance of PAECs implied that small changes in current could produce large changes in potential, perhaps explaining why normoxic resting membrane potentials in PAECs have varied between ⫺88 and ⫹5 mV (276–279). Endothelial cells have been classified on the basis of the ion channels which appeared to dominate regulation of resting membrane potential (280): K⫹-type cells had potentials of ⫺70 to ⫺60 mV, close to the equilibrium potential for K⫹, whereas Cl⫺-type cells had potentials of ⫺40 to ⫺10 mV, close to the equilibrium potential for Cl⫺. The significance of these differences in resting membrane potential is not clear. Inwardly rectifying K⫹ currents have been repeatedly demonstrated in PAECs (281–287). These currents were inhibited by Ba2⫹, ET-1, GTPgS, 2-deoxyglucose, KCN, or LP-805, an agent thought to cause NO release (276,281,283,287). They were insensitive to [Ca2⫹ ] i, quinidine, TEA, and activation of PKA or PKC (276,281). Recent molecular analysis suggest that KIR2.1 may be the responsible channel (281). Similarly, there is abundant evidence for the presence of Cl⫺ currents in PAECs (280,288–298). Ca2⫹-sensitive Cl⫺ currents (280,288,297,298) exhibited strong outward rectification and small single-channel conductance (8 pS at extracellular [Cl⫺] ⫽ 300 mM). They were activated by agents which increased [Ca2⫹ ] i, such as ATP and ionomycin, and inhibited by calmodulin antagonists, DIDS, niflumic acid, and tamoxifen. Activation of volume-sensitive Cl⫺ currents by cell swelling or decreased intracellular ionic strength (288,289,291) apparently utilized transduction pathways which did not include PKC, tyrosine kinase, MAP kinase, PI-3 kinase, or p70S6 kinase (295). Channel activity was potentiated by proteolytic activation of the thrombin receptor (293) and inhibited by quinidine, tamoxifen, inositol tetrakisphosphates, trifluoperazine, gossypol, antiviral agents (acyclovir, 3′azido-3′-deoxythymidine), and increased pHi (289,290,294,295). Although Ca2⫹and volume-sensitive Cl⫺ channels appear to be functionally distinct, their molecular identity remains uncertain (280). The extent to which other mechanisms contribute to regulation of membrane potential in PAECs is unclear. Calcium-activated K⫹ channels have been documented in PAECs (283). Observations that TEA or charybdotoxin depolarized bovine PAECs suggested that KCa channels regulated membrane potential under resting conditions (299), but this has not been confirmed. Other possibilities include ATPdependent K⫹ channels (300,301), nonspecific cation channels (278,302,303), Na⫹K⫹ ATPase (280), and electrical coupling among confluent cells (280). Exposure of PAECs to hypoxia caused membrane depolarization (299,304). Because similar depolarization was generated by TEA and charybdotoxin, it was suggested that hypoxia may have acted by inhibiting KCa channels (299). Intracellular Ca2⫹ Concentration
As in smooth muscle cells, endothelial [Ca2⫹ ] i is determined by Ca2⫹ influx from extracellular fluid, Ca2⫹ release from endoplasmic reticulum (ER), and ER Ca2⫹ uptake. Ca2⫹ influx may occur through ‘‘leak,’’ mechanosensitive, receptor-linked, or store-operated Ca2⫹-permeable channels (305,306). Influx through leak channels
Acute Hypoxic Pulmonary Vasoconstriction
331
may serve to maintain [Ca2⫹ ] i and refill intracellular Ca2⫹ stores (279,305,306). Shear stress and stretch caused Ca2⫹ influx through mechanosensitive Ca2⫹-permeable cation channels, perhaps leading to activation of NOS and release of NO (307,308). Bradykinin, thrombin, histamine, ATP, and other agents activated Ca2⫹ influx through receptor-linked nonselective cation channels (279,306). Depletion of intracellular Ca2⫹ stores by activation of ER IP3 receptors or inhibition of Ca2⫹ATPase promoted Ca2⫹ influx through nonselective cation channels possibly distinct from those linked to receptor activation (305,309,310). Although a few studies suggested that voltage-dependent Ca2⫹ channels were expressed in some endothelial cells (311–314), most investigators have been unable to demonstrate their presence (306). Consequently, membrane depolarization would be expected to decrease (rather than increase) Ca2⫹ influx through the above pathways and to lower (rather than raise) cytosolic Ca2⫹ concentration. The factors that regulate Ca2⫹ influx pathways in PAECs have not been well defined, and the molecular identities of the responsible channels remain unclear; however, it has been proposed that mammalian counterparts of the trp family of proteins may be components of endothelial leak, receptor-linked, and store-operated Ca2⫹-permeable cation channels (305,310). Ca2⫹ release is thought to occur primarily by receptor-linked activation of IP3 receptors on smooth ER, the activity of which may be modulated by [Ca2⫹ ] i and PKA-mediated phosphorylation (305). IP3 receptors exist in several isoforms, which may play different functional roles (315); however, the isoforms present in PAECs have not been characterized. Ca2⫹ may also be released from ryanodine-sensitive receptors on ER, but this has been difficult to demonstrate consistently (305). Increases in [Ca2⫹ ] i resulting from Ca2⫹ release or influx are limited or terminated by a family of proteins called sarco(endo)plasmic reticululum Ca2⫹-ATPases (SERCA), which pump Ca2⫹ from the cytosol into the ER (305). Which SERCA isoforms are present in PAECs and how their activity is modulated is unknown. In primary cultures of bovine PAECs, hypoxia decreased [Ca2⫹ ] i and Ca2⫹ influx (299). These effects were associated with depolarization and not prevented by thapsigargin, suggesting that hypoxia decreased Ca2⫹ influx by decreasing the transmembrane electrochemical gradient for Ca2⫹. Other investigators, however, found that [Ca2⫹ ] i was increased by hypoxia (316,317), as reported for systemic vascular endothelium (318–320). The increases in [Ca2⫹ ] i were either prevented (316) or unaffected (317) by removal of extracellular Ca2⫹, and blocked by ryanodine or thapsigargin (317) but not verapamil (316), suggesting that hypoxia caused release of Ca2⫹ from ER. The inconsistencies in these studies may be due in part to unrecognized hypoxia-induced alterations in calibration of fluorophores used to measure [Ca2⫹ ] i (321). Other Signal Transduction Pathways
Acute hypoxia decreased adenylate cyclase activity and cAMP concentration in association with increased monolayer permeability and inositol mono-, bi-, and triphosphate concentrations (257,322). The decrease in adenyl cyclase activity was prevented by downregulation of PKC, suggesting that it was due to hypoxiastimulated phosphoinositide turnover and PKC activation (322). Hypoxia increased
332
Sylvester et al.
catalytic activity and mRNA of calpain, a calcium-regulated neutral cysteine protease thought to react with a wide variety of substrates, such as cytoskeletal proteins, growth factor receptors, adhesion molecules, and ion transporters, and to play a role in intracellular mobilization of L-arginine (323,324). Hypoxia also enhanced degradation of nuclear factor-κB (NF-κB) inhibitor, IκB, and translocation of the p50 subunit of NF-κB to the nuclear membrane (323). Since these effects were prevented by calpain inhibitors, calpain may have been responsible for hypoxic activation of NF-κB, an important regulator of gene expression. Release of Vasoactive Mediators Nitric Oxide
Acute hypoxia decreased basal and agonist-induced relaxing activity of endothelium-derived NO in isolated pulmonary arteries, but did not prevent relaxation or increased smooth muscle cGMP concentration in response to NO donor compounds such as nitroprusside (26,27). These results indicated that hypoxia inhibited NO production in endothelium, rather than transduction of NO-mediated relaxation in vascular smooth muscle. The most likely mechanism is substrate limitation of the NOS-catalyzed reaction of O2, L-arginine, and NADPH to produce NO, L-citrulline, and NADP⫹. In vascular endothelium, the rate of this reaction was half-maximal at O2 tensions of 8 to 40 mm Hg (59,62). Although L-arginine transport into endothelial cells was reduced by hypoxia, probably because of membrane depolarization (304), L-arginine content was maintained or increased, probably because of calpain-dependent proteolytic mobilization of L-arginine from intracellular proteins (324). Another possible mechanism for reduced NO production during acute hypoxia is decreased [Ca2⫹ ] i, which could decrease activity of constitutive (Type III) NOS, a Ca2⫹-dependent enzyme . With prolonged hypoxia, other mechanisms could come into play, such as decreased synthesis of Type III NOS (265,325–328). Eicosanoids
In PAECs grown under normoxic conditions, acute hypoxia increased release of prostacyclin, PGF2a, and PGE2 (329–332); however, thromboxane release increased (332) or did not change (329,331). Similar results were obtained in systemic vascular endothelium, where release occurred more rapidly (320,331,332). The mechanisms of these effects are unclear but may involve increased release of precursor arachidonic acid secondary to activation of phospholipase A2 (320,333,334) or increased synthesis of cyclooxygenase protein (131,330,335). Some investigators found that severe hypoxia decreased prostaglandin production (336), suggesting substrate limitation of the cyclo-oxygenase reaction by molecular O2. In PAECs grown under hypoxic conditions (3% to 5% O2 ), acute hypoxia (near 0% O2 ) decreased production of PGE2, PGF2α, prostacyclin, and thromboxane (331,332,337). This result was explained by decreased arachidonic acid release, rather than decreased cyclooxygenase activity or arachidonic acid uptake (331). Acute hypoxia did not alter release of leukotrienes from perfused pulmonary arterial endothelial cells grown to confluence on microcarrier beads (329).
Acute Hypoxic Pulmonary Vasoconstriction
333
Endothelin
The effects of acute hypoxia on endothelin release by PAECs have not been reported; however, prolonged hypoxia (ⱖ24 h) decreased or did not change production of ET-1 protein and mRNA by these cells (338–340). In bovine coronary artery endothelial cells exposed to 2% O2, ET concentration in the culture media was unaltered at 4 h but increased at 24 h (341). Exposure of human umbilical vein endothelial cells to 1% O2 reduced media PO2 to 60 mm Hg and increased preproendothelin mRNA twofold at 1 h, but ET concentrations in the media did not increase until 6 h (342). It is possible that ET secretion increased earlier, but was not detected due to assay insensitivity. Several laboratories have confirmed that, unlike its effects in PAECs, prolonged hypoxia increased ET expression in systemic vascular endothelium (343–345), perhaps due to activation of tyrosine kinase (344) and/or the ET1 gene by the transcription factor, hypoxia-inducible factor 1 (343). Reactive Oxygen Species
The effects of acute hypoxia on endothelial production of reactive oxygen species have not been thoroughly examined. Prolonged hypoxia increased plasma membrane fluidity and malondialdehyde and conjugated diene concentrations in porcine PAECs, suggesting membrane lipid peroxidation (346); however, production of H2 O 2 and •O2⫺ was decreased at 2 h (347). These results may be species dependent, since porcine cells had no detectable xanthine oxidase/dehydrogenase activity, a potential source of reactive oxygen species which increased in rat and bovine cells during prolonged hypoxia (348–350). Prolonged hypoxia also increased CuZn superoxide dismutase, an effect shared by other interventions designed to increase oxidant production (351). Interestingly, membrane depolarization increased production of reactive oxygen species by cultured bovine PAECs and isolated rat lungs (352,353). Moreover, this increase was blocked by inhibitors of NADPH oxidase and abolished in mice with a knockout of gp91(phox), a cytochrome component of NADPH oxidase (354). Since hypoxia depolarized PAECs (299,304), its effects on production of reactive oxygen species need to be clarified.
III. Mechanisms of Acute HPV A. Effector Pathways in Pulmonary Arterial Myocytes
It has been proposed that the primary event leading to acute HPV is decreased conductance of KV channels in PASMCs, resulting in membrane depolarization, activation of voltage-dependent Ca2⫹ channels, Ca2⫹ influx, increased [Ca2⫹ ] i , calmodulinmediated activation of myosin light-chain kinase, and contraction (197,355–357). There is much evidence consistent with this hypothesis. First, hypoxia caused contraction in isolated pulmonary arteries denuded of endothelium and PASMCs (11,15,141,358), reduced KV currents in PASMCs (15,145,163,164), depolarized isolated pulmonary arteries and myocytes (2,11,15), increased [Ca2⫹ ] i in isolated pulmonary arteries and myocytes (34,143,144,146,147), and increased phosphorylated myosin light-chain content in PASMCs (39,138,141), but did not cause con-
334
Sylvester et al.
traction or inhibit K⫹ currents in systemic arteries or arterial myocytes (11,163,164). Second, pharmacological antagonists of KV channels caused depolarization of PASMCs and vasoconstriction in isolated lungs and pulmonary arteries (163,176, 212,359). Third, antibodies raised against a KV channel subtype found in pulmonary arterial smooth muscle (KV1.5) partially inhibited HPV in isolated lungs and diminished the increase in [Ca2⫹ ] i induced by hypoxia in pulmonary arterial myocytes (148,195). The strongest evidence against the KV hypothesis are findings that 4-AP, a KV channel antagonist, either did not alter or potentiated HPV in isolated lungs, pulmonary arteries, and PASMCs (140,161,212,359). Other data also seem inconsistent. In normoxic rabbit PASMCs, 4-AP did not alter resting membrane potential (187). Cytoplasmic dialysis of patch-clamped PASMCs with an antibody against KV1.5 protein did not alter (148) or increased (15) membrane potential, and subsequent hypoxia had no effect on potential but still increased [Ca2⫹ ] i (15). In PASMCs treated with charybdotoxin and niflumic acid to prevent obscuration of KV currents by KCa and ClCa currents, hypoxic increases in [Ca2⫹ ] i preceded membrane depolarization (145). Depletion of Ca2⫹ stores in sarcoplasmic reticulum (SR) with thapsigargin, ryanodine, cyclopiazonic acid, or caffeine prevented hypoxic constriction in isolated pulmonary arteries and hypoxic inhibition of KV currents, increases in [Ca2⫹ ] i , and depolarization in PASMCs (15,38,145–147). In some hands, the effects of hypoxia on myocyte length, [Ca2⫹ ] i , and KV currents were statistically significant but small (140), and other investigators could demonstrate no effect at all unless the cells were depolarized before hypoxic exposure with agents such as KCl or endothelin-1 (ET-1), suggesting that depolarization increased hypoxic sensitivity by activating KV channels, thereby permitting channel closure and further depolarization upon hypoxic exposure (142,165). These results suggest that (1) factors other than KV channel inhibition can generate HPV; (2) a decrease in O2 tension alone may be insufficient to stimulate HPV; (3) the initial elevation of [Ca2⫹ ] i leading to hypoxic contraction may be due to Ca2⫹ release from SR; and (4) given evidence that HPV requires Ca2⫹ influx through voltage-dependent Ca2⫹ channels, SR Ca2⫹ release or some other effect of hypoxia must lead to myocyte depolarization. Depolarization could occur via Ca2⫹-mediated inhibition of KV channels, as recently proposed (15,145,180,360); however, the inability of 4-AP to block HPV (140,161, 212,359) suggests that depolarization was either mediated by factors other than KV channels (such as ClCa channels) or unnecessary. Many studies have indicated that HPV requires depolarization and secondary influx of extracellular Ca2⫹ through L-type Ca2⫹ channels. Pharmacological antagonists of voltage-dependent Ca2⫹ channels inhibited hypoxia-induced increases in [Ca2⫹ ] i in PASMCs (144) and HPV in intact animals, isolated lungs, and isolated pulmonary arteries (4,5,11,12,24,29,151,359,361,362). Conversely, pharmacological agonists of voltage-dependent Ca2⫹ channels potentiated hypoxia-induced increases in [Ca2⫹ ] i in PASMCs (144) and HPV in intact animals, isolated lungs, and pulmonary arteries (29,152,154). However, some investigators have emphasized the nonspecificity of such results, pointing out that Ca2⫹ channel antagonists could diminish basal vasomotor tone and deplete intracellular Ca2⫹ stores as well as inhibit
Acute Hypoxic Pulmonary Vasoconstriction
335
Ca2⫹ influx, and that Ca2⫹ channel agonists could cause Ca2⫹ influx through L-type Ca2⫹ channels and potentiate any vasoconstrictor response (38,120). Moreover, Ca2⫹ channel antagonists have not always been completely effective, and have occasionally been ineffective, in blocking hypoxic responses (16,18,120,151,361,363). Recent preliminary findings (364) that late hypoxic contraction in rat pulmonary arteries was unaltered after depolarization with KCl, blockade of Ca2⫹ channels with nifedipine, and precontraction with PGF2α also questioned the need for depolarization and L-type Ca2⫹ channel activation in HPV. Such results indicate that the roles of Ca2⫹ release, store-operated Ca2⫹ entry, receptor-activated Ca2⫹ channels, Na⫹Ca2⫹ exchange, and myofilament Ca2⫹ sensitivity in HPV need to be evaluated. B. Oxygen Sensing
One of the most attractive features of the KV hypothesis is the mechanism it provides for O2 sensing (197,356). Inactivation of the KV channel is thought to depend on the redox state of a cysteine residue in its N-terminal region: inactivation is slowed when this cysteine is oxidized and accelerated when it is reduced (365). It is also possible that cellular reduction interfered with assembly of KV channel α- and βsubunits, which has been associated with inactivation (366). Thus, it was hypothesized that KV channels in PASMCs exposed to high O2 tensions were activated due to ROS production and NADH utilization by mitochondria, leading to hyperpolarization and relaxation. Conversely, KV channels were inactivated at low O2 tensions due to decreased ROS production and NADH utilization, leading to depolarization and contraction. Consistent with this hypothesis, agents that promoted cytosolic oxidation (diamide, oxidized glutathione) were reported to activate KV currents in PASMCs, whereas agents which promoted cytosolic reduction (N-acetylcysteine, reduced glutathione, duroquinone) or inhibited mitochondrial electron transport upstream from major sites of •O2⫺ generation (rotenone, antimycin A) caused inhibition of these currents (174,175,187,188,197). Moreover, rotenone, antimycin A, and hypoxia caused vasoconstriction and decreased luminol-enhanced chemilumenescence in isolated lungs, suggesting decreased ROS production (174,367). Other results seem inconsistent with redox signalling. Regulation of KV channel activity by oxidizing and reducing agents was similar in pulmonary and systemic myocytes (187), but the latter did not respond to hypoxia. Although reduction of KV channels with glutathione enhanced the rate of current inactivation, hypoxia did not (187,365). In some preparations, antimycin A increased, rather than decreased, ROS production (368,369). Cyanide, which inhibits mitochondrial electron transport at cytochome oxidase, increased chemilumenscence (174) but caused vasoconstriction in isolated lungs (367,370). Such inconsistencies might be expected, since •O2⫺ can act as both oxidant and reductant (371,372) and redox state can affect a wide variety of cellular processes. Moreover, many of the interventions employed to change redox state may also have altered energy state, the effects of which could be equally global. The possibility that HPV is signaled by a decrease in energy state due to hypoxic limitation of oxidative phosphorylation has long been considered (373,374).
336
Sylvester et al.
This hypothesis first requires that hypoxia not impair the ability of vascular smooth muscle to contract, and this has been confirmed (375). Consistent with the hypothesis, agents that impaired oxidative phosphorylation (rotenone, antimycin A, cyanide, FCCP) caused pulmonary vasoconstriction in isolated lungs (367,370,376). How decreased energy state might lead to HPV is unknown. Impaired phosphorylation of ion channels or downregulation of phosphorylation reactions in regulatory pathways are among the many possibilities. In pulmonary (but not systemic) arterial myocytes, blocking glycolysis with 2-deoxyglucose or uncoupling mitochondrial ATP production with FCCP caused inhibition of KV currents and depolarization, similar to the effects of hypoxia (188,189). Moreover, KV channel activity was enhanced by intracellular ATP and PKA- and PKG-dependent phosphorylation, and the effects of hypoxia on membrane potential and KV currents were abolished by 2-deoxyglucose. These results suggested that hypoxia caused depletion of subsarcolemmal ATP, leading to reduced phosphorylation and secondary inhibition of sacrolemmal KV channels (188,189). A similar mechanism has been proposed to explain hypoxic inhibition of KCa channels (217–219). Several arguments have been raised against a primary role for ATP or energy state in O2 sensing. Hypoxia-induced depolarization and current inhibition in PASMCs occurred rapidly (⬍1 min), whereas significant reductions in [ATP] i should occur slowly (197). Glycolytic ATP production, which fuels most sarcolemmal transporters and ion channels, should increase rather than decrease during hypoxia (98,377,378). A critically low ATP in the subsarcolemmal compartment could open KATP channels, causing hyperpolarization and relaxation instead of depolarization and contraction (92,94,104). Hypoxia inhibited K⫹ currents in PASMCs dialyzed with high concentrations of ATP (15,145,163,164). Whole-tissue ATP and adenylate charge (a measure of energy state) were unchanged during HPV in isolated lungs (370). Late hypoxic contraction in isolated pulmonary arteries was associated with improvement rather than a deterioration in myocyte energy state (91,377). These findings suggest that changes in energy state may play a modulatory or permissive role in HPV, rather than signal the response. It remains possible that HPV is signaled by some variable linked to mitochondrial electron transport other than energy state. In cardiac myocytes, hypoxia increased mitochondrial •O2⫺ production due to a decrease in O2 affinity of cytochrome c oxidase and secondary upstream accumulation of electrons at sites of •O2⫺ production (369,379). The effects of antioxidants and other pharmacological interventions suggested that this increase in •O2⫺ production signaled adaptive responses to hypoxia, such as myocyte hibernation and ischemic preconditioning (380,381). A preliminary report suggests that similar mechanisms may be operative in HPV (382): in the rat, hypoxia increased mitochondrial production of reactive oxygen species by PASMCs; and antioxidants or agents which block mitochondrial electron transport upstream from sites of •O2⫺ production inhibited pressor responses to hypoxia (but not U46619) in isolated lungs. These results appeared to be inconsistent with previous reports indicating that hypoxia decreased production of reactive oxygen species (72,383,384); however, these data were obtained in isolated lungs (383), where production by pulmonary arteries may have been obscured; large pulmonary arteries
Acute Hypoxic Pulmonary Vasoconstriction
337
subjected to severe hypoxia, where PO2 may have been rate limiting (384); and pulmonary arterial homogenates, which may not reflect characteristics of intact tissue (72). Two other mechanisms of O2 sensing in pulmonary arteries are under active investigation, and they both involve reactive oxygen species. One hypothesis, originally developed for O2 sensing in the carotid body (385–387), proposed that HPV is signalled by O2-dependent changes in •O2⫺ production by a sarcolemmal NADPH oxidase similar to that found in neutrophils (139,388–390). Supporting evidence includes demonstration by Western blot analysis, low-temperature difference spectrophotometry, and immunohistochemistry that cytochrome b⫺245, thought to be a unique component of the NADPH oxidase complex, was present in pulmonary arterial smooth muscle (388). In addition, diphenyleneiodinium (DPI), an inhibitor of NADPH oxidase, blocked HPV in isolated lungs (389,390), reduced •O2⫺ production and hypoxic contractions in isolated pulmonary arteries (384,388), and inhibited hypoxic contractions in PASMCs (139). Initially, it was thought that high O2 tensions would increase •O2⫺ production by NADPH oxidase, and this increase would keep pulmonary arteries relaxed by altering ion currents or other transduction pathways, along lines proposed for O2-dependent responses in carotid and neuroepithelial bodies (387,391–393); however, several reports do not support this possibility. In isolated lungs, both DPI and the •O2⫺ scavenger nitroblue tetrazolium (NBT) blocked HPV, but neither agent caused vasoconstriction during normoxia, as would be predicted (389,394). In isolated pulmonary arteries, inhibitors of SOD potentiated (rather than depressed) hypoxic contractions (13). In PASMCs, hypoxia increased (rather than decreased) •O2⫺ production, and this increase was blocked by DPI (388). Supporting evidence is weakened by the nonspecificity of DPI, which inhibited mitochondrial electron transport, NO synthase, and K⫹ and Ca2⫹ channels (388,395,396), and blocked hypoxic contractions but not Ca2⫹ responses in PASMCs (139). Also, recent experiments indicated that HPV was intact in mice lacking the gp91(phox) subunit of NADPH oxidase (397). Finally, it seems illogical that a decrease in PO2 could increase production of reactive oxygen species by a heme protein; however, this possibility should not be rejected out of hand, since production of reactive oxygen species by hemoglobin was increased during hypoxia, possibly due to conformational changes in the ‘‘flexibility’’ of the heme pocket (398– 400). The other hypothesis proposed that •O2⫺ produced in direct proportion to PO2 by a smooth muscle microsomal NADH oxidase is metabolized by SOD to H2 O 2, which interacts with catalase to activate soluble guanylate cyclase independently of NO, increase cGMP, and cause relaxation. Thus, hypoxia would decrease cGMP, resulting in vasoconstriction. This hypothesis is supported by observations in isolated pulmonary arteries that H2 O 2 and reoxygenation after hypoxia caused relaxations which were blocked by SOD, catalase, or inhibitors of sGC (20,67–69). In pulmonary artery homogenates, NADH increased lucigenin-enhanced chemilumenescence, and the increase was inhibited by SOD or NBT. This activity fractionated with microsomes and was associated with absorption spectra typical of cytochrome b558 (70–72).
338
Sylvester et al. C. Role of Endothelium
As discussed above, there is considerable evidence that endothelial cells play an essential role in acute HPV. In general, endothelium could directly mediate or indirectly facilitate hypoxic contraction of pulmonary arterial myocytes by releasing vasoactive mediators into the extracellular fluid surrounding vascular smooth muscle (77,401–403) or by transmitting electrical signals to smooth muscle cells through high conductance gap junctions (280,404,405). Presumably, these actions would result from direct effects of hypoxia on endothelial cells, leading to alteration of electrophysiological properties and/or intracellular messengers. Many laboratories have attempted to determine whether HPV was endothelium dependent. Most (1,5–8,23,26,29,30,33,40,46,48,49,53,66,112,133,406), but not all (9,11,15,19,24,42,69), concluded that it was. Endothelium dependence of HPV would explain recent observations that endothelin receptor antagonists blocked acute HPV in intact animals (111,113-117). Consistent with the possibility that ET1 mediates HPV, acute hypoxia was found to increase ET-1 production in humans, intact animals, isolated lungs, and cultured endothelium (342,407–410). Arguing against this possibility are the temporal differences between vasoconstrictor responses to ET-1 and HPV, which reverse slowly and rapidly, respectively. Thus, if ET-1 plays a role in HPV, it may be more subtle than direct activation of contraction. In the pig, BQ123 blocked endothelium-dependent late hypoxic contraction in proximal pulmonary arteries and abolished HPV in distal pulmonary arteries (52,112). Moreover, pretreatment of myocytes from distal porcine arterioles with a concentration of ET-1 (10⫺10 M), which did not itself alter [Ca2⫹ ] i or cell length markedly, potentiated hypoxic contraction but did not alter the hypoxia-induced increase in [Ca2⫹ ] i (140). These results indicate that full expression of HPV required endothelial priming of vascular smooth muscle and that ET-1 mediated this priming. Low concentrations of ET-1 could prime PASMCs by increasing myofilament Ca2⫹ sensitivity, resting membrane potential, or the probability of Ca2⫹ channel activation, allowing PASMCs to contract in response to signals which otherwise might be ineffective (122–124,411). Other endogenous mediators might share this ability. Such redundancy could explain observations that endothelin antagonists, despite consistent efficacy in intact animals, did not always prevent HPV in isolated lungs and pulmonary arteries (33,35,119), preparations in which multiple mediators might be released. IV. Summary and Future Directions Hope that the powerful approaches of cellular and molecular biology would reveal the mechanisms of HPV has not yet been realized. Indeed, the surfeit of new information produced by this work has increased the number of apparently conflicting possibilities. Assuming that HPV is signaled by a specific O2-linked event in a specific cell, such inconsistency could be attributed to artifacts introduced by unphysiologic preparations or conditions; however, it may be more productive to assume that
Acute Hypoxic Pulmonary Vasoconstriction
339
HPV results from multiple, redundant O2-linked transduction pathways in multiple cells. Since HPV is central to oxygen transport, such redundancy may be important for evolutionary success, but it complicates elucidation of mechanisms. Figure 1 depicts a mechanistic schema for HPV which attempts to synthesize currently available information. It is presented not as an answer, but as a source of questions for future investigation. In pulmonary arterial smooth muscle, hypoxia alters production of reactive oxygen species, redox state, and energy state. These or other signals initiate HPV by causing release of Ca2⫹ from ryanodine-sensitive stores in SR. As SR Ca2⫹ stores empty, influx of Ca2⫹ through store-operated Ca2⫹ channels in the sarcolemma begins. The increase in [Ca2⫹ ] i caused by SR Ca2⫹ release and store-operated Ca2⫹ influx has several effects. In the cytosol, it initiates contraction by triggering calmodulin-dependent activation of myosin light-chain kinase. At the plasma membrane, it inhibits KV and activates ClCa channels, leading to membrane depolarization, activation of voltage-dependent Ca2⫹ channels, and Ca2⫹ influx. KV channels may also be inhibited directly by hypoxia-induced alterations of redox state. At the SR, the initial increase in [Ca2⫹ ] i causes Ca2⫹-induced Ca2⫹ release, leading to further depletion of SR Ca2⫹ stores and enhancement of store-operated Ca2⫹ entry. These new sources of Ca2⫹ could augment the initial increase in [Ca2⫹] i , resulting in a progressive increase in vasomotor tone. As stores empty and the activity of Ca2⫹ pumps increase, [Ca2⫹] i would achieve a steady elevated level set by the balance between Ca2⫹ removal and entry, the latter now determined by Ca2⫹ influx through voltagedependent and store-operated Ca2⫹ channels and SR Ca2⫹ release. As a result, HPV is maintained. Note that several pathways lead to elevation of [Ca2⫹ ] i , providing for redundancy of transduction. Whether this sequence of events occurs, however, depends critically on endothelium. During normoxia, basal release of endothelium-derived factors primes myocytes to contract to hypoxia. EDCFs, such as ET-1, act at several loci, providing for additional redundancy of transduction. At the sarcolemma, they raise resting membrane potential and increase the open probability of voltage-dependent Ca2⫹ channels, so that small increases in membrane potential cause large increases in Ca2⫹ influx. At the SR, they promote turnover of Ca2⫹ stores, so that small increases in [Ca2⫹ ] i or other signals cause large increases in Ca2⫹ release. In the cytosol, they increase myofilament Ca2⫹ sensitivity, so that small increases in [Ca2⫹ ] i cause large increases in vasomotor tone. During hypoxia, direct effects of hypoxia on endothelial cells may increase release of EDCFs, such as ET-1, and decrease release of EDRFs, such as NO, thereby amplifying endothelial priming actions and potentiating HPV. In the case of NO, substrate limitation and/or NOS inhibition due to hypoxic depolarization and decreased [Ca2⫹ ] i in endothelial cells could turn off NO-mediated activation of myocyte Ca2⫹ pump activity, leading to facilitation of hypoxia-induced increases in [Ca2⫹ ] i and vasomotor tone. The mechanisms by which hypoxia is sensed and transduced to alter release of other relaxing and contracting factors by PAECs are unknown, but presumably involve alterations in [Ca2⫹ ] i and other second messengers.
340
Sylvester et al.
Figure 1 The pulmonary vasoconstrictor response to acute hypoxia depends on the interaction between pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Inhibitory pathways shown by dashed lines and minus signs. All other effects are positive. Shown at lower right is the response of porcine pulmonary arteries, expressed as the time course of internal vascular diameter measured at a constant transmural pressure of 20 mm Hg (baseline internal diameter was 150 to 250 µm). SR, sarcoplasmic reticulum; ET-1, endothelin-1; NOS, nitric oxide synthase; Po, open probability; EDCFs, endothelium-derived contracting factors.
Acute Hypoxic Pulmonary Vasoconstriction
341
Much work will be necessary to clarify the mechanisms of HPV. Investigative momentum has already been established in PASMCs. Here, the pressing need is to determine how hypoxia affects Ca2⫹ mobilization. For example, what are the temporal relationships amoung [Ca2⫹ ] i, membrane potential, and contraction during hypoxia? What sources of Ca2⫹ contribute to [Ca2⫹ ] i, and under what circumstances? How does hypoxia alter local [Ca2⫹ ] i? Does HPV require membrane depolarization and, if so, what ions, channels, and pumps are responsible? The status of research in PAECs is far worse. Virtually nothing is known about the acute effects of hypoxia in these cells. Major areas of ignorance include the identity of endothelium-derived factors released during acute hypoxia, if and how hypoxia alters their release, and how they prime and facilitate HPV in smooth muscle. The area of greatest confusion, and therefore the area in need of greatest investigative attention, is how O2 is sensed in PASMCs and PAECs. Although it is clear that hypoxia exerts direct effects on both cells and likely that HPV results from the integration of these effects, the responsible stimuli remain unclear. Recent work suggests that reactive oxygen species produced by cytochrome oxidase, NADPH oxidase, or NADH oxidase may signal HPV. Given increasing evidence that reactive oxygen species trigger a wide variety of cellular responses (412), the sources of these substances and their role in HPV deserve full evaluation. Given the apparent complexity and redundancy of mechanisms causing HPV, the touchstone of future investigations must remain the intact animal, or at least the isolated lung, where hypotheses developed from cellular and molecular work must be tested for relevance. References 1. Kovitz KL, Aleskowitch TD, Sylvester JT, Flavahan NA. Endothelium-derived contracting and relaxing factors contribute to hypoxic responses of pulmonary arteries. Am J Physiol 1993; 265:H1139–H1148. 2. Madden JA, Dawson CA, Harder DR. Hypoxia-induced activation in small isolated pulmonary arteries from the cat. J Appl Physiol 1985; 59:113–118. 3. Harder DR, Madden JA, Dawson C. A membrane electrical mechanism for hypoxic vasoconstriction of small pulmonary arteries from cat. Chest 1985; 88:233S-235S. 4. Harder DR, Madden JA, Dawson C. Hypoxic induction of Ca2⫹-dependent action potentials in small pulmonary arteries of the cat. J Appl Physiol 1985; 59:1389–1393. 5. Leach RM, Robertson TP, Twort CH, Ward JP. Hypoxic vasoconstriction in rat pulmonary and mesenteric arteries. Am J Physiol 1994; 266:L223–L231. 6. Liu Q, Fan H, Shimoda L, Sham J, Sylvester JT. Hypoxic contraction of isolated pig pulmonary arterioles: role of NO and vasodilator prostaglandins (abstract). Am J Respir Crit Care Med 1998; 153:A382. 7. Liu Q, Sylvester JT. Hypoxic vasoconstriction of isolated porcine pulmonary arterioles: role of endothelin-1 and superoxide (abstract). Am J Respir Crit Care Med 1999; 159: A565. 8. Holden WE, McCall E. Hypoxia-induced contractions of porcine pulmonary artery strips depend on intact endothelium. Exp Lung Res 1984; 7:101–112. 9. Ogata M, Ohe M, Katayose D, Takishima T. Modulatory role of EDRF in hypoxic contraction of isolated porcine pulmonary arteries. Am J Physiol 1992; 262:H691–H697. 10. Ohe M, Mimata T, Haneda T, Takishima T. Time course of pulmonary vasoconstriction with repeated hypoxia and glucose depletion. Respir Physiol 1986; 63:177–186.
342
Sylvester et al.
11. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Contrasting effects of hypoxia on tension in rat pulmonary and mesenteric arteries. Am J Physiol 1990; 259:H281–H289. 12. Savineau JP, Gonzalez de la Fuente P, Marthan R. Cellular mechanisms of hypoxia-induced contraction in human and rat pulmonary arteries. Respir Physiol 1995; 99:191–198. 13. Abdalla S, Will JA. Potentiation of the hypoxic contraction of guinea-pig isolated pulmonary arteries by two inhibitors of superoxide dismutase. Gen Pharmacol 1995; 26:785– 792. 14. Souhrada JF, Dickey DW. Effect of substrate on hypoxic response of pulmonary artery. J Appl Physiol 1976; 40:533–538. 15. Gelband CH, Gelband H. Ca2⫹ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels. Circulation 1997; 96:3647–3654. 16. Demiryurek AT, Wadsworth RM, Kane KA, Peacock AJ. The role of endothelium in hypoxic constriction of human pulmonary artery rings. Am Rev Respir Dis 1993; 147:283– 290. 17. Demiryurek AT, Wadsworth RM, Kane KA. Effects of hypoxia on isolated intrapulmonary arteries from the sheep. Pulm Pharmacol 1991; 4:158–164. 18. Demiryurek AT, Wadsworth RM, Kane KA. Pharmacological evidence for the role of mediators in hypoxia-induced vasoconstriction in sheep isolated intrapulmonary artery rings. Eur J Pharmacol 1991; 203:1–8. 19. Bennie RE, Packer CS, Powell DR, Jin N, Rhoades RA. Biphasic contractile response of pulmonary artery to hypoxia. Am J Physiol 1991; 261:L156–L163. 20. Burke-Wolin T, Wolin MS. H2 O 2 and cGMP may function as an O2 sensor in the pulmonary artery. J Appl Physiol 1989; 66:167–170. 21. Burke-Wolin TM, Wolin MS. Inhibition of cGMP-associated pulmonary arterial relaxation to H2 O 2 and O2 by ethanol. Am J Physiol 1990; 258:H1267–H1273. 22. Hoshino Y, Obara H, Kusunoki M, Fujii Y, Iwai S. Hypoxic contractile response in isolated human pulmonary artery: role of calcium ion. J Appl Physiol 1988; 65:2468–2474. 23. Hoshino Y, Morrison KJ, Vanhoutte PM. Mechanisms of hypoxic vasoconstriction in the canine isolated pulmonary artery: role of endothelium and sodium pump. Am J Physiol 1994; 267:L120–L127. 24. Jin N, Packer CS, Rhoades RA. Pulmonary arterial hypoxic contraction: signal transduction. Am J Physiol 1992; 263:L73–L78. 25. Jin N, Packer CS, English D, Rhoades RA. Inositol trisphosphate is involved in norepinephrine- but not in hypoxia-induced pulmonary arterial contraction. Am J Physiol 1993; 264: L160–L164. 26. Johns RA, Linden JM, Peach MJ. Endothelium-dependent relaxation and cyclic GMP accumulation in rabbit pulmonary artery are selectively impaired by moderate hypoxia. Circ Res 1989; 65:1508–1515. 27. Rodman DM, Yamaguchi T, Hasunuma K, O’Brien RF, McMurtry IF. Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery. Am J Physiol 1990; 258: L207–L214. 28. Rodman DM, Yamaguchi T, O’Brien RF, McMurtry IF. Methylene blue enhances hypoxic contraction in isolated rat pulmonary arteries. Chest 1988; 93:93S–94S. 29. Rodman DM, Yamaguchi T, O’Brien RF, McMurtry IF. Hypoxic contraction of isolated rat pulmonary artery. J Pharmacol Exp Ther 1989; 248:952–929. 30. Gaine SP, Hales MA, Flavahan NA. Hypoxic pulmonary endothelial cells release a diffusible contractile factor distinct from endothelin. Am J Physiol 1998; 274:L657– L664. 31. Uzun O, Demiryurek AT, Kanzik I. The role of tyrosine kinase in hypoxic constriction of sheep pulmonary artery rings. Eur J Pharmacol 1998; 358:41–47. 32. Zhao Y, Packer CS, Rhoades RA. The vein utilizes different sources of energy than the artery during pulmonary hypoxic vasoconstriction. Exp Lung Res 1996; 22:51–63. 33. Lazor R, Feihl F, Waeber B, Kucera P, Perret C. Endothelin-1 does not mediate the endothelium-dependent hypoxic contractions of small pulmonary arteries in rats. Chest 1996; 110:189–197. 34. Robertson TP, Aaronson PI, Ward JP. Hypoxic vasoconstriction and intracellular Ca2⫹ in
Acute Hypoxic Pulmonary Vasoconstriction
35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.
343
pulmonary arteries: evidence for PKC-independent Ca2⫹ sensitization. Am J Physiol 1995; 268:H301–307. Douglas SA, Vickery-Clark LM, Ohlstein EH. Endothelin-1 does not mediate hypoxic vasoconstriction in canine isolated blood vessels: effect of BQ-123. Br J Pharmacol 1993; 108:418–421. Karamsetty MR, Wadsworth RM, Kane KA. Effect of K⫹ channel blocking drugs and nitric oxide synthase inhibition on the response to hypoxia in rat pulmonary artery rings. J Auton Pharmacol 1998; 18:49–56. Thompson JS, Jones RD, Rogers TK, Hancock J, Morice AH. Inhibition of hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries by diphenyleneiodonium (DPI). Pulm Pharmacol Ther 1998; 11:71–75. Jabr RI, Toland H, Gelband CH, Wang XX, Hume JR. Prominent role of intracellular Ca2⫹ release in hypoxic vasoconstriction of canine pulmonary artery. Br J Pharmacol 1997; 122: 21–30. Zhao Y, Rhoades RA, Packer CS. Hypoxia-induced pulmonary arterial contraction appears to be dependent on myosin light chain phosphorylation. Am J Physiol 1996; 271:L768– L774. Greenberg B, Kishiyama S. Endothelium-dependent and -independent responses to severe hypoxia in rat pulmonary artery. Am J Physiol 1993; 265:H1712–H1720. Mathew R, Burke-Wolin T, Gewitz MH, Wolin MS. O2 and rat pulmonary artery tone: effects of endothelium, Ca2⫹, cyanide, and monocrotaline. J Appl Physiol 1991; 71:30– 36. Mathew R, Omar HA, Cherry PD, Gewitz MH, Wolin MS. Role of cGMP mechanisms in response of rat pulmonary arteries to hypoxia. Am J Physiol 1992; 263:H141–H146. Bonnet P, Argibay JA, Garnier D. Contractile responses to hypoxia of isolated rings from the left branch of rabbit pulmonary artery. Fund Clin Pharmacol 1989; 3:115–126. Bonnet P, Argibay JA, White E, Garnier D. Differences in the hypoxic contraction of small isolated pulmonary arteries of cat and rabbit. J Comp Physiol [B] 1991; 161:543–547. Miller DS, Yaghi A, Hamilton JT, Paterson NA. Role of arachidonic acid metabolites in hypoxic contractions of isolated porcine pulmonary artery and vein. Exp Lung Res 1989; 15:213–222. Villamor E, Ruiz T, Perez-Vizcaino F, Tamargo J, Moro M. Endothelium-derived nitric oxide-dependent response to hypoxia in piglet intrapulmonary arteries. Biol Neonate 1997; 72:62–70. Shigemori K, Ishizaki T, Matsukawa S, Sakai A, Nakai T, Miyabo S. Adenine nucleotides via activation of ATP-sensitive K⫹ channels modulate hypoxic response in rat pulmonary artery. Am J Physiol 1996; 270:L803–L809. Feletou M, Girard V, Canet E. Different involvement of nitric oxide in endothelium-dependent relaxation of porcine pulmonary artery and vein: influence of hypoxia. J Cardiovasc Pharmacol 1995; 25:665–673. Lee YH, Lee HY, Lee EY, Kang BS. Hypoxic contraction of isolated rat pulmonary artery. J Smooth Muscle Res 1995; 31:471–475. Detar R, Gellai M. Oxygen and isolated vascular smooth muscle from the main pulmonary artery of the rabbit. Am J Physiol 1971; 221:1791–1794. Booth GM, Shimoda LA, Liu Q, Sham JSK, Sylvester JT. Endothelium-dependent contractile factor activity and hypoxic responses in prestimulated porcine intra-pulmonary arteries (abstract). Am J Respir Crit Care Med 1997; 155:A790. Shimoda T, Booth G, Liu Q, Shimoda L, Sham J, Sylvester JT. Endothelium-dependent hypoxic contraction of pig proximal intrapulmonary arteries: role of endothelin (abstract). Am J Respir Crit Care Med 1998; 157:A724. Ogawa Y, Kawabe J, Onodera S, Tobise K, Morita K, Harada T, Hirayama T, Takeda A. Role of endothelium in biphasic hypoxic response of the isolated pulmonary artery in the rat. Jpn Circ J 1993; 57:228–236. Jones RD, Morice AH. The ETA antagonist CI-1020 inhibits hypoxic pulmonary vasoconstriction in small isolated rat pulmonary arteries. Pulm Pharmacol Ther 1998; 11:177–181. Berkov S. Hypoxic pulmonary vasoconstriction in the rat. The necessary role of angiotensin II. Circ Res 1974; 35:256–261.
344
Sylvester et al.
56. McMurtry IF. Angiotensin is not required for hypoxic constriction in salt solution-perfused rat lungs. J Appl Physiol 1984; 56:375–380. 57. Leach RM, Twort CH, Cameron IR, Ward JP. A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat. Clin Sci 1992; 82:55–62. 58. Ozaki M, Marshall C, Amaki Y, Marshall BE. Role of wall tension in hypoxic responses of isolated rat pulmonary arteries. Am J Physiol 1998; 275:L1069–L1077. 59. Rengasamy A, Johns RA. Determination of Km for oxygen of nitric oxide synthase isoforms. J Pharmacol Exp Ther 1996; 276:30–33. 60. Grimminger F, Spriestersbach R, Weissmann N, Walmrath D, Seeger W. Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J Appl Physiol 1995; 78:1509–1515. 61. Kantrow SP, Huang YC, Whorton AR, Grayck EN, Knight JM, Millington DS, Piantadosi CA. Hypoxia inhibits nitric oxide synthesis in isolated rabbit lung. Am J Physiol 1997; 272:L1167–L1173. 62. Whorton AR, Simonds DB, Piantadosi CA. Regulation of nitric oxide synthesis by oxygen in vascular endothelial cells. Am J Physiol 1997; 272:L1161–L1166. 63. Tamaoki J, Tagaya E, Yamawaki I, Konno K. Hypoxia impairs nitrovasodilator-induced pulmonary vasodilation: role of Na-K-ATPase activity. Am J Physiol 1996; 271:L172– L177. 64. Archer SL, Tolins JP, Raij L, Weir EK. Hypoxic pulmonary vasoconstriction is enhanced by inhibition of the synthesis of an endothelium derived relaxing factor. Biochem Biophys Res Commun 1989; 164:1198–1205. 65. Hasunuma K, Yamaguchi T, Rodman DM, O’Brien RF, McMurtry IF. Effects of inhibitors of EDRF and EDHF on vasoreactivity of perfused rat lungs. Am J Physiol 1991; 260: L97–L104. 66. Zhang F, Woodmansey PA, Morice AH. Acute hypoxic vasoconstriction in isolated rat small and large pulmonary arteries. Physiol Res 1995; 44:7–18. 67. Burke TM, Wolin MS. Hydrogen peroxide elicits pulmonary arterial relaxation and guanylate cyclase activation. Am J Physiol 1987; 252:H721–H732. 68. Cherry PD, Omar HA, Farrell KA, Stuart JS, Wolin MS. Superoxide anion inhibits cGMP-associated bovine pulmonary arterial relaxation. Am J Physiol 1990; 259:H1056– 1062. 69. Omar HA, Wolin MS. Endothelium-dependent and independent cGMP mechanisms appear to mediate O2 responses in calf pulmonary resistance arteries. Am J Physiol 1992; 262: L560–L565. 70. Mohazzab KM, Wolin MS. Properties of a superoxide anion-generating microsomal NADH oxidoreductase, a potential pulmonary artery PO2 sensor. Am J Physiol 1994; 267: L823–L831. 71. Mohazzab KM, Kaminski PM, Wolin MS. NADH oxidoreductase is a major source of superoxide anion in bovine coronary artery endothelium. Am J Physiol 1994; 266:H2568– H2572. 72. Mohazzab KM, Wolin MS. Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol 1994; 267:L815–L822. 73. Woodmansey PA, Zhang F, Channer KS, Morice AH. Effect of the calcium antagonist amlodipine on the two phases of hypoxic pulmonary vasoconstriction in rat large and small isolated pulmonary arteries. J Cardiovasc Pharmacol 1995; 25:324–329. 74. Golovina VA, Blaustein MP. Spatially and functionally distinct Ca2⫹ stores in sarcoplasmic and endoplasmic reticulum. Science 1997; 275:1643–1648. 75. Tribe RM, Borin ML, Blaustein MP. Functionally and spatially distinct Ca2⫹ stores are revealed in cultured vascular smooth muscle cells. Proc Natl Acad Sci USA 1994; 91: 5908–5912. 76. Rodman DM, McMurtry IF, Peach JL, O’Brien RF. Comparative pharmacology of rat and porcine endothelin in rat aorta and pulmonary artery. Eur J Pharmacol 1989; 165:297– 300. 77. Vanhoutte PM, Rubanyi GM, Miller VM, Houston DS. Modulation of vascular smooth muscle contraction by the endothelium. Annu Rev Physiol 1986; 48:307–320.
Acute Hypoxic Pulmonary Vasoconstriction
345
78. Coburn RF, Grubb B, Aronson RD. Effect of cyanide on oxygen tension-dependent mechanical tension in rabbit aorta. Circ Res 1979; 44:368–378. 79. Namm DH, Zucker JL. Biochemical alterations caused by hypoxia in the isolated rabbit aorta. Correlation with changes in arterial contractility. Circ Res 1973; 32:464–470. 80. Coburn RF, Baron C, Papadopoulos MT. Phosphoinositide metabolism and metabolismcontraction coupling in rabbit aorta. Am J Physiol 1988; 255:H1476–H1483. 81. Coburn RF, Eppinger R, Scott DP. Oxygen-dependent tension in vascular smooth muscle. Does the endothelium play a role? Circ Res 1986; 58:341–347. 82. Coburn RF, Moreland S, Moreland RS, Baron CB. Rate-limiting energy-dependent steps controlling oxidative metabolism-contraction coupling in rabbit aorta. J Physiol 1992; 448: 473–492. 83. Scott DP, Coburn RF. Phosphocreatine and oxidative metabolism-contraction coupling in rabbit aorta. Am J Physiol 1989; 257:H597–H602. 84. Katayama Y, Coburn RF, Fillers WS, Baron CB. Oxygen sensors in vascular smooth muscle. J Appl Physiol 1994; 77:2086–2092. 85. Matsumoto H, Baron CB, Coburn RF. Inositol trisphosphate and energy-force coupling in rabbit aorta. J Pharmacol Exp Ther 1994; 270:708–712. 86. Moreland RS, Coburn RF, Moreland S. Decreased PO2 and rabbit aortic smooth muscle mechanics. J Vasc Res 1995; 32:313–319. 87. Baron CB, Pompeo JN, Coburn RF. Inositol 1,4,5-trisphosphate, inositide flux rates and pool sizes during smooth muscle relaxation. Am J Physiol 1992; 262:L100–L104. 88. Moreland S, Coburn RF, Baron CB, Moreland RS. Mechanical and biochemical events during hypoxia-induced relaxations of rabbit aorta. Adv Exp Med Biol 1991; 304:147–157. 89. Scott DP, Davidheiser S, Coburn RF. Effects of elevation of phosphocreatine on force and metabolism in rabbit aorta. Am J Physiol 1987; 253:H461–H465. 90. Coburn RF, Azim S, Fillers WS, Baron CB. Smooth muscle guanine nucleotides and receptor-effector coupling following inhibition of oxidative energy production. Am J Physiol 1993; 264:L1–L6. 91. Leach RM, Sheehan DW, Chacko VP, Sylvester JT. Energy state, pH, and vasomotor tone during hypoxia in precontracted pulmonary and femoral arteries. Am J Physiol 2000; 278: L294–L304. 92. Wiener CM, Banta MR, Dowless MS, Flavahan NA, Sylvester JT. Mechanisms of hypoxic vasodilation in ferret pulmonary arteries. Am J Physiol 1995; 269:L351–L357. 93. Clapp LH, Gurney AM. ATP-sensitive K⫹ channels regulate resting potential of pulmonary arterial smooth muscle cells. Am J Physiol 1992; 262:H916–H920. 94. Quayle JM, Standen NB. KATP channels in vascular smooth muscle. Cardiovasc Res 1994; 28:797–804. 95. Herget J, McMurtry IF. Effects of ouabain, low K⫹, and aldosterone on hypoxic pressor reactivity of rat lungs. Am J Physiol 1985; 248:H55–H60. 96. Wiener CM, Sylvester JT. Effects of glucose on hypoxic vasoconstriction in isolated ferret lungs. J Appl Physiol 1991; 70:439–446. 97. Wiener CM, Sylvester JT. Effects of insulin, glucose analogues, and pyruvate on vascular responses to anoxia in isolated ferret lungs. J Appl Physiol 1993; 74:2426–2431. 98. Leach RM, Hill HS, Ward JPT. The role of glycolysis in hypoxic pulmonary artery vasoconstriction (HPV). Thorax 1998; 53:A13. 99. Sylvester JT, Harabin AL, Peake MD, Frank RS. Vasodilator and constrictor responses to hypoxia in isolated pig lungs. J Appl Physiol 1980; 49:820–825. 100. Peake MD, Harabin AL, Brennan NJ, Sylvester JT. Steady-state vascular responses to graded hypoxia in isolated lungs of five species. J Appl Physiol 1981; 51:1214–1219. 101. Suggett AJ, Mohammed FH, Barer GR, Twelves C, Bee D. Quantitative significance of hypoxic vasoconstriction in the ferret lung. Respir Physiol 1981; 46:89–104. 102. Malik AB, Kidd BS. Time course of pulmonary vascular response to hypoxia in dogs. Am J Physiol 1973; 224:1–6. 103. Tucker A, Reeves JT. Nonsustained pulmonary vasoconstriction during acute hypoxia in anesthetized dogs. Am J Physiol 1975; 228:756–761. 104. Wiener CM, Dunn A, Sylvester JT. ATP-dependent K⫹ channels modulate vasoconstrictor responses to severe hypoxia in isolated ferret lungs. J Clin Invest 1991; 88:500–504.
346
Sylvester et al.
105. Quilley J, Fulton D, McGiff JC. Hyperpolarizing factors. Biochem Pharmacol 1997; 54: 1059–1070. 106. Urakami-Harasawa L, Shimokawa H, Nakashima M, Egashira K, Takeshita A. Importance of endothelium-derived hyperpolarizing factor in human arteries. J Clin Invest 1997; 100: 2793–2799. 107. Feletou M, Vanhoutte PM. Endothelium-derived hyperpolarizing factor. Clin Exp Pharmacol Physiol 1996; 23:1082–1090. 108. MacLean MR, McCulloch KM, Baird M. Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles. J Cardiovasc Pharmacol 1994; 23: 838–845. 109. MacLean MR, McCulloch KM. Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia. Br J Pharmacol 1998; 123:991–999. 110. Leach RM, Twort CH, Cameron IR, Ward JP. The mechanism of action of endothelin-1 on small pulmonary arterial vessels. Pulm Pharmacol Ther 1990; 3:103–109. 111. Wang Y, Coe Y, Toyoda O, Coceani F. Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. J Physiol 1995; 482:421–434. 112. Liu Q, Fan HB, Sylvester JT. Hypoxic contraction of isolated porcine pulmonary arterioles: role of endothelin-1 (abstract). Circulation 1998; 98:3494S. 113. Oparil S, Chen SJ, Meng QC, Elton TS, Yano M, Chen YF. Endothelin-A receptor antagonist prevents acute hypoxia-induced pulmonary hypertension in the rat. Am J Physiol 1995; 268:L95–L100. 114. Willette RN, Ohlstein EH, Mitchell MP, Sauermelch CF, Beck GR, Luttmann MA, Hay DW. Nonpeptide endothelin receptor antagonists. VIII. Attentuation of acute hypoxiainduced pulmonary hypertension in the dog. J Pharmacol Exp Ther 1997; 280:695–701. 115. Holm P, Liska J, Franco-Cereceda A. The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo. Cardiovasc Res 1998; 37:765–771. 116. Holm P, Liska J, Clozel M, Franco-Cereceda A. The endothelin antagonist bosentan: hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs. J Thorac Cardiovasc Surg 1996; 112:890–897. 117. Holm P, Liska J, Franco-Cereceda A. The endothelin ETB receptor antagonist BQ-788 reduces the pulmonary vasodilator effect of endothelin-1 during acute hypoxia in pigs. Eur J Pharmacol 1997; 323:83–87. 118. Hague D, Aaronson PI, Ward JPT. Endothelin does not play a role in hypoxic pulmonary vasoconstriction of rat pulmonary artery (abstract). Am J Respir Crit Care Med 1999; 159: A567. 119. Takeoka M, Ishizaki T, Sakai A, Chang SW, Shigemori K, Higashi T, Ueda G. Effect of BQ123 on vasoconstriction as a result of either hypoxia or endothelin-1 in perfused rat lungs. Acta Physiol Scand 1995; 155:53–60. 120. Ward JPT, Aaronson PI. Mechanisms of hypoxic pulmonary vasoconstriction: can anyone be right? Respir Physiol 1999; 115:261–271. 121. Di Salvo J, Pfitzer G, Semenchuk LA. Protein tyrosine phosphorylation, cellular Ca2⫹, and Ca2⫹ sensitivity for contraction of smooth muscle. Can J Physiol Pharmacol 1994; 72: 1434–1439. 122. Shaw LM, Ohanian J, Heagerty AM. Calcium sensitivity and agonist-induced calcium sensitization in small arteries of young and adult spontaneously hypertensive rats. Hypertension 1997; 30:442–448. 123. Bruce L, Nixon GF. Increased sensitization of the myofilaments in rat neonatal portal vein: a potential mechanism. Exp Physiol 1997; 82:985–993. 124. Nishimura J, Moreland S, Ahn HY, Kawase T, Moreland RS, van Breemen C. Endothelin increases myofilament Ca2⫹ sensitivity in alpha-toxin-permeabilized rabbit mesenteric artery. Circ Res 1992; 71:951–959. 125. Demoliou-Mason CD. G-protein-coupled receptors in vascular smooth muscle cells. Biol Signals Recept 1998; 7:90–97. 126. Di Salvo J, Raatz Nelson S. Stimulation of G-protein coupled receptors in vascular smooth muscle cells induces tyrosine kinase dependent increases in calcium without tyrosine phosphorylation of phospholipase C gamma-1. FEBS Lett 1998; 422:85–88.
Acute Hypoxic Pulmonary Vasoconstriction
347
127. Epstein AM, Throckmorton D, Brophy CM. Mitogen-activated protein kinase activation: an alternate signaling pathway for sustained vascular smooth muscle contraction. J Vasc Surg 1997; 26:327–332. 128. Koide M, Kawahara Y, Tsuda T, Ishida Y, Shii K, Yokoyama M. Endothelin-1 stimulates tyrosine phosphorylation and the activities of two mitogen-activated protein kinases in cultured vascular smooth muscle cells. J Hypertens 1992; 10:1173–1182. 129. Liu CY, Sturek M. Attenuation of endothelin-1-induced calcium response by tyrosine kinase inhibitors in vascular smooth muscle cells. Am J Physiol 1996; 270:C1825–C1833. 130. Karaki H, Ozaki H, Hori M, Mitsui-Saito M, Amano K, Harada K, Miyamoto S, Nakazawa H, Won KJ, Sato K. Calcium movements, distribution, and functions in smooth muscle. Pharmacol Rev 1997; 49:157–230. 131. Ji YS, Xu Q, Schmedtje JF Jr. Hypoxia induces high-mobility-group protein I(Y) and transcription of the cyclooxygenase-2 gene in human vascular endothelium. Circ Res 1998; 83:295–304. 132. Wiener CM, Banta MR, Flavahan NA, Sylvester JT. Adenosine does not activate ATPdependent K⫹ channels or contribute to hypoxic vasodilation in isolated ferret pulmonary arteries (abstract). Am J Respir Crit Care Med 1994; 149:A25. 133. Liu Q, Sylvester JT. Effects of hypoxia on transmural pressure-diameter relationships in porcine pulmonary arterial microvessels (abstract). Am J Respir Crit Care Med 1997; 155: A791. 134. Shirai M, Sada K, Ninomiya I. Effects of regional alveolar hypoxia and hypercapnia on small pulmonary vessels in cats. J Appl Physiol 1986; 61:440–448. 135. Madden JA, al-Tinawi A, Birks E, Keller PA, Dawson CA. Intrinsic tone and distensibility of in vitro and in situ cat pulmonary arteries. Lung 1996; 174:291–301. 136. Liu Q, Sylvester JT. Development of intrinsic tone in isolated pulmonary arterioles. Am J Physiol 1999; 276:L805–L813. 137. Halpern W, Kelley M. In vitro methodology for resistance arteries. Blood Vessels 1991; 28:245–251. 138. Murray TR, Chen L, Marshall BE, Macarak EJ. Hypoxic contraction of cultured pulmonary vascular smooth muscle cells. Am J Respir Cell Mol Biol 1990; 3:457–465. 139. Zhang F, Carson RC, Zhang H, Gibson G, Thomas HMR. Pulmonary artery smooth muscle cell [Ca2⫹ ] i and contraction: responses to diphenyleneiodonium and hypoxia. Am J Physiol 1997; 273:L603–L611. 140. Sham JSK, Crenshaw BR, Shimoda LA, Sylvester JT. Effects of hypoxia on length and [Ca2⫹ ] in porcine pulmonary arterial myocytes: roles of KV channel and endothelin-1. Am J Physiol 2000; 279:L262–L272. 141. Madden JA, Vadula MS, Kurup VP. Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells. Am J Physiol 1992; 263:L384–L393. 142. Bakhramov A, Evans AM, Kozlowski RZ. Differential effects of hypoxia on the intracellular Ca2⫹ concentration of myocytes isolated from different regions of the rat pulmonary arterial tree. Exp Physiol 1998; 83:337–347. 143. Cornfield DN, Stevens T, McMurtry IF, Abman SH, Rodman DM. Acute hypoxia increases cytosolic calcium in fetal pulmonary artery smooth muscle cells. Am J Physiol 1993; 265: L53–L56. 144. Cornfield DN, Stevens T, McMurtry IF, Abman SH, Rodman DM. Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am J Physiol 1994; 266:L469–L475. 145. Post JM, Gelband CH, Hume JR. [Ca2⫹ ] i inhibition of K⫹ channels in canine pulmonary artery. Novel mechanism for hypoxia-induced membrane depolarization. Circ Res 1995; 77:131–139. 146. Salvaterra CG, Goldman WF. Acute hypoxia increases cytosolic calcium in cultured pulmonary arterial myocytes. Am J Physiol 1993; 264:L323–L328. 147. Vadula MS, Kleinman JG, Madden JA. Effect of hypoxia and norepinephrine on cytoplasmic free Ca2⫹ in pulmonary and cerebral arterial myocytes. Am J Physiol 1993; 265: L591–L597. 148. Archer SL, Souil E, Dinh-Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, NguyenHuu L, Reeve HL, Hampl V. Molecular identification of the role of voltage-gated K⫹
348
149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170.
Sylvester et al. channels, KV1.5 and KV2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 1998; 101:2319–2330. Urena J, Franco-Obregon A, Lopez-Barneo J. Contrasting effects of hypoxia on cytosolic Ca2⫹ spikes in conduit and resistance myocytes of the rabbit pulmonary artery. J Physiol 1996; 496:103–109. Sham JS, Song LS, Chen Y, Deng LH, Stern MD, Lakatta EG, Cheng H. Termination of Ca2⫹ release by a local inactivation of ryanodine receptors in cardiac myocytes. Proc Natl Acad Sci USA 1998; 95:15096–15101. McMurtry IF, Davidson AB, Reeves JT, Grover RF. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res 1976; 38:99–104. McMurtry IF. BAY K 8644 potentiates and A23187 inhibits hypoxic vasoconstriction in rat lungs. Am J Physiol 1985; 249:H741–H746. Roberts JD Jr, Chen TY, Kawai N, Wain J, Dupuy P, Shimouchi A, Bloch K, Polaner D, Zapol WM. Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circ Res 1993; 72:246–254. Tolins M, Weir EK, Chesler E, Nelson DP, From AH. Pulmonary vascular tone is increased by a voltage-dependent calcium channel potentiator. J Appl Physiol 1986; 60:942–948. Putney JW Jr. Capacitative calcium entry revisited. Cell Calcium 1990; 11:611–624. Putney JW Jr, McKay RR. Capacitative calcium entry channels. Bioessays 1999; 21:38– 46. Archer SL, Hampl V, Nelson DP, Sidney E, Peterson DA, Weir EK. Dithionite increases radical formation and decreases vasoconstriction in the lung. Evidence that dithionite does not mimic alveolar hypoxia. Circ Res 1995; 77:174–181. Salvaterra CG, Rubin LJ, Schaeffer J, Blaustein MP. The influence of the transmembrane sodium gradient on the responses of pulmonary arteries to decreases in oxygen tension. Am Rev Respir Dis 1989; 139:933–939. Vandier C, Delpech M, Rebocho M, Bonnet P. Hypoxia enhances agonist-induced pulmonary arterial contraction by increasing calcium sequestration. Am J Physiol 1997; 273: H1075–H1081. Hottenstein O, Mitzner W, Bierkamper G. Hypoxia alters membrane potentials in rat main pulmonary artery: a possible calcium mechanism (abstract). Physiologist 1982; 25:276. Archer SL. Diversity of phenotype and function of vascular smooth muscle cells. J Lab Clin Med 1996; 127:524–529. Archer SL, Huang JM, Reeve HL, Hampl V, Tolarova S, Michelakis E, Weir EK. Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res 1996; 78:431–442. Post JM, Hume JR, Archer SL, Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 1992; 262:C882–C890. Yuan XJ, Goldman WF, Tod ML, Rubin LJ, Blaustein MP. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol 1993; 264:L116–L123. Turner JL, Kozlowski RZ. Relationship between membrane potential, delayed rectifier K⫹ currents and hypoxia in rat pulmonary arterial myocytes. Exp Physiol 1997; 82:629– 645. Osipenko ON, Evans AM, Gurney AM. Regulation of the resting potential of rabbit pulmonary artery myocytes by a low threshold, O2-sensing potassium current. Br J Pharmacol 1997; 120:1461–1470. Yuan XJ, Goldman WF, Tod ML, Rubin LJ, Blaustein MP. Ionic currents in rat pulmonary and mesenteric arterial myocytes in primary culture and subculture. Am J Physiol 1993; 264:L107–L115. Smirnov SV, Robertson TP, Ward JP, Aaronson PI. Chronic hypoxia is associated with reduced delayed rectifier K⫹ current in rat pulmonary artery muscle cells. Am J Physiol 1994; 266:H365–H370. Clapp LH, Gurney AM. Outward currents in rabbit pulmonary artery cells dissociated with a new technique. Exp Physiol 1991; 76:677–693. Reeve HL, Archer SL, Weir EK. Ion channels in the pulmonary vasculature. Pulm Pharmacol Ther 1997; 10:243–252.
Acute Hypoxic Pulmonary Vasoconstriction
349
171. Reeve HL, Weir EK, Archer SL, Cornfield DN. A maturational shift in pulmonary K⫹ channels, from Ca2⫹ sensitive to voltage dependent. Am J Physiol 1998; 275:L1019– L1025. 172. Frid MG, Moiseeva EP, Stenmark KR. Multiple phenotypically distinct smooth muscle cell populations exist in the adult and developing bovine pulmonary arterial media in vivo. Circ Res 1994; 75:669–681. 173. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 268:C799–C822. 174. Archer SL, Huang J, Henry T, Peterson D, Weir EK. A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 1993; 73:1100–1112. 175. Reeve HL, Weir EK, Nelson DP, Peterson DA, Archer SL. Opposing effects of oxidants and antioxidants on K⫹ channel activity and tone in rat vascular tissue. Exp Physiol 1995; 80:825–834. 176. Yuan XJ. Voltage-gated K⫹ currents regulate resting membrane potential and [Ca2⫹ ] i in pulmonary arterial myocytes. Circ Res 1995; 77:370–378. 177. Shimoda LA, Sylvester JT, Sham JSK. Inhibition of voltage-gated K⫹ current in rat intrapulmonary arterial myocytes by endothelin-1. Am J Physiol 1998; 274:L842-L853. 178. Evans AM, Osipenko ON, Gurney AM. Properties of a novel K⫹ current that is active at resting potential in rabbit pulmonary artery smooth muscle cells. J Physiol 1996; 496:407– 420. 179. Okabe K, Kitamura K, Kuriyama H. Features of 4-aminopyridine sensitive outward current observed in single smooth muscle cells from the rabbit pulmonary artery. Pflugers Arch 1987; 409:561–568. 180. Gelband CH, Ishikawa T, Post JM, Keef KD, Hume JR. Intracellular divalent cations block smooth muscle K⫹ channels. Circ Res 1993; 73:24–34. 181. Evans AM, Clapp LH, Gurney AM. Augmentation by intracellular ATP of the delayed rectifier current independently of the glibenclamide-sensitive K-current in rabbit arterial myocytes. Br J Pharmacol 1994; 111:972–974. 182. Salter KJ, Wilson CM, Kato K, Kozlowski RZ. Endothelin-1, delayed rectifier K channels, and pulmonary arterial smooth muscle. J Cardiovasc Pharmacol 1998; 31:S81–S83. 183. Salter KJ, Kozlowski RZ. Differential electrophysiological actions of endothelin-1 on Cl⫺ and K⫹ currents in myocytes isolated from aorta, basilar and pulmonary artery. J Pharmacol Exp Ther 1998; 284:1122–1131. 184. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. NO hyperpolarizes pulmonary artery smooth muscle cells and decreases the intracellular Ca2⫹ concentration by activating voltage-gated K⫹ channels. Proc Natl Acad Sci USA 1996; 93:10489–10494. 185. Smirnov SV, Aaronson PI. Modulatory effects of arachidonic acid on the delayed rectifier K⫹ current in rat pulmonary arterial myocytes. Structural aspects and involvement of protein kinase C. Circ Res 1996; 79:20–31. 186. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Inhibition of cytochrome P-450 reduces voltage-gated K⫹ currents in pulmonary arterial myocytes. Am J Physiol 1995; 268:C259– C270. 187. Park MK, Bae YM, Lee SH, Ho WK, Earm YE. Modulation of voltage-dependent K⫹ channel by redox potential in pulmonary and ear arterial smooth muscle cells of the rabbit. Pflugers Arch 1997; 434:764–771. 188. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Deoxyglucose and reduced glutathione mimic effects of hypoxia on K⫹ and Ca2⫹ conductances in pulmonary artery cells. Am J Physiol 1994; 267:L52–L63. 189. Yuan XJ, Sugiyama T, Goldman WF, Rubin LJ, Blaustein MP. A mitochondrial uncoupler increases KCa currents but decreases KV currents in pulmonary artery myocytes. Am J Physiol 1996; 270:C321–C331. 190. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Hypoxic and metabolic regulation of voltagegated K⫹ channels in rat pulmonary artery smooth muscle cells. Exp Physiol 1995; 80: 803–813. 191. Berger MG, Vandier C, Bonnet P, Jackson WF, Rusch NJ. Intracellular acidosis differentially regulates KV channels in coronary and pulmonary vascular muscle. Am J Physiol 1998; 275:H1351–H1359.
350
Sylvester et al.
192. James AF, Okada T, Horie M. A fast transient outward current in cultured cells from human pulmonary artery smooth muscle. Am J Physiol 1995; 268:H2358–H2365. 193. Evans AM, Osipenko ON, Haworth SG, Gurney AM. Resting potentials and potassium currents during development of pulmonary artery smooth muscle cells. Am J Physiol 1998; 275:H887–H899. 194. Yuan XJ, Wang J, Juhaszova M, Golovina VA, Rubin LJ. Molecular basis and function of voltage-gated K⫹ channels in pulmonary arterial smooth muscle cells. Am J Physiol 1998; 274:L621–L635. 195. Wang J, Juhaszova M, Rubin LJ, Yuan XJ. Hypoxia inhibits gene expression of voltagegated K⫹ channel alpha subunits in pulmonary artery smooth muscle cells. J Clin Invest 1997; 100:2347–2353. 196. Patel AJ, Lazdunski M, Honore E. KV 2.1/KV 9.3, a novel ATP-dependent delayed-rectifier K⫹ channel in oxygen-sensitive pulmonary artery myocytes. EMBO J 1997; 16:6615– 6625. 197. Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 1995; 9:183–189. 198. Osipenko ON, Alexander D, MacLean MR, Gurney AM. Influence of chronic hypoxia on the contributions of non-inactivating and delayed rectifier K currents to the resting potential and tone of rat pulmonary artery smooth muscle. Br J Pharmacol 1998; 124: 1335–1337. 199. Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA 1994; 91:7583–7587. 200. Albarwani S, Heinert G, Turner JL, Kozlowski RZ. Differential K⫹ channel distribution in smooth muscle cells isolated from the pulmonary arterial tree of the rat. Biochem Biophys Res Commun 1995; 208:183–189. 201. Cornfield DN, Reeve HL, Tolarova S, Weir EK, Archer S. Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel. Proc Natl Acad Sci USA 1996; 93:8089–8094. 202. Peng W, Hoidal JR, Karwande SV, Farrukh IS. Effect of chronic hypoxia on K⫹ channels: regulation in human pulmonary vascular smooth muscle cells. Am J Physiol 1997; 272: C1271–C1278. 203. Peng W, Karwande SV, Hoidal JR, Farrukh IS. Potassium currents in cultured human pulmonary arterial smooth muscle cells. J Appl Physiol 1996; 80:1187–1196. 204. Peng W, Hoidal JR, Farrukh IS. Regulation of Ca2⫹-activated K⫹ channels in pulmonary vascular smooth muscle cells: role of nitric oxide. J Appl Physiol 1996; 81:1264–1272. 205. Bae YM, Park MK, Lee SH, Ho WK, Earm YE. Contribution of Ca2⫹-activated K⫹ channels and non-selective cation channels to membrane potential of pulmonary arterial smooth muscle cells of the rabbit. J Physiol 1999; 514:747–758. 206. Smirnov SV, Knock GA, Aaronson PI. Effects of the 5-lipoxygenase activating protein inhibitor MK886 on voltage-gated and Ca2⫹-activated K⫹ currents in rat arterial myocytes. Br J Pharmacol 1998; 124:572–578. 207. Salter KJ, Kozlowski RZ. Endothelin receptor coupling to potassium and chloride channels in isolated rat pulmonary arterial myocytes. J Pharmacol Exp Ther 1996; 279:1053–1062. 208. Lee SH, Earm YE. Caffeine induces periodic oscillations of Ca2⫹-activated K⫹ current in pulmonary arterial smooth muscle cells. Pflugers Arch 1994; 426:189–198. 209. Lee S, Park M, So I, Earm YE. NADH and NAD modulates Ca2⫹-activated K⫹ channels in small pulmonary arterial smooth muscle cells of the rabbit. Pflugers Arch 1994; 427: 378–380. 210. Salter KJ, Turner JL, Albarwani S, Clapp LH, Kozlowski RZ. Ca2⫹-activated Cl⫺ and K⫹ channels and their modulation by endothelin-1 in rat pulmonary arterial smooth muscle cells. Exp Physiol 1995; 80:815–824. 211. Farrukh IS, Peng W, Orlinska U, Hoidal JR. Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: a Ca2⫹-activated K⫹-channel opener. Am J Physiol 1998; 274: L186–L195. 212. Hasunuma K, Rodman DM, McMurtry IF. Effects of K⫹ channel blockers on vascular tone in the perfused rat lung. Am Rev Respir Dis 1991; 144:884–887.
Acute Hypoxic Pulmonary Vasoconstriction
351
213. Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 1992; 256:532–535. 214. Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ, Lederer WJ. Relaxation of arterial smooth muscle by calcium sparks. Science 1995; 270:633–637. 215. Jaggar JH, Wellman GC, Heppner TJ, Porter VA, Perez GJ, Gollasch M, Kleppisch T, Rubart M, Stevenson AS, Lederer WJ, Knot HJ, Bonev AD, Nelson MT. Ca2⫹ channels, ryanodine receptors and Ca2⫹-activated K⫹ channels: a functional unit for regulating arterial tone. Acta Physiol Scand 1998; 164:577–587. 216. Peng W, Michael JR, Hoidal JR, Karwande SV, Farrukh IS. ET-1 modulates KCa-channel activity and arterial tension in normoxic and hypoxic human pulmonary vasculature. Am J Physiol 1998; 275:L729–L739. 217. Albarwani S, Robertson BE, Nye PC, Kozlowski RZ. Biophysical properties of Ca2⫹- and Mg-ATP-activated K⫹ channels in pulmonary arterial smooth muscle cells isolated from the rat. Pflugers Arch 1994; 428:446–454. 218. Robertson BE, Corry PR, Nye PC, Kozlowski RZ. Ca2⫹ and Mg-ATP activated potassium channels from rat pulmonary artery. Pflugers Arch 1992; 421:94–96. 219. Hartley SA, Kozlowski RZ. ATP increases Ca2⫹-activated K⫹ channel activity in isolated rat arterial smooth muscle cells. Biochim Biophys Acta 1996; 1283:192–198. 220. Kozlowski RZ, Ashford ML. ATP-sensitive K⫹-channel run-down is Mg2⫹ dependent. Proc R Soc Lond B Biol Sci 1990; 240:397–410. 221. Thuringer D, Findlay I. Contrasting effects of intracellular redox couples on the regulation of maxi-K channels in isolated myocytes from rabbit pulmonary artery. J Physiol 1997; 500:583–592. 222. Kirber MT, Ordway RW, Clapp LH, Walsh JV Jr, Singer JJ. Both membrane stretch and fatty acids directly activate large conductance Ca2⫹-activated K⫹ channels in vascular smooth muscle cells. FEBS Lett 1992; 297:24–28. 223. Snetkov VA, Gurney AM, Ward JP, Osipenko ON. Inward rectification of the large conductance potassium channel in smooth muscle cells from rabbit pulmonary artery. Exp Physiol 1996; 81:743–753. 224. Park MK, Lee SH, Ho WK, Earm YE. Redox agents as a link between hypoxia and the responses of ionic channels in rabbit pulmonary vascular smooth muscle. Exp Physiol 1995; 80:835–842. 225. Park MK, Lee SH, Lee SJ, Ho WK, Earm YE. Different modulation of Ca-activated K channels by the intracellular redox potential in pulmonary and ear arterial smooth muscle cells of the rabbit. Pflugers Arch 1995; 430:308–314. 226. Clapp LH, Davey R, Gurney AM. ATP-sensitive K⫹ channels mediate vasodilation produced by lemakalim in rabbit pulmonary artery. Am J Physiol 1993; 264:H1907– H1915. 227. Clapp LH, Gurney AM, Standen NB, Langton PD. Properties of the ATP-sensitive K⫹ current activated by levcromakalim in isolated pulmonary arterial myocytes. J Membr Biol 1994; 140:205–213. 228. Clapp LH. Regulation of glibenclamide-sensitive K⫹ current by nucleotide phosphates in isolated rabbit pulmonary myocytes. Cardiovasc Res 1995; 30:460–468. 229. Miyoshi Y, Wakatsuki T, Nomura M, Saito K, Nakaya Y, Inoue I. Endothelin blocks ATPsensitive K⫹ channels and depolarizes smooth muscle cells of porcine coronary artery. Jpn J Pharmacol 1992; 58:338P. 230. Sheridan BC, McIntyre RC Jr, Meldrum DR, Fullerton DA. KATP channels contribute to β- and adenosine receptor-mediated pulmonary vasorelaxation. Am J Physiol 1997; 273: L950–L956. 231. Bruch L, Rubel S, Kastner A, Gellert K, Gollasch M, Witt C. Pituitary adenylate cyclase activating peptides relax human pulmonary arteries by opening of KATP and KCa channels. Thorax 1998; 53:586–587. 232. Cornfield DN, Chatfield BA, McQueston JA, McMurtry IF, Abman SH. Effects of birthrelated stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus. Am J Physiol 1992; 262:H1474–H1481. 233. Yuan XJ. Role of calcium-activated chloride current in regulating pulmonary vasomotor tone. Am J Physiol 1997; 272:L959–L968.
352
Sylvester et al.
234. Hogg RC, Wang Q, Helliwell RM, Large WA. Properties of spontaneous inward currents in rabbit pulmonary artery smooth muscle cells. Pflugers Arch 1993; 425:233–240. 235. Wang Q, Large WA. Action of histamine on single smooth muscle cells dispersed from the rabbit pulmonary artery. J Physiol 1993; 468:125–139. 236. Clapp LH, Turner JL, Kozlowski RZ. Ca2⫹-activated Cl⫺ currents in pulmonary arterial myocytes. Am J Physiol 1996; 270:H1577–H1584. 237. Hartley SA, Kozlowski RZ. Electrophysiological consequences of purinergic receptor stimulation in isolated rat pulmonary arterial myocytes. Circ Res 1997; 80:170–178. 238. Guibert C, Marthan R, Savineau JP. Oscillatory Cl⫺ current induced by angiotensin II in rat pulmonary arterial myocytes: Ca2⫹ dependence and physiological implication. Cell Calcium 1997; 21:421–429. 239. Wang Q, Wang YX, Yu M, Kotlikoff MI. Ca2⫹-activated Cl⫺ currents are activated by metabolic inhibition in rat pulmonary artery smooth muscle cells. Am J Physiol 1997; 273: C520–C530. 240. Bakhramov A, Hartley SA, Salter KJ, Kozlowski RZ. Contractile agonists preferentially activate Cl⫺ over K⫹ currents in arterial myocytes. Biochem Biophys Res Commun 1996; 227:168–175. 241. Yamazaki J, Duan D, Janiak R, Kuenzli K, Horowitz B, Hume JR. Functional and molecular expression of volume-regulated chloride channels in canine vascular smooth muscle cells [see comments]. J Physiol 1998; 507:729–736. 242. Benham CD, Hess P, Tsien RW. Two types of calcium channels in single smooth muscle cells from rabbit ear artery studied with whole-cell and single-channel recordings. Circ Res 1987; 61:I10–I16. 243. Rubart M, Patlak JB, Nelson MT. Ca2⫹ currents in cerebral artery smooth muscle cells of rat at physiological Ca2⫹ concentrations. J Gen Physiol 1996; 107:459–472. 244. Fleischmann BK, Murray RK, Kotlikoff MI. Voltage window for sustained elevation of cytosolic calcium in smooth muscle cells. Proc Natl Acad Sci USA 1994; 91:11914–11918. 245. Nelson MT, Patlak JB, Worley JF, Standen NB. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol 1990; 259:C3–C18. 246. Clapp LH, Gurney AM. Modulation of calcium movements by nitroprusside in isolated vascular smooth muscle cells. Pflugers Arch 1991; 418:462–470. 247. Franco-Obregon A, Lopez-Barneo J. Low PO2 inhibits calcium channel activity in arterial smooth muscle cells. Am J Physiol 1996; 271:H2290–H2299. 248. Franco-Obregon A, Lopez-Barneo J. Differential oxygen sensitivity of calcium channels in rabbit smooth muscle cells of conduit and resistance pulmonary arteries. J Physiol 1996; 491:511–518. 249. Franco-Obregon A, Urena J, Lopez-Barneo J. Oxygen-sensitive calcium channels in vascular smooth muscle and their possible role in hypoxic arterial relaxation. Proc Natl Acad Sci USA 1995; 92:4715–4719. 250. Muramatsu M, Tyler RC, Rodman DM, McMurtry IF. Possible role of T-type Ca2⫹ channels in L-NNA vasoconstriction of hypertensive rat lungs. Am J Physiol 1997; 272:H2616– H2621. 251. Wang J, Golovina VA, Bakst AE, Yuan JX-J. hTRP mRNA expression is enhanced in proliferating pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 1999; 159:A346. 252. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 1999; 397: 259–263. 253. Csutora P, Su Z, Kim HY, Bugrim A, Cunningham KW, Nuccitelli R, Keizer JE, Hanley MR, Blalock JE, Marchase RB. Calcium influx factor is synthesized by yeast and mammalian cells depleted of organellar calcium stores. Proc Natl Acad Sci USA 1999; 96:121–126. 254. Vannier B, Peyton M, Boulay G, Brown D, Qin N, Jiang M, Zhu X, Birnbaumer L. Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletionactivated capacitative Ca2⫹ entry channel. Proc Natl Acad Sci USA 1999; 96:2060–2064. 255. Okabe K, Kitamura K, Kuriyama H. The existence of a highly tetrodotoxin sensitive Na channel in freshly dispersed smooth muscle cells of the rabbit main pulmonary artery. Pflugers Arch 1988; 411:423–428.
Acute Hypoxic Pulmonary Vasoconstriction
353
256. Partridge CA. Hypoxia and reoxygenation stimulate biphasic changes in endothelial monolayer permeability. Am J Physiol 1995; 269:L52–L58. 257. Ogawa S, Koga S, Kuwabara K, Brett J, Morrow B, Morris SA, Bilezikian JP, Silverstein SC, Stern D. Hypoxia-induced increased permeability of endothelial monolayers occurs through lowering of cellular cAMP levels. Am J Physiol 1992; 262:C546–C554. 258. Cutaia MV, Parks N, Centracchio J, Rounds S, Yip KP, Sun AM. Effect of hypoxic exposure on Na⫹ /H⫹ antiport activity, isoform expression, and localization in endothelial cells. Am J Physiol 1998; 275:L442–L451. 259. Bhat GB, Block ER. Serotonin transport in reconstituted endothelial cell plasma membrane proteoliposomes: effect of hypoxia. Am J Respir Cell Mol Biol 1992; 6:633–638. 260. Bhat GB, Block ER. Hypoxia directly increases serotonin transport by porcine pulmonary artery endothelial cell plasma membrane vesicles. Am J Respir Cell Mol Biol 1990; 3: 363–367. 261. Bhat GB, Block ER. Effect of hypoxia on phospholipid metabolism in porcine pulmonary artery endothelial cells. Am J Physiol 1992; 262:L606–L613. 262. Bhat GB, Tinsley SB, Tolson JK, Patel JM, Block ER. Hypoxia increases the susceptibility of pulmonary artery endothelial cells to hydrogen peroxide injury. J Cell Physiol 1992; 151:228–238. 263. Tretyakov AV, Farber HW. Endothelial cell tolerance to hypoxia. Potential role of purine nucleotide phosphates. J Clin Invest 1995; 95:738–744. 264. Tucci M, Nygard K, Tanswell BV, Farber HW, Hill DJ, Han VK. Modulation of insulinlike growth factor (IGF) and IGF binding protein biosynthesis by hypoxia in cultured vascular endothelial cells. J Endocrinol 1998; 157:13–24. 265. Kourembanas S, Morita T, Liu Y, Christou H. Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature. Kidney Int 1997; 51:438– 443. 266. Liu Y, Cox SR, Morita T, Kourembanas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 1995; 77:638–643. 267. Vender RL. Role of endothelial cells in the proliferative response of cultured pulmonary vascular smooth muscle cells to reduced oxygen tension. In Vitro Cell Dev Biol 1992; 28A:403–409. 268. Hassoun PM, Pasricha PJ, Teufel E, Lee SL, Fanburg BL. Hypoxia stimulates the release by bovine pulmonary artery endothelial cells of an inhibitor of pulmonary artery smooth muscle cell growth. Am J Respir Cell Mol Biol 1989; 1:377–384. 269. King SJ, Booyse FM, Lin PH, Traylor M, Narkates AJ, Oparil S. Hypoxia stimulates endothelial cell angiotensin-converting enzyme antigen synthesis. Am J Physiol 1989; 256: C1231–C1238. 270. Rao UJ, Denslow ND, Block ER. Hypoxia induces the synthesis of tropomyosin in cultured porcine pulmonary artery endothelial cells. Am J Physiol 1994; 267:L271–L281. 271. Graven KK, Zimmerman LH, Dickson EW, Weinhouse GL, Farber HW. Endothelial cell hypoxia associated proteins are cell and stress specific. J Cell Physiol 1993; 157:544–554. 272. Graven KK, Farber HW. Endothelial cell hypoxic stress proteins. J Lab Clin Med 1998; 132:456–463. 273. Graven KK, McDonald RJ, Farber HW. Hypoxic regulation of endothelial glyceraldehyde3-phosphate dehydrogenase. Am J Physiol 1998; 274:C347–C355. 274. Aaronson RM, Graven KK, Tucci M, McDonald RJ, Farber HW. Non-neuronal enolase is an endothelial hypoxic stress protein. J Biol Chem 1995; 270:27752–27757. 275. Zimmerman LH, Levine RA, Farber HW. Hypoxia induces a specific set of stress proteins in cultured endothelial cells. J Clin Invest 1991; 87:908–914. 276. Voets T, Droogmans G, Nilius B. Membrane currents and the resting membrane potential in cultured bovine pulmonary artery endothelial cells. J Physiol 1996; 497:95–107. 277. Campbell DL, Strauss HC, Whorton AR. Voltage dependence of bovine pulmonary artery endothelial cell function. J Mol Cell Cardiol 1991; 23(suppl 1): 1:133–144. 278. Koliwad SK, Kunze DL, Elliott SJ. Oxidant stress activates a non-selective cation channel responsible for membrane depolarization in calf vascular endothelial cells. J Physiol 1996; 491:1–12.
354
Sylvester et al.
279. Johns A, Lategan TW, Lodge NJ, Ryan US, Van Breemen C, Adams DJ. Calcium entry through receptor-operated channels in bovine pulmonary artery endothelial cells. Tissue Cell 1987; 19:733–745. 280. Nilius B, Viana F, Droogmans G. Ion channels in vascular endothelium. Annu Rev Physiol 1997; 59:145–170. 281. Kamouchi M, Van den Bremt K, Eggermont J, Droogmans G, Nilius B. Modulation of inwardly rectifying potassium channels in cultured bovine pulmonary artery endothelial cells. J Physiol 1997; 504:545–556. 282. Pasyk EA, Cipris S, Daniel EE. A G protein, not cyclic AMP, mediates effects of VIP on the inwardly rectifying K⫹ channels in endothelial cells. J Pharmacol Exp Ther 1996; 276: 690–696. 283. Inazu M, Zhang H, Daniel EE. Properties of the LP-805-induced potassium currents in cultured bovine pulmonary artery endothelial cells. J Pharmacol Exp Ther 1994; 268:403– 408. 284. Silver MR, Shapiro MS, DeCoursey TE. Effects of external Rb⫹ on inward rectifier K⫹ channels of bovine pulmonary artery endothelial cells. J Gen Physiol 1994; 103:519–548. 285. Packer CS, Bennie RE, Powell DR, Rhoades RA. Neonatal hypoxia: long term effects on pulmonary arterial muscle. Respir Physiol 1994; 96:213–229. 286. Pasyk E, Mao YK, Ahmad S, Shen SH, Daniel EE. An endothelial cell-line contains functional vasoactive intestinal polypeptide receptors: they control inwardly rectifying K⫹ channels. Eur J Pharmacol 1992; 212:209–214. 287. Zhang H, Inazu M, Weir B, Daniel E. Endothelin-1 inhibits inward rectifier potassium channels and activates nonspecific cation channels in cultured endothelial cells. Pharmacology 1994; 49:11–22. 288. Nilius B, Szucs G, Heinke S, Voets T, Droogmans G. Multiple types of chloride channels in bovine pulmonary artery endothelial cells. J Vasc Res 1997; 34:220–228. 289. Nilius B, Prenen J, Voets T, Eggermont J, Bruzik KS, Shears SB, Droogmans G. Inhibition by inositoltetrakisphosphates of calcium- and volume-activated Cl⫺ currents in macrovascular endothelial cells. Pflugers Arch 1998; 435:637–644. 290. Nilius B, Prenen J, Droogmans G. Modulation of volume-regulated anion channels by extra- and intracellular pH. Pflugers Arch 1998; 436:742–748. 291. Nilius B, Prenen J, Voets T, Eggermont J, Droogmans G. Activation of volume-regulated chloride currents by reduction of intracellular ionic strength in bovine endothelial cells. J Physiol 1998; 506:353–361. 292. Voets T, Manolopoulos V, Eggermont J, Ellory C, Droogmans G, Nilius B. Regulation of a swelling-activated chloride current in bovine endothelium by protein tyrosine phosphorylation and G proteins. J Physiol 1998; 506:341–352. 293. Manolopoulos GV, Prenen J, Droogmans G, Nilius B. Thrombin potentiates volume-activated chloride currents in pulmonary artery endothelial cells. Pflugers Arch 1997; 433: 845–847. 294. Szucs G, Buyse G, Eggermont J, Droogmans G, Nilius B. Characterization of volumeactivated chloride currents in endothelial cells from bovine pulmonary artery. J Membr Biol 1996; 149:189–197. 295. Szucs G, Heinke S, De Greef C, Raeymaekers L, Eggermont J, Droogmans G, Nilius B. The volume-activated chloride current in endothelial cells from bovine pulmonary artery is not modulated by phosphorylation. Pflugers Arch 1996; 431:540–548. 296. Szucs G, Heinke S, Droogmans G, Nilius B. Activation of the volume-sensitive chloride current in vascular endothelial cells requires a permissive intracellular Ca2⫹ concentration. Pflugers Arch 1996; 431:467–469. 297. Nilius B, Prenen J, Szucs G, Wei L, Tanzi F, Voets T, Droogmans G. Calcium-activated chloride channels in bovine pulmonary artery endothelial cells. J Physiol 1997; 498:381–396. 298. Nilius B, Prenen J, Voets T, Van den Bremt K, Eggermont J, Droogmans G. Kinetic and pharmacological properties of the calcium-activated chloride-current in macrovascular endothelial cells. Cell Calcium 1997; 22:53–63. 299. Stevens T, Cornfield DN, McMurtry IF, Rodman DM. Acute reductions in PO2 depolarize pulmonary artery endothelial cells and decrease [Ca2⫹ ] i. Am J Physiol 1994; 266:H1416– H1421.
Acute Hypoxic Pulmonary Vasoconstriction
355
300. Katnik C, Adams DJ. An ATP-sensitive potassium conductance in rabbit arterial endothelial cells. J Physiol 1995; 485:595–606. 301. Katnik C, Adams DJ. Characterization of ATP-sensitive potassium channels in freshly dissociated rabbit aortic endothelial cells. Am J Physiol 1997; 272:H2507–H2511. 302. Inazu M, Zhang H, Daniel EE. LP-805, a releaser of endothelium-derived nitric oxide, activates an endothelial calcium permeable non-specific cation channel. Life Sci 1993; 53: PL315–PL320. 303. Yamamoto Y, Chen G, Miwa K, Suzuki H. Permeability and Mg2⫹ blockade of histamineoperated cation channel in endothelial cells of rat intrapulmonary artery. J Physiol 1992; 450:395–408. 304. Zharikov SI, Herrera H, Block ER. Role of membrane potential in hypoxic inhibition of L-arginine uptake by lung endothelial cells. Am J Physiol 1997; 272:L78–L84. 305. Moore TM, Chetham PM, Kelly JJ, Stevens T. Signal transduction and regulation of lung endothelial cell permeability. Interaction between calcium and cAMP. Am J Physiol 1998; 275:L203–L222. 306. Adams DJ, Barakeh J, Laskey R, Van Breemen C. Ion channels and regulation of intracellular calcium in vascular endothelial cells. FASEB J 1989; 3:2389–2400. 307. Noris M, Morigi M, Donadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A. Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res 1995; 76:536–543. 308. Busse R, Fleming I. Pulsatile stretch and shear stress: physical stimuli determining the production of endothelium-derived relaxing factors. J Vasc Res 1998; 35:73–84. 309. Fasolato C, Nilius B. Store depletion triggers the calcium release-activated calcium current (ICRAC ) in macrovascular endothelial cells: a comparison with Jurkat and embryonic kidney cell lines. Pflugers Arch 1998; 436:69–74. 310. Moore TM, Brough GH, Babal P, Kelly JJ, Li M, Stevens T. Store-operated calcium entry promotes shape change in pulmonary endothelial cells expressing Trp1. Am J Physiol 1998; 275:L574–L582. 311. Bkaily G, d’Orleans-Juste P, Naik R, Perodin J, Stankova J, Abdulnour E, Rola-Pleszczynski M. PAF activation of a voltage-gated R-type Ca2⫹ channel in human and canine aortic endothelial cells. Br J Pharmacol 1993; 110:519–520. 312. Bossu JL, Feltz A, Rodeau JL, Tanzi F. Voltage-dependent transient calcium currents in freshly dissociated capillary endothelial cells. FEBS Lett 1989; 255:377–380. 313. Bossu JL, Elhamdani A, Feltz A, Tanzi F, Aunis D, Thierse D. Voltage-gated Ca entry in isolated bovine capillary endothelial cells: evidence of a new type of BAY K 8644sensitive channel. Pflugers Arch 1992; 420:200–207. 314. Bossu JL, Elhamdani A, Feltz A. Voltage-dependent calcium entry in confluent bovine capillary endothelial cells. FEBS Lett 1992; 299:239–242. 315. Ross CA, Danoff SK, Schell MJ, Snyder SH, Ullrich A. Three additional inositol 1,4,5trisphosphate receptors: molecular cloning and differential localization in brain and peripheral tissues. Proc Natl Acad Sci USA 1992; 89:4265–4269. 316. Hu QH, Wang DX. Hypoxia increases cytosolic free calcium in porcine pulmonary arterial endothelial cells. J Tongji Med Univ 1993; 13:14–17. 317. Hampl V, Cornfield DN, Cowan NJ, Archer SL. Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells. Eur Respir J 1995; 8:515–522. 318. Arnould T, Michiels C, Alexandre I, Remacle J. Effect of hypoxia upon intracellular calcium concentration of human endothelial cells. J Cell Physiol 1992; 152:215–221. 319. Ikeda M, Ariyoshi H, Sakon M, Kambayashi J, Yoshikawa N, Shinoki N, Kawasaki T, Monden M. A role for local calcium gradients upon hypoxic injury in human umbilical vein endothelial cells (HUVEC). Cell Calcium 1998; 24:49–57. 320. Michiels C, Arnould T, Knott I, Dieu M, Remacle J. Stimulation of prostaglandin synthesis by human endothelial cells exposed to hypoxia. Am J Physiol 1993; 264:C866–C874. 321. Stevens T, Fouty B, Cornfield D, Rodman DM. Reduced PO2 alters the behavior of Fura2 and Indo-1 in bovine pulmonary artery endothelial cells. Cell Calcium 1994; 16:404– 412. 322. Resink T, Buravkova L, Mirzapoyazova T, Kohler E, Erne P, Tkachuk V. Involvement
356
323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344.
Sylvester et al. of protein kinase C in hypoxia-induced desensitization of the beta-adrenergic system in human endothelial cells. Biochem Biophys Res Commun 1996; 222:753–758. Zhang J, Patel JM, Block ER. Hypoxia-specific upregulation of calpain activity and gene expression in pulmonary artery endothelial cells. Am J Physiol 1998; 275:L461–L468. Su Y, Block ER. Acute hypoxia increases intracellular L-arginine content in cultured porcine pulmonary artery endothelial cells. J Cell Physiol 1996; 167:349–353. Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 1997; 272:31725–31729. Phelan MW, Faller DV. Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells. J Cell Physiol 1996; 167:469–476. Ziesche R, Petkov V, Williams J, Zakeri SM, Mosgoller W, Knofler M, Block LH. Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue. Proc Natl Acad Sci USA 1996; 93:12478–12483. Liao JK, Zulueta JJ, Yu FS, Peng HB, Cote CG, Hassoun PM. Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen. J Clin Invest 1995; 96:2661–2666. Martin LD, Barnes SD, Wetzel RC. Acute hypoxia alters eicosanoid production of perfused pulmonary artery endothelial cells in culture. Prostaglandins 1992; 43:371–382. North AJ, Brannon TS, Wells LB, Campbell WB, Shaul PW. Hypoxia stimulates prostacyclin synthesis in newborn pulmonary artery endothelium by increasing cyclooxygenase1 protein. Circ Res 1994; 75:33–40. Holden WE, Burnham EM, Lee MA, Bagby SP. Influence of growth oxygen level on eicosanoid release from lung endothelial cells during hypoxia. Am J Physiol 1992; 263: L454–L459. Farber HW, Barnett HF. Differences in prostaglandin metabolism in cultured aortic and pulmonary arterial endothelial cells exposed to acute and chronic hypoxia. Circ Res 1991; 68:1446–1457. Murakami M, Nakatani Y, Atsumi G, Inoue K, Kudo I. Regulatory functions of phospholipase A2. Crit Rev Immunol 1997; 17:225–17:283. Whatley RE, Zimmerman GA, McIntyre TM, Prescott SM. Lipid metabolism and signal transduction in endothelial cells. Prog Lipid Res 1990; 29:45–63. Schmedtje JF Jr, Ji YS, Liu WL, DuBois RN, Runge MS. Hypoxia induces cyclooxygenase-2 via the NF-κB p65 transcription factor in human vascular endothelial cells. J Biol Chem 1997; 272:601–608. Watkins MT, Haudenschild CC, al-Badawi H, Velazquez FR, Larson DM. Immediate responses of endothelial cells to hypoxia and reoxygenation: an in vitro model of cellular dysfunction. Am J Physiol 1995; 268:H749–H758. Madden MC, Vender RL, Friedman M. Effect of hypoxia on prostacyclin production in cultured pulmonary artery endothelium. Prostaglandins 1986; 31:1049–1062. Markewitz BA, Kohan DE, Michael JR. Hypoxia decreases endothelin-1 synthesis by rat lung endothelial cells. Am J Physiol 1995; 269:L215–L220. Hassoun PM, Thappa V, Landman MJ, Fanburg BL. Endothelin 1: mitogenic activity on pulmonary artery smooth muscle cells and release from hypoxic endothelial cells. Proc Soc Exp Biol Med 1992; 199:165–170. Wiebke JL, Montrose-Rafizadeh C, Zeitlin PL, Guggino WB. Effect of hypoxia on endothelin-1 production by pulmonary vascular endothelial cells. Biochim Biophys Acta 1992; 1134:105–111. Hieda HS, Gomez-Sanchez CE. Hypoxia increases endothelin release in bovine endothelial cells in culture, but epinephrine, norepinephrine, serotonin, histamine and angiotensin II do not. Life Sci 1990; 47:247–251. Kourembanas S, Marsden PA, McQuillan LP, Faller DV. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest 1991; 88:1054–1057. Hu J, Discher DJ, Bishopric NH, Webster KA. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun 1998; 245:894–899. Bodi I, Bishopric NH, Discher DJ, Wu X, Webster KA. Cell-specificity and signaling pathway of endothelin-1 gene regulation by hypoxia. Cardiovasc Res 1995; 30:975–984.
Acute Hypoxic Pulmonary Vasoconstriction
357
345. Gertler JP, Ocasio VH. Endothelin production by hypoxic human endothelium. J Vasc Surg 1993; 18:178–82; discussion 182–184. 346. Block ER, Patel JM, Edwards D. Mechanism of hypoxic injury to pulmonary artery endothelial cell plasma membranes. Am J Physiol 1989; 257:C223–C231. 347. Yang W, Block ER. Effect of hypoxia and reoxygenation on the formation and release of reactive oxygen species by porcine pulmonary artery endothelial cells. J Cell Physiol 1995; 164:414–423. 348. Hassoun PM, Yu FS, Shedd AL, Zulueta JJ, Thannickal VJ, Lanzillo JJ, Fanburg BL. Regulation of endothelial cell xanthine dehydrogenase xanthine oxidase gene expression by oxygen tension. Am J Physiol 1994; 266:L163–L171. 349. Terada LS, Guidot DM, Leff JA, Willingham IR, Hanley ME, Piermattei D, Repine JE. Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci USA 1992; 89:3362–3366. 350. Lanzillo JJ, Yu FS, Stevens J, Hassoun PM. Determination of xanthine dehydrogenase mRNA by a reverse transcription-coupled competitive quantitative polymerase chain reaction assay: regulation in rat endothelial cells by hypoxia and hyperoxia. Arch Biochem Biophys 1996; 335:377–380. 351. Kong XJ, Fanburg BL. Regulation of Cu,Zn-superoxide dismutase in bovine pulmonary artery endothelial cells. J Cell Physiol 1992; 153:491–497. 352. Al-Mehdi AB, Ischiropoulos H, Fisher AB. Endothelial cell oxidant generation during K⫹induced membrane depolarization. J Cell Physiol 1996; 166:274–280. 353. Al-Mehdi AB, Shuman H, Fisher AB. Oxidant generation with K⫹-induced depolarization in the isolated perfused lung. Free Radic Biol Med 1997; 23:47–56. 354. Al-Mehdi AB, Zhao G, Dodia C, Tozawa K, Costa K, Muzykantov V, Ross C, Blecha F, Dinauer M, Fisher AB. Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K⫹. Circ Res 1998; 83:730–737. 355. Weir EK, Reeve HL, Cornfield DN, Tristani-Firouzi M, Peterson DA, Archer SL. Diversity of response in vascular smooth muscle cells to changes in oxygen tension. Kidney Int 1997; 51:462–466. 356. Weir EK, Reeve HL, Peterson DA, Michelakis ED, Nelson DP, Archer SL. Pulmonary vasoconstriction, oxygen sensing, and the role of ion channels: Thomas A. Neff lecture. Chest 1998; 114:17S–22S. 357. Archer SL, Will JA, Weir EK. Redox status in the control of pulmonary vascular tone. Herz 1986; 11:127–141. 358. Murray TR, Marshall BE, Macarak EJ. Contraction of vascular smooth muscle in cell culture. J Cell Physiol 1990; 143:26–38. 359. Barman SA. Potassium channels modulate hypoxic pulmonary vasoconstriction. Am J Physiol 1998; 275:L64–L70. 360. Gelband CH, Hume JR. [Ca2⫹ ] i inhibition of K⫹ channels in canine renal artery. Novel mechanism for agonist-induced membrane depolarization. Circ Res 1995; 77:121–130. 361. Archer SL, Yankovich RD, Chesler E, Weir EK. Comparative effects of nisoldipine, nifedipine and bepridil on experimental pulmonary hypertension. J Pharmacol Exp Ther 1985; 233:12–17. 362. Tucker A, McMurtry IF, Grover RF, Reeves JT. Attenuation of hypoxic pulmonary vasoconstriction by verapamil in intact dogs. Proc Soc Exp Biol Med 1976; 151:611–614. 363. Wadsworth RM. Vasoconstrictor and vasodilator effects of hypoxia. Trends Pharmacol Sci 1994; 15:47–53. 364. Ward JPT, Aaronson PI, Hague D. Hypoxic pulmonary vasoconstriction in the absence of voltage-gated calcium channel activation (abstract). Am J Respir Crit Care Med 1999; 159:A569. 365. Ruppersberg JP, Stocker M, Pongs O, Heinemann SH, Frank R, Koenen M. Regulation of fast inactivation of cloned mammalian IK(A) channels by cysteine oxidation. Nature 1991; 352:711–714. 366. Rettig J, Heinemann SH, Wunder F, Lorra C, Parcej DN, Dolly JO, Pongs O. Inactivation properties of voltage-gated K⫹ channels altered by presence of beta-subunit. Nature 1994; 369:289–294. 367. Rounds S, McMurtry IF. Inhibitors of oxidative ATP production cause transient vaso-
358
368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. 390.
Sylvester et al. constriction and block subsequent pressor responses in rat lungs. Circ Res 1981; 48:393– 400. Sanders SP, Zweier JL, Kuppusamy P, Harrison SJ, Bassett DJ, Gabrielson EW, Sylvester JT. Hyperoxic sheep pulmonary microvascular endothelial cells generate free radicals via mitochondrial electron transport. J Clin Invest 1993; 91:46–52. Duranteau J, Chandel NS, Kulisz A, Shao Z, Schumacker PT. Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J Biol Chem 1998; 273:11619– 11624. Buescher PC, Pearse DB, Pillai RP, Litt MC, Mitchell MC, Sylvester JT. Energy state and vasomotor tone in hypoxic pig lungs. J Appl Physiol 1991; 70:1874–1881. Peterson DA, Archer SL, Weir EK. Superoxide reduction of a disulfide: a model of intracellular redox modulation? Biochem Biophys Res Commun 1994; 200:1586–1591. Peterson DA, Peterson DC, Archer SL, Weir EK. Superoxide dismutase: an antireductant enzyme? Biochem Soc Trans 1993; 21:88S. McMurtry IF, Rounds S, Stanbrook HS. Studies of the mechanism of hypoxic pulmonary vasoconstriction. Adv Shock Res 1982; 8:21–33. Fishman AP. Hypoxia on the pulmonary circulation. How and where it acts. Circ Res 1976; 38:221–231. Harabin AL, Peake MD, Sylvester JT. Effect of severe hypoxia on the pulmonary vascular response to vasoconstrictor agents. J Appl Physiol 1981; 50:561–565. Rounds SS, McMurtry IF, Reeves JT. Glucose metabolism accelerates the decline of hypoxic vasoconstriction in rat lungs. Respir Physiol 1981; 44:239–249. Leach RM, Sheehan DW, Chacko VP, Sylvester JT. Effects of hypoxia on energy state and pH in resting pulmonary and femoral arterial smooth muscles. Am J Physiol 1998; 275:L1051–L1060. Arnqvist HJ, Lundholm L. Influence of oxygen tension of the metabolism of vascular smooth muscle: demonstration of a Pasteur effect. Atherosclerosis 1976; 25:245–253. Chandel NS, Budinger GRS, Schumacker PT. Molecular oxygen modulates cytochrome c oxidase function. J Biol Chem 1996; 271:18672–18677. Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem 1998; 273:18092–18098. Budinger GR, Duranteau J, Chandel NS, Schumacker PT. Hibernation during hypoxia in cardiomyocytes. Role of mitochondria as the O2 sensor. J Biol Chem 1998; 273:3320–3326. Waypa GB, Chandel NS, Kulisz A, Schumacker PT. Mitochondrial reactive oxygen species are involved in hypoxic pulmonary vasoconstriction (HPV) (abstract). Am J Respir Crit Care Med 1999; 159:A569. Archer SL, Nelson DP, Weir EK. Detection of activated O2 species in vitro and in rat lungs by chemiluminescence. J Appl Physiol 1989; 67:1912–1921. Mohazzab KM, Fayngersh RP, Kaminski PM, Wolin MS. Potential role of NADH oxidoreductase-derived reactive O2 species in calf pulmonary arterial PO2-elicited responses. Am J Physiol 1995; 269:L637–L644. Acker H. Mechanisms and meaning of cellular oxygen sensing in the organism. Respir Physiol 1994; 95:1–10. Acker H, Bolling B, Delpiano MA, Dufau E, Gorlach A, Holtermann G. The meaning of H2 O 2 generation in carotid body cells for PO2 chemoreception. J Auton Nerv Syst 1992; 41:41–51. Acker H, Dufau E, Huber J, Sylvester D. Indications to an NADPH oxidase as a possible PO2 sensor in the rat carotid body. FEBS Lett 1989; 256:75–78. Marshall C, Mamary AJ, Verhoeven AJ, Marshall BE. Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction. Am J Respir Cell Mol Biol 1996; 15: 633–644. Grimminger F, Weissmann N, Spriestersbach R, Becker E, Rosseau S, Seeger W. Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs. Am J Physiol 1995; 268:L747–L752. Thomas HM, Carson RC, Fried ED, Novitch RS. Inhibition of hypoxic pulmonary vasoconstriction by diphenyleneiodonium. Biochem Pharmacol 1991; 42:R9–R12.
Acute Hypoxic Pulmonary Vasoconstriction
359
391. Cross AR, Henderson L, Jones OT, Delpiano MA, Hentschel J, Acker H. Involvement of an NAD(P)H oxidase as a PO2 sensor protein in the rat carotid body. Biochem J 1990; 272:743–747. 392. Youngson C, Nurse C, Yeger H, Cutz E. Oxygen sensing in airway chemoreceptors. Nature 1993; 365:153–155. 393. Youngson C, Nurse C, Yeger H, Curnutte JT, Vollmer C, Wong V, Cutz E. Immunocytochemical localization on O2-sensing protein (NADPH oxidase) in chemoreceptor cells. Microsc Res Tech 1997; 37:101–106. 394. Weissmann N, Grimminger F, Voswinckel R, Conzen J, Seeger W. Nitro blue tetrazolium inhibits but does not mimic hypoxic vasoconstriction in isolated rabbit lungs. Am J Physiol 1998; 274:L721–L727. 395. Weir EK, Wyatt CN, Reeve HL, Huang J, Archer SL, Peers C. Diphenyleneiodonium inhibits both potassium and calcium currents in isolated pulmonary artery smooth muscle cells. J Appl Physiol 1994; 76:2611–2615. 396. Holland PC, Clark MG, Bloxham DP, Lardy HA. Mechanism of action of the hypoglycemic agent diphenyleneiodonium. J Biol Chem 1973; 248:6050–6056. 397. Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, Weir EK. O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci USA 1999; 96:7944–7949 [Medline record in process]. 398. Balagopalakrishna C, Abugo OO, Horsky J, Manoharan PT, Nagababu E, Rifkind JM. Superoxide produced in the heme pocket of the beta-chain of hemoglobin reacts with the beta-93 cysteine to produce a thiyl radical. Biochemistry 1998; 37:13194–13202. 399. Balagopalakrishna C, Manoharan PT, Abugo OO, Rifkind JM. Production of superoxide from hemoglobin-bound oxygen under hypoxic conditions. Biochemistry 1996; 35:6393– 6398. 400. Rifkind JM, Zhang L, Heim JM, Levy A. The role of hemoglobin in generating oxyradicals. Basic Life Sci 1988; 49:157–162. 401. Barnes PJ, Liu SF. Regulation of pulmonary vascular tone. Pharmacol Rev 1995; 47:87– 131. 402. Luscher TF, Boulanger CM, Dohi Y, Yang ZH. Endothelium-derived contracting factors. Hypertension 1992; 19:117–130. 403. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3:2007–2018. 404. Davies PF, Olesen SP, Clapham DE, Morrel EM, Schoen FJ. Endothelial communication. State of the art lecture. Hypertension 1988; 11:563–572. 405. Daut J, Standen NB, Nelson MT. The role of the membrane potential of endothelial and smooth muscle cells in the regulation of coronary blood flow. J Cardiovasc Electrophysiol 1994; 5:154–181. 406. Ward JP, Robertson TP. The role of the endothelium in hypoxic pulmonary vasoconstriction. Exp Physiol 1995; 80:793–801. 407. Allen SW, Chatfield BA, Koppenhafer SA, Schaffer MS, Wolfe RR, Abman SH. Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Association with acute hypoxic pulmonary vasoreactivity. Am Rev Respir Dis 1993; 148:519–522. 408. Helset E, Kjaeve J, Bjertnaes L, Lundberg JM. Acute alveolar hypoxia increases endothelin-1 release but decreases release of calcitonin gene-related peptide in isolated perfused rat lungs. Scand J Clin Lab Invest 1995; 55:369–376. 409. Takeda S, Nakanishi K, Inoue T, Ogawa R. Delayed elevation of plasma endothelin-1 during unilateral alveolar hypoxia without systemic hypoxemia in humans. Acta Anaesthesiol Scand 1997; 41:274–280. 410. Horio T, Kohno M, Yokokawa K, Murakawa K, Yasunari K, Fujiwara H, Kurihara N, Takeda T. Effect of hypoxia on plasma immunoreactive endothelin-1 concentration in anesthetized rats. Metabolism 1991; 40:999–1001. 411. Inoue Y, Oike M, Nakao K, Kitamura K, Kuriyama H. Endothelin augments unitary calcium channel currents on the smooth muscle cell membrane of guinea-pig portal vein. J Physiol 1990; 423:171–191. 412. Lander HM. An essential role for free radicals and derived species in signal transduction. FASEB J 1997; 11:118–124.
13 Pulmonary Edema Formation and Reabsorption
MICHAEL A. MATTHAY
TSUTOMU SAKUMA
University of California at San Francisco San Francisco, California
Kanazawa Medical University Ishikawa, Japan
I.
Introduction
The overall objective of this chapter is to consider the mechanisms that are responsible for the formation and the resolution of pulmonary edema. Several experimental and clinical studies have examined the pathophysiologic basis for the formation of pulmonary edema. In general, the etiology of pulmonary edema is divided into highpressure (hydrostatic) or increased permeability. However, there is evidence that in some circumstances these distinctions do not adequately describe the pathogenesis of pulmonary edema. There is evidence that both hydrostatic and increased permeability may contribute to the development of pulmonary edema in some clinical conditions. Therefore, the first part of this chapter will discuss the formation of pulmonary edema with a review of the classic distinction between hydrostatic and increased permeability, but will also consider conditions in which both mechanisms may contribute to the development of pulmonary edema. The second section of the chapter will consider the development of pulmonary edema from both increased hydrostatic pressure and increased lung vascular permeability. The third part of the chapter will review new evidence regarding the resolution of pulmonary edema. Some of the information in this chapter has been discussed in other chapters or review articles (1,2). 361
362
Matthay and Sakuma II. Formation of Pulmonary Edema
In order to understand the formation of pulmonary edema, the structural and physiologic basis for the exchange of fluid and protein in the lung must be considered. First, this section will deal with the morphology of the blood-gas barrier, including the microvascular barrier, the interstitial space and the alveolar barrier. Second, the Starling equation, which describes the movement of liquid and protein across these semi-permeable barriers, will be considered. This equation also provides a means of classifying pulmonary edema into two types: edema resulting from increased microvascular pressure; and edema resulting from increased permeability. Finally, the pathophysiology of high pressure edema, both interstitial and alveolar, along with a discussion of the possible role of increased permeability from high vascular pressures, will close this section. A. The Structural Basis of Pulmonary Edema
Most of the available evidence indicates that the major function of protein and fluid exchange occurs in the microvessels of the lung. On the arterial side, these vessels are without media and adventitia, consisting only of endothelial and basal lamina, measuring ⬍75 µm in diameter. On the venous side, the microvessels can be up to 200 µm in diameter, also made up of endothelium and basal lamina. The thicker walls and relatively lower total surface area probably prevent any meaningful exchange across the larger vessels. The capillaries in the lung are surrounded by the alveolar space and the interstitial space (Fig. 1). Normally, the barrier has a thin side, where the capillary endothelium and the alveolar epithelium are attenuated and their basement membranes are fused. This reduces the distance of gas diffusion to 1 µm or less. The opposite side of the barrier is the ‘‘thick’’ side. Here, the endothelium and epithelium are not attenuated, and the basement membranes are not fused. Ground substance, cells, and connective tissue fibrils are found on this side (3). Interstitial edema collects primarily on the thick side of the barrier, and this is where most endothelial cell junctions are found. Physiologic movement of proteins and fluid probably occurs primarily through these intercellular junctions (3). To support this theory, freeze-fracture studies have shown that endothelial cell junctions are relatively leaky (4). In fact, some of these junctions can be opened by very high distending pressures (3). Recent evidence suggests that some water may move across lung endothelial cells through aquaporins, transcellular water channels, in the presence of a hydrostatic stress (5). After filtration through the microvascular barrier, the fluid and proteins enter the interstitial space of the lung. The interstitium of the alveolar walls differs from that of the extra-alveolar space in at least two ways that influence the movement of filtered fluid. First, lymphatic vessels are not found in the alveolar walls, but occur only in the loose connective tissue of the peribronchovascular cuffs, interlobular septa, and pleura. Second, although the compartments are continuous, the hydrostatic pressure of the extra-alveolar interstitial space is negative relative to the pressure
Pulmonary Edema
363
Figure 1 Electron photomicrograph of a human lung. Two capillaries containing red blood cells (RBC) are suspended in the interalveolar septum between two alveolar spaces (AS). The basement membranes (BM) of the epithelium (EP) and endothelium (EN) appear to be fused over the thin portion of the septum (or air-blood barrier) and are separated over the thick portion of the septum containing the interstitial space (IS). Magnification ⫻ 11,000. (From Ref. 3a.)
in the alveolar wall interstitium. This theory was confirmed by Bhattacharya and Staub (6) with micropuncture of the interstitium around alveolar walls, arterioles, venules, and hilum. This pressure gradient allows the loose connective tissue spaces to serve as sumps for the alveolar wall interstitium, draining fluid proximally toward the peribronchovascular spaces. The loose connective tissue spaces are also very distensible. This allows them to collect a large volume of fluid without a large rise in interstitial pressure. Even
364
Matthay and Sakuma
while containing a substantial volume of fluid, a pressure gradient still exists in the interstitium, and edema fluid can drain toward the hilum from the alveolar interstitial space. This prevents a rise in pressure in the alveolar walls, which could result in alveolar edema. Gee and Williams (7) demonstrated that the bronchovascular cuffs are able to contain up to 500 mL in this capacity. The fluid in the extra-alveolar spaces is in turn drained by the lymphatics running through them. Normally, the lymph vessels return all filtered fluid to systematic circulation at the rate of 10 to 20 mL/hour (5). Under normal conditions, and even in the early phase of pulmonary edema, fluid in the alveolar wall interstitium does not cross the epithelium into the alveolar space unless the tight barrier has been altered by high pressure or direct cell injury. The alveolar barrier consists of two primary cell types. Flat, attenuated type I cells are less numerous but cover 95% of the total surface area of the alveolar space. Rounded, surfactant-producing type II cells are greater in number, but cover much less area. These cells are arranged in a single cell layer. Although the alveolar barrier is very thin, the junctions between the cells are extremely tight. These non-leaky tight junctions give the alveolar epithelium very low permeability to fluid, proteins, and even small solutes. Thus, there can be considerable fluid accumulation in the interstitium without the development of alveolar edema. B. Physiologic Basis of Pulmonary Edema
Movement of fluid and proteins through the pulmonary endothelium is believed to obey the Starling equation. The Starling equation predicts that the net filtration of fluid and proteins across a semipermeable barrier is the product of the driving pressure and the conductance, or permeability, of the barrier. The total driving pressure is the sum of the hydrostatic and osmotic pressures. Thus: Qf ⫽ K[(Pmv–Ppmv)–σ(IImv–IIpmv)] In this equation, Qf is the net filtration rate, K is the filtration coefficient of the conductance across the barrier, Pmv stands for the microvascular hydrostatic pressure, Ppmv is hydrostatic pressure of the perimicrovascular space, IImv is the microvascular osmotic pressure, and IIpmv is the osmotic pressure of the perimicrovascular space. The reflection coefficient, σ, indicates the effectiveness of the osmotic pressure difference across the barrier. For example, if σ is 1, the barrier will be totally impermeable to protein molecules. On the other hand, a reflection coefficient of zero would indicate that the barrier is freely permeable to proteins. In the lung, σ is estimated to be around 0.9 for the endothelial barrier, and very close to 1 for the alveolar epithelium (3). These values are consistent with the structural studies previously mentioned, in which the endothelial cell junctions were found to be relatively leaky, while those of the alveolar epithelium are very tight. The Starling equation fails to account for two factors affecting fluid and protein exchange in the lung. First, fluid balance depends on the function of the lymphatics, which remove much of the fluid that is filtered across the microvascular barrier. Second, fluid and protein exchange depend on the surface of filtration and the per-
Pulmonary Edema
365
fused vascular surface area in the lung can change under pathologic or normal conditions, as in the recruitment of vessels during exercise. An increase in surface area can lead to an increase in lung lymph flow without changing any of the variables in the Starling equation (8). In clinical practice, pulmonary edema is classified into two types by using the Starling equation: high-pressure or increased-permeability pulmonary edema (9). These headings are not mutually exclusive, and cases of increased permeability can be complicated by an increase in hydrostatic pressure. Also, it is possible that some extreme cases of hydrostatic pressure edema may be complicated by increased permeability edema. For purposes of initial explanation, however, the two types will be considered separately, and then the clinical conditions in which a combination of hydrostatic and increased permeability mechanisms may occur will be considered. High-Pressure Pulmonary Edema
The Starling equation predicts that high-pressure pulmonary edema will develop from a large increase in the difference between microvascular and perimicrovascular hydrostatic pressures. This often arises in the context of left-sided congestive heart failure (9), but can also result from pulmonary venous hypertension (10). Theoretically, a drop in lung interstitial pressure should also lead to high-pressure edema; this concept has received some support in studies in dog lungs (11,12). As hydrostatic pressure increases in the microvasculature of the lung, the rate of filtration increases (Fig. 2). Note, however, that the reflection coefficient of the endothelium is quite high (⬃0.9), and that even in severe edema, the protein content of the edema fluid is less that that of plasma. The filtrate in the alveolar interstitium flows down a pressure gradient into the loose connective tissue of the bronchovascular cuffs. The extra-alveolar interstitium is very distensible, and can collect a large volume of fluid without a significant increase in pressure (3). Interstitial lung edema can cause dyspnea and is detectable on the chest radiograph, but usually does not interfere with gas exchange because no alveolar flooding occurs (13). Several safety factors attenuate the development and progression of pulmonary edema. As already mentioned, a functional lymphatic system is a crucial safeguard. The lymphatics drain off fluid from the interstitial space and prevent a rise in perimicrovascular hydrostatic pressure that might lead to alveolar flooding. Second, even if the lymph vessels cannot keep up with fluid formation, the loose connective tissue of the peribronchovascular cuffs can contain 500 mL of edema fluid (9). Third, when fluid filters through the microvascular barrier, it dilutes the protein in the interstitium, reducing the osmotic pressure. Following the Starling equation, this would lead to greater tendency for fluid to flow into the vessels, since plasma has a relatively high protein content. The lowering of the perimicrovascular osmotic pressure probably offsets about half of the increase in microvascular hydrostatic pressure (14). Finally, although the peribronchovascular cuffs are very distensible, some small increase in interstitial hydrostatic pressure must occur that would at least partly diminish the pressure gradient from the vessels to the interstitium.
366
Matthay and Sakuma
Figure 2 Time course of the effect of increased pulmonary microvascular pressure on lung lymph flow and the lymph-to-plasma protein concentration ratios in unanesthetized sheep. After 2 hours of baseline study, left atrial pressure was elevated by inflating a chronically implanted balloon. Note the rise in lymph flow is more than double baseline values, and the lymph-to-plasma concentration falls. (From Ref. 12a.)
When the edema fluid exceeds the capacity of the interstitial space, a change in the alveolar barrier occurs and fluid enters the air spaces, resulting in alveolar edema (3,9). The sites of flooding into the air spaces, as well as the precise changes in the epithelial tight junctions, are unknown. Channels in the terminal airway epithelium as well as in the alveolar epithelium may play a part. However, when alveolar flooding occurs, the reflection coefficient of the epithelium changes from 1 to zero, and the barrier is freely permeable to liquid and protein. Experimental studies have demonstrated that edema fluid in the interstitium and the alveolar spaces have the same protein content (15,16). Most of the pathophysiologic changes that have been observed with highpressure pulmonary edema follow logically from the flooding of the air spaces. The fluid in the alveoli prevents ventilation and causes ventilation-perfusion mismatch or shunt, depending on the extent of flooding. The edema fluid in the alveoli may inactivate some of the surfactant and can result in atelectasis, increasing the shunt. Experimental studies of high-pressure edema have shown that alveolar flooding cor-
Pulmonary Edema
367
responds with a decrease in arterial oxygenation and an increase in the alveolararterial oxygen difference (13). Increased-Permeability Pulmonary Edema
The Starling equation predicts that a change in the permeability of the microvascular membrane will result in a marked increase in the quantity of fluid and protein that leaves the vascular space and enters the interstitium of the lung. Pulmonary edema fluid of this type would have a high protein concentration because the vascular membrane no longer has the capacity to restrict the outward movement of large molecules such as plasma proteins. The results of a number of studies have confirmed that the alveolar edema fluid has a high protein concentration (75% or higher) compared with the plasma protein concentration (17,18). Experimentally, a variety of agents have been used to injure the lung, some given by the intravenous route and others directly into the air spaces of the lung. Severe hemorrhagic edema is produced in sheep or dogs when oleic acid is injected in doses of 0.08 mL/kg body weight (19). One of the limitations of all these experimental approaches to injuring the lung is that they are severe and produce changes that are not reversible and are therefore suitable for acute studies only. Some investigators have been able to reduce the severity of injury by lowering the dose (particularly of oleic acid) to sublethal doses that allow unanesthetized animals to be studied for a few days. One useful experimental approach for producing reversible acute lung injury has been achieved with intravenous air emboli (20) or E. coli endotoxin in unanesthetized spontaneously breathing sheep (21). Both these means of producing acute lung injury have allowed investigators to study the early phase of acute lung injury. In a live bacterial model of acute lung injury, there is an early rise in pulmonary artery pressure with an abrupt rise in lymph flow accompanied by a decrease in the lymph-to-plasma protein concentration ratio (Fig. 3) (21a). This pattern is similar to the effect of left atrial hypertension on lymph flow (Fig. 2), suggesting that the elevated pulmonary artery pressure is transmitted to fluid exchanging vessels in the lung. After 1 to 2 hours of E. coli endotoxin infusion, the pulmonary artery pressure declines (but not to baseline levels) and lung lymph flow rises to very high levels in association with a rise in the lymph protein concentration and a return of the lymph-to-plasma protein concentration ratio to baseline levels. This is the classic pattern of increased permeability pulmonary edema. Venous air emboli given to sheep produces a rise in pulmonary vascular pressures, a marked increase in lymph flow, and no change in the lymph-to-plasma protein concentration ratios (20). Since the air emboli actually decrease lung surface area for filtration, the unchanged lymph-to-plasma protein concentration ratio indicates a significant increase in lung vascular permeability. In both endotoxin- and air emboli-induced lung injury, interstitial edema and mild hypoxemia develop in parallel with the increase in lymph flow. Both forms of acute lung injury are partially mediated by neutrophils, perhaps in part by the release of toxic oxygen free radicals
368
Matthay and Sakuma
Figure 3 Effects of infusion of Pseudomonas aeruginosa on lung vascular pressures, lymph flow, and lymph-to-plasma protein concentration in unanesthetized sheep. Note that there is an initial rise in lymph flow associated with a fall in the lymph-to-plasma protein concentration ratio when pulmonary artery pressure has returned toward baseline levels. This is the late phase of increased vascular permeability with protein-rich lymph. A similar response occurs with E. coli endotoxin. (From Ref. 21a.)
from degranulated neutrophils. These physiologic studies have been complemented by morphologic studies to determine the ultrastructural basis for the increasedpermeability pulmonary edema. Interestingly, the primary vascular lesions are located in different portions of the pulmonary circulation. In some experimental studies, it has been difficult to determine whether an increase in the lung lymph flow develops because of a change in vascular permeability or an increase in the perfused vascular surface area. One approach to differentiating an increase in lung vascular permeability from an increase in surface area is to increase microvascular pressure and follow the lymph-to-plasma protein concentration ratios. For example, Ohkuda et al. (20) demonstrated that after venous air emboli were given to sheep, left atrial pressure elevations resulted in a further rise in lymph flow but no decline in the lymph-to-plasma protein concentration ratio, demonstrating that the primary lesion was an increase in vascular permeability. In contrast, when left atrial pressure elevation results in a decline in the lymph-
Pulmonary Edema
369
to-plasma protein concentration ratio (Fig. 2), it is likely that a major change in vascular permeability has not occurred. For example, a study from our laboratory was designed to test the overperfusion theory of pulmonary edema and determine if high blood flow to a restricted portion of the lung with and without hypoxia would result in a high-pressure or an increased-vascular permeability pulmonary edema (22). Anesthetized sheep were prepared surgically so that pulmonary and systematic hemodynamics and lung lymph flow could be measured, then 65% of the lung mass was resected. There was a substantial rise in lymph flow from the remaining lung with a small decrease in the lymph-to-plasma protein concentration ratio. To be certain that there was no significant change in permeability, left atrial pressure was elevated with and without hypoxia. The results consistently showed a further rise in lymph flow that was accompanied by a marked decrease in the lymph-to-plasma protein ratio. These results indicated that the endothelial barrier continued to restrict the movement of macromolecules, suggesting that the increase in lymph flow was related to high pressure alone and not to an increase in vascular permeability. C. Pulmonary Edema That Develops from Both Increased Hydrostatic Pressure and Increased Vascular Permeability
Several studies, both clinical and experimental, have suggested that in some cases, increased hydrostatic pressure in the microcirculation can injure the endothelium, increasing its permeability. Very high pressures resulting from left ventricular failure and the dynamic effect of blood flowing through a restricted vascular bed at high velocity, resulting from pulmonary emboli or resection and transfusion, have been proposed as mechanisms for physically injuring the endothelial barrier (23,24). It is thought that this stress on the vascular walls could open the intercellular junctions. However, as described in the prior section, by overperfusing the lungs of sheep, we found that high pressure and increased flow through a restricted vascular bed resulted in hydrostatic pulmonary edema, but not an increase in vascular permeability (22). However, some recent studies have raised the possibility that elevated hydrostatic vascular pressures may result in injury to the microcirculation. For example, work from the laboratory of Bachofen and colleagues (25,26) indicated that epithelial lesions can be found in isolated perfused lungs ventilated with positive pressure when vascular pressures were raised to markedly elevated levels. Interestingly, the morphologic studies indicated that there was regional distribution of hydrostatic pulmonary edema that was not entirely accounted for by gravity dependence. Pulmonary edema within one lung was found to be inhomogeneous and changes in alveolar architecture occurred with bulging of alveolar capillaries apparently due to loss of air-liquid surface tension. There were significant epithelial lesions that seemed to occur in areas where the pulmonary capillary endothelium was not apparently injured. One concern regarding these studies is that the technique for preparation of the lungs for histologic analysis was done by vascular fixation so that pressures were returned to normal before the fixatives were injected. Bachofen and colleagues interpreted their findings as indicating that elevated vascular pressures with elevated interstitial edema caused the epithelial lesions.
370
Matthay and Sakuma
There are also some studies from the laboratory of West and associates (27) indicating that high perfusion and inflation pressures can cause endothelial lesions. Their studies showed a direct relationship between the number of endothelial cell lesions and the levels of both lung perfusion and lung inflation (27,28). These studies raise the possibility that hydrostatic stress may cause endothelial injury, although the actual model for the studies is not entirely physiologic. Nevertheless, these studies do raise the intriguing possibility that under some conditions hydrostatic stress may cause lung endothelial and pulmonary epithelial lesions. Are there any clinical circumstances under which pulmonary edema may form that might be modeled by the mechanisms explored in these studies? Two obvious candidates are high-altitude pulmonary edema and neurogenic pulmonary edema (24). High-altitude pulmonary edema is known to be associated with markedly elevated pulmonary vascular pressures, and it may be that regional overperfusion occurs in the presence of hypoxia with injury to the capillary endothelium and/or epithelium occurring in some portions of the lung (29). Firm evidence supporting this hypothesis is still not available, but it is certainly a reasonable possibility. In this circumstance, lowering of vascular pressures should prevent or attenuate the development of pulmonary edema. One study showed that nifedipine could prevent the development of high-altitude pulmonary edema in mountain climbers who had previously experienced high-altitude pulmonary edema. This finding suggests that overperfusion with subsequent vascular injury may occur with high-altitude pulmonary edema (30) and that this was alleviated by nifedipine. Neurogenic pulmonary edema has been studied experimentally and clinically (31). The results have indicated that in some cases animals develop hydrostatic pulmonary edema with a low protein concentration in the edema fluid, while in other cases there is an increased permeability edema with a high protein concentration. A recent clinical study from our institution found that patients with neurogenic pulmonary edema had a hydrostatic profile in edema fluid in 60% of the cases and an increased permeability profile in the other 40% of cases (32). It is possible that the primary hydrostatic lesion may be related to pulmonary venoconstriction, a mechanism that has been explored experimentally. Although for years there was a major interest in the possibility that transient elevations of pulmonary vascular pressures might cause permeability lesions in the human pulmonary circulation in neurogenic edema, human studies have not specifically supported this hypothesis, although more work needs to be done. In any case, it is possible that in some cases neurogenic edema may represent a combination of both hydrostatic and increased vascular permeability in the lung. How often is increased permeability pulmonary edema complicated by elevations in hydrostatic pressure? It has been recognized for many years that an increase in lung vascular permeability can be complicated by elevations in pulmonary microvascular pressure. Several animal studies demonstrated that elevations of hydrostatic pressure above normal will markedly increase the quantity of edema fluid that enters the extravascular space of the lung in the presence of an increase in lung vascular permeability (33–35). Clinical studies have suggested that this certainly occurs in some patients (35). Thus, while the primary lesion might be related to an increase
Pulmonary Edema
371
in lung vascular permeability, the mechanism of pulmonary edema clinically may be related to both elevations of hydrostatic pressure and an increase in lung vascular permeability. Work from our own laboratory suggests that there are patients who have a pulmonary edema fluid to plasma protein concentration that is midway between criteria for hydrostatic edema and criteria for increased permeability. In general, hydrostatic edema is defined as an edema fluid total protein-to-plasma ratio ⬍0.65 and increased permeability is defined as a ratio ⬎0.75. We have found that somewhere between 10% and 15% of patients will have an initial edema fluid to plasma protein concentration ratio between 0.65 and 0.75, suggesting that they may have a combination of a mild increase in vascular permeability possibly complicated by a modest elevation in pulmonary vascular pressures (17). In some patients with hydrostatic pulmonary edema, there are significant numbers of alveolar neurophils, a finding that may relate to proinflammatory factors in the air spaces of the lung (36). Is it necessary to abandon the traditional classification of pulmonary edema as either hydrostatic or increased permeability? We believe the answer is no. Most cases of pulmonary edema can be correctly classified clinically as either hydrostatic or increased permeability. However, there may well be 10% to 15% of cases in which both mechanisms are present and contribute to the development of pulmonary edema. Further clinical and experimental studies may help to identify this particular overlap group.
III. Resolution of Pulmonary Edema Considerable progress has been made in understanding the basic mechanisms that are responsible for the resolution of alveolar and interstitial edema in the lung. We will review evidence that active sodium transport is the primary mechanism that regulates in vivo alveolar fluid clearance, the data that show how catecholaminedependent and -independent mechanisms can upregulate alveolar fluid transport, the recent evidence that implicates transcellular water channels in alveolar epithelial fluid transport, and finally how the transport function of the alveolar epithelial barrier under pathological conditions is relevant to clinical pulmonary edema and the acute respiratory distress syndrome. For many years, it was generally believed that differences in hydrostatic and protein osmotic pressures (Starling forces) somehow accounted for removal of excess fluid from the air spaces of the lung (37). This misconception persisted in part because experiments that were designed to measure solute flux across the epithelial and endothelial barriers of the lung were done at room temperature (38). Also, these studies were done in dogs, a species that we subsequently learned has a low rate of alveolar epithelial sodium and fluid transport (39). However, in the early 1980s, experimental work from both in vivo and in vitro studies provided direct evidence that active sodium transport drives alveolar fluid transport across the alveolar barrier (40). The principal findings of some of the in vivo studies are summarized below.
372
Matthay and Sakuma
Experiments in anesthetized or unanesthetized sheep over 4, 12, and 24 hours indicated that spontaneous alveolar fluid clearance occurs in the face of a rising alveolar protein concentration (41,42). The final alveolar protein concentration exceeded plasma protein concentration by 3 to 6 g/100 mL. The same pattern was documented subsequently in humans in the resolution phase of pulmonary edema (43). The final alveolar protein concentration in some patients exceeded 10 g/100 mL with a simultaneous plasma protein concentration of 5 to 6 g/100 mL. These observations strongly suggested that an active ion transport mechanism was responsible for the removal of alveolar fluid. If active ion transport were responsible for alveolar fluid clearance, then alveolar fluid clearance should be temperature dependent. In an in situ goat lung preparation, the rate of alveolar fluid clearance progressively declined as temperature was lowered from 37 to 18°C (44). In the isolated human lung, alveolar fluid clearance ceased when temperature was lowered to 20°C (48). In addition, if active ion transport were primarily responsible for alveolar fluid clearance, then the elimination of transpulmonary hydrostatic pressure generated by ventilation should not alter the rate of alveolar fluid clearance. Indeed, studies in rabbits and sheep have indicated that the rate of alveolar fluid clearance was unchanged in the absence of ventilation (45). Additional evidence for active fluid transport was obtained in intact animals with the use of amiloride, an inhibitor of sodium uptake by the apical membrane of alveolar epithelium and distal airway epithelium. Amiloride inhibited 40% to 70% of basal alveolar fluid clearance in sheep, rabbits, rats, and in the human lung (41,45–47), similar to the data obtained in isolated rat lung preparations (52–54). To further explore the role of active sodium transport, experiments were designed to inhibit the Na,K-ATPase in alveolar type II cells. It is difficult to study the effect of ouabain in intact animals because of cardiac toxicity. However, in the isolated rat lung, ouabain was shown to inhibit ⬎90% of clearance (51). Subsequently, in an in situ sheep preparation for measuring alveolar fluid clearance in the absence of blood flow, ouabain inhibited 90% of alveolar fluid clearance over a 4-hour period (45). Important species differences in the basal rates of alveolar fluid clearance have been identified. To normalize for differences in lung size or the available surface area, different instilled volumes were used ranging from 1.5 to 6.0 mL/kg. The slowest alveolar fluid clearance was measured in dogs (39), intermediate rates of alveolar fluid clearance in sheep and goats (40,42,44,52), and the highest basal alveolar fluid clearance rates have been measured in rabbits and rats (46,47) and, most recently, in mice (53). The basal rate of alveolar fluid clearance in the human lung has been difficult to estimate, but based on the isolated, nonperfused human lung model, basal clearance rates appear to be intermediate to fast (54). In fact, clearance in the ex vivo human lung is approximately half of the rate in the ex vivo rat lung (59). On the other hand, recent clinical studies on the maximal rates of alveolar fluid clearance during the resolution of hydrostatic pulmonary edema indicate that clearance rates can be as high as 15% to 40%/h in some patients (55). These high rates may represent stimulation from catecholamine-dependent or -independent
Pulmonary Edema
373
mechanisms (see below). The explanation for the species differences in the basal rates of alveolar fluid clearance is not apparent, although there may be a difference in the number or activity of sodium channels or the density of Na,K-ATPase pumps in alveolar epithelium in different species. However, morphometric studies (56) demonstrated no significant difference in the number of alveolar type II cells in different species. Currently, it appears that alveolar epithelial type II cells are probably responsible for most of the net vectorial sodium transport from the alveolar to the interstitial side of the alveolar epithelial barrier (Fig. 4) (40). However, as illustrated in the figure, the distal airway epithelium may contribute to vectorial alveolar epithelial sodium and fluid transport as well. Alveolar epithelial type I cells comprise ⬎90% of the alveolar surface, but their role in lung fluid balance has been difficult to determine because they are difficult to isolate and to culture in vitro. Recent evidence that will be discussed in the section on water transport indicates that they are probably important in moving the water volume across the alveolar epithelial barrier after an osmotic gradient has been created by transport of sodium by type II cells (see the next section on water transport across alveolar epithelium). It is possible, of course, that alveolar type I cells also participate in ion transport although there is no definite evidence at this time to support a role for type I cells in vectorial ion
Figure 4 Schematic diagram of the major pathways for ion and water transport across alveolar and distal airway epithelium under basal and stimulated conditions. Other known membrane transporters that are not involved directly in vectorial fluid transport, such as sodium/hydrogen exchange and potassium conductance, are not depicted. (From Ref. 40.)
374
Matthay and Sakuma
transport across the epithelial barrier. In the near future, it may be possible to culture alveolar type I cells and to determine their capacity for ion transport with standard techniques. A. Catecholamine-Dependent Upregulation of Alveolar Fluid Clearance
Studies in newborn lambs suggested that endogenous release of catecholamines, particularly epinephrine, may stimulate reabsorption of fetal lung fluid from the air spaces of the lung (57,58). In fact, recent data provide definitive evidence for a major role for endogenous epinephrine in upregulating alveolar fluid clearance at the time of birth (59). In addition, studies of isolated alveolar type II cells indicated that sodium transport could be augmented with β-adrenergic agonists, probably by cAMP-dependent mechanisms (60,61). The cAMP stimulation appears to be mediated by protein kinase A, but further information is needed to determine the critical signalling events following cAMP stimulation. The enhancement of alveolar fluid clearance by catecholamine stimulation was confirmed in short-term isolated perfused lung studies in which terbutaline increased alveolar fluid clearance and the effect was inhibited by propranolol (40,61,62). Subsequent experiments in isolated lungs (63,64) and in vivo studies provided further evidence that cAMP is the second messenger for the β-adrenergic effects, whereas activation of protein kinase C does not appear to be involved (65). In vivo studies over 4 hours were carried out in anesthetized, ventilated sheep to examine the potential physiological factors that might influence alveolar fluid clearance, including systemic and pulmonary hemodynamics, pulmonary blood flow, and lung lymph flow (52). Terbutaline was administered in the instilled serum and nearly doubled alveolar fluid clearance over 4 hours in sheep; the increase was 90% prevented by coadministration of amiloride in the instilled solution. Although terbutaline increased pulmonary blood flow, this factor was not important, since nitroprusside, an agent that increased pulmonary blood flow to an equivalent degree, did not increase alveolar fluid clearance. There was an increase in lung lymph flow, a finding that reflected removal of some of the alveolar fluid volume to the interstitium of the lung. All of the β-adrenergic agonist effects were prevented by coadministration of propranolol into the air spaces. Terbutaline given into the air spaces of the dog lung also doubled alveolar fluid clearance (39). Subsequent studies have demonstrated that alveolar fluid clearance is markedly increased in the intact rat lung by β-adrenergic agonists (40). Interestingly, β-adrenergic agonist therapy does not increase alveolar fluid clearance in rabbits and hamsters (40). The explanation for this lack of effect is unclear, particularly since there are β-receptors in rabbit type II cells that stimulate surfactant secretion (66). Recent data indicate that in some species, particularly the guinea pig and the mouse, β-1 receptor stimulation is more important than β-2 receptor stimulation for upregulating alveolar fluid clearance (53,67). Do β-adrenergic agonists increase alveolar fluid clearance in the human lung? Based on studies of the resolution of alveolar edema in humans, it has been difficult to quantify the contribution of endogenous catecholamines to the basal alveolar fluid clearance rate (43). However, studies by Sakuma and colleagues (54) of alveolar
Pulmonary Edema
375
fluid clearance in the isolated human lung have demonstrated that β-adrenergic agonist therapy increases alveolar fluid clearance, and the increased clearance can be inhibited with propranolol or amiloride. The magnitude of the effect is similar to that observed in other species, with a β-agonist-dependent doubling of alveolar fluid clearance over baseline levels. These data are particularly important based on recent evidence indicating that aerosolized β-agonist therapy with salmeterol, a long-acting, lipid-soluble β-agonist, markedly increased the rate of alveolar fluid clearance in sheep (68). Also, there are recent data that the long-acting lipid soluble β-agonists are more potent than hydrophilic β-agonists in the ex vivo human lung (54) (Fig. 5). The data in this study suggested that salmeterol was more potent than terbutaline, although the work was done in the ex vivo human lung. Thus, aerosolized β-agonist treatment in some patients with pulmonary edema might accelerate the resolution of alveolar edema. Also, one recent experimental study supported the hypothesis that beta-agonist therapy could hasten the resolution of hydrostatic edema (68a). B. Catecholamine Independent Upregulation of Alveolar Fluid Clearance
In addition to the well-studied effects of β-adrenergic agonists, there is new evidence that several catecholamine-independent pathways can increase the rate of alveolar fluid clearance. Incubation of isolated alveolar type II cells with epidermal growth factor for 24 to 48 hours increases their capacity to transport sodium (69). Transforming growth factor-α (TGF-α) has been reported to increase alveolar fluid clearance acutely in anesthetized, ventilated rats. Compared to controls, 50 ng/ml TGFα in the instilled fluid increased alveolar liquid clearance by 45% over 1 hour and
Figure 5 Alveolar fluid clearance in ex vivo human lungs over 4 hours. Salmeterol (10⫺6 M), a lipid-soluble beta2 agonist, had a significantly greater effect than a comparable dose of terbutaline. (From Ref. 54.)
376
Matthay and Sakuma
by 53% over 4 hours. This increase was similar to the 50% increase in alveolar fluid clearance in rats treated with a β-agonist (70). Interestingly, since cAMP was only minimally increased in isolated alveolar type II cells exposed to TGF-α, it is possible that the TGF-α effect is mediated by an alternative signal transduction pathway that does not require elevation of cAMP. New evidence suggests that cytokines stimulate sodium uptake and alveolar fluid clearance. It is well known that alveolar instillation of endotoxin or exotoxin releases several proinflammatory cytokines from alveolar macrophages. For example, exotoxin A from P. aeruginosa can stimulate alveolar fluid clearance in rats by a catecholamine-independent pathway (71). In another study, instillation of endotoxin from E. coli into the distal air spaces of rats upregulated epithelial sodium transport and alveolar fluid clearance for up to 48 hours by catecholamine-independent mechanisms (72). The mechanisms for the endotoxin effect may depend on release of tumor necrosis factor-α (TNF-α), since a monoclonal antibody against TNF-α inhibited the increase in alveolar fluid clearance that occurred 24 hours after instillation of bacteria into the distal air spaces of the rat lung (73). Another recent study demonstrated that TNF-α could increase alveolar fluid clearance after septic peritonitis in rats (73a). The mechanism that mediates this effect requires further study. Proliferation of alveolar epithelial type II cells may provide another catecholamine-independent mechanism for increasing fluid transport across the alveolar epithelial barrier. Work with bleomycin-injured rat lungs indicate that hyperplasia of alveolar type II cells contributes to increased alveolar fluid clearance, especially in the subacute phase following acute lung injury (74). In addition to an increase in the number of alveolar type II cells, there may also be an oxidant-dependent mechanism that increases the sodium transport capacity of individual type II cells exposed to hyperoxia for several days (75,76), although not all studies of hyperoxia demonstrate this effect (77,78). A recent article summarizes the results of many of the different experimental studies of the effects of hyperoxia on alveolar epithelial fluid transport (79).
IV. Role of Aquaporins in Alveolar Fluid Transport The existence of specialized water transporting proteins had been proposed for many years based on biophysical measurements showing that osmotic water permeability in erythrocytes and certain kidney tubules was high and weakly temperature dependent (40). Evidence from radiation inactivation and expression of heterologous mRNAs in Xenopus oocytes suggested that the putative water channel was an ⬃30kDa protein encoded by a single mRNA. A family of related water-transporting proteins (aquaporins) was subsequently identified over the past 4 years (40,80). Each member of the family is a small (⬃30-kDa), integral membrane protein with 30% to 50% amino acid sequence identity to the major intrinsic protein of lens fiber (MIP), and related proteins from plants, bacteria, and yeast. Hydropathy plots of these proteins are similar, suggesting up to six transmembrane helical segments.
Pulmonary Edema
377
Homology in amino acid sequence between the first and second halves of each protein suggests genesis from tandem, intragenic duplication of a three-transmembrane segment. A. Localization and Distribution of Water Channels in the Lung
The first localization of a water channel in lung was an in situ hybridization study that indicated diffuse expression of CHIP28 (AQP-1) transcript in the perialveolar region (40). Subsequent studies indicate that AQP-1 is expressed primarily in lung endothelium, although there is some expression in alveolar type II cells as well. The next water channel to be identified in the lung was mercurial-insensitive water channel (MIWC, AQP-4) that was cloned from a lung cDNA library. Two other proteins, GLIP (AQP-3) and AQP-5, were cloned from other sources and then found to be expressed in trachea and/or lung. AQP-5 is located on the apical surface of alveolar epithelial type I cells. Over the past 5 years, considerable work has been done by our laboratory to determine the functional significance of these water channels in lung fluid balance. B. Measurement of Water Permeability in the Lung
More than 20 years ago, Effros demonstrated rapid translocation of pure solute-free water into the vascular space following injection of a hypertonic solution into the perfusate of isolated perfused lungs (81). However, direct evidence for the existence of specific transcellular water pathways in the lung was not available until recently, when a combination of molecular, cellular, isolated airway, and whole-lung studies were utilized in our laboratory to test the hypothesis that osmotically driven water movement in the lung occurs across plasma membrane water channels (40). An in situ perfused sheep lung model was utilized to measure transalveolar osmotic water permeability. Intact lungs were perfused continuously with an isosmolar dilute blood solution. Hypertonic fluid (900 mOsm) was instilled bronchoscopically into the airspaces, and the time course of water movement from capillary to airspace was deduced from the dilution of instilled radiolabeled albumin and from air space fluid osmolality (82). In control lungs, osmotically induced water movement was rapid (equilibration half-time ⬃45 sec) and had an apparent Pf of ⬃0.02 cm/sec, similar to that in erythrocytes. Osmotic water permeability in the contralateral lung was inhibited by ⬃70% by HgCl2. These results indicated that mercurialsensitive water channels facilitated the transcellular movement of water between the airspace and capillary compartments in lung. Subsequent to these large animal studies, high osmotic water permeability was found recently in mouse lung utilizing a novel fluorescence method described earlier (40). It has also been possible to measure water permeability across the alveolar barrier in perinatal rabbit lungs (83). Interestingly, osmotic water permeability increased immediately after birth, potentially consistent with the need to reabsorb alveolar fluid in the newborn lung. In addition, the osmotic water permeability of isolated alveolar type I cells is very high, consistent with the hypothesis that the large surface area of these cells functions to move water across the alveolar epithe-
378
Matthay and Sakuma
lium (84). However, in spite of the circumstantial evidence favoring a role for aquaporins in regulating isomolar alveolar fluid transport, studies of aquaporin-1 and -5 knockout mice demonstrated no reduction in the rate of alveolar fluid transport (84a,84b). V.
Alveolar Fluid Transport Under Pathological Conditions
The fluid transport capacity of the alveolar epithelial barrier under pathological conditions, particularly in patients with pulmonary edema and acute lung injury, is of major interest to both basic science and clinical investigators. More than 10 years ago, clinical studies indicated that protein-rich pulmonary edema can be collected from patients with acute lung injury, whereas patients with cardiogenic or hydrostatic pulmonary edema have a significantly lower protein concentration in the edema fluid (43). However, there was no direct information in these clinical studies regarding the contribution of the epithelial barrier to the development or resolution of the alveolar edema. Until recently, pathological studies provided the only direct information regarding the status of the alveolar epithelial barrier in patients with acute lung injury. For example, postmortem studies of patients who die with acute lung injury report diffuse alveolar damage to both the endothelial and epithelial barriers of the lung with protein-rich edema, inflammatory cells, and intra-alveolar exudate, the pathological hallmarks of the pulmonary response to acute lung injury (85). Ultrastructural studies indicate widespread necrosis and denuding of alveolar epithelial type I cells, usually with some evidence of alveolar epithelial type II cell hyperplasia. However, these postmortem studies represent a biased sampling of only the most severe cases of acute lung injury. Other clinical studies indicate that there is considerable heterogeneity in the fluid transport and barrier properties of the alveolar epithelial barrier of patients with acute lung injury (43,86). A. Clinical Studies of Alveolar Epithelial Fluid Transport in Patients
Two properties of the epithelial barrier can be assessed clinically. First, since the epithelial barrier is normally impermeable to protein, the quantity of protein that accumulates in the distal air spaces is a good index of epithelial permeability. Secondly, since concentration of protein in alveolar fluid reflects net clearance of alveolar fluid, measurement of protein concentration in sequential alveolar edema fluid samples provides a physiologic estimate of the ability of the alveolar epithelial barrier to remove edema fluid. In one study, ⬃40% of patients were able to reabsorb some of the alveolar edema fluid within 12 hours of intubation and acute lung injury (43). These patients had a more rapid recovery from respiratory failure and a lower mortality (Fig. 6). In contrast, the patients who had no evidence of net reabsorption of alveolar edema fluid in the first 12 hours following acute lung injury had protracted respiratory failure and a higher mortality. Based on clinical studies, the ability of the alveolar epithelial barrier to reabsorb alveolar edema fluid from acute lung injury within the first 12 hours after acute lung injury is preserved in 30% to 40% of patients (43).
Pulmonary Edema
379
Figure 6 The concentration (mean ⫾ SD) of protein in the alveolar edema fluid obtained from patients with acute lung injury. The initial sample was obtained within 1/2 hour of endotracheal intubation; the subsequent sample was obtained within 12 hours after intubation. Patients were classified into group A if their alveolar edema fluid protein concentration increased by 10% or more above their initial value, thus indicating net alveolar fluid clearance. Patients in group A had a more rapid recovery from respiratory failure and a lower mortality than patients in group B, suggesting that intact alveolar fluid transport mechanisms in the early phase of acute lung injury provide a favorable prognostic indicator. (From Ref. 43.)
B. Experimental Studies of Alveolar Fluid Transport in Acute Lung Injury
Many experimental studies have provided new insights into the function of the alveolar epithelial barrier under clinically relevant pathological conditions. In each of the studies, the primary focus was to assess the net fluid transport capacity of the alveolar and distal airway epithelium under specific physiologic stresses as well as well-defined pathological insults. Interestingly, the results indicate that the alveolar epithelium is remarkably resistant to injury, particularly compared to the adjacent lung endothelium. Even when mild to moderate alveolar epithelial injury occurs, the capacity of the alveolar epithelium to transport salt and water is often preserved. In addition, several mechanisms may result in an upregulation of the fluid transport capacity of the distal pulmonary epithelium, even after moderate to severe epithelial injury. The first evidence demonstrating the resistance of the alveolar epithelial barrier to injury evolved from studies in which large numbers of neutrophils and mono-
380
Matthay and Sakuma
Pulmonary Edema
381
cytes crossed the tight alveolar epithelial barrier without inducing a significant change in either permeability to protein or the transport capacity of the alveolar epithelium. Instillation of autologous serum or plasma into the distal airspaces of sheep was associated with an influx of neutrophils and monocytes. Despite the influx of inflammatory cells, there was no increase in epithelial permeability to plasma protein; in addition, alveolar fluid clearance was normal (41). In a subsequent study, in normal human volunteers, large numbers of neutrophils were recruited to the distal air spaces by instillation of the potent neutrophil chemotactic factor, leukotriene B4, without influx of plasma protein into the air spaces (87). Instillation of a hyperosmolar solution (seawater) into rabbit lungs caused a rapid translocation of a large volume of water into the distal airspaces as well as the influx of large numbers of neutrophils (88). However, there was only a transient change in epithelial permeability to protein. Moreover, after osmotic equilibration occurred, the rate of alveolar sodium and fluid transport was normal in rabbits (88) and in one well-described clinical case (89). Finally, recent data indicate that alveolar epithelial transport mechanisms in the human lung are not altered by 6 to 8 hours of severe hypothermia (7°C) followed by rewarming to 37°C (90). Even when lung endothelial injury occurs, the alveolar epithelial barrier may remain normally impermeable to protein and retain its normal fluid transport capacity. For example, intravenous endotoxin or bacteria have been used to produce lung endothelial injury in sheep (91) or rats (92), but permeability to protein across the lung epithelial barrier was not increased. When septic shock was produced in rats, there was a marked increase in plasma epinephrine levels. Even though there was endothelial injury and mild interstitial pulmonary edema, alveolar epithelial fluid transport was increased from 45% over 4 hours in control rats to 75% over 4 hours in the septic rats. The effect was inhibited with instillation of amiloride (10⫺4 M) or propranolol (10⫺4 M) into the distal airspaces, proving that the stimulated clearance depended on β-agonist stimulation of alveolar epithelial sodium transport. When more severe septic shock was produced in sheep, the alveolar epithelial barrier was
Figure 7 (A) Alveolar liquid clearance was measured by increase in alveolar protein concentration (final-to-instilled protein concentration ratio) in aspirated fluid from distal air spaces in sheep with normal left atrial pressures with and without salmeterol. (B) Alveolar liquid clearance was significantly increased in animals treated with aerosolized salmeterol (* P ⬍ .05). (C) Lung lymph flow in sheep with aerosolized salmetrol. Lung liquid clearance was also significantly increased by aerosolized salmeterol (䊉) and in control sheep with aerosolized NaCl (䊊). The arrow indicates instillation of 5% albumin solution into distal air spaces. Lung lymph flow tended to increase more in salmeterol-treated sheep than in control sheep, although difference did not reach statistical significance. (D) Lung lymph-to-plasma ratios in sheep with aerosolized salmeterol (䊉) and in control sheep with aerosolized NaCl (䊊). The lymph-to-plasma protein ratio was significantly less in salmeterol-treated sheep from 90 to 150 min in the study (P ⬍ .05). The lung lymph-to-plasma protein ratio decreased significantly more with aerosolized salmeterol than in control sheep. Data are mean ⫾ SD. (From Ref. 68.)
382
Matthay and Sakuma
resistant to injury in the majority of sheep with confinement of the edema to the pulmonary interstitium (93). In some sheep, however, more severe systemic and pulmonary endothelial injury was associated with alveolar flooding, a marked increase in epithelial permeability to protein, and the inability to transport fluid from the airspaces of the lung. The inability to remove excess fluid from the airspaces in these sheep may be related more to a marked increase in paracellular permeability from injury to the epithelial tight junctions rather than to a loss of salt and water transport capacity of alveolar epithelial cells. In some experimental studies, such as acid aspiration induced lung injury (94), the injury to the epithelial barrier is so severe that recovery does not occur. In other types of severe lung injury, as occurs from intravenous oleic acid, the initial injury to the tight junctions results in severe alveolar flooding, although recovery may occur within a few hours, presumably from reestablishment of the normal tight barrier characteristics of the alveolar barrier (19). A similar pattern of severe injury may develop in animal models of pneumonia in which large numbers of virulent bacteria are used, although studies with less virulent bacteria are associated with less epithelial injury and a preserved capacity to transport fluid from the distal airspaces of the lung (95). Although much has been learned about the resistance of the alveolar epithelial barrier to injury and its capacity for preserved transport function after injury, more work is needed to understand the local and systemic factors that regulate sodium and water transport across the alveolar epithelium under pathological conditions. Upregulation of alveolar fluid clearance from endogenous β-adrenergic stimulation has been clearly demonstrated in several clinically relevant animal models (40). Aerosolized β-adrenergic agonist therapy can upregulate alveolar fluid clearance in sheep with normal left atrial pressure (Fig. 7) (68) as well as in the resolution of hydrostatic edema (68a). Recent evidence indicates that alveolar fluid clearance can be stimulated with exogenous β-agonist therapy in the presence of lung injury (96,97,98). New evidence suggests that alveolar epithelial type II cell hyperplasia can be associated with a sustained upregulation of alveolar epithelial fluid clearance, an important potential mechanism in the recovery phase following acute lung injury (99,100,101). VI. Summary Several studies have established that transport of sodium from the airspaces to the lung interstitium is the primary mechanism driving alveolar fluid clearance. While there are significant differences among species in the basal rates sodium and fluid transport, the basic mechanism depends on sodium uptake by channels on the apical membrane of alveolar type II cells followed by extrusion of sodium on the basolateral surface by the Na,K-ATPase. This process can be upregulated by several catecholamine-dependent and -independent mechanisms. The identification of water channels expressed in lung, together with the high water permeabilities, suggests a role for rapid channel-mediated water movement between the airspace and capillary compartments to accompany the net fluid transport.
Pulmonary Edema
383
The application of this new knowledge regarding salt and water transport in alveolar epithelium to pathological conditions has been successful in clinically relevant experimental studies, as well as in a few clinical studies. The studies of exogenous and endogenous catecholamine regulation of alveolar fluid clearance are a good example of how new insights into the basic mechanisms of alveolar sodium and fluid transport can be translated to clinically relevant experimental studies. Exogenous catecholamines can increase the rate of alveolar fluid clearance in several species, including the human lung, and it is also apparent that release of endogenous catecholamines can upregulate alveolar fluid clearance in animals with septic or hypovolemic shock. It is possible that therapy with beta adrenergic agonists might be useful to accelerate the resolution of alveolar edema in some patients. In some patients, the extent of injury to the alveolar epithelial barrier may be too severe for β-adrenergic agonists to enhance the resolution of alveolar edema, although some experimental studies indicate that alveolar fluid clearance can be augmented in the presence of moderately severe lung injury. More clinical research is needed to evaluate the use of exogenous β-adrenergic agonists in patients with pulmonary edema and the conditions that predispose to the development of acute lung injury. Acknowledgments This work was supported in part by NIH grants HL51854 and HL51856. References 1.
Matthay MA, Tibayan F. Mechanisms for the formation and reabsorption of pulmonary edema. In: Cansentina AM, Martin RJ, eds. Cardiothoracic Interrelationships in Clinical Practice 1997:31–53. 2. Matthay MA, Flori HR, Conner ER, Ware LB. Alveolar epithelial fluid transport: Basic mechanisms and clinical relevance. Proceedings of the Association of American Physicians 1998; 110(6):496–505. 3. Staub NC. The pathogenesis of pulmonary edema. Prog Cardiovasc Dis 1980; 23:53–80. 3a. Murray JA. The normal lung. Philadelphia: WB Saunders, 1976. 4. Howell JBL, Permutt S, Proctor DF, et al. Effect of inflation of the lungs on different parts of the pulmonary vascular bed. J Appl Physiol 1961; 16:71–76. 5. Staub NC, Nagano H, Pearce MC. Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol 1967; 22:227–240. 6. Bhattacharya J, Staub NC. Direct measurement of microvascular pressures in the isolated perfused dog lung. Science 1980; 210:327–328. 7. Gee MH, Williams DO. Effect of lung inflation on perivascular cuff fluid volume in isolated dog lung lobes. Microvasc Res 1979; 19:209–216. 8. Coats G, O’Brodovich H, Jeffries AL, et al. Effects of exercise on lung lymph flow in sheep and goats during normoxia and hypoxia. J Clin Invest 1984; 74:133–141. 9. Matthay MA. Pathophysiology of pulmonary edema. Clin Chest Med 1985; 6:301–314. 10. Hakim TS, Venderzee H, Malik AB. Effects of sympathetic nerve stimulation on lung fluid and protein exchange. J Appl Physiol 1979; 47:1025–1030. 11. Albert RK, Lakshminarayan S, Hilkebrandt J, et al. Increased surface tension favors pulmonary edema formation in anesthetized dogs’ lungs. J Clin Invest 1979; 63:1015–1016. 12. Nieman GF, Bredenberg CE. High surface tension pulmonary edema induced by detergent aerosol. J Appl Physiol 1985; 58:129–136.
384
Matthay and Sakuma
12a. Erdmann A, Vaughan T, Brigham K, Woolverton W, Staub NC. Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ Res 1975; 37:271–284. 13. Bongard FS, Matthay MA, Mackensie RC, et al. Morphologic and physiologic correlates of increased extravascular lung water. Surgery 1984; 96:395–403. 14. Gee MH, Spath JA. The dynamics of lung fluid filtration system in dogs with edema. Circ Res 1980; 46:796–801. 15. Vreim CF, Snashall PD, Demling RH, et al. Lung lymph and free interstitial fluid protein composition in sheep with edema. J Appl Physiol 1976; 230:1650–1653. 16. Vreim CF, Staub NC. Protein composition of lung fluids in acute alloxan edema in dogs. Am J Physiol 1976; 230:376–379. 17. Matthay MA, Eschenbacher WC, Goetzl EJ. Elevated concentrations of leukotriene D4 in pulmonary edema fluid of patients with the adult resiratory distress syndrome. J Clin Immunol 1984; 4:479–483. 18. Aberle D, Wiener-Kronish JP,Webb R, et al. The diagnosis of hydrostatic versus increased permeability pulmonary edema based on chest radiographic criteria in critically ill patients. Radiology 1988; 168:73–79. 19. Wiener-Kronish JP, Broaddus VC, Albertine KH, Gropper MA, Matthay MA, Staub NC. Relationship of pleural effusions to increased permeability pulmonary edema in anesthetized sheep. J Clin Invest 1988; 82:1422–1429. 20. Ohkuda K, Nakahara K, Binder A, et al. Venous air emboli in sheep: reversible increase in lung vascular permeability. J Appl Physiol 1981; 51:887–894. 21. Heflin AC, Brigham KL. Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest 1981; 68:1253–1260. 21a. Brigham K, Woolverton W, Blare L, Staub NC. Increased sheep lung vascular permeability caused by Pseudomonas bacteremia. J Clin Invest 1974; 54:792–804. 22. Landolt CC, Matthay MA, Albertine KH, et al. Overperfusion, hypoxia, and increased pressure caused only by hydrostatic pulmonary edema in anesthetized sheep. Circ Res 1983; 52:335–341. 23. Gibbon JH Jr, Gibbon MH. Experimental pulmonary edema following lobectomy and plasma infusion. Surgery 1942; 12:694–704. 24. Hultgren HN. High altitude pulmonary edema. In: Matthay MA, Ingbar DH, eds. Pulmonary Edema. New York: Marcel Dekker, 1998:355–378. 25. Bachofen H, Schurch S, Michel RP, et al. Experimental hydrostatic pulmonary edema in rabbit lungs: Morphology. Am Rev Respir Dis 1993; 147:989–996. 26. Bachofen H, Schurch S, Michel RP, et al. Experimental hydrostatic pulmonary edema in rabbit lungs: barrier lesions. Am Rev Respir Dis 1993; 147:997–1004. 27. West JB, Tsukimoto K, Mathieu-Costello O, et al. Stress failure in pulmonary capillaries. J Appl Physiol 1991; 70:1731–1742. 28. Fu X, Costello ML, Tsukimoto K, et al. High lung volume increases stress failure in pulmonary capillaries. J Appl Physiol 1992; 73:123–133. 29. West JB, Mathieu CO. High altitude pulmonary edema is caused by stress failure of pulmonary capillaries. Int J Sports Med 1992; S54. 30. Bartsch P, Maggiorini M, Ritter M, et al. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 1991; 325:1284. 31. Colice GL, Matthay MA, Bass E, et al. Neurogenic pulmonary edema. Am Rev Respir Dis 1984; 5:43–50. 32. Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest 1997; 111:1326–1333. 33. Prewitt RM, McCarthy J, McCarthy LDH. Treatment of acute low pressure pulmonary edema in dogs. J Clin Invest 1981; 67:409–418. 34. Matthay MA, Broaddus VC. Fluid and hemodynamic management in acute lung injury. Sem Respir Med 1994; 15:271–288. 35. Unger KM, Shibel EM, Moser KM. Detection of left ventricular failure in patients with the adult respiratory distress syndrome. Chest 1975; 67:8–13. 36. Cohen AB, Steven MD, Miller EJ, et al. Neutrophil-activating peptide-2 in patients with pulmonary edema from congestive heart failure or ARDS. Am J Physiol 1993; 264:L490– L495.
Pulmonary Edema 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61.
385
Staub NC. Pulmonary edema. Physiol Rev. 1974; 54:678–811. Taylor AE, Guyton AC, Bishop VS. Permeability of the alveolar epithelium to solutes. Circ Res 1965; 16:353–362. Berthiaume Y, Broaddus VC, Gropper MA, Tanita T, Matthay MA. Alveolar liquid and protein clearance from normal dog lungs. J Appl Physiol 1988; 65:585–593. Matthay MA, Folkesson HG, Verkman AS. Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol (Lung Cell Mol Physiol) 1996; 270: L487–L503. Matthay MA, Berthiaume Y, Staub NC. Long-term clearance of liquid and protein from the lungs of unanesthetized sheep. J Appl Physiol 1985; 59:928–934. Matthay MA, Landolt CC, Staub NC. Differential liquid and protein clearance from the alveoli of anesthetized sheep. J Appl Physiol 1982; 53:96–104. Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 1990; 142:1250–1257. Serikov VB, Grady M, Matthay MA. Effect of temperature on alveolar liquid and protein clearance in an in situ perfused goat lung. J Appl Physiol 1993; 75:940–947. Sakuma T, Pittet JF, Jayr C, Matthay MA. Alveolar liquid and protein clearance in the absence of blood flow or ventilation in sheep. J Appl Physiol 1993; 74:176–185. Jayr C, Garat C, Meignan M, Pittet J-F, Zelter M, Matthay MA. Alveolar liquid and protein clearance in anesthetized ventilated rats. J Appl Physiol 1994; 76:2636–2642. Smedira N, Gates L, Hastings R, Jayr C, Sakuma T, Pittet J-F, Matthay MA. Alveolar and lung liquid clearance in anesthetized rabbits. J Appl Physiol 1991; 70:1827–1835. Basset G, Crone C, Saumon G. Fluid absorption by rat lung in situ: pathways for sodium entry in the luminal membrane of alveolar epithelium. J Physiol (Lond) 1987; 384:325– 345. Crandall ED, Brown SES, Heming TH, Palombo RL, Goodman BE. Effect of terbutaline on sodium transport in isolated perfused rat lung. J Appl Physiol 1986; 60:289–294. Effros RM, Mason GR, Hukkanen J, Silverman P. New evidence for active sodium transport from fluid-filled rat lungs. J Appl Physiol 1988; 66:906–919. Basset G, Crone C, Saumon G. Significance of active ion transport in transalveolar water absorption: a study on isolated rat lung. J Physiol (Lond) 1987; 384:311–324. Berthiaume Y, Staub NC, Matthay MA. Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep. J Clin Invest 1987; 79:335–343. Garat C, Carter EP, Matthay MA. New in situ mouse model to quantify alveolar epithelial fluid clearance. J Appl Physiol 1998; 84:1763–1767. Sakuma T, Folkesson HG, Suzuki S, Okaniwa G, Fujimura S, Matthay MA. Beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am J Respir Crit Care Med 1997; 155:506–512. Verghese GM, Daniel B, Kallet R, Tibayan F, Matthay BA, Matthay MA. Maximal alveolar fluid clearance rates are high in resolution of clinical hydrostatic pulmonary edema (abstract). Am J Respir Crit Care Med 1997; 155:A322. Crapo JD, Young SL, Fram EK, Pinkerton KE, Barry BE, and Crapo RO. Morphometric characteristics of cells in the alveolar region of mammalian lungs. Am Rev Respir Dis 1983; 128:S42–S46. Brown MJ, Olver RE, Ramsden CA, Strang LB, and Walters DV. Effects of adrenaline and of spontaneous labour on the secretion and absorption of lung liquid in the fetal lamb. J Physiol (Lond) 1983; 344:137–152. Walters DV, Olver RE. The role of catecholamines in lung liquid absorption at birth. Pediatr Res 1978; 12:239–242. Finley N, Norlin A, Baines DL, Folkesson HG. Alveolar epithelial fluid clearance is mediated by endogenous catecholamines at birth in guinea pigs. J Clin Invest 1998; 101:972– 981. Goodman BE, Brown SE, Crandall ED. Regulation of transport across pulmonary alveolar epithelial cell monolayers. J Appl Physiol 1984; 57:703–710. Matalon S, Benos DJ, Jackson RM. Biophysical and molecular properties of amiloride– inhibitable sodium channels in alveolar epithelial cells. Am J Physiol 1996; 271: L1– L22.
386 62.
Matthay and Sakuma
Effros RM, Mason GR, Sietsema K, Silverman P, Hukkanen J. Fluid reabsorption and glucose consumption from edematous rat lungs. Circ Res 1987; 60:708–719. 63. Goodman BE, Kim KJ, Crandall ED. Evidence for active sodium transport across alveolar epithelium of isolated rat lung. J Appl Physiol 1987; 62:2460–2466. 64. Goodman BE, Anderson JL, Clemens JW. Evidence for regulation of sodium transport from airspace to vascular space by cAMP. Am. J. Physiol 1989; 257:L86–L93. 65. Berthiaume Y, Sapijaszko M, MacKenzie J, Walsh MP. Protein kinase C activation does not stimulate lung liquid clearance in anesthetized sheep. Am Rev Respir Dis 1991; 144: 1085–1090. 66. McDonald JV Jr, Gonzales LW, Ballard PL, Pitha J, Roberts JM. Lung beta-adrenoreceptor blockade affects perinatal surfactant release but not lung water. J Appl Physiol 1986; 60: 1727–1733. 67. Norlin A, Finley N, Abedinpour P, Folkesson HG. Alveolar liquid clearance in the anesthetized ventilated guinea pig. Am J Physiol 1998; 274:L235–L243. 68. Campbell A, Folkesson HG, Berthiaume Y, Gutkowska J, Suzuki S, Matthay MA. Alveolar epithelial fluid clearance persists in the presence of moderate left atrial hypertension in sheep. J Appl Physiol 1999; 86:139–151. 68a. Frank J, Wang Y, Osorio O, Matthay MA. Beta agonists therapy enhances alveolar fluid clearance during the resolution of hydrostatic edema in sheep and rats. J Appl Physiol 2000; 89:1255–1265. 69. Borok Z, Hami A, Danto SJ, Lubman RL, Kim K-J, Crandall, ED. Effects of EGF on alveolar epithelial junctional permeability and active sodium transport. Am J Physiol 1996; 270:L559–L565. 70. Folkesson HG, Pittet J-F, Nitenberg G, Matthay MA. Transforming growth factor-a increases alveolar liquid clearance in anesthetized, ventilated rats. Am J Physiol (Lung Cell Mol Physiol) 1996; 271:L236–L244. 71. Pittet JF, Hashimoto S, Pian M, McElroy M, Nitenberg G, Wiener-Kronish JP. Exotoxin A stimulates fluid reabsorption from distal airspaces in anesthetized rats. Am J Physiol 1996; 270:L232–L241. 72. Garat C, Rezaiguia S, Meignan M, d’Ortho MP, Harf A, Matthay MA, Jayr C. Alveolar endotoxin increases alveolar liquid clearance in rats. J Appl Physiol 1995; 79:2021–2028. 73. Rezaiguia S, Garat C, Delclaux C, Meignan M, Matthay MA, Jayr C. Acute bacterial pneumonia in rats increases alveolar epithelial fluid clearance by a tumor necrosis factora dependent mechanism. J Clin Invest 1997; 99:325–335. 73a. Borjesson A, Norcin A, Wang X, Andersson R, Folkesson HG. TNF-α stimulates alveolar liquid clearance during intestinal ischemia-reperfusion in rats. Am J Physiol (Cell and Mol) 2000; 273:L3–L12. 74. Nitenberg G, Folkesson HG, Osorio O, Cohen-Solal JM, Matthay MA. Alveolar epithelial liquid clearance is markedly increased 10 days following acute lung injury from bleomycin (abstract). Am J Respir Crit Care Med 1995; 151:A620. 75. Nici L, Dowin R, Gilmore-Hebert M, Jamieson JD, Ingbar DH. Upregulation of rat lung Na-K-ATPase during hyperoxic injury. Am J Physiol 1991; 261:L307–L314. 76. Yue G, Russell WJ, Benos DJ, Jackson RM, Olman MA, Matalon S. Increased expression and activity of sodium channels in alveolar type II cells of hyperoxic rats. Proc Natl Acad Sci USA 1995; 92:8418–8422. 77. Olivera W, Ridge K, Wood LD, Sznajder JI. Active sodium transport and alveolar epithelial Na-K-ATPase increase during subacute hyperoxia in rats. Am J Physiol 1994; 266:L577– L584. 78. Sznajder JI, Olivera WG, Ridge KM, Rutschman DH. Mechanisms of lung liquid clearance during hyperoxia in isolated rat lungs. Am J Respir Crit Care Med 1995; 151:1519–1525. 79. Zheng LP, Du RS, Goodman BE. Effects of acute hyperoxic exposure on solute fluxes across the blood-gas barrier in rat lungs. J Appl Physiol 1997; 82:240–247. 80. Agre P, Preston GM, Smith BL, Jung JS, Raina S, Moon C, Guggino WB, Nielsen S. Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol 1993; 265:F463– F476. 81. Effros RM. Osmotic extraction of hypotonic fluid from the lungs. J Clin Invest 1974; 5: 935–947. 82. Folkesson HG, Matthay MA, Hasegawa H, Kheradmand F, Verkman AS. Transcellular
Pulmonary Edema
387
water transport in lung alveolar epithelium through mercury-sensitive water channels. Proc Natl Acad Sci USA 1994; 91:4970–4974. 83. Carter EP, Umenishi F, Matthay MA, Verkman AS. Developmental changes in water permeability across the alveolar barrier in perinatal rabbit lung. J Clin Invest 1997; 100:1071– 1078. 84. Dobbs L, Gonzalez R, Matthay MA, Carter EP, Verkman AS. Highly water-permeable type I alveolar epithelial cells confer high transalveolar water permeability in rat lung. Proc Natl Acad Sci USA 1998; 95:2991–2996. 84a. Bai C, Fukuda N, Song Y, Ma T, Matthay MA, Verkman AS. Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice. J Clin Invest 1999; 103:555–561. 84b. Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS. Lung fluid transport in aquaporin5 knockout mice. J Clin Invest 2000; 105:93–100. 85. Fukuda YM, Ishizaki M, Masuda Y, Kimura G, Kawanami O, Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol 1987; 126:171–182. 86. Hastings RH, Grady M, Sakuma T, and Matthay MA. Clearance of different-sized proteins from the alveolar space in humans and rabbits. J Appl Physiol 1992; 73:1310–1316. 87. Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 1989; 84:1609–1619. 88. Folkesson HG, Kheradmand F, Matthay MA. The effect of salt water on alveolar epithelial barrier function. Am J Respir Crit Care Med 1994; 150:1555–1563. 89. Cohen DS, Matthay MA, Cogan MG, Murray JF. Pulmonary edema associated with salt water near-drowning: new insights. Am Rev Respir Dis 1992; 146:794–796. 90. Sakuma T, Suzuki S, Usuda K, Handa M, Okaniwa G, Nakada T, Fujimura S, Matthay MA. Preservation of alveolar epithelial fluid transport mechanisms in the rewarmed human lung after severe hypothermia. J Appl Physiol 1996; 80:1681–1686. 91. Wiener-Kronish JP, Albertine KH, Matthay MA. Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest 1991; 88:864–875. 92. Pittet J-F, Wiener-Kronish JP, McElroy MC, Folkesson HG, Matthay MA. Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats. J Clin Invest 1994; 94:663–671. 93. Pittet JF, Wiener-Kronish JP, Serikov V, Matthay MA. Resistance of the alveolar epithelium to injury from septic shock in sheep. Am J Respir Crit Care Med 1995; 151:1093– 1100. 94. Folkesson HG, Matthay MA, He´bert CA, Broaddus VC. Acid aspiration induced lung injury in rabbits is mediated by interleukin-8 dependent mechanisms. J Clin Invest 1995; 96:107–116. 95. Wiener-Kronish JP, Sakuma T, Kudoh I, Pittet JF, Frank D, Dobbs L, Vasil ML, Matthay MA. Alveolar epithelial injury and pleural empyema in acute P. aeruginosa pneumonia in anesthetized rabbits. J Appl Physiol 1993; 75:1661–1669. 96. Garat C, Meignan M, Matthay MA, Luo DF, Jayr C. Alveolar epithelial fluid clearance mechanisms are intact after moderate hyperoxic lung injury in rats. Chest 1997; 111: 1381– 1388. 97. Lasnier JM, Wangenstein OD, Schmitz LS, Ingbar DL. Terbutaline stimulates alveolar fluid resorption in hyperoxic lung injury. J Appl Physiol 1996; 81:1783–1789. 98. Sznajder JJ. Strategies to increase alveolar epithelial fluid removal in the injured lung. Am J Resp Crit Care Med 1999; 160:1441–1442. 99. Folkesson HG, Nitenberg G, Oliver BL, Jayr C, Albertine KH, Matthay MA. Upregulation of alveolar epithelial fluid transport after subacute lung injury in rats from bleomycin. APS 1998; 275:L487–L490. 100. Guery B, Mason C, Dobard E, Beaucaire G, Summer W, Nelson S. Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs. Am J Resp Crit Care Med 2000; 155:1777–1784. 101. Wang Y, Folkesson H, Jayr C, Ware C, Matthay M. Alveolar epithelial fluid transport can be simultaneously upregulated by both KGF and β-agonist therapy. J Appl Physiol 2000; 87:1852–1860.
14 Respiratory-Circulatory Interactions in Obstructive Sleep Apnea
VIREND K. SOMERS and MIKOLAJ WINNICKI Mayo Clinic Rochester, Minnesota
I.
KRZYSZTOF NARKIEWICZ Medical University of Gdansk Gdansk, Poland
Introduction
There is increasing recognition of the widespread prevalence of obstructive sleep apnea and the implications of sleep apnea for understanding the pathophysiology of cardiac and vascular disease (1,2). Obstruction of the upper airway during sleep results in striking changes in neural and circulatory measurements. Consequent disturbances in cardiovascular control may persist into the daytime with abnormalities in neural control evident even during normoxic daytime wakefulness. Abnormalities in cardiac and vascular function during sleep and wakefulness in patients with obstructive sleep apnea speak directly to the importance of interactions between respiration and neural circulatory control in these patients. Sleep apnea elicits hypoxia and hypercapnia, secondary to obstructed breathing during sleep. This review will seek to examine briefly the individual responses to hypoxemic and hypercapnic chemoreflex activation, the Mueller maneuver (obstructed breathing) and sleep in normal humans. Because of the pressor responses to sleep apnea and because of the significance of baroreflex-chemoreflex interactions, the potential contribution of the arterial baroreflexes will also be explored, as will the possible influence of hypertension (which is highly prevalent in sleep apnea). We will then outline those abnormalities in neural circulatory control that are present 389
390
Somers et al.
in otherwise normal patients with obstructive sleep apnea. Last, we will review the changes that occur during sleep in obstructive sleep apnea, the reflex mechanisms mediating these changes, and the effects of treatment. This review will focus mainly on studies in humans. Relevant animal data are addressed comprehensively in the companion chapters. II. Chemoreflex Responses to Hypoxemia, Hypercapnia, and Apnea The peripheral chemoreflexes located in the carotid bodies respond primarily to hypoxemia (3,4). The response to hypoxemia consists of hyperventilation, tachycardia, and increases in sympathetic vasoconstrictor activity (5,6). By activating pulmonary afferents, hyperventilation inhibits or buffers the sympathetic response to hypoxemia (6). During apnea, when the inhibitory influence of the pulmonary afferents is eliminated, there is loss of this inhibitory effect, and sympathetic vasoconstrictor activity increases dramatically (6). This vasoconstriction has direct and predictable pressor effects. Cessation of breathing during apnea also elicits the primary cardiac response to peripheral chemoreflex activation, namely, bradycardia (7,8). Sympathetic vasoconstriction and vagal bradycardia constitute part of what is generally known as the diving reflex (7,8). In brief, the absence of lung inflation together with hypoxemia results in withdrawal of cardiac sympathetic activity and increased cardiac vagal activity, eliciting cardiac slowing with often profound bradycardia and heart block. Coexisting stimuli such as irritation of the upper airway would potentiate the vagally mediated bradycardia. Sympathetic vasoconstriction occurs in muscle, renal and mesenteric beds. Note that this is a unique response wherein there is simultaneous activation of cardiac vagal and vascular sympathetic activity. In effect this diving response redirects blood flow towards the heart and the brain, two organs in which the sympathetic vasoconstrictor response to hypoxia and apnea is not present. Hypercapnia also elicits increased ventilation and increased sympathetic activation to peripheral blood vessels (9). Hypercapnia acts primarily via the central chemoreceptors located in the brainstem (10). Nevertheless, there is a small component of the hypercapnic response which is mediated via the peripheral chemoreceptors. In comparison to hypoxia, hypercapnia does not elicit vagally mediated bradycardia as seen during hypoxia. Nevertheless, apnea during hypercapnia (with elimination of hyperventilation) also results in potentiated sympathetic activity, although this is less marked than is seen with hypercapnia (9). This differential interaction between ventilation and sympathetic activation, whereby apnea during hypoxemia increases sympathetic drive more markedly than is seen with apnea during hypercapnia, led to the concept that there was a more direct and preferential interaction between the pulmonary afferents and the peripheral chemoreflex response than between the pulmonary afferents and the central chemoreflex response (9). This may in part be because afferents from the peripheral chemoreceptors and the pulmonary afferents both synapse in anatomically adjacent regions in the nucleus tractus solitarius. In understanding the relevance of these responses to sleep apnea, it is important to recognize that during sleep apnea there is combined simultaneous hypoxemia
Obstructive Sleep Apnea
391
and carbon dioxide retention. Thus, it is important that in normal humans during wakefulness, combined hypoxemia and hypercapnia result in synergistic effects on minute ventilation (9). Sympathetic activation is also greater than either of the individual stimuli alone. The increase in sympathetic activity is especially apparent when the inhibitory influence of ventilation is eliminated by apnea. Note that all the responses described above have been characterized in normal healthy humans during wakefulness. Nevertheless, subsequent studies in patients with sleep apnea during sleep suggest that these responses in healthy awake humans have direct relevance to understanding the respiratory-neural-circulatory interactions that are operative in patients during obstructive apneic events. III. The Mueller Maneuver A primary component of obstructive apnea is inspiration against an obstructed airway. This inspiration against a closed airway is also known as the Mueller maneuver. This maneuver is important to understanding sleep apnea because of the profound changes induced in the configuration of intrathoracic structures, and consequent neural and hemodynamic effects. Inspiration against an obstructed airway generates marked negative intrathoracic pressure, resulting in distortion of cardiac configuration (11,12). In studies in normal subjects exposed to 20 sec of inspiration against a closed airway, the Mueller maneuver elicited an initial dramatic reduction in blood pressure with paradoxical decreases in sympathetic activity and no increase in heart rate (13). Towards the second half of the Mueller maneuver, sympathetic activity increased gradually as did blood pressure. This differential interaction at different phases of the Mueller maneuver is not fully understood. One possibility is that distortion of the cardiac chambers may activate vasodepressor and sympathetic inhibitory afferents that are located in the inferoposterior wall of the left ventricle. These receptors have generally been linked to the Bezold-Jarisch reflex. During actual obstructive sleep apnea, multiple repeated Mueller maneuvers are carried out during any given apnea. The sympathetic inhibitory response to the early phase of a Mueller maneuver superimposed on changes in ventricular loading conditions may hence explain the dramatic beat-by-beat fluctuations in blood pressure that are evident during apneic events. IV. Baroreflex-Chemoreflex Interactions The arterial baroreflexes, located in the carotid sinuses, respond to increases in blood pressure. They seek to maintain blood pressure stability by modulating heart rate and vascular resistance. Animal studies have demonstrated that activation of the arterial baroreceptors inhibits the ventilatory and vasoconstrictor responses to peripheral chemoreflex activation (14). Studies in humans have confirmed an interaction between the chemoreflex responses to hypoxemia and baroreflex activation (15). In other words, activation of the baroreflexes markedly inhibits the sympathetic response to peripheral
392
Somers et al.
chemoreflex activation. This interaction appears to differentially affect peripheral, as compared to central, chemoreflex function. The baroreflexes have a much lesser effect on the sympathetic responses to hypercapnia or to a nonspecific stimulus such as the cold pressor test. This differential interaction may be again explained by the anatomical proximity of synapses of the arterial baroreceptor afferents and the peripheral chemoreceptor afferents in the nucleus tractus solitarius. Activation of the baroreflex results in bradycardia. Chemoreflex activation in the setting of apnea also results in bradycardia. When chemoreflex activation and apnea are conducted in a setting of increased baroreflex activation, the bradycardic response is attenuated. Thus, the arterial baroreflex inhibits not only the chemoreflex-mediated sympathetic vasoconstrictor response, but also the vagal bradycardic response (16). The clinical implications are relevant to disease states in which baroreflex function is impaired. These include hypertension and heart failure, and perhaps may also be relevant to premature infants. In these situations, baroreflex function is impaired or immature. Thus, the normal buffering influence of the baroreflex on the chemoreflex is diminished, resulting in excessive potentiation of chemoreflex sensitivity (see Chapter 7). Thus, similar levels of hypoxemic stimulation in these conditions may elicit greater levels of sympathetic activation and/or bradydysrhythmias. V.
Chemoreflex Responses in Hypertension
There is evidence of a strong association between hypertension and obstructive sleep apnea (17,18). Thus, it is important to understand whether hypertension confers any distinct characteristics on the chemoreflex responses to hypoxemia and apnea. Animal studies have suggested that spontaneously hypertensive rats may have potentiated chemoreflex responses (19). Subsequent studies in humans looking at inspiratory drive confirmed that young hypertensive humans had greater inspiratory force in response to hypoxemia than control subjects (20). Evaluation of the sympathetic responses to hypoxemia showed that for a given level of hypoxemic stimulus, young borderline hypertensive subjects had about double the sympathetic response that was seen in closely matched normal control subjects (21). However, it was during apnea that the most compelling features of the hypertensive chemoreflex response were apparent. With apnea during hypoxemia, patients with hypertension had an increase in sympathetic activity about 12-fold the response seen in normal subjects (21). This would suggest that in sleep apnea patients who also have hypertension, the sympathetic vasoconstrictor (and hence the pressor) response would be markedly potentiated. While the mechanism underlying the enhanced chemoreflex response in hypertension is not known, baroreflex-chemoreflex interactions described earlier may be implicated. VI. Neural Circulatory Control in Normal Sleep To appreciate fully the disturbed cardiovascular control in sleep apnea, it is important to compare the neural circulatory profile in apneic sleep with that of normal
Obstructive Sleep Apnea
393
sleep (22–24). Normal sleep is divided into non-REM and REM stages. These classifications represent very heterogeneous states of autonomic activation. In brief, nonREM sleep is divided further into stages I, II, III, and IV, representing progressively deeper stages of sleep, with progressive reductions in blood pressure, heart rate, and sympathetic activity. Thus, it is during stage IV of sleep when blood pressure, heart rate and sympathetic activity are usually at their nadir. REM sleep, by contrast, is a state of neural activation. It is characterized by sporadic rapid eye movements and is the time of sleep when dreams are most likely to occur. In contrast to non-REM sleep, during REM there is marked sympathetic activation with intermittent surges in blood pressure and heart rate. On average, sympathetic activity is about twofold the levels recorded during quiet wakefulness, and blood pressure and heart rate are similar to wakefulness measures. Surges in blood pressure are frequently linked to REM twitches, which are momentary increases in postural muscle tone during REM sleep (24). Arousal stimuli during sleep elicit K-complexes and trigger brief increases in sympathetic activity and consequent increases in blood pressure (22–24).
VII. Neural Circulatory Control in Sleep Apnea A. Studies During Wakefulness
An intriguing and important component of the pathophysiology of sleep apnea has been the persistence of striking abnormalities in cardiovascular control mechanisms during daytime wakefulness, when sleep apnea patients are breathing normally and in the absence of any hypoxemia or carbon dioxide retention. These findings suggest that abnormalities in cardiovascular function may be part of the underlying neural substrate of sleep apnea patients and do not necessarily derive directly from the responses to the apneic events themselves. Alternatively, apneas during sleep elicit very striking increases in autonomic and hemodynamic measures. Repetitive sympathetic and pressor responses during sleep may induce carryover effects that persist into the daytime even when patients are breathing normally. Attempts to understand the extent to which neural circulatory mechanisms are disturbed in normoxic awake sleep apneic patients have been limited considerably by the extensive comorbidities that characterize patients with sleep apnea. These include obesity, hypertension, and heart failure. Furthermore, many sleep apnea patients are often on medications which may themselves affect neural circulatory control. Another limitation is imposed by the unequivocal importance of comparing findings in sleep apnea patients with age-, gender-, and body mass index-matched control subjects. This is especially a problem in matching patients with similar body mass indices. There is a very high prevalence of occult sleep apnea in obese patients, even if these patients have no history of suggestive of significant sleep apnea (25). It therefore follows that it is imperative that those subjects considered as controls for purposes of comparison with sleep apnea patients undergo polysomnographic evaluation to exclude the presence of occult sleep apnea. The abnormalities emphasized below derive primarily from those studies in which the findings in otherwise
394
Somers et al.
healthy sleep apnea patients have been compared to findings obtained in rigorously matched control subjects in whom sleep apnea has been excluded by overnight polysomnographic evaluation. Several studies have demonstrated that patients with sleep apnea have very high levels of sympathetic activity, whether measured as circulating plasma norepinephrine (26) or by direct intraneural recordings using microneurography (27,28). These high levels of sympathetic drive are present in the absence of any oxygen desaturation and in the absence of any other disease states that may explain the high sympathetic drive. It has been suggested that obesity may also be linked to high sympathetic activity (29,30). Thus, obesity may contribute to higher sympathetic drive in sleep apnea. A direct test of this hypothesis, however, showed that obese subjects with high levels of sympathetic activity in fact had occult sleep apnea (31). When only obese subjects in whom sleep apnea had been excluded by polysomnography were considered, sympathetic drive measured using microneurography was not significantly different from that evident in normal-weight subjects. While obesity may be less relevant to high sympathetic drive in sleep apnea, tonic chemoreflex activation may contribute substantially. The peripheral chemoreceptors maintain a significant physiological activity in normoxia, referred to as ‘‘resting drive’’ (32–34). Studies in animals suggest that this tonic chemoreflex resting drive, present even during normoxia, has significant effects on blood pressure and heart rate, probably mediated by sympathetic activation (19). In a double-blind randomized vehicle control study, chemoreflex deactivation using 100% oxygen in patients with sleep apnea resulted in significant decreases in heart rate, blood pressure, and muscle sympathetic nerve activity (MSNA) (35) (Fig. 1). The similar protocol in closely matched normal subjects did not decrease MSNA or blood pressure. Reductions in blood pressure would normally be accompanied by reflex increases in heart rate and sympathetic activity. The simultaneous decrease in all three of these variables suggests that the primary mechanism may be a decrease in sympathetic traffic both to the heart and to peripheral blood vessels, with a consequent blood pressure reduction. Thus, the heightened sympathetic drive and higher blood pressures in patients with sleep apnea may in part be linked to the effects of tonic chemoreflex activation. While direct intraneural sympathetic measurements and plasma norepinephrine are consistent with heightened sympathetic drive in sleep apnea patients, there has been increasing interest in abnormalities in more indirect indices of autonomic function in this patient population. Specifically, abnormalities in sympathetic drive may also be accompanied by impairments in cardiovascular variability. Studies of cardiovascular variability have shown that cardiovascular disease states such as hypertension and heart failure are accompanied by decreases in heart rate variability and, particularly in hypertension, increased blood pressure variability. Decreased heart rate variability in patients with heart failure (36–38), patients with idiopathic dilated cardiomyopathy (39), and patients after myocardial infarction (40–42) appear to be strong and independent prognostic indicators of morbidity and mortality.
Obstructive Sleep Apnea
395
Figure 1 Recordings of muscle sympathetic nerve activity in a single patient with obstructive sleep apnea during administration of 100% oxygen (top) and room air (bottom). Muscle sympathetic nerve activity, mean arterial pressure (MAP) and heart rate (HR) decreased during administration of 100% oxygen but did not change during administration of room air. (From Ref. 36.)
Increased blood pressure variability in hypertension is linked independently to target organ damage (43–45). In studies of time domain measures of cardiovascular variability in patients with obstructive sleep apnea, compared to closely matched healthy control subjects proven to be free of sleep disordered breathing, there was a clear-cut alteration in both heart rate and blood pressure variability in sleep apnea patients (46) (Figs. 2, 3). This was true even though the sleep apnea patients were free of hypertension, heart failure, or other disease states and were not on any medications. Traditional measurements showed that patients with moderate to severe sleep apnea had faster heart rates and increased sympathetic burst frequency (46). RR interval (the interval between heartbeats) variability was reduced, as low as one-third of normal, and blood pressure variability was increased, to about double that in normal subjects. The blood pressure variability was excessive even though absolute blood pressures were very comparable to those of control subjects. These abnormalities in cardiovascular variability in sleep apnea patients are remarkably similar to those evident in overt cardiovascular diseases such as hypertension and heart failure (36–42). It is
396
Somers et al.
Figure 2 ECG, heart rate, blood pressure, sympathetic neurogram, and respiration in a control subject on the left and a patient with severe obstructive sleep apnea (OSA) on the right, showing faster heart rate, increased blood pressure variability and increased sympathetic nerve activity in the sleep apnea patient. The sleep apnea patient had a body mass index very similar to that of the control subject and was free of any other diseases and on no medications. (From Ref. 46.)
important, however, that these patients with sleep apnea had no evidence of cardiovascular disease. Thus, abnormalities in cardiovascular variability may be implicated in the subsequent development of overt cardiovascular disease in patients with obstructive sleep apnea. B. Studies During Sleep
As described earlier, patients with sleep apnea undergo repetitive airway obstructions with consequent profound hypoxia and hypercapnia, all of which occur during sleep. In healthy awake humans, these interventions elicit sympathetic neural vasoconstriction and occasionally vagal bradycardia. Similar responses are evident during sleep in patients with sleep apnea, even though these patients already have very high sympathetic activity, and frequently hypertension, during wakefulness. The organized sleep stage-related changes in neural and hemodynamic measures that are evident during normal sleep are completely disrupted in patients with sleep apnea. Responses to the apneic events overwhelm any sleep stage-related regulatory pattern. It is the duration and severity of apnea that determines the sympathetic and pressor measurements during sleep rather than the sleep stage itself. Apneic events elicit progressive increases in sympathetic activity during apnea (27,28) (Fig. 4). On release of apnea when breathing resumes, there is a tachycardia
Obstructive Sleep Apnea
397
Figure 3 RR interval, systolic blood pressure and their variances in control subjects (n ⫽ 16), patients with mild OSA (n ⫽ 18), and patients with moderate to severe OSA (n ⫽ 15). RR interval was decreased in the patients with moderate to severe sleep apnea compared to control subjects. Patients with mild obstructive sleep apnea and patients with moderate to severe sleep apnea had an attenuated RR variance in comparison with control subjects. Systolic blood pressure variance was markedly increased in patients with moderate to severe OSA compared with either control subjects or patients with mild OSA. *P ⬍ .05 vs. control subjects. †P ⬍ .05 vs. mild OSA. (From Ref. 46.)
and an increase in cardiac output. This increased cardiac output enters a highly vasoconstricted peripheral vasculature with consequent marked increases in blood pressure. During resumption of breathing after apnea, several factors contribute to an abrupt suppression of sympathetic tone. These include breathing and stretch of pulmonary afferents, arousal from sleep with consequent increased muscle tone, baroreflex activation by increased arterial pressure, and attenuation of the hypoxic and hypercapnic stimuli. Thus, there is a pattern of increased sympathetic activity during apnea with abrupt sympathetic inhibition and blood pressure surges at the end of apnea. It is important to recognize that although sympathetic activity is inhibited at the end of apnea, vasoconstriction persists for some time after cessation of norepinephrine release at the neurovascular junction. Thus, blood pressure surges at the end of apnea are evident even though sympathetic neural traffic is inhibited briefly (Fig. 4). This pattern of cyclic surges in sympathetic drive and blood pressure are evident throughout sleep as long as apneas persist. Overall, during sleep there is no reduction in mean blood pressure in patients with severe sleep apnea (28). Sympathetic activity, already high during wakefulness, is on average increased further dur-
398
Somers et al.
Figure 4 Recordings of sympathetic activity, respiration and intra-arterial blood pressure in a patient with sleep apnea on no medications and free of other diseases. Measurements were obtained during wakefulness (top left), during obstructive sleep apnea in REM sleep (bottom), and during REM sleep after treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP). During wakefulness sympathetic activity was high and blood pressure was approximately 130/60 mm Hg. During REM sleep, repetitive apneas resulted in hypoxia and chemoreflex stimulation with consequent sympathetic activation. The vasoconstriction resulting from sympathetic activation causes marked surges in blood pressure, to levels as high as 250/110 mm Hg at the end of apnea, because of increases in cardiac output at termination of apnea. Treatment of sleep apnea and elimination of apneic episodes by CPAP resulted in stabilization and lower levels of both blood pressure and sympathetic activity during REM sleep. (From Ref. 28.)
ing stage II and REM in sleep apnea (28). The heightened sympathetic drive, high levels of circulating norepinephrine, surges in blood pressure to levels as high as 240/130 mm Hg, hypoxemia, and hypercapnia may all interact to induce profound circulatory stress. In patients with abnormal cardiovascular substrates, such as those with preexisting cerebrovascular or coronary occlusive disease, this level of hemodynamic, autonomic, and metabolic derangement may result in compromised cardiovascular function with consequent cardiovascular ischemia and heart failure. A sub-
Obstructive Sleep Apnea
399
set of sleep apnea patients may develop reflex bradycardia and even significant bradyarrhythmias, particularly evident toward the end of apnea. VIII. Effects of Treatment of Sleep Apnea The acute effect of treatment with continuous positive airway pressure (CPAP) is a marked reduction in sympathetic activity and blood pressure surges (28) (Fig. 5). This appears to be related directly to alleviation of apneas and the absence of severe hypoxemia. Nevertheless, even though the autonomic-hemodynamic profile during sleep approaches normality after treatment, the measurements obtained still differ substantially from those evident in normal people during sleep (28). This may be due to one or more of the following. Patients with sleep apnea may have abnormalities in neural control that complement, but are not directly consequent on, repetitive apneic episodes. Alternatively, CPAP may induce its own particular level of hemodynamic stress and airway stimulation with consequent neural and circulatory responses. Chronic treatment with CPAP has been shown to result in an overall reduction in catecholamine levels (47,48). Nevertheless, there is no clear indication of whether blood pressure also decreases significantly. Some studies have reported no change in blood pressure after chronic CPAP treatment (48,49), while other studies have
Figure 5 Recordings of the electrocardiogram (EKG), sympathetic activity (SNA), respiration, and blood pressure in a sleep apneic patient undergoing CPAP therapy during REM sleep. The arrow indicates reduction of CPAP from 8 to 6 cm H2 O, allowing the development of obstructive apnea with consequent increased SNA and BP. In normal humans, BP and SNA are highest during REM sleep. In patients with OSA, apneic events during REM result in further increases in both SNA and BP. (From Ref. 28.)
400
Somers et al.
suggested that treatment with CPAP may lower ambulatory blood pressure (50,51). There is increasing evidence that initiation of CPAP in patients with combined heart failure and obstructive sleep apnea (52) may induce dramatic improvements in cardiac ejection fraction (53,54). IX. Conclusion Sleep apnea represents a disease state that imposes dramatic stressors on the respiratory and cardiovascular system, among others. The metabolic derangements, secondary to airway obstruction and consequent hypoxemia and carbon dioxide retention, have distinct and dramatic effects on neural mechanisms governing cardiovascular function. These effects represent the integrated responses to activation of several reflex mechanisms including the peripheral and central chemoreflexes, the arterial baroreflexes, and possibly the Bezold-Jarisch reflex. It is important to recognize the interaction between these reflexes as well as the interaction between autonomic control and lung inflation. The mechanisms described in this review provide some explanation for the neural circulatory profile evident during apneic events. However, other mechanisms not addressed here may also be operative. These include humoral mediators such as endothelin which may contribute to hypertension and heart failure in sleep apnea through several possible mechanisms. It is also important to recognize that the reasons for persistence of abnormalities in sympathetic activity and cardiovascular variability during daytime wakefulness in sleep apnea patients are poorly understood. It is not known if these abnormalities constitute a consequence of sleep apnea or represent part of the substrate of respiratory-cardiovascular dysfunction in the sleep apnea patient. These abnormalities may precede the development of overt cardiovascular disease in obstructive sleep apnea. Acknowledgments V.K.S. is an Established Investigator of the American Heart Association and is a Sleep Academic Awardee of the National Institutes of Health. His work is also supported by NIH grants HL61560, 60618 and M01-RR-00585. K.N. and V.K.S. are recipients of NIH R03 TWO 1148. K.N. and M.W. are recipients of Fogarty International Fellowships from the NIH. K.N. is also the recipient of a Perkins Memorial Award from the American Physiological Society. We gratefully acknowledge Linda Bang for expert typing of this manuscript. References 1. 2.
Phillipson EA. Sleep apnea—a major public health problem. N Engl J Med 1993; 328: 1271–1273. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230–1235.
Obstructive Sleep Apnea 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
401
Wade JG, Larson Jr CP, Hickey RF, Ehrenfeld WK, Severinghaus JW. Effect of carotid endartectomy on carotid chemoreceptor and baroreceptor function in man. N Engl J Med 1970; 282:823–829. Lugliani RB, Whipp BJ, Seard C, Wasserman K. Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man. N Engl J Med 1971; 285:1105– 1111. Somers VK, Abboud FM. Chemoreflexes—responses, interactions and implications for sleep apnea. Sleep 1993; 16:S30–S34. Somers VK, Zavala DC, Mark AL, Abboud FM. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol 1989; 67: 2095–2100. de Burgh Daly M, Scott MJ. An analysis of the primary cardiovascular reflex effects of stimulation of the carotid body chemoreceptors in the dog. Am J Physiol 1962; 162:555– 573. de Burgh Daly M, Angell-James JE, Elsner R. Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. Lancet 1979; i:764–767. Somers VK, Zavala DC, Mark AL, Abboud FM. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol 1989; 67:2101– 2106. Gelfand R, Lambertsen CJ. Dynamic respiratory response to abrupt change of inspired CO2 at normal and high PO2. J Appl Physiol 1973; 35:903–913. Condos WR, Latham RD, Hoadley SD, Pasipoularidies A. Hemodynamics of the Mueller maneuver in man: right and left heart micromanometry and Doppler echocardiography. Circulation 1987; 76:1020–1028. Scharf SM, Brown R, Warner KG, Khuri S. Intrathoracic pressures and left ventricular configuration with respiratory maneuvers. J Appl Physiol 1989; 66:481–491. Somers VK, Dyken ME, Skinner JL. Autonomic and hemodynamic responses and introduction during the Mueller maneuver in humans. J Auton Nerv Syst 1993; 44:253–259. Heistad DD, Abboud FM, Mark AL, Schmid PG. Interaction of baroreceptor and chemoreceptor reflexes: modulation of the chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest 1974; 53:1226–1236. Somers VK, Mark AL, Abboud FM: Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 1991, 87:1953–1957. Somers VK, Dyken MK, Mark AL, Abboud FM. Parasympathetic hyperresponsiveness and bradyarrhythmias during apnea in hypertension. Clin Auton Res 1992; 2:171–176. Fletcher EC, DeBehnke RD, Lovoi MS, Gorin AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103:190–195. Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997; 157:1746–1752. Przybylski J, Trzebski A, Czyzewski T, Jodkowski J. Responses to hyperoxia, hypoxia, hypercapnia and almitrine in spontaneously hypertensive rats. Bull Eur Physiopathol Respir 1982; 18:145–154. Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res 1982; 16:163–172. Somers VK, Mark AL, Abboud F. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 1988; 11:608–612. Hornyak MM, Cejnar M, Elam M, Matousek M, Wallin BG. Sympathetic muscle nerve activity during sleep in man. Brain 1991; 114:1281–1295. Okada H, Iwase S, Mano T, Sugiyama Y, Watanabe T. Changes in muscle sympathetic nerve activity in sleep during sleep in humans. Neurology 1991; 41:1961–1966. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic nerve activity during sleep in normal humans. N Engl J Med 1993; 328:303–307. Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med 1994; 154:1705–1711. Marrone O, Riccobono L, Salvaggio A, Mirabella A, Bonanno A, Bonsignore MR. Catecholamines and blood pressure in obstructive sleep apnea syndrome. Chest 1993; 103:722–727.
402 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.
Somers et al. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens 1988; 6 (Suppl):S529–S531. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897–1904. Scherrer U, Randin D, Tappy L, Vollenweider P, Je´quier E, Nicod P. Body fat and sympathetic nerve activity in healthy subjects. Circulation 1994; 89:2634–2640. Grassi G, Seravalle G, Cattaneo BM, Bolla GB, Lanfranchi A, Colombo M, Giannattasio C, Brunani A, Cavagnini F, Mancia G. Sympathetic activation in obese normotensive subjects. Hypertension 1995; 25:560–563. Narkiewicz, K., Van de Borne P, Cooley R, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation, 1998; 98:772– 776. Binet L, Dejours P. Le role des chemorecepteurs arteriels dans la controle de la repiration pulmonaire chez l’homme. Arch Int Pharmacodyn 1962; 139:328–335. Loeschke GC. Spielen fu¨r die Ruheatmung des Menschen vom O2-Druck abha¨ngige Erregungen der Chemoreceptoren eine Rolle ? Pfluegers Arch 1953; 257:349–362. Honig A. Peripheral arterial chemoreceptors and reflex control of sodium and water homeostasis. Am J Physiol. 1989; 26:R1282–R1302. Narkiewicz K, Van de Borne PJH, Montano N, Dyken ME, Phillips BG, Somers VK. The contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation 1998; 97:943–945. Saul JP, Arai Y, Berger RD, Lilly LS, Colucci WS, Cohen RJ. Assessment of autonomic regulation in chronic congestive heart failure by spectral analysis. Am J Cardiol 1988; 61: 1292–1299. Guzzetti S, Cogliati C, Turiel M, Crema C, Lombardi F, Malliani A. Sympathetic predominance followed by functional denervation in the progression of chronic heart failure. Eur Heart J. 1995; 16:1100–1117. Van de Borne P, Montano N, Pagani M, Oren R, Somers VK. Absence of low frequency variability of sympathetic nerve activity in severe heart failure. Circulation. 1997; 95:1449– 1454. Fauchier L, Babuty D, Cosnay P, Autret ML, Fauchier JP. Heart rate variability in idiopathic dilated cardiomyopathy—characteristics and prognostic value. J Am Coll Cardiol. 1997; 30:1009–1014. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987; 59: 256–262. Fei L, Copie X, Malik M, Camm AJ. Short- and long-term assessment of heart rate variability for risk stratification after acute myocardial infarction. Am J Cardiol. 1996; 77:681– 684. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: Standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–1065. Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of 24-hour blood pressure variability. J Hypertens 1993; 11:1133–1137. Palatini P, Penzo M, Racioppa A, Zugno E, Guzzardi G, Anaclerio M, Pessina AC. Clinical relevance of nighttime blood pressure and of daytime blood pressure variability. Arch Intern Med. 1992; 152:1855–1860. Van Vliet BN, Hu L, Scott T, Chafe L, Montani JP. Cardiac hypertrophy and telemetered blood pressure 6 wk after baroreceptor denervation in normotensive rats. Am J Physiol. 1996; 271:R1759–R1769. Narkiewicz K, Montano N, Cogliati C, Van de Borne P, Dyken ME, Somers VK. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998; 98:1071–1077. Fletcher EC, Miller J, Schaaf JW, Fletcher JG. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987; 10: 35–44. Hedner J, Darpo B, Ejnell H, Carlson J, Caidahl K. Reduction in sympathetic activity after
Obstructive Sleep Apnea
49. 50. 51. 52. 53. 54.
403
long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J 1995; 8:222–229. Engleman HM, Gough K, Martin SE, Kingshott RN, Padfield PL, Douglas NJ. Ambulatory blood pressure on and off continuous positive airway pressure therapy for the sleep apnea/ hypopnea syndrome: effects in ‘‘non-dippers.’’ Sleep 1996; 19(5):378–381. Suzuki M, Otsuka K, Guilleminault C. Long-term nasal continuous positive airway pressure administration can normalize hypertension in obstructive sleep apnea patients. Sleep 1993; 16:545–549. Wilcox I, Grunstein RR, Hedner JA, et al. Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep 1993; 16: 539–544. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle G. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 1998; 97:2154–2159. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991; 338:1480–1484. Bradley TD, Floras JS. Pathophysiological and therapeutic implications of sleep apnea in congestive heart failure. J Cardiac Failure 1996; 2:223–240.
15 Effects of Respiratory Muscle Afferent on the Breathing and the Afferent Hypothesis
SHELDON MAGDER McGill University Health Center Montreal, Quebec, Canada
I.
Introduction
A respiratory pattern of rapid shallow breathing is very common in patients with respiratory muscle failure. This respiratory pattern also predicts the failure of patients to wean from a ventilator (1–3). Indeed, this pattern is the basis of a very useful predictor of weaning success which was described by Yang and Tobin (4). They found that patients with a ratio of tidal volume to respiratory frequency of greater than approximately 100, which indicates that they have a high respiratory frequency and low tidal volume, were very unlikely to wean successfully from the ventilator. On the other hand, patients with a ratio of less than approximately 100 were likely to successfully wean. The pattern of rapid shallow breathing is such a strong predictor of a failure to wean, because as discussed below, this pattern of breathing is a very maladaptive behaviour and is associated with a large increase in the energy cost of breathing. The question then arises why does it occur? Ventilatory muscles can be activated voluntarily, but by in large they contract in a rhythmic pattern which is regulated by the ventilatory centers. For there to be an increase in respiratory frequency, there must be a signal which changes the output of the ventilatory centers. In this chapter I present an hypothesis for the mechanism of rapid shallow breathing in patients with failing ventilatory muscles and suggest a therapeu405
406
Magder
tic approach which has yet to be tested. In the first part of this chapter I will discuss the consequences of rapid shallow breathing. I will then present experimental data from animals which may explain why this pattern develops. Finally, I will speculate on possible therapeutic approaches. II. Changes in Respiratory Mechanics During Weaning Respiratory muscle failure is a hard process to study because of its unpredictable nature. (See Chapter 3 for thorough review of the physiology of the muscles of inspiration). An exception is the respiratory failure which occurs during an attempt at weaning. Thus, much of our knowledge on this subject has been accumulated under weaning conditions. In an early study by Tobin et al., the mechanics of respiratory failure where characterized (2). They found that patients who were successfully weaned from the ventilator, as well as patients who were not successfully weaned from the ventilator, started with similar initial minute ventilation (Vi), tidal volume (Vt) and respiratory frequency (F). In the group that developed respiratory failure during weaning, Vi did not change, but F increased and Vt decreased. In the end, the group who had respiratory failure, also had an increase in arterial CO 2 (PaCO 2). The failure group also had an increase in indexes of respiratory drive, including ratio of tidal volume to inspiratory time. In a later study, Jubran and Tobin extended these observations, and measured the mechanical consequences of this type of breathing (1). They found that patients who failed to wean had a 111% increase in the intrinsic part of end-expiratory pressure (PEEPi, or autoPEEP) component, a 33% in the elastic component, and a 42% increase in the resistive component. Despite an increase in the pressure-time product, which indicates that the respiratory muscles were actually generating more force, the PaCO 2 rose as a consequence of the inefficiency of this respiratory pattern. The product of the pressure- time product and PaCO 2 could be used as a index of the inefficiency of CO 2 clearance. That these patients had an increase in force generation by the respiratory muscles at the same time as the PaCO 2 rose indicates that the rise in PaCO 2 was not due to failure of the respiratory muscles to contract. Thus, the muscle failure cannot be explained simply on respiratory muscle fatigue as previously suggested (5–7), but is rather due to a dysfunctional and inefficient breathing pattern which drives the muscle into failure. In the next section, I will go through the mechanical consequences of rapid shallow breathing which make this pattern so inefficient. III. Mechanical Effects of High Respiratory Rate A high respiratory rate is very costly for the respiratory system (Table 1). The first consequence is that the total tension per minute is increased. This occurs because there are more breaths per minute. When the frequency of breathing increases, the contraction time is relatively more preserved and the relaxation phase is shortened, so that the total tension per minute is increased. Since the generated muscle tension
Respiratory Muscle Afferent Table 1 1. 2. 3. 4. 5.
407
Energy Costs of Rapid Breathing
Increased tension per minute Increased heat of activation Increased ventilation of dead space Increased inspiratory flow rate which increases inspiratory flow resistance Decreased expiratory time: autoPEEP hyperinflation diaphragmatic flattening decreases diaphragmatic force production decreased lung and chest wall compliance decreased inspiratory reserve limitation of muscle blood flow
is the major determinant of the energy demands of a muscle and thus of the blood to a muscle, this increase in tension per minute must be matched by an increase in energy supply and an increase in blood flow. Beside the effect that an increase in total tension per minute has on the energy needs of the muscle, there is also an increase in the ventilatory muscle energy demands with an increase in rate even when the total tension per minute is kept constant. This has been shown in animal studies by artificially stimulating the diaphragm at different rates while altering the contraction time to keep the total tension per minute constant, despite the increase in rate (8). When this was done, there was a marked increase in the blood flow to the diaphragm which indicates that there must have also been a marked increase in diaphragmatic oxygen consumption. Since the total tension per minute was not changed, this increase in blood flow, and presumed increase in oxygen consumption, was attributed to an increase in the heat of activation which is required to start the contraction process. An increase in respiratory frequency with a decrease in tidal volume means that more ventilation is required to ventilate the anatomic dead space. Thus, a larger amount of the total ventilation is wasted and there is less efficient removal of CO 2. When the tidal volume falls sufficiently, there may only be ventilation of the dead space. As a rough guide, ventilation becomes highly inefficient when the tidal volume is ⬍ 5 mL/kg. This is because the normal dead space to tidal volume ratio is ⯝ 0.3. At a tidal volume of ⱕ 5 mL/kg, this only leaves 3.5 mL/kg of alveolar ventilation. If the dead space to tidal volume ratio is greater than 0.3, then even less of the total ventilation is available for alveolar ventilation. An increase in the respiratory rate with a failure to wean is associated with an increase of mean respiratory flow rate (2). Since the resistance of endotracheal tube is curvilinear with increases in flow, an increase in expiratory flow rate results in an exponential increase in inspiratory flow resistance which will markedly increase the energy demands on the respiratory muscle. Probably the most important consequence of an increase in respiratory rate is the shortening of the time of expiration. This is especially important in patients with
408
Magder
chronic obstructive lung disease because of their need for a prolonged expiratory time. It is also a problem in intubated patients because of the increased resistance through the endotracheal tube increases the time needed to expire the tidal breath. This becomes progressively more significant when the tube fills with secretions. Under these conditions, the increase in respiratory rate does not allow time for full expiration, and this results in air stacking. This increases the intrathoracic volume which results in an increase in the transpulmonary pressure at the end of expiration which creates autoPEEP. The cardiovascular consequences of autoPEEP are similar to those of PEEP applied during mechanical ventilation, and include decreased venous return (see chapter by Fessler in this volume). The autoPEEP increases the threshold load for each subsequent breath. The autoPEEP also results in further air trapping, which in turn results in a progressive increase in intrathoracic volume and transpulmonary pressures and further increases in autoPEEP. On the inspiratory side, the increase in lung volume means that each tidal breath is closer to the limits of the inspiratory reserve. As well, the increase in lung volume means that these patients have to operate on the upper part of the thoracic volume/pressure relationship where the chest wall elastance is markedly increased. The increase in lung volume also results in flattening of the diaphragm. The diaphragm thus, no longer functions at its optimal length-tension relationship which further decreases the efficiency of the diaphragmatic muscle function. Thus, as shown by Jubran and Tobin (1), respiratory muscle function is very inefficient and respiratory failure eventually ensues. Just prior to failing, these patients generate much greater respiratory muscle force than needed for normal breathing. Therefore, they would have had sufficient reserves to wean if they had not adapted this inefficient pattern. Another negative consequence of an increase in respiratory rate is the effect on respiratory muscle blood flow. When tension in the muscle is ⬎30% of the maximum force of contraction, flow is decreased (9). When the generated muscle tension is high, flow to the muscle must be provided during the phase of muscle relaxation. When the respiratory rate is high, the period of relaxation is reduced; thus, there may not be sufficient time to provide the blood flow which is required for high forces of contraction. This occurs at the very time when the need for flow is increased and this will further compromise the energy supply of the diaphragm. In summary, an increase in respiratory rate produces great stresses on the ventilatory system. The consequence can be hypercapnic respiratory failure despite a marked increase in respiratory force production and energy consumption. Before presenting our hypothesis for this dysfunctional pattern I will review some of the mechanisms involved in the control of breathing.
IV. Control of Breathing Although respiratory muscles are under voluntary control, they contract with a rhythmicity which is determined by a complex interaction of at least six types of neurons. These are mainly concentrated in two locations, the ventral and dorsal respiratory groups, which have many interconnections (10,11). The dorsal group are in close
Respiratory Muscle Afferent
409
relationship to the tractus solitarius where visceral afferents from cranial nerves IX and X terminate. This is the primary site of the inspiratory nerves which regulate the timing of upper motor neurons. Fibers pass from this site to the inspiratory anterior horn cells of the opposite side (11). Nuclei of the ventral respiratory group, regulate expiratory muscles, dilator function of the larynx and pharynx, and the tongue. One nucleus in this region also controls the force of contraction of inspiratory muscles. In addition to the dorsal and ventral regions, there are also neurons in the pons that regulate the pattern of breathing. There are numerous inputs from other centers onto the upper motor respiratory neurons. These include input from the cerebral cortex, hypothalamus, pons, peripheral chemoreceptors, vagal and sympathetic afferent nerves, and other, peripheral, nonrespiratory afferents (11). These can have important effects on the pattern of discharge by the respiratory neurons and can be both inhibitory and stimulatory. During regular tidal breathing, there is a relatively constant pattern of breathing which includes a constant frequency, EMG, inspiratory velocity and inspiratory time, and therefore, a fixed expiratory time. This pattern can be altered both rhythmically and nonrhythmically by which I mean brief intermittent interruption in the overall pattern. There are many modulators of respiratory pattern. These include involuntary pattern generators (Chapter 7), voluntary inputs and chemical drive. The major chemical regulators of the respiratory patterns are the arterial concentrations of carbon dioxide (PaCO 2) and hydrogen H⫹ which act on both peripheral and central chemoreceptors. Thus ventilation is increased with increases in PaCO 2 and H⫹ and ventilation decreases with decreases in PaCO 2 and H⫹. At very low levels, hypoxemia also increases respiratory motor activity and acts synergistically with increases in PaCO 2 (11). There are also many central nervous system interactions between respiratory and autonomic centers (Chapter 7). For example, rhythmic alterations in ventilatory motor output can be induced by changes in baroreceptor tone. An increase in arterial blood pressure results in a decrease in ventilation and a decrease in blood pressure results in an increase in ventilation (11). Stretch receptors in the left atrium can also stimulate breathing (12–15). An important cause of changes in the rhythmic pattern of ventilatory motor output is anxiety and response to pain which are characterized by increases in ventilation with a decrease in PaCO 2. Many voluntary activities briefly interrupt the respiratory pattern. These were reviewed in detail by Levers and Road (16). For example, the rhythmic ventilatory pattern is interrupted by the voluntary efforts associated with phonation tasks including the efforts involved in talking, singing and working wind instruments. There are also interruptions in respiratory muscle activation for tasks which require stabilization of the thorax, such as lifting heavy objects, defecation, eating, and even responding to commands that regulate ventilation. Some of these responses may have reflex components from receptors in the pharynx and upper airways, whereas others are purely voluntary. There are also many primarily reflex adjustments of the ventilatory pattern, including coughing, sneezing, and hiccups. Important afferents for these pathways exist in the upper airways.
410
Magder
There are important reflexes that come from the lower airways, including the slowly adapting receptors which include the classic Herring-Breuer reflex and rapidly adapting receptors (16). These are both carried by myelinated fibers within the vagus and non myelinated vagal afferents from pulmonary receptors and are strong regulators of the respiratory pattern. Input from these receptors usually produce an increase in the rhythmic pattern in ventilation as occurs for example with a pulmonary embolism or pulmonary edema. Their location next to the pulmonary capillaries makes them particularly sensitive to changes in interstitial fluid and lung inflammation. Afferents from abdominal viscera can have important inhibitory effects on breathing. This can be shown with a blow to the abdomen or simply by stimulating abdominal viscera at surgery (17). Activation of these afferents can inhibit diaphragmatic function even after laparoscopic surgery (18), which minimally disturbs the abdomen muscles and indicates that the inhibition is from afferent activity from visceral sources. Similar to other skeletal muscles, the respiratory muscles too, have afferent nerves which help regulate the force of respiratory muscle contraction. These are classified into four groups based on their conduction velocities (19) (Table 2). Group I fibers are myelinated with diameters ranging from 2 to 20 µm and conduction velocities of 79 to 114 m/sec (20). These fibers include 1A fibers which end on muscle spindles and 1B afferents which end on the Golgi tendon organs. The 1A fibers are very sparse in the diaphragm compared to other muscles, but are found more frequently in the intercostal muscles. The muscle spindle is attached to an intrafusal muscle which is parallel to the main muscle (11). These fibers are stimulated to contract by gamma motor neurons when the contraction of the main muscle occurs through the activation of alpha motor neurons. When the muscle shortens and intrafusal fibers shorten in synchrony, there is no stretch of the annulospiral endings in the center of the intrafusal fibers and no afferent signal is sent. On the other hand, if the main muscle does not shorten, but the intrafusal fibers do shorten, the annulospiral ending is stretched and the afferents discharge. These afferent signals are carried to the anterior horn cell where they have a direct excitatory effect on the contraction and by this means help match the motor output to the load (11). The Golgi tendon organ consists of fascia or tendonous fibers which occur at the junction of the muscle and its tendon. They thus are sensitive to stretch of the
Table 2 Afferent Fiber Types Afferent fiber type I II III IV
Mylenated
Fiber size (µm)
Conduction velocity (m/sec)
Yes Yes Yes No
12–20 2–16 1–5 0.2–2
70–120 30–75 36,614 0.3–2
Respiratory Muscle Afferent
411
tendons. They increase their discharge when tension rises and send an inhibitory signal. In the phrenic nerve this results in a decrease in phrenic motor discharge. It has been suggested that this might mediate the decline in diaphragmatic EMG activity, which occurs with airway occlusion (21). This pathway could also explain the reflex decline in diaphragmatic contractions with abdominal compression (22). To assess the functional role of afferents from the Golgi tendon apparatus, Teitelbaum et al. (23) studied the vascularly and mechanically isolated left hemidiaphragm of dogs. They found that selective paralysis of this hemi diaphragm resulted in increased EMG activity to the right diaphragm, parasternal and alae nasae muscles and an increase in the frequency of breathing of 24%. This activation did not occur when the muscle started in a flaccid position which would not stretch the Golgi apparatus and it also did not occur when the left phrenic nerve was cut, which indicates that the reflex is mediated by afferents carried through the phrenic nerve. Group II fibers are also myelinated, but are thinner, 2 to 16 µm, and therefore conduct more slowly; i.e. 30 to 65 m/sec than Group I fibers. These fibers carry afferents primarily from muscle spindles and therefore have little significance in the diaphragm since the diaphragm has only a few muscle spindles (19). The group III and IV fibers are classified as thin fiber afferents. The group III fibers have a thin myelin sheath, a diameter of 1 to 6 µm, and conduct with velocities of 3.6 to 15 m/sec. They may have some connections with muscle spindles, but largely originate from free nerve endings. Group IV fibers have diameters of less than 2 mm and conduct the slowest at 2 m/sec. Thin fiber afferents respond to chemical signals—noscioreceptors and mechanical stretch receptors. The physiological role of small fiber afferents in the reflex control of cardiovascular system was first established by McClosky and Mitchell (24) and Webb-Peploe et al. (25). Webb-Peploe injected capsaicin, the active ingredient in chili peppers, into the vasculature of the skinned hindlimb of dogs (25). The limbs where skinned to remove potential afferents from the skin. They observed an increase in arterial pressure, heart rate, and cardiac contractility, and this response was abolished by cutting the nerves. Similar observations were later made by others (26,27). Kaufman et al. characterized the afferent fibers which are activated (28). They found that capsaicin directly activates group III and group IV afferents with the greatest activation being the group IV afferents. Capsaicin had no effect on group I and II afferents. Bradykinin also stimulated group III and group IV afferents. In a subsequent study, Kaufman and coworkers (29) characterized the chemical signals which activate these fibers. They found that lactic acid but not lactate and cyclo-oxygenase products stimulate these afferents. Adenosine and monobasic sodium phosphate had no effect in other studies (29). It was also found that static muscle contractions can activate ergoreceptors (30). The specific effect of small afferent fibers on ventilatory drive was studied by Hussain et al. (31). They electrically stimulated the cut end of the nerve to the gastrocnemius muscle and observed an increase in respiratory frequency, tidal volume, total ventilation, inspiratory time, and EMG to the diaphragm, genioglossus, parasternal, transverse abdominus, triangularis sterni, and alae nasae muscles. They also eliminated the potential effects of changes in arterial pressure on the activation
412
Magder
of these afferents by isolating the baroreceptors and keeping the arterial pressure constant. In summary, the above evidence indicates that small fiber afferents from skeletal muscles including the ventilatory muscles can increase cardiovascular activity— i.e., heart rate, blood pressure and cardiac contractility—and increase ventilatory muscle activity. What is the potential physiological role for this reflex response? An exercising muscle has an increased need for oxygen and other nutrients, as well as an increase in blood flow and ventilation to help clear metabolic byproducts. Thus, from a systems control point of view, it is important to have coordination between ventilation and cardiovascular function and muscle activity. One way this can be achieved is by the brain receiving afferent signals from the working muscles which are sensitive to the increasing products of metabolism in the muscle as well as mechanical signals related to the degree of effort. Thus, signals from small afferents can help coordinate the central cardiovascular and ventilatory responses to the needs of the muscles (Fig. 1A). Respiratory muscles are skeletal muscles and thus they have the same muscle afferent pathways as other skeletal muscles and can respond in the same way to nocioreceptive and ergoreceptive signals. Interestingly, the first studies on the afferent activity from respiratory muscles concentrated on their potential to inhibit ventilation (32). The thought was that perhaps signals from muscle afferents can explain why apnea occurs with respiratory muscle fatigue (32). Jammes et al. used electrical stimulation and selective blockade with procaine of small muscle afferents and concluded that small afferents inhibit respiration (32). However, the electrical stimulation they used, and the method of blockade, may not have been selective enough. Their results can likely be explained by activation of group I and group II afferents which are known to inhibit ventilatory motor function through the Golgi tendon apparatus. Opposite results were obtained by Road et al. (33). They found that stimulation of the cut ends of the phrenic nerve increased ventilation by 45% and increased blood pressure by 18%. The response was similar when the cut end of the gastrocnemius nerve was stimulated. Less intense stimulation, however, was required to produce a response in the gastrocnemius, presumably because the gastrocnemius has a greater number of group III and group IV afferents. The specific roll of the stimulation of Group IV afferents in the diaphragm was studied by Revelette et al. (34). They injected capsaicin into the phrenic artery and found excitation of phrenic motor neurons. They also found that cutting the spinal cord at the second cervical vertebra removed most of this reflex. They concluded that the reflex was at a spinal level. However, they did not isolate the diaphragmatic vasculature and it is likely that some of the capsaicin escaped into the pulmonary and systemic circulations and activated pulmonary C fibers and other vagal afferents. The central role of this reflex pathway was established by Hussain and coworkers (19,35,36). They first established a neuro-intact vascularly isolated hemidiaphragm preparation in dogs (37) and injected capsaicin to activate thin-fiber afferents as performed previously Revelette et al. (34). They found that capsaicin resulted
Respiratory Muscle Afferent
413
Figure 1 The afferent hypothesis. A shows the normal physiological response with afferent activation in working muscles. During exercise, metabolic signals in the muscles increase afferent discharge, which increased the drive to breath and sympathetic activity. This allows the matching of O 2 delivery and CO 2 removal to the needs of the muscle. B shows the positive feedback loop that occurs in pathological conditions. Increased diaphragmatic work or ischemia results in increased afferent activity which increases the drive to breath and causes a further increase in metabolic buildup in the ventilatory muscles and further afferent discharge.
414
Magder
in an increase in muscle activity as characterized by an increase in EMG activity in the diaphragm, parasternal muscles and mylohyoid (35) (Fig. 2). There was also an increase in the respiratory frequency and a decrease in the inspiratory time. In a few animals they also documented activation of the genioglossus and alae nasae muscles which are innervated by cranial nerves. This observation plus the observation of increased respiratory frequency indicates that the reflex was acting centrally and directly increases the respiratory center activity. Indeed, projections go from phrenic afferents to the somatosensory cortex (38,39) and cuneate nucleus (40). It has also been shown that activation of phrenic group III afferents has a marked excitatory affect on the medullary dorsal and ventral respiratory groups (41). Not only does stimulation of small phrenic afferents increase ventilatory motor activity as occurs in nonrespiratory muscles, but there is also activation of sympathetic nerve activity (36). Following an injection of capsaicin into the vascularly isolated hemidiaphragm, there is an immediate increase in blood pressure and heart rate (Fig. 3). There is also an effect on the regional distribution of flow. Injection of capsaicin into the vascularly isolated diaphragm decreased flow in the superior mesenteric and renal arteries and increased flow to the carotid and femoral arteries (36) (Fig. 4). There was a calculated increase in resistance in the superior mesenteric and renal arteries and no change in resistance in the femoral and carotid arteries
Figure 2 EMG (E) activity of the mylohyoid muscle (Mylo), parasternal (Para), and right (Rt) and left (Lt) diaphragm (Edi) after 1, 10, and 50 µg/ml of capsaicin. There was minimal response with 1 µg, a large response with 10 µg, and a further increase with 50 µg. This occurred after a lag time of about 6 sec, suggesting a central effect. The start of the capsaicin infusion is marked by the arrows. Values are mean ⫾ SE.
Respiratory Muscle Afferent
415
Figure 3 Changes in heart rate (HR), mean arterial pressure (Pa), and phrenic blood flow (Qphr) in response to 1, 10, and 50 µg/mL capsaicin infusion (arrows mark injection into left phrenic artery). Values are mean ⫾ SE. Capsaicin injection decreases phrenic artery flow. There was a small rise in arterial pressure with 10 µg/mL and a larger rise with 50 µg/mL in Pa and heart rate.
(Fig. 5). Injection of capsaicin into the gastrocnemius muscle produced similar, but greater responses; there were significant increases in the systemic vascular resistance of the carotid and femoral arterial beds. The difference in the responses of the gastrocnemius muscle and the diaphragm is likely because the gastrocnemius muscle has a greater density of thin fiber afferents than the diaphragm. To determine if phrenic small fiber afferents are activated by more physiological stimuli, Hussain and coworkers determined whether diaphragmatic ischemia would increase the inspiratory motor drive by activating small-fiber afferents (42). They again used the neurointact, vascularly isolated canine hemidiaphragm. They reasoned that ischemia results in an increase in lactic acid and phosphate, which increase small fiber afferent activity (29,43) as well increase bradykinin, which has also been shown to increase afferent activity (44) To assess activation of the ventilatory motor drive they monitored the EMG activity in a number of respiratory muscles. After 20 min they found that EMG activity rose in both sides of the diaphragm, the parasternal intercostals and alae nasae muscles (Figs. 6, 7). There was also an increase in the frequency of breathing. In previous work, these investigators showed that the afferent response to capsaicin is decreased after repeated injections. This is because one of the central neurotransmitters for these afferents is substance P (45,46). The capsaicin injection results in depletion of substance P, and thus subsequent injections have no effect. As discussed earlier, capsaicin is the active ingredi-
416
Magder
Figure 4 Relative changes in left carotid, femoral, left phrenic, left renal, and superior mesenteric arterial (Art) flows after the injection of 1 mg capsaicin into the left phrenic artery. Stars indicate significantly different from control values. The injection resulted in a fall in the phrenic artery flow due to a direct effect on the vessel. There was a fall in superior mesenteric and renal arterial flow and a rise in the flows to the carotid and femoral arteries.
ent in hot chili peppers and the sensation of ‘‘hot’’ food thus occurs through activation of thin-fiber afferents in the oral cavity and the release of substance P centrally. This depletes central stores of substance P, and it takes time to replenish these stores. The depletion of substance P explains why people who like hot food require a greater and greater dose of chilies to feel the ‘‘hot’’ sense. However, it should be appreciated, that after a few weeks to months, stores of substance P are repleted and the nerves are again sensitive to a stimulus. One must therefore, be cautious after a period of abstinence about returning to the same dose of hot chilies that were taken previously. Teitelbaum et al. used the depletion of substance P by capsaicin to confirm that small-fiber afferents are responsible for the increase in ventilatory motor activity
Respiratory Muscle Afferent
417
Figure 5 Relative changes in vascular resistance of the left carotid, femoral, phrenic, superior mesenteric, and renal arteries (Art) in response to an injection of 1 mg capsaicin into the left phrenic artery. Values are mean ⫾ SE. Phrenic arterial resistance rose because of a direct effect of capsaicin on the vessel. There was a rise in resistance in the superior mesenteric and renal artery beds, and no change in the carotid and femoral arterial beds.
seen with diaphragmatic ischemia (47). They first injected a large dose of capsaicin into the phrenic artery of the vascularly isolated hemidiaphragm and showed that after repeated injections of capsaicin, there was no further response, presumably because substance P was depleted. They then invoked ischemia by clamping the phrenic artery. After pretreatment with capsaicin, they found no change in the respiratory motor activity with ischemia, which indicates that small phrenic afferents were responsible for the increase in ventilatory drive (47). In a subsequent study, Wilson (48) investigated the role of prolonged ischemia. After 1 hour of ischemia to the hemidiaphragm, there was the expected fall in tension generated by the ischemic muscle. As in previous work, there was a rise in EMG activity to the alae nasae, parasternal, and diaphragm and an increase in respiratory frequency (Fig. 8). However, after 90 mins, the EMG activities fell back to baseline
418
Magder
Figure 6 Changes in peak integrated electromyographic activity (EMG) of the left (top) and right (bottom) diaphragm in response to left diaphragmatic ischemia. Ischemia produced a progressive increase in EMG activity on both sides of the diaphragm. Values are mean ⫾ SE. *P ⬍ .05; **P ⬍ .01.
or even below. This might be explained by the lose of substance P centrally with the prolonged stimulation. On reperfusion after 180 min, there was initially no change in the response. This indicates that there was no direct inhibitory reflex. After 60 minutes there was some recovery in EMG activity to the alae nasae, parasternals, and diaphragm, which suggests that there was also some central adaptations to the afferent activity. In all the above studies, the changes in respiratory frequency and ventilation were not as large as are seen in patients who develop rapid shallow breathing during weaning. However, it should be appreciated, that in the animal studies afferent signals only came from a hemidiaphragm. In the real-life situation, afferent activity would come from the whole diaphragm as well as all the other working respiratory
Respiratory Muscle Afferent
419
Figure 7 Changes in peak integrated EMG activity of the parasternal intercostal (top) and alae nasi (bottom) muscles during periods of ischemia and recovery. There was a progressive rise in EMG activity of both muscle groups with left diaphragmatic ischemia. *P ⬍ .05; **P ⬍ .01.
muscles. Furthermore, it appears that the intercostal muscles might have a richer source of afferent activity than the diaphragm. The effect of large afferent fibers was discussed above. Of these, fibers connected to the muscle spindles also could play a role. It is unlikely, however, that they alone are responsible for the rise in ventilatory muscle activity because pretreatment with capsaicin, which specifically knocks out thin fiber afferents, preventing the ventilatory muscle activation in the working diaphragm. If spindles played a major role, there still should have been an increase in ventilatory drive. However, activation of the muscle spindles could still play an additional role. For example, they might become important when there is air trapping and an increase in the volume of the thorax . This would lead to less efficient force production by
420
Magder
Figure 8 Changes in peak integrated EMG activities of the alae nasi (AN), parasternal (Ps), right hemidiaphragm (Rdi), and left hemidiaphragm (Ldi) and spontaneous Ldi tension (spont Ldi tension) during ischemia-reperfusion of the left hemidiaphragm. Values are mean ⫾ SE. *P ⬍ .05; **P ⬍ .01. There was a rise in EMG activity which was significant in Rdi oat 90 min, and then the EMG declined. On reperfusion, there was an initial fall in EMG followed by recovery.
the ventilatory muscles which then would require greater neuroactivation for a given motor output and this is the type of condition which activates muscle spindle afferents. In summary, these studies have shown that activation of thin fiber afferents by metabolites in working muscle can increase ventilatory motor output. As discussed previously, this has a positive survival effect when the reflex is associated with
Respiratory Muscle Afferent
421
normal working skeletal muscle, because it helps coordinate the activation of ventilatory centers and sympathetic centers and the needs of the working muscle. Under the condition of heavy exercise in normal subjects, afferent activity from the ventilatory muscles would also contribute in a helpful way to the adaptation to exercise (Fig. 1A). However, a problem occurs under pathological conditions when the force output of the ventilatory muscles is low compared to metabolic demands. This leads to what I call the ‘‘afferent hypothesis,’’ that is, activation of thin fiber afferents in working ventilatory muscles leads to increased motor drive which creates a positive feedback loop which eventually results in ventilatory muscle failure (Fig. 1B). The explanation is as follows. Activation of afferents occurs because of increased demands on the ventilatory muscles, and thus in response to increased work. This results in an increase in the metabolic by-products of muscle work which in turn increases the activation of thin fiber afferents in the ventilatory muscles. This increases the ventilatory drive, which results in a further buildup of metabolites in the working muscle and greater activation of thin fiber afferents. This results in further activation of the already limited respiratory muscles. In particular, the increase in respiratory frequency and decrease in tidal volume will lead to the pattern of rapid shallow breathing, which, as discussed at the beginning of this chapter, is a very inefficient breathing pattern. The muscle must thus work even harder to maintain the needed ventilation. This leads to a buildup of even more metabolites, which drives the respiratory center even more. Eventually, this positive feedback loop drives the patient into hypercapnic respiratory muscle failure. The respiratory muscles cannot keep up with the metabolic demand because of the dysfunctional breathing pattern and the excessive demands brought on by this inefficient pattern of breathing. The rise of PaCO 2 produces stupor, coma and apnea. Thus, with low force output, the ventilatory muscles, driven by metabolic load, through small fibers afferents, enter a vicious cycle leading to respiratory failure.
V.
Potential Clinical Approach
It is clear that once the vicious cycle is entered, little can be done during a weaning trial except to put the patient back on ventilatory assist and wait for conditions to improve. It might be possible to prevent the patient from entering this cycle, however, in certain cases. Whereas the potentially maladaptive reflex pathway is hypothetical, although based on empirical data from animals, the therapeutic approach to this problem is completely speculative with no experimental data. I present it here to stimulate some thinking into directions for study in the future. Because the reflex pathway involves activation of central neural pathways, it is possible that decreasing the central response to afferent input could blunt the increase in respiratory drive which occurs in patients who are difficult to wean. Preventing the increase in respiratory drive, and in particular, the increase in respiratory rate, would prevent the development of dyscoordinated breathing, avoid the pattern of rapid shallow breathing, and allow weaning of the patient. However, the
422
Magder
use of sedation for weaning contradicts the usual teaching which recommends stopping all sedation before weaning a patient to maximize their respiratory response (49). We have applied the reasoning behind the afferent hypothesis in our approach to weaning. Although we have not systematically studied it, we have frequently given patients who are difficult to wean, long-acting benzodiazepines such as clonazepam. These are given in a sufficient amount to sedate the patient while maintaining wakefulness. It is our impression that this approach has helped us to wean these difficult patients by maintaining a calmer ventilatory pattern. The ideal drug for the prevention of rapid shallow breathing is also very speculative. We use benzodiazepines because they have only mild ventilatory depressant effects and therefore do not usually result in apnea. On the other hand, an argument could be made for the use of opioids. The ventilatory depressant effects of opioids are well recognized (50–52) and opiate receptors and endogenous opiate ligands have been documented in the brain stem (53). The applications of the opioid antagonist nalaxone, restores flow-resistive load compensation in patients with chronic obstructive lung disease (54,55) and patients with asthma (56), as well as in animals (57–59). Opioids could thus be applied either systemically or possibly intrathecally. However, the use of opiates requires very careful titration of the dose, because of the potential for apnea, and therefore we have not used them. VI. Conclusion Afferent nerve fibers from working muscles play an important role in normal physiological function by coordinating the activation of ventilatory and neuroautonomic centers with the needs of the working muscles. The ventilatory muscles, like other skeletal muscles, have afferent fibers which interact with central regulatory centers for ventilation and autonomic activity. This has been demonstrated by direct activation of thin fiber afferent fibers in muscle under experimental conditions. The ‘‘afferent hypothesis’’ says that activation of these thin fibers under pathological conditions leads to rapid shallow breathing which is a very inefficient pattern for ventilation. This leads to air trapping, increased energy demands on ventilatory muscles, and eventually ventilatory muscle failure. The implication of this hypothesis is that patients with difficult weaning problems would benefit from pharmacological suppression of central ventilatory centers during weaning. I put forth as an hypothesis that these patients should be weaned when sedated sufficiently to suppress the maladaptive central response, and not after the withdrawal of sedation. References 1. 2.
Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trail of weaning from mechanical ventilation. Am J Respir Crit Care Med 1997; 155: 906–915. Tobin MJ, Perez W, Guenther SM, Semmes BJ, Mador MJ, Allen SJ, Lodato RF, Dantzker
Respiratory Muscle Afferent
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
423
DR. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1986; 134:1111–1118. Capdevila X, Perrigault PF, Ramonatxo M, Roustan JP, Peray P, d’Athis F, Prefaut C. Changes in breathing pattern and respiratory muscle performance parameters during difficult weaning. Crit Care Med 1998; 26:79–87. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991; 324:1445–1450. Cohen CA, Zagelbaum G, Gross D, Roussos C, Macklem PT. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982; 73:308–316. Roussos CS, Macklem PT. Diaphragmatic fatigue in man. J Appl Physiol 1977; 43:189–197. Roussos C, Gross D, Fixley M, Macklem PT. Fatique in inspiratory muscles and their synergic behaviour. J Appl Physiol 1979; 46:897–904. Buchler B, Magder S, Roussos C. Effects of contraction frequency and duty cycle on diaphragmatic blood flow. J Appl Physiol 1985; 58:265–273. Hussain SNA, Magder S. Diaphragmatic intramuscular pressure in relation to tension, shortening, and blood flow. J Appl Physiol. 1991; 71:159–167. Dick TE, Van Lunteren E, Kelsen SG. Control of respiratory motor activity. In: Roussos C, ed. The Thorax, 2d ed. New York: Marcel Dekker, 1995:753 Nunn JF. Nunn’s Applied Respiratory Physiology, 5th ed. Woburn, MA: ButterworthHeinemann, 1999. Uchida Y. Tachypnea after stimulation of afferent cardiac sympathetic nerve fibers. Am J Physiol 1970; 230:1003–1007. Lloyd TCJ. Breathing response to lung congestion with and without left heart distension. J Appl Physiol. 1988; 65:131–136. Lloyd TCJ. Control of breathing in anesthetized dogs by a left-heart baroreflex. J APPL PHYSIOL. 1986;61:2095–2101. Lloyd TCJ. Effect of increased left atrial pressure on breathing frequency in anesthetized dog. J Appl Physiol 1990; 69:1973–1980. Leevers A, Road JD. Reflex influences acting on the respiratory muscles of the chest wall. In: Roussos C, ed. The Thorax, 2d ed. New York: Marcel Dekker, 1995:821. Reeve EB, Nanson EM, Rundle FF. Observations on inhibitory respiratory reflexes during abdominal surgery. Clin Sci 1950; 10:65–87. Erice F, Fox GS, Salib YM, Romano E, Meakins JL, Magder SA. Diaphragmatic function before and after laparoscopic cholecystectomy. Anesthesiology 1993; 79:966–975. Hussain SNA, Roussos C. The role of small-fiber phrenic afferents in the control of breathing. In: Roussos C, ed. The Thorax, 2d ed. New York: Marcel Dekker, 1995:860. Rexed B. Contributions to the knowledge of postnatal development of the peripheral nervous system in man. Acta Psychiatr Neurol Suppl 1944; 33. Cordo M, Euler CV, Lennerstrand G. Reflex and cerebellar influences on alpha and on ‘rhythmic’ and ‘tonic’ gamma activity in the intercostal muscle. J Physiol (Lond) 1966; 184:898–923. Cheeseman M, Revelette WR. Phrenic afferent contribution to reflexes elicited by changes in diaphragm length. J Appl Physiol 1990; 69:640–647. Teitelbaum J, Borel CO, Magder S, Traystman RJ, Hussain SNA. Effect of selective diaphragmatic paralysis on the inspiratory motor drive. J Appl Physiol. 1993; 74:2261–2268. McCloskey DI, Mitchell JH. Reflex cardiovascular and respiratory responses originating in exercising muscle. J Physiol (Lond) 1972; 224:173–186. Webb-Peploe MM, Brender D, Shephard JT. Vascular responses to stimulation of receptors in muscle by capsaicin. Am J Physiol 1972; 222:189–195. Longhurst JC, Zelis R. Cardiovascular responses to local hindlimb hypoxemia: relation to the exercise reflex. Am J Physiol 1979; 237:359–365. Clayton SC, Mitchell JH, Payne FCI. Reflex cardiovascular response during injection of capsaicin into skeletal muscle. Am J Physiol 1981; 240:H315–H319. Kaufman MP, Iwamoto GA, Longhurst JC, Mitchell JH. Effects of capsaicin and bradykinin on afferent fibers with endings in skeletal muscle. Circ Res 1982; 50:133–139. Rotto DM, Kaufman MP. Effect of metabolic products of muscular contraction on discharge of group 111 and 1V afferents. J APPL PHYSIOL. 1988; 64:2306–2313.
424 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.
Magder Kaufman MP, Longhurst JC, Rybicki KJ, Wallach JH, Mitchell JH. Effects of static muscular contraction on impulse activity of groups III and IV afferents in cats. J Appl Physiol 1983; 55:105–112. Hussain S, Ward M, Gatensby A, Roussos C, Deschamps A. Respiratory muscle activation by limb muscle afferent stimulation in anesthetized dogs. Respir Physiol 1991; 84:185– 198. Jammes Y, Buchler B, Delpierre S. Phrenic afferents and their role in inspiratory control. J Appl Physiol 1986; 60:854–860. Road JD, West NH, Van Vliet BN. Ventilatory effects of stimulation of phrenic afferents. J Appl Physiol 1987; 63:1063–1069. Revelette R, Jewell LA, Frazier DT. Effect of diaphragm small-fiber afferent stimulation on ventilation in dogs. J Appl Physiol. 1988; 65:2097–2106. Hussain SNA, Magder SA, Chatillon A, Roussos C. Chemical activation of thin-fiber phrenic afferents: respiratory responses. J Appl Physiol 1990; 69:1002–1011. Hussain SNA, Magder SA, Roussos C, Chatillon A, Comtois A. Chemical activation of thin-fiber phrenic afferents 2. Cardiovascular responses. J Appl Physiol 1991; 70:77–86. Hussain SNA, Roussos C, Magder S. In situ isolated perfused and innervated left hemidiaphragm preparation. J Appl Physiol 1989; 67:2141–2146. Davenport PW, Thompson FJ, Reep RL, Freed AN. Projection of phrenic nerve afferents to the cat sensorimotor cortex. Brain Res 1985; 328:150–153. Marlot D, Macron JM, Duron B. Projections of phrenic afferents to the cat cerebellar cortex. Neurosci Lett 1984; 44:95–98. Marlot D, Macron JM, Duron B. Projection of phrenic afferents to the external cuneate nucleus in the cat. Brain Res 1985; 327:328–330. Speck DF, Revelette WR. Attenuation of phrenic motor discharge by phrenic nerve afferents. J Appl Physiol 1987; 62:941–945. Teitelbaum JS, Magder SA, Roussos C, Hussain SNA. Effects of diaphragmatic ischemia on the inspiratory motor drive. J Appl Physiol 1992; 72:447–454. Stebbins CL, Maruoka Y, Longhurst JC. Prostaglandins contribute to cardiovascular reflexes evoked by static muscular contraction. Circ Res 1986; 59:645–654. Wilson CR, Vanelli G, Magder S, Hussain SNA. Phrenic afferent stimulation by bradykinin and the disruption of the inspiratory motor drive. Respir Physiol 1994; 96:1–12. Matthews MR, Cuello AC. Substance P–immunoreactive peripheral branches of sensory neurons innervate guinea pig sympathetic neurons. Proc Natl Acad Sci USA 1982; 79:1668– 1672. Cuello AC, Del Fiacco M, Paxinos.G. The central and peripheral ends of the substance Pcontaining sensory neurons in the rat trigeminal system. Brain Res 1978; 152:499–509. Teitelbaum J, Vanelli G, Hussain SNA. Thin-fiber phrenic afferents mediate the ventilatory response to diaphragmatic ischemia. Respir Physiol 1993; 91:195–206. Wilson CR. The role of diaphragmatic afferents in the control of breathing. McGill University, thesis, 1-1-1994. Lessard MR, Brochard LJ. Weaning from ventilatory support. Clin Chest Med 1996; 17: 475–489. Weil JV, McCullough RE, Kline JS, Sodal IE. Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man. N Engl J Med 1975; 292:1103–1106. Santiago TV, Edelman NH. Opioids and breathing. J Appl Physiol. 1985; 59:1675–1685. Kryger MH, Yacoub O, Dosman J, Macklem PT, Anthonisen NR. Effect of meperidine on occlusion pressure responses to hypercapnia and hypoxia with and without external inspiratory resistance. Am Rev Respir Dis 1976; 114:333–340. Atweh SF, Kuhar MJ. Distribution of physiological significance of opioid receptors in the brain. Br Med Bull 1983; 39:47–52. Santiago TV, Remolina C, Scoles V, Edelman NH. Endorphins and the control of breathing. Ability of naloxone to restore flow-resistive load compensation in chronic obstructive pulmonary disease. N Engl J Med 1981; 304:1190–1195. Bellofiore S, Di Maria GU, Privitera S, Sapienza S, Milic-Emili J, Mistretta A. Endogenous opioids modulate the increase in ventilatory output and dyspnea during severe acute bronchoconstriction. Am Rev Respir Dis 1990; 142:812–816.
Respiratory Muscle Afferent 56. 57. 58. 59.
425
Scardella AT, Petrozzino JJ, Mandel M, Edelman NH, Santiago TV. Endogenous opioid effects on abdominal muscle activity during inspiratory loading. J Appl Physiol 1990; 69: 1104–1109. Petrozzino JJ, Scardella AT, Edelman NH, Santiago TV. Respiratory muscle acidosis stimulates endogenous opioids during inspiratory loading. Am Rev Respir Dis 1993; 147:607– 615. Scardella AT, Parisi RA, Phair DK, Santiago TV, Edelman NH. The role of endogenous opioids in the ventilatory response to acute flow-resistive loads. Am Rev Respir Dis 1986; 133:26–31. Scardella AT, Santiago TV, Edelman NH. Naloxone alters the early response to an inspiratory flow-resistive load. J Appl Physiol 1989; 67:1747–1753.
16 Neurohumoral Aspects of Respiratory-Cardiovascular Interactions
SAMI I. SAID State University of New York Stony Brook, New York and Department of Veterans Affairs Medical Center Northport, New York
I.
Introduction: Functional Interactions
In both their structure and their function, the lungs and the cardiovascular systems are closely interrelated and intimately intertwined. The two systems are, in many ways, coupled together. It is no wonder, therefore, that events in either system may elicit responses in the other, or that failure of the heart or the lungs often leads to failure of both circulatory and respiratory function. Such cardiovascular-pulmonary interactions are examined throughout this volume. This chapter focuses on those interactions that occur both under physiological conditions and in disease states, where humoral agents appear to play a key role.
II. Neurohumoral Substances Participating in Cardiovascular-Respiratory Interactions For the sake of this discussion neurohumoral substances are all biologically active compounds released locally or into the bloodstream. These include biogenic amines, e.g., histamine and serotonin; lipids, especially arachidonic acid metabolites and platelet-activating factor (PAF); peptides, both circulating or hormonal peptides, such as antidiuretic hormone (ADH, arginine vasopressin) and antriopeptins and 427
428
Said
related natriuretic peptides, and locally acting neuropeptides serving as neurotransmitters, like vasoactive intestinal polypeptide (VIP), the neurokinins (tachykinins), and opioid peptides, and a variety of cytokines, such as tumor necrosis factor (TNF)α, chemokines (e.g., interleukins), and growth factors; enzymes, especially proteolytic enzymes or proteases, and phospholipases; and the simple but multipotent molecule nitric oxide (NO). References are made in this chapter to ‘‘conventional’’ neurotransmitters, such as acetylcholine and norepinephrine, but these are primarily discussed elsewhere in this volume under neurogenic influences. The biological effects of neurotransmitters/mediators are multiple and wideranging (Table 1). They include, but are not limited to, systemic and pulmonary vasodilation or vasoconstriction, airway relaxation or constriction, systemic hypo-
Table 1 Chemical Mediators of Cardiovascular and Respiratory Responses Compounds Biogenic amines Histamine Serotonin Lipids Prostaglandins Prostacyclin Thromboxanes Leukotrienes
Peptides Endothelins Bradykinin Neurokinins (tachykinins) Opioid peptides Atriopeptins, urodilatin VIP
Cytokines, chemokines Growth factors Other Nitric oxide
Biological activities Bronchoconstriction, system vasodilatation Bronchoconstriction Bronchoconstriction (PGD2, PGF2α), bronchial relaxation (PGE2) Pulmonary and systemic vasodilation, inhibition of platelet aggregation Bronchoconstriction, pulmonary vasoconstriction, platelet aggregation Bronchoconstriction, pulmonary vasoconstriction, pulmonary edema (LTC4, LTD4); neutrophil aggregation and secretion (LTB4) Bronchoconstriction, pulmonary vasoconstriction Systemic hypotension, inflammation Bronchoconstriction, airway inflammation Modulation of cholinergic responses Natriuresis, diuresis, bronchial relaxation Bronchial relaxation, pulmonary and systemic vasodilatation, anti-inflammatory activity, inhibition of airway smooth muscle proliferation Mediation or modulation of inflammation chemotaxis of inflammatory cells Cell survival and proliferation Vascular and nonvascular smooth muscle relaxation, pulmonary and systemic vasodilation, inhibition of platelet aggregation (at physiological levels); cell and tissue injury (in excessive concentrations)
Respiratory-Cardiovascular Interactions
429
tension or hypertension, promotion or modulation of inflammation, stimulation or suppression of cell proliferation, and sodium and fluid retention or natriuresis and diuresis.
III. Physiological Interactions A. Central Coordination of Cardiorespiratory Interactions
Several physiological stimuli originating in the respiratory or cardiovascular system may trigger responses in both cardiovascular and pulmonary function. The linkage between the mechanisms controlling the respiratory and the cardiovascular systems has long been recognized; many physiological responses include appropriate changes in both systems (1). Examples of this linkage are: 1. To balance the increase in oxygen uptake and transport, minute ventilation and cardiac output are closely matched during exercise. 2. Many reflex responses initiated by stimulation of peripheral afferents elicit changes simultaneously in both the cardiovascular and respiratory systems. 3. Central mechanisms exist by which the ventilatory and vascular control systems are coupled, for example: a. Stimulation of cardiovascular afferents from arterial baroreceptors, as by increases in arterial blood pressure, leads to depression of respiratory output; b. Arterial chemoreceptor stimulation augments respiratory drive, in addition to altering heart rate and vascular resistance. B. Hyperinflation/Hyperventilation and the Release of Pulmonary and Systemic Vasodilators
Stroking of Lung Surface and Stirring of Lung Fragments
Gentle stroking or massaging of the external surface of isolated, perfused guinea pig lungs caused the appearance in the perfusate of prostaglandin (PG)-like biological activity and other substances (2). In related experiments, suspensions of chopped guinea pig or human lung tissue, stirred with a nylon rod for 5 to 6 min, released a mixture of smooth-muscle active substances. A similar release occurred when stirring was repeated, but the concentration of released materials decreased (2,3). Hyperinflation of Isolated, Perfused Lungs
These observations suggested that more physiological forms of physical stimulation of the lung, such as stretching by hyperinflation, also may provoke the release of active agents. This possibility was tested in isolated dog lungs, mechnically ventilated with 5% CO2 in O2, and perfused at constant flow with Krebs’ solution (4). The perfusate continually superfused strips of rat stomach and rat colon—suitable organs for bioassay of PGs—that had been rendered insensitive to catecholamines,
430
Said
Figure 1 Characeristic responses of isolated, superfused segments of rat stomach strip (RSS) and rat colon (RC) to PGF2 and PGE1 (left panel) and to lung perfusate during hyperinflation (right panel). Upward movement represents contraction of smooth muscle.
histamine, sterotonin (5-hydroxytryptamine), and acetylcholine (Figs. 1,2) During control ventilation, there was no evidence of activity in the perfusate. On increasing tidal volume by 50% to 100%, while maintaining the same minute ventilation and affluent pH, both smooth-muscle strips contracted. The contraction began within 2 min of increasing the tidal volume, correlating directly with breath size, and were
Figure 2 Release of PGs from isolated, perfused dog lung during ventilation at increased tidal volumes (VT, 200, 300, and 300 mL).
Respiratory-Cardiovascular Interactions
431
consistent with the liberation of PGs into the perfusate, in concentrations of up to 150 ng/min of PGE1 equivalent (5,6). Simultaneously, the perfusion pressure of the lung decreased, indicating pulmonary vasodilation. After the infusion of aspirin (1 mg) into the pulmonary circulation, the hyperinflations no longer resulted in contractions of the smooth-muscle organs (Fig. 3) or decrease in pulmonary perfusion pressure. These findings suggested that stretching of the lung was capable of provoking increased pulmonary synthesis of vasodilator PG-like compounds (and possibly other active substances), and their subsequent release into the circulation (4). Similar conclusions were reached by Berry et al. (7) in isolated guinea pig and rat lungs. Hyperinflation and Hyperventilation In Vivo
Could a similar release of vasodilator PGs occur in the whole animal? If so, could it contribute to the systemic hypotension that frequently complicates mechanical ventilation at large tidal volumes? These questions were investigated in open-chested dogs, which were anesthetized with pentobarbital, paralyzed with succinylcholine, and mechanically ventilated (8,9). After a control period of normal ventilation, tidal volume was increased fivefold and kept at that level for 5 min, without changing the frequency of respiration; then normal ventilation was restored. To separate the effects of hyperinflation alone from those of resultant respiratory alkalosis, the increased ventilation was carried out with two different inspired
Figure 3 Left: Release of PGs from isolated, perfused dog lungs with ventilation at increased tidal volumes (up to six times control volume). The PG-like biological activity was assayed on RSS (see Fig. 1). Right: Pretreatment with aspirin totally prevented RSS contractions under same conditions. Numbers of experiments are indicated in parentheses. (From Ref. 6.)
432
Said
mixtures: air alone and air plus 5% CO2. Arterial blood pressure and cardiac output were monitored throughout these experiments. Hyperinflation with air (hyperventilation) led to severe hypocapnia (arterial blood PCO2 decreased from 41 to 15 mm Hg) and respiratory alkalosis (pH increased from 7.32 to 7.52). With CO2 added to the inspired air, however, arterial PCO2 and pH remained unaltered during the increased ventilation. When hyperventilation was accompanied by respiratory alkalosis, the mean arterial blood pressure fell by 32% (⫾18) (Fig. 4). During hyperinflation alone, in the absence of respiratory alkalosis, the fall in blood pressure in the same animals was only 13% (⫾12) of control value (P ⬍ .001). Cardiac output did not change significantly during hyperventilation, with or without supplemental CO2. In a group of animals that were pretreated with aspirin (30 mg/kg in saline, infused intravenously), the fall in blood pressure was significantly attenuated to 18 ⫾ 10% in the presence of respiratory alkalosis, and to 8 ⫾ 5% without respiratory alkalosis (Fig. 4). These experiments provided evidence that (1) the systemic hypotension complicating mechanical hyperventilation is attributable, in large measure, to the release of vasodilator agents; (2) this release is greater in the presence of respiratory alkalosis than in its absence; and (3) the responsible vasodilator substances probably include PGs (possibly PGEs) or PG-like compounds (5,6,9). Pulmonary Release of Prostacyclin
In related studies, increased ventilatory frequency (up to 80 breaths/min) in anesthetized cats stimulated the pulmonary release of prostacyclins (PGI2)-like activity
Figure 4 Fall in mean aterial blood pressure (measured in femoral artery, PFA) in anesthetized dog during hyperventilation (left) and hyperinflation (right; PaCO2 maintained constant). In both instances, experiments were carried out before (open circles) and after (triangles) treatment with aspirin.
Respiratory-Cardiovascular Interactions
433
(equivalent to 0.5 to 1.0 ng/mL) (10). Increased release of PGI2 (and, to a lesser degree, of thromboxane A2) also occurred during rapid ventilation of isolated rat lungs (11). These observations suggested that the vasodilator activity of lung inflation described in earlier reports and previously attributed to PGs alone was, in part, due to PGI2, which had not yet been chemically identified. High-Frequency Ventilation
In one study in anesthetized sheep (12), high-frequency ventilation (HFV) did not increase plasma PGI2 levels and did not alter pulmonary lymph flow or the lymph/ plasma protein concentration ratio under normal hemodynamic conditions or histamine infusion (2 mg ⋅ kg⫺1min⫺1). In another study, on isolated, blood-perfused sheep lungs (13), HFV attenuated hypoxic pulmonary vasoconstriction. In the same experiments, the output of PGI2 metabolite in lung perfusase during hypoxia was markedly increased with HFV. Other Hormonal Effects of Hyperinflation and PEEP
Besides stimulating the synthesis and release of prostaglandins, prostacyclin, and the peptides ADH and atriopeptins, as described below, mechanical ventilation, especially with PEEP, may provoke the release of other biologically active substances: 1. Mechanical ventilation in dogs, especially with positive end-expiratory pressue (PEEP, 15 cm H2O), led to increased plasma fibrinolytic activity resulting from pulmonary secretion of plasminogen activator (14). 2. The use of PEEP (14 ⫾ 2.5 cm H2O) induced a moderate rise in plasma norepinephrine level in patients with acute respiratory failure (15). In the same patients, plasma renin activity (a measure of the rate of renal secretion of renin) increased in parallel with the increased sympathetic activity. 3. Conversely, both lung inflation and PEEP (5 cm H2O) reduced overall angiotensin-converting activity of rabbit lungs, but the reduction was secondary to decreased pulmonary blood flow, rather than to reduced enzyme function (16). C. Acute Alveolar Hypoxia and the Release of Vasoactive Compounds
Alveolar hypoxia induces pulmonary vasoconstriction through complex mechanisms that remain incompletely understood. Hypoxic pulmonary vasoconstriction is probably mediated by a variety of vasoconstrictor substances, including histamine, serotonin, prostaglandins, leukotrienes, platelet-activating factor, angiotensin II. The constrictor endothelin peptides (17,18), released by systemic and pulmonary endothelial cells, may be involved in the response; removal of endothelium from pulmonary artery strips abolishes hypoxic pulmonary vasoconstriction (19–21). The identities of the mediators of this response, and the nature of interactions among them, have been the subject of numerous investigations (22). Alveolar hypoxia also provokes the release of vasodilators, including prostacyclin (23), atriopeptins (24) (see be-
434
Said
low), and NO (25), all of which would tend to modulate the severity of pulmonary vasoconstriction. D. Perinatal Respiratory and Cardiovascular Adaptations
Within minutes of birth, the lungs and the pulmonary circulation undergo dramatic changes: The fluid-filled fetal lungs fill up with air after the onset of normal respiration, and pulmonary vascular resistance falls sharply to allow perfusion of the ventilated alveoli. The nearly 10-fold increase in pulmonary blood flow triggered by ventilation of the fetal lung is mainly due to the increased PO2 to which the pulmonary vessels are exposed and to the physical expansion of alveoli (26). Vasodilator PGs and PGI2 appear to play an important role in two key neonatal adaptive responses to the pulmonary circulation: (1) the rapid decrease in vascular resistance with the first breath, and (2) the gradual decrease in resistance subsequent to its increase with ductal ligation (27,28). Indomethacin abrogates both of these adaptive responses in neonatal rabbit lungs (28). The output of PGI2 metabolite is augmented in the venous effluents of perfused lungs of fetal goats and sheep (29). Recent knowledge of the biology of NO has added much to our understanding of the changes in the pulmonary circulation in the perinatal period. As just mentioned, the fetal pulmonary circulation is characterized by high resistance and low pulmonary blood flow. Right-to-left shunting through the foramen ovale and/or patent ductus arteriosus is necessary to perfuse the placenta and ensure fetal life. At birth, the marked increase in pulmonary arterial blood flow allows normal pulmonary gas exchange and postnatal life. In some circumstances, this adaptation to extrauterine life is inadequate, because of persistent pulmonary hypertension. The expression of endothelial NO synthase in the lung increases dramatically during late gestation, heightening the capacity for NO production and promoting the reversal of pulmonary vasoconstriction at the time of birth (30). Attenuated expression of this enzyme may, therefore, contribute to the pathogenesis of various forms of neonatal pulmonary hypertension. Administered by inhalation, in low concentrations (parts per billion), NO selectively dilates the constricted pulmonary vessels, with little effect on systemic vessels, because it is rapidly taken up by hemoglobin. Inhaled NO can reverse right-to-left shunting and correct the refractory hypoxemia (31). See Chapter 36 for review of the use of NO in pulmonary hypertension of the newborn. In considering the therapeutic use of NO, however, the question of its potential toxicity must be kept in mind. NO, a free radical that interacts with a number of proteins, reacts with superoxide radical to form the highly toxic peroxynitrite, which may be responsible for damaging proteins, lipids, and DNA. Peroxynitrite can also induce lipid peroxidation, decreasing the function of surfacant proteins SP-A and SP-B. Excessive NO may be a critical mediator of acute oxidant lung injury due to paraquat or xanthine plus xanthine oxidase (32,33). The premature lung is likely to be sensitive to NO toxicity with resultant lung damage and mutagenicity. Defining the indications, dosage, and limits of inhaled NO therapy is an important objective of experimental and clinical research (34).
Respiratory-Cardiovascular Interactions
435
E. Cardiopulmonary Receptors and the Release of Hormones Regulating Blood Volume, Electrolyte Balance, and Blood Pressure
A number of reflexes, originating from cardiac atria and pulmonary vessels, are of paramount importance in the regulation of water and electrolyte excretion and blood pressure. These reflexes, which can be initiated by atrial distension and by positiveor negative-pressure breathing, are mediated by three major peptide systems. Antidiuretic Hormone
Breathing maneuvers that alter central blood volume, e.g., positive- and negativepressure breathing, have long been known to influence cardiovascular hemodynamics and urine output. Earlier observations demonstrated an antidiuresis in dogs ventilated with positive-pressure breathing; negative-pressure breathing or distension of the left atrium, on the other hand, produced diuresis (35–39). The renal response to left atrial distention could not be elicited in animals in which the cervical vagi had been cooled to block nerve conduction, indicating that the left atrium was the principal site of stretch receptors sensitive to variations in circulating blood volume (40). These experiments led to the hypothesis that atrial distension reflexly inhibited the secretion of ADH, thus causing a water diuresis (40). This posulate for the role of ADH in diuresis, induced by atrial distention in the dog, was later confirmed by direct measurements of plasma levels of the hormone (41). Observations in primates and in humans have largely supported these findings (42). Secetion of ADH is now recognized to be regulated by an interplay of baroreceptor reflexes from carotid and cardiopulmonary sites (43,44), as well as by input fom cardiovascular centers in the brain (45). Increased plasma levels of ADH have similarly been demonstrated in human subjects during PEEP, suggesting that the release of ADH might help explain the fluid retention that often complicates hours or days of beathing with PEEP (46–48). The Renin-Angiotensin-Aldosterone System
First discovered over 100 years ago in kidney extracts, renin is an aspartyl protease secreted by the juxtaglomerular cells in the walls of the afferent renal arterioles. It acts on angiotensinogen, a circulating α2-globulin, to generate angiotension I. The latter is converted, through the action of angiotensin-converting enzyme, into angiotensin II, a potent vasoconstrictor and pressor agent. Pulmonary vascular endothelium is a major site of this conversion (49). Angiotensin II also stimulates the secretion of aldosterone, a key hormone in the regulation of sodium and potassium balance. The renin-angiotensin-aldosterone hormonal axis is thus a major regulator of both blood pressure and sodium-potassium homeostasis (50). This system is activated in congestive heart failure, causing fluid retention and vasoconstriction (51,52). Atriopeptins
Most of the earlier work on the relationship between atrial distention and renal function focused on ‘‘volume control’’ as a function of water diuresis, with little
436
Said
consideration being given to the possible atrial influence on sodium excretion (53,54). Later, left atrial (but not right atrail) distension in the conscious dog was demonstrated to produce a natriuresis together with a reduction in plasma ADH level (55,56). Atrial stretch failed to elicit these responses in dogs with chronically denervated hearts (57). The discovery of the natriuretic and diuretic effect of atrial tissue extracts in rats (58), and the subsequent identification of atriopeptides or atriopeptins as the active peptides in the extracts and in specific granules of atrial myocytes (59,60), suggested that these peptides might mediate the natriuresis caused by atrial distension. Atriopeptin release into the circulation has been demonstrated in animals and in human subjects during atrial distention (61,62). The cardiac atria are thus capable of influencing water and sodium excretion by two mechanisms: (1) atrial stretch receptors that may reflexly alter ADH and the renin-angiotensin system, and (2) release of atriopeptins that promote natriuresis and diuresis (62). The prototype of the natriuretic hormones is cardiodilatin/atrial natriuretic peptide (CDD/ANP), or A-type natriuretic peptide, primarily produced in the cardiac atria (58,63-66). It is synthesized as a prohormone or precursor molecule (CDD/ ANP-1-126) in specific granules of the atrial myoendocrine cells (67). Upon appropriate stimuli the prohormone is cleaved and the C-terminal CDD/ANP-99-126 is liberated into the circulation by exocytosis. Brain natriuretic peptide (BNP, or Btype natriuretic peptide), so called because it was first isolated from brain homogenates, is found in highest concentrations in ventricular myocadium (68,69). C-type natriuretic peptide (CNP) is present mainly in the brain, but also in vascular endothelium (70–72). (See Table 2.) Urodilatin (CDD, ANP-95-126), a recently identified member of this peptide family (73), is chemically related to circulating CDD/ANP-99-126, but N-terminally extended by four amino acid residues. It is synthesized in the kidney and exerts potent paracrine renal effects (74,75). Although not found in human blood or lung (76), urodilatin exerts significant actions on the tracheobronchial tree (77–80). In addition to their natriuretic and diuretic activity, atriopeptins relax vascular and nonvascular smooth muscle (58,64,81–84), oppose the vasoconstrictor effect of angiotensin II, suppress aldosterone and renin secretion, and inhibit the sodiumretaining action of aldosterone (50,85–88).
Table 2
Cardiac Natriuretic Family of Peptides
Tissue presence Circulating hormone? Natriuretic? Smooth muscle relaxant? Receptors, 2nd messengers
ANP
BNP
CNP
Cardiac atria (as prohormone) Yes Yes Yes NPR-A, cGMP
Myocardium, brain Yes Yes Yes NPR-A, cGMP
CNS, vascular endothelium Low No Yes NPR-B, cGMP
Urodilatin Urine No Yes Yes NPR-A, cGMP
Respiratory-Cardiovascular Interactions
437
The biological activities of the natriuretic peptides are mediated by intracellular generation of cyclic guanosine 3′,5′-monophosphate (cGMP) secondary to activation of particulate guanylyl cyclase (89–93). cDNA analysis and cloning revealed three types of natriuretic peptide receptors (NPR): NPR-A, B, and C (94). NPR-A and NPR-B are coupled to the intracellular guanylyl cyclase catalytic domain whereas the third member, NPR-C, is not associated with an intracellular guanylyl cyclase (95). The physiological role of NPR-C is not fully known, but it may function as a clearance receptor. Besides the binding of circulating natriuretic peptides to NPR-C, the peptides are enzymatically degraded in lung, liver, and kidney, principally by metalloendoprotease E.C.3.4.24.11. Among the main sites of degradation are the brush border cells of the proximal tubule and the tracheobronchial system. In contrast to CDD/ANP-99-126, urodilatin is highly resistant to enzymatic degradation, possibly because of its N-terminal extension (71,96–98). Thus, exogenously applied urodilatin may reach the distal tubule and the collecting duct without being degraded, and may bind to biologically active NPR-A receptors in the lung, inducing the pronounced bronchodilatation. The different pharmacokinetic profiles of CDD/ ANP-99-126 and urodilatin explain their potential renal and bronchial effects, respectively, on IV administration (79). IV. Cardiovascular-Pulmonary Interactions in Disease A. Sepsis/Septic Shock
Interactions between macrophages and other cells of the immune system with endotoxin lipopolysaccharide (LPS) of invading bacteria release the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) (Fig. 5). These compounds bring about profound metabolic and functional changes throughout the body, including fever, white blood cell chemotaxis and activation, and increased vascular permeability (99). In addition, bacterial macromolecules interact directy with humoral components of the immune system, and activate the coagulation and complement cascades, leading to the release of additional mediators of inflammation. Further interactions between bacterial cell wall antigens and Hageman factor result in the generation of bradykinin, a potent vasodilator and pro-inflammatory agent (100,101). Excessive NO (see Chapters 29 and 35) appears to play a key role in the pathogenesis of hypotension of septic shock. The existence of an inducible NO synthase has been demonstrated in endothelium and vascular smooth muscle in response to endotoxin, IL-1, and TNF-α. Excessive NO probably mediates the endotoxininduced vascular hyporesponsiveness to vaoconstrictors and the hypotensive effect of TNF-α. Inhibition of NO synthesis can reverse the hyperdynamic response to endotoxin and reverse TNF-induced hypotension, but NO synthase inhibition was associated with increased mortality (25,102). Plasma VIP levels increase sharply in experimental and clinical septic shock (103,104). The role of VIP in sepsis/septic shock has not been ascertained, but it may serve an anti-inflammatory, cell-protective purpose (105).
438
Said
Figure 5 Interactions between bacterial endotoxin lipopolysaccharide (LPS) and macrophages and other immune cells can trigger the production of mediators of systemic hypotension and other features of septic shock (details in text).
B. Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury
ARDS, which commonly complicates or is associated with septis and septic shock, leads to the release of additional inflammatory mediators from damaged lung tissue (106). In the treatment of ARDS, to ensure adequate ventilation and satisfactory tissue oxygenation, ventilation has usually been given at tidal volumes of 10 to 15 mL/kg, usually with PEEP. Recently, however, the potential deleterious effects of mechanical ventilation have become recongized, and it is now generally accepted that mechanical ventilation may contribute to lung injury in such patients (107). This injury is in addition to the complications of alveolar rupture due to overdistension, which include pneumothorax, pneumomed-iastinum, pneumopericardium, pneumoperitoneum, and subcutaneous or parenchymal emphysema. Particularly in patients with ARDS, mehanical ventilation is capable of producing further lung injury, consisting of worsening of lung edema, impairment of surfactant function, and parenchymal damage like that of ARDS. Increased pulmonary edema during mechanical ventilation is attributable in part to increased fluid filtration, due to both decreased interstitial pressure (108) and dilatation of extra-alveolar vessels (109,110), and in part to increased microvascular permeability. Evidence for increased permeability includes the demonstration of an increase in filtration coefficient, reflecting loss of integrity of the alveolar-microvascular barrier (111,112). Experimental pulmonary edema due to overdistension develops rapidly, becoming apparent within minutes of the start of ventilation (113). The
Respiratory-Cardiovascular Interactions
439
lung injury is dose dependent: both higher inflation pressures and larger tidal volumes administered over progressively longer periods of time produce increasingly severe lung injury. The traditional view that increased pressure is the main cause of lung injury (barotrauma) has recently been questioned, in favor of lung overdistension (volutrauma) as the primary culprit. To limit ventilator-induced lung injury, therefore, efforts should be directed at limiting alveolar distention. One approach toward that objective is to limit tidal volume but add PEEP to maintain alveolar patency and prevent cyclic recruitment and derecruitment of alveoli. This approach of limiting overdistention while maximizing alveolar recruitment may result in significant reduction in alveolar ventilation and evalution in PaCO2 (107). Such permissive hypercapnia is preferable to maintaining a normal PaCO2 at the risk of increasing lung injury. A recent study sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health, concluded that the use of tidal volumes of 65, instead of 12, mL/kg significantly reduced mortality from ARDS (114). C. Congestive Heart Failure
Multiple neurohumoral/endocrine abnormalities are associated with, and may be causally related to, congestive heart failure. 1. Catacholamine levels are increased, especially in severe heart failure, and probably contribute to the systemic vasoconstriction and to lethal ventricular arrhythmias (52). 2. The renin-angiotensin-aldosterone system is activated, causing fluid retention and vasoconstriction. 3. Endothelins also contribute to vasoconstriction. 4. Tending to counteract the renin-angiotensin-aldosterone system and other vasoconstrictor influences, are the vasodilator and natriuretic atriopeptins. Atriopeptin secretion is increased, rather than impaired (115), in this condition (72,116). The failure of the increased levels of atriopeptins, especially ANP and BNP, to produce the desired natriuresis and diuresis in congestive heart failure can be explained by downregulation of their receptors, as well as upregulation of the renin-angiotensinaldosterone system (52,62,71,72). Elevated plasma concentrations of atriopeptins appear to correlate with the severity of heart failure (52,71,72). D. Hepatic Cirrhosis and Portal Hypertension
Patients with chronic liver disease and portal hypertension present with a hyperdynamic circulatory syndrome consisting of systemic and splanchnic vasodilatation, sodium and water retention, and plasma volume expansion. Mean arterial blood pressure and systemic vascular resistance are reduced, and cardiac output and regional blood flows are increased (117). The pathogenesis of this hyperdynamic syndrome is still uncertain, but it is most likely related to vasodilatation induced by increased levels of vasodilators that escape hepatic inactivation. NO has been suggested as one of these vasodilators. Increased circulating levels of endotoxin in cir-
440
Said
rhotic patients, resulting from portocaval shunting, could stimulate the expression of inducible NO synthase (25,118–122). An important mediator of this syndrome is TNF-α, produced by mononuclear cells upon activation by several stimuli, particularly endotoxin LPS (123). Plasma levels of TNF-α, which causes marked hypotension in mammals (123), are elevated in liver disease (124,125). The hypotension elicited by TNF-α is mediated by excessive NO production, and is reversed by inhibition of NO synthesis (126,127). Treatment with a specific anti-TNF-α antibody or with thalidomide, a selective inhibitor of TNF-α production, blunts the development of the hyperdynamic circulation in an experimental model of portal hypertension (128,129). Another possible mediator of the hyperdynamic syndrome of chronic liver disease is VIP. This vasodilator peptide can reproduce some of the functional alterations, and its plasma levels are elevated in this condition (130). V.
Concluding Comments
Neurohumeral/endocrine mechanisms mediate or influence many important physiological responses and pathophysiological alterations of the cardiovascular and respiratory systems. Knowledge of these mechanisms, still incomplete but growing rapidly, will doubtless enhance our understanding of the nature and significance of cardiovascular-respiratory interactions in health and disease. Acknowledgments Supported by NIH Grants HL-30450 and HL-55849 and by research funds from the Department of Veterans Affairs References 1. Taylor EW, Jordan D, Coote JH. Central control of the cardiovascular and respiratory systems and their interaction in vertebrates. Physiol Rev 1999; 79:855–916. 2. Piper PJ, Vane JR. The release of prostaglandins from the lung and other tissues. Ann NY Acad Sci 1971; 180:363–385. 3. Piper PJ, Walker JL. The release of spasmogenic substances from human chopped lung tissue and its inhibition. Br J Pharmacol 1973; 47:291–304. 4. Said SI, Kitamura S, Mutt V. Biologically active polypeptide from the lung. In: Meienhofer J, ed. Chemistry and Biology of Peptides: Proceedings of the Third American Peptide Symposium. Ann Arbor, MI: Ann Arbor Science Publishers, 1972:409–414. 5. Said SI, Yoshida T, Kitamura S, Vreim C. Pulmonary alveolar hypoxia: release of prostaglandins and other humoral mediators. Science 1974; 185:1181–1183. 6. Said SI. Release of biologically active materials from the lung: release induced by physical and chemical stimuli. In: Vane JR, Bakhle YS, eds. Metabolic Functions of the Lung. New York: Marcel Dekker, 1977:297–320. 7. Berry EM, Edmonds JF, Wyllie JH. Release of prostaglandin E2 and unidentified factors from ventilated lungs. Br J Surg 1971; 58:189–192. 8. Said SI. The lung in relation to vasoactive hormones. Fed Proc 1973; 32:1972–1976.
Respiratory-Cardiovascular Interactions
441
9. Kitamura S, Preskitt J, Yoshida T, Said SI. Prostaglandin release, respiratory alkalosis, and systemic hypotension during mechanical ventilation. Fed Proc 1973; 32:341. 10. Gryglewski RJ, Korbut R, Ocetkiewicz A, Splawinski J, Worjtaszek B, Sweis J. Lungs as a generator of prostacyclin—hypothesis on physiological significance. Arch Pharmacol 1978; 47:291–304. 11. Korbut R, Boyd J, Eling T. Respiratory movements alter the generation of prostacyclin and tromboxance A2 in isolated rat lungs: the influence of arachidonic acid-pathways inhibitors on the ratio between pulmonary prostacyclin and thromboxane A2. Prostaglandins 1981; 21:491–503. 12. Vander Zee H, Bizios R, Malik AB. Effects of high frequency ventilation on lung lymph dynamics and prostaglandin generation. Respir Physiol 1985; 61:31–42. 13. Wetzel RC, Gordon JB, Gregory TJ, Gioia FR, Adkinson NF Jr, Sylvester JT. High-frequency ventilation attenuation of hypoxic pulmonary vasoconstriction. The role of postacyclin. Am Rev Respir Dis 1985; 132:99–103. 14. Hechtman HB, Shepro D. Lung metabolism and systemic organ function. Circ Shock 1982; 9:457–467. 15. Payen DM, Brunbuisson CP, Carli PA, Huet Y, Leviel F, Cinotti L, Chiron B. Hemodynamic, gas exchange, and hormonal consequences of LBPP during PEEP ventilation. J Appl Physiol 1987; 62:61–70. 16. Toivonen HJ, Catravas JD. Effects of alveolar pressure on lung angiotensin-converting enzyme function in vivo. J Appl Physiol 1986; 61:1041–1050. 17. Rae GA, Henriques MGMO. Endothelins in inflammation. In: Said SI, ed. Proinflammatory and Antiinflammatory Peptides. New York: Marcel Dekker, 1998:163–202. 18. Henry JP, Hay DWP, Goldie RG. Endothelins in the lung. In: Said SI, ed. Proinflammatory and Antiinflammatory Peptides. New York: Marcel Dekker, 1998:203–240. 19. Holden WE, McCall E. Hypoxia-induced contractions of porcine pulmonary artery strips depend on intact endothelium. Exp Lung Res 1984; 7:101–112. 20. O’Brien RF, Robbins RJ, McMurtry IF. Endothelial cells in culture produce a vasoconstrictor substance. J Cell Physiol 1987; 132:263–270. 21. Rodman DM, Yamaguchi T, O’Brien RF, McMurtry IF. Hypoxic contraction of isolated rat pulmonary artery. J Pharmacol Exp Ther 1989; 248:952–959. 22. Voekel NF, Chang SW, McDonnell TJ, Westcott JY, Haynes J. Role of membrane lipids in the control of normal vascular tone. Am Rev Respir Dis 1987; 136:214–217. 23. Hamasaki Y, Tai HH, Said SI. Hypoxia stimulates prostacyclin generation by dog lung in vitro. Prostagland Leuk Med 1982; 8:311–316. 24. Chou J, Kubota E, Paul S, Pakbaz H, Said SI. Atrial natriuretic peptide: release in severe acute respiratory failure. Clin Res 1987; 35:660A. 25. Kuo PC, Schroeder RA. The emerging multifaceted roles of nitric oxide. Ann Surg 1995; 221:220–235. 26. Rudolph AM, Heymann MA, Lewis AB. Physiology and pharmacology of the pulmomary circulation in the fetus and newborn. In: Hodson WA, ed. Development of the Lung. New York: Marcel Dekker, 1977:497–523. 27. Leffler CW, Tyler TL, Cassin S. Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats. Am J Physiol 1978; 234:H346–H351. 28. Hammerman C, Scarpelli EM. Indomethacin and the cardiopulmonary adaptations of transition. Pediatr Res 1984; 18:842–845. 29. Leffler CW, Hessler JR. Perinatal pulmonary prostaglandin production. Am J Physiol 1981; 241:H756–H759. 30. Shaul PW. Ontogeny of nitric oxide in the pulmonary vasculature. Semin Perinatol 1997; 21:381–392. 31. Thebaud B, Mercier C. Inhaled nitric oxide: a phyiological treatment of persistent pulmonary arterial hypertension in the newborn. Arch Pediatr 1997; 4:988–1003. 32. Berisha HI, Pakbaz H, Absood A, Said SI. Nitric oxide as a mediator of oxidant lung injury due to paraquat. Proc Natl Acad Sci USA 1994; 91:7445–7449. 33. Berisha H, Pakbaz H, Absood, A, Foda HD, Said SI. Nitric oxide mediates oxidant tissue injury caused by paraquat and xanthine oxidase. Ann NY Acad Sci 1994; 723:422–425. 34. Hallman M, Bry K. Nitric oxide and lung surfactant. Semin Perinatol 1996; 20:173–185.
442
Said
35. Peters JP, Body Water: The Exchange of Fluids in Man. Springfield, IL: C.C. Thomas, 1935:405. 36. Gauer OH, Henry JP, Sieker HO, Wendt WE. The effect of negative pressure breathing on urine flow. J Clin Invest 1954; 33:287–296. 37. Sieker HO, Gauer OH, Henry JP. The effect of continuous negative pressure breathing on water and electrolyte excretion by the human kidney J Clin Invest 1954; 33:572–577. 38. Henry JP, Pearce JW. The possible role of cardiac atrial stretch receptors in the induction of changes in urine flow. J Physiol (Lond) 1956; 131:572–585. 39. Gauer OH, Henry JP. Circulatory basis of fluid volume control. Physiol Rev 1963; 43: 423–481. 40. Henry JP, Gauer OH, Reeves JL. Evidence of the atrial location of receptors influencing urine flow. Circ Res 1956; 4:85–90. 41. Baisset A, Montestruc P. Polyurie par distention auricularire chez le chien: role de l’hormone antidiuretique J Physiol (Paris) 1957; 49:33–36. 42. Meehan JP. Cadiovascular receptors and fluid volume control. Aviat Space Environ Med 1986l 57:267–275. 43. Thames MD, Schmid PG. Interaction between carotid and cardiopulmonary baroreflexes in control of plasma ADH. Am J Physiol 1981; 241:H431–H434. 44. Eagan B, Grekin R, Isben H, Osterziel K. Julius S. Role of cardiopulmonary mechanoreceptors in ADH release in normal humans. Hypertension 1984; 6:832–836. 45. Brody JM, Johnson AK. Role of the anteroventral third ventricle region in fluid and electrolyte balance, arterial pressure regulation, and hypertension. Front Neuroendocrinol 1980; 6:249–292. 46. Sladen A, Laven MB. Pontoppidan H. Pulmonary complications and water retention in prolonged mechanical ventilation. N Engl J Med 1968; 279:448–453. 47. Baratz RA, Philbim DM, Patterson RW. Plasma ADH and urinary output during continuous positive pressure breathing in the dog. Anesthesiology 1971; 34:510–513. 48. Bark H, LeRoith D, Nyska M, Glick SM. Elevations in plasma ADH levels during PEEP ventilation in the dog: mechanisms involved. Am J Physiol 1980; 239:E474–E481. 49. Ryan US. Processing of angiotensin and other peptides by the lungs. In: Fishman AP, Fisher AB, eds. Handbook of Physiology: The Respiratory System. Bethesda, MD: American Physiological Society, 1987:351–364. 50. Laragh HJ. Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electroltye homeostasis. N Engl J Med 1985; 21:1330–1340. 51. Richards AM. The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides. Heart 1996; 76(suppl 3):3–44. 52. Nicholls DP, Onuoha GN, McDowell G, Elborn JS, Riley MS, Nugent AM, Steele IC, Shaw C, Buchanan KD. Neuroendocrine changes in chronic cardiac failure. Basic Res Cardiol 1996; 91(suppl 1):13–50. 53. Gillespie DJ, Sandber RL, Koike TI. Dual effect of left atrial receptors on excretion of sodium and water in the dog. Am J Physiol 1973; 225:706–710. 54. Goetz Kl, Bond GC, Bloxham DD. Atrial receptors and renal function. Physiol Rev 1975; 55:157–205 55. Reinhardt HW, Kaczmarczyk G, Eisele R, Arnold B, Eigenheer F, Kuhl U. Left atrial pressure and sodium balance in conscious dogs on a low sodium intake. Pflu¨gers Ach 1977; 370:59–66. 56. Schulz HD, Fater DC, Sundet WD, Geer PG, Goetz KL. Reflexes elected by acute stretch of atrial vs. pulmonary receptors in conscious dogs. Am J Physiol 1992; 242:H1065– H1076. 57. Fater DC, Schultz HD, Sundet WD, Mapes JS, Goetz KL. Effects of left atrial stretch in cardiac-denervated and intact conscious dogs. Am J Physiol 1982; 242:H1056–H1064. 58. Debold AJ, Borenstein HB, Veress T, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981; 28:89-94. 59. Debold AJ. Atrial natriuretic factor of the rat heart: Studies on isolation and properties. Proc Soc Exp Biol Med 1982; 170:133–138. 60. Debold AJ. Tissue fractionation studies on the relationship between an atrial natriuretic factor and specific atrial granules. Can J Physiol Pharmacol 1982; 60:324–330.
Respiratory-Cardiovascular Interactions
443
61. Dietz JR. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J. Physiol 1984; 247:R1093–R1096. 62. Goetz KL. Atrial receptors, antriuretic peptides, and the kidney—current understanding. Mayo Clin Proc 1986; 61:600–603. 63. Flynn TG, Debold ML, Debold AJ. The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties. Biochem Biophys Res Commun 1983; 117:859–865. 64. Forssmann WG, Hock D, Lottspeich F, Henschen A, Kreye V, Christmann M, Reinecke M, Metz J, Carlquist M, Mutt V. The right auricle of the heart is an endocrine organ. Anat Embryol 1983; 168:307–313. 65. Forssmann WG, Norkihara K, Gagelmann M, Hock D, Feller SM, Schulz-Knappe P, Herbst F. The heart is the center of a new endocrine, paracine and neuroendocrine system. Arch Histol Cytol 1989; 52:293–315. 66. Kangawa K, Matsuo H. Purification and complete amino acid sequence of alpha-human atrial natriuretic polypeptide (alpha-hANP). Biochem Biophys Res Commun 1984; 118: 131–139. 67. Rosenzweig A, Seidman CE. Atrial natriuretic factor and related peptide hormones. Annu Rev Biochem 1991; 60:229–255. 68. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988; 332:78–81. 69. Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 1990; 168:863–870. 70. Lee D, Lim AT. The heart as an endocrine organ. Singapore Med J 1996; 37:7–17. 71. Wilkins MR, Redondo J, Brown LA. The natriuretic-peptide family. Lancet 1997; 349: 1307–1310. 72. Sagnella GA. Measurement and significance of circulating natriuretic peptides in cardiovascular disease. Clin Sci 1998; 95:519–529. 73. Schulz-Knappe P, Forssmann K, Herbst F, Hock D, Pipkorn R, Forssmann WG. Isolation and structural analysis of ‘‘urodilatin’’ a new peptide of the cardiodilatin-(ANP)-family, extracted from human urine. Klin Wochenschr 1988; 66:752–759. 74. Forssmann WG, Meyer M, Schulz-Knappe P. Urodilatin: from cardiac hormones to clinical trials. Exp Nephrol 1994; 2:318–323. 75. Kirchhoff K, Bub A, Marxen P, Forssmann WG. Urodilatin inhibits sodium reabsorption in the isolated perfused rat kidney. Exp Nephrol 1994; 2:351–357. 76. Drummer C, Fiedler F, Bub A, Kleefeld D, Dimitriades E, Gerzer R, Forssmann WG. Development and application of a urodilatin (CDD/ANP-95-126)-specific radioimmunoassay. Pflugers Arch 1993; 423:372–377. 77. Flu¨ge T, Fabel H, Wagner TO, Forssmann WG. Localization of the bronchdilator effect induced by type A natriuretic peptide in asthmatic subjects. Clin Investig 1994; 72:772–774. 78. Flu¨ge T, Hoymann HG, Hohlfeld J, Heinrich U, Fabel H, Wagner TO, Forssmann WG. Type A natriuretic peptide exhibit different bronchoprotective effects in rats. Eur J Pharmacol 1994; 271:395–402. 79. Meyer M, Flu¨ge T, Kruhøffer M, Forssmann W-F. Basic aspects of vasorelaxant and bronchodilating peptides in clinical use: urodilation (INN: Ularitide), VIP, and PACAP. Ann NY Acad Sci 1996; 805:443–463. 80. Meyer M, Richter R, Forssmann WG. Urodilatin, a natriuretic peptide with clinical implications. Eur J Med Res 1998; 3:103–110. 81. Faison EP, Siegl PKS, Morgan G, Winquist RJ. Regional vasorelaxant selectivity of atrial natriuretic factor in isolated rabbit vessels. Life Sci 1985; 37:1073–1079. 82. Currie MG, Geller DM, Cole BR, Boylan JG, Yusheng W, Holmberg SW, Needleman P. Bioactive cardiac substances: potent vasorelaxant activity in mammalian atria. Science 1983; 221:71–73. 83. Grammer RT, Fukumi H, Inagami T, Misono KS. Rat atrial natriuretic factor: purification and vasorelaxant activity. Biochem Biophys Res Commun 1983; 116:696–703. 84. Goetz KL. Physiology and pathophysiology of the atrial peptides. Am J Physiol 1988; 254:E1–E15. 85. Charter L, Schriffin E, Thibault G. Atrial natriuretic factor inhibits the stimulation of aldo-
444
86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98.
99. 100. 101. 102. 103. 104. 105. 106. 107. 108.
Said sterone secretion by angiotensin II, ACTH and potassium in vitro and angiotensin II-induced steroidogenesis in vivo. Biochem Biophys Res Commun 1984; 122:171–174. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML. Diverse biological actions of atrial natriuretic peptide. Physiol Rev 1990; 70:665–699. Forssmann WG. Cardiac hormones. Review on the morphology, biochemistry, and molecular biology of the endocrine heart. Eur J Clin Invest 1986; 16:439–451. Sonnenberg H, Honrath U, Chong CK, Wilson DR. Atrial natriuretic factor inhibits sodium transport in medullary collecting duct. Am J Physiol 1986; 250:F963–F966. Waldman S, Rapoport RM, Murad F. Atrial natriuretic factor selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat tissues. J Biol Chem 1984; 259: 14322–14334. Chinkers M, Garbers DL, Chang MS, Lowe DG, Chin H, Goeddel DV, Schulz S. A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Nature (Lond) 1989; 338:78–83. Heim JM, Kiefersauer S, Fu¨lle HJ, Gerzer R. Urodilatin and β-ANF: binding properties and activation of particulate guanylate cyclase. Biochem Biophys Res Commun 1989; 163:37–41. Lowe DG, Chang MS, Hellmiss R, Chen E, Singh S, Garbers DL, Goeddel DV. Human atrial natriuretic peptide receptor defines a new paradigm for second messenger signal transduction. EMBO J 1989; 8:1377–1384. Koike J, Nonoguchi H, Terada Y, Tomita K, Marumo F. Effect of urodilatin on cGMP accumulation in the kidney. J Am Soc Nephrol 1993; 3:1705–1709. Maack T. Receptors of atrial natriuretic factor. Annu Rev Physiol 1992; 54:11–27. Koller KJ, Goeddel GV. Molecular biology of the natriuretic peptides and their receptors. Circulation 1992; 86:1081–1084. Gagelmann M, Hock D, Forssmann WG. Urodilatin (CDD/ANP-95-126) is not biologically inactivated by a peptidase from dog kidney cortex membranes in contrast to atrial natriuretic peptide/cardiodilatin (alpha-hANP/CDD-99-126). FEBS Lett 1988; 233:249–254. Kenny AJ, Bourne A, Ingram J. Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C-type natriuretic peptide and some C-receptor ligands by endopeptidase-24.11. Biochem J 1993; 291:83–88. Feller SM, Bub A, Gagelmann M, Forssmann WG. Natriuretic peptides from the heart, brain and kidney: localization, processing, vasoactivity, and proteolytic degradation. In: Lewis BS, Kimchi A, eds. Heart Failure Mechanisms and Management. Berlin: SpringerVerlag, 1991:398–407. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 194; 45:491–503. Geppetti P, Emanueli C, Figini M, Regoli D. Proinflammatory peptides in relation to other inflammatory mediators. In: Said SI, ed. Proinflammatory and Antiinflammatory Peptides. New York: Marcel Dekker, 1998:241–258. Roscher AA, Faussner A. Cellular regulation of kinin receptors: potential role in inflammation. In: Said SI, ed. Proinflammatory and Antiinflammatory Peptides. New York: Marcel Dekker, 1998:259–280. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF. NG-MethylL-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 1990; 87:3629–3632. Revhaug A, Lygren I, Jenssen TG, Giercksky K-E, Burhol PG. Vasoactive intestinal peptide in sepsis and shock. Ann NY Acad Sci 1988; 527:536–545. Brandtzaeg P, Oktendalen O, Kierulf P, Opstad PK. Elevated VIP and endotoxin plasma levels in human gram-negative septic shock. Regul Pept 1989; 24:37–44. Said SI. Antiinflammatory actions of VIP in the lungs and airways. In: Said SI, ed. Proinflammatory and antiinflammatory Peptides. New York: Marcel Dekker, 1998:345–361. Said SI, ed. The Pulmonary Circulation and Acute Lung Injury, 2d ed. Mount Kisco, NY: Futura, 1991. Granton JT, Slutsky AS. Ventilator-induced lung injury. In: Hall JB, Schmidt GA, Wood LDH, eds. Principles of Critical Care. New York: McGraw-Hill, 1998:121–130. Dreyfuss D, Saumon G. Ventilator-induced lung injury. In Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. New York: McGraw-Hill, 1994:793–811.
Respiratory-Cardiovascular Interactions
445
109. Albert RK, Lakshminarayan S, Kirk W, Butler J. Lung inflation can cause pulmonary edema in zone I of in situ dog lungs. J Appl Physiol 1980; 49:815–819. 110. Smith JC, Mitzner W. Analysis of pulmonary vascular interdependence in excised dog lobes. J Appl Physiol 1980; 48:450–456. 111. Egan EA. Lung inflation, lung solute permeability, and alveolar edema. J Appl Physiol 1982; 53:121–125. 112. Parker JC, Townsley MI, Rippe B, Taylor AE, Thigpen J. Increased microvascular permeability in dog lungs due to high peak airway pressures. J Appl Physiol 1984; 57:1809–1816. 113. Dreyfuss D, Soler P, Saumon G. Spontaneous resolution of pulmonary edema caused by short periods of cyclic overinflation. J Appl Physiol 1992; 72:2081–2089. 114. Bernard GR, NIH NHLBI ARDS Network. Report of ongoing and proposed clinical trials. American Thoracic Society–Lung Association International Conference, San Diego, CA, April 23–28, 1999. 115. Chimosky JE, Spielman WS, Brandt MA, Heidemann SR. Cardiac atria of B10 14.6 hamsters are deficient in natriuretic factor. Science 1984; 233:820–822. 116. Burnett JC Jr, Kao PC, Hu DC, Heser DW, Heublein D, Granger JP, Opgenorth TJ, Reeder GS. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 1986; 231:1145–1147. 117. Genecin P, Groszmann RJ. Portal hypertension. In: Schiff E, Schiff L, eds. Disease of the Liver. Philadelphia: J.B. Lippincott, 1993:935–973. 118. Guarner C, Soriano G, Tomas A, Bulbena O, Novella MT, Balanzo J, Vilardell F, Mourelle M, Moncada S. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993; 18:1139–1143. 119. Pizcueta MP, Pique MJ, Bosch J, Whittle BJR, Moncada S. Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension. Br J Pharmacol 1992; 105:184–190. 120. Whittle BJR, Moncada S. Nitric oxide: the elusive mediator of the hyperdynamic circulation of cirrhosis? Hepatology 1992; 16:1089–1092. 121. Lee FY, Albillos A, Colombato LA, Groszmann RJ. The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats. Hepatology 1992; 16: 1043–1048. 122. Pizcueta P, Pique JM, Fernandez M, Bosch J, Rodes J, Whittle BJR, Moncada S. Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology 1992; 103:1909–1915. 123. Old LJ. Tumor necrosis factor (TNF-α). Science 1985; 230:630–632. 124. Yoshioka K, Kakumu S, Arao M, Tsutsumi Y, Inque M. Tumor necrosis factor-alpha production by peripheral blood mononuclear cells of patients with chronic liver disease. Hepatology 1989; 10:769–773. 125. Khoruts A, Stahnke L, McClain C, Logan G, Allen JI. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentration in chronic alcoholic patients. Hepatology 1991; 13:267–276. 126. Westenfelder C, Taintor R, Vavrin Z, Kablitz C, Baranowski RL, Ward JH, Menlove RL, McMurry MP, Kushner JP, Samlowski WE. Evidence for cytokine-inducible nitric oxide synthesis for L-arginine in patients receivin interleukin-2 therapy. J Clin Invest 1992; 89: 867–877. 127. Kilbourn RG, Bellon P. Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst 1990; 82:772–776. 128. Lo´pez-Talavera JC, Merrill W, Groszmann RJ. Tumor necrosis factor-alpha: a major contributor to the hyperdynamic circulation in prehepatic portal hypertensive rats. Gastroenterology 1995; 108:761–767. 129. Lo´pez-Talavera JC, Cadelina G, Olchowski J, Merrill W, Groszmann RJ. Thalidomide inhibits tumor necrosis factor-alpha, decreases nitric oxide synthesis and amerliorates the hyperdynamic circulator syndrome in portal-hypertensive rats. Hepatology 1996; 23:1616– 1621. 130. Hunt S, Vaamonde CA, Rattass T, Berian MG, Said SI, Papper S. Circulating levels of vasoactive intestinal polypeptide (VIP) in liver disease. Arch Intern Med 1979; 139:994–996.
17 Pathophysiology of Pulmonary Hypertension
JASON X.-J. YUAN and LEWIS J. RUBIN University of California School of Medicine San Diego, California
I.
Introduction
Pulmonary hypertension is not a disease, per se, but a hemodynamic abnormality that is common to a variety of conditions. The primary pulmonary hypertension (PPH) Registry initiated by the National Heart, Lung and Blood Institute in 1981 defined pulmonary hypertension as a mean pulmonary arterial pressure (PAP) greater than 25 mm Hg at rest or 30 mm Hg on exercise (1). It should be recognized, however, that PAP varies with age. Between days 1 and 3 of neonatal life the mean PAP falls, from 6 to 45 years of age it remains fairly constant, and it increases beyond 60 to 83 years of age. Consequently, the mean plus 2 SD gives an upper limit of normal of 20 mm Hg from childhood to approximately 60 years of age. The upper limit for pulmonary vascular resistance (PVR) index [(PAP ⫺ wedge pressure)/cardiac index] in normal subjects increases from approximately 2.8 (6– 10 years) to 3.2 (32 to 45 years) to 4.6 mm Hg/L/min/m2 (60–83 years). The prevalence of pulmonary hypertension in the general population is not known. Based on a measurement of the diameter of the right descending pulmonary artery, it has been suggested that a mean PAP ⬎20 mm Hg is present in about 13% of men between 35 and 44 years of age and that this percentage doubles by the age of 65 to 74 years (28%). The incidence of primary pulmonary hypertension (PPH) has been estimated at one to two per million. The incidence in individuals using anorexigens 447
448
Yuan and Rubin
(e.g., fenfluramine), which have been implicated in PPH, increases with duration of use, and is 25 to 50 per million in users of ⬎3 and 6 months, respectively (2). II. Classification of Pulmonary Hypertension In mechanistic terms, the subdivisions of pulmonary hypertension described by Paul Wood in the 1950s (3,4) are still a useful conceptual framework. These are (1) passive pulmonary hypertension, usually related to elevated pulmonary venous or left heart filling pressures; (2) hyperkinetic pulmonary hypertension, usually secondary to high pulmonary blood flow; (3) obstructive or obliterative pulmonary hypertension, usually associated with either intravascular obstruction, such as emboli, or loss of vessels, as in emphysema or pulmonary fibrosis; and (4) vasoconstrictive pulmonary hypertension, a mechanism that occurs at the early stage of the disease and provides a ‘‘reactive’’ element superimposed on the other causes (5,6). A. Passive Pulmonary Hypertension: Elevated Pulmonary Venous or Left Heart Filling Pressures
Pulmonary hypertension secondary to elevated left heart filling pressures has three components: a passive rise in pulmonary vascular pressure, reactive pulmonary vasoconstriction, and structural remodeling of the pulmonary arterial and venous beds. Dilatation and medial hypertrophy of the pulmonary veins and eccentric intimal fibrosis are seen with elevated left atrial pressures. Capillary congestion may be present, and thickening of the capillary basement membrane occurs when pulmonary venous pressure is chronically elevated. Hemosiderin-laden macrophages are present, due to capillary stress failure or venous rupture. When pulmonary capillary wedge pressure exceeds 20 mm Hg, there is usually an additional rise in mean PAP, the ‘‘reactive’’ component of pulmonary hypertension mentioned by Wood (3,4). This is caused by constriction of the small pulmonary arteries, which can be attenuated in an experimental model by use of an α-adrenergic blocker such as phentolamine or a Ca2⫹ channel blocker such as nifedipine. Patients with mitral stenosis may manifest a modest reduction in pulmonary arterial pressure in response to a short-acting intravenous vasodilator such as acetylcholine. Alleviation of the high downstream pressure, as with repair or replacement of the mitral valve, usually results in a rapid return toward normal of pulmonary arterial pressures as the passive and reactive components are reversed. B. Hyperkinetic Pulmonary Hypertension
Normal subjects can increase pulmonary blood flow four-fold without appreciably changing pulmonary arterial pressure. Similarly, when pulmonary blood flow is increased as a result of a left to right shunt at the atrial level, pulmonary hypertension may reflect only high flow rather than vasoconstriction or vascular remodeling. However, if the high flow is the result of a nonrestrictive ventricular septal defect or a patent ductus arteriosus, the pulmonary circulation is directly exposed to the combination of pressure generated by the left ventricle and the increased flow. Under these
Pulmonary Hypertension
449
circumstances, the changes induced by high flow and pressure may be superimposed on a failure of the remodeling of the small pulmonary arteries that usually occurs in the neonate. The normal involution of the thick arterial media, present in the fetus, fails to occur in the presence of pressure/flow overload. The pathological changes in the pulmonary vasculature associated with high flow shunts have been well described and include medial hypertrophy, extension of smooth muscle into small (usually nonmuscular) pulmonary arteries, intimal proliferation, and concentric intimal fibrosis (7–9). If the intimal fibrosis is mild, the changes may regress after the shunt is closed. Other vascular lesions associated with irreversible pulmonary hypertension include plexiform and dilatation lesions, and necrotizing arteritis. Intimal proliferation of myofibroblasts is also frequently observed in the pulmonary veins (10). The exact sequence of pathophysiological events that results in Eisenmenger syndrome is not known. However, it is likely that the high pressure and flow give rise to increased shear stress that causes endothelial dysfunction (11). This dysfunction can be manifest as a loss of response to endothelium-dependent vasodilators such as nitric oxide (NO) (12,13), and may also be associated with increased synthesis of promoters of vasoconstriction and vascular proliferation such as endothelin (14,15). Platelet deposition is enhanced at high shear rates. Consequently, enhanced production or release of thromboxane A2 and serotonin (5-hydroxytryptamine, 5HT) can cause vasoconstriction and vascular smooth muscle proliferation (16), and growth factors released from the platelets and vascular endothelial cells may contribute to intimal proliferation (17). The production of chemotactic and growth factors by the endothelium is further evidence of endothelial dysfunction. Normally, generation of factors that promote or inhibit migration and proliferation is tightly controlled. Intimal proliferation is due to the abnormal migration of smooth muscle cells from the media through the internal elastic lamina, to lie beneath the endothelium. Proliferation of these cells and the laying down of collagen results in encroachment on the lumen of the small pulmonary arteries. Thrombosis occurs, probably because of loss of the antithrombotic properties of the endothelium, in part due to diminished prostacyclin (PGI2 ) and NO production. C. Obstructive and Obliterative Pulmonary Hypertension
Vascular obstruction is common to many forms of pulmonary hypertension and may be the predominant factor (as in thromboembolic pulmonary hypertension) or may result from vascular remodeling. Pulmonary fibrosis as a cause of pulmonary hypertension comes under the ‘‘obliterative’’ heading, along with several other conditions. In the case of the left to right shunts associated with congenital heart disease, discussed above, the pulmonary hypertension is induced by several mechanisms: the high flow (hyperkinetic) mechanism, the vasoconstriction (reactive) mechanism, and the remodeling (obstructive) mechanism. The overlap in terms of responsible mechanisms is emphasized by the fact that vasoconstriction is an important secondary factor in many forms of pulmonary hypertension (3–6), in addition to obstruction or obliteration.
450
Yuan and Rubin
The histopathologic findings described in the pulmonary hypertension associated with intracardiac shunts are not specific and can also be seen in pulmonary hypertension induced by toxic oil syndrome, HIV infection, familial platelet storage pool disease, and schistosomiasis, or associated with portal hypertension, anorexigen ingestion and PPH (2,18,19). As the number and variety of etiologies increase, it becomes apparent that the plexiform lesion and associated intimal fibrosis are nonspecific responses to injury, most probably of the endothelium, leading to vasoconstriction, thrombosis, and cell migration/proliferation. The particular element that predominates may depend on several factors, such as the age and sex of the patient, the presence of coagulation or fibrinolytic defects, and the degree of vascular reactivity or platelet reactivity. Many of the diseases considered to cause pulmonary hypertension by producing obstruction to blood flow affect only a small percent of the population at risk. For example, the prevalence of pulmonary hypertension is 1.5% in the population exposed to denatured rapeseed oil, indicating that some other factor(s) must predispose susceptible individuals to development of pulmonary vascular disease. The same is true of the occasional instances of pulmonary hypertension in eosinophilia myalgia syndrome, anorexigen use, liver disease, and HIV infection (2,18,19). The recognition that a viral illness can be associated with the histological appearance of plexogenic pulmonary arteriopathy raises the possibility that a viral infection might initiate pulmonary vascular injury in some patients. Several viruses are capable of infecting vascular endothelial cells in culture: Herpes simplex virus type 1 can inhibit proteoglycan synthesis by human vascular endothelial cells. Proteoglycans are important in maintaining a nonthrombogenic surface and in inhibiting smooth muscle proliferation. Therefore, viral inhibition of proteoglycan synthesis could, in theory, explain the intimal proliferation and thrombosis seen in some patients. A viral etiology has been advanced for the rare form of PPH known as pulmonary veno-occlusive disease (18). D. Thrombosis and Platelet Activation
Thrombosis is frequently observed in the small muscular pulmonary arteries of patients who die as a result of severe pulmonary hypertension. Whether endothelial dysfunction is primary or secondary, it is not surprising that thrombosis might ensue or those fibrinolytic mechanisms might be depressed. In PPH, plasma fibrinopeptide A level is elevated and the half-life of fibrinogen is prolonged, indicating enhanced procoagulant activity (20). In addition, fibrinolytic activity has been reported to be reduced in seven members of a family with PPH. The presence of a high level of plasminogen activator inhibitor in as many as 70% of patients in one PPH series also suggests diminished fibrinolytic activity (21). Von Willebrand factor, which is present in platelets and endothelial cells, plays an important role in the adhesion of platelets to a damaged vessel wall and in their aggregation. In patients with pulmonary hypertension secondary to congenital heart disease, the pulmonary vascular endothelium shows a marked increase in the intensity of immunostaining for Von Willebrand factor antigen, implying a flow-induced change (22). Abnormalities of Von Willebrand factor have also been found in PPH (23).
Pulmonary Hypertension
451
Platelet activation secondary to pulmonary hypertension is also indicated by elevated urinary levels of a metabolite of thromboxane in patients with both primary and secondary pulmonary hypertension (24,25). Platelet activation could exacerbate pulmonary hypertension by leading to the release of substances that cause vasoconstriction, such as serotonin (5-hydroxytryptamine) and thromboxane A2, and substances that stimulate cell proliferation, such as platelet-derived growth factor. The evidence of platelet activation, thrombus formation and, in some cases, defects in fibrinolysis, makes it apparent that thrombosis can play an important part in the pathophysiology of many forms of pulmonary hypertension. E. Vasoconstrictive Pulmonary Hypertension
Vasoconstriction is a feature of both clinical and experimental pulmonary hypertension and is the reactive element suggested by Wood (3–5). The presence of vasoconstriction in pulmonary hypertension of several different etiologies provides the rationale for the use of vasodilators to treat these disorders. In a study of the use of Ca2⫹ channel blockers, an acute vasodilator effect could be demonstrated in approximately one-quarter of patients with PPH (26,27). Although the pathophysiology of the vasoconstriction is not certain, it may involve enhancement of the mechanisms intrinsic to the pulmonary vascular smooth muscle that determine tone such as ion channel function; Alternatively, it might be caused by an increase in endotheliumderived constricting factors (EDCF; e.g., thromboxane A2 and endothelin-1) or by a reduction in endothelium-derived relaxing factors (EDRF, e.g., NO and prostacylin). Changes in pulmonary vascular endothelial structure and function are frequently seen in pulmonary hypertension (28). Consequently, it is not surprising that endothelium-dependent pulmonary vasodilatation is impaired in patients with PPH and in the pulmonary arteries of those with end-stage chronic obstructive lung disease (13). A lack of production of other endogenous endothelium-derived relaxing factors probably also contributes to the development of pulmonary hypertension in many of the diseases. These observations also provide the rationale for the ‘‘replacement’’ of endogenous NO by inhaled NO or the infusion of prostacyclin as an approach to reduce pulmonary hypertension. Like the Ca2⫹ blockers, NO and prostacyclin may have efficacy through the inhibition of cell proliferation as well as by inducing vasodilatation (29,30). The excessive synthesis and release of constrictor agents may also induce vasoconstriction. The formation of 5-hydroxytryptamine (serotonin) and thromboxane A2 as a result of platelet aggregation has been mentioned earlier. In addition, increased circulating levels of endothelin-1 have been noted in patients with both primary and some secondary forms of pulmonary hypertension (14,15). Endothelin-1 usually acts as a vasoconstrictor; apart from its vasoactive effects, endothelin-1 also enhances smooth muscle proliferation. Therefore, there are many potential mechanisms that can promote vasoconstriction in the pulmonary circulation. Whether any of them by itself is sufficient to cause pulmonary hypertension remains unclear. F. Summary
Pulmonary arterial pressure (PAP) is a function of pulmonary vascular resistance (PVR) and cardiac output (CO). Thus, increased pulmonary blood flow as a result
452
Yuan and Rubin
of the left-to-right shunt (e.g., in patients with ventricular septal defect, patent ductus arteriosus, and Eisenmenger syndrome) causes elevated PAP, namely hyperkinetic pulmonary hypertension. Since PVR is inversely proportional to the fourth power of the radius (rB.) of pulmonary arterial lumen, very small changes of r would result in large changes in PVR and PAP. Therefore, the major elements that produce increased PVR and lead to elevated PAP in patients with pulmonary hypertension are: vasoconstriction (e.g., in patients with vasoconstrictive pulmonary hypertension), vascular remodeling (thickening of vascular wall), and thrombosis (e.g., in patients with obstructive and obliterative pulmonary hypertension). Altered endothelial production of vasoactive substances could cause pulmonary hypertension. Indeed, recent studies have demonstrated increased expression of endothelin-1 (14,15), a potent vasoconstrictor and mitogen; impaired synthesis of NO (12,13), a potent vasodilator and a cell growth inhibitor (31,32); and an imbalance in the ratio of vasoconstrictive (e.g., thromboxane A2 ) and vasodilative (e.g., prostacyclin) prostanoid metabolites (24,25) in patients with pulmonary hypertension. In pulmonary vasculature, the most important effector of the endotheliumdependent vasoconstrictors and vasodilators is vascular smooth muscle; its contraction-relaxation cycling controls vasomotor tone and its apoptosis-growth alternation regulates vascular wall remodeling. Several lines of evidence suggest that intrinsic abnormalities of pulmonary vascular smooth muscle are present and important in the pathogenesis of pulmonary hypertension. Medial hypertrophy, suggesting active vasoconstriction and smooth muscle proliferation, is the earliest and most consistent pathologic finding of pulmonary hypertension (4,5). Smooth muscle stretch and elevated arterial pressure secondary to vasoconstriction are promotoers of smooth muscle cell hypertrophy and hyperplasia (33,34). Vascular rings from PPH patients are more sensitive to vasoconstrictors compared with rings from normal subjects (35). The effective use of Ca2⫹ channel blockers to treat patients with pulmonary hypertension (26,27) suggests that elevated cytoplasmic free Ca2⫹ concentration ([Ca2⫹ ] cyt ) due to enhanced Ca2⫹ influx in pulmonary artery smooth muscle cells (PASMC) be involved in the development and maintenance of pulmonary hypertension.
III. Cellular Mechanisms of Pulmonary Vasoconstriction and Excitation-Contraction Coupling A common hypothesis is that vasoconstriction and cell proliferation use overlapping signaling processes that result in parallel intracellular events in pulmonary hypertension. Therefore, vasoconstriction and vascular remodeling (including proliferation of smooth muscle cells, endothelial cells and fibroblasts, and abnormal accumulation of connective tissues in pulmonary vessels) constitute two linked phenomena in the lung circulation. Cytoplasmic ionized Ca2⫹ is the most important signal transduction element in triggering cell contraction, proliferation, migration and gene expression (36–41). Therefore, abnormalities in the regulation (handling) of cytoplasmic free Ca2⫹, nuclear Ca2⫹, and intracellularly stored Ca2⫹ would play an important patho-
Pulmonary Hypertension
453
physiological role in the development of pulmonary hypertension (Fig. 1; see also Chapter 12). A. Contraction of Vascular Smooth Muscle
Contraction of vascular smooth muscle permits active changes in diameter (or radius, r) and wall tension of pulmonary blood vessels. Force development (tension) and shortening (contraction) of smooth muscle are functions of its contractile apparatus, which are mainly composed of the contractile proteins, actin and myosin (36). The interaction between actin and myosin, activated by the ATP-dependent phosphorylation of myosin, results in contraction. Physiologically, contraction is triggered by a rise in cytoplasmic free Ca2⫹ concentration ([Ca2⫹ ] cyt ). When [Ca2⫹ ] cyt increases from the basal level (⬃50 to 100 nM) to levels 10⫺7 M, Ca2⫹ binds to calmodulin (CaM), an intracellular Ca2⫹-binding protein. The Ca2⫹ /CaM complex activates myosin light chain kinase (MLCK) that subsequently phosphorylates the myosin light chain. The phosphorylation increases the myosin ATPase activity that hydrolyzes ATP to release energy. The subsequent cycling of the myosin crossbridges produces displacement of the myosin filament in relation to the actin filament and causes contraction. Thus, the contractile state of smooth muscle is governed by the activity of myosin light-chain kinase, which is itself regulated by cytoplasmic Ca2⫹ ions, or [Ca2⫹ ] cyt (36). B. Regulation of Cytoplasmic Free Ca2ⴙ Concentration
In pulmonary artery smooth muscle cells (PASMC), [Ca2⫹ ] cyt can be increased by either Ca2⫹ influx through Ca2⫹ channels in the plasma membrane or Ca2⫹ mobilization from intracellular stores (mainly sarcoplasmic reticulum, SR) (42,43), or by both. [Ca2⫹ ] cyt can be decreased by Ca2⫹ extrusion from cytosol to the extracellular
Figure 1 Role of [Ca2⫹ ] cyt rise in PASMC in the development of elevated pulmonary arterial pressure. MLCK, myosin light chain kinase; CaM, calmodulin; PVR, pulmonary vascular resistance; PAP, pulmonary arterial pressure.
454
Yuan and Rubin
site and Ca2⫹ sequestration into SR through the Ca2⫹-Mg2⫹ ATPase in the plasma membrane and SR membrane, respectively (44,45). The mechanism that causes contraction or relaxation through changes in membrane potential (E m ) is called electromechanical coupling, while the complex of mechanisms that can cause contraction or relaxation by mechanisms not mediated by changes in E m is called pharmacomechanical coupling (36). In the plasma membrane, there are at least two types of Ca2⫹ channels: voltagedependent Ca2⫹ channels which are regulated by changes in E m , and receptor-operated Ca2⫹ channels which are regulated by agonist-receptor interactions. Modulation of these Ca2⫹ channels by various vasoactive substances and pharmacological agents markedly affects [Ca2⫹ ] cyt and the contractile capability of vascular smooth muscle. The major electromechanical coupling mechanism is Ca2⫹ influx through voltagedependent Ca2⫹ channels in the plasma membrane. The most important pharmacomechanical coupling mechanisms include Ca2⫹ influx through receptor-operated Ca2⫹ channels and other Ca2⫹permeable channels (e.g., nonselective cation channels and store-operated Ca2⫹ channels); Ca2⫹ mobilization (release) from intracellular stores (e.g., SR); and modulation of Ca2⫹ sensitivity of the contractile apparatus (36,42,44,45). At least two pathways have been proposed for the release of Ca2⫹ from intracellular stores: Ca2⫹-induced Ca2⫹ release (which is sensitive to caffeine and ryanodine), and inositol 1,4,5-triphosphate (IP3 )-induced Ca2⫹ release (which is sensitive to cyclopiazonic acid and thapsygargin) (37,44). E m in PASMC plays a critical role in regulating [Ca2⫹ ] cyt by governing the activity of voltage-dependent Ca2⫹ channels which are opened by membrane depolarization and closed by membrane hyperpolarization (42,46). Furthermore, membrane depolarization regulates Ca2⫹ mobilization from intracellular stores by facilitating the production of IP3 which opens the Ca2⫹release channels in the SR membrane and triggers Ca2⫹ release (43). Regulation of pulmonary vascular tone and contraction depends largely on resting E m and [Ca2⫹ ] cyt in PASMC (Fig. 2). The effective use of the Ca2⫹ channel blockers, nifedipine and diltiazem (26,27), in pa-
Figure 2 Role of membrane depolarization in the regulation of [Ca2⫹ ] cyt in PASMC.
Pulmonary Hypertension
455
tients with pulmonary hypertension suggests that opening of the dihydropyridinesensitive, voltage-dependent Ca2⫹ channels in PASMC contributes to the development and maintenance of pulmonary hypertension. C. Activity of Kⴙ Channels Regulates E m , [Ca2ⴙ ] cyt , and Pulmonary Vascular Tone
E m in vascular smooth muscle cells is a function of the Na⫹, K ⫹ and Cl⫺ concentration gradients across the plasma membrane and the relative ion permeabilities. In resting cells, E m is controlled primarily by K ⫹ permeability and gradient, because the K ⫹ permeability is much greater than Na⫹ and Cl⫺ ; that is, transmembrane K ⫹ permeability, or transmembrane K ⫹ current, is a key determinant of E m when K ⫹ gradient keeps unchanged (47,48). Transmembrane K ⫹ currents are carried by at least four types of K ⫹ channels in vascular smooth muscle cells: (1) voltage-gated K ⫹ (Kv) channels; (2) Ca2⫹-activated K ⫹ (KCa ) channels; (3) ATP-sensitive or -inhibited K ⫹ (KATP ) channels; and (4) inward rectifier K ⫹ channels (47). It has been demonstrated that, under resting conditions, K ⫹ permeability through Kv channels is responsible for determining E m in pulmonary vascular myocytes (49,50). Thus E m is directly related to the wholecell Kv currents (IK(V) ) that is determined by: IK(V) ⫽ N ⫻ iKv ⫻ Popen where N is the number of membrane Kv channels, iKv is the single-cannel Kv current, and Popen is the steady-state open probability of a Kv channel. When Kv channel closes (iKv or Popen is decreased) and/or Kv channel expression declines (N is decreased), E m becomes less negative (depolarization) because of decreased IK(V). When Kv channel opens (iKv or Popen is increased) and/or Kv channel expression rises (N is increased), E m becomes more negative (hyperpolarization) because of increased IK(V) (Fig. 3).
Figure 3 Role of gene expression of Kv channels in the regulation of membrane potential (E m ).
456
Yuan and Rubin D. Summary
A rise in [Ca2⫹ ] cyt in PASMC is a pivotal element in the development and maintenance of pulmonary hypertension by mediating pulmonary vasoconstriction and stimulating pulmonary vascular smooth muscle proliferation. Sustained increase in [Ca2⫹ ] cyt as a result of persistent membrane depolarization induced by dysfunctional K ⫹ channels may play a critical role in the development of pulmonary hypertension. IV. Role of Intracellular Calcium in Pulmonary Vascular Remodeling Pulmonary arteries are histologically classified as elastic or muscular on the basis of the structure of their tunica media. From the main pulmonary arterial trunk to the peripheral arterioles, as the arteries decrease in size, the number of elastic laminae decreases and the smooth muscle increases. The intima of the pulmonary arteries consists of a single layer of endothelial cells and their basement membrane. The muscular pulmonary arteries are characterized by a muscular media bounded by internal and external elastic laminae. Arteriopathy in patients with pulmonary hypertension includes: medial hypertrophy (an increase in the medial smooth muscle of muscular arteries and the development of a well-defined muscle layer in nonmuscularized arterioles; plexiform and dilatation lesions (intimal thickening and fibrosis); thromboli; and arteritis. Medial hypertrophy and muscularization of arterioles are the morphological hallmarks of chronic pulmonary vasoconstriction (7–9). In vascular smooth muscle cells and cardiac myocytes, Ca2⫹ is not only a major trigger for vasoconstriction (36) but also an important stimulus for cell proliferation (37,38,40). One of the early signals in the mitogenic response is an increase in [Ca2⫹ ] cyt due to Ca2⫹ mobilization from intracellular stores and Ca2⫹ influx through Ca2⫹ channels in the plasma membrane. Following mitogenic stimulation (e.g., platelet-derived growth factors, PDGF), a rise in [Ca2⫹ ] cyt can also rapidly (50 to 300 msec) increase nuclear [Ca2⫹ ] ([Ca2⫹ ]n ) (51), and promote cell proliferation by moving quiescent cells into the cell cycle and by propelling the proliferating cells through mitosis (37–40,52). In cell cycle, there appear to be at least four Ca2⫹-sensitive steps: (1) transitions from G0 (resting state) to G1 phase (the beginning of DNA synthesis); (2) from G1 to S phase (an interphase during which replication of the nuclear DNA occurs); (3) from G2 to M phase (mitosis); and (4) through mitosis (Fig. 4). Furthermore, an increase in [Ca2⫹ ] cyt would also activate Ca2⫹-dependent signal transduction proteins in cytosol and stimulate cell proliferation (37,39). For example, a rise in [Ca2⫹ ] cyt can activate MAP II kinase, which is part of the phosphorylation cascade that lead to activation of DNA synthesis-promoting factor (37,53). A close correlation between intracellularly stored [Ca2⫹ ] and onset of DNA synthesis and proliferation was observed in smooth muscle cells (52,54). Depletion of intracellularly stored Ca2⫹ from the IP3-sensitive Ca2⫹ pool arrests cell growth, and refilling of the intracellular Ca2⫹ stores enables the cells reenter S phase followed by normal cell proliferation. These results indicate that Ca2⫹ pool emptying maintains cells in a G0-like quiescent state; upon refilling of the pools, normal progression
Pulmonary Hypertension
457
Figure 4 Ca2⫹-sensitive steps in cell cycle. Ca2⫹ /CaM, Ca2⫹-calmodulin complex.
into the cell cycle is resumed. It is possible that a specific cell cycle event necessary for G0 to G1 transition depends on signals generated from the IP3-sensitive intracellular Ca2⫹ stores (54). Thus, in addition to triggering vasoconstriction, increased [Ca2⫹ ] cyt may also play an important role in the hypertrophy of small pulmonary arteries and muscularization of pulmonary arterioles.
V.
Pathogenic Role of Dysfunctional Potassium Channels in Pulmonary Hypertension
In pulmonary arterial smooth muscle, as described above, Ca2⫹ is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation. E m is one of the critical determinants of [Ca2⫹ ] cyt because of the voltage-dependence of Ca2⫹ influx through voltage-gated Ca2⫹ channels and Ca2⫹ release from IP3-sensitive intracellular stores (41–43). Persistent membrane depolarization and sustained increase in [Ca2⫹ ] cyt should have a constant stimulatary effect on pulmonary vasoconstriction and PASMC proliferation. Derangement of [Ca2⫹ ] cyt homeostasis and irregularities of [Ca2⫹ ] cyt handling in dysfunctional PASMC are likely to be important in the pathogenesis of pulmonary hypertension. Transmembrane K ⫹ permeability through sarcolemmal K ⫹ channels is the key determinant of E m , thereby playing a central role in controlling [Ca2⫹ ] cyt in PASMC and pulmonary vascular tone. Inhibition of K ⫹ channels induces membrane depolarization that opens voltage-gated Ca2⫹ channels, promotes Ca2⫹ influx, increases [Ca2⫹ ] cyt , and causes pulmonary vasoconstriction and cell proliferation (37,40,42,4 9). Activation of K ⫹ channels induces membrane hyperpolarization, closes voltage-
458
Yuan and Rubin
gated Ca2⫹ channels, diminishes Ca2⫹ influx, decreases [Ca2⫹ ] cyt , and causes pulmonary vasodilation (55,56). Enhancement of outward K ⫹ currents has recently been demonstrated to cause cell apoptosis, whereas reduction of K ⫹ currents by increasing extracellular K ⫹ facilitates cell survival and enhances cell proliferation (57). Pulmonary circulation bears many unique properties that are dramatically different from systemic circulation. One of the important differences is that hypoxia causes pulmonary vasoconstriction (see also Chapter 12), but systemic (e.g., cerebral, renal, and coronary) vasodilatation. Therefore, in its simplest form, pulmonary vasoconstriction can be observed and studied in acute hypoxic pulmonary hypertension. That is, one of the basic and unique mechanisms that determine pulmonary vascular smooth muscle tone is the response to changes in oxygen tension (PO2 ). Furthermore, in patients with PPH, systemic arterial pressure is usually within the normal range, suggesting that hypoxia-induced pulmonary hypertension and primary pulmonary hypertension may share similar pathogenic mechanisms that are intrinsic to pulmonary vasculature. A. Inhibition of Kv Channels Causes Hypoxic Pulmonary Vasoconstriction
Hypoxic pulmonary vasoconstriction (HPV) that directs blood flow away from hypoxic regions of lung is a critical mechanism to ensure maximal oxygenation of blood. Persistent HPV, however, causes pulmonary hypertension that may lead to right heart failure. Hypoxia causes contraction in endothelium-denuded pulmonary artery and in isolated PASMC, suggesting that HPV be an intrinsic property of pulmonary vasculature and the mechanism of HPV involve direct oxygen sensing by PASMC (58,59). HPV is inhibited by Ca2⫹ channel blockers (60) and removal of extracellular Ca2⫹ abolishes HPV, suggesting that Ca2⫹ influx through the dihydropyridine-sensitive, voltage-gated Ca2⫹ channels in the plasma membrane be involved in the development of HPV (61,62). Hypoxia Inhibits Kv Channels, Causes Membrane Depolarization, and Increases [Ca2⫹ ] cyt
Acute hypoxia (reducing O2 tension from 135 to ⬍40 Torr for 1 to 3 min) significantly and reversibly inhibits voltage-gated K ⫹ (Kv) channels and decreases outward K ⫹ currents through the Kv channels in PASMC, but not in mesenteric artery smooth muscle cells (Fig. 5A-C) (63–66). Consistently, acute hypoxia reversibly causes membrane depolarization and elicits Ca2⫹-dependent action potentials apparently by opening voltage-gated Ca2⫹ channels, in PASMC superfused with Ca2⫹-containing solution (Fig. 5D) (58,63). Furthermore, acute hypoxia significantly increases resting [Ca2⫹ ] cyt in PASMC (Fig. 5E); the effect greatly depends on availability of extracellular Ca2⫹. Removal of extracellular Ca2⫹ significantly diminishes, but does not abolish, the hypoxia-induced rise in [Ca2⫹ ] cyt, suggesting that both Ca2⫹ influx and release contribute to the rise in [Ca2⫹ ] cyt during acute hypoxia (67,68). The hypoxiainduced inhibition of Kv channels is selective to PASMC because hypoxia negligibly affects Kv channel activity in systemic (mesenteric, renal) artery smooth muscle
Pulmonary Hypertension
459
Figure 5 Effect of acute hypoxia on IK(V) , E m and [Ca2⫹ ] cyt in PASMC. (A) a family of currents, elicited by depolarizing the cell to test potentials between ⫺80 and ⫹80 mV (holding potential, ⫺70 mV), was recorded before, during and after reduction of PO2 from 150 to 7 Torr in the extracellular solution. (B) the current components that were inhibited by hypoxia. (C-E) summarized data showing hypoxia-induced effects on IK(V) (C), E m (D), and [Ca2⫹ ] cyt (E). MASMC, mesenteric artery smooth muscle cells; Nor, normoxic control; Hyp, hypoxia; Rec, recovery; Nif, nifedipine (10 µM). ***P ⬍ .001 vs. Nor.
460
Yuan and Rubin
cells (Fig 5) (63–65). These results suggest that reduced Kv currents during acute hypoxia initiate E m depolarization and [Ca2⫹ ] cyt increase, which then triggers HPV and hypoxia-induced pulmonary hypertension. Prolonged Hypoxia Inhibits mRNA and Protein Expression of Kv Channels, Causes Membrane Depolarization, and Increases [Ca2⫹ ] cyt
The more chronic forms of hypoxic pulmonary hypertension, such as in patients with hypoxic lung disease (cor pulmonale) and in dwellers residing in high-altitude areas, involve both vasoconstriction and remodeling of the small pulmonary arteries, increased medial thickness, and the development of longitudinal muscle in the intima (9). Indeed, chronic (prolonged) hypoxia (reducing O 2 tension from 135–145 to 25– 35 Torr for 24–72 hours) decreased mRNA expression of the Kv channel α subunits (the pore-forming subunits), Kv1.2 and Kv1.5 (Fig. 6A); the effect appears to be specific to only α subunits because hypoxia negligibly affects the mRNA expression of the Kv channel β subunits, Kvβ1.1, Kvβ2, and Kvβ3 (69). The time course of the hypoxia-induced downregulation of Kv channel mRNA expression is somehow distinct among various Kv channel α subunits: Hypoxia causes a sustained inhibition of Kv1.2 and Kv1.5, but only a transient inhibition of Kv1.4 (Fig. 6A, right panel). These results suggest that hypoxia may affect different Kv channel α subunits by divergent mechanisms. Consistently, the protein levels of Kv1.2 and Kv1.5 are also significantly decreased by prolonged hypoxia (Fig. 6B). The inhibitory effect of hypoxia on Kv channels (e.g., Kv1.5) is selective to PASMC because hypoxia does not affect the mRNA expression of Kv1.5 in mesenteric and aortic artery smooth muscle cells (Yuan et al., unpublished data). The selectivity of hypoxia-induced decrease of Kv currents and inhibition of Kv channel α subunit mRNA expression in PASMC suggests that hypoxia regulate the function and expression of Kv channels via intrinsic mechanisms that uniquely exist in PASMC. Consistent with its inhibitory effect on Kv channel expression, prolonged hypoxia (O2 tension ⫽ 25 to 35 Torr for 60 hours) significantly depolarizes the primary cultured, quiescent PASMC. The similar results are also observed in freshly dissociated PASMC isolated from chronically hypoxic animals (70,71). Studies on kinetics of L-type voltage-gated Ca2⫹ channels and its relationship with [Ca2⫹ ] cyt demonstrate that long-term maintenance of depolarized E m at a range of ⫺35 to ⫺20 mV (a voltage range where the Ca2⫹ channel inactivation is incomplete while the channel activation begins) can open the Ca2⫹ channels sufficiently to cause a sustained increase in [Ca2⫹ ] cyt (46). Indeed, prolonged hypoxia, by causing E m depolarization, significantly increases resting [Ca2⫹ ] cyt in PASMC cultured in serum-deprived medium. The increased [Ca2⫹ ] cyt then causes both pulmonary vasoconstriction and PASMC proliferation (that would lead to vascular remodeling). These observations may help to explain the efficacy of drugs (e.g., NO and prostacyclin) that open K ⫹ channels in causing pulmonary vasodilatation, presumably by hyperpolarizing the cell membrane (55,56,72). Ca2⫹ channel blockers act one step further down the sequence of hypoxic pulmonary vasoconstriction and hypertension.
Pulmonary Hypertension
461
Figure 6 Effects of prolonged hypoxia on mRNA (A) and protein (B) levels of Kv channels in PASMC. (A) PCR-amplified products for Kv1.2 (295 bp) and β-actin (244 bp) are displayed in agarose gel. Cells were incubated in normoxia (Nor) and hypoxia (3% O2 , ⬃25 Torr) for 24 (H24), 36 (H36), 48 (H48), and 60 (H60) hours, respectively. M, marker. Right panel: normalized data (to the amount of β-actin) are means ⫾ SE. (B) Western blot analysis of Kv1.2 and Kv1.5 channel proteins from PASMC incubated under normoxic and hypoxia conditions. Right panel: Normalized data (to the amount of α-actin) are means ⫾ SE. **P ⬍ .01 vs. normoxic control. (From Ref. 69.)
Mechanisms Involved in Hypoxia-Induced Inhibition of Kv Channels and Pulmonary Vasoconstriction
The proposed cellular and molecular mechanism responsible for hypoxic pulmonary vasoconstriction appears to be initiated by the E m depolarization due to hypoxiainduced blockade of Kv channels in PASMC. Opening of voltage-gated Ca2⫹ channels augments Ca2⫹ influx and thereby raises [Ca2⫹ ] cyt. In addition to triggering cell contraction, a rise in [Ca2⫹ ] cyt can activate MAP kinase cascade that stimulates synthesis of transcription factors required for cell proliferation, and rapidly increase nuclear Ca2⫹ and promote cell proliferation by moving quiescent cells into the cell cycle and by propelling the proliferating cells through mitosis.
462
Yuan and Rubin
Hypoxia may inhibit Kv channels via multiple different pathways in order to assure the efficacy and the sensitivity of the response. Acute (short-term) hypoxia may inhibit Kv channel function by (1) inhibiting oxidative phosphorylation (73– 75); (2) changing redox status (65,74); (3) altering a membrane-delimited O2-sensitive regulatory moiety (O2 sensor) that is adjacent or coupled to the channel protein (76); (4) activating mitochondrial NAD(P)H oxidase and increasing superoxide production (77–79); (5) inhibiting cytochrome P450 to synthesize endothelium-derived hyperpolarizing metabolites (80–82); and (6) affecting directly the Kv channel protein. Chronic (prolonged) hypoxia may inhibit Kv channel activity by downregulating mRNA and protein expression of Kv channel α subunits. The underlying molecular mechanisms may include inhibition of gene transcription, decrease of mRNA (and/or protein) stability, up- or down regulations of the transcription factors (e.g., NFκB, c-fos/c-jun, and FixL/FixJ) and signal transduction proteins (e.g., P53, P38, MAP kinase, tyrosine kinase) that directly affect the channels (83,84), and induction of transcription factors that upregulate intermediate inhibitors (e.g., endothelin-1) of the Kv channel genes (85). B. Altered Gene Expression of Kv Channels in Primary Pulmonary Hypertension
The mechanism by which hypoxia induces pulmonary hypertension may also be involved in the vasoconstriction and vascular remodeling present in other types of pulmonary hypertension. Indeed, a defect in the gene expression of Kv channels has been shown to be present in PASMC from patients with PPH (86); the PASMC from PPH patients also demonstrate attenuated K ⫹ channel function (87). PPH is a progressive and fatal disease that is characterized by sustained elevation of pulmonary arterial pressure and pulmonary vascular resistance with unknown cause (1). Currently, the knowledge about the precise cellular mechanisms and pathogenic causes of increased pulmonary vascular resistance (due to an increased vascular tone and an abnormal smooth muscle and endothelial proliferation) in PPH patients is lacking. There are many controversial observations and speculations with respect to the pathogenesis of PPH. Which type of cells, smooth muscle cells or endothelial cells, in the pulmonary vasculature are responsible for the primary pathogenesis is one of the key questions which has attracted extensive study among investigators. Endothelial dysfunction, via a decreased synthesis of endothelium-derived relaxing factors (e.g., NO, prostacyclin) and/or an increased production of endothelium-derived constricting factors (e.g., endothelin-1 and thromboxane A2 ) (12– 14,24,25,28), as well as endothelial cell proliferation, which is uniquely monocolonal in plexiform lesion in PPH (28), may significantly contribute to the vascular abnormalities in pulmonary hypertensive patients. Nevertheless, the only pathologic abnormality in the early stages of PPH is medial (smooth muscle) hypertrophy due to vasoconstriction and smooth muscle proliferation, with little changes in intima (endothelium). This suggests that abnormality in smooth muscle cells may predominate in the early stages of PPH.
Pulmonary Hypertension
463
Attenuated Kv Channel mRNA Expression in PASMC from PPH Patients
The mRNA level of Kv1.5, a noninactivating delayed rectifier Kv channel α subunit, in PASMC from patients with pulmonary hypertension secondary (SPH) to cardiopulmonary diseases (e.g., thromboembolic pulmonary hypertension, scleroderma, cystic fibrosis, pulmonary interstitial fibrosis, Eisenmenger’s syndrome) is similar to that in normal subjects (organ donors, Donor) and patients with nonpulmonary hypertensive disease (NPH) (87). However, the mRNA level of Kv1.5 is significantly lower in PASMC from PPH patients (Fig. 7A). The Kvβ1.1 mRNA level in PPH-PASMC is similar to PASMC from normal subjects and patients with NPH and SPH. These data indicate that the decreased mRNA level of the Kv channel α subunit, Kv1.5, is an intrinsic feature of PASMC from PPH patients. Reduced Whole-Cell IK(V) in PASMC from PPH Patients
The whole-cell IK(V) that regulates resting E m and [Ca2⫹ ] cyt in PASMC is partially determined by the number of membrane Kv channels. Inhibition of Kv1.5 channel transcription by antisense oligodeoxynucleotides specifically targeted on the Kv1.5 gene decreases IK(V) (88). Indeed, the amplitude of the steady-state IK(V) in PPHPASMC is significantly lower than in SPH-PASMC (Fig. 7B), whereas mean pulmonary arterial pressure and total pulmonary resistance are comparable between SPH and PPH patients (46 ⫾ 4 and 11.2 ⫾ 1.7 vs. 53 ⫾ 4 mm Hg and 13.6 ⫾ 3 mm Hg/L/min, respectively) from whom PASMC are isolated (87). In this experiment, IK(V) is isolated when Ca2⫹-activated K ⫹ currents (IK(Ca) ) and ATP-sensitive K ⫹ currents are minimized by using 10 mM EGTA- and 5 mM-ATP containing Ca2⫹-free pipette (intracellular) solution (80). The electrophysiological and molecular biological data are consistent, suggesting that reduced IK(V) amplitude in PPH-PASMC should be attributed, at least in part, to the attenuated Kv1.5 mRNA expression which would decrease the number of the Kv1.5 channels. Depolarized Em and Increased [Ca 2⫹ ] cyt in PASMC from PPH Patients
Consistent with the decreased IK(V), resting E m in PPH-PASMC is more depolarized than in SPH-PASMC (Fig. 7C). In smooth muscle cells, the voltage window of sarcolemmal voltage-gated Ca2⫹ channels for sustained elevation of [Ca2⫹ ] cyt ranges from ⫺40 to ⫺15 mV (46). Therefore, the membrane depolarization in PPHPASMC would promote Ca2⫹ influx and cause sustained elevation of [Ca2⫹ ] cyt (42,46). Indeed, the resting [Ca2⫹ ] cyt in PASMC from PPH patients is significantly higher than in PASMC from SPH patients (Fig. 7D). The ratio of cytosolic free Ca2⫹ concentration ([Ca2⫹ ] cyt ) to the stored [Ca2⫹ ] in SR ([Ca2⫹ ] SR ) is about 1:10,000 (44). Thus, very modest changes in [Ca2⫹ ] cyt may be associated with relatively large changes in stored Ca2⫹ levels. The resting [Ca2⫹ ] cyt in PPH-PASMC is about 25% higher than that in SPH-PASMC, which would be expected to result in a significant rise in [Ca2⫹ ]SR. Indeed, the cyclopiazonic acid (CPA)-induced increase in [Ca2⫹ ] cyt in the absence of extracellular Ca2⫹ (due mainly to Ca2⫹ mobilization from the SR) is significantly augmented in PASMC from PPH patients in comparison with the cells from SPH patients. These results
464
Yuan and Rubin
Figure 7 Kv1.5 mRNA levels (A), whole-cell IK(V) (B), resting E m (C), and [Ca2⫹ ] cyt (D) in PASMC from normal subjects (Donor) and patients with non-pulmonary hypertension disease (NPH), secondary pulmonary hypertension (SPH), and primary pulmonary hypertension (PPH). (A) Left panels: PCR-amplified products displayed in agarose gels for Kv1.5 (300 bp) and β-actin (661 bp) in PASMC from Donor and patients with NPH, SPH, and PPH. M, molecular markers. Right panels: Summarized data that were normalized to amount of βactin are expressed as means ⫾ SE. ***P ⬍ .001 vs. SPH. (B) averaged IK(V) in PASMC from SPH and PPH patients. (C and D) summarized data showing resting E m (C) and [Ca2⫹ ] cyt (D) in PASMC from SPH and PPH patients. ***P ⬍ .001 vs. SPH. (From Refs. 86, 87).
suggest that PASMC from PPH patients have a higher [Ca2⫹ ]SR than SPH-PASMC. Agonist-induced vasoconstriction is triggered by an initial release of Ca2⫹ from SR. The high [Ca2⫹ ]SR may thus be responsible for the augmented agonist-mediated pulmonary vasoconstriction in PPH patients (35). Comparable IK(Ca) in PASMC from SPH and PPH Patients
In cell-attached membrane patches of SPH-PASMC, a large-amplitude IK(Ca) and a small-amplitude IK(V) were elicited by depolarization to ⫹90 mV. In all SPH-PASMC
Pulmonary Hypertension
465
membrane patches tested, IK(V) was observed in 73% of the patches, while in all PPH-PASMC patches tested, IK(V) was observed in only 12% of the patches. Consistent with the whole-cell study, the results from the single-channel study further suggest that the small-conductance IK(V) be diminished in PPH-PASMC in comparison with SPH-PASMC (87). Nevertheless, in the SPH-PASMC membrane patches tested, IK(Ca) was evident in 91% of the patches, while in the PPH-PASMC patches tested, IK(Ca) was observed in 100% of the patches (Fig. 8). The calculated slope conductances of IK(Ca) were 217⫾8 pS (ranging from 196 to 250 pS) and 215⫾7 pS (from 207 to 242 pS) in SPH- and PPH-PASMC (P ⫽ .84), respectively. These data suggest that, although the small-conductance IK(V) is diminished in PPH-PASMC, the large-conductance IK(Ca) be comparable in PASMC from SPH and PPH patients (Fig. 8). Therefore, KCa channels may be a good target to develop therapeutic drugs to interfere with membrane depolarization and [Ca2⫹ ] cyt increase induced by dysfunctional Kv channels.
Figure 8 Comparable large-conductance IK(Ca) in cell-attached membrane patches of PASMC from SPH (A) and PPH (B) patients. (C) percentage of patches from SPH- and PPHPASMC in which IK(Ca) was present (left panel), and averaged slope-conductance of IK(Ca) in SPH- and PPH -PASMC (right panel).
466
Yuan and Rubin Increased [Ca2⫹ ] cyt in Proliferating PASMC
Vascular smooth muscle cells proliferate when cultured in the medium containing serum and growth factors, and become quiescent (growth arrested) when cultured in the medium without serum and growth factors. In PASMC obtained from normal subjects and NPH patients, addition of serum and growth factors (human epidermal growth factor, fibroblast growth factor and insulin) to the culture media significantly increases resting [Ca2⫹ ] cyt (89). As a result of the higher resting [Ca2⫹ ] cyt , the CPAmediated Ca2⫹ transient (due mainly to Ca2⫹ mobilization from IP3-sensitive SR) in the absence of extracellular Ca2⫹ is also greater, in the proliferating PASMC, than that in the quiescent cells. Since Ca2⫹ is an important intracellular signaling molecule controlling cell proliferation, gene expression, and protein synthesis (37–39), these data suggest that an increased [Ca2⫹ ] cyt play an important role in initiating and maintaining PASMC proliferation. In summary, in comparison with PASMC from SPH patients, PASMC from PPH patients have (1) attenuated mRNA expression of the Kv channels (Kv1.5); (2) reduced IK(V) ; (3) comparable IK(Ca): (4) depolarized resting E m ; (5) high resting [Ca2⫹ ] cyt ; and (6) increased intracellularly stored Ca2⫹. The SPH and PPH patients from whom PASMC are isolated have similar hemodynamic characteristics, such as mean pulmonary arterial pressure and total pulmonary resistance. Therefore, the observed changes in Kv1.5 mRNA expression, IK(V), E m , and [Ca2⫹ ] cyt in PPHPASMC are not secondary changes that are attributed to the presence of pulmonary hypertension for an extended period of time. The decreased mRNA expression of the Kv channel α subunit (Kv1.5) and reduced IK(V) are rather intrinsic features of PASMC from PPH patients. C. Summary
The downregulation of Kv channel expression and dysfunction of Kv channels in PASMC from PPH patients appear to be similar to the changes of Kv channel expression and function in PASMC exposed to prolonged and severe hypoxia. In other words, inhibition of Kv channel gene expression and increase in [Ca2⫹ ] cyt are likely the common pathways shared in patients with PPH and hypoxia-induced pulmonary hypertension to trigger and maintain pulmonary vasoconstriction and vascular remodeling. Patients with PPH and hypoxia-induced pulmonary hypertension share several hemodynamic and pathological characteristics: normal systemic arterial pressure, persistent pulmonary vasoconstriction, and excessive pulmonary vascular smooth muscle proliferation. Since the inhibition of Kv channel expression and function is selective to PASMC during hypoxia or in PPH patients, the results indicate that dysfunctional Kv channels may play a pathogenic role in the development of pulmonary hypertension. The molecular and cellular mechanisms by which hypoxia affects Kv channel expression and function, however, may be quite different from those in PPH patients. In PPH, the major mechanisms involved in downregulating Kv channel expression and inhibiting the channel function may include: anorexigens, transcription factors,
Pulmonary Hypertension
467
genetic factors (90), and mutation of Kv channel genes. Abnormalities in transcriptional regulation of Kv channels induced by certain transcription factors (e.g., NFκB, c-fos/c-jun, FixL/FixJ) and signal transduction proteins (e.g., P53 , P38 , Pyk2) may be involved in the decreased Kv channel expression and function both during hypoxia and in patients with PPH. The precise mechanisms responsible for the downregulation of gene expression of Kv channels during hypoxia and in patients with PPH remain incompletely known. VI. Anorexigen-Mediated Pulmonary Hypertension: Effect of Fenfluramine on Potassium Channel Expression Intake of the appetite suppressant fenfluramine is associated with an increased risk of PPH (2). Using PASMC from normotensive (NPH) patients, we studied the effect of fenfluramine on gene transcription and expression of Kv channel α and β subunits. Treatment of the normal PASMC with fenfluramine for 24 to 36 hours significantly decreases mRNA and protein levels of Kv1.4 and Kv1.5, but negligibly affected Kvβ1.1 expression (Fig. 9) (91). In addition, fenfluramine also significantly decreased mRNA level of the pore-forming α subunit of KCa channel, hSlo (data not
Figure 9 The mRNA levels of Kv1.5 (300 bp, A) and Kvβ1.1 (237 bp, A) and the protein level of Kv1.5 (63 kDa, B) in NPH-PASMC before (Cont) and after treatment with fenfluramine (Fen, 200 µM, 60 hours). M, molecular weight marker. Right panels: Data are means ⫾ SE; ***P ⬍ 0.001, *P ⬍ .05 vs. Cont. (From Ref. 91).
468
Yuan and Rubin
shown). The results suggest that the fenfluramine-mediated pulmonary hypertension could be partly due to inhibition of gene transcription and expression of K ⫹ channel α subunits (91). The resultant decrease in K ⫹ current availability (92), membrane depolarization, and increase in [Ca2⫹ ] cyt may play an important role in the development of pulmonary hypertension in the patients who take the appetite suppressant pills over a long period of time. VII. Mechanisms Involved in the Therapeutic Effects of Nitric Oxide and Prostacyclin in Patients with Pulmonary Hypertension Approximately one-quarter of patients with PPH manifest substantial reductions in PAP and increases in cardiac output in response to oral vasodilator administration. The rationale for the use of vasodilators to treat pulmonary hypertension is based on the premise that pulmonary vasoconstriction is a significant contributor to the vascular disease and that even small reductions in afterload will result in substantial improvement in right ventricular function. Although pulmonary vasoconstriction is present to various degrees in some forms of pulmonary hypertension, others are characterized by vascular obstruction or obliteration and vascular-wall remodeling. In the latter setting, long-term application of drugs with vasodilator and other properties will be of benefit because their anti-proliferative or apoptotic effects on pulmonary arterial smooth muscle and endothelial cells. A. NO and Prostacyclin Modulate Pulmonary Vascular Tone by Affecting Ionic Channels, Em, and [Ca2ⴙ ] cyt
NO and prostacyclin are potent endothelium-derived vasodilators (30,93) and inhibitors of smooth muscle cell growth (9,94). Clinically, NO and prostacyclin are effectively used to treat patients with primary and secondary forms of pulmonary hypertension. Short-term infusion of prostacyclin and inhalation of NO decrease pulmonary vascular resistance (30,93), while longterm therapy with prostacyclin produces sustained symptomatic and hemodynamic improvement as well as improved survival in PPH patients (29). NO exerts its vasodilator effect, in part, by activating KCa and Kv channels (55,56), which subsequently causes membrane hyperpolarization (Fig. 10), decreases [Ca2⫹ ] cyt (56,57) and causes pulmonary vasodilation. The effect can be directly mediated by the nitrosylation or oxidization effect on the channel protein and/or indirectly mediated by the increase of cGMP production. NO can also decrease [Ca2⫹ ] cyt by inhibiting agonist-induced Ca2⫹ release (95) and enhancing Ca2⫹ extrusion (96) and sequestration into SR (57,97). In human pulmonary artery, the vasodilator effect of prostacyclin may be partially caused by activating K ⫹ channels (72). Indeed, extracellular application of prostacyclin significantly and reversibly activates the large-conductance IK(Ca) and decreases resting [Ca2⫹ ] cyt in PASMC (Fig. 11). These results suggest that the therapeutic effects of prostacyclin and NO may be, at least in part, due to membrane hyperpolarization induced by enhanced K ⫹ (both KCa and Kv ) currents and de-
Figure 10 Hyperpolarizing effect of NO, derived from the NO donor, sodium nitroprusside (SNP, 5 µM), in PASMC. E m was measured using current-clamp technique.
Figure 11 Effects of PGI2 on large-conductance IK(Ca) and resting [Ca2⫹ ] cyt in PASMC. (A) the single-channel currents were recorded in cell-attached membrane patches before (Control), during (PGI2 ) and after (Washout) application of 100 nM prostacyclin (PGI2 ). Horizontal broken lines denote the current level when the channels are closed. (B) the whole-cell currents were recorded before (Cont) and during (PGI2 ) application of 10 µM prostacyclin. (C) [Ca2⫹ ]cyt was measured in the peripheral area of a cell superfused with the solutions without or with prostacyclin.
470
Yuan and Rubin
creased [Ca2⫹ ] cyt (that resulted from augmented Ca2⫹ extrusion and sequestration into the intracellular stores). B. Inhibitory Effect of PGI2 on Pulmonary Artery Endothelial Cell Proliferation
Continuous intravenous infusion of prostacyclin is the only agent which is approved by the Food and Drug Administration for the treatment of PPH (1). In clinical trials, prostacyclin has been shown to reduce pulmonary arterial pressure and pulmonary vascular resistance, increase exercise capacity, and prolonge life in patients refractory to therapy with Ca2⫹ channel blocking agents. The beneficial effects of chronic therapy with prostacyclin appear to be, at least in part, due to properties of the drug other than vasodilatation, since improvement has been observed in patients in the absence of acute vasodilator effects. These observations suggest that prostacyclin have a beneficial effect on vascular remodeling, such as a direct effect of the drug on smooth muscle and endothelial cell proliferation. Lee et al. (28) recently demonstrate that the endothelial cell proliferation in plexiform lesion in PPH is uniquely monoclonal and plays an etiological role in the development of PPH. In pulmonary artery endothelial cells from normal subjects, chronic treatment with prostacyclin significantly inhibits cell growth in the presence of serum and growth factors (Fig. 12). These results suggest that, in addition to
Figure 12 Inhibitory effect of prostacylin (PGI2 ) on human pulmonary artery endothelial cell growth. The cells were cultured (for 13 days after plating) in endothelium basal medium (EBM, without serum and growth factors), endothelium growth medium (EGM: EBM supplemented with 2% fetal bovine serum, 10 ng/ml human epidermal growth factor, 12 µg/ml bovine brain extract, and 1µg/mL hydrocortisone), and EGM with 100 µM PGI2, respectively Cells were counted every 3 days using a hemacytometer.
Pulmonary Hypertension
471
activating K ⫹ channels in PASMC, prostacyclin also attenuates pulmonary vascular resistance in PPH patients by inhibiting pulmonary endothelial cell proliferation. C. Summary
The possible mechanisms by which NO and prostacyclin treat patients with primary and secondary forms of pulmonary hypertension include (1) activating K ⫹ (Kv and KCa ) channels; (2) causing membrane hyperpolarization; (3) decreasing [Ca2⫹ ] cyt by augmenting Ca2⫹ extrusion and sequestration and blocking Ca2⫹ release; and (4) inhibiting pulmonary arterial endothelial and smooth muscle cell proliferation. To search for drugs that can restore dysfunctional Kv channels by stimulating the channel’s expression and increasing the channel’s conductance in PPH-PASMC and that can selectively open other K ⫹ channels (e.g., KCa and KATP channels) would be greatly beneficial in the treatment of pulmonary hypertension. VIII. Summary and Conclusion This discussion of the pathophysiology of pulmonary hypertension makes it clear that many diseases can give rise to pulmonary hypertension. However, the range of responses of the pulmonary vasculature to these pathologic stimuli is limited, once the initiation of the vascular injury has taken place. Pulmonary vasoconstriction, vascular wall remodeling, and thrombosis all contribute to the increase of pulmonary vascular resistance and the development or progression of pulmonary hypertension. A defect in the gene expression of Kv channels in PASMC, leading to a decrease of whole-cell IK(V) and membrane depolarization, appears to be an important cause for elevating [Ca2⫹ ] cyt . A rise in [Ca2⫹ ] cyt is not only the major trigger for pulmonary vasoconstriction but also a critical stimulus for vascular smooth muscle proliferation (Fig. 13). Impaired production of endothelium-derived relaxing factors (EDRF, e.g., NO and prostacyclin), increased production of endothelium-derived constricting factors (EDCF; e.g., endothelin-1 and thromboxane A2 ), and elevated [Ca2⫹ ] cyt in PASMC potentiate the vasoconstriction and vascular-wall thickening, and cause or contribute to progressive pulmonary hypertension. Development of therapeutic approaches targeting plasma membrane K ⫹ channels and intracellular Ca2⫹ homeostasis may be useful approaches to treat patients with pulmonary hypertension. Acknowledgments The authors would like to express their appreciation for the support of the work by the PPH Cure Foundation, the PPH Research Foundation, and the National Institutes of Health (HL 54043 and HL 64945). Dr. J.X.-J. Yuan is an Established Investigator of the American Heart Association. We also appreciate J. Wang, M.D., A.M. Aldinger, B.S., M. Juhaszova, Ph.D., A.E. Bakst, M.D., E.A. Weiner, M.D., O. Platos-
472
Yuan and Rubin
Figure 13 Schematic diagram depicting the proposed cellular mechanisms responsible for the development of pulmonary hypertension. The process appears to be initiated by abnormal gene transcription and expression of KV channels induced by anorexigen, hypoxia and other unknown genetic and exogenous factors. The resultant reduction of IK(V) causes membrane depolarization and opens voltage-gated Ca2⫹ channels. Increased Ca2⫹ influx through sarcolemmal Ca2⫹ channels and Ca2⫹-induced Ca2⫹ release from intracellular Ca2⫹ stores (mainly sarcoplasmic reticulum, SR) raise [Ca2⫹ ] cyt , which triggers pulmonary vasoconstriction. A rise in [Ca2⫹ ] cyt also increases Ca2⫹ concentration in nuclei ([Ca2⫹ ]n ) and stimulates cell proliferation, which causes pulmonary vascular remodeling. Endothelium-derived relaxing factors (EDRF, e.g., NO and prostacyclin, PGI2 ) may participate in regulating E m and [Ca2⫹ ] cyt through their activation of K ⫹ (KCa and KV ) channels and/or inhibition of voltage-gated Ca2⫹ channels in PASMC. Endothelium-derived constricting factors (EDCF; e.g., endothelin-1) may participate in regulating E m and [Ca2⫹ ] cyt by inhibiting K ⫹ (KCa and KV ) channels and/ or activating voltage-gated Ca2⫹ channels in PASMC. (⫹), increase (or enhance), (⫺) decrease (or inhibit). (From Ref. 87.)
Pulmonary Hypertension
473
hyn, M.S., C.L. Bailey, M.D., S.S. McDaniel, B.A., J.V. Conte Jr., M.D., S.P. Gaine, M.D., and G. Yung, M.D. for their assistance and contribution to the study.
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111–117. Abenheim L, Moride Y, Brenot F, Rich S, Benichou B, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335:509–516. Wood P. Disease of the Heart and Circulation, 2nd ed. (Philadelphia: J.P. Lippincott, 1956. Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958; 20:557–570. Wagenvoort CA. Vasoconstriction and medial hypertrophy in pulmonary hypertension. Circulation. 1960; 22:535–546. Palevsky HI, Schloo BL, Pietra GG, Weber KT, Janicki JS, Rubin E, Fishman AP. Primary pulmonary hypertension, Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation 1989; 80:1207–1221. Pietra GG. The pathology of primary pulmonary hypertension. In: Rubin LJ, Rich S, eds. Primary Pulmonary Hypertension. New York: Marcel Dekker, 1997:19–61. Reid LM, Davies P. Control of cell proliferation in pulmonary hypertension. In: Weir EK, Reeves JT, eds. Pulmonary Vascular Physiology and Pathophysiology. New York: Marcel Dekker, 1989:541–641. Stenmark KR, Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol 1997; 59:89–144, 1997. Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 1995; 146(2):389–397, 1995. Davies PF, Tripathi SC. Mechanical stress mechanisms and the cell: an endothelial paradigm. Circ Res 1993; 72:239–245. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333:214–221. Dinh-Xuan AT, Higenbottam TW, Clelland CA, Pepke-Zaba J, Cremona G, Butt AY, Large LR, Wells FC, Wallwork J. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 1991; 324:1539–1547. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328:1732–1739. Cacoub P, Dorent R, Nataf P, Carayon A, Riquet M, Noe E, Piette JC, Godeau P, Gandjbakhch I.. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc. Res 1997; 33:196–200. Fanburg BL, Lee S-L. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 1997; 272:L795-L806. Voelkel NF, Hoeper M, Maloney J, Tuder RM. Vascular endothelial growth factor in pulmonary hypertension. Ann NY Acad Sci 1996; 796:186–193. Golpe R, Fernandez-Infante B, Fernandez-Rozas S. Primary pulmonary hypertension associated with human imunodeficiency virus infection. Postgrad Med J 1998; 74:400–404. Kuo PC, Plotkin JS, Gaine S, Schroeder RA, Rustgi VK, Rubin LJ, Johnson LB. Portopulmonary hypertension and the liver transplant candidate. Transplantation 1999; 67(8):1087– 1093. Eisenberg PR, Lucore C, Kaufman L, Sobel BE, Jaffe AS, Rich S. Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 1990; 82(3):841–847. Welsh Ch, Hassell KL, Badesch DB, Kressin DC, Marlar RA. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996; 110(3):710–717.
474 22. 23. 24. 25. 26. 27. 28. 29.
30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46.
Yuan and Rubin Lopes AA, Maeda NY. Circulating von Willebrand factor antigen as a predictor of shortterm prognosis in pulmonary hypertension. Chest 1998; 114(5):1276–1282. Geggel RL, Carvalho AC, Hoyer LW, Reid LM. Von Willebrand factor abnormalities in primary pulmonary hypertension. Am Rev Respir Dis 1987; 135(2):294–299. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327:70–75. Cacoub P, Dorent R, Carayon A. Thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327:1456–1457. Rich S, Kaufmann E, Levy PA. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327:76–81. Rubin LJ, Nicod P, Hillis LD, Firth BG. Treatment of primary pulmonary hypertension with nifedipine. A hemodynamic and scintigraphic evaluation. Ann Intern Med 1983; 99: 433–438. Lee SD, Shroyer SR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998; 101(5):927–934. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jobsis MM, Blackburn SD Jr, Shortino D, Crow JW. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334:296–301. Rubin LJ, Groves BM, Reeves JT, Frosolono M, Handel F. Prostacyclin-induced pulmonary vasodilation in primary pulmonary hypertension. Circulation 1982; 66:334–338. Kolpakov V, Gordon D, Kulik TJ. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res 1995; 76(2):305– 309. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109–121. Hishikawa K, Nakaki T, Maruno T, Hayashi M, Suzuki H, Kato R, Saruta T. Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. J Clin Invest 1994; 93:1975–1980. Kolpakov V, Rekhtar MD, Gordon D, Wang WH, Kulik TJ. Effect of mechanical forces on growth and matrix protein synthesis in the in vitro pulmonary artery, analysis of the role of individual cell types. Circ Res 1995; 77:823–831. Brink C, Cerrina C, Labat C, Veley J, Benveniste J. The effects of contractile agonists on isolated pulmonary arterial and venous muscle preparations derived from patients with primary pulmonary hypertension. Am Rev Respir Dis 1988; 137(part 2):A106. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994; 372:231–236. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature 1993; 361:315–325. Berridge MJ. Calcium signaling and cell proliferation. BioEssays 1995; 17:491–500. Clapham DE. Calcium signaling. Cell 1995; 80:259–268. Means AR. Calcium calmodulin and cell cycle regulation. FEBS Lett 1994; 347:1–4. Ginty DD. Calcium regulation of gene expression: isn’t that spatial? Cell 1997; 18:183– 186. Nelson MT, Patlak JB, Worley JF, Standen NB. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol 1990; 259:C3–C18. Ganitkevich VY, Isenberg G. Membrane potential modulates inositol 1,4,5-trisphosphatemediated Ca2⫹ transients in guinea-pig coronary myocytes. J Physiol 1993; 470:35–44. Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca2⫹ stores and cell responsiveness. Am J Physiol 1993; 264:C1367–1387. Van Breemen C, Saida K. Cellular mechanisms regulating [Ca2⫹ ]i smooth muscle. Annu Rev Physiol 1989; 51:315–329. Fleischmann BK, Murray RK, Kotlikoff MI. Voltage window for sustained elevation of cytosolic calcium in smooth muscle cells. Proc Natl Acad Sci USA 1994; 91:11914– 11918.
Pulmonary Hypertension 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
475
Nelson MT, Quayle JM. Physiological Roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 268:C799-C822. Yuan JX-J, Blaustein MP. Cellular potassium transport. In: Izzo JL Jr, Black HR, eds. Hypertension Primer: The Essentials of High Blood Pressure, 2nd ed. Dallas: American Heart Association 1999:56–57. Yuan, X-J. Voltage-gated K⫹ currents regulate resting membrane potential and [Ca2⫹ ] i in pulmonary arterial myocytes. Circ Res 1995; 77:370–378. Evans AM, Osipenko ON, Gurney AM. Properties of a novel K ⫹ current that is active at resting potential in rabbit pulmonary artery smooth muscle cells. J Physiol (Lond) 1996; 496(2):407–420. Allbritton NL, Oancea E, Kuhn MA, Meye T. Source of nuclear calcium signals. Proc Natl Acad Sci USA 1994; 91:12458–12462. Mogami H, Kojima I. Stimulation of calcium entry is prerequisite for DNA synthesis induced by platelet-derived growth factor in vascular smooth muscle cells. Biochem Biophys Res Commun 1993; 196(2):650–658. Chao T-S, Byron KL, Lee KM, Villereal M, Rosner MR. Activation of MAP kinases by calcium-dependent and calcium-independent pathways: stimulation by thapsigargin and epidermal growth factor. J Biol Chem 1992; 267(28):19876–19883. Short AD, Bian J, Ghosh TK, Waldron RT, Rybak SL, Gill DL. Intracellular Ca2⫹ pool content is linked to control of cell growth. Proc Natl Acad Sci USA 1993; 90:4986–4990. Archer SL, Huang JMC, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP- dependent protein kinase. Proc Natl Acad Sci USA 1994; 91:7583–7587. Yuan X-J, Tod ML, Rubin LJ, Blaustein MP. NO hyperpolarizes pulmonary artery smooth muscle cells and decreases the intracellular Ca2⫹ concentration by activating voltage-gated K ⫹ channels. Proc Natl Acad Sci USA 1996; 93:10489–10494. Yu SP, Yeh C-H , Sens SL, Gwag BJ, Canzoniero LMT, Farhangrazi ZS, Ying HS, Tian M, Dugan LL, Choi DW. Mediation of neuronal apoptosis by enhancement of outward potassium current. Science 1997; 278:114–17. Yuan X-J. Mechanisms of hypoxic pulmonary vasoconstriction: The role of O2-sensitive voltage-gated K ⫹ channels. In: Lopez-Barnes J, Weir EK, eds. Oxygen Regulation of Ion Channels and Gene Expression. New York: Futura, 1998:207–233. Murray TR, Chen L, Marshall BE, Macarak EJ. Hypoxic contraction of cultured pulmonary vascular smooth muscle cells. Am J Respir Cell Mol Biol 1990; 3:457–465. McMurtry IF, Davidson AB, Reeves JT, Grover RF. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res 1976; 38:99–104. Harder DR, Madden JA, Dawson C. Hypoxic induction of Ca2⫹-dependent action potentials in small pulmonary arteries of the cat. J Appl Physiol 1985; 59:1389–1393. Madden JA, Dawson CA, Harder DR. Hypoxia-induced activation in small isolated pulmonary arteries from the cat. J Appl Physiol 1985; 59:113–119. Yuan X-J, Goldman WF, Tod ML, Rubin LJ, Blaustein MP. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol 1993; 264:L116–L123. Post JM, Hume JR, Archer SL, Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 1992; 262:C882–C890. Archer SL, Huang J, Henry T, Peterson D, Weir EK. A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 1993; 73:1100–1112. Patel AJ, Lazdunski M, Honore E. Kv2.1/Kv9.3, a novel ATP-dependent delayed-rectifier K ⫹ channel in oxygen-sensitive pulmonary artery myocytes. EMBO J 1997; 16:6615–6625. Salvaterra CG, Goldman WF. Acute hypoxia increases cytosolic calcium in cultured pulmonary arterial myocytes. Am J Physiol 1993; 264:L323–L328. Vadula MS, Kleinman JG, Madden JA. Effect of hypoxia and norepinephrine on cytoplasmic free Ca2⫹ in pulmonary and cerebral arterial myocytes. Am J Physiol 1993; 265:L591–L597. Wang J, Juhaszova M, Rubin LJ, Yuan X-J. Hypoxia inhibits gene expression of voltagegated K ⫹ channel α subunits in pulmonary artery smooth muscle cells. J Clin Invest 1997; 100:2347–2353. Shimoda LA, Sylvester JT, Sham JSK. Chronic hypoxia alters effects of endothelin and
476
71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90.
Yuan and Rubin angiotensin on K ⫹ currents in pulmonary arterial myocytes. Am J Physiol 1999; 277:L431– L439. Smirnov SV, Robertson TP, Ward JPT, Aaronson PI. Chronic hypoxia is associated with reduced delayed rectifier K ⫹ current in rat pulmonary artery muscle cells. Am J Physiol 1994; 266:H365–H370. Hall S, Balock M, Clapp LH. Evidence that prostacyclin relaxes isolated guinea-pig aortic muscle strips through activation of Ca2⫹-activated K ⫹ channels. J Physiol 1995; 483:115P– 116P. Evans AM, Clapp LH, Gurney AM. Augmentation by intracellular ATP of the delayed rectifier current independently of the glibenclamide-sensitive K-current in rabbit arterial myocytes. Br J Pharmacol. 1994; 111(4):972–974. Yuan X-J, Tod ML, Rubin LJ, Blaustein MP. Deoxyglucose and reduced glutathione mimic the effects of hypoxia on K ⫹ and Ca2⫹ conductances in pulmonary artery cells. Am J Physiol 1994; 267:L52–L63. Yuan X-J, Sugiyama T, Goldman WF, Rubin LJ, Blaustein MP. A mitochondrial uncoupler increases KCa currents but decreases KV currents in pulmonary artery myocytes. Am J Physiol 1996; 270:C321–C331. Haddad GG, Jian C. O2-sensing mechanisms in excitable cells: role of plasma membrane K ⫹ channels. Annu Rev Physiol 1997; 59:23–43. Marshall C, Mamary AJ, Verhoeven AJ, Marshall BE. Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction. Am J Respir Cell Mol Biol 1996; 15(5): 633–644. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 1998; 95(20):11715–11720. Waypa GB, Chandel NS, Kulisz A, Schumacker PT. Mitochondrial reactive oxygen species are involved in hypoxic pulmonary vasoconstriction (HPV). Am J Respir Crit Care Med 1999; 159(3):A569. Yuan X-J, Tod ML, Rubin LJ, Blaustein MP. Inhibition of cytochrome P-450 reduces voltage-gated K ⫹ currents in pulmonary arterial myocytes. Am J Physiol 1995; 268:C259– C270. Campbell WB, Harder DR. Endothelium-derived hyperpolarizing factors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone. Circ Res 1999; 84(4): 484–488. Lombard JH, Kunert MP, Roman RJ, Falck JR, Harder DR, Jackson WF. Cytochrome P450 omega-hydroxylase senses O2 in hamster muscle, but not cheek pouch epithelium, microcirculation. Am J Physiol 1999; 276:H503–H508. Fanburg BL, Massaro DJ, Cerutti PA, Gail DB, Berberich MA. Regulation of gene expression by O2 tension. Am J Physiol 1992; 262:L235–L241. Bunn HF, Poyton RO. Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 1996; 76:839–885. Shimoda LA, Sylvester JT, Sham JSK. Inhibition of voltage-gated K ⫹ current in rat intrapulmonary arterial myocytes by endothelin-1. Am J Physiol 1998; 274:L842–L853. Yuan X-J, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K ⫹ channel gene transcription in primary pulmonary hypertension. Lancet 1998; 351(9104):726–727. Yuan JX-J, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. Dysfunctional voltage-gated K ⫹ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998; 98:1400–1406. Feng J, Wible B, Li G-R, Wang Z, Nattel S. Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K ⫹ current in cultured adult human atrial myocytes. Circ Res 1997; 80:572–579. Golovina VA. Cell proliferation is associated with enhanced capacitative Ca2⫹ entry in human arterial myocytes. Am J Physiol 1999; 277:C343–C349. Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA III, Newman JH, Conneally PM, Ginsburg D, Loyd JE. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nature Genet 1997; 15:277–280.
Pulmonary Hypertension 91. 92.
93. 94. 95. 96. 97.
477
Wang J, Juhaszova M, Conte JV, Jr, Gaine SP, Rubin LJ, Yuan JX-J. Action of fenfluramine on voltage-gated K ⫹ channels in human pulmonary-artery smooth-muscle cells. Lancet 1998; 352(9124):290. Weir EK, Reeve HL, Huang JMC, Michelakis E, Nelson DP, Hampl V, Archer SL. Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 1996; 93: 2216–2220. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338:1173–1174. Orekhov AN, Tertov VV, Smirnov VN. Prostacyclin analogues as antiatherosclerotic drugs. Lancet 1983; 2:521. Yuan X-J, Bright RT, Aldinger AM, Rubin LJ. Nitric oxide inhibits serotonin-induced calcium release in pulmonary artery smooth muscle cells. 1997; Am J Physiol 1997; 272:L44– L50. Kannan MS, Prakash YS, Sieck GC. Nitric oxide inhibits calcium release from sarcoplasmic reticulum of porcine tracheal smooth muscle cells. Am J Physiol 1997; 272:L1–L7. Twort CHC, van Breemen C. Cyclic guanosine monophophate-enhanced sequestration of Ca2⫹ by sarcoplasmic reticulum in vascular smooth muscle. Circ Res 1988; 62:961–964.
18 Effect of Systemic Inflammation on Cardiovascular Function
BRADLEY D. FREEMAN
CHARLES NATANSON
Washington University School of Medicine St. Louis, Missouri
National Institutes of Health Bethesda, Maryland
I.
Introduction
Despite therapeutic advances, sepsis and septic shock continue to be leading causes of morbidity and mortality in critically ill patients (1). Over the last decade, the incidence of sepsis in U.S. hospitals has increased dramatically, resulting in part from an aging patient population and increasing use of immunosuppressive therapies and life-sustaining treatments (2). Based on our current understanding, this syndrome appears to result from an infectious nidus which has successfully circumvented host defensive barriers (e.g., skin and mucous membranes) (3). Subsequently, due to unique aspects of a given pathogen’s virulence and the host’s immune response, local defenses become overwhelmed, leading to bloodstream invasion by the pathogen, and systemic release of pathogenic products (Fig. 1). The result is activation of systemic host defenses including plasma factors (complement, clotting cascades) and cellular components (neutrophils, monocytes, lymphocytes, macrophages, endothelial cells), which in turn release potentially toxic mediators (cytokines, kinins, eicosanoids, platelet-activating factor, nitric oxide, etc.) that potentiate the inflammatory response (Fig. 2). Unchecked, this escalating immune response, in concert with microbial toxins, leads to hemodynamic instability, organ dysfunction, and death.
479
480
Freeman and Natanson
Figure 1 The pathogenesis and treatment of septic shock. Solid black arrows follow the pathogenesis of septic shock beginning with a nidus of infection and ending in shock and multiorgan system failure. Open arrows represent potential treatment strategies. (From Ref. 3.)
Figure 2 Potential therapeutic targets in the inflammatory cascade. This diagram illustrates a model in which the presence of infection elicits the activation of plasma protein systems and the release of complex cascades of mediators resulting in the sepsis syndrome. Many of these mediators have been targeted in clinical sepsis trials. (From BioWorld Financial Watch, American Health Consultants Inc., Atlanta.)
Systemic Inflammation
481
The hypothesis that excessive inflammation was the principal abnormality underlying the sepsis syndrome prompted the development of therapeutic agents inhibiting specific mediators of the inflammatory cascade (Fig. 2). The biologic activity of these agents, however, appeared to depend in large part on the experimental system in which they were studied. For example, compounds such as TNF-specific antibodies or IL-1 receptor antagonists appeared markedly beneficial when administered in animal models of sepsis, but either failed to show a benefit in numerous prospective randomized human studies, or had only a marginally favorable effect when these studies were considered as a meta-analysis (1,3,4). The collective experience with these anti-inflammatory treatments suggests that our current understanding of how excessive inflammation mediates the physiologic derangements of this syndrome is, at most, incomplete. Myocardial dysfunction is one of the cardinal physiologic manifestations of sepsis and contributes substantially to the morbidity and mortality of this syndrome. To date, the mechanisms responsible for this cardiovascular abnormality or, for that matter, all forms of sepsis-induced organ injury have resisted clear definition. For the past 15 years, we have focused our efforts on characterizing and understanding this phenomenon in both animal models and patients with sepsis. In this chapter, we will review studies performed in our laboratory as well as those reported by other investigators, with particular emphasis on the role of bacterial and host products as central mediators of this abnormality. It is our hope that increased insight into the mechanisms underlying sepsis-induced myocardial dysfunction will ultimately translate into more effective therapies in this syndrome.
II. Descriptive Studies A. Physiologic Response of the Heart to Sepsis
Our interest in the cardiovascular abnormalities occurring during sepsis arose from the observation that patients with sepsis and septic shock developed profound but reversible myocardial depression (5,6). In our initial studies, we focused on better characterizing the nature of these sepsis-induced derangements, and understanding their temporal profile. As an experimental system, we used an awake canine E. coli peritonitis model. We used indwelling arterial and right-heart catheters in conjunction with radionuclide-cineangiography in these animals to allow us to serially measure cardiac output (CO) and left ventricular ejection fraction (LVEF). From these measurements, we could calculate LV end-diastolic volume index (LVEDI) (e.g., LVEDVI ⫽ CO/(HR ⫻ LVEF ⫻ weight). We found that within 24 hours of the onset of sepsis, a decrease in LVEF, and with volume resuscitation, an increase in LVEDVI occurred (Fig. 3). CO, following fluid resuscitation, remained unchanged or increased slightly. Thus, it appeared that preservation of CO in these animals occurred by sepsis-induced tachycardia and maintenance of stroke volume through fluid resuscitation-associated LV dilatation (e.g., Frank-Starling mechanism) (7). (See Chapter 29 for more discussion on control of CO in sepsis.) Comparable changes occurred in right ventricular function. These abnormalities totally resolved
482
Freeman and Natanson
Figure 3 Changes in cardiac function occurring during sepsis. This figure illustrates how cardiac output is maintained during septic shock despite depressed LV ejection fraction. The hearts are shown at end-diastole, or maximum filling, at three separate time points, presepsis (baseline), day 1 to 4 of sepsis, and postsepsis (recovery). The shaded area corresponds to end-systolic volume; the hatched area corresponds to stroke volume. These two areas combined are the end-diastolic volume. On days 1 through 4 of sepsis, the LV ejection fraction decreases, but, because the heart increases in size (large enddiastolic volume), stroke volume is maintained or increased. (From Ref. 44.)
by 7 to 10 days in animals surviving the septic insult (7). The hemodynamic profile we observed in our canine model was identical to that observed in patients with sepsis, suggesting that our experimental system was suitable for further investigating the mechanisms underlying sepsis-induced myocardial changes (5,6). (Fig. 4). B. Determinants of Cardiovascular Dysfunction
Role of Infecting Agent
Our studies of the cardiovascular dysfunction of sepsis first focused on understanding the characteristics of microbial pathogens important in producing hemodynamic abnormalities. Specifically, we examined the roles of bacterial dose, endotoxin con-
Systemic Inflammation
483
Figure 4 Serial LVEF vs. time in (A) humans and (B) canines with septic shock. The hatched region in (A) represents the normal range. Individual LVEFs are indicated by circles; lines connect days. In both humans with septic shock and animals challenged with bacteria, the LVEF markedly decreases over 1 to 2 days and recovers in 7 to 10 days. The similarity in profile of cardiovascular dysfunction comparing humans and canines suggests that our canine model is useful for understanding sepsis induced cardiac abnormalities. (From Ref. 7.)
tained within the bacterial cell wall (e.g., gram-positive vs. gram-negative organisms), and factors associated with bacterial virulence, in producing this syndrome. Dose of Bacteria
To study the relationship between the size of the bacterial inoculum and cardiovascular dysfunction, we challenged animals intraperitoneally with varying colony counts of E. coli (8). We found that increasing E. coli colony counts produced a dosedependent increase in both the magnitude of cardiovascular dysfunction and lethality. These cardiac abnormalities included decreases in LVEF, progressive LV dilatation, and shifts on LV function curves (LV stroke work index vs. EDVI, and peak systolic pressure vs. end-systolic volume index). As in our prior studies, cardiovascular abnormalities were greatest at 2 to 3 days after clot implantation, and full recovery occurred by 10 days (7). This time course was unaffected by the size of the bacterial inoculum. Thus, the burden of bacterial infection appears to be one important factor influencing the severity, but not the temporal profile, of sepsisrelated cardiovascular abnormalities. Endotoxin
It has long been postulated that endotoxin, a lipopolysaccharide molecule common to the outer cell wall of all gram-negative bacteria, is central to producing cardiovas-
484
Freeman and Natanson
cular dysfunction not only during sepsis, but in all forms of shock. According to this model, an acute physiologic insult (hemorrhage, trauma, infection, etc.) compromises gastrointestinal mucosal integrity, resulting in the systemic release of endotoxin from endogenous gut flora. If accurate, this model would explain the ability of gram-positive organisms to produce profound hemodynamic abnormalities while lacking endotoxin. To understand whether the sepsis-induced cardiovascular changes we were observing were all endotoxin mediated, we compared the hemodynamic profiles resulting from infection with gram negative (e.g., E. coli) and gram positive (e.g., S. aureus) organisms in our model, and related these profiles to levels of circulating endotoxin. We found that S. aureus, when corrected for colony counts, was more potent at producing cardiovascular dysfunction than E. coli. However, we were unable to detect endotoxin in the blood of animals infected with S. aureus (9). (Fig. 5) Thus, while endotoxemia appears important in producing sepsis-induced changes, it is not necessary and is only one of multiple bacterial factors which can elicit this cardiovascular response. Our studies demonstrated that bacteria of a diverse cellular composition effectively produce myocardial dysfunction in the absence of endotoxin or endotoxemia. Virulence Factors Versus Endotoxin
We next examined the effects of virulence factors on cardiovascular abnormalities occurring during gram-negative infection. We challenged animals with two distinct gram-negative organisms: a strain of E. coli containing virulence factors associated with human disease (encapsulation, serum resistance, and production of a hemolysin), and an unrelated E. coli strain which lacked these virulence factors (10,11). Both of these bacterial strains produced the distinct profile of cardiovascular abnormalities we had observed previously (7). However, comparing similar colony counts, the virulent E. coli was more potent in producing cardiovascular changes and lethality than the nonvirulent E. coli strain. We hypothesized that these differences may have been due, in part, to differences in either the concentration or potency of the endotoxin these animals produced. However, we found that the nonvirulent E. coli strain produced higher concentrations of circulating endotoxin than the virulent E. coli strain. Further, when we challenged animals with endotoxin isolated from these two organisms, we could not find a difference in potency comparing these strains. Thus, organisms differ in their ability to produce cardiovascular dysfunction during sepsis, and this difference appears to be related to virulence factors associated with specific bacteria. However, the presence, character, or concentration of circulating endotoxin appears to be less important in producing these cardiovascular abnormalities. Summary of Bacterial Factors
These series of experiments suggest that dose, type, and virulence of bacteria affect the severity, but not the time course, of sepsis-induced cardiovascular changes. Further, while endotoxin likely plays a role in mediating hemodynamic changes in some gram-negative infections, neither is it essential to producing these abnormalities,
Systemic Inflammation
485
Figure 5 Plot of LVEF vs. time for animals following peritoneal implantation of clot which is either sterile or containing gram-negative (E. coli) or gram-positive (S. aureus) bacteria. The dashed horizontal line within the shaded area is a mean based on 100 other dogs; the shaded area is a normal range adjusted to the number in the comparison group; the solid line is a serial change between days; and the dashed line originating from the solid line is a response to volume infusion each day. In data from dogs receiving both viable and formalinkilled S. aureus and E. coli, similar patterns of hemodynamic change as measured by LVEF from baseline to day 10 occurs. However, when corrected for colony counts, we found that S. aureus was more potent in producing cardiovascular dysfunction that E. coli, despite lacking endotoxin. The graph from control dogs (top row) demonstrate no serial changes in hemodynamic parameters from baseline to day 10 postsurgery. (From Ref. 9.)
486
Freeman and Natanson
nor is it the common mediator in all types of bacterial infections. It appears that structurally and functionally distinct bacteria and bacterial products interact with the host to produce a uniform pattern of cardiovascular dysfunction, presumably through a common pathway. Our next series of experiments sought to better characterize that pathway. C. Host Factors
Since a wide variety of bacteria and bacterial products produce a qualitatively similar pattern of cardiovascular changes, we next examined the host response to infection as a potential common pathway of injury. As stated above, a current model of sepsis suggests that this syndrome is the result of excessive inflammation due to the elaboration of pro-inflammatory mediators from immune cells in response to a variety of stimuli (3). Tumor necrosis factor (TNF), interleukin-1 (IL-1), granulocyte colonystimulating factor (G-CSF), adhesion molecules present on neutrophils, and the complement system are proinflammatory mediators directly implicated in the pathogenesis of this syndrome (3). In a series of experiments, we examined the importance of these inflammatory mediators in producing myocardial dysfunction in our canine model. Harmful Role of Inflammation
Following intravenous challenge with TNF, canines developed a profile of cardiovascular dysfunction identical to that of animals and humans infected with viable bacteria (12,13). These findings are consistent with subsequent studies demonstrating that serum levels of TNF are elevated in patients with other myocardial disorders including myocarditis and congestive failure (14,15) and that agents which block TNF activity, such as anti-TNF antibodies and tyrosine kinase inhibitors, improve cardiac dysfunction in sepsis (16). In contrast, intravenous challenge with IL-1, even in high doses, failed to produce abnormalities in cardiovascular function in our model (13). Thus, specific pro-inflammatory host mediators, such as TNF, have a central role in producing the cardiac dysfunction occurring in sepsis and septic shock. Beneficial Role of Inflammation
The administration of G-CSF prior to the onset of sepsis, in doses sufficient to induce neutrophilia, prevented subsequent sepsis-induced decreases in LVEF and MAP, through enhanced endotoxin and TNF clearance (17). In contrast, inhibition of neutrophil function with antibodies directed against the surface antigens responsible for cell adhesion had the opposite effect (16). Likewise, animals deficient in the third component of complement developed greater myocardial dysfunction than control animals following endotoxin challenge (18). Collectively, these findings suggest that the role of inflammation in inducing cardiovascular dysfunction during sepsis is amphipathic, with pro-inflammatory mediators simultaneously producing adverse and beneficial effects. These studies
Systemic Inflammation
487
have implications for sepsis therapies that target the inflammatory cascade. Specifically, the beneficial effects of blocking inflammation during sepsis may be negated by the necessity of an intact inflammatory response to both the clearance of bacteria and bacterial toxins, and to normal host function. It appears that many pro-inflammatory mediators are essential to host defense function. Further, even mediators that have been shown to be toxic (e.g., TNF), if completely inhibited, might result in inadequate inflammatory function, thus worsening outcome in sepsis and septic shock. D. Mechanisms of Myocardial Depression in Septic Shock
The mechanisms by which bacterial toxins interact with host mediators to produce the cardiovascular abnormalities of sepsis are unknown. In a series of experiments, we have examined coronary perfusion, myocardial metabolic derangements, microscopic structural abnormalities, alterations in systemic catecholamine homeostasis, and nitric oxide to further delineate the substrate of cardiovascular dysfunction occurring in this syndrome. Coronary Perfusion
An early hypothesis which attempted to explain the myocardial dysfunction occurring in sepsis focused on the potential role of deranged coronary perfusion. It was hypothesized that inflammatory cells may compromise blood flow either via direct vascular injury, or through vasoactive mediators. Thus, one of our early investigations examined coronary blood flow during sepsis. We placed coronary sinus thermodilution catheters in patients with septic shock to both measure coronary sinus blood flow and sample coronary sinus venous blood. We found that despite reductions in LVEF, coronary blood flow was normal or increased in all septic patients. In addition, we could detect no notable increase in net myocardial lactate production to suggest mismatch in oxygen delivery and consumption at the cellular level (19). Our findings were consistent with those subsequently reported by Dhainaut et al. (20), who similarly failed to demonstrate gross changes in coronary sinus blood flow in patients with sepsis. We concluded that the myocardial depression occurring in sepsis was not the result of gross abnormalities in coronary perfusion. Energy Metabolism
One limitation of our coronary perfusion studies, however, was the inability to exclude shunting in the coronary circulation. Specifically, blood obtained from the coronary sinus might not reflect derangement of cellular metabolism. Thus, our next series of experiments directly examined intracellular oxygen utilization during sepsis. In vivo 31 P magnetic resonance spectroscopy (P-MRS) is a useful technique for measuring intracellular concentrations of high-energy phosphate compounds (21–24). We used this technique to study myocardial oxygen utilization in our canine model. Two days following infected clot implantation, the time of maximal
488
Freeman and Natanson
myocardial depression in our model, animals underwent median sternotomy for creation of a coronary sinus–superior vena cava shunt and epicardial placement of a 3-cm P-MRS surface coil. This allowed us to simultaneously measure myocardial oxygen consumption and intracellular high-energy phosphate levels (as reflected by the phosphocreatine to adenosine triphosphate ratio [PCr:ATP]) (21). Animals were then challenged with escalating doses of catecholamines to increase myocardial metabolic demand. We hypothesized that myocardial dysfunction in sepsis may be due to impaired cellular oxygen delivery resulting from inflammatory mediator-induced vascular damage. We speculated that such inadequate oxygen delivery would ultimately result in a decrease in intracellular free-energy stores. Thus, we expected that catecholamine-induced increases in myocardial metabolic demand would produce decreases in intracellular concentrations of high-energy phosphates as measured by P-MRS. We found that catecholamine challenge resulted in a doubling of myocardial oxygen consumption in septic hearts. However, we detected no abnormalities in oxygen extraction, lactate production, or intracellular concentration of high-energy phosphate compounds in the myocardium of septic canines. (Fig. 6). We concluded that sepsis-induced cardiac dysfunction is not caused by impaired myocardial oxygen delivery or utilization (25).
Figure 6 High-energy phosphate stores in septic and normal hearts. Each graph displays mean change (⫾ SE) in response to escalating doses of epinephrine for coronary flow, myocardial oxygen consumption, myocardial lactate consumption, and phosphocreatine/adenosine triphosphate, in septic (open circles) and control (closed circles) animals 2 days after infected and sterile clot implantation. Note, despite increasing metabolic demands, septic hearts maintain high-energy phosphate levels (phosphocreatine:adenosine triphosphate ratios) and consume lactate. (From Ref. 25.)
Systemic Inflammation
489
E. Structural Abnormalities
In an effort to identify a structural basis to explain the cardiovascular abnormalities of sepsis, we microscopically examined cardiac tissue taken from canines during sepsis-induced myocardial depression (25). Light microscopy of left ventricular tissue obtained from canines 2 days after infected peritoneal clot implantation, the time of maximal myocardial depression, revealed only minimal neutrophil infiltration but no gross abnormalities. However, electron microscopy showed evidence of both microvascular and myocyte injury. This included myocyte edema and necrosis, sarcolemmal scalloping, endothelial swelling, perivascular edema, and nonocclusive fibrous bands within the lumen of endothelial cells. Conceivably, activation of host inflammatory factors may result in diffuse microvascular injury through release of toxins into the interstitial space. We next turned our attention to understanding the mechanism resulting in these abnormalities.
Role of Catecholamines
It has been proposed that the cardiac dysfunction of sepsis may be due to derangements in catecholamine homeostasis. This hypothesis is supported by the observation that the administration of high doses of norepinephrine in animal models produces dose-dependent myocardial depression (26). We examined the relationship between circulating catecholamine concentrations and cardiac dysfunction using our peritonitis model. We serially measured serum catecholamine levels following infected clot implantation and found that increases in both total and individual catecholamine levels paralleled the time course of abnormalities in myocardial function, with catecholamine levels being maximally elevated when myocardial depression was most severe (27). Moreover, animals with the most pronounced sepsis-induced cardiovascular depression had the highest catecholamine levels. By 7 to 10 days after clot implantation, cardiovascular abnormalities had resolved and catecholamine levels had normalized. (Figure 7). To study whether these fluctuations in catecholamine levels were causative, or simply reflected sepsis-associated alterations in catecholamine sensitivity, we measured the cardiovascular responses to escalating doses of the catecholamine vasopressors dopamine and norepinephrine in our peritonitis model. We specifically studied these two agents because they are commonly used clinically in the treatment of septic shock. In noninfected (control) animals, both dopamine and norepinephrine increased left ventricular ejection fraction (LVEF) and stroke volume index (SVI), decreased end-systolic volume index (ESVI), and had no effect on end-diastolic volume index (EDVI). In contrast, during sepsis, while these agents had comparable effects, the dose-response curves of both dopamine and norepinephrine were shifted downward. These findings suggest that while the qualitative actions of both agents during sepsis are preserved, catecholamine sensitivity is decreased (28). Moreover, we could find no measurable worsening of cardiovascular function induced by catecholamines during sepsis. Though the mechanism remains unclear, increased cate-
490
Freeman and Natanson
Figure 7 The relationship between circulating catecholamine levels and sepsis-induced cardiac dysfunction. Mean total serum catecholamine levels vs. time are plotted for canines following intraperitoneal placement of an E. coli containing clot. Inset, data from individual catecholamines plotted from 0 to 24 hours following surgery. Note the similarity in time course of increases in catecholamine levels with decrease in LVEF shown in Figure 4B. (From Ref. 27.)
cholamine levels and altered catecholamine sensitivity may partly explain the cardiovascular abnormalities of septic shock. Role of Nitric Oxide (NO)
As noted above, numerous studies support TNF as the central mediator of cardiovascular dysfunction in sepsis. (See Chapter 30 for additional discussion of NO in sepsis.) While the mechanism by which TNF produces this effect remains speculative, a number of hypotheses have been advanced. One such hypothesis suggests that TNF-induced myocardial dysfunction is NO mediated. Evidence for the role of NO is largely derived from in vitro studies demonstrating that pharmacologic inhibition of nitric oxide synthase (NOS) reverses the negative inotropic effects of TNF in isolated myocyte preparations (29–31). These studies are confounded, however, by the failure to consistently demonstrate increased NO production in response to TNF stimulation. Thus, alternative hypotheses have centered on models of TNFinduced myocardial injury which occur independently of NO. For example, binding
Systemic Inflammation
491
of TNF to its 55-kDa receptor results in activation of sphingomyelinase, which rapidly increases the intracellular concentrations of ceramide and sphingosine (32). Sphingosine has recently been shown to reproduce the early, immediate depressive cardiac effects of TNF, and inhibition of the sphingosine pathway inhibits TNFassociated myocardial dysfunction (32). Thus, TNF may produce its cardiotoxic effects, in part, through NO, sphingosine, or other, as yet undiscovered second messengers. To further understand the role of NO in mediating sepsis-induced myocardial dysfunction, we examined the effects of NOS inhibition on myocardial abnormalities induced by TNF challenge in our canine model (33). We chose TNF challenge as an inflammatory stimulus because TNF-associated cardiovascular changes in our model are well characterized. Further, the administration of NOS inhibitors in viable bacterial infection models have produced mixed results (34–38). In our studies, we used L-NMMA, an inhibitor of both the constitutively expressed and inducible form of NOS. It is increased expression of inducible NOS, which has been implicated in mediating the physiologic abnormalities of sepsis (39–41). Six hours following administration, TNF produced characteristic abnormalities in cardiac function, including decreases in LVEF stroke-volume index (SVI), cardiac index (CI), oxygen delivery index (DO2I), and shifts of LV function plots (e.g., downward and rightward shifts of peak systolic pressure [PSP] vs. end-systolic volume index [ESVI] plots and LV stroke work index [LVSWI] vs. end diastolic volume index [EDVI] plots). However, TNF challenge did not produce increases in NO metabolites, suggesting that the abnormalities of cardiac function were not mediated by increases in NO production. Further, while the co administration of L-NMMA attenuated TNF-associated cardiac abnormalities, this effect was negated by the administration of intravenous fluids. This suggested that NOS inhibition improved cardiac performance by maintaining preload through a vasoconstrictive effect on capacitance vessels, and not through inhibition of increased NO production. By 24 hours following TNF infusion, cardiovascular abnormalities had resolved. Thus, our findings suggested that NO was not a principal mediator of acute TNF-induced myocardial changes, e.g., changes that occur within the first few hours following septic challenge. While we concluded that NO is not the predominate mediator of acute TNFinduced myocardial dysfunction, we recognized that there were a number of methodological limitations with our study. Following TNF stimulation in vitro, upregulation of inducible NOS activity and increased NO production does not occur for at least 2 hours(42). If extrapolated to an in vivo system, these findings suggest that it may take several hours for NO-induced injury to become clinically apparent. Thus, hemodynamic measurements obtained 6 hours following TNF challenge in our model may have been too early to detect NO mediated events. To address this issue, we completed a subsequent study evaluating the effects of L-NMMA on TNF-associated cardiovascular dysfunction (43). In this second study, animals received a much higher dose of TNF than we administered previously. TNF given at this higher dose resulted in significant cardiovascular dys-
492
Freeman and Natanson
function over days and, in contrast to our earlier findings, significant increases in metabolites of NO. L-NMMA did not have an effect on early changes in myocardial dysfunction, e.g., changes measured 3 to 6 hours following TNF infusion. In contrast, L-NMMA completely prevented the subacute (late) cardiac dysfunction produced by TNF, that is, cardiac dysfunction occurring 24 hours or later after TNF challenge. Thus, our findings suggest that TNF challenge results in two distinct patterns of myocardial dysfunction: (1) An early pattern occurs within 6 hours following TNF administration which is NO-independent; preliminary evidence from other laboratories suggests that this early dysfunction may be due to activation of the sphingomyelin pathway (32). (2) In addition, a late pattern of cardiac injury occurs 24 hours or more following TNF exposure which is NO dependent and consistent with TNF-induced activation of inducible forms of the enzyme NOS.
III. Conclusion Cardiac dysfunction is a cardinal feature of sepsis and contributes substantially to the morbidity and mortality associated with this syndrome. Our canine model of sepsis has proven a useful tool for furthering our understanding of the cardiovascular abnormalities that characterize septic shock. Collectively, our studies allow us to draw several broad conclusions. 1. The pattern of cardiac dysfunction that occurs during sepsis is programmatic. It presumably represents a common pattern of injury in response to a variety of pathogenic stimuli, and is not related to a particular bacteria or bacterial mediator, such as endotoxin. 2. Specific pro-inflammatory mediators such as TNF appear to have a central mechanistic role in mediating the cardiovascular dysfunction of sepsis, suggesting that anti-inflammatory agents may have therapeutic value in this syndrome. However, the use of some anti-inflammatory therapies in our model actually worsened cardiac function. These findings illustrate the amphipathic nature of inflammation. Conceivably, inhibiting specific pro-inflammatory mediators may provide some benefit. The net effect of such agents, however, will be dependent upon the balance between the adverse effects of inflammation during sepsis and the necessity of an intact inflammatory response for normal host function. 3. The mechanisms by which inflammation mediates cardiac dysfunction during sepsis remain poorly understood. Based on our most recent studies, it appears that NO may mediate late, but not early, cardiac dysfunction. Early derangements of cardiac dysfunction, e.g., those that occur within hours of septic challenge, may be mediated by sphingomyelinase, or other second-messenger pathways. In the last several decades, enormous resources have been invested to develop therapeutic alternatives in sepsis. The mainstay of treatment for this disease, however, remains largely supportive. Continued efforts to more fully understand the physiologic derangements of sepsis will be critical to improving outcome in this syndrome.
Systemic Inflammation
493
References 1. 2. 3. 4. 5. 6. 7. 8. 9.
10.
11.
12.
13. 14. 15. 16.
17. 18.
Stone R. Search for sepsis drugs goes on despite past failures. Science 1994; 264:365. Anonymous. Increase in national hospital discharge data survey rates for septicemia— United States, 1979–1987. MMWR 1990; 39:31. Natanson C, Hoffman WD, Eichacker PQ, Danner RL, Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med 1994; 120: 771–783. Zeni F, Freeman BD, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25:1095–1100. MM Parker, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 1990; 97:131. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parillo JE. Profound but reversible myocardial depression in patients with septic shock. Annals Intern Med 1984; 100:483–490. Natanson C, Fink MP, Ballantyne HK, MacVittie TJ, Conklin JJ, Parillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest 1986; 78:259–270. Natanson C, Danner RL, Fink MP, MacVittie TJ, Conklin JJ, Walker RI, Parillo JE. Cardiovascular performance with E. coli challenges in a canine model of human sepsis. Am J of Physiol 1988; 254:H558–H569 Natanson C, Danner RL, Elin RJ, Hosseini JM, Peart KW, Banks S, MacVittie TJ, Walker RI, Parillo JE. Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J Clin Invest 1989; 83:243–251. (Abstract) Danner RL, Natanson C, Elin RJ, Hosseini JM, Banks S, MacVittie TJ, Parillo JE. Pseudomonas aeruginosa compared with Escherichia coli produces less endotoxemia but more cardiovascular dysfunction and mortaility in a canine model of septic shock. Chest 1998; 98: 1480–1487. Hoffman WD, Natanson C, Danner RL, Koev LL, Banks S, Elin RJ, Hosseini JM, Parillo JE. Bacterial organism virulence factors may be more important than endotoxemia in determining cardiovascular dysfunction and mortality in canine septic shock. Clin Res 1989; 37:344A. Abstract. Natanson C, Eichenholz PW, Danner RL, Eichacker TQ, Hoffman WD, Kuo GC, Banks S, MacVittie TJ, Parillo, J.E. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med 1989; 169:823– 832. Eichenholz PW, Eichacker PQ, Hoffman WD, Banks S, Parillo JE, Danner RL, and Natanson C. Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction. Am J Physiol 1999; 263:H668–H675. Levine B, Kalman J, Mayer H, Fillit H, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323:236–241. Matsumorie A, Yamada T, Suzukim H, Matoba Y, Sasayama S. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 1994; 72:561–566. Eichacker PQ, Hoffman WD, Farese A, Danner RL, Suffredeni A, Waisman Y, Banks S, Mouginis T, Wilson L, Rothlein R, Elin RJ, Hosseini JM, MacVittie TJ, Natanson C. Leukocyte CD18 monoclonal antibody worsens endotoxemia and cardiovascular injury in canines with septic shock. J Appl Physiol 1993; 74:1885–1892. Eichacker PQ, Waisman Y, Natanson C, Farese A, Hoffman WD, Banks SM, McVittie SJ. Cardiopulmonary effects of granulocyte colony-stimulating factor in a canine model of bacterial sepsis. J Appl Physiol 1994; 77:2366–2373. Quezado ZMN, Hoffman WD, Winkelstein JA, Yatsiv I, Koev CA, Cork LC, Elin RJ, Eichacker PQ, Natanson C. The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ dysfunction. J Exp Med 1994; 179: 569–578.
494 19. 20.
21. 22. 23. 24.
25.
26. 27. 28. 29. 30. 31.
32. 33.
34.
35. 36. 37.
Freeman and Natanson Cunnion RE, Schaer G, Parker MM, Natanson C, Parrillo JE. The coronary circulation in human septic shock. Circulation 1986; 73:637–644. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall’Ava-Santucci J, Brunet F, Villemant D, Carli A, Raichvarg, D. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation 1987; 3:533–541. Heinemen FW, Balaban RS. Phosphorous-31 nuclear magnetic resonance analysis of transient changes of myocardial metabolism in vivo. J Clin Invest 1990; 85(3):843–852. Katz LA, Swain JA, Portman MA, Balaban RS. Relation between phosphate metabolites and oxygen consumption of the heart in vivo. Am J Physiol 1989; 256:H265–H274. Portman MA, James S, Heineman FW, Balaban RS. Simultaneous monitoring of coronary blood flow and 31 P-NMR detected myocardial metabolites. Mag Reson Imag 1988; 7:243– 247. Robitaille PM, Merkle H, Lew B, Path G, Hendrich K, Lindstrom P, From AH, Garwood M, Bache RJ, Ugurbil K. Transmural high energy phosphate distribution and response to alterations n workload in the normal canine myocardium as studied with spatially localized 31 P-NMR spectroscopy. Mag Reson Med 1990; 16:91–116. Soloman MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, Roberts WC, Quezado ZMN, Scholz TD, Cunnion RE, Hoffman WD, Bacher J, Yatsiz I, Danner RL, Banks S, Ferrans VJ, Balaban RS, Natanson C. Myocardial energy metabolism and morphology in a canine model of sepsis. Am J Physiol 1994; 266:H757–H768 Reichenbach DD, Benditt EP. Catecholamines and cardiomyopathy: the pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1:125–150. Natanson C, Danner RL, Reilly JM, Doerfler ME, Hoffman WD, Akin G, Hosseini JM, Banks SM, Elin RJ, MacVittie TJ, Parrillo JE. Antibiotics versus cardiovascular support in a canine model of septic shock. Journal of Clinical Investigation 1990; 259:H1440–H1447. Karzai W, Reilly JM, Hoffman WD, Cunnion RE, Danner RL, Banks SM, Parrillo JE, and Natanson C. Hemodynamic effects of dopamine, norepinephrine, and fluids in a dog model of sepsis. Am J Physiol 1995; 268(2):H692–H702. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokine on the heart mediated by nitric oxide. Science 1992; 257:387–389. Brady AJB, Poole-Wilson PA, Wilson, SE, Harding, SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992; 263:H1963–H1966. Balligand JL, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993; 87: 1964–1968. Oral H, Dorn GW, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor in the adult mammalian cardiac myocyte. J Biol Chem 1996; 272: 4836–4842. Quezado ZMN, Karzai W, Danner RL, Freeman, BD Yan, Eichacker PQ, Banks S, Cobb JP, Cunnion RE, Quezado MJN, Sevransky JE, Natanson C. Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs. Am J Respir Crit Care Med 1988; 157:1397–1405. Freeman BD, Zeni F, Banks SM, Eichacker PQ, Bacher JV, Garvey EP, Tuttle JV, Jorgenson CH, Natanson C, Danner RL. Response of the septic vasculature to prolonged vasopressor changes with N-monomethyl-L-arginine and epinephrnie in canines. Crit Care Med 1998; 28:877–886. Decking UKM, Flesche CW, Godecke A, Schrader J. Endotoxin-induced contractile dysfunction in guinea pig hearts is not mediated by nitric oxide. Am J Physiol 1995; 268: H2460–H2465. Bone HG, Waurick R, Aken HV, Booke M, Prien T, Meyer J. 1998. Comparison of the hemodynamic effects of nitric oxide synthase inhibition and nitric oxide scavenging in endotoxemic sheep. Inten Care Med 1998; 24:48–54. Cobb JP, Natanson C, Hoffman WD, Lodato RF, Banks S, Koev CA, Solomon MA, Elin RJ, Hosseini JM, Danner RL. N-amino-L-arginine, an inhibitor of nitric oxide synthase,
Systemic Inflammation
38. 39. 40. 41.
42. 43. 44.
495
raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 1992; 176:1175–1182. Cobb JP, Natanson C, Quezado ZMN, Hoffman WD, Koev CA, Banks S, Correa R, Levi R, Elin RJ, Hosseini JM, Danner RL. Differential effects of L-NMMA in endotoxemic and normal dogs. Am J Physiol 1995; 266:H1634–H1642. Nusslerm AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthesis. J Leuk Biol 1993; 54:171–178. Peterson DA, Peterson DC, Archer A, Weir EK. The non-specificity of specific nitric oxide synthase inhibitors. Biochem Biophys Res Commun 1992; 187:797–801. Ungureanu-Longrois D, Balligand WW, Simmons WW, Okada I, Kobzik L, Lowenstein CJ, Kinkel SL, Michel T, Kelly RA, Smith TW. Induction of nitric oxide synthase activity by cytokines inn ventricular myocytes is necessary but not sufficient to decrease contractile responsiveness to α-adrenergic agonists. Circ Res 1995; 77:494–502. Radomski MW, Palmern RM, Moncada S. Glucocorticoids inhibit the expression of inducible, but not the constituitive, nitric oxide synthase in vascular endothelial cells. Proc Nat Acad Sci USA 1990; 87:10043–10047. Sevransky JE, Vandivier RW, Eichacker PQ, Danner RL, Banks SM, Bacher J, Thomas MC, Natanson C. The effect of L-NMMA on TNF-induced cardiac dysfunction. Am J Respir Crit Care Med 1999. 159:A245. Abstract. Natanson C, Parillo JE. Septic shock. Anesth Clin North Am 1988; 6:73–85.
19 Control of Ventilation in Congestive Heart Failure
HARLY GREENBERG Long Island Jewish Medical Center New Hyde Park, New York
I.
Ventilatory Chemosensitivity in Congestive Heart Failure
Exertional dyspnea remains a significant clinical problem reducing quality of life in congestive heart failure (CHF). While several mechanisms may contribute to this phenomenon, increased ventilatory chemosensitivity to hypoxia and hypercapnia has been proposed as a potential etiologic factor. Augmented ventilatory responsiveness would lead to increased minute ventilation and work of breathing which in turn might potentially increase dyspnea. Peripheral chemosensitivity, determined by carotid and aortic body chemoreceptors, can be assessed by techniques which measure the ventilatory response to rapid and transient administration of hypoxic or hypercapnic gas (1,2). Central chemosensitivity, which represents a somewhat slower response and comprises the majority of hypercapnic ventilatory sensitivity, can be assessed by CO2 rebreathing studies (3). Peripheral ventilatory chemosensitivity was recently assessed in 38 CHF patients (New York Heart Association Functional Class II and III, mean left ventricular ejection fraction 25.7 ⫾ 2.3%) (4). Although considerable overlap exists, as shown in Figure 1, hypoxic ventilatory chemosensitivity was significantly greater in CHF patients than in normal control subjects of similar age and sex (0.707⫹0.076 in patients vs. 0.293 ⫾ 0.056 L/min/% SaO2 in normal controls, P ⬍ .0001). While the peripheral component of hypercapnic ventilatory sensitivity, as assessed by the 497
498
Greenberg
Figure 1 Hypoxic chemosensitivity in normal subjects and patients with CHF. (From Ref. 4.)
ventilatory response to a single breath of 13% CO2, was not greater in CHF patients, the central component of hypercapnic ventilatory responsiveness, assessed by the 4-min CO2 rebreathing technique, was greater in the patient group (3.15 ⫾ 0.41 in patients vs. 2.02 ⫾ 0.25 L/min/mm Hg CO2 in normal controls, P ⫽.025). Interestingly, central hypercapnic chemosensitivity was related to the degree of functional impairment. NYHA functional class III patients showed greater hypercapnic ventilatory responsiveness than class II patients (4). No differences in hypoxic sensitivity were noted between functional classes in this investigation. However, a subsequent study demonstrated that CHF patients with augmented hypoxic chemosensitivity had lower left ventricular ejection fractions than those with a normal hypoxic ventilatory response (21.8 ⫾ 11.8% vs. 29.4 ⫾ 13.1%, P ⬍ .05) (5). Thus, both peripheral and central ventilatory chemosensitivity is increased in CHF and the degree of augmentation may be related to the severity of cardiac dysfunction. As has been reported in normal subjects (6), resting hypoxic and hypercapnic ventilatory sensitivity is related to values obtained during exercise. As such, while exercising, both CHF patients and normal subjects demonstrate augmentation of the both hypoxic and peripheral hypercapnic ventilatory chemosensitivity compared with resting values. However, the hypoxic response remains significantly greater during exercise in the patient group than in normal controls (5). While the mechanisms leading to increased chemosensitivity in CHF are unknown, several theories have been proposed. CHF has long been known to be associated with increased catecholamine levels which can potentiate ventilatory chemosensitivity (7). In addition, since peripheral blood flow is reduced in CHF due to reduced
Control of Ventilation in CHF
499
cardiac output or increased systemic vascular resistance, decreased oxygen delivery to peripheral chemoreceptors may further stimulate their responsiveness (8). Similarly, mechanisms explaining the association of increased ventilatory chemosensitivity at rest with increased ventilatory responsiveness to exercise have not been fully elucidated. The ventilatory response to exercise in CHF will be discussed in detail below.
II. Peripheral Chemoreceptor Sensitivity and Autonomic Tone in CHF The importance of increased peripheral ventilatory chemosensitivity in CHF is not only related to its potential adverse effect on dyspnea, it may also alter autonomic activity. Afferent neurons from the carotid body are known to synapse in regions of the medulla which are closely linked to centers regulating sympathetic neuronal discharge. As such, augmented peripheral chemosensitivity may contribute to increased sympathetic tone in CHF. In support of this premise is an interesting finding that nonsustained ventricular tachycardia, which is in part caused by sympathetic overactivity, occurred more frequently in CHF patients with elevated peripheral ventilatory chemosensitivity than in those with normal ventilatory responsiveness (9). Other lines of evidence also support the hypothesis that augmented peripheral ventilatory chemosensitivity contributes to sympathetic overactivity in CHF. One method of assessing cardiovascular autonomic balance is by power spectral analysis of oscillations of heart rate variability (HRV). Ponikowski et al. (10) performed such an analysis of HRV in CHF patients with and without augmentation of hypoxic ventilatory sensitivity. Three spectral bands of HRV were identified: very low frequency (VLF ⬍ .04 Hz or ⬃30 sec periodicity), low frequency (LF 0.04 to 0.15 Hz or ⬃10 sec periodicity) and high frequency (HF 0.15–0.4 Hz). Previous studies have shown that oscillations within the LF band are modulated primarily by sympathetic activity while fluctuations in the HF band reflect parasympathetic tone (11). When assessed in this manner, CHF patients with elevated peripheral ventilatory chemosensitivity (LVEF of 20 ⫾ 10%) demonstrated a different and abnormal profile of HRV compared with CHF patients with normal peripheral chemosensitivity (LVEF 27 ⫾ 9%). In particular, patients with greater peripheral chemosensitivity demonstrated decreased power within the LF band and increase in VLF power. The finding of elevated VLF power in this population is intriguing but its origins require explanation. While a VLF pattern of R-R interval variability is found in patients with severe CHF, its presence is not correlated with clinical parameters of CHF severity (10,12). Rather, it has been suggested that VLF rhythms may be influenced by autonomic imbalance, chemoreceptor function, respiratory rhythms, or other factors. In particular, Cheyne-Stokes respiration (CSR) has been linked to the presence of VLF oscillations in HRV (13,14). These authors suggested that the presence of CSR may be responsible for the VLF pattern. However, other investigations have shown that CSR is not present in all patients with increased VLF oscilla-
500
Greenberg
tions. Furthermore, a significant coherence between HRV and respiration is not present in many of these cases, suggesting different origins for these rhythms. Thus, the presence of periodic breathing or CSR may not fully account for VLF oscillations in the heart rate pattern (12). More recent data indicate that this rhythm is associated with the presence of severe autonomic imbalance, decreased baroreceptor sensitivity, and increased peripheral chemoreceptor sensitivity (10). Data from patients with more mild CHF demonstrated a pattern of HRV with a predominance of LF power and a reduction of HF power representing increased sympathetic and decreased parasympathetic activity. As CHF progresses, with impaired baroreceptor function, overall heart rate variability declines. This results in a further reduction of both HF and LF power and a shift toward the VLF band. It has been postulated that this pattern may represent a state of extreme sympathetic activation. The putative role of increased peripheral chemosensitivity contributing to sympathetic activation is further suggested by the finding of an inverse correlation between LF power and hypoxic sensitivity. Similarly, a positive correlation was found between peripheral ventilatory chemosensitivity and VLF power. Further evidence for the importance of chemoreceptor input in the generation of VLF oscillations of the R-R interval also comes from studies by Ponikowski and colleagues (10). These investigators demonstrated that VLF oscillations could be substantially reduced or eliminated by suppression of peripheral chemoreceptor activity by hyperoxia with reemergence of the VLF pattern upon resumption of room air breathing. Furthermore, hyperoxic breathing resulted in the greatest suppression of VLF power in those CHF patients with the greatest hypoxic ventilatory chemosensitivity. Thus, increased peripheral chemoreceptor sensitivity to hypoxia appears to be an important factor in the generation of oscillations in the feedback control system regulating cardiorespiratory function. Baroreceptor function is also known to be impaired in CHF. Abnormalities of baroreceptor activity may lead to further abnormalities in ventilatory control and increased sympathetic activity. In a rat model of myocardial infarction induced left ventricular dysfunction, baroreflex modulation of sympathetic outflow, heart rate and ventilation was shown to be significantly impaired compared with control animals. The degree of impairment of baroreceptor activity was related to the size of the myocardial infarction (15). In this model, impairment of baroreceptor reflex activity was observed not only during baroreceptor stimulation by phenylephrine induced arterial hypertension, it was also seen after direct electrical stimulation of baroreceptor afferents in the aortic depressor nerve (Fig. 2). Thus, the site of impairment of the baroreceptor reflex is likely to be in central brainstem regions rather than in the peripheral baroreceptors themselves. The relationship of impaired baroreflex activity and ventilatory control has also been examined in humans with CHF. As shown in Figure 3, baroreflex gain, defined as the slope of the regression relating change in R-R interval to change in systolic arterial pressure during bolus phenylephrine infusion, is inversely correlated with hypoxic ventilatory sensitivity (10). Furthermore, acute exposure to hyperoxia, which diminishes peripheral chemoreceptor input, restores baroreflex gain in CHF
Control of Ventilation in CHF
501
Figure 2 Percent mean decrease in integrated lumbar sympathetic nerve activity in response to aortic depressor nerve stimulation at different frequencies (pulses/s) in control rats (solid line) and rats with left ventricular dysfunction (dotted line). (From Ref. 15.)
Figure 3 Correlation between hypoxic chemosensitivity and baroreflex sensitivity during phenylephrine infusion in 19 patients with CHF. Baroreflex gain is defined as the slope of the regression relating change in R-R interval to change in systolic blood pressure. (From Ref. 12.)
502
Greenberg
patients. Thus, complex interactions among baroreceptor, peripheral chemoreceptor, and sympathetic circuits are likely to be present in CHF. These interactions presumably take place via neuronal interconnections in the medulla. In support of this premise, carotid chemoreceptor and baroreceptor afferents have been demonstrated to synapse in the nucleus tractus solitarius in the medulla (16). From there, complex interconnections have been identified which form functionally characterized circuits involving the rostral ventrolateral medulla. These neuronal circuits have been shown to integrate peripheral chemoreceptor and baroreceptor afferent input and modulate sympathetic outflow to various target organs (17). Thus, a complex interaction of increased peripheral chemoreceptor activity with reduced baroreceptor gain and increased sympathetic outflow occurs in CHF. III. Control of Ventilation During Exercise in CHF Several studies have shown that CHF patients with increased ventilatory chemosensitivity at rest consistently demonstrate reduced exercise tolerance with decreased maximal oxygen consumption (VO2 max). In addition the ventilatory response to exercise (VE /VCO2) is increased in these patients. This may be one factor contributing to the sensation of dyspnea during exercise, although it must be kept in mind that mechanisms leading to exercise hyperpnea and exertional dyspnea are complex and poorly understood. In support of the association of increased ventilatory chemosensitivity with exertional dyspnea, administration of dihydrocodeine, a ventilatory depressant, has been shown to reduce exercise ventilation and exertional dyspnea and increase exercise tolerance in CHF (18). Furthermore, the most severe degrees of heart failure and exercise limitation are associated with the greatest ventilatory response to exercise. In fact, CHF patients with severe exercise limitation exhibited a ventilatory response to exercise that is more than twice that of normal control subjects (19). Three factors may potentially contribute to the increased ventilatory response to exercise in CHF. First, the ventilatory response to a given work load during exercise may be increased in CHF patients due to additional CO2 production resulting form buffering of lactic acid by bicarbonate. Because of reduced muscle perfusion, at any given VO2, lactate levels are greater as the degree of cardiac dysfunction increases (19). As a result, increased CO2 production from lactic acid buffering plays a greater role in driving ventilation as exercise limitation and cardiac function worsens. Second, at the onset of exertional dyspnea during exercise a rapid-shallow pattern of breathing often appears in patients with CHF (20). Thus, for a given minute ventilation, respiratory rate is greater and tidal volume is smaller than is observed in normal subjects. The increase in exertional dyspnea during incremental exercise appears to be temporally associated with the increase in respiratory rate relative to tidal volume. This change in ventilatory pattern indicates alteration in central ventilatory control, possibly due to increased input from peripheral mechanoreceptors and chemoreceptors.
Control of Ventilation in CHF
503
Third, because of the increase in respiratory frequency and reduction in tidal volume observed during exercise in CHF, the contribution of anatomic dead space ventilation is increased. In addition, physiologic dead space might also be increased due to impaired pulmonary perfusion with resultant ventilation-perfusion mismatch. This may be due to right ventricular dysfunction with reduced perfusion of lung apices, uneven elevations in pulmonary venous pressure, or abnormal pulmonary vasomotor tone, among other factors. In fact, VD /VT has been shown to be elevated in CHF patients during exercise. Furthermore, the increase in VD /VT and in the arterial to end tidal PCO2 gradient, which is a reflection of VD /VT, is related to the degree of exercise limitation (19,21). As a result of these findings, the change to a rapid shallow ventilatory pattern during exercise has been proposed to be a major factor contributing to increased dead space ventilation in CHF. However, in a recent study of this phenomenon, despite greater tidal volume in normal control subjects during exercise, the slope of the relationship between tidal volume and respiratory frequency (Vt/f) during exercise was similar in CHF patients and normal controls, although the intercept was greater in control group. Furthermore, only weak correlations were found between Vt/f and the ventilatory response to exercise (22). In support of this finding, at matched workloads, a recent study demonstrated that dead space ventilation represented a similar percentage of total ventilation in both normal control subjects and CHF patients (22). In another study, a decline in dead space ventilation was observed in CHF patients during exercise (23). Thus, controversy exists as to the etiology of the increase in VD /VT during exercise in CHF (19,21). Because of the importance of increased VD /VT in mediating the increased ventilatory response to exercise in CHF, interest has also focused on potential disturbances in the control of the pulmonary circulation which could also contribute to ventilation/perfusion imbalance and an increase physiological dead space. In particular, recent data has shown that increased pulmonary blood flow, such as that occurring with exercise, normally leads to increased production of nitric oxide (NO) by the endothelium (24). In the pulmonary vascular bed, increased NO facilitates vascular recruitment during exercise, while reduced NO production leads to vasoconstriction and increased ventilation/perfusion ratios in these lung regions. Thus, when exhaled NO is measured in normal subjects, significant increases are observed with exercise. In CHF patients, exhaled NO has been shown to be reduced at rest, as well as during exercise, compared with normal control subjects (25). This may result from reduced pulmonary blood flow in regions of the lung with high pulmonary venous pressures. In addition, pulmonary vasoconstriction, due to increased endothelin-1 levels in CHF, may further reduce blood flow decreasing the stimulus for NO production (26). Accordingly, a recent study in CHF patients demonstrated that NO inhalation while exercising produced a decrease in the ventilatory response to exercise (VE /VCO2 ) and in the maximal exercise tidal volume (9). One possible explanation for this finding is a reduction in physiological dead space and high V/ Q regions due to pulmonary vascular vasodilatation. This may, in part, explain the observed reduction in VE /VCO2 with NO (27). Alternatively, it is possible that inhala-
504
Greenberg
tion of NO may have had an effect on central or peripheral ventilatory control mechanisms resulting in alteration of the ventilatory pattern. Resting central and peripheral ventilatory chemosensitivity may also have an important role in mediating the exercise ventilatory response. As such, resting ventilatory chemosensitivity to CO2 has been shown to be correlated with the ventilatory response to exercise (VE /VCO2) in normal subjects (6) and in CHF patients (28). As in the normal population, a wide range of the resting ventilatory response to CO2 is observed in this patient group, indicating individual variability in respiratory center responsiveness. However, if the CO2 response was the sole factor driving ventilation during exercise, one would expect some increase in arterial PCO2 levels during exercise to initiate a feedback loop controlling exercise ventilation. In fact, most studies have failed to demonstrate an increase in PCO2 during exercise and have actually shown a degree of hypocapnia. Thus, it is not likely that CO2 production and hypercapnic ventilatory responsiveness are the sole factors determining the ventilatory response to exercise. Rather, resting hypercapnic ventilatory sensitivity should be viewed as one of several factors potentially contributing to the exercise ventilatory response and as an overall measure of central respiratory center responsiveness. Another factor which may contribute to exercise hyperpnea in CHF is increased sensitivity of peripheral chemoreceptors. Thus, a significant correlation between resting hypoxic chemosensitivity and the ventilatory response to exercise has been demonstrated in CHF as well as in normal subjects (4,29). The contribution of peripheral chemoreceptors to minute ventilation, both at rest and during exercise, can be more accurately assessed by measuring ventilation after transient administration of 100% O2 during exercise. Since hyperoxia greatly decreases or eliminates peripheral chemoreceptor input, if peripheral chemosensitivity were the major factor determining exercise hyperpnea, greater decreases in exercise ventilation should be observed with 100% O2 breathing in CHF patients compared with normals. At rest, inhalation of 100% O2 resulted in an 18% fall in ventilation in both CHF patients and in normal controls (30). Similarly, these authors demonstrated that during submaximal exercise, transient hyperoxia induced comparable declines in ventilation in both normal subjects and CHF patients (20.4% vs. 21%). Thus, despite augmented resting peripheral chemosensitivity in CHF, reducing peripheral chemoreceptor afferent input did not cause a greater reduction in exercise ventilation in CHF patients than in normal subjects. Therefore, increased peripheral chemosensitivity is not the major factor responsible for exercise hyperpnea in CHF. Other factors which might contribute to exercise hyperpnea in CHF are the by products of skeletal muscle metabolism. In particular, lactic acid production from muscle activity has been considered to be a putative ventilatory stimulant during exercise. However, the rise in blood lactate levels does not parallel the rise in exercise ventilation (31). Furthermore, chemical blockade of lactate production does not blunt the ventilatory response to exercise (32). Another putative ventilatory stimulant during exercise is the rise in arterial potassium levels. However, as with lactate, no relation between exercise ventilation and the increase in serum potassium levels has been found in CHF patients (33).
Control of Ventilation in CHF
505
Recently, focus has shifted form circulating metabolic factors to the role of afferent receptors in skeletal muscles as potential sources of afferent input driving both ventilation and sympathetic outflow during exercise. Muscle ergoreceptors have been identified which are responsive to both muscle work load and to the products of muscle metabolism. Activation of these receptors has been shown to increase sympathetic outflow and to mediate the early hemodynamic and ventilatory changes of exercise (23,34). Increased activity of these receptors might occur in CHF and thus might contribute to exercise hyperpnea in this disease. In support of this possibility, significant skeletal muscle abnormalities have been documented in CHF which include dysfunction of oxidative enzyme activity, abnormal high energy phosphate, as well as muscle fiber atrophy and mitochondrial histologic changes (35,36). Since muscle ergoreceptors are sensitive to the metabolic products of exercise, their contribution to the ventilatory, circulatory and autonomic response to exercise can be assessed by limiting the outflow of these metabolites in a particular muscle group during the recovery period after exercise. Accordingly, assessment of the ventilatory, hemodynamic, and autonomic response to hand grip exercise with and without circulatory occlusion of the forearm (by tourniquet) has been used to determine the contribution of the muscle ergoreceptor reflex. Using this technique, Piepoli et al. (37) recently demonstrated an increased contribution of the ergoreflex to the autonomic, hemodynamic, and ventilatory response to exercise in CHF patients compared with normal control subjects. Thus, greater minute ventilation, diastolic blood pressure and vascular resistance in nonexercising muscle beds was observed during post-hand-grip exercise circulatory occlusion in the CHF group. These differences were noted despite workloads which represented a similar percentage of maximal hand grip strength in both groups. As a result of these findings, Piepoli et al. (37) proposed the ‘‘muscle hypothesis’’ for generation of exercise hyperpnea and sympathoexcitation in CHF (Fig. 4). Muscle ergoreceptors, which are sensitive to muscle work and metabolic state, increase ventilation and sympathetic outflow via afferent input traveling in the lateral spinothalamic tract. A vicious cycle is thereby engendered in which decreased cardiac output in CHF leads to muscle wasting and abnormalities of muscle function and metabolism. In turn, this causes increased ergoreceptor activity during exercise which increases the exercise ventilatory response causing increased exertional dyspnea as well as vasoconstriction of skeletal vascular beds. This results in inactivity and muscle wasting which further augments ergoreceptor activity during subsequent exertion. Increased ergoreceptor activity in turn increases sympathetic outflow which causes further ventricular dysfunction. Whatever the mechanism leading to exercise hyperpnea, an increase in the ventilatory response to exercise (VE /VCO2) has been shown to be associated with reduced peak oxygen consumption (VO2 max), poorer functional class, and lower left ventricular ejection fraction (9). Furthermore, increased VE /VCO2 was found to be the only independent determinant of impaired heart rate variability in CHF, a marker of sympathetic overactivity (38). In a recent study of survival in CHF, with a mean follow-up of 759 days, nonsurvivors were in a poorer functional class, had reduced VO2 max, a lower left ventricular ejection fraction and a significantly higher
506
Greenberg
Figure 4 The ‘‘muscle hypothesis’’ of CHF. LV dysfunction leads to skeletal and respiratory muscle myopathy which sensitizes muscle ergoreceptors. In turn this leads to decreased exercise tolerance and inactivity which further worsens muscle function. In addition, ergoreceptor activation causes sympathoexcitation, producing a potentially cardiotoxic effect and increasing afterload. (From Ref. 37.)
VE /VCO2 slope. Further, a multivariate analysis showed that the VE /VCO2 slope is an important predictor of mortality independent of age, VO2 max, functional class, and left ventricular ejection fraction (5,9). The ventilatory response to exercise may be so important because it reflects a variety of physiological parameters including impaired hemodynamic function, ventilation/perfusion mismatch, altered control of ventilation, and sympathetic overactivity.
IV. Control of Ventilation During Sleep in CHF Many investigations have demonstrated that sleep state has an important impact on ventilatory control. This is particularly true in the setting of CHF, where several pathophysiologic mechanisms may contribute to ventilatory instability during sleep. Such instability is commonly manifested by periodic breathing, or Cheyne-Stokes respiration (CSR). This respiratory pattern was first observed by Cheyne in 1818
Control of Ventilation in CHF
507
(39) and was subsequently reported in a systematic study by Harrison (40). More recent studies have shown that the prevalence of periodic breathing during sleep is much greater than was recognized previously. In a group of hospitalized patients recovering from acute cardiogenic pulmonary edema, CSR, defined as cyclic fluctuations in tidal volume and respiratory frequency in a repetitive crescendo-decrescendo pattern interrupted by periods of central apnea or hypopnea, was observed during sleep in 42 of 95 patients, or 44% (40a). Using a similar definition of periodic breathing, 45% of a group of more stable, younger patients on a heart transplant waiting list with left ventricular ejection fractions below 25% exhibited CSR during sleep (41). A similar prevalence was observed in a group of ambulatory patients with clinically stable, optimally treated CHF. In this investigation, 45% of these patients exhibited more than 26 episodes of periodic breathing per hour of sleep (mean 44/h) (42). The presence of periodic breathing during sleep is associated with several major adverse consequences. A prospective evaluation of mortality in CHF patients with similar degrees of left ventricular dysfunction and comparable clinical and demographic features, demonstrated a significantly greater mortality over the ensuing 4.5 years in those patients with CSR during sleep (43). The 3-year mortality in these CHF patients with CSR was 56%. The greater mortality may be due to more severe cardiac dysfunction in patients with CSR, although left ventricular ejection fraction, circulation time, and clinical status were similar in both groups. Alternatively, CSR may itself increase mortality by accelerating the progression of cardiac dysfunction. Furthermore, as described below, sleep fragmentation resulting from nocturnal periodic breathing leads to excessive daytime somnolence which has an adverse impact on quality of life. A. Nature of Periodic Breathing During Sleep
Sleep state and intermittent arousals play a major role in the pathogenesis of CSR. As such, periodic breathing occurs predominantly in stages 1 and 2 non-rapid eye movement (NREM) sleep with a decreased incidence during slow wave and rapid eye movement (REM) sleep (44). In contrast to obstructive sleep apnea (OSA), with CSR arousal occurs at the peak of the hyperpneic phase rather than at the termination of the apneic phase (Fig. 5). The difference in timing of arousal between these two diseases can be understood in the context of recent data which indicate that increasing degrees of inspiratory effort appear to be the most important determinant of arousal (45). Thus, inspiratory effort is greatest at the termination of the obstructive apneic period in OSA, while it is at a maximum during the hyperpneic phase of CSR which follows a central apnea or hypopnea. Arousals during hyperpneic periods may contribute to the sensation of nocturnal dyspnea which is commonly reported in patients with CHF and CSR (46). Furthermore, as discussed below, arousals may perpetuate the cycle of periodic breathing by causing oscillations in the apneic threshold for CO2 from the higher sleep to the lower wakefulness set points. These frequent arousals also cause sleep fragmentation with increased amounts of stage 1 and 2 sleep, increased number of sleep stage shifts and awakenings, decreased total
508
Greenberg
Figure 5 Portion of polysomnogram showing Cheyne-Stokes respiration. Note that the arousals on the EEG and EMG channels occur during the hyperneic phase.
sleep, time and reduced sleep efficiency. Despite normal awake arterial oxygenation, significant oxygen desaturation usually occurs in association with these sleep-disordered breathing events. Sleep fragmentation, which primarily results from multiple arousals associated with periodic breathing, has a profound impact on daytime somnolence. Patients with CHF and CSR have been demonstrated to have pathological multiple sleep latency test (MSLT) scores indicative of excessive daytime somnolence. This contrasts with normal MSLT results in a matched group of CHF patients without CSR. Linear regression analysis demonstrated that arousal index, the duration of light (stage I and II) NREM sleep and the respiratory disturbance index, but not mean nocturnal oxygen saturation, correlated with the MSLT score (47). These findings support the contention that sleep fragmentation resulting from periodic breathing leads to pathologic degrees of daytime hypersomnolence. B. Potential Mechanisms Leading to Ventilatory Instability During Sleep in CHF
The fundamental importance of cardiac dysfunction in the pathogenesis of CSR is emphasized by a recent study which demonstrated virtual elimination of CSR in cardiomyopathy patients who underwent heart transplantation (48). It is possible that normalization of the hemodynamic status led to elimination of periodic breathing. In conjunction with this, marked improvement in sleep continuity, with increased time spent in slow-wave sleep, was observed after cardiac transplantation.
Control of Ventilation in CHF
509
As described above, Cheyne-Stokes respiration occurs predominantly during stage 1 and 2 NREM sleep in patients with CHF. Its link to sleep state may reflect the impact of physiologic changes occurring during sleep which contribute to ventilatory instability. Many of these factors are present, to some degree, in both normal individuals and in patients with CHF, while some are amplified in, or are specific to, this disease state. The absence of wakefulness itself results in several changes which may destabilize ventilation. First, NREM sleep is associated with decreased spontaneous activity of medullary respiratory neurons. Studies by Orem demonstrated that this sleep induced decrease in medullary respiratory neuronal activity is not uniform but rather is greatest in those neurons whose activity is not tightly linked with phasic inspiratory activity. These neurons may be those which activate tonic ventilatory or upper airway muscles or may be related to the behavioral control of ventilation (49). Thus, overall spontaneous activity of ventral medullary respiratory neurons decreases during sleep at any given level of arterial PCO2 (50). This may, in part, be responsible for the decline in minute ventilation and the approximately 2 torr rise in arterial PCO2 observed during sleep in normal subjects. Thus, the ‘‘wakefulness’’ drive to breathe is eliminated with sleep, increasing the importance of metabolic control of respiration particularly during NREM sleep. This may permit the expression of periodic breathing or CSR. During REM sleep, other, nonmetabolic factors contribute to ventilatory control and may inhibit the expression of CSR. Thus, rapid changes in state, such as those induced by brief arousals from sleep, contribute to ventilatory instability by imposing and then rapidly removing the effects of wakefulness on ventilatory control. Brief arousals are responsible for rapid fluctuations in respiratory drive due to changing output of the medullary respiratory oscillator and for changes in the CO2 apneic threshold, or the PCO2 level below which central apnea occurs. Thus, rapid imposition and removal of wakefulness influences on ventilation may cause ‘‘ventilatory overshoots’’ and ‘‘undershoots’’ leading to ventilatory instability. This may be of particular importance in CHF. Increased sensitivity or gain of the ventilatory control system, manifested by increased ventilatory sensitivity to CO2, which as previously discussed is common in CHF, is probably one of the more important mechanisms leading to periodic breathing or CSR during sleep in this disease. When controller gain is high, small increases in PCO2 may lead to ventilatory ‘‘overshoots,’’ or periods of hyperventilation. The resulting hypocapnia may perpetuate periodic breathing by decreasing arterial PCO2 below the apneic threshold. These effects are most pronounced during sleep for two reasons. First, the importance of the apneic threshold is enhanced during sleep since, as mentioned above, wakefulness or behavioral influences on ventilation, which may prevent the occurrence of central apneas, are eliminated. Second, the apneic threshold occurs at a greater arterial PCO2 during sleep than during wakefulness (51). In a comparison of congestive cardiomyopathy patients, several studies have demonstrated that patients with nocturnal CSR have significantly lower awake and sleep PCO2 levels than those patients with a similar degree of LV dysfunction without nocturnal CSR (2,44,52). Chronic hyperventilation and hypocapnia may contribute
510
Greenberg
to ventilatory instability by decreasing the baseline arterial PCO2 to levels closer to the apneic threshold. In support of this, Naughton et al, observed that hypopneic or apneic periods during sleep typically followed periods of hyperventilation with subsequent declines in transcutaneous PCO2 , while hyperpneic episodes closely followed rises in transcutaneous PCO2 (2). This mechanism is further supported by the demonstration of increased central ventilatory sensitivity to CO2 in patients with medically stable CHF and repetitive central apneic episodes during sleep. In this study, the mean awake ventilatory response to CO2 was 5.6 ⫾ 2.9 L/min/mm Hg PCO2 (53). While a concomitant normal control group was not reported, the normal ventilatory response to CO2 is typically in the range of 3 L/min/mm Hg PCO2 or less. Therefore, these patients demonstrated a considerably greater ventilatory sensitivity to CO2 or controller gain than the normal population. Another factor that may theoretically contribute to ventilatory instability is hypoxia. This may be present in CHF due to ventilation perfusion mismatch and decreased FRC. It may theoretically destabilize ventilatory control by augmenting the ventilatory response to CO2. In addition, hypoxia itself may lead to ventilatory instability due to the hyperbolic nature of the hypoxic ventilatory response curve with large increases in ventilatory output occurring in association with relatively small changes in arterial PO2 once the PO2 declines below 60 torr. Both of these mechanisms increase the propensity toward ventilatory ‘‘overshoots’’ and unstable respiration. However, several studies have failed to demonstrate differences in awake arterial PO2 between CHF patients with and without CSR or have shown an essentially normal awake arterial PO2 in these patients (2,44,53). Nevertheless, despite normal awake arterial PO2levels, severe nocturnal hypoxemia may occur during sleep in association with periodic breathing. In one study, 7/10 patients demonstrated nocturnal hypoxemia with 9% to 59% of sleep time spent below 90% O2 saturation. Furthermore, the percent of total sleep time spent in CSR was directly correlated with sleep time spent ⬍90% O2 saturated (44). However, later studies have failed to demonstrate a difference in nocturnal oxygen saturation between CHF patients with and without CSR (52). Thus, nocturnal hypoxia may not be a critical factor in the development of CSR and may simply be a consequence of the apneic or hypopneic periods. Delayed transfer of changes in arterial blood gases to the peripheral and central chemoreceptors due to prolonged circulation time may also lead to ventilatory instability. This mechanism was first elucidated by Guyton who prolonged circulation time in dogs by insertion of long tubes in the carotid arteries which induced a circulatory delay of up to 5 min, which resulted in the appearance of periodic breathing (54). However, most patients with CHF demonstrate a circulatory delay in the range of 25 sec or less (24). Furthermore, two studies have shown that circulatory delay is not significantly greater in CHF patients with CSR than in those without periodic breathing (2,52). For example, lung-ear circulation time (LECT), measured as the time from the first breath after a central apnea to the subsequent nadir of SaO2 as determined by ear oximetry, was 20.7 ⫾ 2.2 sec in CHF patients without CSR and 25.0 ⫾ 1.3 sec in CHF patients with CSR, P ⫽ ns. However, CSR cycle length was
Control of Ventilation in CHF
511
correlated with LECT in this study (2). More recent data demonstrated that circulatory delay, as assessed by LECT, is correlated with length of the hyperpneic, rather than the apneic, phase of periodic breathing in CHF (55). This is consistent with prolongation of transmission of changes in arterial blood gas tensions from the lung to the peripheral and central chemoreceptors. As such, LECT was found to be inversely related to cardiac output and stroke volume. Taken together, these studies indicate that the hypopneic or apneic portion of CSR is primarily determined by the degree of hyperventilation occurring during the previous hyperpneic period and the apneic threshold for CO2. The length of the hyperpneic phase, which is the primary determinant of cycle length, is primarily governed by the degree of circulatory delay (55). One of the mechanisms which counters some of these destabilizing influences on ventilation is the damping effect of lung and total body gas stores. As the major site of body oxygen stores is the lung, the functional residual capacity (FRC) is a major determinant of damping capacity. A decline in FRC, which may occur in association with pulmonary congestion and cardiac enlargement in CHF, may decrease gas stores (56) and diminish damping. Thus, the impact of transient changes in ventilation such as that occurring during brief arousals or with transient imposition of ventilatory loads is magnified. However, evidence for decreased lung volumes in the pathogenesis of CSR is lacking. FRC, measured while awake in the seated position, was found to be within normal limits in a group of CHF patients with CSR (80 ⫾ 17% of predicted) (44). Forced vital capacity, also measured while awake and in the seated position in another study, was not found to be different between CHF patients with and without CSR (2). It is conceivable, though, that FRC may decrease upon assumption of the supine position or with sleep onset. Such measurements are not currently available. Increases in left ventricular (LV) volume may also contribute to periodic breathing by several potential mechanisms. First, greater LV end-systolic volume increases the time required for blood to exit the pulmonary veins, enter the aorta and reach peripheral chemoreceptors. Second, a large reservoir of end-systolic blood in the LV will buffer the acute changes in gas tensions of blood entering the LV during diastole. This may further contribute to a delay in the transmission of these changes to the peripheral and central chemoreceptors (55). Recent data support the contribution of increased LV volume to development of CSR. LV end-diastolic and end-systolic volume were found to be higher in CHF patients with, than those without, CSR despite similar LV ejection fraction and cardiac output (57). Interestingly, the increase in arterial PCO2 from wakefulness to sleep was found to be reciprocally related to LV end-diastolic volume. Thus, increased LV end-diastolic volume was associated with a lower NREM sleep PCO2 which is closer to the apneic threshold. This may be due to increased LV filling pressures causing pulmonary congestion which increase central ventilatory chemosensitivity leading to hyperventilation. Periodic breathing cycle length and length of the hyperpneic period were also observed to be related to LV end-diastolic volume, possibly due to circulatory delay (57). Thus, increased LV end-systolic volume may itself
512
Greenberg
increase the propensity toward CSR. Alternatively, the association of ventilatory instability with increased LV end-systolic volume may be a reflection of increased severity of CHF. The phenomenon of ‘‘short-term potentiation’’ or ‘‘after-discharge’’ is a stabilizing mechanism inhibiting the development of periodic breathing. This stabilizing influence ensures continued excitation of the ventilatory pump immediately after withdrawal of a hyperventilatory stimulus, thereby preventing subsequent central apneas or hypopneas. While mechanisms responsible for short term potentiation are incompletely understood, chronic hypocapnia, which may occur in CHF, may limit the efficacy of this system (51). Recent data have suggested that short-term potentiation is impaired in CHF patients with CSR. In a study of 13 patients with CHF (LVEF ⬍50%) and a history of CSR, brief episodes of hypoxic stimulation (PETO2 of 55 torr) were administered during wakefulness resulting in increased minute ventilation. The inspiratory gas was then abruptly changed to 100% O2. During the subsequent minute of hyperoxia, ventilation decreased gradually to levels at or below the room air baseline. However, the rate of decline of minute ventilation during the post-hypoxic hyperoxic period was significantly greater in CHF/CSR patients than in age-matched control subjects. This observation suggests decreased shortterm potentiation in CHF/CSR (58). Interestingly, the degree of hypoventilation during the hyperoxic phase was correlated with the amount of nocturnal CSR. However, since a subgroup of CHF patients without CSR was not studied, impairment of short term potentiation could not be definitively attributed to CHF. As previously mentioned, the presence of CSR is associated with increased mortality in CHF. This may be related to increased sympathetic activation resulting from CSR, possibly due to recurrent nocturnal hypoxemia and arousals from sleep. In support of this hypothesis, greater overnight urinary catecholamine levels and increased daytime plasma norepinephrine concentrations have been observed in CHF patients with CSR than in those without periodic breathing (59). Increased nocturnal sympathetic activity may contribute to progression of cardiac failure via a direct cardiotoxic effect. In addition, increased sympathetic activity may promote arrhythmias and increase myocardial oxygen consumption by increasing systemic vasoconstriction and afterload as well as heart rate.
V.
Potential Therapeutic Modalities
Because of the adverse impact of CSR on daytime functional status and its association with increased mortality in CHF, several investigations have focused on therapeutic measures to eliminate CSR. The emphasis on the potential role of hypocapnia in the development or perpetuation of periodic breathing during sleep in CHF led to the evaluation of inhaled CO2 as a potential therapeutic modality (34). Six patients with congestive cardiomyopathy and CSR with normal waking arterial blood gases (mean PCO2 36.2 ⫾ 4.4 torr) were fitted with a mask to provide an FiCO2 of 3% during sleep. A dramatic reduction in the percent of sleep time spent in CSR was observed along with signifi-
Control of Ventilation in CHF
513
cant improvements in the sleep time spent ⬍90% oxygen saturated. This finding supports the importance of hyperventilation to a PCO2 level below the apneic threshold as an important cause of CSR as the added CO2 likely increased arterial PCO2 above this level. Alternatively, ventilatory stimulation induced by 3% CO2 may have improved oxygen saturation eliminating nocturnal hypoxia which may reduce controller gain and ventilatory instability as previously described. It is also conceivable that increased oxygen stores resulting from increased minute ventilation increased the damping capacity of the ventilatory system further increasing ventilatory stability. Unfortunately, sleep continuity worsened during the CO2 inhalation night which may have been related to discomfort induced by the mask delivery system. In a more recent study, supplemental O2 at 2 lpm was administered during sleep along with CO2 titrated to eliminate CSR at flow rates ranging from 0.2–1 lpm, not exceeding a transcutaneous PCO2 of 55 torr (60). This protocol virtually abolished CSR, increased nocturnal oxygen saturation and elevated mean transcutaneous PCO2 from 39 ⫾ 2 to 43 ⫾ 2 torr. However, the number of arousals noted on polysomnography actually increased on the treatment compared with the room air night. Furthermore, plasma norepinephrine levels were greater upon awakening after the treatment night. Thus, while added CO2 decreased the amount of periodic breathing, an adverse effect of sympathoexcitation, probably due to hypercapnia, was noted without improvement in sleep quality. Therefore, while theoretically intriguing, CO2 supplementation is not an effective approach for treatment of CSR. Since hypoxia may destabilize ventilation and promote periodic breathing, it is also reasonable to hypothesize that nocturnal oxygen administration by itself would improve CSR. Oxygen therapy theoretically might contribute to ventilatory stability by increasing O2 and CO2 stores and by reduction of the ventilatory response to hypercapnia. In support of this, several studies have shown improvement in nocturnal CSR and sleep continuity with nocturnal oxygen administration even in the absence of daytime hypoxemia (44,61). While these studies either examined only portions of the night or evaluated only one night of therapy, it is reasonable to conclude that oxygen administration may be useful in CHF/CSR. A subsequent study, performed in a randomized, double-blind crossover manner, showed a moderate decrease in the frequency of CSR in CHF patients with one week of nocturnal oxygen therapy at 4 lpm (3). A reduction in the number of nocturnal arousals and an increase in the percent of stage 2 and slow wave sleep was noted as well. Interestingly, an increase in VO2 max during bicycle ergometry was also observed following nocturnal oxygen therapy in these patients, although there was no change in duration of exercise or in measures of quality of life. The mechanism of the increase in VO2 max is unclear. Since arousals interrupting sleep are a potentially destabilizing influence on ventilation, elimination of arousals might improve periodic breathing. In addition, since increased controller gain may contribute to periodic breathing, blunting of ventilatory drive might also be useful in decreasing CSR. Benzodiazepines, which may produce both of these effects, might conceivably be useful in the treatment of CSR. Two studies of patients with CHF/CSR who were given benzodiazepine hypnotics before bedtime demonstrated improvement in sleep continuity, arousal index
514
Greenberg
and nocturnal wake time compared with control nights (62,63). However, no significant change in the amount of sleep time spent in CSR, the central apnea index or nocturnal oxygen saturation was evident. Multiple sleep latency test scores were improved with therapy, probably due to increased in sleep continuity. Nocturnal nasal continuous positive airway pressure (nCPAP) has recently been demonstrated to reduce the incidence of CSR and central sleep apnea in patients with CHF/CSR (64). One mechanism by which nCPAP might improve CSR is by increasing PCO2 above the apneic threshold. In conjunction with this, overall minute ventilation was observed to be reduced with nCPAP (64). In addition, nocturnal oxygen saturation was improved. Last, the arousal index was reduced. All of these factors could theoretically improve ventilatory stability during sleep by mechanisms outlined above. Interestingly, one month of nCPAP also resulted in an improvement in left ventricular ejection fraction. This improvement in cardiac function (see Chapter 24) may have also contributed to the observed improvement in CSR by improvement in hemodynamics and a decrease in circulatory delay. Subsequent studies have demonstrated a decline in overnight urinary and daytime plasma norepinephrine levels after one to three months of nocturnal nCPAP therapy (59). Thus, nCPAP appears to be a potentially useful therapeutic modality in patients with CHF with CSR. Further long term studies are necessary to determine the impact of nCPAP on mortality in CHF.
References 1. 2. 3. 4. 5. 6. 7. 8.
9. 10.
Edelman NH, Lahiri S, Braudo L, Cherniak NS, Fishman AP. The blunted ventilatory response to hypoxia in cyanotic congenital heart disease. N Engl J Med 1970; 282:405–411. Naughton M, Benard D, Tam A, Rutherford R, Bradley TD. Role of hyperventilation in the pathogenesis of sleep apneas in patients with congestive heart failure. Am Rev Respir Dis 1993; 148:330–338. Rebuck AS, Campbell EJM. A clinical method of assessing the ventilatory response to hypoxia. Am Rev Respir Dis 1974; 109:345–350. Chua TP, Clark A, Amadi A, Coats AJS. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1996; 27:650–657. Chua TP, Ponikowski P, Harrington D, Anker S, Webb-Peploe K, Clark A, Poole-Wilson P, Coats AJS. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1997; 29:1585–1590. Rebuck AS, Jones NL, Campbell EJM. Ventilatory response to exercise and to CO2 rebreathing in normal subjects. Clin Sci 1972; 43:861–867. Cunningham DJC, Hey EN, Patrick JM, Lloyd BB. The effect of noradrenaline infusion on the relation between pulmonary ventilation and the alveolar PO2 and PCO2 in man. Ann NY Acad Sci 1963; 109:756–771. Fidone SJ, Gonzalez C. Initiation and control of chemoreceptor activity in the carotid body. In: Cherniak NS, Widdicombe JG, eds. Handbook of Physiology, Sect. 3: The Respiratory System, Vol. 2. Control of Breathing, Bethesda, MD: American Physiological Society, 1986: 247–312. Chua TP, Ponikowski P, Webb-Pepole K, Harrington D, Anker SD, Piepoli M, Coats AJS. Clinical characteristics of chronic heart failure in patients with augmented peripheral chemoflex. Eur Heart J 1997; 18:480–486. Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Pepole K, Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G, Giodano A, Coats AJS. Augmented peripheral
Control of Ventilation in CHF
11. 12.
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
515
chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 1997; 96:2586–2594. Maliani A, Pagnani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1981; 84:482–492. Ponikowski P, Chua TP, Amadi A, Piepoli M, Harrington D, Volterrani M, Colombo R, Mazzuero G, Giordano A., Coats AJS. Detection and significance of a discrete very low frequency rhythm in RR interval variability in chronic congestive heart failure. Am J Cardiol 1996; 77:1320–1326. Ichmaru Y, Yanga T. 24-hr ambulatory electrocardiographic monitoring. Comput Biomed Res 1989; 22:225–233. Millar TW, Hanly PJ, Hunt B, Frais M, Kryger MH. The entrainment of low frequency breathing periodicity. Chest 1990; 98:1143–1148. Jung R, Dibner-Dunlop M, Gilles M, Thames MD. Cardiorespiratory reflex control in rat, with left ventricular dysfunction. Am J Physiol. 268 (Heart Circ Physiol) 1995; 37:H218– H225. Finley JCW, Katz DM. The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res 1992; 572:108–116. Reis D, Golanov DA, Ruggiero M, Sun K. Sympathoexcitatory neurons of the rostral ventrolateral medulla are oxygen sensors and essential elements in the tonic and reflex control of systemic and cerebral circulations. J Hypertens 1994; 10:S159–S180. Chua TP, Harrington D, Ponikowski P, Webb-Pepole K, Poole-Wilson PA, Coats AJS. Effects of dihydrocodeine on chemosensitivity and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 1997; 29:147–152. Wasserman K, Zhang YY, Gitt A, Belardinelli R, Koike A, Lubarsky L, Agostoni PG. Lung function and exercise gas exchange in chronic heart failure. 1997; Circulation 1997; 96: 2221–2227. Yokayama H, Sato H, Hori M, Takeda H, Kamada T. A characteristic change in ventilation mode during exertional dyspnea in patients with chronic heart failure. Chest 1994; 106: 1007–1013. Kobayashi T, Itoh H, Kato K. The role of increased dead space in the augmented ventilation of cardiac patients. In Wassserman K, ed. Exercise Gas Exchange in Heart Disease. Armonk, NY: Futura, 1996:145–156. Clark AJ, Chua TP, Coats AJS. Anatomic dead space, ventilatory pattern and exercise capacity in chronic heart failure. Br Heart J 1995; 74:377–380. Rajifer SA, Nemanich JW, Shurman AJ, Rossen JD. Metabolic responses to exercise in patients with heart failure. Circulation 1987; 76 (suppl VI):46–53. Miller VM, Burnett JC Jr. Modulation of NO and endothelin by chronic increases in blood flow in canine femoral arteries. Am J Physiol 1992; 263:H103–H108. Adachi H, Nguyen PH, Belardinelli R, Hundter D, Jung T, Wasserman K. Nitric oxide production during exercise in chronic heart failure. Am Heart J 1997; 133:196–202. Stewart DJ, Cernacek P, Costello KB, Rouleau JL. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 1992; 85:510–517. Bocchi EA, Auler JO, Guimareaes G, Carmona MJ, Wajmgraten M, Bellotti G, Pileggi F. Nitric oxide inhalation reduces pulmonary tidal volume during exercise in severe chronic heart failure. Am Heart J 1997; 134:737–744. Andreas S, Morguet J, Werner GS, Kreuzer H. Ventilatory responses to exercise and to carbon dioxide in patients with heart failure. Eur Heart J 1996; 17:750–755. Martin BJ, Weil JV, Sparks KE, McCullough RE, FR Grover. Exercise ventilation correlates positively with ventilatory chemoresponsiveness. J Appl Physiol 1979; 45:557–564. Chua TP, Ponikowski P, Harrington D, Chambers J, Coats AJS. Contribution of peripheral chemoreceptors to ventilation and the effects of their suppression on exercise tolerance in chronic heart failure. Heart 1996; 76:483–489. Tibes U, Hemmer B, Boning D. Heart rate and ventilation in relation to venous [K⫹ ], osmolality, pH, PCO2 , [orthophosphate], and [lactate] at transition from rest to exercise in athletes and non-athletes. Eur J Appl Physiol 1977; 36:127–140. Wilson JR, Mancini DM, Feraro N, Egler J. Effect of dichloroacetate on the exercise performance of patients with heart failure. J Amer Coll Cardiol 1988; 12:1464–1469.
516 33.
Greenberg
Clark AL, Poole-Wilson PA, Coats AJS. Exercise limitation in chronic heart failure: central role of the periphery. J Am Coll Cardiol 1996; 28:1092–1102. 34. Steens RD, Millar T, Xiaoling S, Biberdorf D, Buckle P, Ahmed M, Kryger M. Effect of inhaled 3% CO2 on Cheyne-Stokes respiratory in congestive heart failure. Sleep 1994; 17: 61–68. 35. Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H. Alterations of skeletal muscle in chronic heart failure. Circulation 1992; 85:1751–1759. 36. Sullivan MJ, Green JJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990; 81:518–527. 37. Piepoli M, Clark A, Volterrani M, Adamopoulos S, Sleight P, Coats AJS. Contribution of muscle afferents to hemodynamic, autonomic and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training. Circulation 1996; 93:940– 952. 38. Ponikowski P, Chua TP, Piepoli M, Banasiak W, Anker S, Szelemej R, Molenda W, Wrabec K, Capucci A, Coats AJS.. Ventilatory response to exercise correlates with impaired heart rate variability in patients with chronic congestive heart failure. Am J Cardiol 1998; 82: 338–344. 39. Cheyne JA. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin Hosp Rep 1818; 2:216–222. 40. Harrison TR, King CE, Calhoun JA, Harrison WG. Congestive heart failure: Cheyne-Stokes respiration as the cause of paroxysmal dyspnea at the onset of sleep. Arch Intern Med 1934; 53:891–910. 40a. Hoffman R, Agastston A, Krieger B. Cheyne-Stokes respiration in patients recovering from acute cariogenic pulmonary edema. Chest 1990; 97:411–412. 41. Lofaso F, Verschuern P, Rande JLD, Harf A, Goldenberg F. Prevalence of sleep disordered breathing in patients on a heart transplant waiting list. Chest 1994; 106:1689–1694. 42. Javaheri S, Parker T, Wexler L, Michaels S, Staberry E, Nishyama H, Roselle G. Occult sleep disordered breathing in stage congestive heart failure. Ann Intern Med 1995; 122: 487–492. 43. Hanly P, Zuberi-Khokhar N. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996; 153:272–276. 44. Hanly P, Millar T, Steljes D, Baert R, Frais M, Kryger M. Respiration and abnormal sleep in patients with congestive heart failure. Chest 1989; 96:480–488. 45. Gleeson K, Zwillich C. Adenosine stimulation, ventilation and arousal from sleep. Am Rev Resp Dis 1992; 145:453–457. 46. Blackshear J, Kaplan J, Thompson R, Safford R, Atkinson E. Nocturnal dyspnea and atrial fibrillation predict Cheyne-Stokes respiratory in patients with congestive heart failure. Am J Respir Crit Care Med 1995; 155:1297–1302. 47. Hanly P, Suberi-Khokhar N. Daytime sleepiness in patients with congestive heart failure and Cheyne-Stokes respiration. Chest 1995; 107:952–958. 48. Braver HM. Effect of cardiac transplantation on Cheyne-Stokes respiration during sleep. Am J Cardiol 1995; 76:632–634. 49. Orem JM, Osorio I, Brooks E, Dick T. Activity of respiratory neurons during NREM sleep. J Neurophysiol 1985; 54:1144–1156. 50. Simon PM, Dempsey JA, Landry DM, Skatrud JB. Effect of sleep on respiratory muscle activity during mechanical ventilation. Am Rev Respir Dis 1993; 147:32–37. 51. Dempsey JD, Smith CA, Harms CA, Chow C, Saupe K. Sleep induced breathing instability. Sleep 1996; 19:236–247. 52. Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure. Chest 1993; 104:1079–1084. 53. Wilcox I, Grunstein RR, Collins, FL, Berthon-Jones M, Kelly T, Sullivan CE. The role of central chemosensitivity in central apnea of heart failure. Sleep 1993; 16:S37–S38. 54. Guyton AC, Crowll JW, Moore JW. Basic oscillating mechanisms of Cheyne-Stokes breathing. Am J Physiol 1956; 187:395–398. 55. Hall MJ, Cie A, Reutheford R, Andho S, Floras JS, Bradley D. Cycle length of periodic breathing in patients with and without heart failure. Am J Resp Crit Care Med 1996; 154: 376–381.
Control of Ventilation in CHF 56. 57. 58. 59. 60. 61. 62. 63. 64.
517
Hudgel DW, Devadatta P. Decrease in functional residual capacity during sleep in normal humans. J Appl Physiol 1984; 57:1319–1322. Tackova R, Hall MJ, Liu PP, Fitzgerald FS, Bradley TD. Left ventricular volume in patients with heart failure and Cheyne-Stokes respiration during sleep. Am J Respir Crit Care Med 1997; 156:1549–1555. Ahmed M, Serrette C, Kryger MH, Anthonisen NR. Ventilatory instability in patients with congestive heart failure and nocturnal Cheyne-Stokes Breathing. Sleep 1994; 17:527–534. Naughton MT, Bernard DC, Rutherford R. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995; 152:473–479. Andreas S, Weidel K, Hagenah G, Heindi S. Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon dioxide. Eur Respir 1998; 12:414–419. Berssenbrugge A, Dempsey J, Iber C, Skatrud J, Wilson P. Mechanisms of hypoxia induced periodic breathing during sleep. J Physiol (Lond) 1983; 343:507–524. Biberdorf DJ, Steens R, Millar TW, Kryger M. Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-Stokes respiration. Sleep 1993; 16:529– 538. Guilleminault C, Clerk A, Labanowski M, Simmons J, Stoohs R. Cardiac failure and benzodiazepines. Sleep 1993; 16:524–528. Naughton M, Bernard D, Rutherford R, Bradley TD. Effect of continuous positive airway pressure on central sleep apnea and nocturnal PCO2 in heart failure. Am J Respir Crit Care Med 1994; 150:1598–1604.
20 Ventilatory Support in the Failing Heart
STEVEN M. SCHARF Long Island Jewish Medical Center Albert Einstein College of Medicine New Hyde Park, New York
I.
Introduction
The respiratory and cardiovascular systems are both concerned with delivery of oxygen to peripheral tissues. As such, it is not surprising that they interact on many levels: mechanical, humoral and neuroreflex. Failure of one system is often associated with dysfunction or failure of the other. Ventilatory maneuvers have been used to treat cardiovascular disease. For example, continuous positive airway pressure (CPAP) therapy has been used to treat patients with congestive heart failure (CHF) since the early part of this century (1) and has been shown to improve gas exchange and decrease the work of breathing in many affected patients (2–4). Mechanical ventilation, with or without application of positive end-expiratory pressure (PEEP), leads to correction of hypoxemia, hypercarbia, and acidosis, which can have salutary effects on overall cardiocirculatory function. However, it has become clear in recent years that under the right circumstances therapy with respiratory maneuvers can lead to improved function of the failing and/or ischemic heart. The degree and the circumstances under which this is true are currently the topic of both clinical and laboratory investigation. Indeed, using ventilatory maneuvers to treat heart disease may offer some attractive alternatives to the usual drug therapy, in that side effects of pharmacologic therapy may be avoided. In this chapter we will review some relevant recent and older studies. It will be appreciated by the reader that agreement 519
520
Scharf
between studies is often difficult to demonstrate. This is especially true in clinical studies where clinical circumstances, concomitant therapy, and disease type is far from standardized. Further, limitations of clinical studies may make elucidation of responsible mechanisms difficult. We will point out major differences between studies in the literature and attempt, where possible, a reconciliation. This chapter is divided into a number of sections. First, we briefly review those cardiocirculatory interactions which are relevant for understanding the therapeutic use of ventilatory maneuvers in cardiocirculatory disease. Where appropriate, the reader will be referred elsewhere in this volume. Second, we review some specific ways in which ventilatory therapy has been used to treat CHF and ischemic heart disease. Third, we discuss mechanisms which have been proposed to explain the beneficial effects of positive pressure therapy in CHF. Finally, we attempt to draw a few conclusions and raise some questions which might be interesting for future study.
II. Principles of Cardiocirculatory Interaction A. Effects of CHF on Respiratory Function
The balance of forces between hydrostatic and oncotic pressures which determine the flux of water from capillary to lung and ultimately lead to pulmonary edema are well established. Starling’s law determines that the gradient between capillary and interstitial hydrostatic pressure is the force moving fluid out of capillaries into the interstitium. This is opposed the gradient between interstitial and capillary oncotic pressure which tends to hold fluid in capillaries. Further, there is an extensive system of lymphatics which tends to drain excess fluid from the interstitium and prevent water accumulation. When fluid flux is sufficiently great from capillary to interstitium interstitial and alveolar pulmonary edema may occur. Many studies have demonstrated a restrictive ventilatory defect, decreased lung volumes and lung compliance in patients with CHF (5–10). Further, the loss of lung volume is correlated with the severity of left ventricular (LV) failure as judged from the pulmonary artery occlusion pressure (PAOP) (10). In addition to loss of volume, flow rates are reduced and airways resistance is increased (5,11,12). Airways resistance increases because of mechanical compression of small airways by interstitial edema and peribronchiolar vascular distension, and reflex effects of congestion of the vessels, left heart, and interstitial space. Increased pulmonary vascular pressure also increases airways reactivity to nonspecific bronchial challenge (13). These combined effects on airways resistance are likely responsible for ‘‘cardiac asthma’’ described in some patients with acute CHF. Although capillary congestion with acute CHF should lead to an increase in the carbon monoxide diffusing capacity (DCO), impaired DCO is frequently observed in patients with chronic CHF (5,7). Mechanisms for decreased DCO with chronic CHF include concomitant smoking history, pulmonary fibrosis (8), and pulmonary thromboembolic disease (14). Because of the derangements in pulmonary mechanics in CHF, the work of breathing is increased. This leads to an increased load on the muscles of respiration which in
Ventilatory Support in the Failing Heart
521
turn increases the propensity of these muscles to fatigue and contributes to the sense of dyspnea (15, and see Chapter 3). B. Pulmonary Reflexes (See also Chapters 7 and 19)
Many pulmonary abnormalities elicit cardiocirculatory consequences by triggering reflexes based in the lung. Afferent fibers travel in both vagus and thoracic sympathetic nerves. Vagal afferents are better known and synapse in the nucleus tractus solitarius of the medulla, whereas the sympathetic afferents synapse in the dorsal horn of the spinal cord. The vagal afferents of the lungs consist of both myelinated and unmyelinated fibers (16,17). The myelinated afferents are divided into slowly adapting and rapidly adapting (irritant) receptors. Unmyelinated vagal afferents are subdivided into pulmonary C-fibers and bronchial C-fibers. A number of stimulusresponse relations have been described for pulmonary afferents. These include ventilatory and cardiodepressor responses to lung expansion, response to injection of certain chemical stimuli into the pulmonary circulation, and reflexes elicited from the pulmonary vasculature on ventilatory control. Stimuli eliciting pulmonary vascular responses include CO2 delivered into the pulmonary circulation, mechanical effects of increased pulmonary transmural pressure (i.e., pulmonary congestion), and increased pulmonary blood flow. Pulmonary congestion usually elicits increased ventilation (cardiodynamic hyperpnea). Tachypnea in response to pulmonary congestion is often accompanied by bradycardia and hypotension. This response is most likely mediated via C-fibers, and may be related to congestion of the pulmonary interstitium (18) and left atrium (19,20). Studies by Lloyd (21,22) indicate that there are vagally mediated pulmonary depressor afferents which are stimulated by pulmonary vascular congestions which modulate the ventilatory effects of C-fiber stimulation, and that there are separate cardiac and large pulmonary arterial reflexes which lead to ventilatory stimulation during CHF. Other factors such as changes in autonomic tone, anesthesia, analgesia, and chronic pulmonary congestion are likely to influence these responses in clinical situations as well. The implications of the reflex effects of lung inflation and pulmonary congestion during ventilatory maneuvers such as mechanical ventilation or administration of CPAP have not been fully explored in CHF and heart disease. However, it is not unlikely that many of the clinically observed cardiocirculatory consequences of ventilatory maneuvers are due to these reflexes. C. Changes in Lung Volume
With obstructive airways disease as well as with positive pressure ventilation lung volume may increase substantially. A biphasic relationship between lung volume and pulmonary vascular resistance and capacitance has been described (23,24). As lung volume increases from residual volume to functional residual capacity, pulmonary vascular resistance decreases and vascular capacitance increases. As lung volume continues to increase from functional residual capacity to total lung capacity, pulmonary vascular resistance increases and vascular capacitance decreases. The biphasic behavior of pulmonary vascular resistance is explained by postulating two
522
Scharf
types of intraparenchymal pulmonary vessels. Microvasculature located within alveolar septa (intra-alveolar vessels) are constricted or closed as lung volume increases. Microvasculature (extra-alveolar vessels) located in the corners where alveoli join or within peribronchial spaces are exposed to expanding forces when lung volume increases. As lung volume increases in low volume ranges, below functional residual capacity, the effects on extra-alveolar vessels predominate and pulmonary vascular resistance decreases. As lung volume increases above functional residual capacity toward total lung capacity, effects on intra-alveolar vessels predominate and pulmonary vascular resistance again increases. Thus, at the high lung volumes associated with obstructive airways disease or high levels of positive airway pressure, pulmonary vascular resistance is greater than normal. In addition, accumulation of lung water in CHF or adult respiratory distress syndrome (ARDS) mechanically compresses pulmonary vessels and increases pulmonary vascular resistance even further. Right ventricular (RV) afterload is at least partly related to RV wall stress, which in turn is a function of RV end-systolic volume and pressure (25). Thus, as lung volume increases above functional residual volume, as long as cardiac output (CO) is kept reasonably constant, RV end-systolic pressure, and volume will increase. Thus, increasing lung volume can impose a considerable afterload on the RV. In extreme situations, such the application of high levels of PEEP with severe ARDS, this can even lead to RV failure (26). However, in most cases, with increased airway pressure, the effects on venous return (see below) lead to a decrease in RV preload with PEEP. D. Venous Return and the Determination of CO
Changes in CO with ventilatory maneuvers, especially those associated with increased airway pressure, may be understood in terms of the interaction between venous return and cardiac function according to the classic theory of Guyton et al. (27), the basic principles of which remain valid today, in spite of numerous modifications to the basic theory (see Chapter 5). Venous return is determined by the gradient between the pressure in the lumped common peripheral circulatory reservoir (mean circulatory pressure) and right atrial pressure (RAP), which acts as the back pressure to venous return as well as an index of the diastolic filling (preload) of the heart. Figure 1 demonstrates a venous return curve. Note that as RAP increases, venous return decreases until flow is zero. At the point of zero flow point RAP is equal to mean circulatory pressure and the gradient for venous return is zero. Decreasing RAP leads to increases in venous return until RAP falls below the point of flow limitation. Below this point further decreases in RAP fail to elicit increases in venous return. Three cardiac function curves, labeled 1, 2, and 3, are shown in Figure 1. The curves plot CO as a function of RAP. For now we concentrate on curve 1, a ‘‘normal’’ cardiac function curve. Since at equilibrium, venous return must equal CO, under steady-state conditions the system exists at the point of intersection of the venous return and cardiac function curves, indicated as point A in Figure 1.
Ventilatory Support in the Failing Heart
523
Figure 1 Venous return (VR)–cardiac function interactions which determine cardiac output (CO). Cardiac function curve 1 is normal. Cardiac function curve 2 is shifted to the right on the x-axis by the amount by which positive airway pressure increases intrathoracic pressure (ITP), but there is no effect on cardiac function. Cardiac function curve 3 shows a small beneficial effect of increased ITP. See text for discussion. MCP, mean circulatory pressure; RAP, right atrial pressure; FL, point of flow limitation in VR curve.
E. Effects of Increased Intrathoracic Pressure (ITP) on Venous Return
If airway pressure increases, lung volume increases. This leads to an increase in ITP as determined by lung and chest wall compliance in addition to the increase in airway pressure. If there were no effect on cardiac function, then the cardiac function curve would shift to the right along the x-axis by an amount equal to the increase in ITP. This is shown in Figure 1 as curve 2. The point of steady state intersection of the venous return and cardiac function curves moves to point B. Thus, because of rightward shift in the cardiac function curve with increased ITP, the point of intersection between VR and cardiac function curves ‘‘slides’’ down the VR curve. This is because increases in ITP are transmitted through to the right atrium, raising RAP and reducing the gradient for VR (MCP-RAP). Thus, with increased airway pressure, venous return decreases, at least when cardiac function is normal. Even if, as discussed below, cardiac function is improved by the increase in ITP, this would have little effect on the changes in CO in normal hearts. In Figure 1 the theoretic possibility of improved cardiac function with increased ITP is demonstrated by curve 3, which is steeper than curves 1 and 2. In this case the intersection of venous return and cardiac function curves is found at C, with CO only slightly higher than at point B, but still lower than at point A. This is because the theoretic ‘‘best’’ cardiac function curve would be a vertical line. Since normal cardiac func-
524
Scharf
tion curves are not far off the vertical, there is really little room for improvement. Thus, with normal hearts, when ITP is increased, venous return effects prevail over the cardiac function effects and CO decreases. Figure 2 shows the effects of increased ITP in the failing heart. The venous return curve is shown unchanged from Figure 1. The baseline cardiac function curve (curve 1) is depressed relative to normal and is shown shifted down and to the right. Thus, the intersection of VR and cardiac function curves (point A) is at a lower CO and greater RAP than the normal curves. With increased airway pressure, if there were no change in the cardiac function curve, then the cardiac function curve would shift rightward along the x-axis by an amount equal to the increase in ITP (curve 2) and CO would decrease (point B). However, if increased ITP improves cardiac function (see below) then the cardiac function curve could improve (curve 3) considerably and the point of intersection of venous return and cardiac function curves would move back up the venous return curve and CO could even increase (point C). This is because with severely depressed cardiac function curve, there is a great deal of room for improvement in cardiac function and changes in cardiac function could predominate over changes in venous return with increased ITP. Curve 4 shows that if ITP pressure continued to increase, eventually venous return would decrease sufficiently to lead to a decrease in CO (point D). Thus, theory predicts that with failing hearts increasing ITP could allow CO to actually increase. However, there
Figure 2 Venous return–cardiac function curves with failing hearts. Cardiac function curves 1 to 3 are as for Figure 1. Cardiac function curve 4 shows what happens if higher levels of airway pressure than those of curves 2 and 3 are applied, thus continuing to increase ITP. See text for discussion. Abbreviations as in Figure 1.
Ventilatory Support in the Failing Heart
525
would be an ‘‘optimal’’ increase in ITP beyond which further increases would lead to decreased CO again. F. Effects of Increased ITP on Cardiac Function
In the 19th century, Donders (28) recognized that decreasing ITP during inspiration aids the entrance of blood into the chest from the periphery, but impedes the egress of blood from the chest to the periphery. This is because the heart and great vessels are exposed to ITP. Normally, ITP changes are small and respiration has a small effect on blood flow. Figure 3 presents a simplified scheme of the LV located within the chest. At ‘‘baseline’’ during systole LV pressure is shown as 100 units and ITP as ⫺3 units. The LV, thus ‘‘sees’’ a pressure across its wall of 103 units. Hence, the stress on the LV is properly expressed as the pressure gradient, called the transmural pressure, across its wall. Without knowledge of ITP, measurements of intracavitary pressure alone will give incomplete assessments of LV wall stress. During normal quiet breathing changes in ITP are small, and errors introduced by not measuring ITP are therefore also small. However, with abnormal respiration, e.g., with airways obstruction or positive-pressure ventilation, the stress across the LV wall cannot be assessed using measurements of intracavitary pressure alone. For example, if there is a large sustained decrease in ITP (Mueller maneuver), decreasing ITP to ⫺40 units in Figure 3, then at systole, for the same intracavitary LV pressure of 100 units, the LV actually is contracting against a pressure 140 units across its
Figure 3 Model of the LV in the thorax and the influence of changes of ITP on LV function. Ptm, transmural pressure. See text for discussion.
526
Scharf
wall. This is sensed by the LV as an increase in LV afterload, and the ventricle dilates. Conversely, if there is an increase in ITP, as during the performance of a Valsalva maneuver to 20 units in Figure 3, for the same LV intracavitary pressure of 100 units, LV transmural systolic pressure decreases to 80 units, and the LV senses this as a decrease in afterload with improved ventricular ejection. Thus, under the right circumstances, increasing ITP could aid in ventricular ejection. Numerous studies in humans and animals have confirmed these basic principles of the effects of changes in ITP on ventricular function (29–36). G. Changes in Autonomic Function
In addition to pulmonary reflexes, there are a number of other reflex links between the pulmonary and circulatory systems. These include reflex responses to changes in chest wall and/or respiratory mechanoreceptor inputs, and reflex responses to changes in arterial gas tensions. A good example is the cardiocirculatory response to hypoxia. Stimulation of the carotid chemoreceptors by hypoxia increases vagal discharge and leads to cardiac slowing (37). Stimulation of aortic and central chemoreceptors leads to sympathoadrenal discharge and cardioacceleration (38). The balance between these effects can be modulated by the ventilatory, i.e., mechanical, response. For example, when experimental animals are made hypoxic, but hyperventilation is prevented (paralyzed, constant ventilation), severe bradycardia and circulatory collapse may occur at relatively mild levels of hypoxia. But when the hyperventilatory response to hypoxia is allowed to occur, the balance falls in favor of sympathoadrenal tone and tachycardia ensues (39–41). The neural link between respiration and circulation is also illustrated in animal studies demonstrating that when all respiratory motion ceases due to paralysis (apnea), hypoxia induces blood pressure waves with a periodicity of four to eight per minute. The waves are synchronous with continued respiratory motoneuron output (42). Last, with mechanical ventilation, arterial pressure often increases during inspiration. This phenomenon is sometimes called reversed pulsus paradoxus. One of the contributing factors to this is that the sympathetic nervous system synchronizes with the ventilator (43). Changes in lung volume and chest wall afferent input from mechanoreceptors are likely to be important modulators of the central neural coupling between respiratory and circulatory reflexes. Future studies could be directed at elucidating the clinical implications of this physiology. H. Ventricular Interdependence
The RV and LV are connected in series through the pulmonary vessels. Thus, decrease in the output of one ventricle results in a decrease in the output of the other. However, the ventricles share the same fiber bundles, interventricular septum and are found in the same pericardial sac. These features lead to parallel interactions between the ventricles. Both the diastolic and systolic function of one ventricle are influenced by the state of filling and pressure in the other ventricle. For example, if the filling of one ventricle increases, then the diastolic compliance of the other decreases (see 44 for review). This interaction, mediated through the interventricular
Ventilatory Support in the Failing Heart
527
septum is amplified by the presence of the pericardium. For respiratory interactions, the most important diastolic actions are those occurring with increased RV volume. For example, with spontaneous inspiration, decreased ITP leads to increased venous return and filling of the RV during inspiration. This in turn leads to a decrease in LV compliance and decreased LV end-diastolic volume. Until equilibration occurs, as during sustained maneuvers, there is a decrease in LV stroke volume, which contributes to pulsus paradoxus. These interactions are exaggerated during obstructed respiration when the influx of venous return into the RV is increased (45– 47), contributing to pulsus paradoxus. As well, LV compliance decreases with high levels of PEEP, when venous return is preserved (48,49). This effect has also been attributed to increased RV volume due to increased afterload (increased lung volume) with subsequent interdependence effects on the LV. The effects of PEEP on LV compliance are exacerbated by RV ischemia, presumably because RV volume increases more for a given increase in RV afterload with PEEP with RV ischemia and the subsequent interdependence effects are greater (50,51). Maughan et al. (52) have presented a linear model to explain the interactions between the ventricles. These are expressed as the gain between the ventricles. The heart is viewed as a three-compartment structure with three relevant volume elastances—the RV and LV free walls and the septum, respectively. The ‘‘cross-talk’’ between the ventricles is defined as a change in one ventricle chamber relative the other. The ‘‘cross-talk gain’’ is defined as the ratio of the change in pressure in one chamber when the pressure is changed in the other. For a change in RV pressure, when ventricular volumes are held constant: Grl ⫽
∆LVP ∆RVP
(1)
Where Grl is the pressure gain from right to left, and LVP and RVP are RV and LV pressures, respectively. Similarly the left to right gain is defined as: Glr ⫽
∆RVP ∆LVP
(2)
The interaction between the ventricles is mediated through the septum, the common fiber bundles shared by the ventricles, and the pericardium. The gains are related to the ratio of volume elastances between the septum and the sum of the volume elastances between septal and contralateral ventricular free wall. Hence: Grl ⫽
Elf Es ⫹ Elf
(3)
Glr ⫽
Erf Es ⫹ Erf
(4)
and
528
Scharf
where Elf is the elastance of the LV free wall, Erf is the elastance of the RV free wall, and Es is the elastance of the septum. For a relatively stiff interventricular septum, the cross-talk gain is relatively small (52,53) and when septal elastance is increased, gain is increased (54). From the above, it may also be deduced that during systole, pressure generation in one ventricle aids pressure generation in the other. In fact, during systole, approximately 40%–60% of the pressure generated by the RV is actually due to contraction of the LV (55). This finding has been used to explain the observations that the afterload tolerance of the RV during pulmonary arterial occlusion is increased if aortic pressure is increased (56). However, during respiratory maneuvers, systolic interaction probably plays little role, the more important interactions being those during diastole as described above. I.
Mechanical Heart-Lung Interactions
Since the heart is located within the pericardial fossa, mechanical interactions between the lungs and heart would be expected to play an important role in determining cardiac function, especially when the lungs are hyperinflated as in obstructive airways disease or ventilation with high levels of positive airway pressure (57–60). For example, in patients with obstructive airways disease, dynamic hyperinflation during exercise can lead to elevation in PAOP due to mechanical compression (58). It is important to distinguish this from increases which could be due to dysfunction of the LV. Patients with severe emphysema frequently have elevations in PAOP which are unassociated with any evidence of LV systolic dysfunction. Figure 4 shows the relationship of PAOP to LV ejection fraction before and following lung volume reduction surgery in a six severely ill emphysema patients. Clearly PAOP greater than the ‘‘normal’’ range (⬍ 12) did not signify LV systolic dysfunction since all patients had normal LV ejection fraction. Presumably, hyperinflation of the lungs and compression of the heart could limit diastolic filling. This factor is greatest with mechanical ventilation with large tidal volumes and high levels of PEEP. Thus, modes of ventilation which minimize lung volume (apneic or high-frequency ventilation) minimize this problem. Studies have revealed that with levels of PEEP there is a decrease in the septal-free wall dimension of the LV relative to other LV dimensions, consistent with compression of the LV from surrounding lungs (59–61). In addition, compressive effects of the lungs on the heart are greatest when the lower lobes are inflated (57,58). J. Effects of Increased Cardiac Surface Pressure on Coronary Blood Flow
Increasing cardiac surface pressure relative to aortic pressure could lead to a decrease in coronary blood flow. Right atrial pressure could increase or the pressure surrounding epicardial vessels could increase relative to aortic pressure. Either of these changes could decrease the gradient for coronary perfusion and decrease coronary blood flow. In an isolated heart preparation, Fessler et al. (62) raised cardiac surface pressure relative to aortic pressure and demonstrated decreased coronary flow and
Ventilatory Support in the Failing Heart
529
Figure 4 Relationship between pulmonary artery occlusion pressure (PAOP) and LVEF in patients before and 3 months following lung volume reduction surgery. Elevated PAOP does not signify decreased LV ejection fraction and is most likely due to severe resting hyperinflation. The arrows show the change from pre- to postsurgery.
the development of LV ischemia. However, this effect was not seen until cardiac surface pressure increased to ⬎60 mm Hg. At lower levels of cardiac surface pressure, improved LV ejection was seen consistent with the afterload-reducing effects of increased ITP discussed above. A number of workers have studied the effects of PEEP on coronary blood flow and myocardial ischemia. Tucker and Murray (63) reported decreases in coronary blood flow with PEEP. These decreases were out of proportion to decreases in cardiac work. These authors suggested that if PEEP led to decreases in coronary flow out of proportion to metabolic needs, then PEEP could actually be dangerous when coronary flow reserve was limited as in coronary artery disease. Venus and Jacobs (64) found a decrease in LV and septal regional as well as in RV myocardial blood flow with high (15 to 25 cm H2 O) levels of PEEP. The authors suggested that decreased myocardial blood flow could be an effect of reflexes triggered by lung inflation. Tittley et al. (65) studied patients following coronary artery bypass surgery who were on mechanical ventilation with PEEP (to 15 cm H2O). In 17 of the 35 patients studied, decreased lactate utilization was observed at high levels of PEEP. Last, Hassapoyannes et al. (66) studied anesthetized dogs during increases in cardiac surface pressure gated to cardiac systole (see below). Coronary blood flow decreased in proportion to decreased LV energy demands; i.e., the changes were autoregulatory in nature and did not represent a danger. However, the authors pointed out that since aortic diastolic pressure decreased with gated increases in ITP, a limit may exist to increasing cardiac surface pressure above which ischemia
530
Scharf
could be caused as decreases in coronary flow outstrip decreased myocardial energy demands due to decreased preload and afterload. Although the final word is far from being spoken, some caution is urged in treating patients with active ischemic heart disease with high levels of ITP without further study. III. Ventilatory Therapy for CHF and Ischemic Heart Disease In reviewing experimental data one must be careful about extrapolating results between studies, because conditions may vary greatly. For example, mechanical ventilation with PEEP is often considered to be equivalent to CPAP. However, with mechanical ventilation and PEEP, ITP increases throughout all phases of the respiratory cycle, while with CPAP, ITP is increased at end expiration, but decreases during inspiration. Thus, venous return effects of PEEP are far greater than those with CPAP (see Chapter 31). In addition, experimental studies with PEEP are usually performed on anesthetized, often paralyzed, animals. Anesthetic effects on baseline cardiovascular function are profound. It is known that there are sympathetic homeostatic reflexes which buffer the adverse hemodynamic effects of PEEP (67,68). These are likely to be depressed more with general anesthesia. Even more caution is urged in extrapolating to clinical situations. A. Effects of Increased ITP in Heart Failure in Anesthetized Animals
Following up on clinical studies suggesting improved CO with positive-pressure ventilation in heart failure, Pinsky et al. produced heart failure (69) by injecting large doses of propranalol in anesthetized dogs. The animals were ventilated using large tidal volume (30 mL/kg) ventilation, and, to further increase ITP, the chest and abdomen were bound with elastic bandages. With binding, inspiratory ITP increased by 12.1 mm Hg. With mechanical ventilation under the bound condition there was a upward-leftward shift in the Starling function curve of the LV, indicating improved cardiac function. In a similar study on anesthetized humans with heart failure, Pinsky and Summer demonstrated improved cardiac output (70) when ITP was increased during mechanical ventilation by binding the chest and abdomen. Robotham even suggested the term ventilator-assisted myocardial performance to describe the use of ventilatory maneuvers to improve the function of failing hearts (71). Theoretically, increasing cardiac surface pressure would exert its maximum beneficial effect of increasing cardiac ejection during systole. On the other hand, increased ITP during diastole could inhibit ventricular filling which would in turn limit cardiac output. In order to maximize the beneficial effects of increased ITP on LV function and to minimize adverse effects on venous return and ventricular diastolic filling, Pinsky et al. gated increases in ITP to cardiac systole. In initial studies, they studied the phasic increases in ITP produced by a jet ventilator in dogs with propranalol induced cardiac failure (72). When cardiac function was normal, LV stroke volume decreased with phasic pulsed increases in ITP. However, when cardiac function was depressed following propranolol, LV stroke volume increased
Ventilatory Support in the Failing Heart
531
with phasic increases in ITP. Further, these effects were maximal when the pulsed increases in ITP were gated to cardiac systole (73). Similar findings were later observed in anesthetized humans with heart failure (74). This suggested that data from the animal studies could be extrapolated to humans (Fig. 5). Using a mathematical model, Beyer et al. (75) predicted that maximum flow augmentation would occur when the onset of the pulsed increase in ITP is simultaneous with onset of LV isovolumic contraction and lasted for 400 msec. The magnitude of flow augmentation is a function of the amplitude of the rise in ITP. Their predictions were confirmed in experiments in anesthetized dogs. They also found that there was little additional flow augmentation when ITP increased by ⬎30 to 40 mm Hg. Further, these authors used a rapidly inflating external vest rather than jet ventilation. This is potentially important since cardiac assist could be applied by this method in a noninvasive fashion. Other workers have investigated the effects of synchronized jet ventilation in other forms of cardiac dysfunction. Stein et al. (76) found that both systolic and
Figure 5 Effects of high-frequency jet ventilation (HFJV) in humans with CHF. IPPB, standard mechanical ventilation with intermittent positive pressure breathing; asynch HFJV, HFJV at the patient’s heart rate not synchronized to cardiac systole; synch HFJV, HFJV synchronized to cardiac systole. Cardiac output (CO) is normalized to the value at IPPB1. Note that CO increases only with synch HFJV. (From Ref. 74.)
532
Scharf
diastolic timed jet ventilation led to increased stroke volume in experimentally produced mitral regurgitation. Guimond et al. (77) studied the effects of synchronous jet ventilation during endotoxic shock in anesthetized dogs. In this case there were no increases in stroke volume with either synchronous or nonsynchronous increases in ITP. However, as the authors were careful to point out, the interrelationships between cardiac and peripheral circulatory function in endotoxemia are complex. Possibly improvements in cardiac function produced with increases in ITP were masked by arterial vasodilation, increased venous return and fluid resuscitation. Peters and Ihle (78) used chronically instrumented unanesthetized dogs before and following coronary occlusion to study the effects of timed pulsed increases in ITP produced by ECG-gated rapid inflations of a vest. Although single pulses in ITP coupled to late systole augmented stroke volume, repetitive inflations coupled to any cardiac cycle phase led to nonspecific increases in flow. This was not observed after β-adrenergic blockade. Thus, the effects of vest inflation were related to changes in sympathoadrenal tone produced by the vest inflations rather than increased ITP per se. Additionally, these authors concluded that direct compression of the heart, not increased ITP was responsible for increased stroke volume in this model. The demonstration of the importance of sympathoadrenal function in determining the effects of phasic increases in ITP suggests a dimension which is not considered by purely mechanical models of the circulation and studies in animals in which sympathetic blockade is used to produce heart failure. B. CHF and Sympathoadrenal Function
In patients with chronic CHF there are important changes in sympathoadrenal function. These include elevation in tonic sympathetic tone with in chronic elevations in baseline plasma norepinephrine levels (79–81), downregulation of cardiac β-receptors (82), decreased myocardial norepinephrine levels (83), and increased myocardial norepinephrine turnover (84,85). While enhancement of sympathoadrenal function acts beneficially to maintain blood pressure and cardiac function, the chronic effects of CHF on sympathoadrenal function could actually worsen cardiac function by leading to increased LV afterload (vasoconstriction), myocardial necrosis (chronic sympathetic stimulation), and depletion of myocardial catechols and inotropic receptors. Thus, experimental models producing myocardial depression by massive β-adrenergic blockade do not consider one important aspect of CHF in humans. Ventilatory maneuvers may act by affecting autonomic function rather than or in addition to ventricular loading and venous return. This aspect of ventilatory treatment of cardiac failure is considered in the next section. C. Effects of CPAP in CHF
As noted in the beginning of this chapter, CPAP has been used to treat CHF for more than 60 years (1). CPAP refers to the application of pressure to the airway during spontaneous respiration. This may be done via endotracheal tube or via face or nose mask. In addition to its use in the intensive care setting to treat ARDS and CHF with pulmonary edema, CPAP is the most common therapy for obstructive
Ventilatory Support in the Failing Heart
533
sleep apnea (86). Clinical observations in patients with concomitant sleep apnea and CHF being treated with nocturnal CPAP suggested that marked resolution of CHF, associated with improved LV systolic function during the day, often occurred with CPAP treatment (87). Takasaki et al. (88) applied nasal CPAP 12.5 cm H2O to five patients without obstructive sleep apnea but with severe CHF associated with Cheyne-Stokes respiration for 3 months. Sleep fragmentation was reduced and mean arterial O2 saturation was increased. However, more important there was a significant increase in mean resting LV ejection fraction measured during the day following 3 months’ therapy with nocturnal CPAP, from 31% to 38%. The same group later competed a controlled randomized clinical trial in patients with cardiomyopathy and nocturnal Cheyne-Stokes respiration of nocturnal CPAP (89). Preliminary results were confirmed and the CPAP treated group demonstrated improved daytime functioning and improved LV ejection fraction during the day. Although changes in the CPAP-treated group were seen after 1 month of treatment, the maximum effect was seen after 3 months of therapy (see also Chapter 22). No improvement was observed in the control group. Not all trials universally report success in treating CHF with CPAP. Two small uncontrolled patient trials failed to demonstrate significant improvement in LV function with nocturnal CPAP therapy in CHF patients (90,91), and one (90) even reported deterioration in three patients on CPAP therapy. Differences in baseline clinical condition, autonomic function may be partly responsible for different conclusions. The acute effects of CPAP on cardiac function have also been investigated clinically. Pery et al. (92) reported improved cardiac output, increased mixed venous O2 saturation, and decreased PAOP with the application of 7 cm H2O CPAP in a patient with CHF. Baratz et al. (93) studied 13 patients with acute CHF treated with CPAP up to 15 cm H2O. Seven of these patients responded with an increase in cardiac output of at least 400 mL/min. However, the effects of baseline PAOP could not be assessed since all patients had PAOP ⬎ 20 mm Hg. Ra¨sa¨nen et al. (94) studied 14 patients treated with CPAP following acute myocardial infarction. With CPAP treatment, patients with moderate LV dysfunction (stroke volume index ⬎ 20 ml/M2) demonstrated a trend toward decreased CO, whereas patients with severe LV dysfunction (stroke volume index ⬍ 20 mL/M2 ) demonstrated a trend toward increased CO. Similarly, Bradley et al (95) demonstrated improved cardiac output with the application of 5 cm H2O CPAP only in those CHF patients in whom baseline PAOP was ⱖ12. In patients with low PAOP, CPAP led to decreased cardiac output. In a follow-up study (96) from the same laboratory, both control subjects and CHF patients with low PAOP showed dose related decreases in cardiac output with CPAP. Patients with CHF and elevated PAOP showed dose-related increases in cardiac output with CPAP. On the other hand, two recent studies (97,98) have failed to confirm increased CO with CPAP administered in acute CHF. However, both reported decreased PAOP indicating improved LV function. One study (98) reported decreased levels of plasma endothelin, which could be beneficial by decreasing vasoconstriction. Finally, Liston et al. (99) studied seven patients with CHF, all of whom had PAOP
534
Scharf
⬎ 12 mm Hg. Cardiac output fell in all patients on nasal CPAP and systemic vascular resistance increased. These authors cautioned against routine use of CPAP. However, six of the seven patients studied were in atrial fibrillation. The effect of cardiac rhythm on the response to CPAP is unknown. The best conclusion that one can draw from the clinical work on CPAP is that in acute CHF, CPAP has benefits in terms of improved oxygenation and decreased work of breathing. In addition, at least some patients with acute CHF appear to derive hemodynamic benefit from CPAP. These appear to be patients with the most severe cardiac congestion as reflected by the PAOP. The best available data indicate that patients with CHF and Cheyne-Stokes respiration derive benefit from long-term nocturnal domiciliary use of CPAP. It remains to be seen whether these conclusions can be extended to patients with CHF who are not in this category. D. CPAP and CHF in Animal Studies
Because of difficulty standardizing clinical studies, experimental preparations offer some advantages for determining the mechanisms responsible for hemodynamic effects of CPAP. In our laboratory, we have developed a previously instrumented preparation in pigs which allows for study under sedation rather than anesthesia. In stage 1, animals are instrumented using sterile technique under general anesthesia for study of LV function. This includes placement of a left atrial catheter, sonomicrometer crystals across the orthogonal axes of the LV for measurement of LV volume, and an electromagnetic flow probe around the ascending aorta. Catheters and leads are brought out into a subcutaneous pocket. Following recovery, animals are sedated with either fentanyl-droperidol or alphaloxone-alphadolone. The animals remain tranquil, but responsive to pain and loud noises. Under local anesthesia, femoral arterial and venous catheters are placed for administration of fluids and recording blood pressure, the subcutaneous pocket is opened and a high-fidelity catheter-tipped manometer is passed into the LV via the left atrial catheter. Thus, LV end-diastolic (LVEDP) and end-systolic (LVESP) pressures, and LV volumes may be measured. E.
Effects of CPAP on CO
CHF is often associated with cardiac congestion and hypervolemia. In an initial series on sedated pigs the effects of increasing CPAP were studied with the animals normovolemic and then while hypervolemic, produced by infusion of hetastarch 35 mL/kg (100). This infusion was enough to increase LVEDP from the normal value of 10.6 ⫾ 5.9 to 19.1 ⫾ 6.4 mm Hg (P ⬍ .001). Thus, the hypervolemic condition represents at state of volume expansion and central circulatory congestion as seen with CHF. Cardiac index (CI) changes are illustrated in Figure 6 (101). In the figure, values are shown normalized to baseline, set at 1. Note that with normovolemia animals (NV) increasing CPAP to decreased CI. However, with hypervolemia, CI increased at low-level CPAP before decreasing with continued increases in CPAP. The maximum increase in CI was seen at 5 cm H2O CPAP. In a later series, CHF was produced using rapid ventricular pacing for 7 to 10 days before studying the hemodynamics (102). In this case, baseline LVEDP
Ventilatory Support in the Failing Heart
535
Figure 6 Changes in cardiac index (CI) normalized to baseline in two sets of experiments: studies of normal animals while normovolemic (NV) and after being made hypervolemic (HV), and studies of animals following induction of congestive heart failure (CHF). See text for discussion. (From Ref. 101.)
was 21.6 ⫾ 5.3 mm Hg. Changes in CI with CHF are also shown in Figure 6. Note that as in the hypervolemia studies CI was maximal at the lowest level of CPAP. However, even though CI decreased as CPAP was increased, it did not reach baseline even at the greatest level of CPAP. Finally, an interesting phenomenon was observed following removal of CPAP. In the normovolemic and hypervolemic studies (100) CI returned to baseline following removal of CPAP. However, with CHF (102), there was a large increase in CI following CPAP removal which lasted from 30 to 60 min before returning to baseline. F. Effects of CPAP on Ventricular Afterload
In the studies of Genovese et al. cited above (100,102), LV end-systolic volume was used as one indicator of changes in LV afterload. Decreased LV end-systolic volume was taken as evidence for a decrease in LV afterload, since changes in contractility were assumed not to have occurred. Figure 7 shows mean changes in LV volumes from the normal animals. Note decreased LVEDP in both normovolemic and hypervolemic animals, consistent with decreased venous return. In the hypervolemic animals there was also a decrease in LVESV at the 5 cm H2O CPAP which was maintained as CPAP increased to greater levels. LV ejection fraction was also found to increase with CPAP in both the hypervolemic animals (100) and animals with CHF (102).
536
Scharf
Figure 7 Cardiac volumes with CPAP in normovolemic (NV) and hypervolemic (HV) animals. **Statistical significant difference between NV and HV. P values are for change with CPAP (analysis of variance). Open symbols ⫽ normovolemia; closed symbols ⫽ hypervolemia.
In the studies of Pinsky et al. (69,70,72–74), LV afterload was measured as LV end-systolic transmural pressure. This was calculated as LV end-systolic cavitary pressure minus esophageal pressure. This assumes that esophageal pressure represents cardiac surface pressure. While this is a common assumption, when the pericardium is intact, changes in cardiac volume may render this assumption invalid. When
Ventilatory Support in the Failing Heart
537
the heart is small, changes in ITP are transmitted to the cardiac surface and the effect of pericardial elasticity on cardiac surface pressure is small. On the other hand, with cardiac dilatation, the elasticity of the pericardium becomes greater and may have greater effects on LV surface pressure. This is because cardiac surface pressure is the arithmetic sum of ITP and pericardial elastic pressure. As the heart becomes larger, pericardial elastic pressure becomes an increasingly important component of cardiac surface pressure during positive pressure maneuvers (103, 104). This means that changes in esophageal pressure with respiration may not be a good indicator of pressure on the cardiac surface when the heart is dilated, as in CHF or hypervolemia. It follows then, that using esophageal pressure to estimate LV transmural pressure may lead to inaccurate overestimations of LV transmural pressure. In the initial studies in CHF (102), cardiac surface pressure was not measured. Change in airway pressure was used as a maximal estimate of change in cardiac surface pressure. In other words, it was assumed that there was complete transmission of CPAP to the pleural space. Hence, the degree to which LV transmural pressure would decrease during CPAP would have been overestimated using airway pressure to calculate LV transmural pressure. Using this method, no decrease was noted in LV end-systolic transmural pressure with CPAP. Similar results were found in human studies by Liston et al. (99). On the other hand, using esophageal pressure as an estimate of cardiac surface pressure, Naughton et al. (4) demonstrated decreased LV transmural pressure with CPAP in patients with CHF. This occurred because CPAP decreased the work of breathing in their patients and reduced the magnitude of inspiratory swings in esophageal pressure. Since mean esophageal pressure increased, mean LV transmural pressure was calculated to have increased. In sedated pigs Huberfeld et al. (105) measured both esophageal and cardiac surface (pericardial) pressure during the application of CPAP in normal and hypervolemic animals. They confirmed increased CO with CPAP in the hypervolemic animals. Figure 8 shows the changes in esophageal and pericardial pressure with CPAP in their studies. With normovolemia, as CPAP was increased there were parallel increases in pericardial and esophageal pressure. Thus, estimates of LV transmural pressure made from esophageal pressure would accurately reflect measurements of LV transmural pressure using pericardial pressure. When the animals were made hypervolemic, there was an increase in baseline pericardial pressure reflecting cardiac dilation. However, as CPAP increased, pericardial pressure actually fell. In fact calculated LV end-systolic transmural pressure actually increased slightly with CPAP. Thus, with hypervolemia decreasing LV end-systolic transmural pressure could not account for increased CO with CPAP. These studies demonstrated that simple transmission of increased ITP to the cardiac surface did not per se lead to decreased LV afterload as measured by decreased LV end-systolic transmural pressure. Although the observation that cardiac surface pressure decreased with increasing CPAP in hypervolemia seems surprising, it is not unprecedented. In studies on the effect of PEEP on pericardial pressure Cabrera et al. (106) found that, unlike with normovolemia, with hypervolemia there were no changes in pericardial pres-
538
Scharf
Figure 8 Pericardial and esophageal pressure in normovolemic and hypervolemic animals during the application of CPAP. (From Ref. 105.)
sure with increasing PEEP. They concluded that the ‘‘changes in pericardial pressure in response to PEEP reflect both the transmission of airway pressure to the pericardial surface and, presumably, PEEP related changes in cardiac volume and ventricular compliance’’ (106). The explanation can be understood in terms of a model alluded to above in which cardiac surface pressure can be understood as the sum of two pressures as follows: PCs ⫽ ITP ⫹ Pperi
(5)
where PCs ⫽ cardiac surface pressure and Pperi ⫽ pericardial elastic or transpericardial pressure. Transpericardial pressure is determined by the pericardial pressurevolume curve and the volume of heart within the pericardial sac as illustrated in Figure 9. The pericardial pressure volume curve is curvilinear. Thus, at high pericardial volumes there are large decreases in pressure (∆P) associated with decreases in heart volume (∆V). This is because at the high end of the cardiac volume range, the pericardium begins to approach its elastic limit and becomes stiff. On the other hand, at the low end of the cardiac volume range, decreases in cardiac volume are associated with relatively small changes in transpericardial pressure. If CPAP is associated with decreased cardiac volume, by any mechanism whatsoever, then the decrease in transpericardial pressure (Pperi) will be greater (more negative) if initial heart volume is elevated (distended heart). Thus, for a given increase in ITP, PCs could decrease (large enough decrease in Pperi) with CPAP if cardiac volume were large enough to put the pericardium close to the limits of diastolic distension. Under these conditions, the decrease in Pperi would be larger than the increase in ITP with
Ventilatory Support in the Failing Heart
539
Figure 9 Theoretic effects of decreased heart volume on transpericaridial pressure begining from high and low initial cardiac volumes. For a given decrease in heart volume ∆V, the decrease in transpericardial pressure ∆P is greater when initial cardiac volume is close to the limits of pericardial distension. PCs, cardiac surface pressure; ITP, intrathoracic pressure; Pperi, transpericardial pressure; Cperi, pericardial compliance, much less at high than at low cardiac volumes. We assume that ITP increases with CPAP but that heart volume decreases. If initial heart volume is great enough, then transpericardial pressure could decrease more than ITP increases. Thus, PCs could decrease. See text for details.
CPAP and PCS would decrease (Eq. 5). The question only remains, if cardiac volume did not decrease because of increased cardiac surface pressure, then how does CPAP decrease cardiac volume? This will be considered in Section IV. However, discussion of the effects of ventilatory maneuvers and cardiac function would not be complete without consideration of the effects of ventilation on coronary blood flow cardiac ischemia. G. Effects of CPAP on Coronary Blood Flow and Myocardial Energetics
As discussed above, increasing cardiac surface pressure could lead to a decrease in coronary blood flow. This is because of increased epicardial surface pressure and/ or increased right atrial pressure. This could be of special concern in patients with coronary artery disease. Huberfeld et al. (107), in fact, observed a small decrease in coronary blood flow with CPAP in hypervolemic animals. However, no changes in several indices of myocardial O2 consumption, O2 extraction, or regional or global myocardial function were observed. The authors felt that decreased coronary flow was associated with systemic vasodilation and slightly decreased coronary perfusion pressure with CPAP and did not constitute a threat for the development of ischemia. Possibly, the animals were protected from decreased coronary flow because cardiac
540
Scharf
surface pressure does not decrease with CPAP in hypervolemic animals when CO increases. H. CPAP and Sympathoadrenal Function in Sedated Pigs
As discussed, CHF is associated with an upregulation of baseline sympathoadrenal tone, which could itself be a source of cardiac dysfunction. Naughton et al. (108) observed evidence of downregulation of sympathoadrenal tone in patients with CHF and Cheyne-Stokes respiration undergoing chronic CPAP treatment. Using plasma norepinephrine (PNE) as an index of overall sympathoadrenal tone Scharf et al. (109) studied the effects of CPAP on sympathoadrenal tone in normovolemia, hypervolemia, and CHF in sedated pigs. Figure 10 illustrates the results. Both hypervolemia and CHF were associated with increased PNE at CPAP ⫽ 0 relative to normovolemia. However with hypervolemia there was a decrease in PNE with low level CPAP, whereas with CHF there was an increase in PNE. Thus, in this model, consistent decreases in sympathoadrenal function (PNE) were not associated with increased CO with low level CPAP. Differences between the pig study and the human study were explained by differences in species, degree and chronicity of CHF, concomitant cardiac medications in patients, and other variables which might have been present in chronic patient studies but not in the pig studies.
Figure 10 Plasma norepinephrine levels (PNE) with CPAP in sedated pigs. NV, normovolemia; HV, hypervolemia; CHF, congestive heart failure. *Statistically different from CPAP ⫽ 0 (baseline) for each condition. (From Ref. 109.)
Ventilatory Support in the Failing Heart
541
I. Removal of Mechanical Ventilation and Cardiac Ischemia
Generally, when patients are removed from mechanical ventilation there is a small increase in CO. This is most likely related to increased metabolic demands and sympathoadrenal adjustments and a decrease in mean ITP with concomitant increase in venous return. In 1973, Beach et al. (110) reported that CO actually decreased upon removal from mechanical ventilation in 18 of 37 patients. This unexpected finding was not predictable by changes in blood gas tensions. Patients showing postweaning decreases in CO had somewhat worse preweaning cardiac function (greater central venous pressure and lower cardiac output) than patients showing the expected increase in CO. The authors speculated that changes in sympathoadrenal function, probably vasoconstriction, associated with weaning might have been responsible. On the other hand mechanical loading associated with decreased mean ITP might equally have been responsible. In 1984, Ra¨sa¨nen et al. (111) studied the cardiopulmonary effects of ventilatory support in 12 patients with acute myocardial infarction and respiratory failure. Five patients developed ECG evidence of ischemia upon being removed from mechanical ventilation. The ratio between arterial diastolic pressure-time integral and tension-time integral, called the endocardial viability ratio, decreased in these five patients as well. Lemaire et al. (112) studied a group of patients with known ischemic heart disease who could not be weaned off mechanical ventilation following an episode of respiratory failure. Although arterial blood gas tensions were well maintained and there were few indications of acute cardiac ischemia, there were increases in transmural LV filling pressure (PAOP minus esophageal pressure) during weaning attempts. Following several days of therapy for cardiac ischemia, weaning could be easily accomplished. These authors suggested that ischemia during weaning attempts was responsible for failure to wean. Using radiolabeled thallium perfusion studies, Hurford et al. (113) subsequently documented LV ischemia during unsuccessful weaning attempts in 7 of 14 patients with ischemic coronary artery disease. Again, this was not related to abnormalities of blood gas tensions. Thus, silent ischemia may be responsible for failure to wean in patients with coronary heart disease and respiratory failure. Whether this is related to changes in sympathoadrenal function and/or changes in ITP is not known. However, this factor should be remembered when attempting to remove patients with active myocardial ischemia from mechanical ventilation. IV. Models to Explain Improved Cardiac Function with CPAP It would appear that increased CO observed with CPAP may not be easily explained either by a decrease in LV afterload due to increased cardiac surface pressure (decreased LV transmural pressure) or a particular change in overall sympathetic activity (as measured by PNE). It also appears that increased CO is associated with a decrease in cardiac volume, reflecting improved cardiac function rather than increased preload. There are two explanations for this that we have presented in previous studies and will review here.
542
Scharf A. CPAP-Induced Systemic Vasodilatation
In the sedated pig studies (100–102,104,105) presented so far, as well as in acute studies of humans with CPAP (95), systemic vascular resistance decreases with CPAP, along with increased CO (hypervolemia and CHF). This is illustrated in Figure 11. Further, with CHF, during the post-CPAP recovery period when CO increased, systemic vascular resistance also decreased with CPAP. In fact, every time CO increased with CPAP, systemic vascular resistance decreased. Thus, increases in CO with CPAP might be explained by systemic vasodilatation, possibly on a reflex basis, leading to a decrease in the afterload to LV ejection and consequent increases stroke volume and CO. Indeed, lung inflation can lead to systemic vasodilatation via a vagally mediated reflex (16,17), which could result in decreases in cardiac volume secondary to decreased LV afterload. However, changes in lung volume with low-level CPAP are small (105) and it does not seem likely that they are sufficient to initiate a vasodilator relfex. On the other hand, with CHF and hypervolemia, there are changes in baseline sympathoadrenal tone. These changes in baseline autonomic function may predispose to different reflex vascular responses to CPAP from those normally seen. Whatever the basis for vasodilatation, decreased
Figure 11 Systemic vascular resistance (SVR) with CPAP. Open squares ⫽ normovolemia; closed circles ⫽ hypervolemia. *Statistically different from baseline for any condition. Note that when CO increased (CPAP 5 cm H2O for hypervolemia), SVR decreased. SVR actually increased with higher levels of CPAP with normovolemia, probably due to compensatory changes related to decreased cardiac output. (From Ref. 109.)
Ventilatory Support in the Failing Heart
543
impedance to LV emptying on this basis could explain both increased CO and decreased cardiac volumes with CPAP. Whether reflex vasodilatation with CPAP is a prime cause or a secondary finding is not known, and further work will need to be done to clarify the role and mechanisms of vasodilatation with CPAP in hypervolemic states. Another explanation, that cardiac contractility may increase, is considered unlikely since indices of contractility do not change with hypervolemia during CPAP (102, 107). However, there may be small changes in contractility acting synergistically with other mechanisms such as vasodilatation to increase CO with CPAP in CHF (102,109). B. Transfer of Blood Volume from Intrathoracic to Extrathoracic Compartments
Increasing ITP with increased airway pressure can transfer blood volume from intrathoracic to extrathoracic volume compartments (114). Figure 12 illustrates the coupling of peripheral and central (intrathoracic) reservoirs. For simplicity, the normal gradient of pressure for venous return is not shown. P1 and P3 represent the initial pressure in intra and extrathoracic compartments respectively. P2 and P represent pressure in the reservoirs after an increase in ITP. For a given increase in intrathoracic or pleural pressure (Ppl) the following must be true: ∆Ppl ⫽ (P1 ⫺ P2 ) ⫹ (P4 ⫺ P3 )
(6)
Figure 12 Model of coupling between central and peripheral vascular reservoirs. Cc, compliance of central compliant reservoir (heart and lungs); Cp, compliance of peripheral vascular reservoir. With pleural pressure (Ppl) increases, there is transfer of volume from intrathoracic to extrathoracic reservoirs. P1 and P2 ⫽ pressure in central reservoir before and after increase in Ppl respectively; P3 and P4 ⫽ pressure in peripheral reservoir before and after increase in Ppl respectively. See text for discussion.
544
Scharf
The volume transferred from intrathoracic to extrathoracic compartments is: ∆V ⫽ (P1 ⫺ P2 )*Cc ⫽ (P4 ⫺ P3 )*Cp
(7)
where Cc is the compliance of the central and Cp the compliance of the peripheral reservoirs respectively. Combining Equations 3 and 4: (P1 ⫺ P2 ) Cp ⫽ (P4 ⫺ P3 ) Cc
(8)
According to Eq. 6, the amount by which the level in the central reservoir decreases (P1 ⫺ P2 ) is less than the increase in Ppl and the transmural pressure in the central reservoir, which is the level in the reservoir minus Ppl, decreases. Further, the ratio of peripheral to central vascular compliance determines the ratio of the change in pressures between central and peripheral vascular compartments when ITP is increased. The principles of coupling between heart and peripheral circulation have been mathematically modeled by Permutt and Wise (115). Depending on whether heart volume is high or low, the consequences for CO of a decrease in transmural pressure can be quite different. This is illustrated in Figure 13. In the figure are shown diastolic and isovolumic systolic pressure-volume curves for cardiac contractions. For the purposes of this analysis, the pericardium may be thought of as part of the
Figure 13 Effects of increased pleural pressure and decreased cardiac transmural pressure on end-diastolic (ED) and end-systolic (ES) volume, as well as stroke volume (SV). ED and ES pressure-volume curves are shown when initial cardiac volume is low and when initial cardiac volume is high. The cardiac pressure-volume histories are shown stylized. The effects of equal reductions in ED and ES transmural pressures (Ptm) with increased intrathoracic pressure on SV are shown for both volume ranges. SV is represented as the horizontal distance between ED and ES volume. SVb, baseline stroke volume; SVr, stroke volume when Ptm is decreased because of an increase in intrathoracic pressure.
Ventilatory Support in the Failing Heart
545
ventricular wall, adding its constraint to filling to that of the myocardium. The pressure-volume history of single beats is shown stylistically at baseline and following equal decreases in cardiac transmural pressures at end systole and end diastole. The horizontal distance between end-diastolic and end-systolic volumes represents stroke volume. When initial cardiac volume is low (normal situation), because of the shape of the pressure-volume curves, the heart is stiffer (steeper volume-pressure curve) during systole than during diastole. Thus, for equal decreases in transmural pressure due to increased ITP, volume decreases more at end diastole than at end systole. In this case stroke volume decreases. However, when initial cardiac volume is increased enough to push the heart up toward the limits of diastolic distension (hypervolemia, CHF) an interesting phenomenon occurs. The heart is actually stiffer in diastole (steeper volume-pressure curve) than in systole. Thus for equal decreases in transmural pressure, there is actually a greater decrease in end-systolic than end-diastolic volume. This leads to an increase in stroke volume. According to this concept, any time the heart is pushed towards the limit of its diastolic distension, transferring volume out from central reservoirs can lead to an increase in stroke volume. Thus, on a purely mechanical basis increased ITP could increase stroke volume when the heart is distended. This could explain the clinical and experimental observations cited above that in normals CPAP leads to decreased CO, whereas with cardiac distension CPAP could lead to increased CO. Alterations in sympathoadrenal function, vasodilatation and/or increases in cardiac contractility could act synergistically with mechanical effects. The prediction that with cardiac distension removal of from the chest is similar to older observations on the hemodynamic effects of phlebotomy in CHF (116, 117) in which it was reported that phlebotomy in the presence of CHF led to an increase in CO.
V.
Conclusions and Questions
Clearly, ventilatory maneuvers can be used to improve cardiac function at least in some patients in certain specific circumstances. This action is separate from other beneficial changes brought about in the work of breathing and gas exchange. Experimental studies as well as clinical observations suggest that cardiac distension is required for the beneficial actions of increased airway pressure to be great enough to overcome the adverse effects of increased ITP on venous return. While LV unloading due to increased ITP may be one contributing mechanism, this may not be the only, and perhaps not even the major, mechanism for the beneficial action of increased airway pressure with dilated cardiomyopathy. Alterations in sympathoadrenal function and the effects of mechanical coupling between central and peripheral circulations may play an important role in the beneficial effects of ventilatory maneuvers on cardiac function. Future work needs to be directed to specifying under what circumstances and for which patients this specific ventilatory maneuvers can be of benefit. Hence, studies elucidating the mechanisms by which CPAP can have its beneficial effect will help in improving the clinical efficacy of this mode of therapy for failing hearts.
546
Scharf References
1. Poulton EP, Oxon DM. Left-sided failure with pulmonary oedema. Its treatment with the ‘‘pulmonary plus pressure machine.’’ Lancet 1936; 1:981–983. 2. Ra¨sa¨nen M, Heikkila¨ J, Downs J, Niiki P, Va¨isa¨nen I, Viitanen A. Continuous positive airway pressure by face mask in acute cardiogenic pulmonary edema. Am J Cardiol 1985; 55:296–300. 3. Perel A, Williamson DC, Modell JH. Effectiveness of CPAP by mask for pulmonary edema. Inten Care Med 1983; 9:17–19. 4. Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TD. Effect on continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995; 91:1725–1731. 5. Ambrosino N, Plasich C, Crotti P, Cobelli F, Tavazzi L, Rampulla C. Breathing pattern, ventilatory drive and respiratory muscle strength in patients with chronic heart failure. Eur Resp J 1994; 7:17–22. 6. Sharp JT, Griffith GT, Bunnell IL, Greene DG. Ventilatory mechanics in pulmonary edema in man. J Clin Invest 1958; 37:111 -116. 7. Naum CC, Sciurba FC, Rogers RM. Pulmonary function abnormalities in chronic severe cardiomyopathy preceding cardiac transplantation. Am Rev Respir Dis 1992; 145:1334– 1338. 8. Ingram RH Jr, McFadden ER. Respiratory changes during exercise in patients with pulmonary venous hypertension. Prog Cardiovasc Dis 1976; 19:109–115. 9. Depeursinge FB, Depeursinge CD, Boutaleb AF, Feihl F, Perret CH. Respiratory system impedance in patients with acute left ventricular failure: pathophysiology and clinical interest. Circulation 1986; 73:386–395. 10. Ries AL, Gregoratos G, Friedman PJ, Clausen JL. Pulmonary function tests in the detection of left heart failure; correlation with pulmonary artery wedge pressure. Respiration 1986; 49:241–250. 11. Hogg JC, Agarawal JB, Gardiner AJS, Palmer WH, Macklem PT. Distribution of airway resistance with developing pulmonary in dogs. J Appl Physiol 1972; 32: 20–24. 12. Lloyd TC Jr. Reflex effects of left heart and pulmonary vascular distension on airways of dogs. J Appl Physiol 1980; 49:620–626. 13. Kikuchi R, Sekizawa K, Sasaki H, Hirose Y, Matsumoto N, Takishima T, Hildebrandt J. Effects of pulmonary congestion on airway reactivity to histamine aerosol in dogs. J Appl Physiol 1984; 57:1640–1647. 14. Roberts WC, Siegel RJ, McManus BM. Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients. Am J Cardiol 1987; 60:1340–1355. 15. Mancini DM, Henson D, LaManca J, Levine S. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 1992; 86:909–918. 16. Kaufman MR, Cassidy SS. Reflex effects of lung inflation and other stimuli on the heart and circulation. In: Scharf SM, Cassidy SS, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:339–363. 17. Adams L, Schertel ER, Green JF. Reflexes elicited from the pulmonary vasculature in the control of breathing. In: Scharf SM, Cassidy SS, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:365–389. 18. Paintal AS. Mechanism of stimulation of type J pulmonary receptors. J Physiol (Lond) 1969; 203:511–532. 19. Coleridge HM, Coleridge JCG. Afferent vagal C-fibers in the dog lung: their discharge during spontaneous breathing, and their stimulation by alloxan and pulmonary congestion. In: Paintal AS, Gill-Kumar P, eds. Krogh Centenary Symposium on Respiratoy Adaptations, Capillary Exchange and Reflex Mechsisms. New Delhi: Ballabhbhai Patel Chest Institute, University of Dehli, 1977:396–406. 20. Teo KK, Man GC, Kappagoda CT. Responses of pulmonary receptors to acute elevations of left atrial pressure. Fed Proc 1985; 44:835. 21. Lloyd TC Jr. Effect on breathing of acute pressure rise in pulmonary artery and right ventricle. J Appl Physiol 1984; 57:110–116.
Ventilatory Support in the Failing Heart
547
22. Lloyd TC Jr. Breathing response to lung congestion with and without left heart distension. J Appl Physiol 1988; 65: 131–136. 23. Permutt S, Howell JBL, Proctor D, Riley RL. Effects of lung inflation on static pressurevolume characteristics of pulmonary vessels. J Appl Physiol 1961; 16:64–70. 24. Whittenberger JL, MacGregor M, Berglund E, Borst MC. Influence of state of inflation of the lung on pulmonary vascular resistance. J Appl Physiol 1960; 15:878–882. 25. Maughan WL. Right ventricular function. In: Scharf SM, Cassidy SS, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:179–214. 26. Dhainaut JF, Schlemmer B, Monsallier JF, Fourestie´ V, Carli A. Behavior of the right ventricle following PEEP in patients with mild and severe ARDS. Am Rev Respir Dis 1984; 129:A99. 27. Guyton AC, Jones CE, Coleman TB. Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: W.B. Saunders, 1973. 28. Donders FC (1853). Contribution to the mechanism of respiration and circulation in health and disease. In: West JB, ed. Translations in Respiratory Physiology. Stoudsburg, PA: Dowden, Hutchinson and Ross, 1975:298–318. 29. Buda AJ, Pinsky MR, Ingles NB, Daughters GT, Stenson EB, Alderman EL. Effect of intrathoracic pressure and LV performance. N Engl J Med 1979; 301:453–459. 30. Scharf SM, Brown R, Tow DE, Parisi AF. Cardiac effects of increased lung volume and decreased pleural pressure in man. J Appl Physiol 1979; 47:257–262. 31. Scharf SM, Bianco JA, Tow DE, Brown R. The effects of large negative intrathoracic pressure on left ventricular function in patients with coronary artery disease. Circulation 1981; 63:871–875. 32. Scharf SM, O’Beirne Woods B, Brown R, Parisi AF, Miller MM, Tow DE. Effects of Mueller maneuver on global and regional left ventricular function in angina pectoris with or without previous myocardial infarction. Am J Cardiol 1987; 59:1305–1309. 33. Robotham J, Scharf SM. The effects of positive and negative pressure ventilation on cardiac performance. In: Matthay RA, Matthay MA, Dantzker D, eds. Cardiovascular Pulmonary Interaction in Normal and Diseases Lung. Philadelphia: W.B. Saunders, 1983:161–187. 34. Charlier AA. Beat to Beat Hemodynamic Effects of Lung Inflation and Normal Respiration in Anesthetized and Conscious Dogs. Brussels: Editions Arscia, 1967. 35. Brinker JA, Weiss JL, Lappe DL, Rabson JL, Summer WR, Permutt S, Weisfeldt ML. Leftward septal displacement during right ventricular loading in man. Circulation 1980; 61:626–633. 36. Lichtenstein SV, Slutsky A, Salerno TA. Noninvasive right and left ventricular assist. Surg Forum 1985; 36:306–308. 37. Heistad DD, Abboud FM. Circulatory adjustments to hypoxia. Circulation 1980; 61:463–469. 38. Anand A. Reflex stimulation of aortic chemoreceptors through the stellate ganglion durign hypoxia and hypotension in cats. J Physiol (Lond) 1996; 491:853–858. 39. Angell JJE, Daly MdeB. Cardiovascular responses in apnoeic asphyxia: role of arterial chemoreceptors and the modification of their effects by a pulonary vagal inflation reflex. J Physiol (Lond) 1967; 201:87–104. 40. Daly MdeB, Scott MJ. An analysis of the primary cardiovascular reflex effects of stimulation of the carotid body chemoreceptor in the dog. J Physiol 1962; 162:555–573. 41. Kontos H, Mauch H, Richardson D, Peterson J. Mechanism of circulatory responses to systemic hypoxia in the anesthetized dog. Am J Physiol 1965; 209:397–403. 42. Shykoff BE, Naqv M, Slutsky AS. Respiratory sinus arrhythmia in dogs: effects of phasic afferents and chemostimulation. J Clin Invest 1991; 87:1621–1627. 43. Scharf SM, Brown R, Saunders NA, Green LH. Hemodynamic effects of positive pressure inflation. J Appl Physiol. 1980; 49:124–131. 44. Janicki JS, Schroff SG, Weber KT. Ventricular interdependence. In: Scharf SM, Cassidy SS, eds. Heart-Lung Interactions in Health and Disease. New York: Marcel Dekker, 1989:285–309. 45. Tarasiuk A, Chen L, Scharf SM. Effects of periodic obstructive apnoeas on superior and inferior venous return in dogs. Acta Physiol Scand 1997; 161:187–194. 46. Scharf SM, Graver LM, Khilnani S, Balaban K. Respiratory phasic effects of inspiratory loading in left ventricular hemodynamics in vagotomized dogs. J Appl Physiol 1992; 73: 995–1003.
548
Scharf
47. Scharf SM. Cardiovascular effects of airway obstruction. Lung, 1991; 169:1–23. 48. Haynes JB, Carson SD, Whitney WP, Zerbe GO, Hyers TM. Positive end-expiratory pressure shifts left ventricular diastolic pressure-area curves. J Appl Physiol 1980; 48: 670–676. 49. Scharf SM, Brown R, Saunders N, Green LH. Changes in canine left ventricular size and configuration with positive end-expiratory pressure. Circ Res. 1979; 44:672–678. 50. Schulman DS, Biondi JW, Zohghi S, et al.. Coronary flow limits right ventricular performance during positive endexpiratory pressure. Am Rev Respir Dis 1990; 141:1531–1537. 51. Schulman DS, Biondi JW, Zohghi S, et al.. Left ventricular diastolic function during positive end-expiratory pressure. Am Rev Respir Dis 1992; 145:515–521. 52. Maughan WL, Sunagawa K, Sagawa K. Ventricular systolic interdependence: volume elastance model in isolated canine hearts. Am J Physiol 1987; 253:H1381–H1390. 53. Little WC, Badke FR, O⫽Rourke RA. Effect of right ventricular pressure-volume relationship before and after chronic right ventricular pressure overload in dogs without pericardia. Circ Res 1984; 54:719–730. 54. Farrar DJ, Woodard JC, Chow E. Pacing induced dilated cardiomyopathy increases leftto-right systolic interaction. Circulation 1993; 88:720–725. 55. Yamaguchi S, Li KS, Harasawa H, Zhu D, Santamore WP. The left ventricle affects the duration of right ventricular ejection. Cardiovasc Res 1993; 27:211–215. 56. Scharf SM. Right ventricular load tolerance: role of left ventricular function. In: Perspectives en Re´animation. Les Interactions cardio-pulmonaires. Societe´ de Re´animation de langue franc¸aise, Paris: Arnette, 1994:17–28. 57. Marini JJ, O’Quinn R, Culver BH, Butler BH, Butler J. Estimation of transmural cardiac pressures during ventilation with PEEP. J Appl Physiol 1982; 53:384–391. 58. Butler J, Schrijen F, Henriquez A, Polu JM, Albert RK. Cause of the raised wedge pressure on exercise in chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138: 350–354. 59. Wallis TW, Robotham JL, Compean R, Kindred MK. Mechanical heart-lung interactions with positive end-expiratory pressure. J Appl Physiol 1983; 54:1039–1047. 60. Cassidy SS, Ramanathan M. Dimensional analysis of the left ventricule during PEEP. Am J Physiol 1984:246: H792–H805. 61. Scharf SM, Brown R. The influence of the right ventricle on canine left ventricular function with positive end-expiratory pressure (PEEP). J Appl Physiol 1982; 52:254–259. 62. Fessler HE, Brower RG, Wise R, Permutt S. Positive pleural pressure decreases coronary perfusion. Am J Physiol 1990; 258:H814–H820. 63. Tucker HJ, Murray JF. Effects of end-expiratory pressure on organ blood flow in normal and diseased dogs. J Appl Physiol 1973; 34:573–577. 64. Venus B, Jacobs HK. Alterations in regional myocardial blood floes during different levels of positive end-expiratory pressure. Crit Care Med 1984; 12:96–101. 65. Tittley JG, Fremes SE, Weisel RD, Christakis GT, Evans PJ, Madonik M, Ivanov J, Teasdale SJ, Mickle DA, McLaughlin PR. Hemodynamic and myocardial metabolic consequences of PEEP. Chest 1985; 88:496–502. 66. Hassapoyannes C, Harper JF, Stuck LM, Hornung CA, Abel FL. Effects of systole-specific pericardial increases on coronary flow. J Appl Physiol 1991; 71:104–111. 67. Scharf SM, Ingram RH. Influence of abdominal pressure and sympathetic vasoconstriction on the cardiovascular response to PEEP. Am Rev Resp Dis. 1977; 116: 661–670. 68. Fessler HE, Brower RG, Wise RA. Effects of positive end-expiratory pressure on the gradient for venous return. Am Rev Respir Dis 1990; 143:19–24. 69. Pinsky MR, Summer WR, Wise RA, Permutt S, Bromberger-Barnea B. Augmentation of cardiac function by elevation of intrathoracic pressure. J Appl Physiol 1983; 54:950–955. 70. Pinsky MR, Summer WR. Cardiac augmentation by phasic high intrathoracic pressure support in man. Chest 1983; 84:370–375. 71. Robotham JL. Ventilatory-assisted myocardial performance (VAMP). Chest 1983; 84: 366–367. 72. Pinsky MR, Matuschak GM, Klain M. Determinants of cardiac augmentation by elevations in intrathoracic pressure. J Appl Physiol 1985; 58: 1189–1198. 73. Pinsky MR, Matuschak GM, Bernardi L, Klain M. Hemodynamic effects of cardiac cyclespecific increases in intrathoracic pressure. J Appl Physiol 1986; 60:604–612. 74. Pinsky MR, Marquez J, Martin D, Klain M. Ventricular assist by cardiac cycle-specific increases in intrathoracic pressure. Chest 1987; 91:709–715.
Ventilatory Support in the Failing Heart
549
75. Beyar R, Halperin HR, Tsitlik JE, Guerci AD, Kass D, Weisfeldt M, Chandra NC. Circulatory assistance by intrathoracic pressure variations: optimization and mechanisms studied by a mathematical model in relation to experimental data. Circ Res 1989; 64:703–720. 76. Stein KL, Dramer DJ, Killian Pinsky MR. Hemodynamic effects of synchronous highfrequency jet ventilation in mitral regurgitation. J Appl Physiol 1990; 69:2120–2125. 77. Guimond J-G, Pinsky MR, Matuschak GM. Effect of synchronous increase in intrathoracic pressure on cardiac performance during acute endotoxemia. J Appl Physiol 1990; 69:1502– 1508. 78. Peters J, Ihle P. ECG synchronized thoracic vest inflation during autonomic blockade, myocardial ischemia or cardiac arrest. J Appl Physiol 1992; 73:2263–2273. 79. Cohn JN, Levine TB, Oliveri MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. New Engl J Med 1984; 311:819–823. 80. Daly PA, Sole MJ. Myocardial catecholamines and the pathophysiology of heart failure. Circulation 1990; 82(suppl 1):34–38. 81. Swedberg K, Enroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe CHF and their relation to mortality. Circulation 1990; 82: 1730–1736. 82. Bristow MR, Ginsburg P, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and β-adrenergic receptor density in failing human hearts. New Engl J Med 1982; 307:205–211. 83. Chidsey CA, Braunwald E, Morrow AG. Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Am J Med 1965; 39:442–451. 84. Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings G, Esler MD. Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J Am Coll Cardiol 1994; 23:570–578. 85. Kendall MJ, Lynch KP, Hjalmarson A, Kjekshus J. β-Blockers and sudden cardiac death. Ann Intern Med 1995; 123:358–367. 86. McNamara SG, Strohl KP, Cistulli PA, Sullivan CE. Clinical aspects of sleep apnea. In: Sauders NA, Sullivan CE, eds. Sleep and Breathing, 2nd ed. New York: Marcel Dekker, 1994:493–528. 87. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnea in patients with dilated cardiomypathy: effect of continuous positive airway pressure. Lancet 1991; 338:1480–1484. 88. Takasaki Y, Orr D, Popkin J, Rutherford R, Liu P, Bradley TD. Effect of nasal continuous positive airway pressure on sleep apnea in congestive heart failure. Am Rev Respir Dis 1989; 140:1578–1584. 89. Naughton MT, Liu PP, Benard DC, Goldstein RS, Bradley RD. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995; 151:92–97. 90. Buckle P, Millar T, Kryger M. The effect of short-term nasal CPAP on Cheyne-Stokes respiration in congestive heart failure. Chest 1992; 102:31–35. 91. Davies RJO, Harrington KJ, Ormerod OJM, Stradling JR. Nasal continuous positive airway pressure in chronic heart failure with sleep disordered breathing. Am Rev Respir Dis 1993; 147: 630–634. 92. Pery N, Payen D, Pinsky MR. Monitoring the effect of CPAP on left ventricular function using continuous mixed-blood saturation. Chest 1991; 99:512–513. 93. Baratz DM, Westbrook PR, Shah PK, Mohsenifar Z. Effect of nasal continuous positive airway pressure on cardiac output and oxygen delivery in patients with congestive heart failure. Chest 1992; 102:1397–1401.. 94. Ra¨sa¨nen M, Va¨isa¨nen I, Heikkila¨ J, Nikki P. Acute myocardial infarction complicated by left ventricular dysfunction and respiratory failure. The effects of continuous positive airway pressure. Chest 1985; 87:159–162. 95. Bradley TD, Holloway RM, Mclaughlin PR, Ross BL, Walters J, Liu PP. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992; 145:377–382. 96. DeHoyos A, Liu PP, Benard DC, Bradley TD. Haemodynamic effects of continuous posi-
550
97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117.
Scharf tive airway pressure in hymas with normal and impaired left ventricular function. Clin Sci 1995; 88:173–178. Lenique F, Habis M, Lofaso F, Dubois-Rande´ J-L, Harf A, Brochard L. Ventilatory and hemodynamic effects of continuous positive airway pressure in left heart failure. Am J Respir Crit Care Med 1997; 155:500–505. Takeda S, Takano T, Ogawa R. The effect of nasal continuous positive airway pressure on plasma endothelin-1 concentrations in patients with severe cardiogenic pulmonary edema. Anesth Analg 1997; 84:1091–1096. Liston R, Deegan PC, McCreery C, Costello, R, Maurer B, McNicholas WT. Haemodynamic effects of nasal continuous positive airway pressure in severe congestive heart failure. Eur Respir J 1995; 8:430–435. Genovese J, Moskowitz M, Tarasiuk A, Graver LM, Scharf SM. Effects of CPAP on cardiac output in normal and hypervolemic unanesthetized pigs. Am J Respir Crit Care Med 1994; 150: 752–758. Scharf SM. Ventilatory support in cardiac failure. In Kveton V, Dantzker DR, eds. The Critically Ill Cardiac Patients. Philadelphia: Lippincott-Raven, 1996:29–44. Genovese J, Huberfeld S, Tarasiuk A, Moskowitz M, Scharf SM. Effects of CPAP on cardiac output in pigs with pacing induced congestive heart failure. Am J Respir Crit Care Med 1995; 152:1847–1853. Takata M, Robotham JL. Ventricular external constraint by the lung and pericardium during positive end-expiratory pressure. Am Rev Respir Dis 1991; 143:872–875. Scharf SM, Brown R, Warner KG, Khuri S. Esophageal and pericardial pressures and left ventricular configuration with respiratory maneuvers. J Appl Physiol. 1989; 66:481–491. Huberfeld S, Genovese J, Tarasiuk A, Scharf SM. Effects of CPAP on pericardial pressure, transmural left ventricular pressures and respiratory mechanics in hypervolemic unanesthetized pigs. Am J Respir Crit Care Med 1995; 152:142–147. Cabrera MR, Nakamura GE, Montague DA, Cole RA. Effect of airway pressure on pericardial pressure. Am Rev Respir Dis 1989; 140:659–667. Huberfeld SI, Genovese J, Patel U, Scharf SM. Myocardial mechanics and energetics during continuous positive end-expiratory pressure in sedated pigs. Crit Care Med 1996; 24: 2027–2034. Naughton MT, Bernard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995; 152:473–479. Scharf SM, Chen L, Slamowitz D, Rao PS. Effects of continuous positive airway pressure on cardiac output and plasma norepinephrine in sedated pigs. J Crit Care 1996; 11:57– 64. Beach T, Millen E, Grenvik A. Hemodynamic response to discontinuance of mechanical ventilation. Crit Care Med 1973; 1:85–90. Ra¨sa¨nen J, Nikki P, Heikkila¨ J. Acute myocardial infarction complicated by respiratory failure. The effects of mechanical ventilation. Chest 1984; 85:21–28. Lemaire F, Teboul JC, Cinotti L, Gioto G, Abrouk F, Steg G, Mackquin-Mavier I, Zapol WM. Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation. Anesthesiology 1988; 69:171–179. Hurford WE, Lynch KE, Strauss HW, Lowenstein E, Zapol WM. Myocardial perfusion as assessed by thallium-201 scintigraphy during the discontinuation of mechanical ventilation in ventilator-dependent patients. Anesthesiology 1991; 74:1007–1016. Braunwald E, Binion JT, Morgan WL, Sarnoff SF. Alterations in central blood volume and cardiac output induced by positive pressure breathing and counteracted by metarimal (Aramine). Circ Res 1957; 5:670–680. Permutt S, Wise RA. The control of cardiac output through coupling of heart and blood vessels. In: Yin FCP, ed. Ventricular/Vascular Coupling. New York: Springer-Verlag, 1987:159–179. Howarth SJ, McMichael J, Sharpey-Schaefer EP. Effects of venesection in low output heart failure. Clin Sci 1948; 6:41–50. McMicheal J, Sharpey-Schaefer EP. The action of intravenous digoxin in man. Q J Med 1944; 13:123–127.
21 Blood Pressure Regulation and Sleep Apnea
URS A. LEUENBERGER
CLIFFORD W. ZWILLICH
Pennsylvania State University College of Medicine Hershey, Pennsylvania
University of Colorado and Denver Veterans Administration Medical Center Denver, Colorado
I.
Introduction
Many patients with obstructive sleep apnea (OSA) have elevated blood pressure, and many patients with essential hypertension have sleep-disordered breathing. Indeed, epidemiologic studies have confirmed a high prevalence of hypertension among patients presenting with OSA. Other studies demonstrate that OSA or milder forms of sleep-disordered breathing are very common among unselected patients with hypertension. Increased activity of the sympathetic nervous system as indicated by levels of circulating catecholamines, excretion of catecholamine metabolites in the urine, or directly measured sympathetic activity in peripheral nerves has been recognized as a consistent feature of untreated OSA. Furthermore, symptomatic treatment with tracheostomy or more recently with nasal continuous positive airway pressure (CPAP) reduces blood pressure and sympathetic neural activity in many patients with OSA. These observations have prompted the question whether OSA causes hypertension and whether this form of hypertension may be mediated by the sympathetic nervous system. Because both OSA and hypertension are very common and occur frequently in the same patient, and because elevated blood pressure is a major risk factor for cardiovascular morbidity and mortality, the link between OSA and hypertension has major public health implications. The issue of OSA and hypertension is therefore 551
552
Leuenberger and Zwillich
the subject of intense ongoing research and has been the subject of a number of recent review articles (1–8). In general, if blood pressure is ⫾140/90 mm Hg on multiple readings, the diagnosis of hypertension is made. According to large prospective studies, this level of blood pressure is associated with an approximate doubling of the cardiovascular risk compared to a systolic blood pressure of ⬍120 mm Hg (9). Because the relationship between blood pressure and risk shows no clear threshold effect, this definition of hypertension is somewhat arbitrary. It is also important to recall the normal diurnal variation of blood pressure with lower pressure during the night and in the morning and higher pressure during the evening hours. In the United States approximately 50 million adults suffer from arterial hypertension (10). Landmark epidemiological studies have demonstrated convincingly that arterial hypertension is associated with accelerated cardiovascular disease (9,10). Specifically, complications such as stroke, myocardial infarction, heart failure, and premature death have been causally linked to hypertension (10). Furthermore, multiple randomized trials have shown that drug therapy of hypertension reduces cardiovascular morbidity and mortality (10). In the large majority of patients (⬎95%), the cause of hypertension is unknown; i.e., they exhibit ‘‘essential’’ hypertension. This underscores the lack of an understanding of the etiology of most cases of hypertension. The consequences and complications of hypertension exact a large socioeconomic cost. In this review we will discuss the evidence of a link between OSA and hypertension. Special emphasis will be given to the potential role of increased activity of the sympathetic nervous system as a cause of hypertension in OSA. We propose that OSA may cause or at least contribute to elevated blood pressure in a substantial proportion of hypertensives. To examine the potential pathogenetic mechanisms of OSA-related hypertension we will review the mechanisms of the acute neurocirculatory events during obstructive apnea. Finally, we will discuss potential mechanisms responsible for abnormal long-term blood pressure regulation in OSA.
II. Relationship Between Sleep Apnea and Hypertension Soon following the original reports of OSA by Gastaut et al. (11), investigators noted a high prevalence of systemic hypertension in patients with OSA. Guilleminault et al. reported that approximately 60% of their patients with OSA exhibited ‘‘essential hypertension’’ and postulated that via some undefined mechanism OSA was the underlying cause (12,13). Similarly, Hedner et al. reported hypertension to be present in 50% of patients with OSA (14). Curiously, left-ventricular hypertrophy, usually considered a manifestation of longstanding blood pressure elevation, was even found in many OSA patients who were normotensive while awake (14). More recently, Carlson et al. reported on 377 consecutive patients admitted to a sleep laboratory for evaluation of snoring or witnessed apneas (15). Thirty-three percent of these patients fulfilled their diagnostic criteria for OSA (⬎30 O 2 desaturation events per night), and 40% of those with OSA had hypertension. Multivariate regression analy-
Blood Pressure Regulation and Sleep Apnea
553
sis identified age, body mass index and OSA as independent predictors of hypertension (15). Conversely, among patients with essential hypertension, a substantial number were found to have varying degrees of sleep-disordered breathing or frank OSA. Lavie et al. found that 22% of patients with hypertension had OSA as defined by an apnea-hypopnea index of ⬎10 per hour (16). Kales et al. studied a group of 50 patients referred to a University Hypertension Clinic for further evaluation (17). The majority but not all of these middle-aged patients were obese. Their average blood pressure at presentation was 185/108 mm Hg. Thirty percent of these patients had ⫾30 apnea events per night in an overnight sleep study and were therefore diagnosed to have OSA. Another 34% exhibited ‘‘sleep apnea activity,’’ defined as 3 to 29 apnea events per night. Of note, these investigators also found a strong correlation between the level of blood pressure and the severity of OSA as expressed by the apnea-hypopnea index (17). Fletcher et al. examined 46 asymptomatic men with hypertension (average blood pressure 143/94 mm Hg) and found 30% of them to have an apnea-hypopnea index of ⬎10 per hour (18). In that study 9% of weightmatched normotensive controls were also found to have OSA (18). Collectively, these studies suggest that up to two-thirds of patients with the sleep apnea syndrome are hypertensive and that about one third of hypertensives have some degree of OSA. It has been argued that because of confounding factors many of these reports do not prove a causal relationship between OSA and hypertension (19,20). For example, many OSA patients are obese, and obesity in itself may cause hypertension, perhaps via an abnormality of insulin metabolism (21). Furthermore, some OSA patients consume excessive amounts of alcohol, another potential cause of elevated blood pressure (9). Last, the data suggesting a link between OSA and hypertension are cross-sectional rather than longitudinal. Therefore, it could also be argued that hypertension may lead to OSA. Theoretically, increased blood pressure could reflexly decrease pharyngeal dilator muscle tone and may decrease ventilation, thereby promoting ventilatory instability and intermittent airway obstruction (3,22). However, whether hypertension per se may cause or worsen OSA has not been explored in a systematic fashion. Two recent population-based studies from the Wisconsin Sleep Cohort further strengthened the hypothesis that sleep disordered breathing is associated with hypertension. Hla et al. reported on a group of subjects composed of apparently healthy adults and others who were known to snore (23). All subjects underwent a diagnostic sleep study. Daytime blood pressure was highest in those exhibiting OSA (apneahypopnea index ⬎5 per hour) and lowest in the nonapneic nonsnorers (23). Multiple logistic regression analysis was used to control for age, sex, and body mass index and demonstrated an independent association between the apnea-hypopnea-index and hypertension. In a subsequent publication, Young et al. (24) reported on a population sample of 1069 subjects. A series of potential confounding variables such as age, gender, body habitus, smoking, alcohol use, education, and physical activity were all taken into account and adjusted for. The results suggested that even occult sleep-disordered breathing was independently associated with hypertension (24).
554
Leuenberger and Zwillich
Moreover, the study firmly established a dose response relationship between the apnea-hypopnea-index and blood pressure. Blood pressure was higher with increasing severity of sleep-disordered breathing. The odds ratio for hypertension for an apnea-hypopnea index of 15 (vs. 0) was 1.8 and reached ⬃3 for an apnea-hypopnea index of 30 (24). Again, although strongly suggestive, because of their cross-sectional nature, these studies did not prove a causal relationship between OSA and hypertension. These investigators pointed out that if a cause-and-effect relationship existed, varying degrees of sleep-disordered breathing could account for a large number of cases of hypertension in adults (24). To definitively answer the question of whether OSA independently causes hypertension and contributes to cardiovascular morbidity and mortality, a large multicenter study, the Sleep Heart Health Study, has been launched (25). This project is supported by the National Institutes of Health and was designed to enroll over 6000 patients from several existing and prospectively followed cohorts. Data from the Sleep Heart Health Study will be forthcoming within the next couple of years. Whether habitual snoring alone is associated with hypertension independent of obstructive apneas and O 2 desaturations has been disputed (23,26). In some snorers, increased inspiratory efforts appear to result in frequent arousals and blood pressure fluctuations similar to OSA despite the absence of classic apneas and O 2 desaturations (27,28). This presentation has been termed the upper airway resistance syndrome and may play a role in the development of hypertension (27,28).
III. The Sympathetic Nervous System in OSA Much interest has focused on the sympathetic nervous system as a potential link between OSA and hypertension. This is due to two important observations. First, it has been shown consistently that the sympathetic nervous system is activated chronically in untreated OSA. Second, obstructive apneas in these patients have been noted to result in marked transient surges of sympathetic activity and blood pressure. These observations are based on measurements of plasma and urine levels of catecholamine compounds and more recently on direct microneurographic recordings of sympathetic vasoconstrictor nerve activity in peripheral nerves. In 1987, Fletcher et al. reported that the 24-hour urinary excretion of norepinephrine and catecholamine metabolites was elevated in OSA (29). Plasma levels of norepinephrine were also found to be increased in patients with OSA during sleep (30) and while awake (31). Interestingly, plasma norepinephrine was highest in those patients with the most marked apnea-induced O 2 desaturations during sleep (30). Finally, in 1988, Hedner et al. reported that directly measured sympathetic nerve activity in the peroneal nerve was elevated in patients with OSA even while awake (32). These data suggested that the sympathetic nervous system was activated excessively in OSA. The microneurography technique has been an important addition to the armamentarium of techniques to assess sympathetic nervous system function. In these studies, electrodes are placed in peripheral nerves to directly record vasoconstrictor
Blood Pressure Regulation and Sleep Apnea
555
nerve traffic in sympathetic nerve fibers (33). Commonly, these nerve recordings are made in the peroneal nerve because this nerve is relatively large and superficial therefore lending easy access to transcutaneous microelectrodes. In these recordings muscle sympathetic nerve activity (MSNA) can be monitored (33). MSNA has been shown to represent vasoconstrictor nerve traffic directed to the skeletal muscle vasculature and is thought to be representative of MSNA to other skeletal muscle regions (33). Because skeletal muscle makes up ⬃40% of the total body mass, MSNA is an important determinant of vasoconstrictor tone, peripheral vascular resistance, and blood pressure. One major advantage of this technique over measurements of plasma markers of sympathetic activity is its ability to register beat-to-beat variation of sympathetic nerve activity allowing apnea- and arousal-related effects to be quantified. However, in the interpretation of nerve recording studies it must be remembered that these measurements only reflect sympathetic outflow to one organ (skeletal muscle) while others are ignored. Sympathetic neural discharge to different organs can be highly differentiated (34). Studies from several laboratories demonstrated consistently that in awake patients with OSA, the discharge rate of sympathetic vasoconstrictor nerves (MSNA) was approximately double that of a healthy control population (31,32,35–38), was independent of obesity (39), and was similar to that of patients with advanced heart failure (40). The cause of this state of sympathoexcitation is not known. Because MSNA is an index of vasoconstrictor tone directed to an important vascular bed (skeletal muscle), an obvious but unanswered question is whether high MSNA in OSA is responsible for hypertension. In addition to chronic sympathetic activation, obstructive apneas during sleep were noted to be accompanied by marked surges of MSNA (32,35,36,38) and corresponding transient increases of arterial pressure. These acute neurocirculatory effects of obstructive apnea and their potential mechanisms will be discussed later. In an effort to understand the factors that affect short- and long-term blood pressure regulation, in the following section we will first consider the basic hemodynamic abnormalities of hypertension.
IV. Hemodynamic Abnormalities in Hypertension The two principal determinants of blood pressure are cardiac output and systemic vascular resistance. This relationship is expressed in the formula blood pressure equals cardiac output times systemic vascular resistance. Therefore, any blood pressure elevation can be viewed as the result of elevated cardiac output, increased systemic vascular resistance or a combination of both. In the search of potential mechanisms underlying hypertension, factors influencing cardiac output and systemic vascular resistance need to be examined. The main determinants of cardiac output are venous return and cardiac function (see Chapter 5). Cardiac output may be calculated as the product of stroke volume, which is dependent on left-ventricular size, volume and loading conditions, inotropic state, and heart rate, which is controlled by the autonomic nervous system.
556
Leuenberger and Zwillich
Systemic vascular resistance is dependent on neural vasoconstrictor tone but also on nonneural influences such as circulating vasoactive substances, endothelial function, and structural vascular properties (vascular remodeling). Sympathetic neural outflow is the principal neural influence on vasomotor tone. It is important to recognize that because vasomotor tone may be highly tissue specific (34), opposing vasomotor influences in different vascular territories may result in no net change of systemic vascular resistance. V.
Sympathetic Nervous System in Hypertension
It has long been speculated that increased sympathetic nervous system activity may play a role in the pathogenesis of essential hypertension (10,41). Several clinical observations and experimental studies point toward a role for reflex-mediated activation of the sympathetic nervous system. For example, it had been recognized that hypertension complicates certain forms of peripheral neuropathy (e.g., GuillainBarre´ syndrome) and that local anesthesia or surgical removal of baroreceptors is often accompanied by hypertension (41). Presumably, under these circumstances, sympathoinhibitory afferent nerve traffic from baroreceptors is interrupted leaving central sympathetic outflow unopposed (41). On the other hand, patients with spinal cord injury and loss of vascular sympathetic innervation develop labile blood pressure and hypotension (41). Because of the prominent effect of baroreflexes on blood pressure control, an attractive hypothesis suggested therefore that impaired baroreceptor buffering may cause hypertension (41). However, while the role of the baroreflex in the acute minute-to-minute blood pressure regulation is undisputed, despite intense investigations it has been difficult to demonstrate its role as a major longterm regulator of blood pressure. For example, determination of plasma markers or direct measurements of sympathetic activity (MSNA) have demonstrated increased activity only inconsistently and mainly in early (rather than advanced) hypertension (41). Because sympathetic nerve activity is universally high in patients with OSA, efforts to understand the pathogenesis of hypertension in OSA have been devoted to understanding the factors that regulate sympathetic nerve activity. Therefore, much of the attention has been given to cardiovascular reflexes as they affect the autonomic nervous system while other potential mechanisms have been less well explored. A. ‘‘Positive Feedback Interaction’’
An important pathophysiologic concept in hypertension is that of the ‘‘positive feedback interaction’’ (42). In this theory, repetitive functional pressor influences may eventually lead to structural changes in the vascular wall which perpetuate elevated blood pressure. Accordingly, at an advanced stage of hypertension the initial cause could be completely obscured. Furthermore, beyond a certain stage of the disease process even elimination of the original cause may no longer normalize blood pressure. The implications of this ‘‘positive feedback’’ principle may also be relevant
Blood Pressure Regulation and Sleep Apnea
557
to hypertension in OSA. For example, it may explain why in some OSA patients blood pressure may not normalize with CPAP therapy even though obstructive apneas are eliminated by this treatment. B. Similarities Between Essential Hypertension and OSA-Related Hypertension
The association of hypertension and OSA suggests that the hypertension seen in OSA and essential hypertension may have similar hemodynamic features and pathogenetic mechanisms. Therefore, the search for causes of OSA-related hypertension may be in essence an investigation of mechanisms of ‘‘essential’’ hypertension in general. However, as both OSA and hypertension are common, it should be pointed out that in some patients these two conditions may merely coexist by chance alone. The etiology of essential hypertension is largely unknown. In a few cases, a simple genetic defect leading to sodium retention may be the initial abnormality (43). With the advent of increasing sophistication of genetic research it is likely that in the near future more complex modes of inheritance of abnormalities of ion channels and intracellular signal transduction processes will be recognized as important pathogenetic factors in hypertension. Of course, genetic abnormalities (or peculiarities) could also play a role as determinants of the sensitivity of reflex sensors important in autonomic cardiovascular and respiratory regulation. C. Effects of OSA Treatment
Most experts in the field consider nocturnal CPAP therapy as the treatment of choice in symptomatic patients with OSA. This therapy is highly effective in maintaining airway patency during sleep thereby eliminating apneas and intermittent asphyxia as well as preventing the surges of sympathetic nerve activity and blood pressure (36,44). A small randomized controlled trial concluded that CPAP use resulted in symptomatic improvement, but the sample size was too small to demonstrate improvement in objective parameters of cognitive function (45). Although skeptics have expressed their concern (19), most experts believe CPAP therapy is beneficial (46,47). A powerful argument in support of a pathogenetic role of obstructive apnea in the sympathetic overactivity and hypertension in OSA stems from studies on the responses to treatment. Fletcher et al. followed a small group of patients with severe OSA who underwent tracheostomy (29). Following tracheostomy, most of these patients demonstrated lower blood pressure and decreased urinary catecholamines and catecholamine metabolites (29). Jennum et al. studied a group of patients with moderate to severe OSA (48). After 1 week of CPAP therapy, morning blood pressure was decreased. However, while plasma levels of epinephrine were decreased, norepinephrine levels were unchanged (48). Intestinal polypeptide, interpreted as an index of vagal nerve activity, was increased after CPAP. Mayer et al. studied patients with an apnea-hypopnea index (AHI) of ⱖ30 and found that after 6 months of CPAP therapy, blood pressure was lower in compliant patients (49). The blood pressurelowering effect was more prominent during the night than during the daytime (49).
558
Leuenberger and Zwillich
Wilcox et al. measured 24-hour ambulatory blood pressure in OSA patients with an AHI ⬎10 and found a reduction in blood pressure in those patients who complied with the therapy (50). However, 26% of the patients were noncompliant (50). Subsequently, Hedner et al. examined indices of sympathetic neural activity and cardiovascular parameters before and following 14 to 26 months of CPAP (51). They found elevated plasma levels of norepinephrine at baseline which decreased in all subjects following CPAP. Urinary vanilylmandelic acid and metanephrines decreased also while, surprisingly, urinary norepinephrine remained unchanged. In their study 24hour blood pressure and left-ventricular mass did not change (51). Last, in a small study, Waravdekar et al. showed a reduction of directly measured sympathetic nerve activity (MSNA) following at least one month of treatment of OSA with nasal CPAP (37). An important observation in that study was that MSNA was only reduced in patients who complied with CPAP therapy (37). Collectively, these data from small and non-randomized studies suggest that CPAP therapy, in addition to relieving symptoms of OSA, reverses the activity of the sympathetic nervous system and lowers blood pressure in many of these patients. Because decreased sympathetic activity and improved blood pressure control coincided in many of these patients, it appears likely that the hypertension was sympathetically mediated. One important observation that has emerged in several of these studies is that the therapeutic effect of CPAP on both endpoints (blood pressure and sympathetic activity) may depend heavily on the therapeutic compliance. Because, in general, CPAP compliance is limited and because even those patients who use CPAP only do so for part of the night (⬃3 to 5 hours) (37,52,53), any therapeutic effect in the OSA group as a whole may be ‘‘diluted’’ by the lack of an effect in those who are noncompliant.
VI. Blood Pressure Regulation During Sleep and During Obstructive Apnea A. Normal Sleep
Although humans spend a considerable proportion (30%) of their lives asleep, it is curious that the physiologic role of sleep is largely unknown (54). A popular concept is that sleep is essential to maintain normal brain function (54,55). Sleep is accompanied by profound cardiovascular changes and alterations of autonomic tone. Because OSA leads to disruption of the normal sleep wake cycle and to symptoms of sleep deprivation, sleep fragmentation should be considered as a contributor to cardiovascular and autonomic alterations in OSA. During normal non–rapid eye movement (REM) sleep, blood pressure, heart rate and sympathetic nervous activity (MSNA) decrease progressively (56–58). Compared to awake, during stage 4 non-REM sleep, mean systemic blood pressure and MSNA decrease by ⬃10% to 15% and ⬃30% to 50%, respectively, while the decrease in heart rate is small (7,57,58). However, when sleep stage advances to REM sleep, heart rate, blood pressure and MSNA become highly variable and marked oscillations of these parameters occur (56–58). On average, during REM
Blood Pressure Regulation and Sleep Apnea
559
sleep, blood pressure and heart rate return to baseline levels while MSNA is increased substantially and skeletal muscle tone is low (56,58). Even in normal sleep, occasional episodes of awakening occur and may be accompanied by electroencephalographic and electromyographic evidence of arousal (59). Cortical arousal is accompanied by discharges of MSNA, as well as by transient increases of heart rate and systemic pressure (56,60). B. Sleep in Sleep Apnea
OSA is accompanied by marked changes in sleep architecture and cardiovascular function during sleep (59,61). One fundamental observation is that patients with OSA do not exhibit the normal decrease in arterial pressure during sleep but rather exhibit marked apnea-related blood pressure fluctuations (62,63). Early work also showed that pulmonary artery pressure increased in parallel with the systemic pressure during and immediately following apnea (62). The transient rise in pulmonary pressure was interpreted in part as a result of hypoxic pulmonary vasoconstriction (62). Because sleep is interrupted frequently and as a function of the severity of the disease, OSA patients spend less time in deeper stages of sleep and REM sleep. The overall result is that sleep is less restorative and nocturnal blood pressure does not show the normal drop. Therefore, irrespective of daytime blood pressure, the average daily blood pressure is increased in OSA because of the absence of the nocturnal blood pressure dip. Interestingly, heavy snoring, which is associated with large intrathoracic pressure changes, also leads to nocturnal blood pressure fluctuations and prevents the normal nocturnal dip in systemic pressure even in the absence of obstructive apneas (8). It has been postulated that this effect may be due to repetitive arousal and surges of sympathetic activity (28). C. Acute Neurocirculatory Events During Obstructive Apnea
Investigations on the acute neurocirculatory events during obstructive apnea have provided some clues about acute blood pressure regulation in OSA. The principal hemodynamic feature of OSA is dramatic nocturnal blood pressure oscillations which correspond to the repetitive apnea-hyperpnea cycles (62). Because of their transient nature, these blood pressure fluctuations are only fully apparent when blood pressure is measured via an intra-arterial catheter or a noninvasive device capable of registering blood pressure on a beat-by-beat basis (e.g., photoplethysmography). The phasic apnea-related blood pressure swings are also accompanied by marked intermittent surges of sympathetic nerve activity (MSNA) (32,35,36). A typical recording of MSNA, blood pressure, O 2 saturation, and respiration in a patient with OSA during sleep is shown in Figure 1. In general, early during apnea blood pressure tends to drop, while it increases late during apnea. A substantial but transient pressor response is noted in the immediate postapnea phase. Typically, the blood pressure reaches its peak a few seconds following arousal and after the resumption of breathing, i.e., early during the hyperventilatory phase of the apnea-hyperpnea cycle. The heart rate decreases during
560
Leuenberger and Zwillich
Figure 1 Recording of muscle sympathetic nerve activity (MSNA), systemic blood pressure (BP), oxygen saturation (SaO 2), and respiration from a patient with obstructive sleep apnea during sleep. Obstructive apneas are associated with marked surges of sympathetic nerve activity. Blood pressure rises abruptly when breathing resumes. Bradycardia at the end of apnea is replaced by relative tachycardia at the resumption of breathing. The pressor response to obstructive apnea is at least in part the result of transient sympathetically mediated vasoconstriction.
apnea but rises promptly upon resumption of breathing. Occasionally, late during apnea, profound bradycardia and brief periods of heart block occur (64). The apnearelated bradycardia and the transient relative tachycardia upon resumption of breathing are vagally mediated as these transient heart rate fluctuations can be blocked by atropine (64,65). Vasoconstrictor sympathetic nerve activity (MSNA) shows marked and progressive surges late during apnea. Neural silence follows once breathing resumes. Note that the overall responses to apnea are qualitatively similar to the diving reflex (66,67). These responses could be interpreted to represent a protective reflex by decreasing O 2 delivery to non vital areas (vasoconstriction) and lowering myocardial O 2 demand (bradycardia) while maintaining O 2 delivery the brain and to the myocardium (67). As obstructive apnea is accompanied by surges of sympathetic activity and transient blood pressure elevations, the question arises whether this blood pressure response is due to peripheral vasoconstriction or to an increase in blood flow. Thermodilution measurements of cardiac output suggest that cardiac output falls during apnea (68) but do not have the time resolution necessary to determine the precise time course of this effect. Garpestad et al. examined this issue with a nuclear vest technique capable of determining beat-by-beat changes of cardiac output (stroke volume) (69). They found cardiac output to decrease during apnea and reach a nadir
Blood Pressure Regulation and Sleep Apnea
561
at the time of the blood pressure peak. Low cardiac output which coincides with the blood pressure peak suggests a substantial transient increase in peripheral vascular resistance. A preliminary study by Imadojemu et al. measured femoral blood flow during obstructive apneas with a Doppler technique and reached similar conclusions (70). Because this apnea-related vasoconstriction is preceded by discharges of sympathetic vasoconstrictor nerves, it is likely sympathetically mediated. Indeed, in patients with OSA and coexisting autonomic insufficiency (Shy-Drager syndrome), apnea-related increases in systemic pressure were almost completely absent suggesting an important role of the autonomic nervous system in these responses (71). A neurally-mediated basis of apnea-related pressor responses is further supported by data on the effects of ganglionic blockade. Katragadda et al. examined the pressor responses to simulated obstructive and nonobstructive apnea before and after ganglionic blockade with trimethaphan in normal humans (72). Ganglionic blockade completely abolished the pressor responses to both maneuvers, demonstrating an intact sympathetic nervous system to be necessary for this response (72). Similarly, O’Donnell et al. found no pressor response to intermittent airway obstruction in dogs when the autonomic nervous system was blocked with hexamethonium (73). Prior to autonomic blockade neural reflexes elicited by airway obstruction but also arousal contributed each to the acute blood pressure responses to experimental obstructive apnea (73). D. Potential Mechanisms
A number of physiologic mechanisms have been considered as causes or contributors to the pressor responses to obstructive apnea. These include stimulation of arterial or central chemoreceptors by recurring hypoxia and hypercapnia (asphyxia), changes of intrathoracic pressure due to forceful attempted inspiration against a closed glottis, and changes in sleep state and arousal from sleep. Evidence for and against these proposed mechanisms has been collected in patients with OSA and also in normal subjects during experimental interventions. E. Role of Hypoxia
Classic animal experiments by Angell James and de Burgh Daly demonstrated that apneic asphyxia (i.e., combined hypoxia and hypercapnia in the absence of lung inflation) elicited a substantial vasoconstriction (74). This was in sharp contrast to the vasodilation that occurred with similar blood gas disturbances but continued periodic lung inflation (74). Therefore, the blood pressure response seen in humans following obstructive apnea could be related to the concomitant blood gas disturbances and the absence of the sympathoinhibitory effect of breathing (lung inflation or chest wall reflex). Schroeder et al. found that the obstructive apnea-induced blood pressure oscillations during sleep in patients with OSA were attenuated by administration of 100% O 2 (71). Similarly, Shepard noted a direct relationship between the severity of the apnea-induced hypoxia and the blood pressure peak (63). More recently, Leuen-
562
Leuenberger and Zwillich
berger et al. examined the sympathetic neural responses to obstructive apnea before and during administration of 100% O 2 (35). Although during O 2 administration, apneas lasted longer than apneas while exposed to room air, the apnea-induced surges of sympathetic activity (MSNA) and the magnitude of the blood pressure oscillations were markedly attenuated (35) (see Fig. 2). Taken together, these data strongly suggest that the apnea-related blood pressure fluctuations are at least in part related to intermittent hypoxia and stimulation of chemoreceptors. Observations from experimental interventions in normal humans are consistent with this interpretation. Van den Aardweg measured blood pressure fluctuations induced by intermittent breath holding in normal humans (75). During progressive hypoxia, this intervention produced substantial transient blood pressure elevations that were markedly attenuated during administration of 100% O 2 (75). Hardy et al. examined sympathetic nerve activity and blood pressure responses to voluntary apneas (breath holding) (76). Similar to obstructive apneas, voluntary apneas were accompanied by surges of sympathetic activity (MSNA) and transient increases of blood pressure at apnea termination. The sympathetic and blood pressure responses were accentuated by the preceding exposure to hypoxia and were blunted by prior administration of O 2 (hyperoxia) (76). These findings suggested that chemoreceptor
Figure 2 Recording of muscle sympathetic nerve activity (MSNA), systemic blood pressure (BP), oxygen saturation (SaO 2), and respiration from a patient with obstructive apneas during sleep while exposed to 100% oxygen (same patient as in Fig. 1). Note that despite longer duration of apneas, the apnea-related fluctuations of sympathetic nerve activity and blood pressure are attenuated, suggesting that hypoxia is an important determinant of these responses.
Blood Pressure Regulation and Sleep Apnea
563
stimulation (via hypoxia) was an important determinant of these responses. Furthermore, these studies suggested that blood pressure swings qualitatively similar to those characteristic of obstructive apnea could be induced in awake normal humans independent of changes of sleep state or arousal. However, because arterial O 2 saturation remains decreased for several seconds following resumption of breathing, the abrupt decrease of MSNA observed upon termination of voluntary and obstructive apnea cannot be explained by the chemoreflex. Alternatively, sympathoinhibition via lung inflation or baroreceptor loading due to the sudden pressure rise may be responsible. F. Role of Arousal
Typically, during sleep, the abrupt pressor responses to obstructive apneas are preceded by arousal which can be documented on the electroencephalogram. Indeed, a series of investigations suggest that arousal alone may produce a transient blood pressure rise and may therefore contribute to the acute pressor responses to obstructive apnea. Ringler et al. were unable to eliminate the acute pressor responses to obstructive apnea when the apnea-related O 2 desaturations were attenuated with supplemental nasal O 2 (77). These investigators observed similar increases of systemic pressure to those induced by apnea when arousal was produced with auditory stimuli (77,78). In normal humans, arousal from sleep without airway obstruction is associated with brief sympathetic discharges, as well as brief increases in heart rate and blood pressure (60) which may vary as a function of the degree of arousal (79). Interestingly, even arousal stimuli that were not potent enough to evoke evidence of cortical arousal on the electroencephalogram (EEG) were capable of inducing a blood pressure rise (79). Taken together, these findings support the view that arousal may play at least a contributory role in the generation of the acute pressor response to obstructive apnea. G. Role of Mechanical Effects
It has been postulated that dramatic fluctuations of intrathoracic pressure may contribute to the sympathetic and blood pressure responses to obstructive apnea. Such swings of intrathoracic pressure may be transmitted to the heart and may transiently affect right and left ventricular function (80). Markedly negative intrathoracic pressure increases left-ventricular afterload by increasing the transmural pressure. Because this promotes intrathoracic venous and arterial expansion, these pressure changes may affect input to aortic and cardiopulmonary baroreceptors. However, several observations suggest that intrathoracic pressure swings play little role in determining the neurocirculatory effects of obstructive apnea. For example, in normal humans, the sympathetic and blood pressure responses to a Mueller maneuver (large negative intrathoracic pressure produced by vigorous inspiration against an obstructed airway) were similar to those to a breath hold of the same duration (81). This suggested that the principal determinant of the sympathetic and pressor responses was hypoxia rather than a change of intrathoracic pressure (81). Findings
564
Leuenberger and Zwillich
Figure 3 Potential mechanisms responsible for the acute neurocirculatory consequences of obstructive apnea. Evidence to date suggests that neural effects are the principal determinants of the transient blood pressure increases in response to obstructive apnea.
from animal studies agree with this view. In a porcine model, the pressor and vasoconstrictor responses to obstructive apnea were even smaller than those of nonobstructive apneas accompanied by similar levels of asphyxia (82). Taken together, these studies have helped to elucidate mechanisms involved in the acute blood pressure responses to obstructive apnea. Stimulation of arterial and possibly central chemoreceptors as well as arousal emerge as important determinants of the acute pressor responses to (obstructive) apnea while the effects of intrathoracic pressure fluctuations appear to be less important. Furthermore, these studies point to the sympathetic nervous system as an important mediator of the acute pressor response to obstructive apnea. A diagram of the proposed physiologic mechanisms which play a role in the acute pressor response to obstructive apnea is shown in Figure 3. Whether any of these mechanisms play a role in the pathogenesis of sustained systemic hypertension in OSA is unknown. Potential mechanisms responsible for sustained sympathoexcitation and hypertension will be addressed in the following section. VII. Potential Mechanisms of Sustained Increases of Sympathetic Activity and Hypertension in Sleep Apnea Because, independent of obesity, OSA is associated with increased sympathetic activity and in light of evidence that CPAP reduces sympathetic activity and often elevated blood pressure, it is reasonable to speculate that physiologic events associ-
Blood Pressure Regulation and Sleep Apnea
565
ated with obstructive apnea somehow are responsible for sustained increases in sympathetic activity and blood pressure. Any mechanisms that control sympathetic neural outflow should be considered as potential causes of sustained activation of the sympathetic nervous system. Sympathoexcitatory influences include afferent nerve traffic from arterial chemoreceptors and central influences. Conversely, sympathetic activity is inhibited by afferent nerve traffic from arterial and cardiopulmonary baroreceptors. Thus, sustained increases of sympathetic activity could result from increased excitatory influences or from decreased sympathoinhibition. A. Chemoreflex Hypothesis
Acute chemoreflex stimulation in humans leads to an increase in heart rate, ventilation, and sympathetic activity while blood pressure remains unchanged (83,84). Because in OSA episodes of hypoxia and hypercapnia occur repetitively and because many of these patients suffer from hypertension, it has been proposed that repetitive exposure to these chemical stimuli may over time affect long-term blood pressure regulation (85,86). Indeed, as the carotid bodies are enlarged in many patients with hypertension it has also been proposed that increased activity of chemoreceptors might play a role in the pathogenesis of essential hypertension (87). A series of experimental studies have added plausibility to the theory that OSA causes sustained hypertension. (Many of them are reviewed in Chapters 14 and 22.) In a series of important experiments, Fletcher et al. exposed rats to intermittent hypoxia to simulate the O 2 desaturations that occur with obstructive apnea for several weeks (35 to 40 days) (88–90). Intermittent hypoxia was produced by infusion of nitrogen into daytime sleep chambers for 12 secs every 30 sec leading to transient hypoxia (O 2 saturation nadir ⬃70%) for 7 hours each day. This intervention was found to increase mean normoxic blood pressure by ⬃14 mm Hg after 35 days (88). Sinoaortic denervation as well as chemical sympathectomy with 6-hydroxydopamine both prevented the hypertension induced by intermittent hypoxia (89,90). This was interpreted to indicate that intact chemoreceptors and an intact sympathetic nervous system were necessary to induce persistent blood pressure elevation in response to repetitive episodic hypoxia. However, it is important to recognize that the chemoreceptor stimulus in these studies was hypoxia alone whereas obstructive apneas in humans are accompanied by asphyxia (hypoxia plus hypercapnia). More recently, Brooks et al. developed a sophisticated canine model of OSA (91,92). In this model, a tracheal valve occluder is permanently implanted and is activated by a computer when sleep is detected through implanted EEG electrodes. This monitoring-occlusion system was activated an average of 14 to 16 hours per day. After 1 to 3 months of experimental OSA, awake mean blood pressure (direct intra-arterial measurements) rose by ⬃16 mm Hg and decreased again toward baseline when the occluder was not activated during sleep. The effect of arousal alone (without obstructive apnea) was also studied in this model. Repetitive arousal was produced by an acoustic alarm which was triggered when sleep was detected on the EEG monitoring system and did not result in sustained hypertension (91). Sympathetic nerve activity was not reported in this study. To date these findings represent
566
Leuenberger and Zwillich
perhaps the strongest evidence, albeit not in humans, that OSA can cause hypertension (22). For obvious reasons, similar studies in humans, i.e., experimental induction of intermittent airway obstruction during sleep, are not feasible. Several recent human experiments at least indirectly support a contribution by hypoxia to sustained blood pressure elevation, activation of the sympathetic nervous system or both. In important studies in normal humans, exposure to 20 min of combined hypoxia and hypercapnia (asphyxia), but not hypercapnia alone, provoked a rise in MSNA that persisted upon reexposure to normoxia and isocapnia (93). In addition, in normal humans, blood pressure increases after a prolonged sojourn at high altitude, an effect which appears to be mediated by the sympathoadrenal system (94). A mild blood pressure elevation which persists during normoxia can also be induced following two nights of sleeping at a simulated altitude of 4000 m (95). Preliminary microneurographic studies in patients with OSA also support the notion that increased ‘‘chemoreflex gain’’ (change in MSNA per change in SaO 2 or pCO 2, respectively) may contribute to the state of sympathoexcitation in OSA. In these studies, the sympathetic neural responses to acute hypoxia during wakefulness and normal respirations were found to be augmented in OSA (96–98) (see also Chapter 14). Taken together, these findings strongly support the possibility that chemoreflex mechanisms may be involved in acute and long-term increases of sympathetic neural outflow and blood pressure. B. Baroreflex Dysfunction
The simplest interpretation of increased MSNA and the absence of a decreased heart rate in OSA despite hypertension is that baroreflex function is impaired in OSA, i.e., that baroreflex-mediated sympathetic restraint is lessened. Normal baroreflex function would predict a decrease in sympathetic nerve discharge rate and a parasympathetically-mediated decrease in heart rate in response to elevated blood pressure. Therefore, it has been proposed that elevated sympathetic nerve activity and hypertension in OSA may be due to baroreflex dysfunction. Two recent studies have explored this possibility. Carlson et al. found the sympathoexcitatory responses to brief bolus injections of nitroprusside to be less in OSA than those of controls (99). The authors interpreted this to indicate decreased baroreflex sensitivity which they speculated could lessen the ability of the baroreflex to dampen acute blood pressure increases. In a similar study, Narkiewicz et al. tested the effects of intravenous infusion of nitroprusside (to lower blood pressure) and phenylephrine (to raise blood pressure) on MSNA in normotensive OSA subjects (100). The increase of MSNA in response to nitroprusside was attenuated while no differences were found in the sympathoinhibitory effect of phenylephrine between the two groups. These observations do not completely clarify whether MSNA and blood pressure are high in OSA because of altered baroreflex function. C. Repetitive Arousal and Sleep Deprivation
Because arousal appears to play a role in the acute blood pressure response to obstructive apnea, the question has been raised whether repetitive arousal over time
Blood Pressure Regulation and Sleep Apnea
567
could contribute to a state of sustained sympathoexcitation and blood pressure elevation. The data on this issue are limited. In one recent report hypertension was found to be more common in nonapneic snorers who exhibit frequent arousal during the night than in those with less sleep fragmentation (28). This has been interpreted to indicate that frequent arousal alone may contribute to hypertension (28). However, as indicated above, in a dog model of OSA, intermittent arousal without episodes of obstructive apnea and asphyxia did not result in daytime hypertension (91). Daytime sleepiness is a cardinal symptom of OSA and is thought to result from chronic sleep deprivation. In a sophisticated animal model of sleep deprivation, a series of metabolic, hormonal, immunologic, and cardiovascular effects have been noted in rodents that ultimately died (101). Elevated activity of the sympathetic nervous system was also observed after long-term sleep deprivation (101). However, after up to 5 days of sleep deprivation no clear changes of cardiovascular function or hypertension have been noted in humans (55). Thus, to date there is little evidence to support the concept that sleep fragmentation and/or deprivation may be responsible for elevated sympathetic nerve activity and blood pressure in human OSA. D. Hypertension in OSA as a Defense Reaction
In 1929, in a book entitled Bodily Changes in Pain, Hunger, Fear and Rage, W.B. Cannon described adaptive behavioral changes to threatening environmental conditions. These changes, also termed ‘‘defense reaction,’’ include increases in blood pressure and heart rate, a release of various ‘‘stress hormones,’’ and ultimately serve the survival of the organism (102,103). It has been speculated that long-term stress may play a role in the development and maintenance of hypertension (9). Frequent episodes of nocturnal hypoxia and hypercapnia, i.e., asphyxia, may act as such ‘‘stressors.’’ It is therefore conceivable that some of the manifestations of OSA, including elevated activity of the sympathetic nervous system and hypertension, could represent a ‘‘chronic’’ defense reaction. The neurophysiological mechanisms of the defense reaction have been studied extensively in animal models (104). It is interesting to note that in these models manifestations of the defense reaction can be elicited by peripheral chemoreceptor stimulation (104). Conversely, stimulation of the hypothalamic defense area has been shown to facilitate chemoreflex responses while restraining the responses to baroreceptor stimulation (104). As noted above, some evidence in human OSA suggests that baroreflex activity may be impaired (99) while chemoreflex activity may be enhanced (96–98). These observations are therefore consistent with the possibility that altered cardiovascular reflex responses in OSA may reflect a chronic defense reaction. VIII. Vascular Function and Humoral Abnormalities in OSA Abnormal vascular function could contribute to the pathogenesis of hypertension in OSA independent of neural vascular control (105). Vascular function could be altered as a result of the effects of circulating vasoactive substances, endothelial dysfunction or fixed structural changes broadly termed vascular remodeling.
568
Leuenberger and Zwillich
Abnormal vascular responses to hypoxia were recently reported in OSA. In normal humans, moderate to severe hypoxia is accompanied by vasodilation in the forearm (83,84). Generally, blood pressure does not change, probably because vasodilation and an increase in cardiac output are matched. However, unlike in control subjects, Hedner et al. observed pressor responses in patients with OSA who were acutely exposed to hypoxia (86). In another recent report, Remsburg et al. found that hypoxia mediated vasodilation was attenuated in OSA compared to controls (106). These data suggest an impaired ability to vasodilate in OSA. However, whether this defect in vasodilation is independent of neural control is unclear as in both these studies sympathetic neural activity was not measured. A. Endothelial Dysfunction
The vascular endothelium has emerged as a site of intense biochemical processes that affect vascular tone and may play a role in the pathogenesis of hypertension, atherosclerosis and heart failure (107). Endothelial dysfunction may be an early manifestation of these diseases. In some cases, treatment of these conditions has been shown to be associated with an improvement of endothelial function (107). Vascular function in essential hypertension has been studied extensively, while very little research has focused specifically on vascular function in OSA. Since its recent identification, the ubiquitous gas nitric oxide (NO) has emerged as the body’s principal vasodilator system (108). When NO is inhibited pharmacologically with specific NO-synthase inhibitors, blood pressure rises (108). This suggests that the NO pathway may play a role in the development of hypertension. Indeed, abnormalities of endothelium-dependent vascular relaxation have been described in essential hypertension (109,110). In these studies, the peripheral vascular responses to intra-arterial infusion of acetylcholine was examined. Decreased vasodilation in response to acetylcholine but not to the NO donor nitroprusside was interpreted to indicate an impairment of endothelium-dependent vasodilation (110). A similar impairment of endothelium-dependent vasodilation was also observed in OSA (111). Interestingly, these abnormalities were present in OSA whether or not the subjects were hypertensive (111). B. Humoral Factors
Humoral and endocrine abnormalities may contribute to the development of hypertension via an effect on vascular function or on plasma volume. As discussed previously, plasma norepinephrine has been found to be elevated in OSA (30,31) and is thought to reflect activation of the sympathetic nervous system, a conclusion which is supported by measurements of MSNA in OSA discussed earlier. However, unlike in heart failure and some forms of secondary hypertension, the renin-angiotensinaldosterone system does not appear to be activated in OSA (2). Furthermore, there are no data to suggest that hypertension in OSA is associated with a chronic highvolume state. In fact, it has been shown that OSA patients experience an excessive nocturnal diuresis (112). Increased levels of atrial natriuretic peptide (ANP) possibly
Blood Pressure Regulation and Sleep Apnea
569
due to recurrent episodes of hypoxia-induced pulmonary hypertension and right atrial dilatation may be responsible for this (113). Because of its extremely potent vasoconstrictor properties, increased levels of endothelin could contribute to elevated vascular resistance and blood pressure. The role of endothelin in essential hypertension is unclear (114). In one published report, endothelin levels were found to be increased in normotensive and hypertensive OSA patients and did not decrease following CPAP therapy (115). Recent interest in hypertension research has focused on the potential role of insulin resistance as a contributor to the development of hypertension (21). Insulin resistance is common in obese subjects and could represent the link between obesity and hypertension. Insulin could affect blood pressure regulation in a number of ways. For example, insulin stimulates the sympathetic nervous system but also has direct vasodilator properties (116). The overall acute effects of insulin infusion in normal subjects and in borderline hypertensives are sympathoexcitation but no change in blood pressure (116). However, it has been speculated that long-term effects of elevated insulin may lead to structural changes in the vessel wall which could eventually lead to increased vascular resistance. The issue of insulin resistance in OSA has not been investigated intensely. In one study, insulin resistance and hypertension were found in obese but not in nonobese OSA patients (117). Not surprisingly, this would suggest that insulin resistance is primarily due to obesity rather than OSA.
Figure 4 Potential mechanisms responsible for the sustained increases in sympathetic nerve activity and for hypertension in obstructive sleep apnea. Chronically increased sympathetic nerve activity appears to be a central abnormality associated with sleep apnea and may play a key role in the pathogenesis of hypertension.
570
Leuenberger and Zwillich
Findley et al. reported that plasma adenosine levels are increased in OSA (118), a finding which is difficult to interpret because of the extremely short halflife of adenosine in plasma. However, recent investigations suggest that adenosine plays an important role in the peripheral vasodilation noted during acute hypoxia. Neylon and Marshall demonstrated that the adenosine receptor antagonists aminophylline and 8-phenyltheophylline attenuated the hypoxia-induced vasodilation in the rat hindlimb (119). It was later found that during hypoxia adenosine may act via NO (120). Local release of adenosine may also play a role in hypoxia-mediated vasodilation in humans. Interstitial adenosine concentrations rise during hypoxia in humans (121) and adenosine-blocking doses of aminophylline infused in the human forearm attenuate hypoxia-mediated vasodilation (122). Whether adenosine-mediated mechanisms of vascular control are abnormal in OSA has not been investigated. Collectively, these findings suggest that OSA is accompanied by a number of vascular and humoral abnormalities. However, based on the available data it is difficult to argue that any of these abnormalities play a primary role in the development of increased sympathetic activity and hypertension in OSA. A diagram of potential mechanisms that lead to sustained sympathetic activation and hypertension in OSA is shown in Figure 4. IX. Conclusions A statistical association between OSA and systemic hypertension has been firmly documented. In addition, increased activity of the sympathetic nervous system is a consistent feature of OSA. However, because the available data are cross-sectional rather than longitudinal and because of potential confounding factors, a cause-andeffect relationship between OSA and hypertension and between increased sympathetic neural outflow and hypertension has not been firmly established. Therefore, whether OSA is an independent cause of hypertension remains unproven. However, several lines of evidence strongly support this concept (see Table 1). In a significant
Table 1 Evidence in Support of a Causative Role of OSA in Hypertension Clinical
Epidemiologic
Experimental
Many patients with OSA have hypertension. Sympathetic nerve activity is consistently elevated in patients with OSA. Tracheostomy and CPAP therapy decrease sympathetic nerve activity and blood pressure in many patients. Hypertension occurs in 50–60% of patients with OSA. OSA or lesser degrees of sleep-disordered breathing is found in ⬃30% of patients with hypertension. Blood pressure varies as a function of severity of OSA. Repetitive hypoxia causes hypertension in rats. Repetitive airway obstruction causes hypertension in dogs. Acute hyoxia causes sustained sympathetic activation in humans. Exposure to high altitude increases blood pressure in humans.
Blood Pressure Regulation and Sleep Apnea
571
proportion of OSA patients blood pressure and sympathetic activity decrease with effective CPAP therapy. The concept that OSA causes hypertension is also supported by experimental evidence in animal models of OSA. The preponderance of the data to date suggest that the sympathetic nervous system is the critical link between OSA and hypertension. The mechanisms underlying the hypertension and the activation of the sympathetic nervous system in OSA remain speculative. At present, repetitive hypoxia, acting through stimulation of chemoreceptors and perhaps through altered central neural regulation, appears to be a plausible theory. Future research will have to entertain the possibility that hypertension in OSA may be a form of ‘‘stress-induced’’ hypertension. Acknowledgments This work was in part supported by a grant-in-aid from the American Heart Association and a National Institutes of Health (NIH)-sponsored General Clinical Research Center with National Center for Research Resources grant M01 RR10732. The authors would like to express their thanks to Jennifer Stoner for expert secretarial assistance. References 1. Bonsignore MR, Marrone O, Insalaco G, Bonsignore G. The cardiovascular effects of obstructive sleep apnoeas: Analysis of pathogenic mechanisms. Eur Respir J 1994; 7:786– 805. 2. Carlson J, Davies R, Ehlenz K, Grunstein R, Hedner J, Podszus T, Sinoway L, Stradling J, Telakivi T, Zwillich C. Obstructive sleep apnea and blood pressure elevation: What is the relationship? Blood Pressure 1993; 2:166–182. 3. Fletcher EC. The relationship between systemic hypertension and obstructive sleep apnea: facts and theory. Am J Med 1995; 98:118–128. 4. Guilleminault C, Robinson A. Sleep-disordered breathing and hypertension: Past lessons, future directions. Sleep 1997; 20(9):806–811. 5. Hoffstein V, Chan CK, Slutsky AS. Sleep apnea and systemic hypertension: a casual association review. Am J Med 1991; 91:190–196. 6. Levinson PD, Millman RP. Causes and consequences of blood pressure alterations in obstructive sleep apnea. Arch Intern Med 1991; 151:455–462. 7. Shepard JW Jr. Hypertension, cardiac arrhythmias, myocardial infarction, and stroke in relation to obstructive sleep apnea. Clin Chest Med 1992; 13(3):437–458. 8. Silverberg DS, Oksenberg A. Essential hypertension and abnormal upper airway resistance during sleep. Sleep 1997; 20(9):794–806. 9. Anonymous. National High Blood Pressure Education Program Working Group Report on Primary Prevention of Hypertension. Arch Intern Med 1993; 153(2):186–208. 10. Klag MJ, Whelton PK. Hypertension. In: Traill TA, ed. The Principles and Practice of Medicine, 23d ed. Stamford, CT: Appleton & Lange, 1996:104–112. 11. Gastaut H, Tassinari CA, Duron B. Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res 1966; 2:167186. 12. Guilleminault C, Eldridge FL, Tilkian A, Simmons FB, Dement WC. Sleep apnea syndrome due to upper airway obstruction. Arch Intern Med 1977; 137:296–300. 13. Guilleminault C, Simmons FB, Motta J, Cummiskey J, Rosekind M, Schroeder JS, Dement
572
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
Leuenberger and Zwillich WC. Obstructive sleep apnea syndrome and tracheostomy. Long-term follow-up experience. Arch Intern Med 1981; 141:985–988. Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea. J Hypertens 1990; 8(10):941–946. Carlson JT, Hedner JA, Ejnell H, Peterson L-E. High prevalence of hypertension in sleep apnea patients independent of obesity. Am J Respir Crit Care Med 1994; 150:72–77. Lavie P, Ben-Yosef R, Rubin AE. Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984; 108:373–376. Kales A, Bixler EO, Cadieux RJ, Schneck DW, Shawl LC, III, Locke TW, Vela-Bueno A, Soldatos CR. Sleep apnoea in a hypertensive population. Lancet 1984; 2:1005– 1008. Fletcher EC, DeBehnke RD, Lovoi MS, Gorin AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103(2):190–195. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. BMJ 1997; 314:851–860. Stradling J, Davies RJO. Sleep apnea and hypertension. What a mess! Sleep 1997; 20(9): 789–793. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathodrenal system. N Engl J Med 1996; 334(6):374–381. Dempsey JA. Sleep apnea causes daytime hypertension (Editorial Comment). J Clin Invest 1997; 99(1):1–2. Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994; 120(5):382–388. Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997; 157:1746-1752. Quan SF, Howard BV, Iber C, Kiley JP, Nieto FJ, O’Connor GT, Rapoport DM, Redline S, Robbins J, Samet JM, Wahl PW. The sleep heart health study: design, rationale, and methods. Sleep 1997; 20(12):1077–1085. Stradling JR, Crosby JH. Relation between systemic hypertension and sleep hypoxaemia or snoring: analysis in 748 men drawn from general practice. BMJ 1990; 300:75–78. Guilleminault C, Stoohs R, Shiomi T, Kushida C, Schnittger I. Upper airway resistance syndrome, nocturnal blood pressure monitoring, and borderline hypertension. Chest 1996; 109:901-908. Lofaso F, Coste A, Gilain L, Harf A, Guilleminault C, Goldenberg F. Sleep fragmentation as a risk factor for hypertension in middle-aged nonapneic snorers. Chest 1996; 109:896– 900. Fletcher EC, Miller J, Schaaf JW, Fletcher JG. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987; 10(1): 35-44. Eisenberg E, Zimlichman R, Lavie P. Plasma norepinephrine levels in patients with sleep apnea syndrome (Letter). N Engl J Med 1990; 322(13):932–933. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993; 103(6):1763– 1768. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens Suppl 1988; 6(4):S529-S531. ˚ B, Hagbarth K-E, Torebjo¨rk HE, Wallin BG. Somatosensory, proprioceptive and Vallbo A sympathetic activity in human peripheral nerves. Physiol Rev 1979; 59:919–957. Simon E, Riedel W. Diversity of regional sympathetic outflow in integrative cardiovascular control: patterns and mechanisms. Brain Res 1975; 87:323–333. Leuenberger U, Jacob E, Sweer L, Waravdekar N, Zwillich C, Sinoway L. Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 1995; 79(2):581–588.
Blood Pressure Regulation and Sleep Apnea
573
36. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897–1904. 37. Waravdekar NV, Sinoway LI, Zwillich CW, Leuenberger UA. Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med 1996; 153: 1333–1338. 38. Watanabe T, Mano T, Iwase S, Sugiyama Y, Okada H, Takeuchi S, Furui H, Kobayashi F. Enhanced muscle sympathetic nerve activity during sleep apnea in the elderly. J Auton Nerv Syst 1992; 37(3):223–226. 39. Narkiewicz K, Van de Borne PJH, Cooley RL, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation 1998; 98:772– 776. 40. Leimbach WN Jr, Wallin BG, Victor RG, Aylward PE, Sundlo¨f G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986; 73(5):913–919. 41. Eckberg DL, Sleight P. Hypertension. In: Boyd CAR, Brown AG, Fink G, Gillespie JS, Kidd C, Michell CC, eds. New York: Oxford University Press, 1992:327–345. 42. Folkow B. ‘‘Structural factor’’ in primary and secondary hypertension. Hypertension 1990; 16:89–101. 43. Brown MJ. Science, medicine and the future. Hypertension. BMJ 1997; 314:1258–1261. 44. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1:862– 865. 45. Engleman HM, Martin SE, Kingshott RN, Mackay TW, Deary IJ, Douglas NJ. Randomized placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 1998; 53(5):341-345. 46. Pack AI, Young T. Obstructive sleep apnoea: Superficial analysis ignores evidence on efficacy of treatment (Letter). BMJ 1997; 315(7104):367–368. 47. Stradling JR, Davies RJO. Obstructive sleep apnoea: Evidence for efficacy of continuous positive airways pressure is compelling (Letter). BMJ 1997; 315(7104):368. 48. Jennum P, Wildschiødtz G, Christensen NJ, Schwartz T. Blood pressure, catecholamines, and pancreatic polypeptide in obstructive sleep apnea with and without nasal continuous positive airway pressure (nCPAP) treatment. Am J Hypertens 1989; 2:847–852. 49. Mayer J, Becker H, Brandenburg U, Penzel T, Peter JH, Von Wichert P. Blood pressure and sleep apnea: results of long-term nasal continuous positive airway pressure therapy. Cardiology 1991; 79(2):84–92. 50. Wilcox I, Grunstein RR, Hedner JA, Doyle J, Collins FL, Fletcher PJ, Kelly DT, Sullivan CE. Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep 1993; 16(6):539–544. 51. Hedner J, Darpo¨ B, Ejnell H, Carlson J, Caidahl K. Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J 1995; 8(2):222–229. 52. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994; 343:572–575. 53. Reeves-Hoche MK, Meck R, Zwillich CW. Nasal CPAP: An objective evaluation of patient compliance. Am J Respir Crit Care Med 1994; 149(1):149–154. 54. Shapiro CM, Flanigan MJ. Function of sleep. BMJ 1993; 306:383–385. 55. Horne JA. Sleep function, with particular reference to sleep deprivation. Ann Clin Res 1985; 17:199–208. 56. Hornyak M, Cejnar M, Elam M, Matousek M, Wallin BG. Sympathetic muscle nerve activity during sleep in man. Brain 1991; 114:1281–1295. 57. Snyder F, Hobson JA, Morrison DF, Goldfrank F. Changes in respiration, heart rate, and systolic blood pressure in human sleep. J Appl Physiol 1964; 19(3):417–422. 58. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993; 328(5):303–307. 59. Kales A, Kales JD. Sleep disorders. Recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med 1974; 290(9):487–499.
574
Leuenberger and Zwillich
60. Morgan BJ, Crabtree DC, Puleo DS, Badr MS, Toiber F, Skatrud JB. Neurocirculatory consequences of abrupt change in sleep state in humans. J Appl Physiol 1996; 80(5):1627– 1636. 61. Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Ann Rev Med 1976; 27:465–484. 62. Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons B, Dement WC. Hemodynamics in sleep-induced apnea. Studies during wakefulness and sleep. Ann Intern Med 1976; 85(6):714-719. 63. Shepard JW Jr. Gas exchange and hemodynamics during sleep. Med Clin North Am 1985; 69(6):1243–1264. 64. Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin R. Bradycardia during sleep apnea. Characteristics and mechanism. J Clin Invest 1982; 69(6):1286–1292. 65. Guilleminault C, Connolly S, Winkle R, Melvin K, Tilkian A. Cyclical variation of the heart rate in sleep apnoea syndrome. Mechanisms, and usefulness of 24 h electrocardiography as a screening technique. Lancet 1984; 1:126–131. 66. Fagius J, Sundlo¨f G. The diving response in man: Effects on sympathetic activity in muscle and skin nerve fascicles. J Physiol (Lond) 1986; 377:429–443. 67. Rowell LB. Cardiovascular adjustments to hypoxemia. In: Rowell LB, ed. Human Circulation. Regulation During Physical Stress. New York: Oxford University Press, 1986:328– 362. 68. Guilleminault C, Motta J, Mihm F, Melvin K. Obstructive sleep apnea and cardiac index. Chest 1986; 89(3):331–334. 69. Garpestad E, Katayama H, Parker JA, Ringler J, Lilly J, Yasuda T, Moore RH, Strauss HW, Weiss JW. Stroke volume and cardiac output decrease at termination of obstructive apneas. J Appl Physiol 1992; 73(5):1743–1748. 70. Imadojemu VA, Leuenberger U, Sinoway L. Transient arterial hypertension in obstructive apnea during sleep is accompanied by peripheral vasocontriction. Am J Respir Crit Care Med 1998; 157(3):A777. Abstract. 71. Schroeder JS, Motta J, Guilleminault C. Hemodynamic studies in sleep apnea. In: Guilleminault C, Dement WC, eds. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978:177– 196. 72. Katragadda S, Xie A, Puleo D, Skatrud JB, Morgan BJ. Neural mechanism of the pressor response to obstructive and nonobstructive apnea. J Appl Physiol 1997; 83(6):2048–2054. 73. O’Donnell CP, Ayuse T, King ED, Schwartz AR, Smith PL, Robotham JL. Airway obstruction during sleep increases blood pressure without arousal. J Appl Physiol 1996; 80(3): 773–781. 74. Angell James JE, de Burgh Daly M. Cardiovascular responses in apnoeic asphyxia: role of arterial chemoreceptors and the modification of their effects by a pulmonary vagal inflation reflex. J Physiol (Lond) 1969; 201(1):87–104. 75. Van den Aardweg JG, Karemaker JM. Repetitive apneas induce periodic hypertension in normal subjects through hypoxia. J Appl Physiol 1992; 72(3):821–827. 76. Hardy JC, Gray K, Whisler S, Leuenberger U. Sympathetic and blood pressure responses to voluntary apnea are augmented by hypoxemia. J Appl Physiol 1994; 77(5):2360–2365. 77. Ringler J, Basner RC, Shannon R, Schwartzstein R, Manning H, Weinberger SE, Weiss JW. Hypoxemia alone does not explain blood pressure elevations after obstructive apneas. J Appl Physiol 1990; 69(6):2143–2148. 78. Ringler J, Garpestad E, Basner RC, Weiss JW. Systemic blood pressure elevation after airway occlusion during NREM sleep. Am J Respir Crit Care Med 1994; 150:1062–1066. 79. Davies RJO, Belt PJ, Roberts SJ, Ali NJ, Stradling JR. Arterial blood pressure responses to graded transient arousal from sleep in normal humans. J Appl Physiol 1993; 74(3):11231130. 80. Tolle FA, Judy WV, Yu PL, Markand ON. Reduced stroke volume related to pleural pressure in obstructive sleep apnea. J Appl Physiol 1983; 55(6):1718–1724. 81. Morgan BJ, Denahan T, Ebert TJ. Neurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea. J Appl Physiol 1993; 74(6):2969–2975. 82. Chen L, Scharf SM. Comparative hemodynamic effects of periodic obstructive and simulated central apneas in sedated pigs. J Appl Physiol 1997; 83(2):485–494.
Blood Pressure Regulation and Sleep Apnea
575
83. Leuenberger U, Gleeson K, Wroblewski K, Prophet S, Zelis R, Zwillich C, Sinoway L. Norepinephrine clearance is increased during acute hypoxemia in humans. Am J Physiol 1991; 261 (Heart Circ Physiol 30):H1659–H1664. 84. Richardson DW, Kontos HA, Raper AJ, Patterson JL Jr. Modification by beta-adrenergic blockade of the circulatory responses to acute hypoxia in man. J Clin Invest 1967; 46(1): 77-85. 85. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 1988; 11:608–612. 86. Hedner JA, Wilcox I, Laks L, Grunstein RR, Sullivan CE. A specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis 1992; 146:1240– 1245. 87. Trzebski A. Arterial chemoreceptor reflex and hypertension. Hypertension 1992; 19(6): 562–566. 88. Fletcher EC, Lesske J, Qian W, Miller CC, III, Unger T. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 1992; 19:555–561. 89. Fletcher EC, Lesske J, Behm R, Miller CC III, Stauss H, Unger T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 1992; 72(5):1978–1984. 90. Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 1992; 20:612–619. 91. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997; 99(1):106–109. 92. Kimoff RJ, Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Champagne V, Mayer P, Phillipson EA. Ventilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea. Am J Respir Crit Care Med 1997; 156:886–894. 93. Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol 1995; 79(1):205–213. 94. Wolfel EE, Selland MA, Mazzeo RS, Reeves JT. Systemic hypertension at 4,300 m is related to sympathoadrenal activity. J Appl Physiol 1994; 76(4):1643–1650. 95. Arabi Y, Morgan BJ, Goodman B, Puleo DS, Xie A, Skatrud JB. Daytime blood pressure elevation following nocturnal hypoxia. J Appl Physiol 1999; 87(2):689–698. 96. Leuenberger UA, Mawji Z, Waravdekar NV, Zwillich CW. Sympathetic neural responses to transient hypoxia are increased in obstructive sleep apnea. Circulation 1996; 94(8): I-544. Abstract. 97. Narkiewicz K, Pesek CA, Somers VK. Selective potentiation of peripheral chemoreceptor sensitivity in obstructive sleep apnea. Circulation 1998; 98:I-472. Abstract. 98. Smith ML, Niedermaier ONW, Decker MJ, Strohl KP. Treatment of sleep apnea reverses abnormal chemoreflex control of sympathetic activity. Circulation 1998; 98:I-471. Abstract. 99. Carlson JT, Hedner JA, Sellgren J, Elam M, Wallin BG. Depressed baroreflex sensitivity in patients with obstructive sleep apnea. Am J Respir Crit Care Med 1996; 154(5):1490– 1496. 100. Narkiewicz K, Pesek CA, Kato M, Phillips BG, Davison DE, Somers VK. Baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea. Hypertension 1998; 32:1039–1043. 101. Rechtschaffen A, Bergmann BM, Everson CA, Kushida CA, Gilliland MA. Sleep deprivation in the rat. X. Integration and discussion of the findings. Sleep 1989; 12(1):68–87. 102. Herd JA. Cardiovascular response to stress. Physiol Rev 1991; 71(1):305–330. 103. Hilton SM. The defence-arousal system and its relevance for circulatory and respiratory control. J Exp Biol 1982; 100:159–174. 104. Spyer KM. Central nervous mechanisms contributing to cardiovascular control. J Physiol (Lond) 1994; 474(1):1–19. 105. Hedner J. Vascular function in OSA. Sleep 1996; 19(10):S213–S217. 106. Remsburg S, Launois SH, Weiss JW. Patients with obstructive sleep apnea have an abnormal peripheral vascular response to hypoxia. J Appl Physiol 1999; 87(3):1148–1153.
576
Leuenberger and Zwillich
107. Pepine CJ. Clinical implications of endothelial dysfunction. Clin Cardiol 1998; 21:795– 799. 108. Moncada S, Higgs A. The L-arginine–nitric oxide pathway. N Engl J Med 1993; 329(27): 2002–2012. 109. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323:22–27. 110. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993; 87:1468–1474. 111. Carlson JT, Ra˚ngemark C, Hedner JA. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens 1996; 14:577–584. 112. Rodenstein DO, D’Odemont JP, Pieters T, Aubert-Tulkens G. Diurnal and nocturnal diuresis and natriuresis in obstructive sleep apnea. Effects of nasal continuous positive airway pressure therapy. Am Rev Respir Dis 1992; 145(6):1367–1371. 113. Krieger J, Laks L, Wilcox I, Grunstein RR, Costas LJV, McDougall JG, Sullivan CE. Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and during treatment with nasal continuous positive airway pressure. Clin Sci 1989; 77:407–411. 114. Levin ER. Endothelins. N Engl J Med 1995; 333(6):356–363. 115. Saarelainen S, Seppala E, Laasonen K, Hasan J. Circulating endothelin-1 in obstructive sleep apnea. Endothelium 1997; 5(2):115–118. 116. Anderson EA, Balon TW, Hoffman RP, Sinkey CA, Mark AL. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension 1992; 19:621–627. 117. Fischer J, Raschke F. Glucose tolerance, insulin resistance and arterial hypertension in patients with obstructive sleep apnea syndrome. Pneumologie 1995; 49(suppl 1):131–135. 118. Findley LJ, Boykin M, Fallon T, Belardinelli L. Plasma adenosine and hypoxemia in patients with sleep apnea. J Appl Physiol 1988; 64(2):556–561. 119. Neylon M, Marshall JM. The role of adenosine in the respiratory and cardiovascular response to systemic hypoxia in the rat. J Physiol (Lond) 1991; 440:529–545. 120. Skinner MR, Marshall JM. Studies on the roles of ATP, adenosine and nitric oxide in mediating muscle vasodilation induced in the rat by acute systemic hypoxia. J Physiol (Lond) 1996; 495(2):553–560. 121. MacLean DA, Sinoway LI, Leuenberger UA. Systemic hypoxia elevates skeletal muscle interstitial adenosine levels in humans. Circulation 1998; 98(19):1990–1992. 122. Leuenberger UA, Gray K, Herr MD. Adenosine contributes to hypoxia-induced skeletal muscle vasodilation in humans. J Appl Physiol 1999; 87(6):2218–2224.
22 Pathophysiological Interactions Between Sleep Apnea and the Heart
T. DOUGLAS BRADLEY
GERALDO LORENZI-FILHO
Toronto General Hospital and University of Toronto Toronto, Ontario, Canada
University of Sa˜o Paulo Sa˜o Paulo, Brazil
JOHN S. FLORAS Mount Sinai Hospital University of Toronto Toronto, Ontario, Canada
I.
Introduction
The heart and lungs work in concert to extract oxygen from the atmosphere and deliver it to the tissues via the arterial circulation, and to transport metabolic CO 2 from the tissues via the venous circulation to the lungs for exhalation into the atmosphere. Under normal conditions, the respiratory and cardiovascular control systems provide an integrated response to meet widely varying metabolic demands (1). In pathological states, however, these normally harmonious cardiopulmonary interactions can become disrupted as impairment of function in one system exerts pathological stresses on the other. One such pathological state is sleep-disordered breathing. For example, in obstructive sleep apnea (OSA), recurrent apneas during sleep lead to hypoxia and reduced cardiac output at a time when oxygen requirements rise due to increased sympathetic nervous system activity, blood pressure (BP), and heart rate (2–5). Therefore, it is not surprising that from the outset of clinical research in sleep apnea, an association between OSA and cardiovascular disease was recognized. Initially, a high prevalence of nocturnal cardiac arrhythmias, systemic and pulmonary hypertension, and cor pulmonale among patients with OSA was described (6–9). More recently, there has emerged a body of evidence implicating OSA in the development or progression of left ventricular (LV) hypertrophy and dysfunction (10,11). 577
578
Bradley et al.
Another such state is congestive heart failure (CHF). Here, pulmonary congestion can lead to hyperventilation and falls in PCO 2 below the threshold for apnea, especially during sleep. As a consequence, patients with CHF are particularly prone to developing central sleep apnea with Cheyne-Stokes respiratory (CSR-CSA) (12– 15). Thus, while sleep apnea can cause cardiovascular disturbances, it is now equally apparent that cardiac dysfunction can lead to sleep apnea. CSR-CSA is common in patients with severe but stable CHF (12,16,17). More importantly, there is increasing evidence to suggest that CSR-CSA in patients with CHF participates in a vicious cycle that further stresses the failing heart and, in so doing, increases the risk of mortality (18,19). In this chapter we will present our views on the acute pathophysiological effects of sleep-related breathing disorders on right ventricular (RV) and LV function. The causes and acute consequences of CSR-CSA in patients with CHF will also be discussed. Detailed considerations of the long-term consequences of these adverse interactions, and of therapeutic approaches to them, are beyond the scope of this chapter. Readers wishing a more comprehensive discussion of these issues are directed to review articles published elsewhere (10,11). II. Effects of Obstructive Sleep Apnea on the Pulmonary Vessels and Right Ventricle OSA has profound effects in the pulmonary vasculature manifest by pronounced intermittent elevations in pulmonary artery pressure (PPa ) related to intermittent hypoxia during sleep (2,20,21). These fluctuations in PPa parallel oscillation in systemic arterial (BP), and peak just shortly after arousal and the onset of ventilation. The mechanisms involved in these cyclic elevations in PPa are summarized in Table 1. The maximum increase in PPa generally coincides with the maximum degree of arterial oxyhemoglobin desaturation. However, there appears also to be a more
Table 1 Factors Promoting Acute Increases in Pulmonary Arterial Pressure and Right Ventricular Afterload in Obstructive Sleep Apnea Pulmonary vasoconstriction Hypoxia Hypercapnia Exaggerated negative intrathoracic pressure during apnea Increased transmural pulmonary artery and right ventricle pressure during obstructive apneas Impairment of left ventricular function and passive rises in pulmonary artery pressure secondary to elevated left-sided cardiac filling pressures Reduced compliance of the LV due to: Left ventricular dilation in response to a combination of increased BP and exaggerated negative intrathoracic pressure during obstructive apneas Leftward shift of the interventricular septum during diastole Hypoxia
Sleep Apnea and the Heart
579
prolonged effect of hypoxia on PPa . Marrone et al. (22) demonstrated in patients with OSA that no matter how far oxyhemoglobin saturation (SaO 2 ) dropped during apneas, it quickly returned to baseline following their termination. Nevertheless, PPa did not return to baseline, but progressively increased during the interapneic periods as the night went on. This phenomenon, however, was evident only when dips in SaO 2 were pronounced. Therefore, and particularly in patients with severe OSA accompanied by profound dips in SaO 2 , it is possible that the consequence of recurrent hypoxia would be to cause a prolonged increase in PPa throughout both the apneic and ventilatory period during sleep. Administration of supplemental O 2 markedly attenuates but does not abolish these elevations in PPa (23). Thus, although hypoxia-induced pulmonary vasoconstriction undoubtedly plays a role in the pathogenesis of apnea-related elevations in PPa , it is probably not the only contributing factor. Hypercapnia and acidosis can also induce pulmonary vasoconstriction (24). Recently Laks et al. (25) studied PPa responses to acute hypoxia at two different levels of end-tidal CO 2 in normal subjects and in patients with either moderate or severe OSA. They found similar PPa increases in response to acute eucapnic and hypercapnic hypoxia in both groups. Normoxic hypercapnia alone was a weak stimulus. There was a marked intersubject and interpatient variability in the pressor response, ranging from 2 to 12 mm Hg for a 30% decrease in SaO 2 . In a subgroup of OSA patients, hypercapnia caused a marked further increase in PPa in response to hypoxia. In contrast, no such augmentation in PPa was seen in any of the normal subjects when exposed to hypercapnia. Thus, it is unclear to what extent elevations in PaCO 2 cause pulmonary vasoconstriction over and above that due to hypoxia during OSA. It seems that there is interindividual variability in the PPa response to hypercapnia and that patients with OSA may differ in this response from healthy subjects. However, there are insufficient data to draw firm conclusions on this point. Nevertheless, increasing PaCO 2 during apnea may contribute to elevations in PPa , and this might explain why elevations in PPa are not completely abolished by supplemental O 2 (23). When analyzing the PPa responses during OSA, one must also consider the effects of the exposure of the pulmonary vasculature to intrathoracic pressure (Pit). Exaggerated subatmospheric Pit during obstructive apneas could increase pulmonary arterial transmural pressure (i.e., the difference between PPa and Pit) in the absence of any direct pulmonary vasoconstrictive stimulus (26). Marrone et al. (22) demonstrated that transmural systolic PPa increased during inspiratory efforts against the occluded upper airway due to generation of negative esophageal pressure. Such an increase in transmural PPa could increase right ventricular afterload as well. Another factor contributing to elevations in PPa could be passive transmission of elevated LV filling pressures to the pulmonary vasculature. For example, Buda et al. (27) demonstrated that pulmonary capillary wedge pressure rose during obstructive apneas. This occurred in association with intermittent elevations of systolic LV transmural pressure (LVPtm; an index of LV afterload), due to the combined effects of increased systemic BP and exaggerated negative Pit during apneas (28). Consequently, these authors speculated that pulmonary capillary wedge pressure
580
Bradley et al.
may have risen, via Starling mechanisms (29,30), secondary to increases in LV afterload during apneas. If correct, this mechanism would be particularly important for patients with LV systolic dysfunction, whose cardiac performance is much more sensitive to changes in afterload than that of subjects with normal ventricular function. The RV will also be exposed to negative Pit, which increases its afterload over and above that due to elevations in PPa . In summary, transient pulmonary hypertension in response to obstructive events during sleep has been well documented. The combination of elevations in PPa and generation of negative intrathoracic pressure during obstruction apneas, leads to intermittent increases in RV afterload. The mechanisms driving these surges in PPa and RV afterload are part of an integrated response to multiple pathogenic factors acting simultaneously or in rapid succession during obstructive apneas (20). Although these factors account for the intermittent apnea-associated elevations in PPa , PPa characteristically returns to the baseline level on final awakening in patients with OSA (2,21). Thus these mechanisms do not readily explain why in some patients pulmonary hypertension can become sustained or RV failure (RVF) occurs. Most patients usually do not suffer from sustained pulmonary hypertension or RVF, no matter how frequent and severe intermittent nocturnal hypoxia may be (9). While experimental animals may develop RV hypertrophy when exposed to prolonged periods of intermittent severe hypoxia, it has not been shown that this leads to RVF (31). A number of investigators have demonstrated that sustained pulmonary hypertension and RVF in patients with OSA are almost invariably associated with the presence of both nocturnal and diurnal hypoxia and hypercapnia (9,32,33). In addition, forced expiratory volume in 1 sec is generally lower and functional residual capacity and residual volume are higher among patients with than in those without RVF (Table 2). Accordingly, when RVF is present in patients with OSA this is usually in association with chronic airflow obstruction. However, the degree of airflow obstruction is usually only mild to moderate, and would by itself be insufficient to cause daytime hypercapnia (34). Instead, it appears as though CO 2 retention and hypoxia are related to a combination of chronic airflow obstruction, chest wall restriction due to obesity, possibly lower central respiratory drive, and the aftereffects of nocturnal upper-airway obstruction (35). Because these daytime blood gas disturbances are associated with mild chronic obstructive airway disease (COPD), these observations gave rise to the notion of an ‘‘overlap syndrome’’ of OSA and COPD. The combined adverse effects of the two disorders gives rise to cardiopulmonary failure (32,33,36–38). Nevertheless, recent studies have suggested that some OSA patients can have subclinical pulmonary hypertension but not RVF, with no concomitant signs of lung abnormalities or daytime hypoxemia (39–41). Although OSA alone infrequently causes RVF, abolition of OSA by tracheostomy or nasal continuous positive airway pressure (CPAP) can reverse cardiorespiratory complications of OSA even in the presence of obesity and mild to moderate COPD (32,42,43). This indicates that while a number of factors contribute to the development of chronic hypercapnia and cor pulmonale in patients with OSA, rever-
Sleep Apnea and the Heart
581
Table 2 Comparison of Physiological Variables in Obstructive Sleep Apnea Patients with and Without Right Heart Failure Without RHF (n ⫽ 44) Age, yr Weight, % ideal Apnea and hypopneas, no/hr sleep Mean nocturnal SaO 2 , % PaO 2 , mm Hg PaCO 2 , mm Hg FRC, % predicted FEV1 , L FEV1 /FVC, % Ventilatory response to CO 2 , L/min/mm Hg
49 147 60 90 75 36 98 3.3 76 2.4
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 7 5 1 2 1 3 0.1 1 0.2
With RHF (n ⫽ 6)
P value
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
NS ⬍.05 NS ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001
49 186 57 76 52 51 119 1.8 56 1.2
3 12 9 3 4 2 11 0.3 5 0.3
Abbreviations: RHF, right heart failure; FRC, functional residual capacity; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity. Source: Ref. 9. (Copyright by the American Review of Respiratory Disease 1985.)
sal of OSA alone is sufficient in most cases to improve RV function. Thus, OSA must be making a significant contribution to the development of RVF. It remains unclear why reversal of OSA by nocturnal CPAP or tracheostomy leads to reversal of daytime hypercapnia. Relief of upper airway obstruction reduces the mechanical load on the respiratory system and this may lead to improvement in gas exchange at night. Alteration of the chemical milieu of the brain stem during sleep may be the most important factor. Such an effect probably leads to resetting of the chemoreceptor at night and persistent reduction in the set point for a ventilatory response to CO 2 , which persists into the daytime (42). Since cor pulmonale is almost invariably accompanied by respiratory failure, it is likely that the development of respiratory failure precedes the onset of RVF in patients with OSA. Similarly, reversal of respiratory failure is the probable explanation for the reversal of cor pulmonale in these patients (44).
III. Effects of Obstructive Sleep Apnea on the Left Ventricle OSA has been reported to occur in approximately 10% to 30% of patients with stable chronic LV heart failure (12,45). Thus there are a considerable number of patients with CHF in whom OSA has potential pathological consequences. There is general agreement that OSA has adverse effects on LV function both acutely and chronically. However, the nature of these effects and mechanisms through which they are exerted remain controversial. In part, this relates to the question of whether
582
Bradley et al.
observations in experimental animal preparations have any relevance to the intact, conscious or sleeping human. (See Chapters 23 and 24 for additional material.) The first controversy is whether obstructive apneas decrease or increase stroke volume and cardiac output, and whether these hemodynamic indices increase or decrease following termination of apneas (2,46–49). Discrepancies among studies are difficult to reconcile. In human studies, these may arise from differences in techniques used to make hemodynamic measurements as well as to differences in cardiovascular function and severity of OSA in patients with OSA. In animal studies, discordant observations and conclusions may relate to differences in experimental preparations and the duration of exposure to experimentally induced OSA. Since it is neither possible to review the results of all these conflicting studies, nor to formulate a consensus from them, we will present our view, supported by the work of Parker et al. (48), that stroke volume and cardiac output generally decrease during apneas and increase during the ventilatory phase following their termination. There are three key pathophysiologic features of OSA that could adversely affect function of the left ventricle: generation of exaggerated negative Pit, development of asphyxia during apnea, and arousal from sleep at the termination of apnea. A polysomnographic recording illustrating these features is displayed in Figure 1. Table 3 outlines how these three factors could lead to the development or progression of LV dysfunction or failure. Exaggerated negative Pit generated during inspiratory efforts against the occluded upper airway generally has adverse effects both on the heart and circulation. Some investigators believe that the main effect of exaggerated negative Pit during inspiratory efforts is to reduce LV preload, but that it has little effect on LV afterload. According to this view, exaggerated negative intrathoracic pressure increases venous return to the RV. The resultant RV distension causes a leftward shift of the interventricular septum during diastole, thereby impeding LV filling (50–53). As a result, stroke volume falls simply due to a reduction in LV end diastolic volume according to Starling’s mechanism. Another possibility is that exaggerated negative Pit can also reduce the rate of LV relaxation, further increasing the impedance to LV filling and raising LV pressures (27,54). The concept that changes in LV afterload due to reductions in Pit do not play an important role in reducing stroke volume relates to the method of measuring afterload, and to the presence or absence of pericardial constraint. If LVPtm is derived using Pes or pleural pressure as an index of Pit, then LVPtm during systole will increase as Pit falls, as long as the fall in Pit is greater than any fall in LV systolic pressure or systemic BP (55). The key issue is whether Pes or another estimate of Pit such as pleural pressure accurately reflects pericardial pressure (56). It has been argued that if the heart distends sufficiently during inspiratory efforts, the pericardium will limit further cardiac dilation and at this point, pericardial pressure would tend to become less negative or even more positive than Pit (57). Under this scenario, LVPtm may actually fall rather than rise during inspiratory efforts, especially if there is a corresponding fall in BP. If so, then negative intrathoracic pressure during obstructive apneas would not contribute to reductions in stroke volume through an increase in afterload.
Sleep Apnea and the Heart
583
Figure 1 Recording of an obstructive hypopnea in a patient with idiopathic dilated cardiomyopathy during stage 2 sleep. The three key features of obstructive sleep apnea are illustrated. First, paradoxical rib cage motion during hypopnea is accompanied by marked subatmospheric intrathoracic pressure (i.e., esophageal pressure) swings during inspiratory efforts. This negative pressure is generated by the inspiratory muscles, which are being loaded by the upper-airway obstruction, and tends to increase left ventricular transmural pressure (i.e., afterload). Second, over the course of the hypopnea, a marked reduction in oxyhemoglobin saturation (SaO 2) occurs. Third an arousal from sleep (EEG and EMGsm channels) terminates the hypopnea. (From Ref. 3.)
Table 3 Mechanisms by Which Obstructive Sleep Apnea May Impair Left Ventricular Function Exaggerated negative intrathoracic pressure during apnea Increased left ventricular transmural pressure (i.e. afterload) Increased right ventricular volume with leftward shift of interventricular septum and diastolic filling of the left ventricle. Reduced cardiac output with increased O 2 demand. Apnea-related hypoxia Reduced myocardial O 2 supply with reduced myocardial contractility, and cardiac ischemia in patients with ischemic heart disease Increased sympathetic nervous system activity Increased heart rate and systemic blood pressure promoting hypertrophy Sinus bradycardia; atrial and ventricular arrhythmias Arousals Increased sympathetic nervous system activity Increased myocardial O 2 demand in the face of reduced O 2 supply
584
Bradley et al.
An alternate view is that the pericardium is a highly elastic and distensible structure, and that constraint would only occur with acute and marked cardiac dilation, such as might be the case during acute cardiogenic pulmonary edema. However, it is unlikely to occur during obstructive apneas, or representations of apneas, such as Mueller maneuvers. Moreover, any such constraint over the LV would be manifest during diastole when the LV is dilated rather than during systole when the LV contracts. Since LVPtm is measured during systole as an index of LV afterload, pericardial constraint should not be a major consideration (5,58). One means of unraveling this complicated physiological issue would be to measure LV volumes and LVPtm simultaneously. This would allow correlations between independent measures of preload and afterload. Such an approach was recently employed by Parker and colleagues (48). These investigators examined the effects of obstructive apneas on LV preload and afterload in dogs with experimentally induced chronic OSA (59). This dog model has several advantages over other animal models of OSA. Dogs are chronically instrumented and conditioned to the laboratory. They are unanaesthetized and are studied during naturally occurring sleep. OSA is induced by occlusion of a tracheostomy valve that is triggered by a computer that detects the onset of sleep by analyzing the frequency of electroencephalographic waves from implanted cranial electrodes. The valve opens when an arousal from sleep is detected by the computer and closes each time the dog falls back to sleep. Signals are transmitted to the computer by telemetry so that the dog is freely mobile. Consequently, OSA can be induced for several hours a day over several months, and the severity of OSA can be controlled. In most respects, this model replicates the acute and chronic pathological effects of OSA. In this model, intrathoracic pressure during upper airway occlusion was estimated by intratracheal pressure. LV pressure, LV volumes, and stroke volume were measured simultaneously by a high-fidelity micromanometer tipped impedance catheter. During obstructive apneas, stroke volume fell abruptly during apnea and increased abruptly upon their termination (Fig. 2). Inspiratory efforts were accompanied by reductions in LV end diastolic volume. However, LV end diastolic volume increased during expiratory efforts compensating for the reductions observed during inspiratory efforts (48,49). Thus when averaged throughout the apnea during both inspiratory and expiratory efforts, LV end-diastolic volume did not change significantly from control conditions (normal breathing). There was no reduction in end diastolic LVPtm during obstructive apneas. In summary, obstructive apneas did not reduce any measure of LV preload. Furthermore, LV contractility as assessed by measurement of dP/dt, remained constant. Therefore, the fall in stroke volume caused by obstructive apneas could not be attributed either to a decrease in LV preload or to a reduction in LV contractility. Inspiratory efforts during obstructive apneas were accompanied by decreases in LV systolic pressure. However, when averaged over the entire apnea, there was no significant change in LV systolic pressure. Despite this, LVPtm during systole increased because of the negative Pit generated during inspiratory efforts. Remarkably, LV end systolic volume increased throughout the apnea. An increase in LV end systolic volume in the absence of a decrease in cardiac contractility provides
Sleep Apnea and the Heart
585
Figure 2 Beat-to-beat effects of obstructed inspiration on stroke volume in a chronic dog model of obstructive sleep apnea. Preocclusion indicates cardiac cycle immediately preceding obstructed inspiration. During occlusion indicates the first three cardiac cycles during obstructive apneas. Postocclusion represents cardiac cycles immediately after termination of obstructive apneas. Note abrupt decrease in stroke volume at onset of obstructive apneas and abrupt increase in stroke volume upon release of apnea. (From Ref. 48.)
unequivocal evidence of an increase in LV afterload. Accordingly, the fall in stroke volume during obstructive apneas in these dogs can be attributed to an increase in systolic LVPtm due to generation of negative Pit during inspiratory efforts (Fig. 3). Within the first cardiac cycle following termination of obstructive apnea, stroke volume recovered abruptly to baseline (Fig. 2). There was a simultaneous fall in systolic LVPtm, due to an abrupt increase in Pit. After several weeks to months of exposure to OSA, LV ejection fraction decreased significantly, indicating the development of LV systolic dysfunction. These findings are compatible with the results of some studies in humans with normal ventricular function during obstructive apneas and Mueller maneuvers. In patients with OSA, but with normal cardiac function, Tolle et al. (46) observed an initial fall in systolic BP which then remained relatively constant throughout the apnea. However, LV afterload increased and remained elevated throughout the apnea due to the generation of negative Pit which increased LVPtm. Concomitant reductions in stroke volume during obstructive apneas were attributed to the increase in LVPtm and were proportional to the negative Pit generated. Hall et al. (60) made similar observations in healthy subjects while awake during voluntary Mueller maneuvers, which simulated the effects of obstructive apneas. In this study, release of the obstruction was accompanied by an immediate increase in Pit, decrease in
Figure 3 Recordings of absolute left ventricular (LV) pressure, tracheal pressure, and calculated LV transmural (TM) pressure before, during, and after an obstructive apnea in a dog with experimentally induce chronic obstructive sleep apnea. There are marked increases in TM pressure during occluded inspiratory efforts, which are identified by negative swings in LV diastolic pressure and tracheal pressure. Because there is an overall decrease in LV systolic pressure during occluded inspiratory efforts, the rise in LV TM pressure during apnea is due to the generation of exaggerated negative intratracheal (i.e., intrathoracic) pressure. (From Ref. 48.)
Sleep Apnea and the Heart
587
LVPtm and an increase in stroke volume. These findings replicate those of Parker et al. (48) in dogs with chronic OSA. Taken together, these findings strongly suggest, that just as in the chronic canine model of OSA, decreases in stroke volume and cardiac output during obstructive apneas and Mueller maneuvers in humans with normal heart function are due primarily to increases in LV afterload. These increases in LV afterload are a consequence of negative Pit. Conversely, stroke volume and cardiac output recover rapidly after release of airway obstruction in concert with a decrease in afterload due to the sudden increase in Pit. A somewhat different response to obstructive apneas is seen in patients with cardiac disease. Hall et al. (55) found that in patients with CHF, just as in healthy subjects, systolic BP and stroke volume decreased, and LVPtm increased at the onset of Mueller maneuvers due to generation of exaggerated negative Pit and the resultant increase in LVPtm. However, the initial increase in systolic LVPtm during Mueller maneuvers was followed by a decrease due to a progressive and profound fall in systolic BP. By the end of 15-sec Mueller maneuvers, LVPtm had actually fallen below baseline levels. Nevertheless, stroke volume continued to fall progressively throughout the events. Therefore, reductions in stroke volume towards the end of maneuvers could not be attributed to a simultaneous increase in LV afterload, but had to be accounted for either by a decrease in LV preload, or a decrease in contractility, neither of which was assessed. In addition, in another study, these investigators showed that, in patients with heart failure, reductions in stroke volume were more profound and were sustained longer into the immediate post–Mueller maneuver period than in healthy subjects, even though LVPtm fell further (60). Furthermore, in a different population of patients with coronary artery disease, Scharf et al. (61) showed that generation of negative Pit during Mueller maneuvers caused greater reductions in LV ejection fraction in patients with coronary artery disease than in healthy subjects. In summary, through one or more of the above mechanisms, generation of exaggerated negative Pit can induce marked reductions in stroke volume and cardiac output (27,46,62). Because apneas also cause hypoxia and surges in arterial BP, the simultaneous generation of negative Pit appears capable of triggering nocturnal ischemia and acute pulmonary edema that have been reported in some patients with OSA (63–67). The extent to which each of these factors contributes to reductions in cardiac output probably varies over the course of each apnea, and is probably influenced by the presence or absence of coronary artery disease and of underlying myocardial dysfunction. Indeed, as discussed above, patients with cardiac disease should be more susceptible to the adverse hemodynamic effects of obstructive apneas and of negative Pit generated during Mueller maneuvers than subjects without cardiac disease. The most likely explanation for this increased susceptibility is that the diseased myocardium is less capable of compensating for the initial increase in afterload. Accordingly, the observation that generation of negative Pit during Mueller maneuvers has more profound and sustained adverse effects in patients with impaired LV systolic function than in age-matched control subjects should not be surprising (60).
588
Bradley et al.
Intermittent hypoxia during obstructive apneas can adversely affect cardiac performance through several mechanisms. Hypoxia causes pulmonary vasoconstriction, increases PPa and gives rise to the physiologic and clinical consequences described above (2,9,46,50–52,68). Hypoxia can also depress cardiac contractility directly (69) and reduce the rate of relaxation of both ventricles, thus compromising their performance (70). Hypoxia is also a potent stimulator of the sympathetic nervous system (71). This would increase BP and heart rate (HR), which, in turn, would increase metabolic demands of the myocardium in the face of reduced O 2 supply. Acute hypoxia can trigger ischemia in patients with concurrent coronary artery disease (66), which can in turn depress myocardial contractility further. Obstructive apnea is usually terminated by a brief arousal in response to hypoxia, hypercapnia, and ineffectual inspiratory efforts. Arousal from sleep is a form of startle response and, either alone or in concert with other stimuli discussed below, can provoke increases in sympathetic nervous system activity (SNA), BP, and HR (72,73). Consequent increases in myocardial O 2 demand could be another factor, in addition to reduced supply due to hypoxia, that contributes to cardiac ischemia or arrhythmias, particularly in patients with coronary artery disease. In a recent study, the majority of patients referred to a sleep laboratory because of nocturnal angina were found to have OSA (66). Other studies have reported electrocardiographic changes consistent with ischemia in patients with OSA, even in the absence of coronary artery disease (74). Activation of the sympathetic nervous system is an important consequence of obstructive apnea that is elicited by at least five stimuli: hypoxia, hypercapnia, apnea, reduced cardiac output, and arousal from sleep. Sympathetic vasoconstrictive discharge to skeletal muscle is greatest at the termination of airway occlusion (4,62,75,76). The principal hemodynamic consequence is a corresponding surge in BP which occurs just after the peak muscle SNA is reached (75–77). These increases in SNA and systemic BP, combined with reductions in Pit, augment LVPtm, not only during, but also after the termination of apneas. The increase in LV afterload renders such patients susceptible to the development of nocturnal myocardial ischemia (65,66,78,79) and reduced cardiac output (27,47). In addition, OSA has a number of adverse effects on cardiac rhythm that are related to the severity of hypoxia. These include sinus bradycardia, second-degree heart block, and supraventricular and ventricular ectopy and tachycardia (80–82). Patients with underlying coronary artery disease or CHF are probably especially susceptible to these adverse effects (66). There is growing evidence that the acute, repetitive effects of OSA on the cardiovascular system have aftereffects that persist into wakefulness. Daytime muscle SNA and plasma norepinephrine concentrations are higher in such patients than in appropriately matched controls (4,75,83). Although the mechanisms for this sustained sympathetic activation are uncertain, one possible mechanism involves the effects of hypoxia. In a recent study, Morgan et al. (84) demonstrated that shortterm exposure of healthy humans to hypoxia caused an increase muscle SNA that persisted for several minutes after return to normoxia. Another possible mechanism could be an upward resetting of baseline central sympathetic outflow during the awake state due to impairment of baroreflexes. Indirect evidence for this comes from
Sleep Apnea and the Heart
589
patients with CHF and coexisting OSA. In these patients, elimination of OSA by CPAP caused a marked increase in baroreflex sensitivity for heart rate (85), suggesting that baroreflexes were impaired in the baseline state. Such a reduction in baroreflex sensitivity could impair the normal inhibitory influence of baroreceptor stimulation on sympathetic outflow. Acute and sustained sympathetic activation has particularly adverse prognostic implications in patients with coexisting heart failure. Survival in CHF is inversely proportional to cardiac noradrenergic drive (86) and to awake plasma norepinephrine concentrations (87). These adverse prognostic relationships are probably a consequence of the detrimental effects of neurally released and circulating catecholamines on cardiovascular homeostasis, whether at the level of the myocyte (direct catecholamine toxicity or induction of apoptosis), the myocardial beta-receptor complex (number, affinity, or responsiveness to endogenous and exogenous agonists), organ function (altered BP; development of arrhythmias), or functional status of the afflicted patient (88). In addition, because sympathetic activation during sleep arises as a result of apneas and arousals from sleep, not necessarily as a compensatory response to low cardiac output, it may be particularly detrimental to the diseased myocardium. Repetitive obstructive apneas during sleep in dogs with experimentally induced OSA have been shown to cause elevation in BP that are sustained into wakefulness (59). In the same model, chronic OSA led to LV systolic dysfunction as evidenced by a significant reduction in LV ejection fraction, which was also sustained into wakefulness (48). In addition, Hedner and colleagues (89) also found that normotensive patients with OSA had greater LV wall thickness than normotensive subjects without OSA. Furthermore, Malone et al. (3) demonstrated a relationship between OSA and dilated cardiomyopathy in humans with CHF. They further showed that treatment of OSA by CPAP led to significant improvements in LV systolic function (LV ejection fraction increased from 37 ⫾ 4% to 49 ⫾ 5%, P ⬍ .0001) that were not sustained when CPAP therapy was withdrawn. Such findings indicate the potential for OSA to contribute to the development or progression of cardiovascular diseases ranging from hypertension to CHF. They also emphasize the potential to improve cardiovascular outcomes through specific therapy of OSA in patients with coexistant cardiovascular disease.
IV. Mechanisms of Central Sleep Apnea in Association with Cheyne-Stokes Respiration in Congestive Heart Failure Cheyne-Stokes respiration (CSR) is a form of periodic breathing in which apneas and hypopneas alternate with ventilatory periods. As originally described by Cheyne (90), the sine qua non of CSR is the prolonged ventilatory period in which there is a crescendo-decrescendo pattern of tidal volume (VT ). The gradual waxing and waning of ventilation that is almost sinusoidal indicates that CSR is part of a continuum of periodic breathing disorders that arise as a result of oscillations in the chemical stimuli to breathe. The term CSR has been used to describe this abnormal pattern
590
Bradley et al.
of breathing but not to denote any specific underlying etiology. However, recent data from our laboratory (91) confirm that the prolonged hyperpnea with the waxing and waning pattern of VT is a result of a prolonged lung to chemoreceptor circulatory delay and a reduced cardiac output (92). On this basis it is likely that in most patients an element of cardiac dysfunction plays a role in sculpting this abnormal respiratory pattern. In addition, it should be emphasized that it is not possible to determine whether apneas described in the early literature were central or obstructive in nature. Most authors have used the term CSR to describe central apneas alternating with prolonged ventilation periods. However, obstructive apneas have also been described in association with a CSR ventilatory pattern (5,93,94). Therefore, since we will be focusing on central apnea in this section, the term CSR with central sleep apnea (CSR-CSA) will be used throughout. Although CSR had been looked upon as a physiologic curiosity, it is now recognized that CSR-CSA gives rise to clinical problems largely through its effects during sleep (12,19,93,95–97). These effects are similar to those associated with sleep apnea syndromes, and lead to disrupted sleep and its consequences. Hanly and colleagues (98) showed that the sleep latency of patients with CHF and CSR-CSA was significantly shorter than that of CHF patients without this breathing disorder, suggesting that they suffered from hypersomnolence. In addition, they demonstrated that patients with CHF and CSR-CSA had more stage 1 and 2 non–rapid eye movement (NREM) sleep, less rapid eye movement (REM) sleep, and a higher frequency of arousals from sleep than CHF patients without CSR-CSA (98). CSR-CSA is a manifestation of instability of the respiratory control system. This control system instability predisposes to wide fluctuations in arterial blood gas tensions and ventilation. In addition, CSR-CSA has two distinct phases that are determined by different mechanisms: the hyperpneic phase (91,99) and the central apneic phase. We will first discuss those factors involved in the pathogenesis of central apneas. To accomplish this it will be necessary to briefly review some elements of the normal respiratory control system that maintain homeostasis, and then to show how these become disrupted in patients with CHF as summarized in Table 4. Under normal conditions, ventilation is stable and maintains arterial blood gas tensions within narrow limits through a negative feedback circuit. This negative feedback system consists of a central controller that responds to inputs from peripheral and central chemoreceptors which are sensitive to fluctuations in PaO 2 , PaCO 2, and pH, and a plant (the lungs, chest wall, and respiratory muscles), which generates ventilation (100). PaO 2 , PaCO 2, and pH act as negative feedback signals to the central controller. In turn, the central controller maintains blood gas homeostasis by altering its neural output to the respiratory muscles in order to move the chest wall to achieve the appropriate level of ventilation. PaO 2 and PaCO 2 are altered accordingly. Blood gas homeostasis is maintained through certain stabilizing influences inherent in the system. These include maintenance of PaCO 2 well above the threshold for apnea, relatively low gain of the chemoreceptors, a short delay in the transmission of the effects of ventilation on PaO 2 and PaCO 2 to the chemoreceptors (101), rapid correction of deviations in blood gas tensions toward the desired level,
Sleep Apnea and the Heart Table 4
591
Stabilizing and Destabilizing Influences on the Respiratory Control System
Stabilizing mechanisms Normal left ventricular size and filling pressure
Normal peripheral and central chemosenstivity Awake-nonmetabolic drive to breathe present PaCO 2 well above threshold for apnea Stable sleep without arousals
Upper-airway stability with linear response between central drive and ventilation
Normal FRC–large O 2 and CO 2 reservoir in the lungs; damps oscillations in PaO 2 and PaCO 2
Destabilizing mechanisms Increased left ventricular size and filling pressure with pulmonary congestion; stimulation of pulmonary vagal irritant receptors Increased peripheral and central chemosensitivity (tendency to hyperventilate) Sleep onset; nonmetabolic awake drive to breathe abolished; breathing dependent solely on chemical drive Low PaCO 2 close to threshold for apnea Arousals from sleep trigger ventilatory overshoot and reductions in PaCO 2 below apnea threshold Upper airway instability; variable upper airway resistance with nonlinear relation between central drive and ventilation; tendency to under (apnea) and overshoot (hyperventilation) ventilation Low FRC due to pulmonary congestion Reduced O 2 and CO 2 reservoir in lungs Underdamping of oscillations in PaO 2 and PaCO 2
Abbreviations: FRC, functional residual capacity.
a high functional residual capacity acting as a large reservoir of O 2 and CO 2 in the body to damp oscillations in PaO 2 and PaCO 2 during apneas, the nonchemical drive to breathe associated with wakefulness that tends to maintain ventilation even when PaCO 2 is driven below the apnea threshold (102), and stability of central nervous system state that prevents abrupt changes in thresholds and gains of the chemoreceptors. Finally, stability and maintenance of upper-airway patency would allow the central output to the respiratory muscles to be rapidly translated into airflow in a nonfluctuating manner. As a consequence of these mechanisms, under normal circumstances, a nearly optimal balance is struck between stability and speed of response of the control system. Destabilization of these homeostatic mechanisms predisposes to the development of periodic breathing in general, and to CSR-CSA in CHF patients in particular. The key pathophysiologic mechanism leading to CSR-CSA is a fluctuation of PaCO 2 above and below the apneic threshold. A number of destabilizing factors could contribute to this fluctuation in PaCO2. First, a low PaCO 2 close to the apneic threshold could predispose to the development of central apneas. Under this condition, a relatively small increase in ventilation would drive PaCO 2 below threshold and trigger a central apnea (11,13,100,103). Naughton et al. (13) and Hanly and colleagues (14)
592
Bradley et al.
have shown that CHF patients with CSR-CSA have lower PaCO 2 both while awake and while asleep than those without CSR-CSA. The same is true of patients with idiopathic central sleep apnea (ICSA), a disorder that shares many features of CSRCSA but which occurs in the absence of cardiac failure (104,105). Second, elevated chemoreceptor responsiveness (gain) could destabilize the respiratory control system by increasing the tendency to hyperventilate, triggering ventilatory overshoot. Among healthy subjects exposed to hypoxia at high altitude, those with the highest chemoreflex responses are the most prone to developing periodic breathing during NREM sleep (106). Third, shifts in the state of consciousness are likely to destabilize breathing. As one passes from wakefulness to NREM sleep, the waking neural drive to breathe is abolished, and the behavioral control system is quiescent. Therefore, breathing becomes critically dependent on the metabolic control system (100,107). In addition, during NREM sleep, the threshold for a ventilatory response to CO 2 is increased, so that a higher PaCO 2 is necessary to stimulate breathing. If the ambient PaCO 2 during wakefulness is below this new threshold level for sleep, there will be a transient loss of respiratory drive resulting in a central apnea. During the apnea PaCO 2 rises at a rate proportional to metabolic CO 2 production, until it reaches the critical threshold value, and breathing resumes. If sleep becomes firmly established at this point regular breathing follows (105). However, should the central nervous system state shift back momentarily to the awake state, as occurs during arousals from sleep, the increased PaCO 2 level that was present during sleep now represents a state of relative hypercapnia for wakefulness. Accordingly, a period of hyperpnea follows, in accordance with the awake ventilatory response to CO 2 , resulting in the hyperpneic phase of periodic breathing. As long as the central nervous system state continues to fluctuate between wakefulness and sleep, waxing and waning of the waking neural drive results in alternating periods of hyperpnea and apnea until sleep becomes firmly established. Hence, transitions in sleep-wakefulness state are an ideal setting for the generation of respiratory instability and periodic breathing even in normal humans (100). The magnitude of the fluctuations at sleep onset and the determination of an evolution to either a dampening or a perpetuation of periodic breathing over time will depend on several variables including the difference between the waking and sleeping PaCO 2 threshold values and the magnitude of the awake ventilatory responses to chemical stimuli; the presence of factors that would augment ventilatory drive during hyperpnea, such as hypoxia, and on sleep stability (100). In large measure, instability of central nervous system state, and respiration are a consequence of arousals from sleep. Xie and colleagues (104) have shown in patients with ICSA, that central apneas during stage 2 sleep are triggered and propagated by a relative degree of hyperventilation and hypocapnia. The critical role of arousals in sustaining ventilatory overshoot during periodic breathing was demonstrated by the strong relationship between the grade of arousals, and both minute ventilation during hyperpnea and subsequent apnea length. However, arousals did not trigger apnea unless it was associated with an increase in ventilation. Therefore, arousal, through promotion of hyperventilation, appears to facilitate rather than to
Sleep Apnea and the Heart
593
Figure 4 Tidal volume (VT ) and SaO 2 recording from a patient with heart failure and CSRCSA during stage 2 sleep. This is a typical example of how CSR-CSA is triggered by an abrupt increase in VT , which occurred in association with an arousal from sleep (not shown). (From Ref. 13.)
provoke periodic breathing directly. In patients with CSR-CSA, the same principles appear to apply (13). In patients with CHF, an association between CSR-CSA and low PaCO 2 during both wakefulness and NREM sleep has been demonstrated in several reports (13,14,108). Naughton et al. (13) found that CHF patients with CSR-CSA had lower PaCO 2 during wakefulness and NREM sleep than patients without CSR-CSA who had comparable age, LVEF, PaO 2, and lung-to-chemoreceptor circulatory delay. All episodes of CSR-CSA starting during stage 2 sleep were precipitated by hyperventilation most often, but not always, in association with arousals from sleep (Fig. 4). Furthermore, during episodes of CSR-CSA during stage 2 sleep, PtcCO 2 fell on average by 1.5 mm Hg, which mirrored a 23% rise in minute ventilation (VI ) (Fig. 5). In addition, there was a significant inverse correlation between the frequency of apneas and hypopneas and mean PtcCO 2 (r ⫽ ⫺.629, P ⬍ .01). Accordingly,
Figure 5 SaO 2 and transcutaneous PCO 2 (PtcCO 2) during REM and NREM sleep in the same patient as shown in Figure 2. The tracing reads from right to left. Periodic dips in SaO 2 indicate the presence of Cheyne-Stokes respiration with central sleep apnea (CSR-CSA). Note the absence of CSR-CSA during REM sleep. In NREM sleep CSR-CSA starts abruptly in concert with a reduction in PtcCO 2 below 40 mm Hg. PtcCO 2 oscillates and remains below 40 mm Hg throughout CSR-CSA. Later in the night, as PtcCO 2 increases back to 40 mm Hg, CSR-CSA disappears. In addition, SaO 2 is within normal limits prior to the onset of CSR-CSA and dips only marginally during CSR-CSA, indicating that CSR-CSA typically occurs in the absence of hypoxemia. (From Ref. 13.)
594
Bradley et al.
whereas arousal from sleep acts as a critical defense mechanism to terminate apnea and protect from severe asphyxia in OSA, in CSR-CSA arousal can trigger and propagate central apneas, but without any obvious protective effect. Further evidence that hyperventilation and hypocapnia are the major factors that trigger central apneas in CHF patients with CSR-CSA comes from the work of Lorenzi-Filho et al. (109). They showed that in patients with CSR-CSA, an increase in PaCO 2 of 1 to 3 mm Hg induced by administration of a CO 2-enriched gas mixture eliminated central apneas and hypopneas. Similar observations were made by Xie et al. (110) in patients with ICSA. Taken together these data indicate that CSR-CSA has physiological features remarkably similar to ICSA and that, in both cases, central apneas are critically dependent on a reduction in PaCO 2 below the apneic threshold. The mechanisms responsible for nocturnal hypocapnia in patients with CSRCSA have not been fully elucidated. One possible explanation is hypoxia. However, we and others have shown that both awake PaO 2 and mean nocturnal SaO2 in CHF patients with CSR-CSA are within normal limits and are practically identical to those in CHF patients without CSR-CSA (13,14,99). Experiments in animals and patients with CHF demonstrate that increased LV filling pressures and pulmonary congestion are associated with reduced PaCO 2 (111,112). Recently, Tkacova and colleagues (99) found, in a population of patients with CHF due to nonischemic dilated cardiomyopathy, that despite similar LV ejection fraction, LV end diastolic and systolic volumes were twice as high in patients with CSR-CSA as in those without CSR-CSA. In addition, patients with CSR-CSA had a significantly lower PaCO 2 while awake and lower mean PtcCO 2 during stage 2 sleep. Furthermore, the greater the LV end-diastolic volume, the less the rise in PaCO 2 from wakefulness to stage 2 sleep. This relationship suggests that marked LV dilatation in patients with nonischemic dilated cardiomyopathy is associated with a nonchemical drive to breathe that prevents the normal rise in PaCO 2 during the transition from wakefulness to sleep. The most likely explanation for this relationship is that high LV volumes are associated with elevated LV filling pressures. Indeed, a recent paper by Solin et al. (15) demonstrated that CHF patients with CSR-CSA had significantly higher LV filling pressures than did those without CSR-CSA. The resultant pulmonary congestion would stimulate ventilation and reduce PaCO 2 . The potential role of hypoxemia in the pathogenesis of CSR-CSA in heart failure is uncertain. In periodic breathing at high altitude hypoxemia causes hyperventilation and lowers PaCO 2 below the apnea threshold (113). Under these conditions, administration of O 2 suppresses hypoxic drive, allows PaCO 2 to rise above the apneic threshold and thereby abolishes central apneas. The critical dependence of high-altitude periodic breathing on fluctuations in PaCO 2 is further emphasized by the observation that CO 2 inhalation, even in the presence of sustained hypoxia, raises PaCO 2 and abolishes central apneas. However, studies of patients with CHF and CSR-CSA have consistently shown them to be normoxic while awake (13,14,108). Thus hypoxic dips in CSR-CSA are probably the result, rather than the cause, of central apneas. Nevertheless, hypoxic dips during apneas could further the tendency to hyperventilate at the termination of central apneas by amplifying the
Sleep Apnea and the Heart
595
ventilatory response to CO 2 once PaCO 2 rises above the ventilatory threshold (101). Ventilatory overshoot with propagation of CSR-CSA would therefore be facilitated by even mild degrees of apnea-related hypoxia. Dips in SaO 2 would also facilitate arousal from sleep, which in turn contributes to hyperventilation. A number of investigators have studied the effects of supplemental O 2 on CSR-CSA in patients with CHF (114–118). Most but not all of these reported a significant reduction in the total amount of CSR-CSA. For instance, Hanly et al. (116) showed that low flow O 2 administered to patients with CHF reduced the duration of CSR-CSA mainly during stage 1 sleep, with no significant change in severity of CSR-CSA during stage 2, slow-wave, or REM sleep. Administration of O 2 was also associated with more consolidated sleep and a decrease in the number of arousals. Franklin and his colleagues (114) observed that administration of high flow O 2 that rendered patients hyperoxic reduced the frequency of central respiratory events in association with an increase in PCO 2. In contrast, in another study of Franklin et al. (117) and of Lorenzi-Filho and associates (109), administration of low-flow O 2 just sufficient to abolish hypoxic dips in patients with CSR-CSA, had very little or no effect on the frequency of central apneas and hypopneas, nor on PCO 2 . These data suggest that where administration of O 2 alleviates CSR-CSA, it does so by raising PaCO 2 above the threshold for apnea in response to suppression of hypoxic drive. Taken together, these data are consistent with the concept that hypoxia may play a role in aggravating, but is probably not the major determinant of, CSR-CSA in patients with CHF. Increased ventilatory responsiveness to chemical stimuli is another factor that has been implicated in promoting and perpetuating CSR-CSA (101,119,120). Javaheri et al. (121) recently demonstrated that CHF patients with CSR-CSA have higher central chemoresponsiveness to CO 2 than CHF patients without CSR-CSA. Wilcox et al. (119) made similar observations in CHF patients with CSR-CSA. In patients with ICSA, a disorder whose pathogenesis is similar to CSR-CSA (91), both peripheral and central chemoresponsiveness are increased and are related to a lower than normal PaCO 2 (104). However, peripheral chemosensitivity has not yet been tested and compared in CHF patients with and without CSR-CSA. Nevertheless, LorenziFilho et al. (109) found that central apneas in CSR-CSA were triggered by reductions in PaCO 2 that appeared to be detected at the peripheral rather than the central chemoreceptors. In addition, models of periodic breathing predict that increased peripheral chemosensitivity would be more likely to predispose to respiratory instability than would increased central chemosensitivity. This is because the cycle length of most forms of periodic breathing is more in keeping with the relatively short delay in transmission of the stimulatory effects of a change in PCO 2 in the lung to the carotid body chemoreceptors than to the central chemoreceptors. The response time of the central chemoreceptors to a similar change in PCO 2 is more prolonged owing to the buffering influence of cerebral spinal fluid on brainstem pH (101,109,122,123). Enhanced chemosensitivity of the peripheral and central chemoreceptors may also impair baroreceptor function and sensitize the sympathetic nervous system. In patients with CHF, augmented peripheral chemosensitivity is associated with blunting of baroreceptor sensitivity (124). In addition, suppression of peripheral chemore-
596
Bradley et al.
ceptor activity by administration of O 2 in patients with CHF attenuates periodic breathing and reduces urinary norepinephrine levels and corresponding very low frequency oscillations in BP and HR, which are markers of sympathetic activation (118,125). These data suggest that enhanced peripheral chemoreceptor responsiveness plays a role in the pathogenesis of periodic breathing, baroreceptor function impairment, and sympathetic activation. Recently, Sun and colleagues (126) made the intriguing observation that induction of CHF in rabbits by rapid ventricular pacing caused an increase in peripheral sensitivity to hypoxia, in association with increased renal SNA. However, the sensitivity of the central chemoreceptors was not affected. These data indicate that the development of heart failure can upregulate carotid chemoreceptors. Whether this accentuates SNA or vice versa has yet to be determined. Indeed, it has been shown that adrenergic stimulation of the peripheral chemoreceptors stimulates ventilation (127). Nevertheless, Sun and colleagues’ findings demonstrate a strong interaction between the pathological state of heart failure, the peripheral (and possibly the central) chemoreceptors and the sympathetic nervous system. They emphasize the need for further exploration of the mechanisms underlying these intricate pathophysiological interactions. Augmented gain of the chemoreceptors destabilize the respiratory control system by making it prone to ventilatory overshoot (101,122). Whether increases in chemoresponsiveness in CHF patients with CSR-CSA is primary or secondary to pulmonary edema, remains uncertain. However, two observations strongly suggest that such increased chemosensitivity can be induced by the heart failure state. The first is that pulmonary congestion can increase ventilation and lower PaCO 2 by stimulating unmyelinated pulmonary vagal afferents (112,128). As indicated above, development of cardiac failure can cause increased carotid body chemosensitivity (126). It is important to note, however, that increased respiratory drive by itself would not cause periodic breathing, but would only tend to increase ventilation and lower PaCO 2. For periodic breathing to arise, another source of instability is required. Generally, instability is precipitated either by a sudden change in state which alters the slope and set points of ventilatory responses (129) or a large breath or breaths due to sighing or arousal from sleep, which cause ventilatory overshoot (13,105). Furthermore, in order for periodic breathing to be perpetuated, these destabilizing influences must recur regularly. If they do not, then periodic breathing eventually dampens (105). Upper-airway instability may also play a role in the pathogenesis of CSRCSA. Alex et al. (130) described upper-airway occlusion at the onset and at the end of central apneas in patients with CHF. Instability of upper-airway resistance could, at least theoretically, promote the development of CSR-CSA. If upper-airways resistance increases as ventilation decreases during the decrescendo phase of the hyperpneic portion of CSR-CSA, there will be a tendency to cause an undershoot of ventilation (131). The occasional occluded breath at the onset of central apneas during CSR-CSA (130), as shown in Figure 2, is compatible with this possibility. On the other hand, decreasing resistance as ventilation is increasing during the crescendo phase will facilitate ventilatory overshoot, rapidly driving PaCO 2 down and setting up conditions for posthyperventilation apneas. In addition, it is possible that
Sleep Apnea and the Heart
597
upper-airway collapse itself can reflexively precipitate central apneas (132). This suggests an important interaction between upper-airway and central controller instability in the pathogenesis of some cases of CSR-CSA. Furthermore, patients with ICSA, who share many of the pathophysiologic feature of CSR-CSA (104,105,110), have greater upper-airway compliance and lung volume–related change in pharyngeal caliber than control subjects (133). These properties are similar to those in patients with OSA (134,135). It has also been recognized that CSR-CSA is more prominent when moving from upright to supine (136). This shift is associated with an increase in venous return to the heart and with narrowing of the upper airway (137). It is noteworthy in this respect that CPAP, which dilates and stabilizes the upper airway (137,138), has been shown to alleviate both ICSA and CSR-CSA (17,96,139). Although CPAP has many other effects that could damp periodic breathing, such as lung inflation and augmentation of cardiac output, stabilization of the upper airway may be an additional factor promoting abolition of central apneas in these conditions. Even though there is no evidence for upper-airway occlusion in most cases of CSR-CSA (95), this does not preclude a role for upper-airway instability in the pathogenesis of some cases of CSR-CSA. It is possible that the degree to which upper-airway instability contributes to the pathogenesis of CSRCSA will vary from one patient to the next. CHF patients have a low functional residual capacity, which is further reduced by moving from the upright to the supine position. A large functional residual capacity acts as a large reservoir of O 2 and CO 2 in the body and damps oscillations in PaO 2 and PaCO 2 that would occur during apneas (122,123). Therefore, reductions in functional residual capacity decrease lung O 2 and CO 2 reservoirs and allow greater reductions in PaO 2 and greater increases in PaCO 2 during apneas (122,123). This could contribute to instability of the respiratory control system. However, Naughton et al. (13) and Javaheri and colleagues (140) have shown that lung volume in CHF patients with CSR-CSA do not differ from those in patients without CSR-CSA. Thus the role of reduced lung volume in the pathogenesis of CSR-CSA remains uncertain. Prolonged circulation time causing delays in transmitting changes in arterial blood gas tensions within the lungs to the chemoreceptors could theoretically destabilize the respiratory control system. It could do so by changing a negative feedback into a positive feedback system such that maximum feedback stimulation occurs at a time of high ventilatory output (122,141). In support of this theory, Guyton et al. (141) induced CSR in sedated dogs by inserting a length of tubing between the heart and brain to prolong the transit time from the lungs to the chemoreceptors. However, CSR was achieved only when the circulatory delay was a few minutes in duration, far exceeding that seen in patients with CHF. There is now a body of evidence indicating that prolonged circulatory delay is probably not a critical factor predisposing to CSR-CSA. In humans, the circulatory delay for a given chemical stimulus to reach the carotid body from the lungs can be estimated by determining the time from the end of an apnea until the maximum dip in SaO 2 detected by an oximeter on the ear (which is in close proximity to the carotid body). This lung-to-ear circulation time is inversely proportional to the stroke volume and cardiac output in both patients with normal and with abnormal heart
598
Bradley et al.
Figure 6 Recording of a central apnea during stage 2 sleep in a patient with idiopathic central sleep apnea. Apnea length (AB) is 18 sec, hyperpnea length (BD) is 7 sec, total cycle length (AD) is 25 sec, and lung-to-ear circulation time (LECT) from the end of the apnea until the maximum dip in SaO 2 is 8 sec. LECT is short, in keeping with normal cardiac function. Abbreviations as per Figure 1. (From Ref. 91.)
Figure 7 Recording of a central apnea and hyperpnea during stage 2 sleep from a patient with congestive heart failure. It exhibits a crescendo-decrescendo pattern of VT during hyperpnea that is typical of CSR-CSA. Compared to the patient with idiopathic central sleep apnea (Fig. 4), LECT (BC ⫽ 26 sec), hyperpnea length (BD ⫽ 46 sec), and total cycle length (AD ⫽ 65 sec) are substantially longer in keeping with lower cardiac output related to heart failure. However, apnea length (AB ⫽ 21 sec) is similar. Abbreviations as in Figure 1. (From Ref. 91.)
Sleep Apnea and the Heart
599
function. Hall et al. (91) compared patients with ICSA, whose cardiac function and lung-to-ear circulation time are within normal limits, to CHF patients with CSRCSA. They found that, despite having higher stroke volumes and shorter lung-toear circulation time than the CHF patients with CSR-CSA, those with ICSA had the same low and fluctuating PaCO 2 and high frequency of central apneas during sleep. Moreover, in both disorders, there was evidence of positive feedback in that the maximum hypoxic stimulus occurred at the time of greatest ventilatory output. These data indicate that central apneas in patients with ICSA and CSR-CSA are associated with hypocapnia and fluctuations in PaCO 2 below and above the apnea threshold, but are not related to the degree of circulatory delay. A number of investigators have also found no significant differences in lung-to-ear circulation time, LVEF, or cardiac output between CHF patients with and without CSR-CSA (13,15,18,19,142). Hall and colleagues (91) also observed that the longer periodic breathing cycle length in CHF patients with CSR-CSA was related to a longer lung-to-ear circulation time than in the patients with ICSA (Figs. 6, 7). The relationship between lung-to-
Figure 8 Panels A and B demonstrate the significant direct relationships of periodic breathing cycle length and hyperpnea length to LECT, respectively (P ⬍ .001), in patients with idiopathic central sleep apnea (open circles), whose cardiac function is normal, and heart failure patients with CSR-CSA (closed circles). Panel C shows that the rate of oxyhemoglobin desaturation is inversely related to LECT (P ⬍ .001). However, panel D demonstrates that apnea length is not related to LECT (P ⬎ .15). Abbreviations as in Figure 4. (From Ref. 91.)
600
Bradley et al.
ear circulation time and cycle length was found to be due to the correlation of lungto-ear circulation time and hyperpnea length, whereas lung-to-ear circulation time was not related to apnea length (Fig. 8). The characteristic ‘‘sculpting’’ and prolongation of the hyperpnea in CHF patients was due to their longer lung-to-ear circulation time, which in turn was inversely proportional to their lower stroke volumes and cardiac outputs. Therefore, rather than initiating periodic breathing and central apneas, circulatory delay appears to determine hyperpnea length and, secondarily, cycle length once periodic breathing with central apnea has been established. However, it does not affect apnea length, which is influenced by the degree of preceding hyperventilation and hypocapnia (105,143). V.
Pathophysiologic Consequences of Cheyne-Stokes Respiration with Central Sleep Apnea in Congestive Heart Failure
Unlike OSA, which probably contributes to the development of CHF, CSR-CSA appears to arise as a result of CHF, as suggested by Table 5. The question that arises then is: Once established, does CSR-CSA constitute an additional burden, analogous to OSA, on the cardiovascular system and contribute to a deterioration of the LV function? Indeed, there is a growing body of evidence suggesting that CSR-CSA is a marker of poor prognosis in patients with CHF. For example, in an uncontrolled retrospective study, Findley and colleagues (19) reported that patients with CHF
Table 5 Clinical and Pathophysiologic Features of CheyneStokes Respiration with Central Sleep Apnea (CSR-CSA) in Patients with Congestive Heart Failure Prevalence 35% to 45% Clinical features Paroxysmal nocturnal dyspnea Disrupted sleep; insomnia Daytime hypersomnolence and fatigue Risk factors Male sex Severe cardiac dysfunction Low daytime and overnight PaCO 2 Increased left ventricular volumes and filling pressures Atrial fibrillation Pathophysiologic consequences Periodic elevations in nocturnal blood pressure and heart rate Increased sympathetic nervous system activity Ventricular arrhythmias Increased mortality risk
Sleep Apnea and the Heart
601
who also suffered from CSR-CSA during sleep had a higher mortality rate than patients without CSR-CSA. Hanly et al. (18) prospectively followed a group of patients with stable CHF, nine of whom had CSR-CSA and seven of whom did not. Despite comparable LV ejection fraction the combined rate of mortality and heart transplantation was significantly higher in the CSR-CSA group. More recently, Lanfranchi and associates (121) also found a higher mortality rate among CHF patients who had CSR-CSA than among those who did not. Furthermore, they found that the mortality rate was directly related to the frequency of central apneas and hypopneas, even when they controlled for cardiac size. These data suggest that CSRCSA itself may accelerate disease progression in patients with heart failure. In contrast to obstructive apneas, no inspiratory efforts are made during central apneas (96). On the other hand, a substantial degree of negative intrathoracic pressure can be generated during hyperpnea. This inspiratory effort is probably one factor provoking arousal from sleep (144–146) and paroxysmal nocturnal dyspnea in patients with CHF (10,96,97). BP and HR oscillate in concert with CSR-CSA cycles, very much as they do during OSA (117,147): peaks occur during the hypernea and troughs during apnea. The mechanisms mediating these oscillations have not yet been determined. They could be related to the same mechanisms that have been implicated in OSA, including hypoxia and arousals from sleep, both of which can stimulate SNA. However, Franklin and colleagues (117) found that O 2 administration, at a sufficient flow rate to abolish dips in SaO 2 , slightly reduced the frequency of central apneas but did not significantly influence BP or HR oscillations during CSR-CSA. These data indicate that mechanisms other than hypoxic dips are involved in precipitating these surges in BP and HR during CSR-CSA. One possibility is that periodic fluctuations in ventilation entrain oscillations in BP and HR. To test this hypothesis, Lorenzi-Filho et al. (148) had healthy subjects perform voluntary periodic breathing with central apneas during wakefulness, in the absence of hypoxia and arousals from sleep. They found that periodic breathing did entrain BP and HR oscillations at precisely the periodic breathing frequency. In addition, the magnitude of the BP and HR oscillations was proportional to the magnitude of the ventilatory oscillations. They concluded that fluctuations in ventilation can precipitate fluctuations in BP and HR either through coactivation of respiratory and cardiovascular sympathetic neurons in the medulla, or through hemodynamic alterations related to the influence of ventilation on intrathoracic pressure, preload, afterload, and cardiac output. Regardless of the exact mechanisms, once established, CSR-CSA promotes cyclic increases in BP and HR in concert with the ventilatory cycle (117,147). These exaggerated changes in myocardial oxygen demand and loading conditions on the failing heart are likely to contribute to disease progression and poor prognosis of CHF patients with CSR-CSA. As with OSA, CSR-CSA is characterized by sleep fragmentation due to arousals from sleep. Although arousals can occur at the termination of apneas, they frequently occur several breaths into the ventilatory period. This suggests that stimulation of ventilation by these chemical stimuli precedes stimulation of arousal, probably because the threshold for the former is lower than for the latter (107). When arousals occur after the resumption of breathing, they appear not to act as a
602
Bradley et al.
defense mechanism to prevent asphyxia, as is the case in OSA. Indeed, arousals under these conditions may very well act as a pathologic phenomenon that helps to propagate CSR-CSA by provoking sleep state instability and hyperventilation. Arousals probably arise from a combination of mild hypoxia and the effort of breathing, particularly when arousals occur after resumption of ventilation. Sleep fragmentation by arousals is probably an important cause of excessive daytime sleepiness and fatigue in patients with CHF and CSR-CSA (17,96,98). Both hypoxia and arousals from sleep stimulate central sympathetic outflow (4,72,75). Overnight urinary norepinephrine concentrations are markedly higher in CHF patients with than in those without CSR-CSA and are directly related to the frequency of arousals from sleep and degree of apnea-related hypoxia, but not to LV ejection fraction (149). These data strongly suggest, first, that CSR-CSA is an additional independent stimulus to sympathetic activation in certain patients with CHF, and second, that the increased SNA in these patients is not simply a compensatory response to low LV ejection fraction, but is a direct consequence of this sleep apnea disorder. Thus the magnitude of sympathetic activation is greater than that required for cardiovascular stability, and therefore represents pathologic sympathoexcitation. These changes transcend the sleeping state. In the same study, we observed that daytime plasma norepinephrine concentration was also higher in those with CSR-CSA, and was directly related to the frequency of arousals from sleep and the degree of apnea-related hypoxia (149). Higher nocturnal and daytime catecholamine concentrations have the potential to aggravate myocardial dysfunction and likely contribute to the increased risk of death reported in patients with CHF who exhibit CSR-CSA (18,19). Thus, CSR-CSA may accelerate a vicious pathophysiologic cycle involving the cardiovascular, respiratory, and autonomic nervous systems. Recently, Javaheri and colleagues (108) found that CHF patients with hypocapnia (PaCO 2 ⱕ 35 mm Hg) had a higher prevalence of central sleep apnea than did those whose PaCO 2 was ⬎ 35 mm Hg. In addition, they showed that hypocapnic patients had a higher rate of ventricular tachycardia than the eucapnic patients. The underlying cause of this relationship is unknown. It could be that hypocapnia and alkalosis directly contribute to the frequency of arrhythmias. On the other hand, it could be that the mild hypoxic dips, arousals from sleep, sympathetic activation, and elevations in BP associated with CSR-CSA could trigger ventricular arrhythmias. For instance, Findley and colleagues (150) reported one patient with CHF in whom the timing of ectopic beats coincided with the CSR-CSA ventilatory cycle and dips in SaO 2 . On the other hand, CHF patients with CSR-CSA have larger left ventricles than those without CSR-CSA (99). Since ventricular dilatation is associated with an increased likelihood of arrhythmias (151), the link between CSR-CSA (and/or low PaCO 2 ) with ventricular arrhythmias could be one of association rather than of causality. Because one-third of the patients with CHF die of sudden death, presumably related to cardiac arrhythmias (152), this issue deserves further investigation. A detailed discussion of the treatment of CSR-CSA in patients with CHF is beyond the scope of this article. Readers are referred elsewhere for a more detailed
Sleep Apnea and the Heart
603
review of this topic (153). Briefly, since CSR-CSA probably arises from CHF, the first approach to therapy is to optimize the medical therapy of CHF (154). Failing that, there are a number of other therapeutic options. The most extensively tested intervention is CPAP. Although it may not alleviate CSR-CSA on short-term exposure of one or several days (155–157), when used nightly over 1 to 3 months, it has been shown to alleviate CSR-CSA; increase LVEF; reduce mitral regurgitation, atrial natriuretic peptide, and both urinary and plasma norepinephrine levels; improve quality of life; and reduce hospital admissions (17,96,149,158,159). Most importantly, recently published data from a small randomized trial conducted in a single center suggest that long-term treatment with CPAP can reduce death and cardiac transplant rates among CHF patients with CSR-CSA who are compliant with therapy (160). However, larger, multicenter trials will be required to provide more definitive evidence for such a beneficial effect. Oxygen administration has been shown to significantly reduce the severity of CSR-CSA, reduce overnight urinary norepinephrine levels, and cause a modest increase in peak O 2 consumption during graded exercise in randomized trials of 1 to 4 weeks’ duration (61,114–117). However, it has not been shown to improve direct measures of cardiac function or quality of life. Finally, theophylline has been shown to reduce the severity of CSR-CSA over 5 days, but has not been shown to improve cardiac function, neurohumoral activity or quality of life (140). Larger, longer-term randomized trials will be required to determine which, if any, of these interventions are effective for the long-term management of CHF patients with CSR-CSA.
VI. Summary In this chapter, we have reviewed evidence for a link between sleep apnea disorders and impairment of RV and LV function. With respect to RV dysfunction, the major pathway by which this can develop is hypoxic pulmonary vasoconstriction, due to the combined effects of obstructive apneas and underlying lung disease. With respect to LV dysfunction, two primary pathways, common to both OSA and CSR-CSA, by which this might develop are the generation of negative intrathoracic pressure and the activation of the sympathetic nervous system causing elevations in blood pressure. Because the failing heart is exquisitely sensitive to both stimuli (88,163), these pathophysiological consequences of sleep apnea are likely to be most severe in patients with LV dysfunction. The consensus in the literature is that OSA can contribute to the development of RV dysfunction. There is also evidence that OSA can play a role in the development or aggravation of LV heart failure. However, because of the limited number of studies examining this potential relationship, a consensus on this question has not yet been reached. Because of the obvious clinical importance of this question, more research needs to be directed at the acute and chronic effects of OSA, and of its treatment, on LV function. There is general agreement that CSR-CSA is a consequence of CHF, and that the cause of central apneas is fluctuations in PaCO 2 below the apnea threshold. However, controversy remains as to whether CSR-CSA is simply a consequence
604
Bradley et al.
of poor cardiac function, or whether, once established, it participates in a vicious pathophysiological cycle that leads to progression of heart failure. At the moment, there is no consensus as to whether specific therapy of CSR-CSA can lead to improvement in the heart failure syndrome. Nevertheless, there are some promising data on the latter point that provide a strong rationale for the conduct of well-designed, controlled clinical trials of therapy for CSR-CSA in patients with CHF.
References 1. Daly MDB. Interactions between respiration and circulation. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiology, 3rd ed. Bethesda: American Physiological Society, 1986:529–594. 2. Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Dement WC. Hemodynamics in sleep-induced apnea. Studies during wakefulness and sleep. Ann Intern Med 1976; 85:714–719. 3. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991; 338:1480–1484. 4. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897–1904. 5. Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998; 96:2269–2275. 6. Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Dement WC. Sleep-induced apnea syndrome. Prevalence of cardiac arrhythmias and their reversal after tracheostomy. Am J Med 1977; 63:348–358. 7. Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annu Rev Med 1976; 27:465–484. 8. Stradling JR. Sleep apnoea and systemic hypertension. Thorax 1989; 44:984–989. 9. Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H, Phillipson, EA. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131:835–839. 10. Bradley TD, Floras JS. Pathophysiologic and therapeutic implications of sleep apnea in congestive heart failure. J Card Fail 1996; 2:223–240. 11. Bradley TD. Right and left ventricular functional impairment and sleep apnea. Clin Chest Med 1992; 13:459–479. 12. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle, GA. Sleep apnea in 81 ambulatory male patients with stable heart failure. Circulation 1998; 97:2154–2159. 13. Naughton M, Benard D, Tam A, Rutherford R, Bradley TD. Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure. Am Rev Respir Dis 1993; 148:330–338. 14. Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure. Relationship to arterial PCO 2. Chest 1993; 104:1079–1084. 15. Solin P, Bergin P, Richardson M, Kaye DM, Walters HE, Naughton MT. Influence of pulmonary capillary wedge pressure on central sleep apnea in heart failure. Circulation 1999; 99:1574–1579. 16. Javaheri S, Parker TJ, Wexler L, Michaels SE, Stanberry E, Nishyama H, Roselle, GA. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med 1995; 122:487–492. 17. Naughton MT, Liu PP, Benard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995; 151:92–97.
Sleep Apnea and the Heart
605
18. Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996; 153:272– 276. 19. Findley LJ, Zwillich CW, Ancoli-Israel S, Kripke D, Tisi G, Moser KM. Cheyne-Stokes breathing during sleep in patients with left ventricular heart failure. South Med J 1985; 78:11–15. 20. Bonsignore MR, Marrone O, Insalaco G, Bonsignore G. The cardiovascular effects of obstructive sleep apnoeas: analysis of pathogenic mechanisms. Eur Respir J 1994; 7:786– 805. 21. Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Eur Physiopathol Respir 1972; 8:1159–1172. 22. Marrone O, Bonsignore MR, Romano S, Bonsignore G. Slow and fast changes in transmural pulmonary artery pressure in obstructive sleep apnoea. Eur Respir J 1994; 7:2192– 2198. 23. Schroeder JS, Motta J, Guilleminault C. Hemodynamic studies in sleep apnea. In: Guilleminault C, Dement WC, eds. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978:177– 196. 24. Fishman AP. Chronic cor pulmonale. Am Rev Respir Dis 1976; 114:775–794. 25. Laks L, Bronwyn L, Grunstein RR, Sullivan CE. Pulmonary artery pressure response to hypoxia in sleep apnea. Am J Respir Crit Care Med 1997; 155:193–198. 26. Parish JM, Shepard JW Jr. Cardiovascular effects of sleep disorders. Chest 1990; 97:1220– 1226. 27. Buda AJ, Schroeder JS, Guilleminault C. Abnormalities of pulmonary artery wedge pressures in sleep-induced apnea. Int J Cardiol 1981; 1:67–74. 28. Buda AJ, Pinsky MR, Ingels NBJ, Daughters GT, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 301:453–459. 29. Katz AM. Cardiomyopathy of overload: a major determinant of the progress in congestive heart failure. N Engl J Med 1990; 322:100–110. 30. Sarnof S. Myocardial contractility as described by Starling’s law of the heart. Physiol Rev 1955; 35:107–122. 31. Nattie EE, Bartler DJ, Johnson K. Pulmonary hypertension and right ventricular hypertrophy caused by intermittent hypoxia and hypercapnia in the rat. Am Rev Respir Dis 1978; 118:653–657. 32. Fletcher EC, Schaaf JW, Miller J, Fletcher JG. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987; 135:525– 533. 33. Weitzenblum E, Krieger J, Apprill M, Vallee E, Ehrhart M, Ratomaharo J, Oswald M, Kurtz D. Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988; 138:345–349. 34. Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:1364–1368. 35. Bradley TD, Rutherford R, Lue F, Moldofsky H, Grossman RF, Zamel N, Phillipson, EA. Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis 1986; 134:920–924. 36. Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med 1985; 6:651–661. 37. Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995; 151:82–86. 38. Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest 1996; 109:380–386. 39. Laks L, Lehrhaft B, Grunstein RR, Sullivan CE. Pulmonary hypertension in obstructive sleep apnoea. Eur Respir J 1995; 8:537–541. 40. Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997; 157:2483–2487.
606
Bradley et al.
41. Sanner BM, Konermann M, Sturm A, Muller HJ, Zidek W. Right ventricular dysfunction in patients with obstructive sleep apnoea syndrome. Eur Respir J 1997; 10:2079–2083. 42. Berthon-Jones M, Sullivan CE. Time course of change in ventilatory response to CO 2 with long-term CPAP therapy for obstructive sleep apnea. Am Rev Respir Dis 1987; 135:144– 147. 43. Sullivan CE, Berthon-Jones M, Issa FG. Remission of severe obesity-hypoventilation syndrome after short term treatment during sleep with nasal continuous positive airway pressure. Am Rev Respir Dis 1983; 128:177–181. 44. Sullivan CE, Issa FG, Saunders NA. Pathophysiology of sleep apnea. In: Saunders NA, Sullivan CE, eds. Sleep and Breathing. New York: Marcel Dekker, 1984:299–363. 45. Sin D, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160:1101–1106. 46. Tolle FA, Judy WV, Yu PL, Markand ON. Reduced stroke volume related to pleural pressure in obstructive sleep apnea. J Appl Physiol 1983; 55:1718–1724. 47. Garpestad E, Parker JA, Katayama H, Lilly J, Yasuda T, Ringler J, Strauss HW, Weiss JW. Decrease in ventricular stroke volume at apnea termination is independent of oxygen desaturation. J Appl Physiol 1994; 77:1602–1608. 48. Parker JD, Brooks D, Kozar LF, Render-Teixeira CL, Horner RL, Bradley TD, Phillipson EA. Acute and chronic effects of airway obstruction on left ventricular performance. Am J Respir Crit Care Med 1999; 160:1888–1896. 49. Schneider H, Schaub CD, Andreoni KA, Schwartz AR, Smith PL, Robotham JL, O’Donnell CP. Systemic and pulmonary hemodynamic responses to normal and obstructed breathing during sleep. J Appl Physiiol 1997; 83:1671–1680. 50. Scharf SM, Graver LM, Balaban K. Cardiovascular effects of periodic occlusions of the upper airways in dogs. Am Rev Respir Dis 1992; 146:321–329. 51. Robotham JL, Rabson J, Permutt S, Bromberger-Barnea B. Left ventricular hemodynamics during respiration. J Appl Physiol 1979; 47:1295–1303. 52. Peters J, Fraser C, Stuart RS, Baumgartner W, Robotham JL. Negative intrathoracic pressure decreases independently left ventricular filling and emptying. Am J Physiol 1989; 257:H120–H131. 53. Shiomi T, Guilleminault C, Stoohs R, Scnittger I. Leftward shift of the interventricular septum and pulsus paradoxus in obstructive sleep apnea syndrome. Chest 1991;100:894– 902. 54. Virolainen J, Ventila M, Turto H, Kupari M. Effect of negative intrathoracic pressure on left ventricular pressure dynamics and relaxation. J Appl Physiol 1995; 79:455–460. 55. Hall MJ, Ando SI, Floras JS, Bradley TD. Magnitude and time course of the hemodynamic responses to Mueller maneuvers in patients with congestive heart failure. J Appl Physiol 1998; 85:1476–1484. 56. Huberfeld S, Genovese J, Tarasiuk A, Scharf SM. Effects of CPAP on pericardial pressure and respiratory system mechanics in pigs. Am J Respir Crit Care Med 1995; 152:142– 147. 57. Scharf SM, Graver LM, Khilnani S, Balaban K. Respiratory phasic effects of inspiratory loading on left ventricular hemodynamics in vagotomized dogs. J Appl Physiol 1992; 73: 995–1003. 58. Naughton MT, Rahman A, Hara K, Floras JS, Bradley TD. Effects of continuous positive airway pressure on intrathoracic and left ventricular transmural pressure in congestive heart failure. Circulation 1995; 91:1725–1731. 59. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997; 99:106–109. 60. Hall MJ, Ando S, Senn B, Wong A, Fitzgerald FS, Floras JS, Bradley TD. Sustained hemodynamic impairment after simulated obstructive apneas in congestive heart failure. Am J Respir Crit Care Med 1996; 153(part 2):A125. 61. Scharf SM, Bianco JA, Tow DE, Brown R. The effects of large negative intrathoracic pressure on left ventricular function in patients with coronary artery disease. Circulation 1981; 63:871-875.
Sleep Apnea and the Heart
607
62. Morgan BJ, Denahan T, Ebert TJ. Neurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea. J Appl Physiol 1993; 74:2969–2975. 63. Loui WS, Blackshear JL, Fredrickson PA, Kaplan J. Obstructive sleep apnea manifesting as suspected angina: report of three cases. Mayo Clin Proc 1994; 69:244–248. 64. Chaudhary BA, Nadimi M, Chaudhary TK, Speir WA. Pulmonary edema due to obstructive sleep apnea. South Med J 1984; 77:499-501. 65. Chan HS, Chiu HF, Tse LK, Woo KS. Obstructive sleep apnea presenting with nocturnal angina, heart failure, and near-miss sudden death. Chest 1991; 99:1023–1025. 66. Franklin KA, Nilsson JB, Sahlin C. Sleep apnoea and nocturnal angina. Lancet 1995; 345: 1085–1087. 67. Chaudhary BA, Ferguson DS, Speir WA. Pulmonary edema as a presenting feature of sleep apnea syndrome. Chest 1982; 82:122-124. 68. Stoohs R, Guilleminault C. Cardiovascular changes associated with obstructive sleep apnea syndrome. J Appl Physiol 1992; 72:583–589. 69. Kusuoka H, Weisfeldt ML, Zweier JL, Jacobus WE, Marban E. Mechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of maximal Ca 2⫹-activated force by inorganic phosphate. Circ Res 1986; 59:270–282. 70. Cargill RI, Kiely DG, Lipworth BJ. Adverse effects of hypoxaemia on diastolic filling in humans. Clin Sci 1995; 89:165-169. 71. Somers VK, Mark AL, Zavala DC, Abboud FM. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol 1989; 67:2101– 2106. 72. Hornyak M, Cejnar M, Elam M, Matousek M, Wallin BG. Sympathetic muscle nerve activity during sleep in man. Brain 1991; 114:1281–1295. 73. Morgan BJ, Crabtree DC, Puleo DS, Badr MS, Toiber F, Skatrud JB. Neurocirculatory consequences of abrupt change in sleep state in humans. J Appl Physiol 1996; 80:1627– 1636. 74. Hanly P, Sasson Z, Zuberi N, Lunn K. ST-segment depression during sleep in obstructive sleep apnea. Am J Cardiol 1993; 71:1341–1345. 75. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens 1988; 6(suppl):S529-S531. 76. Somers VK, Dyken ME, Skinner JL. Autonomic and hemodynamic responses and interactions during the Mueller maneuver in humans. J Auton Nerv Syst 1993; 44:253–259. 77. Weiss JW, Remsburg S, Garpestad E, Ringler J, Sparrow D, Parker JA. Hemodynamic consequences of obstructive sleep apnea. Sleep 1996; 19:388–397. 78. Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in men. Lancet 1990; 336:261–264. 79. Galatius-Jensen S, Hansen J, Rasmussen V, Bildsoe J, Therboe M, Rosenberg J. Nocturnal hypoxaemia after myocardial infarction: association with nocturnal myocardial ischaemia and arrhythmias. Br Heart J 1994; 72:23–30. 80. Shepard JW Jr. Hypertension, cardiac arrhythmias, myocardial infarction, and stroke in relation to obstructive sleep apnea. Clin Chest Med 1992; 13:437–458. 81. Shepard JW Jr, Garrison MW, Grither DA, Dolan GF. Relationship of ventricular ectopy to oxyhemoglobin desaturation in patients with obstructive sleep apnea. Chest 1985; 88: 335–340. 82. Millar WP. Cardiac arrhythmias and conduction disturbances in the sleep apnea syndrome. Am J Med 1982; 73:317–321. 83. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgran J, Wallin BJ. Augmented resting sympathetic nerve activity in awake patients with obstructive sleep apnea. Chest 1993; 103:1763– 1768. 84. Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol 1995; 79:205–213. 85. Tkacova R, Dajani HR, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Continuous positive airway pressure improves nocturnal baroreflex sensitivity of patients with heart failure and obstructive sleep apnea. J Hypertens 2000; 18:1257–1262. 86. Kaye DM, Lambert GM, Lefkovits J, Morris M, Jennings G, Esler MD. Neurochemical
608
87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110.
Bradley et al. evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J Am Coll Cardiol 1994; 23:570-578. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with congestive heart failure. N Engl J Med 1984; 311:819–823. Daly PA, Sole MJ. Myocardial catecholamines and the pathophysiology of heart failure. Circulation 1990; 82:I35-I43. Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea. J Hypertens 1990; 8:941–946. Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted to fat. Dublin Hospital Reports 1818; 2:216-223. Hall MJ, Xie A, Rutherford R, Ando S, Floras JS, Bradley TD. Cycle length of periodic breathing in patients with and without heart failure. Am J Respir Crit Care Med 1996; 154:376–381. Lange RL, Hecht HH. The mechanism of Cheyne-Stokes respiration. J Clin Invest 1962; 41:42–52. Dowdell WT, Javaheri S, McGinnis W. Cheyne-Stokes respiration presenting as sleep apnea syndrome. Clinical and polysomnographic features. Am Rev Respir Dis 1990; 141: 871–879. Onal E, Lopata M. Periodic breathing and the pathogenesis of occlusive sleep apneas. Am Rev Respir Dis 1982; 126:676–680. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH. Respiration and abnormal sleep in patients with congestive heart failure. Chest 1989; 96:480–488. Takasaki Y, Orr D, Popkin J, Rutherford R, Liu P, Bradley TD. Effect of nasal continuous positive airway pressure on sleep apnea in congestive heart failure. Am Rev Respir Dis 1989; 140:1578–1584. Harrison TR, King CE, Calhoun JA, Harrison WG. Cheyne-Stokes respiration as the cause of paroxysmal dyspnea at the onset of sleep. Arch Intern Med 1934; 53:891–910. Hanly P, Zuberi-Khokhar N. Daytime sleepiness in patients with congestive heart failure and Cheyne-Stokes respiration. Chest 1995; 107:952–958. Tkacova R, Hall MJ, Liu PP, Fitzgerald FS, Bradley TD. Left ventricular volume in patients with heart failure and Cheyne-Stokes respiration during sleep. Am J Respir Crit Care Med 1997; 156:1549–1555. Bradley TD, Phillipson EA. Central sleep apnea. Clin Chest Med 1992; 13:493–505. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing periodic breathing in humans: a general model. J Appl Physiol 1982; 53:644–659. Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983; 55:813–822. Bradley TD, Floras JS. Pathophysiologic and therapeutic implications of sleep apnea in congestive heart failure. J Card Fail 1996; 2:223–240. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med 1995; 152:1950–1955. Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley TD. Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med 1994; 150:489–495. Lahiri S, Maret K, Sherpa MG. Dependence of high altitude sleep apnea on ventilatory sensitivity to hypoxia. Respir Physiol 1983; 52:281–301. Phillipson EA. Control of breathing during sleep. Am Rev Respir Dis 1978; 118:909–939. Javaheri S, Corbett WS. Association of low PaCO 2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med 1998; 128: 204-207. Lorenzi-Filho G, Rankin F, Bies I, Bradley TD. Effects of inhaled CO 2 and O 2 on CheyneStokes respiration in patients with heart failure. Am J Respir Crit Care Med 1999; 159: 1490–1498. Xie A, Rankin F, Rutherford R, Bradley TD. Effects of inhaled CO 2 and added dead space on idiopathic central sleep apnea. J Appl Physiol 1997; 82:918–926.
Sleep Apnea and the Heart
609
111. Bradley TD, Holloway RM, McLaughlin PR, Ross BL, Walters J, Liu PP. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992; 145:377–382. 112. Churchill ED, Cope O. The rapid shallow breathing resulting from pulmonary congestion and edema. J Exp Med 1929; 49:531-537. 113. Berssenbrugge A, Dempsey J, Iber C, Skatrud J, Wison P. Mechanisms of hypoxia-induced periodic breathing during sleep in humans. J Physiol (Lond) 1983; 343:507–524. 114. Franklin KA, Eriksson P, Sahlin C, Lundgren R. Reversal of central sleep apnea with oxygen. Chest 1997; 111:163–169. 115. Andreas S, Clemens C, Sandholzer H, Figulla HR, Kreuzer H. Improvement of exercise capacity with treatment of Cheyne-Stokes respiration in patients with congestive heart failure. J Am Coll Cardiol 1996; 27:1486–1490. 116. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH. The effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med 1989; 111:777–782. 117. Franklin KA, Sandstrom E, Johansson G, Balfors EM. Hemodynamics, cerebral circulation, and oxygen saturation in Cheyne-Stokes respiration. J Appl Physiol 1997; 83:1184–1191. 118. Staniforth AD, Kinnear WJM, Starling R, Hetmanski DJ, Cowley AJ. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J 1998; 19:922–928. 119. Wilcox I, Grunstein RR, Collins FL, Berthon-Jones M, Kelly DT, Sullivan CE. The role of central chemosensitivity in central apnea of heart failure. Sleep 1993; 16:S37-S38. 120. Ahmed M, Serrette C, Kryger MH, Anthonisen NR. Ventilatory instability in patients with congestive heart failure and nocturnal Cheyne-Stokes breathing. Sleep 1994; 17:527–534. 121. Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G, Colombo R, Donner CF, Giannuzzi P. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999; 99:1435–1440. 122. Cherniack NS, Longobardo GS. Cheyne-Stokes breathing. An instability in physiologic control. N Engl J Med 1973; 288:952-957. 123. Longobardo GS, Cherniack NS, Fishman AP. Cheyne-Stokes breathing produced by a model of the human respiratory system. J Appl Physiol 1966; 21:1839–1846. 124. Ponikowski P, Chua TP, Piepoli M, Ondusova K, Webb-Peploe K, Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G, Giordano A, Coats AJS. Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 1997; 96:2586–2594. 125. Ponikowski P, Chua TP, Piepoli M, Amadi AA, Harrington D, Webb-Peploe K, Volterrani M, Colombo R, Mazzuero G, Giordano A, Coats AJS. Chemoreceptor dependence of very low frequency rhythms in advanced chronic heart failure. Am J Physiol 1997; 272(Heart Circ Physiol 41):H438–H447. 126. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol 1999; 86:1264–1272. 127. Heistad DD, Wheeler RC, Mark AL, Schmidi PG, Abboud FM. Effects of adrenergic stimulation on ventilation in man. J Clin Invest 1972; 51:1469–1475. 128. Paintal AS: Mechanisms of stimulation of type J pulmonary receptors. J Physiol (Lond) 1969; 203:511–532. 129. Trinder J, Whitworth F, Kay A, Wilkins P. Respiratory instability at sleep onset. J Appl Physiol 1992; 73:2462–2469. 130. Alex CG, Onal E, Lopata M. Upper airway occlusion during sleep in patients with CheyneStokes respiration. Am Rev Respir Dis 1986; 133:42–45. 131. Younes M. The physiologic basis of central apnea and periodic breathing. Current Pulmonol 1989; 10:265–326. 132. Sullivan CE, Murphy E, Kozar LF. Waking and ventilatory responses to laryngeal stimulation in sleeping dogs. J Appl Physiol 1978; 45:681–689. 133. Bradley TD, Brown IG, Zamel N, Phillipson EA, Hoffstein V. Differences in pharyngeal properties between snorers with predominantly central sleep apnea and those without sleep apnea. Am Rev Respir Dis 1987; 135:387–391. 134. Bradley TD, Brown IG, Grossman RF, Zamel N, Martinez D, Phillipson EA, Hoffstein
610
135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157.
Bradley et al. V. Pharyngeal size in snorers, nonsnorers, and patients with obstructive sleep apnea. N Engl J Med 1986; 315:1327–1331. Brown IG, Bradley TD, Phillipson EA, Zamel N, Hoffstein V. Pharyngeal compliance in snoring subjects with and without obstructive sleep apnea. Am Rev Respir Dis 1985; 132: 211–215. Altschule MD, Iglauer A. The effect of position on periodic breathing in chronic cardiac decompensation. N Engl J Med 1958; 259:1064–1066. Brown IG, MacLean PA, Boucher R. Changes in pharyngeal cross-sectional area with posture and applications of continuous positive airway pressure in patients with obstructive sleep apnea. Am Rev Respir Dis 1987; 136:628–632. Sullivan CE, Issa FG, Berthon-Jones M. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet l98l; 1:862–865. Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest 1986; 90: 165–171. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med 1999; 341:949–954. Guyton AC, Crowell JW, Moore JW. Basic oscillating mechanism of Cheyne-Stokes breathing. Am J Physiol 1956; 187:395–398. Hoffman R, Agatston A, Krieger B. Cheyne-Stokes respiration in patients recovering from acute cardiogenic pulmonary edema. Chest 1990; 97:410–412. Datta AK, Shea AA, Horner RL, Guz A. The influence of induced hypocapnia and sleep on the endogenous respiratory rhythm in humans. J Physiol (Lond) 1991; 440:17–33. Vincken W, Guilleminault C, Silvestri L, Cosio M, Grassino A. Inspiratory muscle activity as a trigger causing the airways to open in obstructive sleep apnea. Am Rev Respir Dis 1987; 135:372–377. Yasuma F, Kozar LF, Kimoff RJ, Bradley TD, Phillipson EA. Interaction of chemical and mechanical respiratory stimuli in the arousal response to hypoxia in sleeping dogs. Am Rev Respir Dis 1991; 143:1274–1277. Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis 1992;72:985–992. Trinder J, Merson R, Rosenberg JI, Fitzgerald F, Kleiman J, Bradley TD. Interactions of ventilation, arousals and blood pressure oscillations during Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med 2000; 162:808–813. Lorenzi-Filho G, Dajani HR, Leung RST, Floras JS, Bradley TD. Entrainment of blood pressure and heart rate oscillations by periodic breathing. Am J Respir Crit Care Med 1999; 159:1147–1154. Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995; 152:473–479. Findley LJ, Blackburn MR, Goldberger AL, Mandell AJ. Apneas and oscillation of cardiac ectopy in Cheyne-Stokes breathing during sleep. Am Rev Respir Dis 1984; 130:937–939. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol 1986; 57:3B-7B. Goldman S, Johnson G, Cohn JN, Cintron G, Smith R, Francis G. Mechanism of death in heart failure. The vasodilator-heart failure trials. Circulation 1993; 87:VI-24-VI-31. Naughton MT, Bradley TD. Sleep apnea in congestive heart failure. Clin Chest Med 1998; 19:99–113. Dark DS, Pingleton SK, Kerby GR, Crabb JE, Gollub SB, Glatter TR, Dunn MI. Breathing pattern abnormalities and arterial oxygen desaturation during sleep in the congestive heart failure syndrome. Improvement following medical therapy. Chest 1987; 91:833–836. Buckle P, Millar T, Kryger M. The effect of short term nasal CPAP on Cheyne-Stokes respiration in congestive heart failure. Chest 1992;102:31–35. Guilleminault C, Clerk A, Labanowski M, Simmons J, Stoohs R. Cardiac failure and benzodiazepines. Sleep 1993; 16:524–528. Davies RJO, Harrington KJ, Ormerod OJM, Stradling JR. Nasal continuous positive airway pressure in chronic heart failure with sleep-disordered breathing. Am Rev Respir Dis 1993; 147:630–634.
Sleep Apnea and the Heart
611
158. Granton JT, Naughton MT, Benard DC, Liu PP, Goldstein RS, Bradley TD. CPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1996; 153:277–282. 159. Tkacova R, Liu PP, Naughton MT, Bradley TD. Effect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J Am Coll Cardiol 1997; 30:739–745. 160. Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000; 102:61–66. 161. Andreas S, Hagenah G, Moller C, Werner GS, Kreuzer H. Cheyne-Stokes respiration and prognosis in congestive heart failure. Am J Cardiol 1996; 78:1260–1264. 162. Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med 1996; 335:562–567. 163. Ross JJ. Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 1976; 18:254–264.
23 Cardiovascular Responses to Obstructive Apneas Lessons from Animal Models
STEVEN M. SCHARF
HARLY GREENBERG
Long Island Jewish Medical Center Albert Einstein College of Medicine New Hyde Park, New York
Long Island Jewish Medical Center New Hyde Park, New York
LING CHEN
CHRISTOPHER P. O’DONNELL
University of Western Ontario London, Ontario, Canada
Johns Hopkins University Baltimore, Maryland
I.
Introduction: Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is a common condition, especially of middle-aged males (1). This condition causes substantial morbidity and mortality, including from cardiovascular conditions such as hypertension, heart attacks, and strokes (reviewed in 2). Acute cardiovascular effects of obstructive apneas include swings in heart rate, increases in arterial blood pressure, increases in pulmonary arterial pressure, and even episodes of pulmonary edema (2). Changes in autonomic function, cardiac function, and ventilatory control are thought to induce the chronic adverse daytime changes seen in patients with OSA by mechanisms still under investigation. The link between sleep-disordered breathing at night and daytime cardiovascular function is dramatically illustrated by the finding that patients with concomitant sleep apnea and cardiomyopathy demonstrate substantially improved left ventricular (LV) function when OSA is treated (3). Major physiologic alterations during episodes of sleep disordered breathing thought to influence peripheral circulatory and cardiac function include mechanical effects of large inspiratory decreases in intrathoracic pressure during OSA, direct and reflex autonomic effects of hypoxemia and possibly hypercapnia, reflex of arousals that occur at apnea termination, and reflex effects secondary to post apneic hyperventilation (2). 613
614
Scharf et al. II. Animal Models and the Study of OSA
Studying mechanisms of diseases such as OSA which affect humans is often difficult to do in humans. This is because of the complex interactions among cardiovascular, respiratory, and neurologic systems which make up the constellation of findings. Disease mechanisms must often be inferred rather than directly investigated. This has to do with limitations of the amount by which conditions can be manipulated, the ability to enhance or ablate parts of the system, and the number of studies which can be done per subject. To make up for some of these deficits, investigators have turned to animal models. Animal models can be used to study the natural history of untreated disease and basic pathogenetic mechanisms by which the disease causes damage, and enable the use of surgical, physiological, and pharmacological interventions not possible in humans. Animal models used for studying OSA have included naturally occurring disease, induced disease, and simulated disease. In the first type of model, naturally occurring disease, studies are done on animals in which disease has occurred naturally. The English bulldog, in which obstructive apneas naturally occur, especially during REM sleep, has been used extensively for important studies of mechanisms by which upper airway patency is regulated (4). Naturally occurring OSA in obese miniature pigs has also been described (5). However, few studies of the cardiovascular effects of OSA have been performed using these models. More cardiovascular studies have been done using models whereby OSA is induced, and in which certain features of OSA are simulated. Inducing disease allows studies of many cardiovascular variables before and following induction of OSA. Simulating disease allows extensive manipulation for testing various factors which are important in producing the adverse cardiovascular consequences of OSA. Data from both types of studies need to be integrated and tested against each other as well as against clinical observations to advance our understanding of mechanisms producing morbidity and mortality in this important disorder.
III. Cardiovascular Effects of Induced Sleep Apnea in Animals A new model of induced OSA in chronically instrumented dogs was recently developed by the group in Toronto led by E.A. Phillipson (7). In this elegant, imaginative, and technically difficult model, dogs are given chronic tracheostomies. The opening and closing of the tracheal stoma is managed by a valve which is controlled by an online computer which monitors electroencephalogram, electromyogram, tracheal mucosal oxygen, and airway pressure. When the computer detects sleep, the valve is closed to induce an obstructive apnea. When the computer detects an arousal, the valve is opened. Thus, this model produces nighttime sleep deprivation by upperairway occlusion, thus mimicking major features of OSA during sleep and daytime sleepiness. In fact, animals treated this way for nights on end become increasingly somnolent. A similar model was introduced by O’Donnell et al. (8) in Baltimore. The power of these models is that they allow for the observation of changes in several systems, including cardiovascular, during the development of clinical dis-
Animal Models and OSA
615
ease. Changes in tracheal pressure and the degree of arterial hemoglobin desaturation during airway occlusion are similar to those in clinical OSA. In addition, these models allow for the study of sleep state (non-REM, REM, arousal)-related changes in variables and for some differentiation of the effects of apneas versus postapneic arousal. Clinically significant rates of OSA can be induced and these rates are accentuated by prior sleep deprivation (7–9). In addition, maintaining a patent airway after a night of OSA results in significant REM sleep rebound in the canine model (7). Thus, the chronically instrumented dog reproduces the primary clinical respiratory and sleep events of OSA. A. Effects of Postapneic Arousal and Sleep Fragmentation on the Cardiovascular System
The arousal observed in patients post apnea is associated with increased heart rate (HR) and blood pressure (BP). The mechanisms responsible for this are the changes in sympathetic and parasympathetic function that are affected by numerous mechanisms during arousal. These include changes in blood gas tensions; reflex effects of hyperventilation including tidal volume, respiratory rate, and chest wall afferents; and brainstem-related changes in autonomic outflow. Horner et al. (10) studied the effects of arousal from non-REM sleep in chronically instrumented dogs. During spontaneous breathing, HR increased 31% following spontaneous arousals from non-REM sleep. When spontaneous breathing was eliminated by mechanical hyperventilation, arousal elicited the same increase (29.9%) in HR. Thus, state change elicited a change in autonomic activity. Parasympathetic block (vagal cooling) reduced but did not eliminate the HR change with arousal (⫹12%), whereas betaadrenergic block with propranolol eliminated the response altogether. The results indicated that arousal from non-REM sleep is associated with parasympathetic withdrawal and cardiac sympathetic stimulation. Since these effects persisted during mechanical hyperventilation, presumably the results were not related to changes in blood gas tensions or to changes in afferent input from the respiratory system. Sleep fragmentation due to repetitive arousals is an important feature of clinical OSA, contributing to hypersomnolence. In a follow-up study the Toronto group examined the effects of sleep fragmentation on the surges of blood pressure seen during airway occlusion as well as the responses of tracheal pressure and time to arousal (11). They studied dogs during periods of induced OSA and periods of a similar degree of sleep fragmentation induced by an acoustic alarm. These workers demonstrated a progressive increase in time to arousal, peak negative tracheal pressure, degree of desaturation and surges in blood pressure during both periods of OSA and periods of nonapneic sleep fragmentation which were similar in the two states. Thus, progressive worsening of the effects of airway occlusion with time in OSA was related to the effects of sleep fragmentation induced by apneas, not by the apneas per se. O’Donnell et al. (8) used a different approach. These workers induced apneas with and without arousals that were otherwise matched for duration, arterial hemoglobin desaturation, and negative swings in intrathoracic pressure. As expected, they
616
Scharf et al.
demonstrated that the arousal response is an important mechanism increasing systemic arterial blood pressure and heart rate immediately following apnea termination. Mean BP increased 17.2 ⫾ 1.2 mm Hg after apnea termination when arousal was present but only 5.4 ⫾ 1.2 mm Hg when arousal was not present. In addition, when arousal was not present, following apnea termination, there was no tachycardia. These authors concluded that the arousal response accounts for 69% of the acute systemic hypertension that occurs following apnea termination. Other factors, such as change in gas tensions or alteration of ventilatory reflex afferent input, account for the rest. The role of the autonomic nervous system in the acute hypertensive response to apnea was also examined by O’Donnell et al. (8,10). Autonomic nervous system blockade using 20 mg/kg hexamethonium completely eliminated any increase in systemic arterial pressure in response to apnea. Moreover, in the immediate postapneic period BP actually decreased. A number of conclusions were drawn from the above studies. First, the autonomic nervous system is a critical component in the pressor response during and after apnea. Second, in the absence of an intact autonomic nervous system, the disturbances in blood gases cause a local tissue vasodilatation, probably through the direct vasodilating effects of hypoxia and/or hypercapnia on peripheral vascular beds, normally not seen because of the counteracting effects of autonomic stimulation leading to vasoconstriction. Although the key role for neurally mediated vasoconstriction in the blood pressure response to apnea is established, the afferent components of the reflex arc remains to be established. Several afferent inputs to the autonomic reflex are potentially stimulated by factors related to an obstructive apnea. These include inputs from the chemoreceptors, baroreceptors, and lung afferents. Sorting out these factors is better accomplished in experiments on anesthetized or sedated animals and will be considered below. B. Development of Systemic Hypertension in Animal Models of OSA
The statistical association between OSA in humans and the development of systemic hypertension is well established. Forty percent to 60% of patients with OSA have associated daytime systemic hypertension (12–14). Further, among hypertensive patients unselected for sleep related symptoms, prevalence rates for OSA from 30% to 50% have been found (15–17). A causal relationship between OSA and hypertension is more difficult to establish, however. This is because of the association between OSA and obesity (18). Although there are small studies reporting improved control of BP following treatment of OSA (15,19), there are few definitive controlled, blinded, crossover trials of the treatment of sleep apnea on hypertension. The converse study would be to observe the development of hypertension following the onset of OSA. In this respect, the canine model of induced OSA has been very useful. Brooks et al. (20) induced sleep apnea in dogs. After 4 weeks, BP increased at night by approximately 13 mm Hg. However, of greater interest was a progressive
Animal Models and OSA
617
increase in daytime waking BP by approximately 16 mm Hg over 1 to 2 months of induced OSA (Fig. 1). After cessation of OSA, nighttime BP quickly returned to control values. Daytime hypertension resolved over 1 to 3 weeks following cessation of OSA. In nonapneic dogs, nocturnal sleep fragmentation produced by an acoustic stimulus led to increases in nocturnal BP similar to those observed with induced OSA. However, there was no change in daytime BP. These studies provide powerful evidence that OSA is in fact a potential cause of daytime hypertension. In this sense they support epidemiologic studies demonstrating that OSA is a risk factor for hypertension which is independent of obesity (21,22). Thus, even though postarousal blood pressure surges are related to arousals, these do not translate into systemic daytime hypertension. What is the mechanism whereby OSA can lead to systemic hypertension? There are a number of potential hypertensive stimuli that occur during apneas. These include changes in cardiac output, hypoxia, hypercapnia, and possible sympathostimulatory effects of post apnea hyperventilation (23, 24). It is generally believed that chronic OSA is associated with heightened sympathoadrenal tone during the daytime in man, and that this is at least partly responsible for the development of hypertension (reviewed in Chapter 21). However, it is obviously difficult to sort out the various possible stimuli to daytime hypertension in clinical studies. In this regard chronic animal studies have been helpful in describing possible mechanisms leading to hypertension and sympathoadrenal overdrive.
Figure 1 Mean daytime arterial BP in four dogs during OSA (filled squares) and sleep fragmentation (open circles). The dashed lines indicate the beginning and respectively of the OSA or sleep fragmentation phase. Note that there is a progressive increase in daytime BP following the induction of OSA which abates with the end of the OSA phase. Sleep fragmentation per se did not change daytime BP. (From Ref. 20.)
618
Scharf et al. C. Effect of Episodic Hypoxia on Peripheral and Central Nervous Sympathetic Function in Rats
As has been shown in humans, and in the animal models described above, OSA is not only associated with acute elevations of arterial pressure occurring at the termination of apneic events, it also results in sustained diurnal systemic arterial hypertension (21,25). OSA might lead to hypertension by increasing sympathetic nervous system activity. In support of this premise, prior clinical investigations have demonstrated elevated urinary and plasma catecholamine levels in OSA, as well as increased muscle sympathetic nerve discharge occurring acutely in association with obstructive apneas (25–29). Recent observations showing elevated muscle sympathetic nerve activity, and an abnormal vasopressor response to hypoxia, in awake OSA patients suggest that elevated sympathetic activity might persist beyond the sleep period (25–29). Thus, evidence for an increased level of sympathetic nerve discharge in OSA is strong, although factors leading to sympathetic activation and its relationship to development of sustained systemic hypertension have not been clearly elucidated. Long-term exposure to episodic hypoxia, such as that occurring in association with OSA, might be one factor leading to increased sympathetic activity in OSA. Prior investigations in rats have shown that chronic exposure to continuous hypoxia leads to augmented sympathetic activity (30). To explore the effects of long term exposure to episodic hypoxia, similar to that occurring with apnea in OSA, Fletcher et al. (31) developed a model in which rats were placed in a plexiglass chamber for 7 hours each day during their diurnal sleep period for 35 days. The chamber was flushed with 100% nitrogen alternating with room air to achieve a nadir of ambient oxygen concentration of 3% to 5% for 12 sec, then returning to 21% every 30 sec. Animals were housed under room air conditions for the remainder of the day. At the termination of the exposure period, under room air conditions, systemic arterial pressure was measured in awake rats via a previously placed indwelling arterial catheter. An increase in mean arterial pressure (to 135 mm Hg) was observed in animals previously exposed to episodic hypoxia (31). In addition, these animals demonstrated an increase in left ventricle to body weight ratio. No change was observed in sham-exposed controls. Carotid body denervation eliminated this hypertensive response (32), implicating a role for peripheral chemoreceptor afferent input in mediating the observed sustained elevation of systemic arterial pressure. Further investigation demonstrated that ablation of peripheral sympathetic nerve terminals and adrenal demedullation with the neurotoxin 6-OH dopamine (33) also eliminated this hypertensive response, indicating the importance of the sympathoadrenal system in mediating this response. Subsequent studies specifically demonstrated the role of α-adrenoreceptors in this response (34). Additional experimentation showed that episodic eucapnic hypoxia, at least after 30 min of exposure, led to greater sympathetic nerve traffic and a greater hypertensive response than episodic hypocapnic hypoxia (34). Thus, both hypoxia and CO2 appear to be important in eliciting increased sympathetic nerve activity and hypertension in this model.
Animal Models and OSA
619
Recent studies by Greenberg et al. (35) were subsequently designed to determine if the gain of the response of sympathetic circuits to subsequent chemoreflex stimulation with hypoxia is altered by prior long-term exposure to episodic hypoxia. In addition, these workers wished to determine if this alteration in gain is specific to hypoxia, or if nonspecific alteration in sympathetic gain is induced to stimuli such as hypercapnia to which the animals had not been exposed. In this investigation, Sprague-Dawley rats previously exposed to 30 days of chronic episodic hypoxia exhibited greater facilitation of sympathetic discharge, as recorded from the cervical sympathetic nerve, in response to subsequent acute chemoreflex stimulation than sham-exposed control animals. Interestingly, this phenomenon was observed not only with acute hypoxic challenge, a stimulus that had been repetitively presented over the previous 30 days, but also with hypercapnic and combined hypoxic/hypercapnic challenge, stimuli to which the animals had not received prior exposure or conditioning. Thus, the data indicate that prior long-term exposure to episodic hypoxia increased both baseline sympathetic tone and sympathetic responsiveness to subsequent hypoxic and hypercapnic chemoreflex stimulation. Theoretically, this altered responsiveness should originate in brainstem neural circuits which integrate or regulate sympathetic chemoreflex responses. One potential site where these changes might occur is the medullary sympathoexcitatory neurons located in the rostral ventrolateral medulla (RVLM), or in brainstem circuits modulating their activity. These reticulospinal neurons receive afferent input from arterial chemoreceptors and baroreceptors and excite spinal sympathetic neurons. They are critical for maintenance of resting arterial pressure and are important components of the arterial chemoreflex and baroreceptor reflex responses (36). RVLM neurons also serve as central oxygen sensors as brief (5 to 7 sec) episodes of hypoxia in the rat have been shown to reversibly excite the RVLM increasing sympathetic discharge (36). Evidence for plasticity of brainstem neurons in response to chronic exposure to hypoxia comes from previous findings demonstrating increased tyrosine hydroxylase mRNA levels in caudal nucleus tractus solitarius neurons (NTS) after 14 days of continuous hypoxia in rats (37). Thus, in a subsequent investigation, Greenberg and coworkers (38) hypothesized that chronic episodic hypoxia would produce activity dependent alterations of brainstem sympathoexcitatory neurons or of neuronal circuits involved in integration or modulation of their response, thereby increasing sympathetic responsiveness to chemoreflex stimulation. After 30 days of episodic hypoxia, 12 to 18 hours after the last exposure period, Sprague-Dawley rats were anesthetized and rapidly fixed. Brainstem sections were obtained for immunohistochemical labeling for Fos, the protein product of c-fos. Expression of c-fos, an immediate-early response gene, is a marker of synaptic stimulation and alteration of neuronal genetic transcription which may lead to altered neuronal activity (39). Thirty days of diurnal episodic hypoxia elicited much greater Fos expression in well-defined regions of the medulla oblongata involved in the tonic and reflex control of sympathetic neural discharge than was observed in sham exposed control
620
Scharf et al.
rats. As expected, greater Fos expression was seen in the dorsal and medial subnuclei of the nucleus tractus solitarius (NTS) (Fig. 2) as these neurons receive carotid sinus nerve afferent input (40). Greater Fos expression was also observed in experimental animals in the C1 adrenergic area of the rostral ventrolateral medulla (RVLM) (Fig. 3). Activation in this area is consistent with the importance of this vasomotor area in integrating afferent information processed by the NTS and other areas, and providing synaptic excitation to spinal sympathetic preganglionic neurons (36). Similarly, increased Fos expression was present in intermediate and caudal regions of the ventrolateral medulla, including the A1 noradrenergic area and the adjoining reticular formation. Previous studies have shown that these neurons serve as interneurons modulating RVLM sympathoexcitatory activity (41). Activation of the A1 area sug-
Figure 2 Evidence of c-fos gene induction in the nucleus of the solitary tract and dorsal motor nucleus (NTS-X) after chronic intermittent hypoxia. Camera lucida drawings of the dorsal medulla from transverse sections of the medulla oblongata in experimental (a–c) and control (d–f) rats. Following intermittent hypoxia, note the dramatically larger numbers of Fos-immunopositive nuclei in dorsal (d), lateral (l), and medial (me) NTS subnuclei and a caudal level of dorsomotor nucleus (x) as compared to the control (e–f). Abbreviations: irt, intermediate reticular nuclear zone; nc, nucleus cuneatus; ng, nucleus gracilis; tc, tela choroidea; tr, tractus solitarius; xii, hypoglossal nucleus.
Animal Models and OSA
621
Figure 3 Evidence of c-fos gene induction in the medullary reticular formation and raphe after chronic intermittent hypoxia. Camera lucida drawings of transverse sections of the ventrolateral quadrant of medulla oblongata in experimental (a–d) and control (e–h) rats. In the intermittent hypoxic rat, note the dramatically larger numbers of Fos-immunopositive nuclei (dots) in the subambigual, C1 vasopressor area of rostral vlm and raphe pallidus (rpa) (a,b) as compared to control (e,f ). Induction of the c-fos protein was also clear in hypoxic animals at intermediate (c) and caudal (d) medullary levels of vlm and intermediate reticular nuclear zone (irt) of the lateral tegmental field as compared to controls (g,h). Note the especially high densities in the A1 area at obex in experimental (d) versus control (h). All labeled cells were mapped on each section. Abbreviations: l, m, lateral and medial divisions of lateral reticular nucleus; nac, nucleus ambiguous, compact division; nal, nucleus ambiguous, loose division; p, pyramid; pion, principal inferior olivary nucleus; v, trigeminal nucleus; vii, facial nucleus.
gests that humoral agents may also be involved in the cardiovascular response to chronic episodic hypoxia since A1 noradrenergic circuits stimulate hypothalamic release of arginine vasopressin, a powerful peripheral vasoconstrictor (41). Taken together, these findings provide a potential mechanism whereby chronic exposure to episodic hypoxia might alter neuronal activity of cell groups controlling sympathetic nerve discharge and sympathetic responsiveness to chemoreflex stimulation. This central neurogenic mechanism may be one factor leading to the develop-
622
Scharf et al.
ment of systemic hypertension in this model. It may also be relevant to mechanisms causing hypertension in OSA in which recurrent exposure to intermittent hypoxia occurs nightly. D. Acute Hemodynamic Effects of Induced OSA
Numerous factors work in concert during OSA which could adversely affect right ventricular (RV) and LV function during apneas. These include large decreases in inspiratory intrathoracic pressure, hypoxemia, hypercapnia, and both sympathoadrenal and vagally mediated reflexes. In clinical OSA it is often difficult to sort out the importance of the various factors under different conditions. This is because of the constraints of preserving sleep staging and the difficulty of performing invasive measurements. As a result, clinical studies often yield conflicting results. In addition, clinical studies are subject to confounding influences such as concomitant medical condition, chronicity of OSA, concurrent medications, age, and gender. While induced OSA is subject to many of the same constraints as clinical OSA, the opportunity does exist for obtaining more invasive and exact measures of function. A good example is the possibility of measuring beat-to-beat changes in RV and LV output before, during, and following apneas. With the exaggerated negative swings in intrathoracic pressure occurring during obstructive apneas, it is to be expected that venous return would increase during the inspiratory phase. At the same time, the possibility exists that LV afterload would increase as well (Chapters 5 and 8). Further, because of increased RV preload associated with increased venous return, LV preload may decrease because of the effects of ventricular interdependence (Chapters 4 and 10) mediated via the septum and pericardium. Thus, LV stroke volume (SV) should decrease at the same time that RV SV increases during the inspiratory phase of obstructive apneas. These changes are classically reported during obstructed inspiration (reviewed in 42). The effect of these changes on overall cardiac output in the setting of OSA is poorly studied. In addition to mechanical effects of breathing against an obstructed airway, there are numerous reflexes that could be triggered. There include hypoxia-stimulated increases in vagal and sympathetic tone (reviewed in 43), sympathostimulatory effects of hypercapnia, and sympathetic and vagal reflex effects of pulmonary congestion (44). Finally, as alluded to earlier, there are direct vasodilatory effects of hypoxia and hypercapnia on peripheral vasculature. It is likely that these effects combine in different ways depending on apnea duration, extent to which intrathoracic pressure decreases, the degree of hypoxia and hypercapnia, sleep state, and many other factors, as yet poorly understood. Thus, it is naive to believe that observations under one set of circumstances apply in all circumstances. Observations made on the integrated response seen in OSA must be combined with those made under experimental conditions in which individual factors can be individually controlled. In their canine model Schneider et al. (45) studied the beat-to-beat changes in RV and LV SV before, during, and following apneas by preinstrumenting the dogs with electromagnetic flow probes around the pulmonary artery and aorta. They reasoned that because of the difference between RV and LV output, with large nega-
Animal Models and OSA
623
tive intrathoracic pressures (during obstructed breathing) blood may pool in the pulmonary circuit before being discharged back into the systemic circuit when intrathoracic pressure normalizes. This pattern of events could contribute to the oscillations in systemic and pulmonary artery pressures that are linked to the periodicity of OSA. Studies confirmed that each negative intrathoracic pressure swing during an obstructive apneic event indeed causes an increase in RV SV and a decrease in left ventricular stroke volume LV SV. Thus, blood transiently pools in the pulmonary circulation during the brief periods of obstructed inspiration. Between obstructed inspiratory efforts, however, sufficient time exists in the ‘‘expiratory’’ pause for blood pooled in the systemic circulation to dissipate. This was confirmed by demonstrating that LV SV and RV SV are exactly equal when averaged over a full obstructed inspiratory cycle (i.e., an obstructed inspiratory effort and subsequent expiratory pause). In summary, in this intact model, the large negative swings in intrathoracic pressure that accompany an obstructive apnea cause very transient changes in left and right heart output, but do not contribute to the increase in systemic and pulmonary pressure that develops over the course of the apnea. In these studies effects on LV and RV function and dimensions were not assessed. In a recent study using chronically instrumented sleeping dogs, Parker et al. (46) used an implanted LV impedance catheter to study LV dimensions during obstructive apneas. Echocardiographic studies of LV dimensions were used to assess LV function during waking hours in the animals. These investigators observed an increase in LV end-systolic volume and decrease in ejection fraction over the inspiratory phase during obstructive apneas which corresponded to an increase in measured LV systolic transmural pressure. Further, they observed the development of increased LV end-systolic volume and decreased LV ejection fraction by echocardiography during waking hours over the several weeks following the onset of induced OSA in their animals. This corresponded to the development of systemic hypertension in the animals (20). The above studies certainly confirm the importance of hemodynamic changes during airway obstruction. However, they do not allow for determination of the mechanisms by which changes occur. In addition, caution is urged before extrapolating the results to humans. This is at least partly because of the large sinus arrhythmia observed during inspiratory efforts in dogs which could confound the results. A model of induced apnea in pigs has been published by Pinto et al. (47). In this chronically instrumented model, sleeping pigs were monitored and coronary blood flow was measured before and during induced obstructive apneas. Unlike the dogs, there was very little change in heart rate and BP during apneas, but there were increases in both following arousal. Further, coronary blood flow and coronary vascular resistance increased during the arousal phase. Compared to non-REM sleep, arousal from REM sleep was associated with greater increases in blood pressure and coronary vascular resistance. Alpha-adrenergic blockade with phentolamine abolished the BP and coronary vascular resistance response, indicating the importance of alpha-adrenergic stimulation in contributing to the observed changes. However, O2 saturation was not monitored and apneas were short (⬃10 sec). Thus cardiovascular alterations due to changes in arterial blood gas tensions due to repeated
624
Scharf et al.
apneas of longer duration, as seen in humans and the dog studies, were likely not seen in this model. However, the model does point out the importance of phasic, arousal, and sleep state related swings in sympathetic outflow in contributing to hemodynamic changes in OSA. Indeed, in early studies on sleeping cats (48), sympathetic discharge increased during arousal, as expected from the observations noted in this section that BP, HR, and coronary vascular resistance increase. Finally, Launois et al. (49) demonstrated that arousals from sleep were associated with generalized vasoconstriction in many organs as well as tachycardia. The effects of arousals post apnea are presumably similar. The effects of periodic intermittent generalized vasoconstriction on peripheral organ are not well known and require further study. IV. Anesthetized Animal Models in Which Certain Features of OSA Are Simulated Studies in anesthetized and sedated animals have been designed to isolate and study the hemodynamic effects of certain features of the OSA syndrome. These include the effects of swings in intrathoracic pressure, hypoxemia, hypercapnia, and neuroreflex arcs active in OSA. Because of the effects of anesthesia on cardiopulmonary reflexes, extrapolation to clinical OSA must be done with caution. This model only simulates the mechanical effects of breathing against an obstructed airway and associated hypoxemia. No arousals occur, and arousal responses are thus not studied. A. Effects of Obstructive Apneas on Left Heart Function
Scharf et al. (50 ) simulated the periodic upper-airway obstruction of OSA in anesthetized dogs by occluding the endotracheal tube for 60 sec followed by 60 sec of spontaneous breathing. Changes in hemodynamics, LV function, and coronary blood flow were examined after five to seven cycles of the apnea-interapnea cycle. The role of hypoxemia was examined by performing these studies with room air breathing (arterial PO2 decreases to ⬃40 mm Hg during occlusion) and with O2 breathing (arterial PO2 remains ⬎200 mm Hg). In these studies intrathoracic (esophageal) pressure decreased by 18 to 22 mm Hg (24 to 30 cm H2O) during obstructed inspiration. Under all conditions, obstructive apneas (airway occlusion) led to a decrease in cardiac output. These results were similar to studies in humans with OSA (51,52). However, unlike most clinical and unanesthetized animal studies of OSA, in the dogs, arterial BP fell along with the decrease in cardiac output. Thus, systemic vascular resistance did not change during apneas. Decreased heart rate was observed with obstructed apneas. Since there was no pressor response, decreased heart rate could not have been due to a baroreceptor response, but was due to either primary or reflex effects of hypoxia, or airway obstruction (see below). The absence of apneic pressor response was explained by the suppression of cardiopulmonary reflexes associated with anesthesia. Although this model did not mimic the pressor response usually observed in human or induced OSA, or even in apneas in anesthetized primates (53), the model does mimic the blood pressure response reported in some elderly humans during OSA by McGinty et al. (54). These investigators suggested
Animal Models and OSA
625
that blunting of hypoxic drive in the older individuals led to blunting of the pressor response normally observed with hypoxia. However the finding (51) in the anesthetized dogs that decreased cardiac output was observed even with hyperoxia suggests that hypoxic drive was not the only mechanism responsible for blood pressure maintenance during apneas. Why did cardiac output decrease with obstructive apneas? As outlined in Chapter 5, regulation of cardiac output is the result of complex interactions between factors controlling venous return and those controlling cardiac function. The latter include preload (venous return), afterload, and contractility. In the anesthetized dog studies (50), LV function appeared to deteriorate somewhat as demonstrated by a decrease in LV maximum dp/dt. Both preload and afterload decreased (decreased BP). Studies of venous return in the anesthetized dogs demonstrated a decrease with obstructive apneas. In studies on sedated animals, the pressor response to apneas was a major factor contributing to decreased cardiac output. Likely, a combination of these factors was responsible for decreased cardiac output. The decrease in peripheral O2 delivery associated with decreased cardiac output could be potentially serious in patients, especially those with limited peripheral flow reserve. Finally, coronary blood flow and regional myocardial function were studied in the original paper by Scharf et al. (49). When hypoxia was present (room air breathing), coronary flow increased by up to 70% over baseline conditions. Coronary flow decreased slightly when hyperoxia was present, probably due to the decrease in perfusion pressure. In these studies critical stenosis of the left anterior descending coronary artery was produced. Critical stenosis was defined as stenosis sufficient to eliminate coronary reactive hyperemia but not sufficient to cause a decrease in baseline coronary blood flow. While there was no change in baseline (preapneic) coronary or regional myocardial function, during apneas regional shortening clearly decreased and myocardial pH decreased. This was interpreted as the onset of coronary ischemia. Thus, in the presence of critical coronary stenosis, regional ischemia was produced during apneas (Fig. 4). During apneas in the presence of critical coronary stenosis, the decreases in cardiac output and LV dp/dt were greater than when the coronary artery was nonstenotic, suggesting that impairment of regional myocardial function contributed to greater impairment of global LV function during apneas. This study, therefore, emphasizes the importance of the interactions among coronary flow, LV function, and total O2 delivery during apneas. B. Effects of Periodic Apneas on Venous Return
As discussed in Chapter 5, venous return is controlled by the interaction between mean circulatory pressure (MCP), the resistance to venous return, and right atrial pressure. During obstructed inspiration, right atrial pressure, which is the back pressure to venous return, decreases, which may lead to considerable increases in venous return during inspiration, but right atrial pressure meaned over the respiratory cycle does not change greatly during obstructive apneas. Thus, changes in venous return averaged over the entire respiratory cycle must reflect changes in MCP and resistance to venous return. Measurements of MCP involve stopping the circulation for
626
Scharf et al.
Figure 4 Effects of obstructive apneas, called periodic upper-airway obstruction (PUO) in this figure of an anesthetized dog with and without critical stenosis (CS) of the left anterior descending (LAD) coronary artery. Regional intramyocardial pH is recorded from myocardium perfused by the LAD and from myocardium perfused by the circumflex (CFX). Without CS, PUO has no effect on regional stenosis. After CS is induced in the LAD, the onset of PUO is associated with decreased pH in myocardium perfused by the stenotic (LAD) but not the non-stenotic (CFX) coronary artery. When the stenosis is released during PUO, myocardial pH returns to control. The time span between ‘‘Begin PUO’’ and ‘‘End PUO’’ is 15– 20 min. Decreased myocardial pH is considered an early sign of regional ischemia.
short periods of time and therefore cannot be accomplished in unanesthetized experiments. Tarasiuk and Scharf (54) studied the mechanisms whereby venous return could fall in the anesthetized dog preparation with periodic obstructive apneas described above. Using a stop-flow technique they developed for closed chest animals, these investigators demonstrated that apneas associated with hypoxia (room air breathing) were associated with an increase in MCP (Fig. 5). Normally, this should have increased venous return. However, there was a concomitant increase in the resistance to venous return which lead to a decrease in overall venous return. No change in venous return parameters was observed when hypoxia was prevented (O2 breathing). The increase in MCP was thought to be due to sympathoadrenal stimulation associated with hypoxia. The reason for the increase in resistance to venous return which prevented cardiac output from increasing during apneas was not clear. However, collapse of the great veins of the chest during inspiration (ohmic increase in resistance) or to sympathoadrenal induced venoconstriction in resistance veins during hypoxia could explain these findings.
Animal Models and OSA
627
Figure 5 Measurement of mean circulatory pressure (MCP) and effects of obstructive apnea in an anesthetized dog. (A) Effect of temporary circulatory shut down produced by simultaneous occlusion of the the inferior and superior vena cavae. Note that venous pressure (Pven) increases to a plateau which is the MCP. (B) Effects of apnea on MCP. Note that compared with baseline there is an increase in MCP during apnea. BP, blood pressure; Qpa, pulmonary arterial flow (electromagnetic flow probe around the pulmonary artery). (From Ref. 54.)
Another series of studies on venous return during apneas had its origin in a study of chronic airflow obstruction by Salejee et al. (55). In these studies the trachea of young rats was banded, producing a normoxic, mildly hypercapnic model of chronic respiratory failure in which intrathoracic swings of ⫺30 to ⫺40 cm H2O occur during inspiration. After several months, the animals were sacrificed. There were no changes in the LV, but RV hypertrophy was found in the animals. These changes were not attributed to hypoxic pulmonary vasoconstriction since hypoxia was not found. The authors speculated that large increases in venous return during apneas could have led to flow overload of the RV. The extent to which venous return could increase during inspiration during apneas was studied in anesthetized dogs by Tarasiuk et al. (56). In this study, the inferior and superior venae cavae were cannulated and venous return was diverted through a shunt in which flow could be measured before returning to the right atrium. The chest was closed, and obstructive apneas were produced by periodic occlusion of the endotracheal tube as described above. During apneas, inspiratory venous return was demonstrated to be four- to five-fold that of expiratory venous return (Fig. 6), although mean venous return did not change greatly. These findings may relate to human studies of Podszus et al. (2), who observed that pulmonary hypertension was greater during obstructive than nonobstructive (central) apneas for the same degree of hypoxia. Podzus et al. (2) speculated that inspiratory increases in venous return with obstructive apneas could have accounted for the findings. The studies of Tarasiuk et al. (56) certainly lend support to this hypothesis and raise the possibility that flow-mediated overload
628
Scharf et al.
Figure 6 Effects of obstructive apneas on inferior (IVC) and superior (SVC) vena cava flow. Obstructed inspiration is noted by the decrease in right atrial pressure (RAP). Note that both IVC and SVC flow increase considerably during inspiration relative to expiration during obstructed inspiratory efforts.
of the RV could contribute to pulmonary hypertension and chronic cor pulmonale in OSA patients. C. Comparison of Obstructive and Nonobstructive Apneas in Anesthetized Animals
During OSA in patients, there are large negative swings in intrathoracic pressure during the inspiratory efforts against a closed glottis, by as much as ⫺60 to ⫺80 cm H2O (55), although ⫺20 to ⫺30 cm H2O is more usual (2). In addition to the venous return effects discussed above, studies in humans and animals performing Mueller maneuvers have confirmed that sustained decreases in intrathoracic pressure lead to an increase in LV systolic transmural pressures, in effect increasing LV afterload (58–61). Thus, it is often assumed that the large but periodic swings in intrathoracic pressure observed with Mueller maneuvers would lead to adverse effects on LV function above and beyond those associated with changes in blood gas tensions and reflex effects secondary to these and other changes during obstructive apneas. To test this hypothesis in anesthetized dogs, Tarasiuk and Scharf (62) produced obstructive apneas by occlusion of the endotracheal tube and nonobstructive apneas by turning a mechanical ventilator on and off with the animals paralyzed. Apneas were matched for periodicity and blood gas changes. They observed greater decreases in cardiac output and greater increases in left atrial filling pressure during nonobstructive (called ‘‘simulated central’’ in the paper) apneas than during obstructive apneas. A pressor response was not observed. The greater decrease in cardiac
Animal Models and OSA
629
output with nonobstructive apneas was attributed to the greater decrease in heart rate with this apnea type than with obstructive apneas. During obstructive apneas, right heart blood volume increased, whereas during non obstructive apneas, left heart volume increased. Thus, these studies demonstrated, surprisingly, that nonobstructive apneas led to greater adverse effects on LV function than did obstructive apneas. This finding was attributed to differences between apnea type in the reflex overlay of hypercapnic hypoxia. The authors speculated that during obstructive apneas, reflex afferent input to the brainstem, possibly from the muscles of respiration, and/or activation of pulmonary or chest wall mechanoreceptors (but not lung inflation receptors which would have been inactive), modulated the effects of hypoxia and/or hypercapnia on heart rate, and produced less bradycardia. Increased RV volume during obstructive apneas was attributed to the venous return effects discussed above. LV effects were thought to depend more on neurocirculatory, especially autonomic nervous system, responses to apneas than the mechanical effects of intermittent inspiratory decreases in intrathoracic pressure. Several afferent inputs to the autonomic nervous system are stimulated by the events of an obstructive apnea. These include inputs from the chemoreceptors, baroreceptors, and lung and possibly chest wall afferents. In anesthetized cats, O’Donnell et al. (9) studied the relative importance of each of these inputs by measuring changes in renal sympathetic nerve activity. Non obstructive apneas were induced by turning off a mechanical ventilator with the animal either breathing room air or 100% oxygen. The study determined that the dominant stimulus increasing renal sympathetic nerve activity during an apnea was hypoxic stimulation of chemoreceptors. Stimulation of chemoreceptors by hypercapnia per se produced only small increases in renal sympathetic nerve activity, but a role for hypercapnia augmenting the hypoxic stimulus could not be ruled out. During the period of apnea, chemoreceptor input was dominant and overwhelmed any inhibitory input from arterial baroreceptors as blood pressure rose. Immediately after the apnea there was a rapid decline in renal sympathetic nerve activity between the first and second postapneic breaths. This fall in activity was due to a sudden loss of excitatory input from the chemoreceptors allowing inhibitory input from the arterial baroreceptors (arterial blood pressure maximal) to temporarily dominate. Input from lung stretch receptors played only a modulating role related to phasic inhibition during inspiration. Thus, in this model, the chemoreceptors were the dominant afferent input increasing renal sympathetic nerve activity in response to apnea. We have used the term ‘‘nonobstructive’’ apneas to characterized periodic apneas produced by turning a ventilator on and off in paralyzed animals. Nonobstructive apneas produced in this manner should not be confused with ‘‘central’’ apneas. During nonobstructive apneas ventilatory drive continues (63), whereas in true central apneas respiratory motoneuron output stops, often because of hyperventilation. Thus, nonobstructive apneas are neurologically equivalent to obstructive apneas minus the mechanical and neurocirculatory reflexes engendered by the obstructive respiratory efforts. To explore some factors responsible for triggering the bradycardia of apneas, Tarasiuk and Scharf (64) studied the influence of hypoxia, vagally carried reflexes, and lung inflation on the heart rate response to nonobstruc-
630
Scharf et al.
tive apneas in anesthetized dogs (Fig. 7). Compared with baseline during nonobstructive apneas, heart rate fell 47% when breathing room air, but only by 27% when breathing O2. As in the O’Donnell (9) studies, heart increased immediately upon resuming ventilation. After vagotomy, apneas on room air produced increases in BP and small (10%) decreases in heart rate. Heart rate decreased by approximately the same (16%) during apneas when O2 was administered postvagotomy. Finally, prevagotomy, with ventilation continuing, intermittent hypoxia was produced to match periodicity and hypoxia observed during room air apneas. This produced no change in heart rate. Thus the decrease in heart rate during apneas appeared to be due to the additive effects of (1) hypoxic chemoreflexes, the efferent limb of which is carried in the vagus, and (2) the absence of lung inflation, the afferent reflex limb of which is carried by the vagus. Both factors were necessary to produce apnea related bradycardia. Both these factors depend on an intact vagus to operate. Thus, vagotomy severely limited apnea-related bradycardia. Indeed, since in anesthetized dogs bradycardia is the most important component of the depressor effect of apneas, it is not surprising that when bradycardia is curtailed blood pressure no longer falls. In fact, blood pressure increases, probably due to the effects of unopposed sympathetic stimulation. The complex interactions among afferent impulses related to chemoreflexes, lung chest wall mechanoreceptor reflexes, and lung inflation reflexes, and the interaction between sympathetic and vagal autonomic activity in producing the cardiocirculatory response to apneas are best appreciated from these animal studies. However, the depressant effect of anesthesia on cardiopulmonary reflexes and brainstem activ-
Figure 7 Example of changes in BP and heart rate in an anesthetized dog during nonobstructive apnea under four conditions: RA, room air ventilation; ventilation with 100% O2 ; RA ⫹ V, RA after bilateral cervical vagotomy; and 100% O2 after V. Arrow indicates onset of the apnea; the asterix indicates apnea termination. Note that the depressor response to apneas is reversed by V, and that the pressor response to apneas following V is eliminated by giving 100% O2 . (From Ref. 64.)
Animal Models and OSA
631
ity makes interpretation of these data cautious. To overcome some of these obstacles, studies on unanesthetized, sedated animals have been done which readdress some of these issues. V.
Sedated Animal Models Without Arousal During Apneas
To minimize suppressive effects of anesthesia on cardiopulmonary reflexes, a preinstrumented sedated model in female Yorkshire farm pigs was developed which can be used to simulate many features of clinical OSA (65–69). Sensors and catheters are placed under general anesthesia, during thoracotomy and sterile conditions. Depending on experimental needs, instruments are place to allow the investigation of changes in global and regional beat-by-beat cardiovascular function during apnea. Data are collected 7 to 10 days after instrumentation under moderate to heavy sedation with a mixture of 0.9% alphaxolone and 0.3% alphadolone (SaffanR ). Inspiratory decreases in intrathoracic pressure during obstructive apnea are greater than those seen in the anesthetized dog model and are comparable to those measured in clinical studies (2,57). There is relative preservation of autonomic responses associated with baroreceptor and chemoreceptor stimulation (70,71). However, arousals during or postapnea are not seen with this model (66). Periodic nonobstructive apneas are produced by upper airway occlusion with periodicity of 30-sec occlusion (apnea) following by 30-sec ventilation (interapnea interval). Periodic non-obstructive apneas are produced as for anesthetized animals by paralyzing and mechanically ventilating the animals and then turning the ventilator on and off at the same periodicity as for obstructive apneas. Thus, apneas may be studied with and without the mechanical effects of negative inspiratory swings in intrathoracic pressure with control over oxygenation and apnea periodicity. A. Systemic Cardiovascular Responses and Mechanisms
Numerous clinical and animal studies have been done to investigate blood pressure and heart rate changes during periodic apneas. However, beat-by-beat changes in cardiac output and LV dimensions during apneas are not well defined because of the difficulties in accurately measuring these variables in clinical settings. Chen and Scharf (65) studied the responses of the LV to obstructive and non-obstructive apneas matched for periodicity and blood gas changes. In both apnea types, there were increases in blood pressure and decreases in heart rate during apneas compared to preapneic baseline. Measurements of cardiac output as well as BP during apnea allowed the conclusion that increased BP was due to arterial vasoconstriction since systemic vascular resistance increased. Depression of cardiac output and SV compared to preapneic baseline was observed during the late part of obstructive apnea and immediately following apnea termination. Though heart rate fell during the late apnea phase, depression of cardiac output was primarily due to decreases in SV. LV aflerload, as estimated by blood pressure and LV regional myocardial end-systolic lengths, increased compared to pre-apneic baseline during apneas and immediately following apnea termination. The inverse relationship between stroke volume
632
Scharf et al.
and afterload suggested that increased afterload was the prime mechanism responsible for decreased stroke volume during apneas. There were small changes in LV end-diastolic dimensions but large increases in LV end-diastolic transmural pressure during apneas. This suggested a decrease in LV compliance, possibly due to interdependence effects of the large increases in venous return during obstructed inspiration (56) and/or increased RV afterload (hypoxia vasoconstriction). Absence of a change in segmental shortening during obstructive apneas (67) suggested that changes in myocardial contractility are not major cause of decreased stroke volume. The most interesting finding from these studies was that the pressor and bradycardic response to apneas was greater more in the nonobstructive than the obstructive apneas (Fig. 8). Since BP rose more during nonobstructive apneas, there were greater adverse effects on LV function and cardiac output with this type of apnea than with obstructive apneas. This suggested that the neurocirculatory reflex effects associated with apneas, greater in nonobstructive apneas, not the effects of decreased intrathoracic pressure, were the more important determinants of changes in LV function during apneas. It is not clear why arterial vasoconstriction, and hence the pressor response, was greater in nonobstructive than obstructive apneas, although sympathetic responses were assumed to be the responsible efferent limb. It was postulated that mechanical reflexes, associated with either central vascular congestion or respiratory muscle contraction, modified the pressor response to apneas. Clinical studies have demonstrated a parallel relationship between hypoxemia and cardiovascular changes during periodic apneas (72). Data from sedated pigs support the important role of hypoxemia during apneas in triggering cardiovascular reflexes. In the sedated pigs, eliminating hypoxemia by oxygen supplementation abolished changes in cardiac output and stroke volume during obstructive (67) and nonobstructive apneas (66, 68). However, hypoxemia is not the sole factor triggering cardiovascular responses, since small but significant increases in blood pressure were observed even in the absence of hypoxia (66,68). Nonhypoxic mechanisms contributing to the pressor response are still unclear. Arousal cannot be a mechanism, since this does not occur. Hypercapnia can cause increased BP in this model. However, during hypercapnia unassociated with apneas, there is an increase in cardiac output associated with vasodilatation, the opposite of what is seen during apneas (66). Possibly, cyclical changes (loss and regain) in mechanoreceptor input during periodic apneas contribute to the pressor response during apneas. Clearly, though, the causes of nonhypoxic vasoconstrictor mechanisms during apneas need elucidation. Elevations in plasma and urinary catecholamine level and in muscle sympathetic nerve activity have been reported in sleep apnea patients (73). Sympathoadrenal activation was examined in the sedated pig model with periodic nonobstructive apneas (68). There was a parallel relationship between hemodynamic responses and sympathetic activation as reflected in plasma catecholamine level during apneas. Hypoxic apneas led to maximal increases in plasma catecholamines and maximal changes in blood pressure and cardiac output. Pretreatment with ganglionic blockade (hexamethonium) diminished both catecholamine and pressor responses. Thus, sympathoadrenal activation is a major efferent pressor mechanism during apneas.
Animal Models and OSA
633
Figure 8 Mean arterial pressure and heart rate in obstructive (OA) and nonobstructive (NOA) apneas in sedated pigs. BASE, baseline before the onset of apneas; downward arrow, apnea termination. Data are taken during the fifth to seventh apnea cycle. Data are taken in early apnea (5 sec into apnea), midapnea (15 sec into apnea), end apnea (25 to 29 sec into apnea), early preapnea (5 sec following apnea termination), and immediately preapnea (end of interapneic interval at 60 sec). For significance from baseline, *P ⬍ .05, **P ⬍ .01. For significance of values within the apnea cycle relative to early apnea ## P ⬍ .01. Note that NOA demonstrate greater increases in arterial pressure relative to baseline. There are greater decreases in heart rate over the apnea cycle with NOA as well. Note that immediately following apnea termination (after the arrow) there is an increase in heart rate. Time ⫽ time into apnea-interapnea cycle. During apneas, arterial PO2 decreased to approximately 40 mm Hg and PCO2 increased to approximately 55 mm Hg. (From Ref. 64.)
634
Scharf et al.
Specific afferent pathways of autonomic reflex during periodic apneas have not been thoroughly investigated. In a recent study (74) bilateral cervical vagotomy substantially blunted or eliminated the pressor response to apneas (Fig. 9). This unexpected finding suggested an important role for vagally mediated afferents in mediating the pressor response. One possible afferent limb is stimulation of aortic chemoreceptors. Vagal section (74) would have cut the aortic depressor nerve which travels alongside the left vagus in the pig. To test this hypothesis, in recent studies the aortic depressor nerve was isolated and sectioned with the vagus left intact. Following apnea testing, completion vagotomy was performed. Section of aortic depressor nerve by itself was sufficient to blunt the pressor response to apneas. Complete section of the vagi did not produce any further changes in the response. Thus, the effects of vagotomy appear to be related to denervation of receptor fields of the aortic depressor nerve, probably chemoreceptors. Interestingly, as in the anesthetized dog studies (64), vagotomy led to an increase in heart rate during apneas (74). As in the anesthetized dog studies, this was explained by postulating that since apneas activate both sympathetic and parasympathetic efferents, loss of parasympathetic efferents (vagotomy) would lead to a shift in the balance to the sympathetic efferents, hence increasing heart rate. In the aortic nerve section experiments, the heart rate response to apneas was not altered by section of the aortic nerve alone. Therefore, the apneic pressor response is mediated by autonomic reflexes probably
Figure 9 Effect of bilateral vagotomy on pressor response to nonobstructive apneas. MAP, mean arterial pressure; Bsln, preapneic baseline; Apnea, late apnea; Interapnea, late interapneic period; Recov, recovery following resumption of mechanical ventilation. For significance relative to baseline: *P ⬍ .05, ***P ⬍ .001.
Animal Models and OSA
635
activated via aortic chemoreceptor input whereas the heart rate response is mediated by efferent impulses carried by the vagus nerve. B. Regional Myocardial Function
Myocardial ischemic disease and cardiac dysfunction can occur in sleep apnea patients. LV myocardial circulation, metabolism, and contractile function during obstructive apneas were investigated in sedated pigs (67). Unlike the short apneas studied in pigs with induced OSA, coronary blood flow increases and coronary vascular resistance decreases during obstructive apneas, similar to responses seen in anesthetized dogs (49). Oxygen supplementation but not autonomic ganglionic blockade eliminated this response. Thus, local myocardial effects of hypoxemia rather than sympathetic vasodilation appear to account for coronary vasodilatation during apneas. If one combines the data from the induced apneas in pigs (47) with those from Refs. 49 and 67, it may be possible to conclude that local vasodilator effects of hypoxia during the apneic phase interact with sympathetic vasoconstrictor effects during arousal to produce overall effect on coronary blood flow. Which effects predominate could depend on the degree to which hypoxemia occurs, apnea duration, and postapneic arousal. In the sedated pigs, the effects of limitation of coronary vasodilator reserve (critical stenosis) was also tested during obstructive apneas. As in the anesthetized dogs (49), with critical stenosis of the LAD, periodic obstructive apneas led to acute myocardial ischemia as indicated by decreases in both regional myocardial pH and regional shortening in myocardium supplied by the stenotic coronary artery, although there were no changes in preapneic baseline function. Regional myocardial ischemia exaggerated the systemic cardiovascular effects of periodic apneas and led to greater decreases in cardiac output and stroke volume during apneas than normally seen without critical stenosis even though all other conditions, including blood gas alterations and apnea periodicity, remained the same with and without coronary stenosis (Fig. 10). Thus, the combination of hypoxia associated with limitation of coronary vasodilator reserve led to regional myocardial ischemia, which in turn led to greater adverse effects on global myocardial function during apneas. These studies suggest great awareness on the part of the clinician in diagnosing sleep apnea in patients at risk for coronary artery disease. Further, they provide a physiological explanation of the high prevalence of sleep apnea in patients with myocardial infarction (75). C. Cardiovascular Response to Apneas in Failing Hearts
Sleep apnea is a common complicated disease in patients with congestive heart failure and has an adverse effects on disease progression. Effects of periodic obstructive apneas have been tested in sedated pigs with pacing-induced congestive heart failure (67). In failing hearts obstructive apneas led to a smaller pressor response but greater decreases in cardiac output and stroke volume than in nonfailing hearts. Moreover, unlike in normal hearts, oxygen supplementation or hexamethonium pre-
636
Scharf et al.
Figure 10 Mean arterial pressure and cardiac output in a series of sedated pigs undergoing obstructive apneas with and without critical stenosis of the LAD coronary artery while breathing room air. RA, breathing room air with no stenosis of the coronary artery; CS, critical stenosis of the LAD. Note that relative to baseline, there is a greater decrease in cardiac output with CS. This indicates that regional ischemia produced during apneas in myocardium perfused by the LAD can influence global function and worsen the adverse hemodynamic consequences of apnea. The increases in arterial pressure were the same with RA and CS conditions. Thus, the afterload applied against the LV was the same in both cases. Differences in output were most likely related to differences in global LV function. BASE, baseline values before the onset of apneas. Data from the fifth to seventh apnea-interapnea cycle. EAP, early apnea; LAP, late interapnea; EIA, early interapnea; LIA, late interapnea; RECOV, recovery after normal ventilation was resumed. For differences relative to baseline: **P ⬍ .01. (From Ref. 67.)
Animal Models and OSA
637
treatment did not eliminate depression of cardiac output and stroke volume even though blood pressure, and hence LV afterload, decreased during apneas. Both nonobstructive and obstructive apneas demonstrated the same trends, suggesting that periodic decreases in intrathoracic pressure were not responsible for decreased cardiac output in failing hearts. However, in contrast to normal hearts, in failing hearts LV preload was observed to decrease. It was suggested that decreased preload is a major mechanism responsible for depression of cardiac output and stroke volume in failing hearts. Though the mechanism responsible for decreased preload remains to be clarified, it is possible that the decrease in LV preload during apnea is related to interdependence effects during apneas because of increased venous return, as discussed above. Possibly in the failing hearts, myocardial and subsequent pericardial dilatation exaggerates the effects of interdependence (76) and causes greater decreases in LV preload due to increases in RV volume than in normals. VI. Conclusions If nothing else, animal models of apneas have shown that the response to apneas is far from simple, and that preconceived easy answers are incomplete. For example, in 1984, one of us (S.M.S.) postulated that the responses to apneas could be understood in terms of the responses to the LV to the Mueller maneuver (77). The animal work seems to show that this effect, if occurring at all with the transient decreases in intrathoracic pressure of apneas, is minor. Rather, the neurocirculatory reflex effects engendered by apneas are predominant. Further, the animal studies provide solid evidence for a causal relationship between OSA and important cardiovascular sequelae such as heart attacks (acute ischemia) and hypertension. Animal models are also aiding in the dissection of the afferent and efferent limbs of the neurocirculatory responses to apneas. Thus, the animal studies will continue to play an important role in advancing our understanding of this important and common disorder. References 1. 2. 3. 4. 5. 6. 7.
Young T, Palta M, Dempsey J, Skatrud D, Weber S, Badr S. The occurrence of sleepdisordered breathing among middle aged adults. N Engl J Med 1993; 328:1230–1235. Podszus TE, Greenberg H, Scharf SM. Influence of sleep state and sleep-disordered breathing on cardiovascular function. In: Sullivan CE, Saunders NA, eds. Sleep and Breathing II. New York: Marcel Dekker, 1994:257–310. Malone S, Liu PP, Holloway RM, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991; 338:1480–1484. Hendricks JC, Pack AI. Animal models of sleep apnea. In: Saunders NA, Sullivan CE, eds. Sleep and Breathing II. New York: Marcel Dekker, 1994:847- 866. Lonergan PR III, Ware JC. Atkinson RL, Winter WC, Suratt PM. Sleep apnea in obese miniature pigs. J Appl Physiol 1998; 84:531–536. Kimoff RJ, Makino H, Horner RL, Kozar LF, Lue F, Slutsky A, Phillipson EA. Canine model of obstructive sleep apnea: model description and preliminary application. J Appl Physiol 1994; 76:1810–1817. O’Donnell CP, King ED, Schwartz AR, Smith PL, Robotham JL. The effect of sleep depriva-
638
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
Scharf et al. tion on responses to airway obstruction in the sleeping dog. J Appl Physiol 1994; 77: 1811– 1818. O’Donnell CP, Ayuse T, King EA, Schwartz AR, Smith PL, Robotham JL. Airway obstruction during sleep increases blood pressure without arousal. J Appl Physiol 1996; 80: 773– 781. O’Donnell CP, Schwartz AR, Smith PL, Robotham JL, Fitzgerald RS, Shirahata M. Reflex stimulation of renal sympathetic nerve activity and blood pressure in response to apnea. Am J Respir Crit Care Med 1996; 154:1763–1770. Horner RL, Brooks D, Kozar LF, Tse S, Phillipson EA. Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs. J Appl Physiol 1995; 79:151–162. Brooks D, Horner RL, Kimoff RJ, Kozar LF, Tender-Teixera CL, Phillipson EA. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Respir Crit Care Med 1997; 155:1609–1617. Millman RP, Redline S, Carlisle CC, Asaf A, Levinson PD. Daytime hypertension in obstructive sleep apnea. Prevalence and continuing risk factors. Chest 1991; 100:861–866. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea (experience in 385 male patients). Chest 1988; 94:9–14. Hoffstein V, Mateika S, Rubinstein I, Slutsky AS. Determinants of blood pressure in snorers. Lancet 1988; 2: 992–994. Fletcher EC, DeBehnke RD, Lavoi MS, Goren AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103:190–195. Lavie P, Ben-Yosef R, Rubin AE. Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984; 108:373–376. Scharf SM, Garshick E, Brown R, Tishler PV, Tosteson T, McCarley R. Screening for subclinical sleep-disordered breathing. Sleep 1990; 13:344–353. Grunstein R, Wilcox I, Yang TS, Hedner JA, Gould Y, Dodd MJ. Sleep apnoea: a confounding factor in the relationship between pattern of obesity and systemic hypertension? J Sleep Res 1992; 1(suppl 1):87. Guillemenault C, Blair Simmons F, Motta J, Cumminsky J, Roseking M, Schroeder JS, Dement WC. Obstructive sleep apnea syndrome and tracheostomy. Long term follow-up experience. Arch Intern Med 1981; 141:985–989. Brooks D, Horner RL, Kozar LF, Render-Teixera CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. J Clin Invest 1997; 99:106–109. Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep apnea and hypertension. A population based study. Ann Intern Med 1994; 120:382–388. Grunstein R, Wilcox I, Yang TS, Gould Y, Hedner J. Snoring and sleep apnoea in men: association with central obesity and hypertension. Int J Obesity 1993; 17:533–540. O’Donnell CP, Schwartz AR, Smith PL, Robotham JL, Fitzgerald RS, Shirahata M. Reflex stimulation of renal sympathetic nerve activity and blood pressure in response to apnea. Am J Respir Crit Care Med 1996; 154:1763–1770. Tarasiuk A, Scharf SM. Cardiovascular effects of periodic obstructive and central apneas in dogs. Am J Respir Crit Care Med 1994; 150:83–89. Shepard JW. Gas exchange and hemodynamics during sleep. Med Clin North Am 1985; 69:1243–1264. Sommers VK, Dyken ME, Clary M, Abboud M. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897–1904. Fletcher EC, Miller J, Schaaf W, Fletcher J. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987; 10:35–44. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. chest 1993; 103:1763–1768. Hedner J, Wilcox I, Laks L, Grunstein R, Sullivan C. A specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis 1992; 146:1240–1245. Johnson TS, Young JB, Landsberg L. Sympathoadrenal responses to acute and chronic hypoxia in the rat. J Clin Invest 1983; 71:1263–1272. Fletcher EC, Lesske J, Qian W, Miller CC, Unger T. Repetitive episodic hypoxia causes diurnal elevations of systemic blood pressure in rats. Hypertension 1992; 19:555–561.
Animal Models and OSA 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.
639
Fletcher EC, Lesske J, Behm R, Miller CC, Staus H, Unger T. Carotid chemoreceptors, systemic blood pressure and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 1992; 72:1978–1984. Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 1992; 20:612–619. Bao G, Randhawa PM, Fletcher EC. Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. J Appl Physiol 1997; 82:1071–1078. Greenberg HE, Sica A, Batson D, Scharf SM. Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 1999; 86:298–305. Reis D, Golanov E, Ruggiero D, Sun MK. Sympatho-excitatory neurons of the rostral ventrolateral medulla are oxygen sensors and essential elements in the tonic and reflex control of the systemic and cerebral circulations. J Hypertension 1994; 12(suppl 10):S159–S180. Dumas S, Pequingnot JM, Ghilini G, Mallet J, Denavit-Saubre M. Plasticity of tyrosine hydroxylase gene expression in the rat nucleus tractus solitarius after ventilatory acclimatization to hypoxia. Mol Brain Res 1996; 20: 188–194. Greenberg HE, Sica AL, Scharf SM, Ruggiero DA. Expression of c-fos in the rat brainstem after chronic intermittent hypoxia. Brain Res 1999; 816:638–645. Morgan JI. Proto-oncogene expression in the nervous system. Neuroscience 1991; 7:1–50. Finley JCW, Katz DM. The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res 1992; 572:108–116. Hirooka Y, Polson JW, Potts PD, Dampney RAL. Hypoxia-induced FOS expression in neurons projecting to the pressor region in the rostral ventrolateral medulla. Neuroscience 1997; 80:1209–1224. Scharf SM. Cardiovascular effects of airway obstruction. Lung 1991; 169:1–23. Heistad DD, Abboud FM. Circulatory adjustments to hypoxia. Circulation 1980; 61:483– 469. Kaufman MP, Cassidy SS. Reflex effects of lung inflation and other stimuli on the heart and circulation. In: Scharf SM, Cassidy SS, eds. Heart-Lung Interactions in Health and Disease, 1st ed. New York: Marcel Dekker, 1989:339–364. Schneider H, Schaub CD, Andreoni K, Schwartz AR, Smith PL, Robotham JL, O’Donnell CP. Systemic and pulmonary hemodynamic responses to normal and obstructed breathing during sleep J Appl Physiol 1997; 83:1671- 1680. Parker JD, Brooks D, Kozar LF, Tender-Teixera CL, Horner RL, Phillipson EA. Acute and chronic effects of obstructive sleep apnea (OSA) on left ventricular performance in a canine model. Am J Respir Crit Care Med 1998; 157(suppl):A 776. Pinto JMB, Garpestad E, Weiss JW, Bergau DM, Kirby DA. Hemodynamic changes associated with obstructive sleep apnea followed by arousal in a porcine model. J Appl Physiol 1993; 75:1439–1443. Baust W, Weidinger H, Kirchner F. Sympathetic activity during natural sleep and arousal. Arch Ital Biol 1968; 106: 379–390. Scharf SM, Graver LM, Balaban K. Cardiovascular effects of periodic occlusions of the upper airways in dogs. Am Rev Respir Dis 1992; 146:321–329. Guillemenault C, Motta J, Mihm F, Melvin K. Obstructive sleep apnea and cardiac index. Chest 1986; 89:331–334. Tolle FA, Judy WV, Pao-Lo Y, Markand ON. Reduced stroke volume related to pleural pressure in obstructive apnea. J Appl Physiol 1983; 55:1718–1724. White SG, Fletcher EC, Miller CC III. Acute systemic blood pressure elevation in obstructive and nonobstructive breath hold in primates. J Appl Physiol 1995; 79:324–330. McGinty D, Beahm E, Stern N, Littner M, Savers J, Reige W. Nocturnal hypotension in older men with sleep related breathing disorders. Chest 1988; 94:305–311. Tarasiuk A, Scharf SM. Effects of periodic obstructive apneas on venous return in closedchest dogs. Am Rev Respir Dis 1993; 148:323–329. Salejee I, Tarasiuk A, Reder I, Scharf SM. Chronic upper airways obstruction produces right but not left ventricular hypertrophy in rats. Am Rev Respir Dis 1993; 148:1346–1350. Tarasiuk A, Chen L, Scharf SM. Effects of periodic obstructive apnoeas on superior and inferior venous return in dogs. Acta Physiol Scand 1997; 161:187–194. Lugaresi E, Cirignotta F, Coccagna G, Montagna P. Clinical significance of snoring. In:
640
58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77.
Scharf et al. Saunders NA, Sullivan CE, eds. Sleep and Breathing. New York: Marcel Dekker, 1984: 283–298. Buda AJ, Pinsky MR, Ingels NG, Daughters GI, Stinson EB, Alderman EL. Effects of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 30:453–459. Scharf SM, Brown R, Tow DE, Parisi AF. Cardiac effects of increased lung volume and decreased pleural pressure in man. J Appl Physiol. 1979; 47:257–262. Scharf SM, Brown R, Saunders NA, Green LH. Effects of normal and loaded spontaneous inspiration on cardiovascular function. J Appl Physiol. 1979; 47:582–590. Scharf SM, Bianco JA, Tow DE, Brown R. The effects of large negative intrathoracic pressure on left ventricular function in patients with coronary artery disease. Circulation 1981; 63:871–875. Tarasiuk A, Scharf SM. Cardiovascular effects of periodic obstructive and central apneas in dogs. Am J Respir Crit Care Med 1994; 150:83–89. Shykoff BE, Naqvi SSJ, Menon AS, Slutsky AS. Respiratory sinus arrhythmia in dogs: effects of phasic afferents and chemostimulation. J Clin Invest 1991; 87:1621–1627. Tarasiuk A, Scharf SM. Mechanism of circulatory depression during simulated central apneas in the anesthetized dog. J Basic Clin Physiol Pharm 1994; 5:253–267. Chen L, Scharf SM. Hemodynamic effects of periodic obstructive and simulated central apneas in sedated pigs. J Appl Physiol 1997; 83:485–497. Chen L, Sica AL, Greenberg H, Scharf SM. Role of hypoxemia and hypercapnia in acute cardiovascular response to periodic apneas in sedated pigs. Respir Physiol 1998; 111:247– 246. Chen L, Scharf SM. Systemic and myocardial hemodynamics during periodic obstructive apneas in sedated pigs. J Appl Physiol 1998; 84;1289–1298. Chen L, Sica A, and Scharf SM. Mechanisms of acute cardiovascular response to periodic apnea in sedated pigs. J Appl Physiol 1999; 86:1236–1246. Chen L, DiBlasi M, Scharf SM. Cardiovascular response to periodic apneas in sedated pigs with congestive heart failure. Am J Respir Crit Care Med 1998; 157:A775. Hilton SM, Marshall EM. The pattern of cardiovascular response to carotid chemoreceptor stimulation in the cat. J Physiol (Lond) 1985; 326:495–513. Blake DW, Korner PI. Effects of ketamine and althesin anesthesia on baroreceptor heart rate reflex and hemodynamics of intact and pontine rabbits. J Auton Nerv System 1982; 5: 291–301. Bonsignore MR, Marrone O, Insalaco G, Bonsignore G. The cardiovascular effects of obstructive sleep apnoeas: analysis of pathogenic mechanisms. Eur Respir J 1994; 7:786–805. Coy TV, Dimsdale JE, Ancoli Israel S, Clausen J. Sleep apnoea and sympathetic nervous system activity: a review. J Sleep Res 1996; 5:42–50. Slamowitz D, Chen L, Scharf SM. Effects of vagotomy on cardiovascular response to periodic apneas. Am J Respir Crit Care Med 1998; 157:A775. Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in man. Lancet 1994; 336:261–264. Janicki JS, Weber KT. The pericardium and ventricular interaction, distensibility and function. Am J Physiol 1980; 238:H494–H503. Scharf SM. Influence of sleep state and breathing on cardiovascular function. In: Saunders NA, Sullivan T, eds. Sleeping and Breathing. New York: Marcel Dekker, 1984:221–282.
24 Sleep Apnea and Right Ventricular Function
THOMAS E. PODSZUS
CHRISTIAN OLE FEDDERSEN
Klinikum Hof Hof, Germany
Kreiskrankenhaus Aurich Aurich, Germany
STEVEN M. SCHARF Long Island Jewish Medical Center Albert Einstein College of Medicine New Hyde Park, New York
I.
Introduction
Obstructive sleep apnea is associated with a variety of hemodynamic abnormalities. Most of the scientific work dealing with these issues has centered on the relation between sleep-disordered breathing (SDB) and hypertension as well as SDB and left heart failure. Since the 1960s, studies in patients with pickwickian syndrome and obstructive sleep apnea (OSA) have been performed during the day- and nighttime. Furthermore, epidemiological studies and basic research using animal models have been done to examine the relationships among obstructive sleep apnea, hypertension, and other cardiovascular sequelae. Most of these studies have focused on the left ventricle and systemic hypertension. However, several questions of the pathophysiological link between cardiocirculatory abnormalities and SDB, i.e., obstructive sleep apnea, remain to be answered. What is the relation between nocturnal and daytime cardiovascular abnormalities? Is obstructive sleep apnea a risk factor for coronary heart disease and ischemic stroke? Which specific factors in patients with obstructive sleep apnea contribute to cardiocirculatory sequelae? It is of interest that most of the studies done in this field deal with hypertension, pulmonary hypertension, left heart failure, and coronary heart disease. 641
642
Podszus et al.
Table 1 Number of Publications on RV Function and OSA per Year from 1968 to 1997 1968 1976 1978 1984 1985 1987 1989 1991 1992 1993 1994 1995 1996 1997 1
2
1
2
1
2
1
3
3
5
1
3
2
2
Only relatively few studies have specifically examined the right ventricle (RV) and right ventricular function in patients with SDB. The aim of this chapter is to highlight the effects of SDB on RV function, a topic which is probably located in the scientific shadow but is of more importance than usually considered. For example, a literature search for right ventricle and OSA resulted in 29 references, homogeneously distributed over the years since 1968 with a small increase in interest in the early 1990s (Table 1). Changes of RV function are able to impair left ventricular function in several ways. Thus, in patients with OSA, it is of great importance to define the role of RV function in the complex of the hemodynamic alterations. II. Right Heart Morphology in OSA The earliest report of right as well as left ventricular enlargement during obstructive apnea was presented by Lugaresi (1). Here, the development of pulmonary edema during obstructive apneas while asleep was demonstrated by means of cineradiographic methods. Stauffer (2) showed data on RV dimensions in asymptomatic snoring. Patients with an apnea/hypopnea index (AHI) ⬎10/h did not demonstrate a different right atrial and RV area, RV wall thickness, systolic pulmonary artery pressure, and LV mass index than patients with AHI ⬍ 10/h. However, the RV and RA were enlarged in 5 out of 11 patients by 2-D echocardiography. In a larger group of patients (3) no morphological right heart abnormalities were found in patients with OSA. In this investigation a left ventricular mass index of 117.6 g/m2 was found in a group of 30 OSA patients, compared to 101.2 g/m2 in the control group. This left ventricular hypertrophy was not explained by the presence of hypertension or obesity. Left atrial size was normal in this study, indicating that diastolic left ventricular function was not the cause of major hemodynamic disturbances. However, parameters of left ventricular diastolic function were not calculated. The main finding was the increased thickness of the interventricular septum (13.5 mm vs. 11.1 mm) and the left ventricular posterior wall (11.7 mm vs. 9.6 mm) compared with controls. Similarly increased thickness of the intraventricular septum (11.4 mm in OSA) as well as left ventricular posterior wall (12.1 mm in OSA vs. 9.6 in hypertensives) was published earlier (4). These findings of beginning LV concentric hypertrophy were not related to hypertension. The highest prevalence of RV hypertrophy in OSA was reported by Rao (5) with a prevalence of 63% in children with OSA. These children had morphological abnormalities of the upper airways including tonsillar and adenoidal hypertrophy.
Sleep Apnea and RV Function
643
Therefore, upper-airway obstruction was probably not only a sleep-related problem but was present while awake. Hence, the patients are not strictly be comparable with adult OSA patients. In another investigation (6), performed in 50 patients suspected of OSA, the prevalence of RV hypertrophy was significantly higher in OSA patients (71% of all OSA patients) compared to controls. RV hypertrophy was not related to age or weight. Patients with RV hypertrophy had a longer duration of apneas, and more pronounced desaturations. However, multivariate testing failed to find significant predictors of RV hypertrophy. In contrast, Davidson (7) found a clear correlation between RV hypertrophy and OSA. RV wall thickness correlated linearly with AHI independent of left ventricular mass. Additionally, pulmonary arterial pressure influenced RV wall thickness despite pressure values ⬍ 40 mmHg (8). Similarly, no correlation between pulmonary arterial pressure and RV hypertrophy was found by Kober (9), even when intermittent increases of nocturnal pulmonary arterial pressure were taken into account. Noda (10) found the prevalence of RV hypertrophy was 21.4% in patients with OSA. Six out of 28 patients with an AHI ⬎ 20/h had RV hypertrophy, compared with no RV hypertrophy in patients with an AHI ⬍20/h. Left ventricular hypertrophy was more common in both groups (7 out of 23 patients and 14 out of 28 patients). All patients with RV hypertrophy also demonstrated LV hypertrophy. The intraventricular septum was only slightly thicker in the group with an AHI ⬎20/ h (11.6 mm vs. 10.2 mm). This was also true for the left ventricular posterior wall (10.4 mm vs. 9.3 mm). The authors speculated that hypoxia and increased sympathetic drive may play an important role in the development of RV hypertrophy. Hanly (11) failed to find any abnormalities of RV dimension and RV wall thickness when comparing patients with OSA and snorers. The dimensions were within a normal range in the whole group as well as in a subgroup of patients with an AHI ⬎40/h. This is in contrast to most studies showing differing prevalence of RV hypertrophy between OSA patients and snorers. Table 2 summarizes the incidence of RV hypertrophy in patients with snoring and obstructive sleep apnea. In one study (12) an animal model was used to investigate the influence of upper-airway obstruction on RV as well as LV hypertrophy. After 7 weeks of tracheal obstruction RV weight was significantly greater in the obstructed group than in controls (0.77 and 0.74 versus 0.54 and 0.59). Interestingly, there were no significant
Table 2 Incidence of RV Hypertrophy in Patients with Snoring and Obstructive Sleep Apnea Author Motz (4) Stauffer (2) Hedner (3) Berman (6) Noda (10) Rao (5)
No. of patients
RV hypertrophy
28 11 61 28 51 40
No data 27.3 No RV abnormalities 20 11.8 63
644
Podszus et al.
differences in LV weight between the two groups in this model of normoxic airway obstruction. The effect persisted even after 1 year following obstruction. RV dry/ wet ratio was 0.67 in the obstructed compared to 0.45 in the control group. Since the animals were normoxic, diastolic left ventricular failure, intrathoracic pressure swings resulting in preload changes, and hypercapnia and acidosis were discussed as possible mechanisms for the development of RV hypertrophy due to upper airway obstruction (see Chapter 23). In autopsy reports thicker RV walls could be measured in OSA patients with obesity-hypoventilation syndrome compared with a control group (13). The difference of 7.1 mm to 4.2 mm was statistically significant. Myocardial fibrosis and a medial hypertrophy of muscular pulmonary arteries were the predominat findings in these patients. The result supported two possible pathophysiological mechanisms leading to myocardial hypertrophy: Hypertension and increased left ventricular afterload are responsible for the development of left ventricular (LV) hypertrophy, and pulmonary hypertension for RV hypertrophy. Similarly there is little agreement concerning the mechanisms of desease. Reasons for the discrepancies include different concomitant clinical conditions, duration of disease, different algorithms for detecting, and different definitions of RV hypertrophy. Many authors believe that pulmonary hypertension at rest during the daytime is necessary for the development of RV hypertrophy. However, this well-known finding in other diseases is not present in all references. Obesity and intrathoracic blood volume changes, pulmonary hypertension, apnea related intrathoracic pressure swings with RV pre- and afterload changes, impairment of RV compliance, hypoxia, hypercapnia and acidosis may act together and result in structural changes of the right ventricle. The relative importance of each mechanism in the pathogenetic chain is not clear.
III. Right Heart Function in OSA The classic description of the pickwickian syndrome includes cor pulmonale and RV failure (14). It later became obvious that most pickwickian patients suffered from severe obstructive sleep apnea (15). However, patients fulfilling the criteria of the pickwickian syndrome are only a minor part in the group of patients with obstructive sleep apnea. The prevalence of RV dysfunction and clinical signs of right heart failure have been addressed in only a few studies. Bradley (16) investigated 50 patients with OSA and found right heart failure in six patients (12%). Right heart failure was associated with nocturnal as well as daytime hypoxemia. This finding underlines the importance of the development of pulmonary hypertension leading to RV failure. Similar conclusions about the pathophysiology of RV function were drawn by Whyte (17): 18 out of 65 sleep apnea patients (27 %) had peripheral edema without any explanation. In this study patients with right heart failure were more obese and had lower oxygen saturation during wakefulness. Here also, the importance of both daytime and nighttime hypoxemia as a condition for the development of RV failure
Sleep Apnea and RV Function
645
was also underlined. Another study (18) defined right heart failure as leg edema together with an increased mean right atrial pressure: 27 out of 70 patients (38.6%) fulfilled these criteria of right heart failure. The authors speculated that right heart failure is not related to hypoxemia but to the hemodynamic effects of morbid obesity. However, it is not clear, what specifically these hemodynamic effects should be. The earliest report of RV enlargement with nocturnal apneas was given by Lugaresi et al. (1). Here, RV enlargement was accompanied by LV dilatation and alveolar edema induced by recurrent obstructive apneas. In a study by Fletcher (19) nine patients with both OSA and lung disease had cor pulmonale and decreased RV ejection fraction. Additionally, two of five patients with OSA without additional lung disease demonstrated signs of cor pulmonale; 18 out of 24 patients who enrolled in the study were described as having cor pulmonale. The prevalence of RV failure in this study is obviously influenced by concomitant lung diseases. However, following tracheostomy, patients showed a significant improvement of RV ejection fraction in follow-up investigations. Additional studies used radionuclide ventriculography to determine RV ejection fraction. Of 107 OSA patients right ventricular ejection fraction was impaired in 19 (18%); 18 out of these 19 patients had clinical signs of RV failure. A multiple logistic regression analysis resulted in a significant association with respirartory disturbance index and nocturnal desaturation. Using similar methods Guidry (20) also found reduced RV ejection fraction despite normal left ventricular function at rest. In contrast in OSA patients Nahmias (21) found a lower left ventricular ejection fraction in association with RV dysfunction; 20 (24%) out of 48 patients suffered from RV dysfunction. Nocturnal saturation in these patients was not lower than in the control group but there was a tendency for lower awake paO2 values. In another study, the same author (22) found a prevalence of 31.3% (35 out of 112 patients) of RV dysfunction is OSA patients. However, in this investigation patients with RV dysfunction showed a lower nocturnal arterial oxygen saturation of 82% versus 87% in patients without RV dysfunction. Here RV dysfunction appeared to be related to nocturnal oxygen desaturation and was reversible during treatment with nasal continuous positive pressure. Gro¨tz (23) studied 20 OSA patients including 10 patients with an abnormally high RV/LV ratio. Here, RV dysfunction was not correlated to the presence of pulmonary hypertension. In summary, most of the studies focusing on RV dysfunction and cor pulmonale agree that there is a significant prevalence of RV dysfunction in OSA patients. The methods and data evaluation used are different, so comparisons are not easily done. However, there is a tendency for RV dysfunction to be more common in OSA and clinical signs of right heart failure are detected in 12% to 27% of the patients. RV dysfunction diagnosed using different methods seems to be present in more than 30% of patients. Bradley (24) has postulated a threshold level of respiratory disturbance which is lowered if chronic obstructive pulmonary disease is present. Thus concomitant lung disease lowers the respiratory disturbance level required to produce RV failure. In patients with only obstructive sleep apnea, treatment with nasal continuous positive pressure is able to reverse RV failure. Only a few studies dealing with the prevalence of clinical signs of RV failure have been published. Few sufficient data from long-term investigations stratify the
646
Podszus et al.
OSA patients into groups with or without lung diseases. The methods used to describe RV dysfunction as well as morphological changes differ in many points in the presented studies. It is still true to say. ‘‘Determining the true incidence awaits further refinement in the methodology and technique of determining RVH and in better delineation of the population under study’’ (25).
IV. Right Heart Pathophysiology in OSA In the last three decades many hemodynamic abnormalities have been described in patients withOSA. Most of these studies have focused on the systemic circulation and the function of the left ventricle. In patients with OSA many factors work together to alter RV function during the day and at night. During nighttime, OSA causes hypoxemia, acidosis, and hypercapnia which stiffens not only the left but also right ventricular musculature. Decreasing ventricular compliance is always associated with increased filling pressures as a result of diastolic dysfunction. During obstructive apneas in non-REM sleep, as is seen clearly in Figure 1. The right atrial pressure (relative to atmosphere) decreases during inspiration and rises continuously during expiration until the end of the apnea. During inspiration, transmural right atrial pressure (tmPRA ) reflects the changes of venous return and increases to a certain degree. Figure 2 shows the tmPRA values from a patient with OSA evaluated out of all obstructed inspirartory efforts during sleep. At a value of ⫺2 mm Hg tmPRA plateus and venous return increases only a little when the negative inspiratory pressure swings are more pronounced. These findings are in agreement with animal experiments (26) and can be explained by increasing venous return during obstructive apnea. Changes of venous return during apneas seem to be related to hypoxemia and to shifts of blood volume from the peripheral to the central circulation (27). Additionally, RV cardiac output decreases during the apnea episode but increases afterward due to tachycardia (28). The result is seen in a right ventricular volume overload during inspiration leading to a leftward shift of the interventricular septum impairing left ventricular function (29). Hypoxia, and to a minor degree hypercapnia, leads to precapillary vasoconstriction of the pulmonary arteries resulting in an increased transmural pulmonary arterial pressure during obstructive apneas. The increased pulmonary arterial pressure represents an increase in right ventricular afterload during the apnea. Impaired left ventricular function can contribute to this effect via elevated end-diastolic pressures which act retrograde by increasing pulmonary arterial pressure (30). Many sleep apnea patients are obese. Obesity itself is able to produce many hemodynamic abnormalities. For example, total blood volume, cardiac output, and central blood volume increase in obese patients (31). Such findings have been confirmed by other authors who have described an increased intravascular blood volume and cardiac output as well as increased venous return. Total peripheral resistance is diminished and reduced distensibility in the central circulation results in increased
Sleep Apnea and RV Function
647
Figure 1 Obstructive apnea episode during NREM sleep. Shown are from top to bottom: ECG, air flow (Flow), esophageal pressure (Pes ), systemic arterial pressure (PART ), pulmonary arterial pressure (PPA ), and right atrial pressure (PRA ).
filling pressures of the right and left heart (32,33). Such hemodynamic changes have been thought to cause eccentric hypertrophy of the left ventricle in obese patients due to the described changes in total blood volume and cardiac output (34). In further studies an increased heart weight in obese patients and increased numbers of adipocytes has been shown (35). Obesity currently is thought to be responsible for an adiposity cordis (35). The physiological cardiac cycle cannot work without alterations when the above described structural changes of the myocardium are present. As has been shown in clinical studies, the first distolic function of the right ventricle is impaired significantly by obstructive sleep apnea. Daytime and nighttime hypoxemia, hypercapnia, acidosis, changes in total blood volume and central blood volume, structural changes due to obesity, reduced distensibility of the central circulation, increased venous return, and mechanical alterations due to large intrathoracic pressure swings seem to be the mechanisms which may cause right heart failure in
648
Podszus et al.
Figure 2 Changes of transmural right atrial pressure (tmPRA ) related to esophageal pressure (Pes ) in a patient with OSA. TmPRA values are calculated for each inspiratory effort in all obstructive apneas in one night.
patients with obstructive sleep apnea. The role of each piece in this mosaic has to be worked out in further studies.
References 1. 2. 3. 4. 5. 6. 7.
Lugaresi E, Cirignotta F, Coccagna G, Montagna P. Clinical significance of snoring. In: Saunders NA, Sulliva CE, eds. Sleep and Breathing. New York: Marcel Dekker, 1984:283– 298. Stauffer JL, Davidson jr. WR, Zwillich CW. Echocardiographic and electrocardiographic findings in asymptomatic snoring men (abstr). Am Rev Respir Dis 1989; 139:A113. Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea. J Hypertens 1990; 8:941–946. Motz W, Bethge C, Klepzig M, Blanke H, Strauer BE. Echocardiographic findings in sleep apnoea. In: Peter JH, Podszus T, von Wichert P, eds. Sleep Related Disorders and Internal Diseases. Berlin: Springer-Verlag, 1987:326–329. Rao M, Shapir Y, Abal G, Rao S, Schiller M, Kravath R, Steiner P. Correlation of echocardiography with sleep study in children with obstructive sleep apnoea (abstr). Clin Res 1989; 37:867a. Bermann EJ, DiBenedetto RJ, Causey DE, Mims T, Conneff M, Goodman L, Rollings RC. Right ventricular hypertrophy detected by echocardiography in patients with newly diagnosed obstructive sleep apnea. Chest 1991; 100:347–350. Davidson WR Jr, Stauffer JL, Reeves-Hoche MK, Zwillich CW. Cardiac sequelae of sleep-
Sleep Apnea and RV Function
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
649
disordered breathing in obstructive sleep apnoea: new evidence for right ventricular dysfunction (abstr). Am Rev Respir Dis 1993; 147:A1015. Davidson WR Jr. Ventricular hypertrophy in sleep apnoea. J Sleep Res 1995;4(suppl 1): 176–181. Kober J, Tomkowski W, Fjalkowska A, Koziej M, Filipecki S, Zielinski J. Echocardiographic analysis of cardiac size and function in patients with severe obstructive sleep apnea. Allergol Pol 1996; 64(suppl 2):187–192. Noda A, Okada T, Yasuma F, Nakashima N, Yokota M. Cardiac hypertrophy in obstructive sleep apnea syndrome. Chest 1995; 107:1538–1544. Hanly P, Sasson Z, Zuberi N, Alderson M. Ventricular function in snorers and patients with obstructive sleep apnea. Chest 1992; 102:100–105. Salejee I, Tarasiuk A, Reder I, Scharf SM. Chronic upper airway obstruction produces right but not left ventricular hypertrophy in rats. Am Rev Respir Dis 1993; 148:1346–1350. Ahmed Q, Chung-Park M, Tomashewski JF Jr. Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome. Hum Pathol 1997; 28(3):261–263. Burwell CS, Robin ED, Whaley RD, Bickelman AG. Extreme obesity associated with alveolar hypoventilation-a pickwickian syndrome. Am J Med 1956; 21:811–818. Doll E, Kuhlo W, Steim H, Keul J. Zur Genese des cor pulmonale beim Pickwick-Syndrome. Dtsch Med Wochensch 1968; 93:2361–2365. Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H, Phillipson EA. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131:835–839. Whyte KF, Douglas NJ. Peripheral edema in the sleep apnea/hypopnea syndrome. Sleep 1991; 14(4):354–356. Gold AR, Gold S, Diggs P, Dervan JP. The prevalence and clinical correlates of right heart failure among patients with sleep apnea (abstr). Am Rev Respir Dis 1997; 155:A868. Fletcher EC, Schaaf JW, Miller J, Fletcher JG. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987; 135:525– 533. Guidry GG, Anderson W, Chesson AL Jr, Goel YS, Reed MD, Bairnsfather L. Myocardial performance at rest and during exercise in patients with obstructive sleep apnea (abstr). Am Rev Respir Dis 1990; 141:A373. Nahmias JS, Karetzky MS. Ventricular dysfunction and pulmonary function in OSA syndrome. N J Med 1993; 90:538–544. Nahmias JS, Karetzky MS. Right ventricular dysfunction in obstructive sleep apnoea: reversal with nasal continuous positive airway pressure. Eur Respir J 1996; 9:945–951. Gro¨tz J, Konermann M, Sanner B, Wiemann J. Radionuklidventrikulographie zur Diagnostik rechtsventrikula¨rer Funktionssto¨rungen bei Patienten mit obstructivem Schlafapnoesyndrom. Herz/Kreislauf 1993; 25:305–308. Bradley TD. Right and left ventricular functional impairment and sleep apnea. Clinics in Chest Medicine 1992; 13:459–479. DiBenedetto RJ, Goodman L, Rollings R, Berman E, Causey D. Whither goest the right ventricle in obstructive sleep apnea. Chest 1992; 102:5–6. Tarasiuk A, Scharf SM. Cardiovascular effects of periodic obstructive and central apneas in dogs. Am Rev Respir Dis 1994; 150:83–89. Tarasiuk A, Scharf SM. Effects of periodic obstructive apneas on venous return in closedchest dogs. Am Rev Respir Dis 1993; 148:323–329. Schneider H, Schaub CD, Andreoni KA, Schwartz AR, Smith PL, Robotham JL, O‘Donnell CP. Systemic and pulmonary hemodynamic responses to normal and obstructed breathing during sleep. J Appl Physiol 1997; 83(5):1671–1680. Scharf SM. Influence of sleep state and breathing on cardiovascular function. In: Saunders NA, Sullivan CE, eds. Sleep and Breathing. New York: Marcel Dekker, 1984:221–239. Podszus TE, Greenberg H, Scharf SM.. Influence of sleep state and sleep disordered breathing on cardiovascular function. In: Saunders NA, Sullivan CE, eds. Sleep and Breathing, ed 2. New York: Marcel Dekker, 1994:257–310. Kaltman AJ, Goldring RM. Role of circulatory congestion in the cardiorespiratory failure of obesity. Am J Med 1976; 60:645–653.
650 32. 33. 34. 35.
Podszus et al. Messerli FH, Christie B, DeCarvalho JG, Aristimuno GG, Suarez DH, Dreslinski GR, Frohlich ED. Obesity and essential hypertension. Hemodynamics, intravascular volume, sodium excretium, and plasma renin activity. Arch Intern Med 1981; 141:81–85. Reisin E, Frohlich ED, Messerli FH, Dreslinki GR, Dunn FG, Jones MM, Batson HM Jr. Cardiovascular changes after weight reduction in obesity hypertension. Ann Intern Med 1983; 98:315–319. House AA, Walley VM. Right heart failure due to ventricular adiposity: ‘adipositas cordis’—an old diagnosis revisited. Can J Cardiol 1996; 12:485–489. Alpert MA, Terry BE, Kelly D. Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity. Am J Cardiol 1985; 55:783–786.
25 Chronic Obstructive Pulmonary Disease
SAMUEL L. KRACHMAN
MARTIN J. TOBIN
Temple University Philadelphia, Pennsylvania
Loyola University of Chicago Stritch School of Medicine and Hines Veterans Administration Hospital Maywood, Illinois
I.
Background
The development of acute respiratory failure in patients with chronic obstructive pulmonary disease (COPD) is a common cause for admission to the intensive care unit (ICU) (1–3). Most patients with this complication start out with severe underlying lung disease, and experience a further problem that tips them over into acute respiratory failure. Another variant among patients with COPD in acute respiratory failure is the wide discrepancy in the use of mechanical ventilation, ranging from 3% to 45% (1,2,4). The in-hospital mortality for all patients with COPD in acute respiratory failure is reported to be 11% to 24% (1,2,4), with rates as high as 30% in those patients ⬎65 years of age (1). Those patients who receive mechanical ventilation have higher hospital mortalities (1,2). Nonrespiratory, including circulatory, variables appear to be more important than the severity of underlying lung disease in predicting in-hospital mortality during an episode of acute respiratory failure (1,4). In contrast, respiratory variables appear to be more important in explaining long-term mortality (1). Abnormalities in pulmonary gas exchange, the development of respiratory muscle pump dysfunction, and abnormalities in the control of breathing are important pathophysiological factors in the development of acute respiratory failure in 651
652
Krachman and Tobin
patients with COPD. This chapter will focus on the pathological mechanisms by which these factors lead to acute respiratory failure in patients with COPD.
II. Pulmonary Gas Exchange in COPD A. Mechanisms of Hypoxemia During Acute Respiratory Failure in COPD
During acute respiratory failure, hypoxemia may result from hypoventilation, changes in ventilation/perfusion (V/Q) distribution within the lungs, or a decrease in the oxygen content of mixed venous blood. Using the inert gas technique, Wagner et al. (5) noted three different types of V/Q abnormalities in patients with stable COPD. First was a pattern characterized by a relative increase in blood flow to low V/Q regions; such a pattern could arise from mucous plugging and atelectasis leading to an overall decrease in ventilation. A second pattern consisted of alveolar units with high V/Q ratios; this pattern could arise from ablation of pulmonary vasculature in lung units destroyed by emphysema. The third pattern consisted of a mixture of the two preceding patterns. Interestingly, significant shunting was not observed in these patients, while dead space (VD /VT ) was slightly to moderately increased (5). Similar, but more severe, patterns of V/Q abnormalities are observed in patients who require ventilator support. Simple measurement of arterial blood gases can underestimate the severity of gas exchange disturbances because extrapulmonary factors, such as an increase in cardiac output, by increasing mixed venous PO 2 , can cause an improvement in oxygenation. Such an occurrence was nicely demonstrated in a study of eight patients with COPD by Torres et al. (6). Compared with mechanical ventilation, the patients exhibited more severe V/Q mismatching during spontaneous breathing, secondary to an increase in blood flow to low V/ Q units. Although overall minute ventilation did not change on discontinuation of mechanical ventilation, patients developed an inefficient pattern of rapid shallow breathing, which necessarily resulted in an increase in VD /VT and a decrease in alveolar ventilation. Despite these abnormalities in V/Q distribution, neither PaO 2 nor alveolar-arterial PO 2 gradient changed, because of accompanying increases in cardiac output and mixed venous PO 2. Similar changes in V/Q distribution, cardiac output, and breathing pattern upon discontinuation of mechanical ventilation were noted by Beydon et al. (7) in another study of eight ventilator-supported patients with COPD in acute respiratory failure. Employing isotopic scanning, they found that the low V/Q regions were predominantly in the lung bases. Interestingly, the magnitude of the craniocaudal gradient in V/Q was closely correlated with the decrease in tidal volume during spontaneous breathing. They postulated that the abnormality in V/Q distribution may have arisen because the diaphragm was unable to support the weight of the abdomen in the supine position, and consequently low V/ Q units developed in the lung bases. In a landmark study, Lemaire et al. (8) demonstrated the importance of extrapulmonary factors in deciding overall gas exchange in patients with acute respiratory failure. A group of 15 ventilator-supported patients, each of whom also had underly-
COPD
653
Figure 1 Measurements of esophageal pressure (PESO) and transmural pulmonary artery occlusion pressure (PAOP) in a patient who failed a weaning trial. Measurements were obtained during mechanical ventilation (baseline) and after 5 and 9 min of spontaneous ventilation (SV). Note that markedly negative swings in PESO and the increase in PAOP during spontaneous ventilation. (From Ref. 8.)
ing cardiovascular disease, developed a decrease in PaO 2 10 min after the onset of spontaneous breathing. The hypoxemia was accompanied by an increase in the pulmonary artery occlusion pressure—from 8 to 25 mm Hg (Fig. 1)—and markedly negative swings in pleural pressure. Such swings in negative intrathoracic pressure not only increase venous return but also increase left ventricular afterload. Other factors such as sympathoadrenal stimulation may have been present as well. These authors suggested that latent left ventricular failure may have contributed to failure to wean. In summary, worsening of the V/Q relationship appears to be the major reason for hypoxemia in patients with COPD during acute respiratory failure. Extrapulmonary factors, especially an increase in cardiac output, can compensate for these abnormalities, with the result that simple arterial blood gases may not reflect the true severity of the dysfunction. B. Mechanism of Hypercapnia During Acute Respiratory Failure in COPD
The development of hypercapnia in patients with COPD experiencing acute respiratory failure is probably due to several mechanisms, which can be brought together in the following equation: PaCO 2 ⫽ KVCO2 /VE (1-VD /VT ) where VCO2 is the metabolic production of CO 2 , K is a constant that converts measurement of VCO2 from standard conditions to body temperature conditions; VE is minute ventilation; VD is the physiologic dead space; and VT is tidal volume. The preceding equation can be rearranged as follows: PaCO 2 ⫽ KVCO2 /f (V T-VD )
654
Krachman and Tobin
where f is the respiratory frequency. In patients with COPD during acute respiratory failure (9,10), VCO2 has been found to be normal or slightly decreased. The development of rapid shallow breathing, with an inevitable increase in dead space ventilation, appears to play an important role in the development of hypercapnia during acute respiratory failure. In patients developing hypercapnia during an unsuccessful trial of weaning from mechanical ventilation, Tobin et al. (11) found that 81 percent of the variance in PaCO 2 could be accounted for by the combination of the low tidal volume and high respiratory frequency (Fig. 2). In eight critically ill patients with COPD in whom mechanical ventilation was discontinued, Torres et al. (6) observed rapid shallow breathing accompanied by an increase in PaCO 2 from 49 mm Hg during mechanical ventilation to 58 mm Hg after 30 min of spontaneous breathing. Beydon et al. (7) found that dead-space ventilation was 18% higher during a spontaneous breathing trial in eight patients. A worsening of pulmonary mechanics may also lead to alveolar hypoventilation in patients with COPD who experience acute respiratory failure. As a rule of thumb, stable patients with COPD do not develop hypercapnia until the FEV1 falls below 25% of the predicted normal value. It has also been suggested that alveolar hypoventilation may result from a downregulation of the respiratory controller out-
Figure 2 Relationship between tidal volume (VT ), respiratory frequency (f ), and arterial carbon dioxide tension (PaCO 2 ) during spontaneous breathing in a group of patients who failed a trial of weaning from mechanical ventilation. Eighty-one percent of the variance in Pa CO 2 could be accounted for by the combination of the lowVT and the high f. This significant relationship suggests that the low VT that resulted in a relative increase in dead-space ventilation was the predominant mechanism responsible for the increased PaCO 2 in these patients. Further evidence in support of this mechanism was the lack of widening of the alveolar-toarterial PO 2 gradient, which indicated no change in the ventilation-to-perfusion relationships. (From Ref. 11.)
COPD
655
put, occurring as a defense mechanism to minimize the work of breathing, so-called ‘‘controller wisdom.’’ Finally, some patients may have blunting of the chemical drive to breathe. III. Control of Breathing in COPD The notion that most patients with COPD and hypercapnia have respiratory center depression has been challenged by the results of several studies (11–14). Employing mean inspiratory flow (VT /TI ) as an index of resting respiratory drive, Tobin et al. (13) found that 75% of a group of hypercapnic patients with COPD and 69% of eucapnic patients with COPD had values above the 95% confidence of normal subjects (Fig. 3); moreover, not a single patient had a VT /TI below the normal range. These findings are even more impressive in that VT /TI tends to underestimate respiratory drive in the setting of abnormal pulmonary mechanics. In 7 patients who failed a weaning trial, some of whom had COPD, and developed severe alveolar hypoventilation (12 mm Hg increase in PaCO 2 and decrease in pH of 0.08), Tobin et al. (11) noted an increase in VT /TI from 265 ⫾ 27(S.E.) to 328 ⫾ 32(S.E.) mL/sec. These data indicate that respiratory central drive tends to be increased rather than decreased in patients with COPD who develop acute respiratory failure, even in those with hypercapnia. A. Response to Oxygen
About 30% of patients with COPD develop a marked increase in PaCO 2 when they inhale a high concentration of oxygen (15). The mechanism of this oxygen-induced
Figure 3 Mean inspiratory flow (VT /TI ), an index of respiratory drive, during resting breathing in patients with chronic obstructive pulmonary disease. The shaded area represents the 95% confidence limits of VT /TI in healthy subjects. (From Ref. 13.)
656
Krachman and Tobin
hypercapnia has long been the subject of controversy. It had been thought that these patients had a blunted central respiratory response to CO 2 and were highly dependent on their hypoxic drive (16,17). Following this line of thinking, administration of supplemental oxygen should depress the hypoxic drive to breathe, resulting in alveolar hypoventilation and hypercapnia. Most studies, however, have not supported this theory (9,18–20). In 22 patients with COPD and acute respiratory failure, Aubier et al. (9) measured minute ventilation and gas exchange while the patients inhaled 100% oxygen. Minute ventilation fell initially by 18%, and reached its nadir after a mean of 71 sec. The decrease in minute ventilation was mediated by decreases in both respiratory frequency and tidal volume. Subsequently, minute ventilation increased, and the final value after 15 min was 93% of the initial minute ventilation. Such a small decrease in minute ventilation can explain only a 5 mm Hg increase in PaCO 2 , which is much less than the value of 23 mm Hg actually observed. Another 7 mm Hg of the increase in the PaCO 2 could be explained by the ‘‘Haldane effect,’’ which refers to the preferential binding of oxygen to hemoglobin with consequent displacement of bound CO 2. The remaining increase in PaCO2 presumably resulted from the significant increase in VD /VT. Given that tidal volume had not changed by 15 min, the increase in VD /VT was thought to have resulted from the reversal of hypoxic vasoconstriction in poorly ventilated regions of the lung, with consequent worsening of the V/Q inequality. More recently, Dick et al. (18) reexamined the mechanism of oxygen induced hypercapnia in 11 stable patients with COPD. They first assessed the hypoxic and hypercapnic ventilatory responses in each patient. Following this, the patients inspired 100% oxygen for 15 minutes. Arterial oxygen saturation (SaO 2 ) was found to increase by 7.6 ⫾ 3.6%, PaCO 2 to increase by 6.6 ⫾ 3.3 mm Hg, and overall minute ventilation did not change (Fig. 4). Knowing each patient’s separate ventilatory response to hypoxia and to hypercapnia and their respective increases in SaO 2 and PaCO 2 during oxygen breathing, the investigators predicted the effect of oxygen breathing on minute ventilation (VE ) as follows: ∆VE pred ⫽ (∆V/∆PaCO 2 ) ⫻ ∆PaCO 2 ⫹ (∆V/∆SaO 2 ) ⫻ ∆SaO 2 here ∆V/∆PaCO 2 and ∆V/∆SaO2 are the hypoxic and hypercapnic ventilatory response slopes that were measured initially, and ∆PaCO 2 and ∆SaO2 are the O 2 induced changes in PaCO 2 and SaO 2 , respectively. The predicted change in VE during inspired oxygen was ⫺0.96 ⫾ 2.24 (S.D.) L/min, which is remarkably similar to the observed change of ⫺0.08 ⫾ 2.04 (S.D.) L/min. These data suggest that the decrease in VE due to O 2-induced suppression of hypoxic drive was closely matched by the increase in ventilation due to an increase in PaCO2. The investigators also found that VCO 2 did not change during the 15 minute period. In summary, the O 2induced increase in PaCO 2 appeared to be due to both the Haldane effect and an increase in VD /VT secondary to the release of hypoxic pulmonary vasoconstriction. A different experimental approach was employed by Dunn et al. (19) to study the question of oxygen-induced hypercapnia in 13 patients with COPD and acute respiratory failure. They measured the change in the CO2 recruitment threshold, which provides a means for evaluating the chemical control system, in terms of the
COPD
657
Figure 4 Changes in minute ventilation (top panel), PaCO2 (middle panel) and SaO2 (bottom panel) in 11 patients with stable COPD who breathed 100% oxygen. While both PaCO2 and SaO2 increased significantly over the 15-min period, minute ventilation did not change. *Significant change (P ⬍ .001) from baseline. (From Ref. 18.)
‘‘on switch’’ to CO 2 after phasic respiratory muscle activity has been suppressed with mechanical ventilation (21). This methodology allows the assessment of ventilatory control independent of respiratory mechanics, thus reflecting the response of the unloaded respiratory system to CO 2. After increasing the FIO 2 to ⬎ 95%, the PaO 2 was noted to increase from 61 ⫾ 7 to 370 ⫾ 67 (S.D.) mm Hg, the CO 2 recruitment threshold increased from 42 ⫾ 6 to 45 ⫾ 6 mm Hg (P ⬍ .05), and VD / VT increased from 0.49 ⫾ 0.09 to 0.55 ⫾ 0.06 (P ⬍ .05), independently of any change in breathing pattern. The observed increase in the CO 2 recruitment threshold
658
Krachman and Tobin
suggests inhalation of oxygen caused suppression of hypoxic drive. The increase in VD /VT , secondary to loss of hypoxic vasoconstriction, and the Haldane effect also contributed to O 2-induced hypercapnia. In summary, suppression of hypoxic drive appears to be less important as a mechanism of oxygen-induced hypercapnia in patients with COPD, with other factors, including the Haldane effect and release of hypoxic vasoconstriction, playing a more important role. B. Response to CO 2
The airway occlusion pressure (P0.1 ) technique has been used to investigate respiratory controller performance in patients with COPD experiencing acute respiratory failure. Immediately after 25 patients were disconnected from a ventilator, Tardif et al. (22) measured the minute ventilation and P0.1 responses during which time the patients rebreathed CO 2. Compared with control measurements in 26 healthy subjects, the slope of the minute ventilation response to CO 2 decreased by 90% in the patients, 0.17 ⫾ 0.04 (S.E.) L/min/mm Hg vs. 1.67 ⫾ 0.15 (S.E.) L/min/mm Hg,
Figure 5 Response of minute ventilation (VE), tidal volume (VT), respiratory frequency (f ), and airway occlusion pressure (P0.1 ) to end-tidal CO 2 (PETCO2 ) during breathing in 25 patients with COPD in acute respiratory failure (closed symbols) and 26 healthy subjects (open symbols). The slopes of the VE and VT responses to CO 2 in the patients were only 10% and 5% of the control group, respectively; the P0.1 response was better preserved at 60% of the normal response; the f response was 146% percent of the normal response. Bars represent ⫾ S.E. (From Ref. 22.)
COPD
659
(P ⬍ .001); the tidal volume response in the patients was only 5% percent of the control value; the respiratory frequency was 146% of the control value (Fig. 5). The P0.1 response to CO 2 was relatively better preserved—0.37 ⫾ 0.07 in the patients versus 0.61 ⫾ 0.07 (S.E.) cmH2 O/mm Hg in the control group—and similar to that in stable patients with COPD. These data indicate that patients in acute respiratory failure exhibit considerable chemoreceptor responsiveness, and the investigators estimated that about one-third of the minute ventilation in the average patient in acute respiratory failure results from CO2 stimulation. The scatter of the responses among patients, however, was very large: 0.06 to 0.50 L/min/mm Hg for VE and 0.04 to 1.40 cmH2 O/mm Hg for P0.1 , suggesting that chemoreceptor blunting could be an important factor in some patients. Matthews and Howell (23,24) utilized a technique similar to the P0.1 —namely, the maximal rate of change in airway pressure [(dP/dt)max] at the onset of an inspiratory effort against a brief occlusion. In stable patients with COPD, 18 having hypercapnia and 22 normocapnia, the investigators noted that the minute ventilation response to CO 2 was depressed in both patient groups. In contrast, the (dP/dt)max response to CO 2 in the normocapnic group, 1.54 ⫾ 0.18 cmH2 O/sec/mm Hg, was similar to that in normal subjects, whereas it was significantly lower in hypercapnic patients, 0.43 ⫾ 0.10 cmH2 O/sec/mm Hg, than in either the normal subjects or normocapnic patients (both P ⬍ .001) (Fig. 6). The authors speculated that (dP/dt) max might prove useful in detecting a blunted central respiratory drive and, thus, increased vulnerability to ventilatory failure during an acute exacerbation.
Figure 6 Rate of isometric pressure development [(dP/dt)max] (closed symbols) and ventilatory (open symbols) response to CO 2 during rebreathing in a healthy subject (left panel), a normocapnic patient with COPD (middle panel), and a hypercapnic patient with COPD (right panel). The VE response to CO 2 was virtually identical to the (dP/dt) max response in the healthy subject, whereas the VE response was significantly depressed in both patients. The (dP/dt)max response to CO 2 in the normocapnic patient was similar to the healthy subject, but it was depressed in the hypercapnic patient. (From Ref. 23.)
660
Krachman and Tobin IV. Respiratory Muscle Pump Dysfunction
The respiratory muscles are profoundly challenged by COPD due to an increase in the mechanical load and a decrease in capacity of the muscles to cope with this load. Several factors contribute to respiratory muscle dysfunction in these patients. (See Chapter 3 for more review of the muscles of respiration.) A. Hyperinflation
Of conditions causing a decrease in respiratory muscle strength and/or endurance, hyperinflation is of prime importance. Worsening of lung mechanics leads to prolongation of the respiratory time constant (i.e., resistance ⫻ compliance) and is commonly associated with an increase in respiratory frequency (11,25). As a result, expiratory time is not sufficient for lung emptying with consequent dynamic hyperinflation. Hyperinflation has several adverse effects on respiratory muscle function (26) (Fig. 7). Most important, an increase in lung volume causes the inspiratory muscles to operate at an unfavorable position on the length tension curve (see Chapter 3). Maximum contractile force normally is generated at the muscle’s resting or optimal length. As lung volume increases, the inspiratory muscles shorten and their ability to generate negative inspiratory pressure decreases (27–29). Hyperinflation also affects the curvature of the diaphragm. To function as an ideal inspiratory pump, the diaphragm should be curved with its convexity directed upward (30,31)—a phenomenon best understood in terms of Laplace’s law: Pdi ⫽ 2Tdi /Rdi , where Pdi represents transdiaphragmatic pressure, Tdi represents the tangential tension of the dia-
Figure 7 The detrimental effects of hyperinflation on respiratory muscle function. (See text for explanation.) (From Ref. 26.)
COPD
661
phragm, and Rdi represents the radius of curvature of the diaphragm. Muscle tension in a tightly curved diaphragm (small Rdi ) generates a greater transdiaphragmatic pressure than does tension in a flattened diaphragm (large Rdi ). With hyperinflation (32), thoracic elastic recoil is directed inward rather than outward; thus, the inspiratory muscles work not only against the elastic recoil of the lungs but also against that of the thoracic cage, representing an added elastic load. Hyperinflation decreases the zone of apposition between the diaphragm and the rib cage; consequently, the usual expansion of the chest wall secondary to an increase in intra-abdominal pressure is diminished (33). The axial direction of the diaphragmatic fibers is altered with hyperinflation. These fibers are normally oriented in a cephalocaudal direction, such that their contraction pulls up the ribs—the so-called ‘‘bucket-handle’’ expansion of the rib cage. With hyperinflation, the fibers are directed medially. Diaphragmatic contraction will then deflate the rib cage rather than inflate it (33), this action is detected clinically as Hoover’s sign (35). Hyperinflation also shifts the ribs from their normal oblique position to a more horizontal position, making it more difficult for the respiratory muscles to lift and expand the rib cage. Finally, increased swings in transdiaphragmatic pressure and increased inspiratory time can impair diaphragmatic blood supply (36), although it is not clear whether this occurs in patients (37). B. Decreased Peripheral Oxygen Delivery
The oxygen supply to a muscle is impaired secondary to decreases in cardiac output (38), the O2 content of arterial blood (hypoxemia, anemia) (39), or O 2 extraction (sepsis) (40,41). In patients with COPD who failed a weaning trial (8), Lemaire et al. observed an increase in left ventricular end diastolic volume with no change in left ventricular ejection fraction. More recently, Jubran et al. (42) investigated the role of hemodynamic performance and global tissue oxygenation as determinants of weaning outcome in eight ventilator-supported patients who failed a trial of spontaneous weaning and in 11 patients who tolerated the trial and were successfully extubated. Throughout the period of mechanical ventilation and at the start of the trial, mixed venous oxygen saturation (SvO2 ) was not significantly different between the two groups. Mixed venous oxygen saturation, however, progressively decreased over the course of the trial in the failure group but did not change in the success group (Fig. 8). Although oxygen consumption was equivalent at the end of the trial in the two groups, the manner in which these demands were met differed. In the success group, oxygen transport increased largely due to an increase in cardiac index, whereas O 2 demand in the failure group was met by an increase in oxygen extraction, resulting in a decrease in SvO2. The inability of the failure group to increase cardiac index, and thus oxygen transport, was partly explained by increases in both right and left ventricular afterload. The decrease in SvO2 , combined with the increase in venous admixture, led to a rapid decrease in SaO2 in the failure group; SaO 2 did not change in the success group. These data indicate that inability to increase oxygen delivery to the tissues, including the respiratory muscles, during a period of increased O 2 demand can contribute to the development of acute respiratory failure.
662
Krachman and Tobin
Figure 8 Ensemble averages of the interpolated values of mixed venous oxygen saturation (SvO2 ) during mechanical ventilation and a trial of spontaneous breathing in the success group (open symbols) and failure group (closed symbols). During mechanical ventilation, SvO2 was similar in the two groups (P ⫽ .28). Between the onset and the end of the trial, SvO2 decreased in the failure group (P ⬍ .01) whereas it remained unchanged in the success group (P ⫽ 0.48). Over the course of the trial, SvO2 was lower in the failure group than in the success group (P ⬍ .02). Bars represent S.E. (From Ref. 42.).
C. Metabolic Alterations
Acute respiratory acidosis has been shown to decrease the contractility and the endurance time of the diaphragm in healthy subjects (43). In a study in dogs, respiratory acidosis was shown to produce diaphragmatic impairment (44); an equivalent degree of metabolic acidosis did not affect diaphragmatic performance. Hypophosphatemia impairs diaphragm function and its correction increases transdiaphragmatic pressure in patients with acute respiratory failure (45). Abnormalities in potassium, calcium (46), and magnesium (47) also adversely affect respiratory muscle function. Approximately 20% of patients with COPD have a body weight of ⬍85% of predicted (48). Such a decrease in body weight is accompanied by a proportional decrease in diaphragmatic muscle mass. In patients who had an average weight at the time of death that was 71% of the predicted normal value, Arora and Rochester (49) noted that diaphragmatic muscle mass, area, and thickness were reduced by 43%. A decrease in muscle mass can have a significant effect on muscle strength;
COPD
663
in one study, 65% of the variance in PE max could be explained by body weight (50). D. Respiratory Muscle Fatigue
All skeletal muscles are susceptible to fatigue, a state in which there is a decrease in contractile force for a given degree of neural stimulation (51,52). The importance of respiratory muscle fatigue in the development of acute respiratory failure in COPD is not known, because techniques that yield unequivocal proof of fatigue have not been applied in this setting. Most information regarding respiratory muscle fatigue has been obtained from experimental animals or healthy volunteers. Respiratory muscle fatigue has been defined as a condition in which there is loss in the capacity for developing force and/or velocity of a muscle, resulting from activity under load, which is reversible by rest (53). It is important to recognize two distinct forms of muscle fatigue, which can be distinguished by measuring force generation at different stimulation frequencies of the motor nerves (54) (Chapter 3). Soon after a muscle is exposed to a high load, it experiences a decrease in contractile force at high discharge frequencies (50 to 100 Hz); after removal of the load, the muscle recovers very rapidly. This condition is termed high-frequency fatigue and is thought to result from the accumulation of hydrogen ions and inorganic phosphates (55–57), as well as impaired propagation of the action potential along the T-tubules with a resulting decrease in intracellular calcium (58). The clinical implication of this form of fatigue is not clear, since human subjects generate high discharge frequencies only when exposed to a very heavy load, and they can sustain them only for a very brief time (59,60). During regular breathing, the discharge frequency of the phrenic motor neurons is 9 to 12 Hz in healthy subjects and 14 to 22 Hz in patients with COPD (61). A decrease in contractile force at this stimulation frequency is termed low-frequency fatigue. A much longer period of loading is required to produce low-frequency fatigue, and recovery also requires a longer time, at least 24 hours (62). This form of fatigue is thought to result from load-induced injury (63–66), which may be mediated by the production of oxygen free radicals. These oxygen free radicals can damage intracellular organelles (67–69) and disrupt the sarcolemma and/or sarcoplasmic reticulum (70); as a result, calcium enters the cytoplasm, where it activates lipolytic and proteolytic enzymes and degrades membrane phospholipid and myofilament proteins (70,71). The possible development of low-frequency fatigue is a real concern in patients with COPD since they have decreased neuromuscular capacity and increased respiratory load. The decrease in mortality in patients with COPD experiencing acute respiratory failure following early institution of noninvasive ventilation (72) could, conceivably, be due to the avoidance of respiratory muscle fatigue, although other explanations also exist. The possible presence of fatigue also influences decision making at the time that a patient is being weaned from mechanical ventilation, because resting the respiratory muscles with a ventilator is the major means of reversing fatigue (73).
664
Krachman and Tobin
Since low-frequency fatigue can result in severe structural damage to the muscles (63), it has been postulated that the respiratory centers might decrease their output as a means of decreasing force generation and avoiding destructive muscle damage. This downregulation is termed central fatigue, and is even regarded as a form of central wisdom. Proof of central fatigue requires that the force generated by a voluntary maximal contraction is less than that generated by external supramaximal stimulation of the motor nerve (74). A final form of fatigue, termed transmission fatigue, represents a decrease in neural impulse transmission resulting from axonal conduction failure, inadequate neurotransmitter release, binding or reuptake, or reduced sensitivity of the muscle membrane (75). Transmission fatigue results in a decrease in the electromyographic response to phrenic nerve stimulation. Information on the performance of the respiratory muscles can be gleaned from physical examination. Abnormal rib cage–abdominal motion can be separated into three major types: asynchronous breathing, due to a time lag between motion of the rib cage and abdomen; paradoxical breathing, where the two compartments move in opposite directions; and increased variability in compartmental contribution, where the relative contributions of the rib cage and abdomen to tidal volume vary on a breath to breath basis (76–78). It had been suggested that abdominal paradox was virtually pathognomonic of diaphragmatic fatigue (79) if diaphragmatic paralysis and inversion were excluded (76,80). In subsequent studies, however, rib cage–abdominal paradox and variation in the relative contribution of the rib cage and abdomen to tidal volume were found to be caused by increases in respiratory load rather than muscle fatigue per se (81). Bellemare and Grassino (82) developed an index that quantified the magnitude and duration of inspiratory muscle contraction. They reasoned that because the diaphragm contracts primarily during inspiration, the relative duration of inspiration (TI ) to total respiratory cycle time (TTOT ) should be an important determinant of diaphragmatic fatigue (82). In healthy subjects breathing against resistive loads of varying magnitude, they measured mean swings in transdiaphragmatic pressure in relation to maximal transdiaphragmatic pressure (mean Pdi / Pdimax ) and TI / TTOT in relationship to the time that a target pressure could be sustained. The ratios of mean Pdi / Pdimax and TI / TTOT were equally important as determinants of diaphragmatic fatigue. They combined the two fractions into the tension-time index of the diaphragm (Ttdi); that is TTdi ⫽ mean Pdi/Pdi max ⫻ TI /T TOT Healthy subjects were able to sustain inspiratory resistive loads indefinitely, provided the tension-time index was ⬍0.15 (82). The normal resting tension-time index is 0.02, indicating an approximate eightfold reserve. In 17 patients with COPD who failed a trial of weaning from mechanical ventilation and 14 patients who tolerated such a trial and were extubated, Jubran and Tobin (14) found that the tension-time index was not different in the two groups at the onset of the trial (Fig. 9) The failure group developed an increase in the tension-time index from 0.06 ⫾ 0.01 (S.E.) at onset of the trial to 0.10 ⫾ 0.01 by the end of trial—the increase being due to an increase in mean Pes , with no change in TI /TTOT. The success group showed no
COPD
665
Figure 9 Relationship between mean esophageal pressure/maximum inspiratory pressure ratio (Pes /PImax ) and duty cycle (TI /TTOT ) in 17 ventilator-supported patients with COPD who failed a trial of spontaneous breathing and 14 patients who tolerated the trial. Circles and triangles represent values at the start and end of the trial, respectively; closed symbols indicate patients who developed an increase in PaCO2 during the trial. Of the 17 patients in the failure group, 5 developed a tension time index of ⬎ 0.15 (indicated by the isopleth), suggesting respiratory muscle fatigue. N represents value in a normal subject. (From reference 14 with permission).
change in tension-time index. Five of the failure patients developed a tension-time index ⬎0.15 by the end of the trial, whereas none of the success patients showed such a change. These results suggest that respiratory muscle fatigue may be responsible for some instances of weaning failure in patients with COPD. An increase in the load on the respiratory muscle pump may occur in some patients with COPD experiencing acute respiratory failure as a result of either increased ventilatory demands or an increase in the work of breathing. V.
Increased Respiratory Muscle Pump Load
A. Increased Ventilatory Requirements
Factors causing an increase in ventilatory requirements include increased dead space ventilation, previously discussed, and increased CO 2 production. While an increase in CO2 production predisposes to CO 2 retention, it is never the sole cause of hypercapnia. Minute ventilation is elevated in stable patients with COPD, and will further increase during acute respiratory failure (9,14). As such, the O 2 cost of breathing may increase from the normal value of about 1% to 2% of total body oxygen con-
666
Krachman and Tobin
sumption to more than 15% in patients with COPD (83–87). The associated increase in CO2 production causes an increase in ventilatory demands, and probably contributes to the development of hypercapnia in these mechanically disadvantaged patients. An increase in CO 2 production may occur with feeding as a result of two major factors. CO 2 production is about 22% higher with the combustion of glucose versus that of lipids (88). In addition, when administered in excess of metabolic demands carbohydrates are converted to fat for storage, which markedly affects the respiratory quotient (RQ) (i.e., the rate of CO 2 production relative to O 2 consumption). Carbohydrates and fats are metabolized with RQs of 1.0 and 0.7, respectively, whereas lipogenesis or fat production has an RQ of 8.0 (88). In healthy subjects, an associated increase in alveolar ventilation prevents the development of hypercapnia. Many patients with respiratory compromise are unable to increase alveolar ventilation sufficiently to prevent hypercapnia. B. Increased Work of Breathing
Mechanical work is performed when a force moves its point of application through a distance. In the case of a three-dimensional fluid system, work (W) is done when a pressure (P) changes the volume (V) of the system: W ⫽ P ⫻ V ⫽ ∫ v P ⋅ dv When a muscle contracts, mechanical work is performed only if displacement takes place. During a miometric contraction, the muscle shortens; the performed work is called positive (i.e., the muscle does work on something), and is performed in the direction of muscle shortening. For a respiratory muscle, work, pressure, and volume have the same directional change in this circumstance. During a pliometric contraction, the muscle lengthens as the result of a larger, opposite applied force and the work performed is called negative (i.e., something does work on the muscle). In this case, changes in pressure and volume are opposite in sign; for respiratory muscle work, the pressure-volume product is due to continued inspiratory muscle tone during expiration. During an isometric contraction, no displacement takes place; therefore no mechanical work is performed—there is of course, a metabolic cost for exerting the force. The respiratory muscles perform work against a number of forces. Changes in these forces may result in an increase in the mechanical work of breathing, as occurs during acute respiratory failure in patients with COPD. These include changes in dynamic lung elastance and airway resistance, as well as the development of auto- or intrinsic-PEEP. Dynamic Lung Elastance and Airway Resistance
In 11 patients with COPD and acute respiratory failure, Fleury et al. (89) noted that dynamic elastance was six times higher than normal, and that inspiratory and expiratory flow resistance was four to five times higher than normal. Total inspiratory and resistive work rates were significantly increased.
COPD
667
More recently, Jubran and Tobin (14) measures dynamic lung elastance and inspiratory flow resistance in 17 ventilator-supported patients with COPD who failed a trial of spontaneous breathing and 14 patients who tolerated such a trial and were extubated. At the onset of the trial, dynamic lung elastance was higher in the failure group, 21.2 ⫾ 3.4 cmH2 O/L, than in the success group, 9.9 ⫾ 1.7 cmH2 O/L (P ⬍ .01), whereas inspiratory resistance was not significantly different, 9.0 ⫾ 1.7 cmH2 O/L/sec and 5.3 ⫾ 1.1 cmH2 O/L/sec, respectively. Over the course of the trial, dynamic lung elastance increased to a greater extent in the failure group than the success group, 34.1 ⫾ 4 cmH2 O/L and 14 ⫾ 2 cmH2 O/L , respectively (P ⬍ .02), and the inspiratory resistance increased in the failure group to 14.8 ⫾ 2, whereas it did not change in the success group (P ⬍ .008, between the two groups) (Fig. 10). The pressure-time product was not different at the onset of trial between the failure and success groups, 255 ⫾ 59 and 158 ⫾ 23 cmH2 O.s/min, respectively—normal
Figure 10 Inspiratory resistance of the lung (RLinsp ) and dynamic lung elastance (ELdyn ) in 17 ventilator-dependent patients with COPD who failed a trial of spontaneous breathing and 14 patients who tolerated the trial and were extubated. Data displayed were obtained during the second and last minutes of the trial and at one-third and two-thirds of the trial duration. Between the onset and the end of the trial, increases in RLinsp (P ⬍ .009) and ELdyn (P ⬍ .0001) occurred in the failure group, and an increase in Eldyn (P ⬍ .0006) occurred in the success group. Over the course of the trial, the failure group had higher values of RLinsp (P ⬍ .003) and ELdyn (P ⬍ .0006). (From Ref. 14.)
668
Krachman and Tobin
value 94 ⫾ 12 cmH2 O.s/min; but at the end of the trial, pressure-time product increased to 388 ⫾ 68 cmH2 O.s/min in the failure group (Fig. 11). The failure group developed an increase in PaCO 2 to 58 ⫾ 4 mm Hg by the end of the weaning trial. An increase in PaCO 2 is all the more striking because the accompanying increase in patient effort should have lowered PaCO 2 , since PaCO 2 ⬀ 1/PTP, where PTP is the pressure-time product. This concept can be restated as PaCO 2 ⯝ k ⫻ 1/PTP, or PTP x PaCO 2 ⯝ k, where k reflects the efficiency of the ventilatory pump in clearing CO 2. If the ventilatory pump is efficient, the value of k is low, and vice versa. At the end of the trial, the PTP x PaCO 2 product was 27.6 ⫾ 3.6 x103 cmH2 O.s.min⫺1 in the failure group, which is more than double that in the success group, 11.3 ⫾ 1.3 cmH2 O.s.min-1 (Fig. 12). Thus, inefficient clearance of CO 2 in patients failing a weaning trial appears in part to be a consequence of worsening pulmonary mechanics with increased respiratory muscle energy expenditure.
Figure 11 Measurements of upper-bound (UB) and lower-bound (LB) pressure-time product per minute (PTP/min) in 17 ventilator-supported patients with COPD who failed a trial of weaning and 14 patients who tolerated the trial and were extubated. Between the onset and end of a trial of spontaneous breathing, both indexes of pressure-time product increased in the failure group (P ⬍ .0001 in both instances) and in the success group (P ⬍ .006 in both instances). Over the course of the trial, the failure group had higher values of both upper bound PTP/min (P ⬍ .006) and lower-bound PTP/min (P ⬍ .02) than the success group (bars, ⫾ 1 S.E.) (From Ref. 14 with permission).
COPD
669
Figure 12 PTP/min ⫻ PaCO2 product, and index of the inefficiency of the respiratory pump in clearing CO 2 , at the end of a trial of spontaneous breathing was higher in 17 patients with COPD who failed the trial than in 14 patients who were successfully weaned (P ⬍ .0005). (From Ref. 14.)
Intrinsic PEEP
In normal subjects, the lung volume at end expiration generally approximates the relaxation volume of the respiratory system, i.e., the lung volume determined by the static balance between the opposing elastic recoil of the lung and chest wall (90). As such, the static recoil pressure of the respiratory system is normally zero at end expiration. In patients with hyperinflation, however, the end-expiratory volume is no longer determined by an equilibrium between static forces and exceeds the predicted functional residual capacity. The associated elevation in static recoil pressure of the respiratory system and thus alveolar pressure (91–93) is termed auto or intrinsic PEEP (PEEPi ) (94,95). In patients with airflow limitation, hyperinflation results from dynamic airway collapse. Static PEEPi represents the average level of PEEPi in nonhomogeneous lung after equilibration of alveolar pressure among lung units with varying time constants. Static PEEPi of the total respiratory system is measured as the change in airway pressure after the airway is occluded at end-expiration (Fig. 13) (94,96). Dynamic PEEPi represents the lowest regional value of PEEPi that needs to be overcome in order to initiate lung inflation. Dynamic PEEPi of the total respiratory system is measured as the negative deflection in airway pressure from the start of inspiratory effort to the onset of inspiratory flow (97) (Fig. 14). When airway pressure is oc-
Figure 13 Representative record with measurement of PEEPi by single-breath end-expiratory airway occlusion (EEO) in a mechanicallly ventilated patient with acute exacerbation of COPD during controlled ventilation. (From Ref. 95.)
Figure 14 Recordings of flow (V) and esophageal pressure (Pes) illustrating the method for measuring dynamic intrinsic positive end-expiratory positive pressure (PEEPi,dyn). The latter is measured as the negative deflection in Pes from the start of inspiratory effort to the onset of inspiratory flow (dotted line). (From Ref. 97.)
COPD
671
cluded at end inspiration, there is an initial rapid fall in airway pressure (P1) from its preocclusion value (Ppeak ), followed by a slower decrease that eventually plateaus a few seconds later (P2) (Fig. 15). This secondary change in pressure (∆P) reflects the time constant inequalities and viscoelastic tissue properties of the respiratory system. In patients with COPD, dynamic PEEPi has been shown to considerably underestimate static PEEPi whereas the two values more closely approximate each other in the absence of airways obstruction (98). In addition, the ratio of dynamic PEEPi to static PEEPi has been shown to be inversely correlated with ∆P (Fig. 16), suggesting that the discrepancy between dynamic PEEPi and static PEEPi in patients with COPD represents gas redistribution between lung units with different regional pressures at end expiration, a phenomenon referred to as Pendelluft, and increased viscoelastic pressure losses of the respiratory system. Measurements of PEEPi are valid only if one assumes that there is no expiratory muscle activity. Recent studies using needle electrodes, however, have revealed prominent phasic expiratory activity of the transversus abdominis in patients with COPD (99,100). As such, some of the measured PEEPi does not represent hyperinflation but is due to expiratory muscle contraction leading to an increase in abdomi-
Figure 15 Experimental record illustrating the method used to determine respiratory mechanics. Occluding the airway at endinspiration results in a rapid initial fall in airway pressure (Paw) from its preocclusion value (Ppeak) to P1 , followed by a slower decrease in Paw a few seconds later. This secondary change in Paw (P1-P2 ) represents time constant inequalities and viscoelastic tissue properties of the respiratory system. (From Ref. 98.)
672
Krachman and Tobin
Figure 16 Relationship between ∆P, the pressure losses due to pendelluft and viscoelastic tissue properties, and the ratio of dynamic to static intrinsic PEEP (PEEPi,dyn /PEEPi,stat) in all patients. A highly significant inverse relationship was found between these two parameters (y ⫽ ⫺6.8⫻ ⫹ 8.7, r ⫽ .64) (p ⬍ 0.0005). Open and filled circles represent patients with (AWO) and without (non-AWO) airway obstruction, respectively. (From Ref. 98.)
nal pressure which is transmitted through the relaxed diaphragm into the pleural space. Consensus has not been reached on the optimal method of correcting for the effect of expiratory muscle activity to arrive at a more accurate estimate of the true elastic recoil pressure in patients exhibiting PEEPi. Adverse Effects of PEEPi
PEEPi can cause adverse hemodynamic effects, similar to those seen with the application of external PEEP (101) (see Chapter 33). The increase in end-expiratory alveolar pressure may decrease venous return and cardiac output. Pepe and Marini (94) reported three patients experiencing hemodynamic embarrassment that resolved upon discontinuation of mechanical ventilation. On occluding the ventilator circuit at end-expiration, they recorded pressures of 10, 14, and 26 cmH2 O. In a number of reports, discontinuation of manual ventilation resulted in a return of spontaneous circulation, which further supports the likelihood that dynamic hyperinflation is an important mechanism of cardiac dysfunction. Other adverse effects associated with the presence of PEEPi include elevating the pulmonary artery occlusion pressure due to transmission of elevated intrathoracic pressure and underestimating the true static compliance of the respiratory system.
COPD
673
PEEPi increases the risk of alveolar rupture leading to the development of mediastinal emphysema and pneumothorax (barotrauma). In addition, the presence of positive pressure in the alveolus at the end of expiration means that the patient has to first generate a negative inspiratory pressure equal in magnitude to this positive pressure before inspiratory flow can be initiated. This threshold inspiratory load can lead to a substantial increase in the work of breathing. Recently, Jubran and Tobin (14) noted that the increased pressure-time product that developed in 17 patients with COPD who failed a weaning trial was associated with 111% increase in PEEPi (Fig. 17). Patients who were successfully weaned developed a significantly smaller increase in pressure-time product, which was not accompanied by any change in PEEPi (Fig. 17). Application of External PEEP
The addition of external PEEP has been shown to decrease the inspiratory threshold load associated with PEEPi (95,102). For alveolar pressure to fall below ambient
Figure 17 Partitioning of pressure-time product (PTP/min) into intrinsic positive end-expiratory pressure (PEEPi ), non-PEEPi elastic, and resistive components at the start and end of a trial of spontaneous breathing in 17 patients who failed the trial and 14 patients who were successfully weaned. At the end of the trial, the increase in PTP/min in the failure group was due to increases in the PEEPi component by 111% (P ⬍ .0001), non-PEEPi elastic component by 33% (P ⬍ .0001), and resistive component by 42% (P ⬍ .0001). The increase in PTP/min at the end of the trial in the success group resulted from an increase in non-PEEPi elastic component by 23% (P ⬍ .02) and in the resistive component by 26% (P ⬍ .01), while the PEEPi fraction did not change. (From Ref. 14.)
674
Krachman and Tobin
pressure in the presence of hyperinflation and PEEPi , a much greater decrease in pleural pressure is required. If ambient pressure is elevated by the application of external PEEP, inspiration is more easily accomplished because alveolar pressure needs to be decreased only below the level of external PEEP (rather than below zero). This situation can be understood by employing the analogy of a waterfall, where the height of the waterfall represents the critical closing pressure of the airways (103) (Fig. 18). This counteracting effect of external PEEP operates only in the setting of airflow limitation. When PEEPi results from expiratory muscle activity, the addition of external PEEP will be a hindrance and add to the work of expiration. Determination of the appropriate amount of external PEEP in the setting of airflow limitation is somewhat difficult due to regional inhomogeneities among lung units, each with its own critical closing pressure (104). Since static PEEPi represents an average level of PEEPi , it must be greater than the lowest regional alveolar pressure. Accordingly, application of external PEEP equal to PEEPi could lead to hyperinflation in the faster emptying lung units. In a group of seven patients with COPD who had a mean PEEPi of 9.9 ⫾ 1.1 cmH2 O, Petrof et al. (105) noted a significant decrease in the inspiratory work of breathing with a CPAP of 5 cmH2 O, without a change in end expiratory lung volume. Although CPAP levels of 10 and 15 cmH2 O led to further decreases in the inspiratory work of breathing, they were associated with a significant increase in end-expiratory lung volume. In patients with COPD and PEEPi of 6.3 to 18.2 cmH2 O, Georgopoulos et al. (106) found that trapped volume increased from 661 ⫾ 187 (S.E.) ml without external PEEP to 794 ⫾ 202 (S.E.) ml when PEEP was set at 86% of PEEPi . In nine ventilator-supported patients with COPD who had a mean PEEPi of 9.8 cmH2 O, Ranieri et al. (107) found that
Figure 18 Analogy of a waterfall over a dam (indicated by the solid block) is used to explain the effect of external PEEP (‘‘downstream pressure’’) on PEEPi (‘‘upstream pressure’’) during expiration. Elevation of downstream pressure with external PEEP has no influence on either expiratory flow or upstream pressure (PEEPi ) until it is equal to the critical closing pressure. When downstream pressure exceeds the critical closing pressure, the pressure upstream increases and hyperinflation is exacerbated. (From Ref. 103.)
COPD
675
the application of a level of PEEP that was more than 85% of the PEEPi value caused an increase in end-expiratory lung volume and decrease in cardiac output. Rossi et al. (108) applied external PEEP to levels equivalent to 50% and 100% of PEEPi in eight ventilator supported patients with COPD. When external PEEP approximated 50% of PEEPi , gas exchange improved without a change in respiratory mechanics or hemodynamics. Increasing the applied PEEP to 100% of PEEPi resulted in no further improvement in gas exchange and an increase in airway pressures. The optimal level of external PEEP for use in patients with PEEPi has not been conclusively determined, although values up to 70% of the PEEPi value seem reasonable. VI. Conclusion Patients with COPD commonly develop acute respiratory failure, requiring admission to the ICU and the institution of mechanical ventilation. Abnormalities in pulmonary gas exchange, control of breathing, and respiratory muscle function contribute to the development of acute respiratory failure. Achieving a better understanding of the involved pathophysiological factors has resulted in more prudent employment of therapeutic measures, which, hopefully, have improved patient outcome. References 1. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbations of chronic obstructive pulmonary disease. JAMA 1995; 274:1852–1857. 2. Connors AF, Dawson NV, Thomas C, Harrell RE Jr, Desbiens N, Fulkerson WJ, Kussin P, Ballamy P, Golman L, Knaus WA. Outcomes following acute exacerbation of severe chronic obstructive lung disease. Am J Respir Crit Care Med 1996; 154:959–967. 3. Derenne JP, Fleury B, Pariente R. Acute respiratory failure of chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138:1006–1033. 4. Jeffrey AA, Warren PM, Flenley DC. Acute hypercapnic respiratory failure in patients with chronic obstructive lung disease: risk factors and use of guidelines for management. Thorax 1992; 47:34–40. 5. Wagner PD, Dantzker DR, Dueck R, Clausen JL, West JB. Ventilation-perfusion inequality in chronic obstructive pulmonary disease. J Clin Invest 1977; 59:203–216. 6. Torres A, Reyes A, Roca J, Wagner PD, Rodriguez-Roisin R. Ventilation-perfusion mismatching in chronic obstructive pulmonary disease during ventilator weaning. Am Rev Respir Dis 1989; 140:1246–1250. 7. Beydon L, Cinotti L, Rekik N, Radermacher P, Adnot S, Meignan M, Harf A, Lemaire F. Changes in the distribution of ventilation and perfusion associated with separation from mechanical ventilation in patients with obstructive pulmonary disease. Anesthesiology 1991; 75:730–738. 8. Lemarie F, Teboul JL, Cinotti L, Guillen G, Abrouk F, Steg G, Macquin-Mavier I, Zapol WM. Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation. Anesthesiology 1988; 69:171–179. 9. Aubier M, Murciano D, Milic-Emili J, Touaty E, Dagfous J, Pariente R, Derenne JP. Effects of the administration of O 2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122: 747–754.
676
Krachman and Tobin
10. Sassoon CS, Hassell KT, Mahutte CK. Hyperoxic-induced hypercapnia in stable chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135:907–911. 11. Tobin MJ, Perez W, Guenther SM, Semmes BJ, Mador MJ, Allen SJ, Lodato RF, Dantzker DR. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1986; 134:1111–1118. 12. Grassino A, Sorli J, Lorange G, Milic-Emili J. Respiratory drive and timing in chronic obstructive pulmonary disease. Chest 1978; 73(suppl 2):290–293. 13. Tobin MJ, Chadha TS, Jenouri G, Birch SG, Gazerolu HB, Sackner MA. Breathing patterns: 2. Diseased subjects. Chest 1983; 84:286–294. 14. Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 1997; 155: 906-915. 15. Campbell EJM. The management of acute respiratory failure in chronic bronchitis and emphysema. Am Rev Respir Dis 1967; 96:626–639. 16. West JB. Pulmonary Pathophysiology. The Essentials, 2d ed. Baltimore: Williams and Wilkins, 1982:161. 17. Richards DW. The nature of cardiac and pulmonary dyspnea. Circulation 1953; 7:15–29. 18. Dick CR, Liu Z, Sassoon CSH, Berry RB, Mahutte CK. O 2-induced change in ventilation and ventilatory drive in COPD. Am J Respir Crit Care Med 1997; 155:609–614. 19. Dunn WF, Nelson SB, Hubmayr RD. Oxygen-induced hypercarbia in obstructive pulmonary disease. Am Rev Respir Dis 1991; 144:526-530. 20. Tobin MJ, Jubran A. Oxygen takes the breath away: Old sting, new setting. Mayo Clin Proc 1995; 70:403–404. 21. Prechter GC, Nelson SB, Hubmayr RD. The ventilatory recruitment threshold for carbon dioxide. Am Rev Respir Dis 1990; 141:758–764. 22. Tardif C, Bonmarchand G, Gibon JF, Hellot MF, Leroy J, Pasquis P, Milic-Emili J, Derenne JP. Respiratory response to CO 2 in patients with chronic obstructive pulmonary disease in acute respiratory failure. Eur Respir J 1993; 6:619–624. 23. Matthews AW, Howell BL. The rate of isometric inspiratory pressure development as a measure of responsiveness to carbon dioxide in man. Clin Sci Mol Med 1975; 49:57–68. 24. Matthews AW, Howell JBL. Assessment of responsiveness to carbon dioxide in patients with chronic airways obstruction by rate of isometric pressure development. Clin Sci Mol Med 1976; 50:199–205. 25. Jubran A, Tobin MJ. Passive mechanics of lung and chest wall in patients who failed or succeeded in trials of weaning. Am J Respir Crit Care Med 1997; 155:916–921. 26. Tobin MJ. Respiratory muscles in disease. Clin Chest Med 1988; 9:263–286. 27. Rahn H, Otis AB, Chadwick LE, et al.. The pressure-volume diagram of the thorax and lung. Am J Physiol 1946; 146:161–178. 28. Kim M, Druz WS, Danon J, Machinach W, Sharp JT. Mechanics of the canine diaphragm. J Appl Physiol 1976; 41:369–382. 29. Rochester DF, Braun NMT. Determinants of maximal inspiratory pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 132:42–47. 30. Marshall R. Relationships between stimulus and work of breathing at different lung volumes. J Appl Physiol 1962; 17:917-921. 31. Sharp JT. The respiratory muscles in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 134:1089–1091. 32. Sharp JT. The respiratory muscles in emphysema. Clin Chest Med 1983; 4:421–432. 33. Mead J. Functional significance of the area of apposition of diaphragm to rib cage. Am Rev Respir Dis 1979; 119:31–32. 34. Minh VD, Loan GF, Konopka RE, Moser KM. Effect of hyperinflation on inspiratory function of the diaphragm. J Appl Physiol 1976; 40:67–73. 35. Kelsen SG, Fleegler B, Altose MD. The respiratory neuromuscular response to hypoxia, hypercapnia, and obstruction to airflow in asthma. Am Rev Respir Dis 1979; 120:517– 527. 36. Buchler B, Nagder S, Katsardis H, Jammes Y, Roussos C. Effects of pleural pressure and abdominal pressure on diaphragmatic blood flow. J Appl Physiol 1985; 58:691–697.
COPD
677
37. Supinski GS, Bark H, Guanciale A, Kelsen SG. Effect of alterations in muscle fiber length on diaphragm blood flow. J Appl Physiol 1986; 60:1789–1796. 38. Aubier M, Trippenbach T, Roussos CH. Respiratory muscle fatigue during cardiogenic shock. J Appl Physiol 1981; 51:499-508. 39. Jardim J, Farkas G, Prefaut C, Thomas D, Macklem PT. The failing inspiratory muscles under normoxic and hypoxic conditions. Am Rev Respir Dis 1982; 124:274–279. 40. Hussain SNA, Simkus G, Roussos C. Respiratory muscle fatigue: a cause of ventilatory failure in septic shock. J Appl Physiol 1985; 58:2033–2040. 41. Hussain SNA, Roussos C. Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs. J Appl Physiol 1985; 59:1802–1805. 42. Jubran A, Mathru M, Dries D, Tobin MJ. Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 1998; 158:1763–1769. 43. Juan G, Calverley P, Talamo C, Schnader J, Roussos C. Effect of carbon dioxide on diaphragmatic function in human beings. N Engl J Med 1984; 310:874–879. 44. Yanos J, Wood LDH, Davis K, Kearny M. The effect of respiratory and lactic acidosis on diaphragm function. Am Rev Respir Dis 1993; 147:616–619. 45. Aubier M, Murciano D, Lecocguic Y, Viires N, Jacqyens Y, Squara P, Pariente R. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985; 313:420–424. 46. Aubier M, Viires N, Piquet J, Murciano D, Blanchet F, Marty C, Gherardi R, Pariente R. Effects of hypocalcemia on diaphragmatic strength generation. J Appl Physiol 1985; 58: 2054–2061. 47. Molloy DW, Dhingra S, Solven F, Wilson A, McCarthy DS. Hypomagnesemia and respiratory power. Am Rev Respir Dis 1984; 129:497–498. 48. Rochester DF, Arora Ns. Respiratory muscle failure. Med Clin North Am 1983; 67:573– 597. 49. Arora NS, Rochester DF. Effect of body weight and muscularity on human diaphragm muscle mass, thickness, and area. J Appl Physiol 1982; 52:64–70. 50. Arora NS, Rochester DF. Respiratory muscle strength and maximal voluntary ventilation in undernourished patients. Am Rev Respir Dis 1982; 126:5–8. 51. Aldrich TK. Respiratory muscle fatigue. In: Tobin MJ, ed. The Respiratory Muscles. Philadelphia: Lippincott, 1990:329–342. 52. Moxham J. Respiratory muscle fatigue: mechanisms, evaluation and therapy. Br J Anaesth 1990; 65:43–53. 53. NHLBI Workshop Summary. Respiratory muscle fatigue: report of the respiratory muscle fatigue workshop group. Am Rev Respir Dis 1990; 142:474–480. 54. Tobin MJ, Haghi F. Monitoring of muscle function In: Tobin MJ, ed. Principles and Practice of Intensive Care Monitoring. New York: McGraw-Hill, 1998:497–544. 55. Miller RG, Boska MD, Moussavi RS, Carson PJ, Weiner MW. 31 P nuclear magnetic resonance studies of high energy phosphates and pH in human muscle fatigue: comparison of aerobic and anaerobic exercise. J Clin Invest 1988; 81:1190–1196. 56. Weiner MW, Moussavi RS, Baker AJ, Boska MD, Miller RG. Constant relationship between force, phosphate concentration, and pH in muscles with differential fatigability. Neurology 1990; 40:188–1893. 57. Kent-Braun JA, Miller RG, Weiner MW. Phases of metabolism during progressive exercise to fatigue in human skeletal muscle. J Appl Physiol 1993; 75:573–580. 58. Westerblad H, Lee JA, Lannergren J, Allen DG. Cellular mechanisms of fatigue in skeletal muscles. Jam J Physiol 1991; 261:C195–C209. 59. Jones DA, Bigland-Ritchie B, Edwards RHT. Excitation frequency and muscle fatigue mechanical responses during voluntary and stimulated contractions. Exp Neurol 1979; 64: 401–413. 60. Bigland-Ritchie B. Muscle fatigue and the influence of changing neural drive. Clinics Chest Med 1984; 5:21–34. 61. De Troyer A, Leeper J, McKenzie D, Gandevia S. Neural drive to the diaphragm in patients with severe COPD. Am J Respir Crit Care Med 1997; 155:1335–1340.
678
Krachman and Tobin
62. Laghi F, D’alfonso N, Tobin MJ. Pattern of recovery from diaphragmatic fatigue over 24 hours. J Appl Physiol 1995; 79:539-546. 63. Reid WD, Huang J, Bryson S, Walker DC, Belcastro AN. Diaphragm injury and myofibrillar structure induced by resistive loading. J Appl Physiol 1994; 76:176–184. 64. Vollestd NK, Scjersted OM. Biochemical correlates of fatigue: a brief review. Eur J Appl Physiol 1988; 57:336–347. 65. Newham D. The consequences of eccentric contractions and their relationship to delayed onset pain. Eur J Appl Physiol 1988; 57:353–359. 66. Zhu E, Petrof BJ, Gea J, Comtois N, Grassino AE. Membrane and sarcomere injury in diaphragm following inspiratory resistive loading. Am J Repir Crit Care Med 1997; 155: 1110–1116. 67. Anzueto A, Andrade FH , Maxwell LC, Levine SM, Lawrence RA, Gibbons WJ, Jenkinson SG. Resistive breathing activates the glutathione redox cycle and impairs contractile performance of rat diaphragm. J Appl Physiol 1992; 72:529–534. 68. Reid MB, Haack KE, Francik KM, Valberg PA, Kobzik L, West MS. Reactive oxygen in skeletal muscle: I. Intracellular oxidant kinetics and fatigue in vitro. J Appl Physiol 1992; 72:529–534. 69. Khawali FA, Reid MB. N-acetylcysteine depresses contractive function and inhibits fatigue of diaphragm in vitro. J Appl Physiol 1994; 77:317–324. 70. Armstrong RB, Warren GI, Warren JA. Mechanisms of exercise-induced muscle fibre injury. Sports Med 1991; 12:184–207. 71. McNeil PL, Ito S. Molecular traffic through plasma membrane disruptions of cells in vivo. J Cell Sci 1990; 96(Pt3):349–356. 72. Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, Simonneau G, Benito S, Gasparetto A, Lemaire F, Isabey D, Harf A. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333:817–822. 73. Tobin MJ, Alex CG. Discontinuation of mechanical ventilation In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. New York: McGraw-Hill, 1994:1177–1206. 74. Merton PA. Voluntary strength and fatigue. J Physiol (Lond) 1954; 123:553–564. 75. Aldrich TK. Transmission fatigue of the rabbit diaphragm. Respir Physiol 1987; 69:307– 319. 76. Cohen CA, Zagelbaum G, Gross D, Roussos C, Macklem PT. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982; 73:308–316. 77. Huttemann U, Huckauf H. Mechanical effects of the compressibility of alveolar gas in patients with chronic obstructive lung disease. Bull Physiopathol Respir 1971; 7:445–455. 78. Tobin MJ. Respiratory monitoring in the intensive care unit. Am Rev Respir Dis 1988; 138:1625–1642. 79. Grassino A, Macklem PT. Respiratory muscle fatigue and ventilatory failure. Annu Rev Med 1984; 35:625–647. 80. Roussos C. Macklem PT. The respiratory muscles. N Engl J Med 1982; 307:786–797. 81. Tobin MJ, Perez W, Guenther SM, Lodato RF, Dantzker DR. Does rib cage–abdominal paradox signify respiratory muscle fatigue? J Appl Physiol 1987; 63:851–860. 82. Bellemare F, Grassino A. Effect of pressure and timing of contraction human diaphragm fatigue. J Appl Physiol 1982; 53:1190–1195. 83. Campbell EJM, Westlake EK, Cherniack RM. Simple methods of estimating oxygen consumption and efficiency of the muscles of breathing . J Appl Physiol 1957; 11:303–308. 84. Cherniack RM. The oxygen consumption and efficiency of the respiratory muscles in health and emphysema. J Clin Invest 1959; 38:494–499. 85. Levison H, Cherniack RM. Ventilatory cost of exercise in chronic obstructive pulmonary disease. J Appl Physiol 1968; 25:21–27. 86. Milic-Emili G, Pete JM. Mechanical efficiency of breathing. J Appl Physiol 1960; 15:359– 362. 87. Otis AB. The work of breathing. Physiol Rev 1954; 34:449–458. 88. Silberman H, Silberman AW. Parenteral nutrition, biochemistry, and respiratory gas exchange. JPEN 1986; 10:151-154. 89. Fleury B, Murciano D, Talamo C, Aubier M, Pariente R, Milic-Emili J. Work of breathing
COPD
90. 91. 92. 93. 94. 95.
96. 97. 98. 99. 100. 101. 102. 103. 104. 105.
106. 107. 108.
679
in patients with chronic obstructive pulmonary disease in acute respiratory failure. Am Rev Respir Dis 1985; 131:816–821. Vinegar A, Sinnett EE, Leith DE. Dynamic mechanisms determine functional residual capacity in mice, Mus musculus. J Appl Physiol 1979; 46:867–871. Kimball WR, Leith DE, Robins AG. Dynamic hyperinflation and ventilatory dependence in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 126:991–995. Martin J, Powell E, Shore S, Emrich J, Engel LA. The role of respiratory muscles in the hyperinflation of bronchial asthma. Am Rev Respir Dis 1980; 121:441–447. Martin J, Aubier M, Engel LA. Effects of inspiratory loading on respiratory muscle activity during expiration. Am Rev Respir Dis 1982; 125:352–358. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982; 126:166–170. Rossi A, Gottfried SB, Zocchi L, Higgs BD, Lennox S, Calverley PMA, Begin P, Grassino A, Milic-Emili J. Measurement of static compliance of the total respiratory system in patients with acute respiratory failure: the effect of intrinsic positive end-expiratory pressure. Am Rev Respir Dis 1985; 131:672–677. Gottfried SB, Reissman H, Ranieri M. A simple method for the measurement of intrinsic positive end-expiratory pressure during controlled and assisted modes of mechanical ventilation. Crit Care Med 1992; 20:621–629. Haluszka J, Chartrand DA, Grassino A, Milic-Emili J. Intrinsic PEEP and arterial PCO2 in stable patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141: 1194–1197. Maltais F, Reissmann H, Navalesi P, Hernandez P, Gursahzney A, Ranieri VM, Sovilj M, Gottfried SB. Comparison of static and dynamic measurements of intrinsic PEEP in mechanically ventilated patients. Am J Respir Crit Care Med 1994; 150:1318–1324. De Troyer A, Estenne M, Ninane V, Van Gansbeke D, Gorini M.. Transversus abdominis muscle function in humans. J Appl Physiol 1990; 68:1010–1016. Ninane V, Yernault J-C, De Troyer A. Intrinsic PEEP in patients with chronic obstructive pulmonary disease: role of expiratory muscles. Am Rev Respir Dis 1993; 148:1037–1042. Miro AM, Pinsky RM. Heart-lung interaction. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. New York: McGraw Hill, 1994:647–671. Smith TC, Marini JJ. Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction. J Appl Physiol 1988; 65:1488–1499. Tobin MJ, Lodato RF. PEEP, auto-PEEP, and waterfalls (editorial). Chest 1989; 96:449– 451. Schnader J. Estimation of auto-PEEP (letter). Chest 1991; 99:520. Petrof BJ, Legare M, Goldberg P, Milic-Emili J, Gottfried SB. Continuous positive airway pressure reduces work of breathing and dyspnea during weaning from mechanical ventilation in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141:281– 289. Georgopoulos D, Giannouli E, Patakas D. Effects of extrinsic positive end-expiratory pressure on mechanically ventilated patients with chronic obstructive pulmonary disease and dynamic hyperinflation. Intens Care Med 1993; 19:197–203. Ranieri VM, Guiliani R, Cinnella G . Physiologic effects of positive end-expiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis 1993; 147:5–13. Rossi A, Santos C, Roca J, Torres A, Felez MA, Rodriguez-Roisin R. Effects of PEEP on V/Q mismatching in ventilated patients with chronic airflow obstruction. Am J Respir Crit Care Med 1994; 149:1077–1084.
26 Circulatory Effects of COPD
BARTOLOME R. CELLI
REGINA FRANTS
St. Elizabeth’s Medical Center Tufts University School of Medicine Boston, Massachusetts
St. Elizabeth’s Medical Center Boston, Massachusetts
I.
Introduction
It is well recognized that chronic obstructive pulmonary disease (COPD) affects the pulmonary and systemic circulation. However, the complexity of the heart-lung interplay has made this subject very difficult to study. The goal of this chapter is to review our current understanding of the cardiopulmonary interactions with an emphasis on the effect that exercise has in patients with COPD. Functionally, COPD is characterized by a decrease in elastic recoil, a reduction in airflow, an increase in airway resistance, and in the ventilation required to maintain adequate gas exchange. In addition, during situations of increased metabolic and ventilatory demand, when breathing frequency increases and therefore expiratory time becomes shorter, patients with COPD may develop air trapping and worsening hyperinflation (1,2). This resulting ‘‘dynamic’’ hyperinflation is very detrimental to lung mechanics and adversely affects the cardiopulmonary system (3). Decreased lung elastic recoil is a major contributor of airway narrowing in emphysema (4–7). Because elastic recoil is relatively well preserved at high lung volumes where maximal expiratory flow can be achieved, large negative pleural pressures are required to overcome both the elastic and the resistive properties of the respiratory system (7). In the setting of persistent lung hyperinflation intrathoracic pressure fluctuates over a wide range (⫹20 to ⫺60 cm H2O) with spontaneous respiratory 681
682
Celli and Frants
effort (7,8), and the pressure environment in which the heart functions is different during the inspiratory and expiratory phases of the respiratory cycle. Several investigators (9–11) have suggested that the exercise capacity limitations commonly seen in severe COPD may be related to altered right and left ventricular performance. This has been primarily manifested by a low oxygen pulse (VO 2 / heart rate) at peak exercise (O 2 Pmax ). Montes de Oca et al. (11) also observed a significant correlation between intrathoracic inspiratory pressures (Pplimax , and Ppli ) and O 2 Pmax . Recent advances in lung volume reduction surgery with its major physiologic outcome in the form of increased lung elastic recoil (12–14) and alleviated hyperinflation (15), permit a better understanding of cardiopulmonary interactions in the unique clinical setting of changing pulmonary function and steady cardiac variables. Four components of the circulatory system are affected by ventilation: systemic venous return, right ventricular (RV) output, pulmonary venous return, and left ventricular (LV) output (16). We will analyze the available data on COPD using this systematic approach.
II. Systemic Venous Return The exquisite sensitivity of systemic venous return (see also Chapter 5) to respiratory-induced changes has been described in the classic experiments of Guyton et. al. (17,18). It is necessary to appreciate the factors that regulate the venous return curve in order to understand cardiorespiratory interactions. The basic principle is that the systemic venous return is the major determinant of circulation and it is equal to the left ventricular output in steady state conditions (8,16,19–21). Guyton et. al. (17,18) demonstrated that the right atrial pressure (Pra) represents the outflow pressure (backpressure) for venous return. Since the right atrium is a highly compliant structure, Pra would reflect variations in Ppl. The venous return curve (constructed for a single peripheral venous compartment) displays the relationship between venous return and Pra (Fig. 1) (22). As Ppl increases (becomes more positive), venous return decreases. Pra becomes equal to the upstream pressure driving venous return at the point of zero flow, i.e., the mean circulatory pressure (Pms). Decrease in Ppl would cause increase in venous return until Pra drops a few torr below atmospheric pressure. Any further lowering of right atrial pressure fails to elicit increases in venous return due to the collapse of the highly compliant large veins as they enter the thorax. This flow limitation effect in the vascular bed occurs because of the phenomenon of fluttering of the venous flow (known as a Starling resistor mechanism) at the entrance into the thorax. The process is analogous to the expiratory airflow limitation during forced expiration. Once flow limitation occurs, the difference between the upstream pressure (Pms) and the pressure surrounding the collapsed vessels downstream become the major determinants of flow. With flow limitation, further decreases in Ppl (the downstream pressure) would not increase venous return more than when the Pra relative to the periphery is zero (16,20). Several investigators (17,18,23–25) experimentally demonstrated the relevance of the Starling resistor mechanism in the regulation of venous return from the abdomen. Those studies
Circulatory Effects of COPD
683
Figure 1 Graphic representation of the venous return curve in a single-circuit model (single peripheral venous compartment). The venous return intersects the abscissa at the right atrial pressure (Pra ) required to stop all venous return, i.e., mean systemic pressure (Pms ). The reciprocal of the slope of the venous return curve is equal to the venous resistance (Rv ). Q, cardiac output; Pms , mean systemic pressure; Pra , right atrial pressure. (From Ref. 22.)
showed that, in general, decrease in pleural pressure augments venous return, even when the Pra exceeds the abdominal pressure. Only when the abdominal pressure was greater than the inferior vena cava (IVC) pressure by more than 5 cmH2 O did flow appear limited by further increases in abdominal pressure (24). These findings underscore the very important concept of transmural pressure (i.e., pressure within an element relative to the surrounding pressure) which becomes essential in comparing the driving pressures through multiple compartments (16,26). The use of the right atrial transmural pressure (Prat ⫽ Pra ⫺ pressure surrounding the heart or Ppl ) instead of the absolute value of Pra makes interpretation of the hemodynamic effects of hyperinflation on systemic venous return more physiologically sound. This approach has been validated by Cobelli et al. (27), who studied the effect of inspiratory muscle resistive breathing (IMRB) on pulmonary hemodynamics in moderate COPD. They performed right heart catheterization on all study subjects and analyzed the data in terms of right atrial (Prat ) and pulmonary artery transmural pressures (PAPt). The patients were made to breath against a resistor to generate progressively more negative mouth pressures up to 40% of the maximal inspiratory pressure (Pi max) (Fig. 2). The mean absolute value of recorded inspiratory Pra become progressively lower than zero (relative to atmospheric pressure) with resistive inspiratory breathing. This placed the systemic venous return theoretically on the plateau part of the venous return curve. If that were the case, one would predict no increase in cardiac output in response to the marked decrease in intrathoracic pressure. However, the authors found that the inspiratory Prat was correlated with mouth pressure with dramatic increase in right atrial transmural pres-
684
Celli and Frants
Figure 2 (Left) Mean ⫾ S.D. PAP values during inspiratoy resistive breathing. (Right) Mean ⫾ S.D. RAP values during the same maneuvers. The inspiratory transmural values were obtained from the inspiratory PAP and RAP values with the algebraic addition of the corresponding pressure at the mouth. PAP, pulmonary artery pressure; RAP, right atrial pressure; %Pi mx, % of the maximal inspiratory mouth pressure; R3′ 3rd min of recovery. (From Ref. 27.)
sure (⫹332% from baseline) which corresponded with a rise in the cardiac output (CO), best explained by an increase in systemic venous return. This study illustrates the aforementioned association between negative inspiratory intrathoracic pressure, negative Pra and increases in cardiac output. In this setting the high right atrial transmural pressure better reflected the high volume status of the right atrium and therefore the elevated RV preload. Only when both the Pra (relative to atmosphere) and the Prat (relative to intrathoracic) are considered can the data be logically interpreted (19). Cobelli et al. (27) also noted that the increase of inspiratory Prat was more prominent than the corresponding values of inspiratory transmural pulmonary arterial pressure (⫹332% vs ⫹76% at the last step). This possibly indicates not only a difference in compliance between the right atrium and the pulmonary vascular bed, but also the presence of some physiologic variables which were not factored in the study design.
Circulatory Effects of COPD
685
As mentioned, pleural pressure per se is not the only force affecting venous return to the right atrium. Brookhart and Boyd (28) studied the local effects of intrathoracic pressure on cardiac filling pressures and recognized that inflated lungs can directly compress the heart (the heart-lung interdependence). This phenomenon has been recently examined by numerous investigators (29–32) using various models of positive-pressure ventilation. They demonstrated that, as lung volume increases, the respiratory system restricts cardiac filling similar to cardiac tamponade effect (30). Furthermore, this effect is independent of the changes in intrathoracic pressure. The overall effects of the abdominal vascular zone conditions on systemic venous return during respiration depend on multiple factors. This includes blood flow from the legs, volume status of the splanchnic vessels, and the complex intraabdominal pressure characteristics. Recently Wise and Robotham (25) and Takata et. al. (33) developed a model that attempted to explain the isolated effects of changes in abdominal pressure on IVC pressure/flow and subsequently on cardiac output. Applying the principle of vascular zones originally described by West et. al. (34) for the pulmonary circulation, the authors were able to demonstrate how in conditions associated with markedly elevated abdominal pressure this pressure and not the right atrial pressure, would become the effective backpressure for global IVC venous return therefore effectively ‘‘disconnecting’’ the right atrial pressure from the IVC system (16) (zone II condition or Starling resistor when femoral venous pressure ⬎ intraabdominal pressure ⬎ right atrial pressure). It is possible that conditions associated with increased functional residual capacity (FRC), such as in severe COPD, the diaphragmatic descent and the recruitment of the abdominal muscles during forced respiration could cause enough increase in abdominal pressure to cause IVC flow limitation therefore reproducing the Starling resistor effect. Nakhjavan et. al. (35) showed cineangiographic evidence of IVC flow reduction, including complete flow arrest, at the level of diaphragm during spontaneous inspiration in patients with very high lung volumes due to severe emphysema (FRC ⬎ 112% pred, gross hyperinflation of the lungs and a low diaphragmatic position on the chest X-ray). They suggested that this effect occurs as a consequence of the diaphragm acting as a sphincter at the thoracic inlet. It is also possible that their observation could represent extreme zone II condition (see above) or direct compression of the IVC by hyperinflated lungs. It is important to note that in this study there was no correlation between fluctuations in gastric pressure and the pattern of venous return. Their findings correspond with the observation by Montes de Oca et al. (11) that elevated gastric pressure appears to bear no relationship with the low O 2Pulse detected in patients with severe COPD during exercise. These observations suggest that venous return may be limited by critical closure of the IVC independently of the gradient for venous return. Independent of the intrathoracic environment, the right atrial volume and pressure characteristics are closely related to left ventricular function and ventricular compliance via ventricular interdependence (29,30,32,36). This in turn is related to the pulmonary vascular bed conditions (16,19). In summary, to evaluate the influence of the respiration on global cardiac function it is crucial to appreciate the continuity of the vascular compartments as
686
Celli and Frants
well as the extreme sensitivity of venous return to relatively small pressure changes in downstream or critical closing pressures.
III. Right Ventricular Function and Ventricular Interdependence The cardiopulmonary unit (37) is a unique physiologic system, which consists of the two muscle pumps functioning in series as well as in parallel, and mechanically coupled by the lungs. The right ventricle (RV) is a flat, highly compliant chamber, which under normal conditions, including vigorous exercise in healthy individuals, functions as a low-pressure, high-volume displacement pump (37). The normal respiratory variation in RV output is more pronounced than that of LV output (19,38– 41). The respiratory motion of the thorax assists right atrial and right ventricular filling by reducing intrathoracic pressure, thereby elevating the gradient between extrathoracic and intrathoracic veins (37). The RV shares a free wall contiguous with the LV free-wall fibers. The anatomical continuity of the free-wall ventricular muscle fibers suggests that when contracting they pull together toward a common center functionally enhancing each other’s systolic performance (42–45). The RV has a septal wall in common with the left ventricle (LV), serving as an anchor for systolic contraction. In normal conditions its movement during diastole influences the diastolic compliance of each ventricle to a significant degree thereby determining ventricular filling pressures and subsequently regulating ventricular output (46– 48). In a dog preparation, with intact heart and pericardium, Angle et al. (49) showed that when venous return effects were eliminated, the incremental rise in right atrial pressure (Pra ) would initially increase cardiac output, up to a Pra of 18 mm Hg when the CO would plateau. At levels above Pra 30 mm Hg the CO would precipitously fall. They concluded that increasing Pra may depress both cardiac function and output. The authors speculated that the RV impingement on the septal wall, along with increasing intrapericardial pressure, would cause the left atrial pressure to rise in order to maintain LV preload and cardiac output (ventricular interdependence mechanism). The retrograde increase in the pulmonary arterial pressure would place an intolerable afterload on an optimally preloaded RV, resulting in cardiac decompensation. This study illustrates the complexity of the intracardiac interactions and also the role the pericardium may play by transmitting changes of the intraventricular pressures over the entire surface of the heart. The function of the pericardium in relation to respiratory-induced changes has been recently evaluated by Takata et al. (32). They found that once the elastic limits of the pericardium are reached (as the ventricle increases in size) the pericardium produces a proportional increase in pressure over the ventricle. This serves a dual purpose. In diastole, it would limit preload increase and venous return (an adverse circumstance in tamponade, but a useful one in a dilated failing ventricle). In systole, the potential energy stored during diastole will assist the myocardium during the subsequent ventricular ejection.
Circulatory Effects of COPD
687
The role of ventricular interdependence in pathologic conditions like COPD is less clear. The RV may act either like a very compliant structure and therefore be susceptible to larger respiratory variation in end-diastolic volume chamber, or— if hypertrophy develops—much like a stiffer structure behaving as a thick-walled, pressure-generating pump. If the septum hypertrophies as well, this would diminish the influence of the RV on LV performance via ventricular interdependence (16). A group of investigators (50–52) evaluated the cardiovascular function of patients with chronic obstructive bronchitis during COPD exacerbations (mean FEV1 during exacerbation of 0.79 ⫾ 0.08 L, 50% of predicted) and the subsequent recovery. An age-matched group of surgical patients without concomitant pulmonary and cardiovascular diseases served as controls. They described three types of hemodynamic response to the acute exacerbation. Patients with a CO elevation of ⬎10% during the COPD exacerbation in relation to the recovery period formed group I. Group II consisted of patients whose CO was within 10% during and after the exacerbation. Group III included patients whose CO decreased more than 10% during the exacerbation. This group had the most severe COPD. Patients in group I had significantly higher cardiac index (CI) and slightly increased mean stroke volume index (SI) during exacerbation than the patients in the other groups. In group I (the increased CO) the systolic and end-diastolic RV pressures were significantly higher, while the pulmonary artery pressures (PAP) were not different from normals. In group II (with unchanged CO), the SI was significantly lower and RV systolic and especially diastolic pressures significantly higher than in the control group. The pulmonary artery systolic pressure in this group was the highest of all three groups. Patients in group III demonstrated dramatic decreases in both CI and SI during the exacerbation along with a significant increase in end-diastolic RV (RVEDP) and diastolic PAP. The PAWP in this group was also the highest among all study groups. The central venous pressure (CVP) was significantly elevated in all three groups, being the highest in group II (unchanged CO) and the lowest in group III (low CO). The statistical analysis revealed a strong direct correlation between CVP and RVEDP in the high CO group (r ⫽ .7, P ⬍ .001). There was a lack of correlation between the same variables in the low-CO group (r ⫽ ⫺.1, P ⬎ .05). The same trends were observed in the relationships between the CVP and diastolic PAP and PAWP. There was no correlation between CVP and stroke volume indices, and RVEDP and stroke volume indices in any of the study groups. There was no correlation between FEV1 and stroke volume index in group I (r ⫽ ⫺.1, P ⬎ .05) while there was a trend in group III (r ⫽ .5, P ⬎ .05). There was a strong inverse correlation (r ⫽ ⫺.75, P ⬍ .01) between FEV1 and RVEDP in group II, while the pulmonary artery pressure trended to correlate inversely with FEV1 in this group (r ⫽ ⫺.57 to ⫺.65, P ⬎ .05). However, there was no relationship between the ventilatory and hemodynamic parameters in groups I and III. Despite the fact that all study patients presented with a similar degree of airway obstruction during the exacerbation of the COPD, the groups were significantly different one from the other. In group I with less severe COPD, none of the patients had any clinical evidence of cor pulmonale. Group II included the patients with
688
Celli and Frants
moderately severe COPD (9 out of 10) and symptomatic disease duration of ⬎10 years (50%). Most of the patients in group III had longstanding severe COPD at baseline, and two of them had overt signs of cor pulmonale at the time of original presentation. A review of the venous return–RV function relationships across all the study groups demonstrated a transition from a situation of high and direct correlation between CVP and RVEDP in group I to one of lack of correlation between the elevated RVEDP (‘‘filling pressure,’’ or preload) and the CVP in group III. This confirms that factors other than the venous return influences RV performance as COPD progresses. The absence of correlation between CVP and RV preload, and the stroke volume index, illustrates the relative lack of importance of systemic venous return and ventricular interdependence per se on left ventricular output in a given clinical circumstances. This finding could also be explained by a transient development of tricuspid regurgitation in the group with low CO, however, the available hemodynamic data are insufficient to make such a conclusion. Based on the strong inverse correlation between the FEV1 and RVEDP and between FEV1 and PAP in the moderately severe COPD group (group II) (but not in the mild and severe COPD group) we suggest that as the disease progresses the most important interaction in the cardio pulmonary unit takes place in the pulmonary vascular bed that, due to its large reserve, may act as a buffer protecting cardiac function during changes in lung volumes. We hypothesize that, with progressive loss of pulmonary function, the pulmonary circulation response to the recurrent stresses of COPD exacerbation, likely becomes more fixed as pulmonary vascular pressure increases. As the disease evolves, the pulmonary vasculature—the second of the three compartments of the cardiopulmonary unit—develops ‘‘functional rigidity,’’ further decreasing the plasticity of the whole system, therefore making it less flexible and less able to adapt to the repeated insults of deteriorating lung function. It seems logical to suggest that under these conditions the cardiac function becomes more vulnerable to intrathoracic events and therefore more dependent upon variations in the respiratory system as illustrated by the increasing correlation between the FEV1 and stroke volume index from group I to group III. Berger et. al. (10) studied a group of patients with COPD of different severity (FEV1 range from 0.70 to 2.5 L) with baseline normal (⬎45%) or low (38% to 45%) right ventricular ejection fraction (RVEF). They showed that 75% of patients (12 out of 16) demonstrated an abnormal RV response to a submaximal exercise test. The RVEF either remained the same or diminished with exercise (average ⫺6%) (Fig. 3). Nine of the 12 patients demonstrated isolated abnormal exercise RV reserve in the presence of normal LV reserve. They noted that patients with low RV reserve were more hypoxemic at rest, and their FEV1 was lower than that of normal responders (45 ⫾ % vs. 68 ⫾ 5% predicted, P ⬍ .05). The authors suggested that the primary mechanism responsible for an abnormal RV response to exercise is likely related to increased RV afterload secondary to pulmonary arterial hypertension. The presence of a normal LV performance in the majority of the patients with altered RV reserve indicated that ventricular interdependence per se either does not play a significant role in overall cardiac function in COPD, or alternatively that it could
Circulatory Effects of COPD
689
Figure 3 Right and left ventricular ejection fractions at rest and exercise in 16 patients with COPD. Black circles represent individual patients. Open circles represent the mean value. For the entire group, RV ejection fraction was unchanged by exercise. The LV ejection fraction rose normally with exercise. (From Ref. 10.)
be counterbalanced by other mechanisms, i.e., the RV developed some degree of hypertrophy, became less compliant, and therefore less responsive to changes in LV output. Sciurba et al. (14) reported improvement in right ventricular systolic function after lung reduction surgery for diffuse emphysema (Fig. 4). They found no correlation between the changes in right ventricular function and maximal elastic-recoil pressure or changes in lung volumes. They concluded therefore that the improvement in RV systolic function after surgery was most likely due to a reduction in pulmonary vascular resistance (PVR) and therefore RV afterload. They also speculated that the reduced intrathoracic pressure may augment RV preload. The aforementioned studies show that events affecting ventricular performance in severe COPD are intimately related to intracardiac/intravascular as well as extracardiac/extravascular conditions. A significant volume of experimental data (1,2,30,40,53–57) supports the evidence that the cardiac impairment seen in conditions of lung hyperinflation, may be linked to the peculiar pressure environment that the heart is functioning within. However, most of the experimental studies were designed to investigate the acute effects of pleural pressure swings on heart function. This most closely resemble the events occurring during an acute asthma attack in an otherwise healthy individual. That is to say, changes that occur in a person with
690
Celli and Frants
Figure 4 Fractional change in right ventricular area during cardiac contraction in patients with diffuse emphysema before and after lung reduction surgery. The two horizontal bars represent the mean value for the group. (From Ref. 14.)
an overall normal lung function and an intact pulmonary circulation between attacks. In chronic conditions like COPD, the cardiopulmonary unit has lost a significant portion of its natural reserve. Under these conditions it is possible that even less dramatic acute change in intrathoracic pressure could cause similar deleterious effect on global cardiac performance.
IV. Pulmonary Vascular Compartment Normally, pulmonary arterial pressure changes in a cyclical manner during spontaneous respiration, with pressures being greater during expiration than inspiration. Alveolar transmural pressure is a function of lung volume. When the lungs are passively inflated, intrathoracic pressure will normally increase by less than half the inflation pressure. The increase will be even less if the lungs are stiff. It is in this way that low lung compliance protects the circulation from inflation pressure (58). Emphysema is unique in that static pulmonary compliance is increased, as a result of destruction of pulmonary tissue and loss of both elastin and surface retraction. Although FRC is increased, the distribution of inspired gas may be grossly distorted and therefore the dynamic compliance is commonly reduced (58). These compliance abnormalities most likely affect the pulmonary vasculature by changing the way pressure is transmitted through the lung tissue, but to what degree and in which direction remains unclear. It is tempting to assume that, in contrast to stiff lungs, emphysematous lungs would expose the vascular bed to more of the inflation pressure and make it more vulnerable to overall pressure swings. The strong inverse correlation between FEV1 and PAP in moderately severe COPD reported by Frants (51) and Memetov et. al. (52) supports this concept.
Circulatory Effects of COPD
691
Normal pulmonary circulation can adapt to large changes in cardiac output with only small increases in pulmonary arterial pressure (58). The pulmonary circulation readjusts to increased flow partly by recruitment and, most importantly, by passive dilatation of pulmonary vessels (59). Under normal conditions the pulmonary vascular resistance decreases as flow increases. The relationship between lung inflation and pulmonary vascular resistance (PVR) has been investigated (60–62). Pulmonary vascular resistance is minimal at functional residual capacity. Lung volume changes above or before FRC result in increases in pulmonary vascular resistance (Fig. 5). A review of the mechanisms responsible for the increase in pulmonary arterial pressure as a response to increases in cardiac output (63) in obstructive lung disease lies beyond the scope of this chapter. Nevertheless, it is essential to appreciate the pulmonary circulation in the context of its participation in the gas exchange function of the lungs. Exposure to intermittent and chronic alveolar hypoxia induces pulmonary arterial vasoconstriction (64) and causes alterations in the vascular tone (65– 67), and subsequent vascular remodeling (67–71). The above-mentioned changes in turn modify the vascular circuit. Consequently, the pressure response to flow and volume load becomes different from that seen in persons with intact vessels. Whether pulmonary artery pressure measurements in patients with obstructive lung disease, specifically the determination of diastolic pressure, predominantly reflects the severity of the morphological circulatory changes and RV afterload, and is there-
Figure 5 Pooled experimental data displaying the change in pulmonary vascular resistance (PVR) as a function of lung volume in normal lungs. PVR is minimal at point A corresponding to the functional residual capacity. It is apparent that PVR increases with changes in lung volume. (From Ref. 58.)
692
Celli and Frants
fore relatively independent of left ventriclar status, or whether PAWP, which in normals is assumed to be equal to the left atrial pressure and therefore an indirect reflection of left ventricular contractility, remains unclear up to date (63,72–80) and needs to be the subject of further studies. Lokhart et al. (78) investigated the level of pulmonary wedge pressure in chronic bronchitis and studied its relationship to left-ventricular end-diastolic pressure and with intrathoracic pressure at rest and during exercise. All patients had moderate degree of airway obstruction and minimal air trapping (RV/TLC 31.0% to 32.0%). Patients with any evidence of left ventricular disease were excluded from the study. They were divided into three groups based on the clinical degree of the RV failure. The PAWP was normal at rest in all study groups with the highest values seen in the group with evident RV failure. During exercise PAWP rose an average of 5 mm Hg, but remained within normal limits in all but one case. The authors observed that the higher the PAWP at rest, the higher it was during exercise. The study revealed that mean PAWP was almost identical to LV end-diastolic pressure both at rest and during exercise, suggesting absence of a significant resistance to flow along the venous side of the pulmonary circulation. Thus elevated, but still within normal limits, PAWP virtually excludes LV dysfunction as a major contributor to pulmonary hypertension in this population. In that study no correlation was observed between pulmonary artery diastolic pressure (PAPd) and PAWP. The difference between the two pressures was most prominent in the RV failure group, where the PAPd was 10.3 mm Hg higher than the PAWP. This observation supports our previous speculation that PAPd and PAWP become uncoupled as pulmonary vascular disease progresses. The linear correlation between PAWP and RVEDP found in the study could not be explained by relating those values to high intrathoracic pressures simultaneously affecting both parameters, since the esophageal pressure was slightly positive in the supine position at rest and did not rise with exercise, although all the pressures within the intrathoracic vascular structures did. We believe that this data could be logically interpreted by the phenomenon of ventricular interdependence discussed earlier in this chapter. Interestingly, despite the low mean esophageal pressure value and their lack of correlation with PAWP, the maximal amplitude of the respiratory swings of esophageal pressure closely correlated with that of PAWP. The nature of these intriguing relationships was further investigated by Butler et al. (80). The study was designed to test the hypothesis that rises in left atrial pressure (and therefore PAWP) on exercise in patients with obstructed airflow might be due to an augmentation of the juxtacardiac pressure, because of lower lobe distention associated with gas trapping during the tachypnea of exercise. Patients with moderate and severe COPD (and secondary pulmonary hypertension) were compared with patients with the same degree of pulmonary hypertension of different etiologies, but without airflow limitation. Spontaneously breathing patients with airflow obstruction developed significant air-trapping (apparent as an increase in FRC) during tachypnea of any nature – similar to the ‘‘auto-PEEP’’ phenomenon noted in mechanically ventilated COPD patients (81). The authors further showed that in COPD patients, right atrial, pulmonary artery, and wedge pressure demonstrated
Circulatory Effects of COPD
693
similar upward increment during tachypnea with and without exercise (Fig. 6). In contrast, in the control patients with pulmonary hypertension, the right atrial pressure change with exercise did not reflect that of the left atrium either in extent or direction. They concluded that the increase in pulmonary artery wedge pressure observed with hyperinflation in COPD was likely due to a rise in the pressure in the cardiac fossa associated with lower-lobe gas trapping. This study was the first to confirm previous experimental data that demonstrated that the respiratory system imposes a finite compliant load on the heart (30). The observation by Butler et al. (80) also corresponds with that of Brookhart and Boyd (28), who demonstrated that the intrathoracic pressure is not uniform throughout the chest, but is rather higher in the region of the heart. In the range of normal pleural pressure swings this effect is likely not hemodynamically significant, but when large variations in intrathoracic pressure are present, the circulatory effects become much more apparent. Burrows et. al. (79) performed a longitudinal 7-year study of 50 patients with severe chronic airway obstruction (FEV1 /FVC 37.1 ⫾ 8.7%) and described two patterns of cardiovascular abnormality. Patients with predominant emphysema demonstrated relatively normal arterial blood gas values (mild hypoxemia, without chronic carbon dioxide retention), low cardiac output, near normal resting pulmonary artery pressures, and high PVR. Patients with predominant chronic obstructive bronchitis (chronic inflammatory changes) were markedly hypoxemic and hypercapnic with resting pulmonary hypertension, and increased PVR. The cardiac output was preserved in this group. Both groups of patients showed significant increase in their PAP, but no further increase in PVR values during mild exercise. They also demonstrated normal baseline PAWP level with mild increase during exercise. Simultaneous measurements of PAWP and the left atrial pressure revealed their close correlation. Administration of supplemental 100% oxygen throughout the exercise
Figure 6 Effect of hyperventilation (left panel) and exercise (right panel) on mean right atrial pressure (Pra ) and wedge pressure (Pw ) in patients with COPD. (From Ref. 80.)
694
Celli and Frants
resulted in only partial reduction of the exercise-induced pulmonary hypertension in both groups. These facts indicate the likely presence of irreversible changes in the pulmonary vasculature even in the patients with baseline normal PAP. The authors proposed that those changes are due to anatomic destruction of the vascular bed, and concluded that when blood gas tensions are reasonably normal but the anatomic emphysema is severe, increases in PAP are minimized by reductions in CO. However, it remained unclear whether in the emphysema group the observed findings could be related to a simple anatomical loss of the vascular bed, with the remaining vasculature being normal, or whether there was additional vascular remodeling/ malfunctioning causing physiologic ‘‘stiffness’’ of the vascular compartment with inability to adapt to increased blood flow. A recent study by Oswald-Mammosser et al. (82) demonstrated an improvement in pulmonary hemodynamics following lung volume reduction surgery (LVRS) for severe emphysema. They showed a significant decrease in PAPd both at rest and during exercise post-LVRS with no changes in mean PAP (indicating therefore elevation in systolic PAP) in the setting of slightly improved cardiac index. They also observed a decrease in the respiratory swings of the PAPd. They explained this as a consequence of the decrease in the swings of intrathoracic pressures secondary to the improved mechanical properties of the respiratory system after LVRS, with an increase in elastic recoil and less hyperinflation. Their findings confirmed the observation made by Sciurba et al. (14) and Gelb et. al. (13). A significant reduction of the vascular bed is unlikely after LVRS, and argues against the concept of anatomical destruction because of emphysema, since diffusion capacity for CO at rest post-LVRS remained unchanged in this (82) and Scriuba et al. (14) studies and actually increased in the study by Gelb et al. (13). These observations suggest that well-targeted resection either causes minimal damage to the vascular bed, or, that by improving pulmonary mechanics and decreasing intrathoracic pressure swings, some mechanical load is taken off the vasculature and the heart, which in turn partially alleviates the baseline pulmonary hypertension. On the other hand, Weg et al. (83) recently reported an increase in pulmonary pressures post LVRS. These authors suggested that loss of vascular bed could be caused by resection of pulmonary parenchyma, even in target areas. One difference between the studies of Oswald-Mammoser et al. (82) and those of Weg et al. (83) is that in the latter, baseline pulmonary pressures were higher. Thus, there may have been less reserve in their patients and inadvertent vascular resection with LVRS led to increases in pulmonary pressures. Clearly, more studies are necessary to resolve this situation. Variations in both preload and afterload determine overall ventricular function. The pulmonary circulation serves simultaneously as the afterload for the right ventricle and the preload for the left ventricle, mechanically and functionally coupling the right and the left heart. During respiration, the phasic changes in right heart volume, via ventricular interdependence, influence LV compliance and, therefore, the downstream pressure for pulmonary venous return (16). However, as spontaneous inspiration increases right heart volume, it could increase pulmonary venous return via augmentation of the RV output. In conditions associated with elevated
Circulatory Effects of COPD
695
pulmonary vascular resistance, especially in the setting of large intrathoracic pressure swings, the RV afterload–LV preload interaction becomes even more complex. Franklin et al. (38) showed that in healthy animals the output of the two ventricles demonstrated minimal fluctuations during normal respiratory activity. In dogs with hydrothorax and pulmonary atelectasis, the right and left ventricular outputs fluctuate in greatly exaggerated fashion with each forced respiratory effort. Under such conditions, the changes in right and left ventricular stroke volume are nearly 180° out of phase. Pulmonary outflow resistance is increased and the RV ejection pattern closely resembles that typical of the left ventricle. Those fluctuations became attenuated as the hydrothorax was alleviated by thoracentesis. This study underscores the importance of the pulmonary vascular bed characteristics (resistance, compliance, and inertia) (16) in the transmission of RV status changes to the left heart. It also indirectly supports our concept of ‘‘functional rigidity’’ of the cardiopulmonary unit in pathologic conditions such as chronic obstructive lung disease.
V.
Left Ventricular Performance
The LV performance status in chronic obstructive lung disease has remained a subject of controversy over the last six decades. Robotham et al. (16) stated that ‘‘few subjects in cardiorespiratory physiology have engendered more discussion and confusion than the effects of respiration on LV performance.’’ A comprehensive review of the experimental data analyzing the effect of the phasic changes in intrathoracic pressure and lung volume on the cardiac cycle (i.e., systolic and diastolic events) can be found in other chapters of this volume. We would use some of this data in our analysis of the hemodynamic phenomenon observed in the patients with acute and chronic obstructive lung diseases. Since the 1940s, pathologists have been reporting an appreciable incidence of LV hypertrophy along with increase in RV wall thickness at necropsy in patients suffering from chronic bronchitis and emphysema (84–89). Rao et al. (77) evaluated patients with severe COPD. In six out of eight patients in whom lung volumes were measured, a significant hyperinflation was observed (RV/TLC 130% to 246% predicted). All patients had cor pulmonale as well as LV failure which was either present during episodes of ventilatory failure (four patients) or was chronic and progressive (four patients). They proposed COPD as the primary cause of this type of left heart failure, since no other etiology of left ventricular abnormality was identified. LV failure in this study was determined clinically and also documented by findings of concomitant elevation in PAWP, LAP, and LVEDP (left ventricular enddiastolic pressure) in three patients. Autopsy data were available in five patients. Hypertrophy and dilation of both ventricles were present in all cases. The authors discussed multiple factors (hypoxemia, hypercapnia, respiratory acidosis, RV failure, and intermittent pulmonary infections) possibly contributing to the pathogenesis of LV dysfunction in COPD. Significant lung hyperinflation was noted in the study; however, its potential role in the development of LV dysfunction was not discussed.
696
Celli and Frants
Baum et al. (90) confirmed the presence of the LV hypertrophy or increased diastolic chamber size (or both) in a group of 15 patients with COPD. They stated that the presence or absence of right-sided heart failure did not influence the degree of LV functional impairment. The pressure environment within which the heart is functioning in patients with COPD, at rest and with exercise, has been studied by Potter et al. (1). They found progressive increases in intrathoracic pressure swings with exercise (at cessation of exercise: mean peak Ppli ⫺22 cmH2 O, mean peak Pple ⫹ 22 cmH2 O). They also documented an increase in FRC with treadmill exercise—from an average of 35% of the vital capacity (VC) at rest to an average of 47% at peak exercise. Due to the significant positive pressure swings the mean intrathoracic pressure during exercise is higher (i.e., less negative) in COPD patients, and speculated that this might affect the venous return and could impose a limitation on the cardiovascular response. Franklin et al. (38) demonstrated that during inspiration, RV stroke volume increases but LV stroke volume decreases—changes, attributed to alteration in ventricular filling secondary to intrathoracic pressure variation. Best et al. (91) suggested that decreased LV preload could result from a decrease in pulmonary venous return due to the blood being pooled in the lungs during inspiration. However, this hypothesis was not confirmed by other studies (61,92–94). Scharf et al. (54) studied the cardiac effects of two of the major pulmonary mechanical changes occurring during bronchospasm: increase in functional residual capacity, and decreased mean pleural pressure (isolated and in combination) in healthy man. They demonstrated a decrease in LV end-systolic volume and no change in LV diastolic volume with increased lung volume alone. Mueller maneuvers from FRC or from high lung volume produced large statistically significant increase in both diastolic and end-systolic volume. The authors concluded that, of the two features of acute airway obstruction (increased FRC and decreased pleural pressure), the effect of large negative pleural pressures, which act to impede the left ventricular outflow (i.e., afterloading), predominates over those of increased lung volumes. Scharf et al (55) further investigated the effects of normal and loaded spontaneous inspiration on LV function. The study was designed to evaluate the role of LV compliance alteration in inspiration-induced fall in LV stroke volume. They observed that at least two factors affect the LV stroke volume during inspiration: a decrease in LV preload that is associated with decreased LV compliance (likely, secondary to increase in RV size through the mechanism of ventricular interdependence), and increased impedance to LV emptying, as reflected by the increase in aortic transmural pressure. They concluded that those factors might play a greater role during inspiratory loading when the inspiratory swings in pleural pressure are exaggerated. Buda et al. (56) evaluated the effects of negative and positive intrathoracic pressures (ITP) independently of changes in lung volume (Mueller and Valsalva maneuvers, respectively) on left ventricular performance. They demonstrated statistically significant decreases in LVEDV, stroke volume, and cardiac output during the Valsalva maneuver. These findings show that decreases in LV transmural pressure during positive ITP likely indicates a decrease in LV afterload at a time when
Circulatory Effects of COPD
697
the preload is diminishing. The net result of those changes is a decline in cardiac output without alteration in LV contractility. The authors observed an increase in LV end-diastolic volume during the Mueller maneuver. However, instead of increases in indices of ventricular function (by the Frank-Starling mechanism), they observed significant decreases in ejection fraction (LVEF) along with increase in LV endsystolic volume with marked negative ITP (⫺60 cmH2 ). This observation corresponds with the findings reported by Summer et al. (95) and Robotham et al. (40), and is consistent with a decline in LV performance during sustained negative ITP. They showed that the LV transmural pressure closely correlated with end-systolic volume index, and therefore most accurately reflected the LV systolic pressure load. The authors reasoned that, in the setting of significant changes in ITP, the pleural pressure swings affect LV function not only by altering ventricular filling but also by changing afterload. They also proposed that, since negative ITP can impose a functional afterload on the LV, the LV hypertrophy observed in patients with COPD may occur due to the recurrent episodes of airway obstruction exposing the heart to intermittent large changes in negative intrathoracic pressure. In part to test this hypothesis, Salejee et al. (96) studied the long-term effect of tracheal banding in rats (up to 1 year), a model which produces normoxia, mild hypercapnia, and large inspiratory swings in pleural pressure. They found no evidence of LV heprtrophy, but did observe RV hepertrophy. They concluded that the LV afterload effects of airway obstruction were minimal, but that RV afterload is increased, possibly due to large inspiratory increases in venous return. We previously reported significant declines in O 2 Pulse (45 ⫾ 15% predicted) during maximal exercise in patients with very severe COPD (FEV1 ⬍ 35% predicted) (11). We also demonstrated that peak exercise capacity, O 2 Pmax, and inspiratory intrathoracic pressures were strongly correlated. This suggests that severe respiratory mechanical derangement in patients with severe COPD may contribute to their hemodynamic abnormalities and diminished exercise performance. In order to clarify the relationships between the intrathoracic pressure swings, dynamic hyperinflation and ventricular performance, we designed a protocol which included submaximal (50% of their maximal exercise capacity) upright exercise in a group of patients with very severe COPD (FEV1 ⬍ 40%) screened for lung volume reduction surgery (LVRS). The pleural pressures were measured at rest and throughout exercise. A radionuclide ventriculogram (RVG) was also incorporated into the routine physiological studies done prior to the LVRS and 3 months after surgery. The procedure was performed at rest in the upright position, at the end of submaximal exercise, and after complete symptomatic recovery following the test. Our findings are illustrated by the case of a 61-year-old female with very severe COPD (FEV1 0.91 L, or 39% predicted; RV 4.30, or 243% predicted; RV/TLC 70%; FRC 4.94, or 182% predicted; FRC/TLC 78%). As part of the routine evaluation prior to the LVRS, three studies were carried out on the same date: (1) Dobutamine-exercise echocardiographic study which detected normal myocardial contractility and no evidence of stress-related ischemia; (2) cardiopulmonary submaximal exercise test with concomitant RVG and pleural pressure measurements; (3) coronary arteriography (50% ostial right coronary artery and 70% first diagonal left coronary artery lesions—
698
Celli and Frants
stable in comparison to a 1995 study) confirmed normal myocardial contractility by left ventriculography. At peak cardiopulmonary exercise the patient demonstrated a decrease in her O2 Pmax to 61% predicted. The RVG at rest showed a left ventricular ejection fraction (LVEF) of 70%, which decreased to 26% at the end of the submaximal exercise without evidence for myocardial ischemia (Fig. 7). The resting and end of exercise FRC values were–4.81 L (FRC/ TLC 78%) and 5.30 (FRC/
Figure 7 Radionuclide ventriculographic images of a patient with severe COPD. The four images and numerical values show the results of the radionuclide ventriculogram (RVG). The left upper panel corresponds to the study at rest before lung volume reduction surgery. The left lower panel shows the values during submaximal (50% maximal) exercise. PostLVR the resting RVG is shown in the right upper panel. The right lower panel shows the results 3 months after LVR, at the same level of exercise. Whereas LVEF dropped from 70% to 26% with exercise at baseline, it actually increased after LVR, from 69% to 77% Each viewport displays percent regional ejection fraction (%REF), percent radial shortening (%RS), and regional ejection fractions and radial shortenings corresponding to points on the region of interest (ROI). The outer frame on each image represents end-diastolic frame; the inner one, end-systolic frame. EF, left ventricular ejection fraction. (Courtesy of Alan B. Ashare, M.D., and Janet Tierney, R.N., Department of Nuclear Medicine, St.Elizabeth’s Medical Center, Boston. Reprinted with permission; unpublished data.)
Circulatory Effects of COPD
699
Figure 8 Pleural pressure swings (cmH2O) at rest and at the end of submaximal exercise. (Left) Rest: dotted line represents pleural pressure changes prior to LVRS; solid line, pleural pressure swings after LVRS. (Right) End of submaximal exercise: dotted line, pleural pressure swings prior to LVRS; solid line, pleural pressure swings after LVRS. Pga, gastric pressure, Ppl, pleural pressure; I, Inspiratory pressure; E, Expiratory pressure. After LVR there was less generation of intrathoracic pressure sswings at the same submaximal exercise intensity. (Courtesy R. Frants, M.D., and B.R. Celli, M.D.—unpublished data.)
TLC 86%), respectively. The absolute difference in FRC reached 500 ml by the end of exercise. The pleural pressure swings at rest and at the end of submaximal exercise were 20 cmH2 O and 47 cmH2 O, respectively (Fig. 8). After LVRS the pleural pressure swings at rest were similar to baseline (⫺17 cm H2 O). At end exercise the value was 33 cmH2 O, a 30% decrease compared to the pre-LVRS value. LV ejection fraction was 69% at rest and increased to 77% (Fig. 7). This represents the normal response to exercise. We believe that the decrease in pleural pressure swings due normalization in lung mechanics after lung volume reduction surgery (13–15) corresponded with normalization of left ventricular performance in this patient with very severe COPD.
VI. Conclusions The heart-lung interplay in chronic obstructive lung disease continues to fascinate the physiologist and represents a major challenge for the pulmonologist. In this review we analyzed cardiorespiratory interaction in COPD under different physiologic conditions. We have proposed the concept that in COPD the cardio-pulmonary unit loses a significant portion of its natural reserve and this may lead to the development ‘‘functional rigidity’’ of the system. The decrease in the plasticity of the whole system makes it less flexible to adapt to the repeated insults of the deteriorating
700
Celli and Frants
lung function. In turn this causes the heart to become more vulnerable to intrathoracic events. The available data shows that decreases in pleural pressure swings due to improvement in lung elastic recoil following lung volume reduction surgery may lead to normalization of the LV performance. This new therapeutic strategy may help us gain insight into the complex interaction between heart and lung in COPD.
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
Potter W, Olafsson S, Hyatt R. Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung disease. J Clin Invest 1971; 50:910–918. Stubbing D, Pengelly L, Morse J, Jones N. Pulmonary Mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol 1980; 49:511–515. Celli B. Pathology of chronic obstructive pulmonary disease. Chest Surg Clin North Am 1995; 5:623–634. Bates D. Respiratory Function in Disease. Philadelphia: W.B. Saunders, 1989:172–187. Greaves I, Colebatch H. Elastic behavior and structure of normal and emphysematous lungs postmortem. Am Rev Respir Dis 1980; 121:127–128. Hogg J, Macklem P, Thurlbeck W. Site and nature of airway obstruction in chronic obstructive lung diseas. N Engl J Med 1968; 278:1355–1359. Rodarte J. Lung and chest wall mechanics. Basic concepts. In: Scharf SM, ed. Heart-Lung Interactions in Health and Disease, Vol. 46. New York: Marcel Dekker, 1989:221–242. Pinsky M. Effects of changing intrathoracic pressure on the normal and failing heart. In: Scharf SM, ed. Heart-Lung Interactions in Health and Disease, Vol. 46. New York: Marcel Dekker, 1989:839–876. Minh VD, Lee H, Vasquez P, Shepard J, Bell J. Relation of VO2max to cardiopulmonary function in patients with chronic obstructive lung disease. Bull Eur Physiopathol Respir 1979; 15:359–375. Berger H, Matthay R, Davies R, Zaret B, Gottschlack A. Comparison of exercise right ventricular performance in chronic obstructive pulmonary disease and coronary artery disease: noninvasive assessment by quantitative radionuclide angiocardiography. Invest Radiol 1979; 14:342–352. Montes de Oca M, Rassulo J, Celli B. Respiratory muscle and cardiopulmonary function during xercise in very severe COPD. Am J Respir Crit Care Med 1996; 154:1284–1289. Cooper J, Trulock E, Triantafillou A. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–119. Gelb A, Zamel N, McKenna R, Brenner M. Mechanism of short-term improvement in lung function after emphysema resection. Am J Respir Crit Care Med 1996; 154:945–951. Sciurba F, Rogers R, Keenan R, et al. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for Diffuse Emphysema. N Engl J Med 1996; 334:1095– 1099. Martinez F, Montes de Oca M, Whyte R, Stetz J, Gay S, Celli B. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997; 155:1984–1990. Robotham J, Peters J, Takata M. Cardiorespiratory interactions. In: Pulmonary and Critical Care Medicine, Vol. 3. St. Louis: Mosby–Year Book, 1993:1–25. Guyton A, Lindsey A, Abernathy B, Richardson T. Venous return at various right atrial pressures and the normal venous return curve. Am J Physiol 1957; 189:609–615. Guyton A, Jones C, Coleman T. Effect of right atrial pressure on venous return: the normal venous return curve. In: Guyton A, ed. Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: W.B. Saunders, 1973:188–204. Robotham J, Peters J. Mechanical effects of intrathoracic pressure on ventricular performance. In: Scharf SM, ed. Heart-Lung Interactions in Health and Disease, Vol. 46. New York: Marcel Dekker, 1989:251–283.
Circulatory Effects of COPD 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46.
701
Scharf S. Effect of normal and stressed inspiration on cardiovascular function. In: Scharf SM, ed. Heart-Lung Interaction in Health and Disease, Vol. 46. New York: Marcel Dekker, 1989:427–461. Pinsky M. Instantaneous venous return curves in an intact canine preparation. J Appl Physiol 1984; 56:765–771. Sylvester J, Goldberg H, Permutt S. The role of the vasculature in the regulation of cardiac output. Clin Chest Med 1983; 4:111–126. Natori H, Tamaki S, Dira S. Ultrasonographic evaluation of ventilatory effect on inferior vena cava configuration. Am Rev Respir Dis 1979; 120:421–427. Lloyd T, Cooper J. Effect of diaphragm contraction on canine heart and pericardium. J Appl Physiol Respir Environ Exercise Physiol 1983; 54:1261–1268. Wise R, Robotham J. Determinants of inferior vena cava (IVC) blood flow with changes in abdominal pressure. Am Rev Respir Dis 1987; 135(suppl):A115 (abstr). Permutt S. Physiologic changes in the acute asthmatic attack. In: Austen KF, ed. Asthma: Physiollogy, Immunology and Treatment. New York: Academic Press, 1973:15–24. Cobelli F, Ambrosino N, Opasich C, et al. Pulmonary hemodynamics during resistive load breathing in chronic obstructive lung disease. In: Morpurgo M, ed. Pathophysiology and Treatment of Pulmonary Circulation. New York: Springer-Verlag, 1988:77–87. Brookhart L, Boyd T. Local differences in intrathoracic pressure and their relation to cardiac filling pressure in the dog. Am J Physiol 1947; 148:434–444. Marini J, Culver B, Butler J. Mechanical effect of lung distention with positive pressure on cardiac function. Am Rev Respir Dis 1981; 124:382–386. Lloyd T. Respiratory system compliance as seen from the cardiac fossa. J Appl Physiol Respir Environ Exercise Physiol 1982; 65:57–62. Lloyd T. Mechanical cardiopulmonary interdependence. J Appl Physiol Respir Environ Exercise Physiol 1982; 52:333–339. Takata M, Robotham J. Ventricular external constraint by the lung and pericardium during positive end-expiratory pressure. Am Rev Respir Dis 1991; 143:872-875. Takata M, Ra W, Robotham J. Effects of abdominal pressure on venous return: abdominal vascular zone conditions. J Appl Physiol 1990; 69:1961–1972. West J, Dollery C, Naimark A. Distribution of blood flow in isolated lung: relation to vascular and alveolar pressure. J Appl Physiol 1964; 19:713–724. Nakhjavan F, Palmer W, McGregor M. Influence of respiration on venous return in pulmonary emphysema. Circulation 1966; 33:8–16. Wallis T, Robotham L, Compean R, Kindred M. Machanical heart-lung interaction with positive end-expiratory pressure. J Appl Physiol 1983; 54:1039–1047. Weber K, Janicki J, Shroff S, Likoff M. The Cardiopulmonary Unit. The Body’s Gas Transport System. Clinics in Chest Medicine, Vol. 4. Philadelphia: W.B. Saunders, 1983:101– 110. Franklin D, Van Citters R, Rushmer R. Balance between right and left ventricular output. Circ Research 1962; 10:17–26. Chevalier P, Weber K, Engle J, Gerasch D, Fox J. Direct measurements of right and left heart outputs in a Valsalva like maneuver in dogs. Proc Soc Exp Biol Med 1972; 139:1429– 1437. Robotham J, Lixfeld W, Holland L, MacGregor D, Bryon A, Rabson J. Effects of respiration on cardiac performance. J Appl Physiol 1978; 44:703–709. Scharf S, Brown R, Saunders N, Green L. Hemodynamic effects of positive-pressure inflation. J Appl Physiol 1980; 49:124–131. Oboler A, Keefe J, Gaasch W, Banas J, Levine H. Influence of left ventricular isovolumic pressure upon right ventricular pressure transients. Cardiology 1973; 58:1171–1177. Santamore W, Lynch P, Heckman J, Bove A, Meier G. Left ventricular effects on right ventricular developed pressure. J Appl Physiol 1976; 41:925–930. Santamore W, Lynch P, Meier G, Heckman J, Bove A. Myocardial interaction between the ventricles. J Appl Physiol 1976b; 41:362–368. Slinker B, Glantz S. End-systolic and end-diastolic ventricular interaction. Am J Physiol 1986; 25:H1062-H1075. Dornhorst, AC, Howard P, Leathart G. Pulsus paradoxus. Lancet 1952; 1:746–748.
702 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.
Celli and Frants Elzinga G, Piene J, deJons J. Left and right ventricular pump function and consequences of having two pumps in one heart. Circ Res 1980; 46:564–574. Bove A, Santamore W. Ventricular interdependence. Prog Cardiovasc Dis 1981; 23:365– 388. Angle M, Roussos C, Permutt S. Increasing right atrial pressure can depress cardiac output. Am Rev Respir Dis 1986; 132:A304 (abstr). Trofimov V, Memetov K, Orlov L. Charasteristics of changes in the function of external respiration and central hemodynamics in patients with bronchial asthma during an attack of suffocation [in Russian]. Terapevticheskii Arkhiv 1978; 50:135–138. Frants R. Pulmonary function, systemic and pulmonary hemodynamics in patients with acute chronic obstructive lung disease exacerbation [in Russian]. In IXth International Medical Student Symposium Proceedings, Prague, 1982; 9:81–85. Memetov K, Trofimov V, Boikov M, Ipatov A, Makoeva L. Central hemodynamics of patients during an attack of bronchial asthma [in Russian]. Terapevticheskii Arkhiv 1987; 59:39–42. Charlier A, Jaumin P, Pouleur H. Circulatory effects of deep inspirations, blocked expirations and positive pressure inflations at equal transpulmonary pressures in conscious dogs. J Physiol 1974; 241:589–605. Scharf S, Brown R, Tow D, Parisi A. Cardiac effects of increased lung volume and decreased pleural pressure in man. J Appl Physiol 1979; 47:257–262. Scharf S, Brown R, Saunders N, Green L. Effects of normal and loaded spontaneous inspiration on cardiovascular function. J Appl Physiol 1979; 47:582–590. Buda A, Pinsky M, Ingels NJ. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 301:453–459. Karam M, Wise R, Natarajan M, Permutt S, Wagner H. Mechanism of decreased left ventricular stroke volume during inspiration in man. Circulation 1984; 69:866–873. Nunn J. Nunn’s Applied Respiratory Physiology. Cambridge: Butterworth-Heinemann, 1995. Marshall B, Marshall C. Pulmonary Circulation during anaesthesia. In: Stanley TH, ed. Anaesthesia and the Lung. Dordrecht: Kluwer, 1992:31. Howell J, Permutt S, Proctor D, Riley R. Effect of inflation of the lung on different parts of pulmonary vascular bed. J Appl Physiol 1961; 16:71–76. Permutt S, Howell J, Proctor D, Riley R. Efects of lung inflation on static pressure-volume characteristics of pulmonary vessels. J Appl Physiol 1961; 16:64–70. Barer G, Howard P, McCurrie J, Shaw J. Changes in the pulmonary circulation after bronchial occlusion in anaesthetized dogs and cats. Circ Res 1969; 25:747–764. Harris P, Segel N, Bishop J. The relation between pressure and flow in the pulmonary circulation in normal subjects and patients with chronic bronchitis and mitral stenosis. Cardiovasc Res 1968; 2:73–83. Von Euler U, Liljestrand G. Observation on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 1946; 12:301–320. Reid L. The pulmonary circulation: remodeling in growth and disease. Am Rev Respir Dis 1979; 119:531-546. Eddahibi S, Raffestin B, Braquet P, Chabrier P, Adnot S. Pulmonary vascular reactivity to endothelin-1 in normal and chronically pulmonary hypertensive rats. J Cardiovasc Pharmacol 1991; 17(suppl 7):S358-S361. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328:1732–1739. Harris P, Heath D. Pulmonary hemodynamics in chronic bronchitis and emphysema. In: Harris P, ed. The Human Pulmonary Circulation. Edinburgh: Churchill Livingstone, 1977: 522–544. Meyrick B, Reid L. Pulmonary hypertension, anatomic and physiologic correlates. Clin Chest Med 1983; 4:199–217. Heath D, Williams D. Man at High Altitude. Edinburgh: Churchill Livingstone, 1981. Giaid A. Nitric Oxide and Endothelin-1 in Pulmonary Hypertension. Chest 1998; 14(suppl): 208S–212S.
Circulatory Effects of COPD 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.
703
Charms B, Brofman B, Adicoff A. Factors affecting the pulmonary ‘‘capillary’’ pressure. Am J Cardiol 1960; 5:328–332. Kitchen A, Lowther C, Matthews M. The effects of exercise and of breathing oxygenenriched air on the pulmonary circulation in emphysema. Clin Sci 1961; 21:93–106. Rabinowitz M, Niden A, Pickard S, Reisler H, Lopez F. Evidence for pulmonary venous obstruction in pulmonary emphysema. J Lab Clin Med 1962; 60:1006–1007. Segel N, Bishop J. The circulation in patients with chronic bronchitis and emphysema at rest and during exercise, with special reference to the influence of changes in blood viscosity and blood volume on the pulmonary circulation. J Clin Invest 1966; 45:1555-1568. Horsfield K, Segel N, Bishop J. The pulmonary circulation in chronic bronchitis at rest and during exercise breathing air and 80% oxygen. Clin Sci 1968; 34:472–483. Rao B, Cohn K, Eldridge F, Hancock E. Left ventricular failure secondary to chronic pulmonary disease. Am J Med 1968; 45:229–241. Lockhart A, Tzareva M, Nader F, Lablanc P, Schrijen F, Sadoul P. Elevated pulmonary artery wedge pressure at rest and during exercise in chronic bronchitis: Fact or fancy. Clin Sci 1969; 37. Burrows B, Kettel L, Niden A, Rabinowitz M, Diener C. Pattern of cardiovascular dysfunction in chronic obstructive lung disease. N Engl J Med 1972; 286:912–918. Butler J, Schirijen F, Henriques A, Polu J-M, Albert R. Cause of the raised wedge pressure on exercise in chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138:350– 354. Pepe P, Marini J. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982; 126:166–170. Oswald-Mammosser M, Kessler R, Massard G, Wihlm J-M, Weitzenblum E, Lonsdorfer J. Effect of lung volume reduction surgery on gas exchange and pulmonary hemodynamics at rest and during exercise. Am J Respir Crit Care Med 1998; 158:1020–1025. Weg I, Rossoff L, Mckeon K, Graver L, Scharf S. Development of pulmonary hypertension after lung volume reduction surgery. Am J Respir Crit Care Med 1999; 159:552–556. Fluck D, Chandrasekar R, Gardner F. Left ventricular hypertrophy in chronic bronchitis. Br Heart J 1966; 28:92–97. Zimmerman H, Ryan J. Cor pulmonale. Dis Chest 1951; 20:286–289. Scott R, Garvin C. Cor oulmonale: observation in 50 autopsy cases. Am Heart J 1941; 22: 56–63. Parker R. Pulmonary emphysema: a study of its relation to the heart and pulmonary arterial system. Ann Intern Med 1940; 14:795–798. Kountz W, Alexander H, Prinzmetal M. The heart in emphysema. Am Heart J 1936; 11: 163–172. Michelson N. Bilateral ventricular hypertrophy due to chronic pulmonary disease. Dis Chest 1966; 38:435–446. Baum G, Schwartz A, Llamas R, Castillo C. Left ventricular function in chronic obstructive lung disease. N Engl J Med 1971; 285:361–365. Best C, Taylor N. The Physiologic Basis of Medical Practice. Baltimore: Williams and Wilkins, 1966. Goldblatt A, Harrison D, Glick G, Braunwald E. Studies on cardiac dimensions in intact, unanesthetized man. II. Effect of respiration. Circ Res 1963; 13:455–460. Morgan B, Abel F, Mullins G, Guntheroth G. Flow pattern in cavae, pulmonary artery, pulmonary vein, and aorta in intact dogs. Am J Physiol 1966; 20:865–877. Brower R, Wise R, Hassapoyannes C, Bromberg-Barnea B, Permutt S. Effect of lung inflation on lung blood volume and pulmonary venous return. J Appl Physiol 1985; 58:954– 963. Summer W, Permutt S, Sagawa K, Shoukas A, Bromberg-Barnea B. Effect of spontaneous respiration on canine left ventricular function. Circ Res 1979; 45:719–728. Salejee I, Tarasiuk A, Reder I, Scharf S. Chronic upper airway obstruction produces right but not left ventricular hypertrophy in rats. Am Rev Respir Dis 1993; 148:1346–1350.
27 Invasive and Noninvasive Assessment of Cardiocirculatory Function Balloon-Tipped Catheters and Echocardiography
CLAUDE PERRET and FRANCOIS FEIHL Lausanne University Hospital Lausanne, Switzerland
I.
ALAIN CARIOU Cochin-Port Royal University Hospital Paris, France
Introduction
With the advent of positive-pressure mechanical ventilation, the critical-care physician is faced with new clinical problems related to interference with the physiological patterns of cardiorespiratory interactions. Actually, a large part of knowledge in this area was borne of the need to avoid the adverse cardiocirculatory effects of mechanical ventilation. To understand the mechanisms involved in this clinical setting, the ability to measure blood flow and pressures in the implicated structures was essential. The development of pulmonary artery catheterization (PAC) at the bedside provided one of the most effective tools in this respect. Its success was largely due to the apparent ease of utilization. In fact, the collection and interpretation of data so obtained proved much more complex than anticipated and this was revealed in part by complementary information provided by echocardiography. This first chapter devoted to clinical problems of critical care is a general review of PAC. We shall consider successively the history of PAC development, the current status of the controversy surrounding its use in critical care, the general information, with emphasis on the too frequently neglected pitfalls of interpretation, and finally the complementary role of echocardiography, which until now has been relatively underestimated. 705
706
Perret et al. II. History
The potential benefits of right heart catheterization were appreciated many years after Werner Forssmann (1) passed a catheter through one of his antecubital veins to enter the right atrium. Indeed, his objective was not to investigate the cardiac pump but simply to provide a direct access to the heart which, he thought, might be of interest to deliver drugs locally in patients with shock or severe heart disease. More than 10 years later, in the early 1940s, Cournand and Richards (2,3) used a cardiac catheter for the first time as a tool to investigate cardiovascular function in man. This was the beginning of a series of important studies which provided fundamental information regarding the hemodynamic conditions in health and disease. The ability to measure cardiac output, O 2 content, and pressures in the right heart chambers was certainly of great interest, but of equal importance was the demonstration that positioning the pulmonary catheter in a distal branch of the pulmonary artery made it possible to determine a ‘‘ wedge ’’ pressure (4) which under certain conditions reflected left venticular filling pressure. Thus, pulmonary artery catheterization quickly became accepted as a standard technique to diagnose congenital abnormalities, valvular defects, and left ventricular failure. In particular, the information provided was considered essential in the assessment of patients in whom heart surgery was contemplated. For more than two decades, the procedure was restricted to special-purpose laboratories. The rigid catheters were inserted for the brief duration necessary for collecting the physiological data. The limitation was essentially due to the fact that manipulation of stiff material within the vascular system could produce endocardial injury and induce arrhythmias or conduction disturbances. Two developments extended its use outside the laboratory: (1) the development of an inflatable balloon which was shown to greatly facilitate the entry of the catheter tip in the pulmonary artery (5), and (2) the development of flexible miniature catheters (6,7) permitted performance of right heart catheterization without fluoroscopy. In 1970, Swan and Ganz (8), combining these two approaches, described a flow-guided balloon-tipped catheter which was directly applicable to the bedside. Fluoroscopy was no longer necessary, and the risk of severe ectopy was largely reduced. Hemodynamic investigation at the bedside proved to be of great interest, all the more since the addition of a temperature probe at the catheter tip allowed the repeated measurement of cardiac output. Clinicians realized that PAC provided specific and accurate information that could not be supplied by careful physical examination. The advantage of the method over classical right heart catheterization was the ability to leave the catheter in place and thus permit monitoring of hemodynamically unstable patients. Soon after its introduction the method became widespread in critical care units. It was futher improved by several technical developments such as ventricular pacing, mixed venous O 2 saturation monitoring, right ventricular ejection fraction determination, and continuous cardiac output measurement. Clinicians progressively used bedside catheterization not only as a diagnostic tool, but also as an invaluable guide to therapy: analysis and interpretation of cardiocirculatory disturbances induced by disease became a prerequisite for selective therapeutic interven-
Invasive and Noninvasive Assessment
707
tions with the ability to measure the response to therapy and to judge its adequacy (9–12). Actually, the ability to monitor and interpret hemodynamic data has produced profound changes in therapeutic strategies in patients with unstable cardiocirculatory conditions related to both cardiac and noncardiac disease: In acute left ventricular failure, for example, optimizing loading conditions with PAC monitoring has become a widely accepted technique. Similarly, monitoring of PA occlusion pressure has become a routine procedure in patients with acute respiratory distress syndrome for preventing further accumulation of extravascular water in the lung. PAC has been also proposed prospectively for augmenting systemic oxygen delivery to supranormal values, a strategy supposed to improve organ-specific outcomes and survival prior to high-risk surgery. The success has been such that the number of catheters sold grew every year. Today there are more than 1 million used annually in the United States and 300,000 in the European Community. However, the enthusiasm is not unanimous. There have been criticisms of the use of PAC and doubts casted on its effectiveness. In 1985, Robin expressed his concern for ‘‘overuse and abuse’’ of the PAC (13) and two years later called for a moratorium on its use arguing that the risks of the catheter might well outweigh its benefits (14). Over the past decade, several observational studies in AMI reported a higher risk of death for patients managed with PAC than for those in whom the catheter was not inserted (15–17). Furthernore, PAC insertion was shown to prolong the patient stay in the ICU and to increase the intensity of care, leading to substantially higher costs (18). In spite of these disturbing results, the use of the device was not restricted. Most critical-care clinicians were convinced, based on a personal experience, that invasive hemodynamic monitoring was safe, effective, and beneficial. It was argued that the higher mortality rate apparently associated with the use of PAC in fact reflected a selection bias of sicker patients. In addition, it was considered unlikely that PAC per se could account for an increased fatality rate when taking into account the low incidence of direct severe complications (19,20). The controversy was further stimulated by the publication in September 1996 of a study conducted between l989 and 1994 in a large cohort of critically ill patients in five U.S. teaching hospitals (21). In this study, Connors et al. examined the association between the use of PAC during the first 24 hours of care in the ICU and subsequent survival, length of stay, and intensity and cost of care. This study was observational; it was neither randomized nor controlled. Nevertheless, an impressive unprecedented effort was made to minimize methodological bias. Multivariate regression modeling techniques were used. An index of the probability of any individual patient to receive a PAC was constructed from high quality and exhaustive data collected prospectively on patients at admission. The effect of PAC on outcome was evaluated in each disease category from the matching of subject with the same propensity score. On a total of 5735 critically ill adult patients, PAC use was shown to be associated with a significantly higher mortality rate and increased utilization of resources. An accompanying editorial called for the immediate undertaking of a
708
Perret et al.
multicenter randomized controlled clinical trial; alternatively, if such a trial was not carried out, a moratorium on the use of flow-directed PAC was proposed (22). As expected, these two papers exacerbated the debate and raised numerous concerns. The composition of the patient population was criticized; having been essentially made of noncardiac subjects (23), it excluded certain disease categories which might have taken better advantage of hemodynamic monitoring (24,25) Several commentators considered the retrospective case-matching methodology unreliable (24,26). The accuracy of the propensity score to predict the likelihood of placement of a PAC was contested (27). The potential effect of unmeasured confounders was found not to be correctly estimated, so that a missing covariate, i.e., an unidentified clinical factor, that would increase both the propensity to insert a PAC and the probability of death could possibly account for the observed association (28). Also the question was raised concerning the significance of relating directly the use of PAC to outcome, implying that the role of therapeutic interventions had been controlled. Clearly, the determination of the hemodynamic profile is not expected to modify the outcome, but more likely the therapeutic interventions triggered by the physiological disorders disclosed. Most importantly, the study did not take into account the large variablity among physicians in skill and basic pathophysiological knowledge, which might well have interfered with data interpretation and subsequent therapeutic decisions (29,30). In response to the debate and the numerous requests for statements and clarification, several scientific societies decided to host consensus conferences. The Society of Critical Care Medicine invited a panel of experts to answer questions and propose recommendations concerning the use and the indications of PAC in criticalcare patients on the basis of the most relevant investigations available (31, 32) Similarly, the American College of Cardiology published an Expert Consensus Conference to provide peer comments on the study by Connors et al. (21) and to reassess the role of bedside right heart catheterization in patients with cardiac disease (28). Another panel convened by the American College of Chest Physicians and the American Thoracic Society (33) wrote some preliminary basic recommendations waiting for the results of a large, prospective, randomized, controlled trial undertaken to evaluate the use of PAC in the monitoring of patients scheduled to undergo major surgical procedures. Intuitively, the availability of objective physiological data suggests that a more rational approach should lead to more effective therapy, but there is no proof that such information improves patient outcome (34,35). Nevertheless, a recent mail survey/examination among U.S. members of the Society of Critical Care Medicine has shown that a large majority (75%) of responders are in favor of an appropriately designed, prospective, randomized, controlled trial and that most of them (94%) consider that a moratorium on the PAC use is not warranted (34). Performing a controlled trial has already been undertaken in Canada, but it failed because of too many crossovers between groups (35). A large proportion of the patients randomized to the control group were finally catheterized because their physician estimated non ethical to deprive them of the benefits of PAC. Clearly, the resources would be better invested in improving physicians training to optimize the use and interpretation of
Invasive and Noninvasive Assessment
709
PAC. Before blaming the tool, an educational program has to be developed to avoid the numerous pitfalls of the method (38,39). III. Information Provided by the PAC The PAC basically provides three different kinds of primary data—intravascular pressures, cardiac output, and measurement of blood gases in mixed venous blood. From those, additional variables may be calculated to aid interpretation. Here, we shall briefly review the principles that underly the measurement of primary data; technical details regarding the acquisition of data will not be discussed here, because they are easily found elsewhere (40–42). The pitfalls inherent in the pathophysiologic interpretation of such data will then be described. A. Pathophysiologic Determinants and Interpretation of Primary Measurements
Right Atrial Pressure
According to the Guytonian view, right atrial pressure (RAP) is the variable which couples the flows generated by the venous return circuit and by the cardiac pump, maintaining them equal in the steady state. Thus, circuit changes which tend to enhance (e.g., hypervolemia, increased venous tone) or diminish venous return (e.g., hypovolemia, venous pooling) will act to increase or decrease the value of RAP, respectively. Conversely, changes in afterload, contractility, or diastolic function of either ventricle which tend to enhance or diminish cardiac output will act to decrease or increase RAP. Although essential (43), these considerations often do not allow the unambiguous interpretation of a single RAP measurement, due to the relatively wide normal range (0–8 mm Hg), the frequent coexistence of circuit and cardiac pump problems, and the confounding effects of nonatmospheric intrathoracic pressure (see below). Changes observed over time, in response to therapy or to a fluid challenge, may be more enlightening. In the healthy heart, RAP is below LAP. Thus, RV dysfunction is suggested if RAP is high relative to PAOP (RAP/LAP ⬎ 0.8) (44). In the presence of refractory hypoxemia, a right-to-left intracardiac shunt caused by the reopening of the foramen ovale should be suspected if RAP is equal to or greater than PAOP (45). Pulmonary Artery Pressure
In healthy supine subjects, the mean pulmonary artery pressure (PAP) ranges from 9 to 19 mm Hg at rest (46), and increases only by a few mm Hg on doubling of cardiac output induced by submaximal exercise (47). These characteristics reflect the much lower resistance of the normal pulmonary circulation than in the normal systemic circulation. A resting mean PAP ⬎20 mm Hg is indicative of pulmonary arterial hypertension (PHT) due either to left heart failure (‘‘postcapillary’’ hypertension), or to an abnormality of the pulmonary vascular bed (‘‘precapillary’’ hypertension). Owing to the limited ability of the normal right ventricle (RV) to function
710
Perret et al.
as a pressure generator, an acute increase in pulmonary vascular resistance (acute cor pulmonale) seldom leads to a mean PAP ⬎ 40 mm Hg in a previously healthy patient (48). Higher levels of PHT imply the existence of RV hypertrophy and thus of a chronic increase in RV afterload (chronic cor pulmonale). At rest, the normal diastolic PAP (PAPd) is equal to or slightly higher than LAP or PAOP (within 5 mm Hg), reflecting the fact that end-diastolic pulmonary blood flow is close to zero in these conditions. A PAPd-PAOP difference ⬎ 5 mm Hg is indicative of substantial end-diastolic flow, which may be due to a shortened diastole (tachycardia), to a high stroke volume (high cardiac output), or to an abnormally slow runoff (increased pulmonary vascular resistance) (49,50). A mean PAOP above PAPd must be considered artifactually high (overwedging of the catheter, nonzone III conditions), unless reflecting the presence of giant v-waves on the PAOP pressure trace (see below). Pulmonary Artery Occlusion Pressure
Inflation of the balloon interrupts flow in a segment of the pulmonary circulation, resulting in a static column of blood which extends from the catheter tip, through a regional capillary bed, to a point of confluence with the venous outflow from the remaining parts of the lung (point J, Fig. 1). Thus, the pressure downstream from the inflated balloon, i.e., PAOP, is the pressure at point J (41,50), which is intermediate between pulmonary capillary pressure and left atrial pressure (LAP). Under normal conditions, these latter pressures are close to each other (within 2 mm Hg) (47), such that PAOP, ranging from 4 to 12 mm Hg (46), is a good approximation to both. However, it may cease to be the case in pathological conditions, as detailed below. It must then be kept in mind that the difference between
Figure 1 Measurement of pulmonary artery occlusion pressure (PAOP). Due to interruption of flow (gray area), the pressure downstream from the inflated balloon equilibrates with that existing at point J. (From Ref. 41.)
Invasive and Noninvasive Assessment
711
capillary pressure and PAOP depends on cardiac output and venous resistance upstream from point J. Similarly, the difference between PAOP and LAP depends on cardiac output and venous resistance downstream from point J. PAOP as an Estimate of Left Ventricular Filling Pressure
In normal circumstances, the mean LAP is a close approximation of left ventricular end-diastolic pressure (LVEDP). This relates mainly to the fact that the pressure gradient accross the normal, open mitral valve is very small. More precisely, the instantaneous LAP tracks left ventricular pressure (LVP), and remains below LVEDP during early and middiastole. As atrial pressure builds up against the closed mitral valve in ventricular systole, LAP rises slightly above LVEDP. As a net result, beat-averaged LAP is almost equal to LVEDP (50). In such conditions, and inasmuch as it approximates mean LAP, PAOP constitutes a good approximation to intramural left ventricular filling pressure. These relationships may break down in a number of pathological circumstances, which is important to keep in mind when using PAOP as surrogate to LVEDP. The most important one is an abnormally low left ventricular compliance, an event of great frequency in critically ill patients, whether related to altered relaxation (e.g., acute myocardial ischemia or infarction), to diastolic ventricular interaction (mechanical interference of a dilated right ventricle), or to a chronic alteration of the left ventricular wall (e.g., hypertrophy, fibrosis) (51, 52). In such conditions, LVEDP may substantially exceed mean LAP because of the pressure generated by atrial contraction just before ventricular systole (Fig. 2) (53). In aortic regurgitation, the diastolic reflux may cause an early closure of the mitral valve, such that mean LAP underestimates LVEDP (54). By contrast, with mitral regurgitation, mean LAP may be greater than LVEDP, due to systolic reflux (54). A diastolic pressure gradient between the left atrium and ventricle may be introduced by mechanical obstruction to atrioventricular flow due to mitral stenosis (51) or, more rarely, to an atrial myxoma (55). In exceptional instances, a discrepancy berween PAOP and LAP is caused by an abnormally high resistance to blood flow between point J and the left atrium, related to fixed lesions (thrombosis of pulmonary veins, lungs or mediastinal tumors, vasculitis, atrial myxomas, mediastinal fibrosis) (56) and perhaps from functional compression during low-flow states (50). Somewhat more commonly, the pressure downstream from the inflated balloon may fail to equilibrate with that at point J due to a functional compression of the microvascular bed, occurring when hypovolemia or PEEP create non–zone III conditions in the region of the lung where the catheter is located (see below). A discrepancy between PAOP and LAP, attributed to abnormally high closing pressures in the pulmonary microcirculation, has been described in several experimental circumstances, including acute lung injury (57), sepsis (58), and pulmonary embolism (59,60). Whether such phenomena also occur in the corresponding clinical settings is unknown. In the intensive care setting, as stated above, variations of left ventricular compliance occur frequently, either among patients or over time in the same subject. Thus, depending on the particular conditions, the same LV filling pressure may
712
Perret et al.
Figure 2 Pulmonary artery occlusion (wedge) pressure plotted against left ventricular enddiastolic pressure in control patients without cardiac disease and in patients examined 3 to 6 weeks after an acute myocardial infarction. (From Ref. 53, with permission.)
correspond to widely different LV volumes and preloads. For example, in the acute phase of even an apparently uncomplicated myocardial infarction, filling pressures above the normal range may be required to maintain adequate preload (61). The relationship of LV volume to intramural LV pressure is further complicated by the effects of changes in intrathoracic pressure, as described below. Considering in addition that PAOP only imperfectly evaluates intramural LVEDP, its complete lack of correlation with independently measured LVEDV is hardly surprising in critically ill patients (62,63). Since so many factors blur the relationship of PAOP to LV volume, it has been proposed that, whenever the adequacy of LV preload is an issue, it should be tested by monitoring the hemodynamic effects of the rapid (10 to 20 min) IV administration of a moderate volume of fluid (⬍ 200 mL) (10,50,64). Depending on particular conditions, such a fluid challenge may be justified even if the baseline PAOP appears moderately elevated (⬍ 18 mm Hg). PAOP as an Estimate of Pulmonary Capillary Pressure
An important use of the PAOP at the bedside is to define the mechanism of pulmonary edema (65). A capillary pressure (Pc) in excess of 20 to 25 mm Hg is required to produce a purely hydrostatic form of pulmonary edema, a threshhold which is not much lowered by concomitent hypoproteinemia. However, a permeability mechanism should not be automatically inferred from the observation of a relatively low PAOP (e.g., ⬍ 18 mm Hg), for at least two reasons. First, the clearance of extravas-
Invasive and Noninvasive Assessment
713
cular lung water may delay the reduction in pulmonary vascular pressures by as much as 24 hours during resolution of cardiogenic pulmonary edema—whether spontaneous or induced by therapy (66). Second, since point J is located downstream from the capillaries, PAOP is only a low range estimate of, but is not identical with, Pc. While the two pressures are almost equal in the normal lung, a substantial difference may exist when pulmonary vascular resistances are elevated, since as much as 40% of the PVR resides downstream from the capillaries (67,68). These considerations are of practical importance whenever pulmonary edema is associated with PHT. An impressive but rare example of the dissociation between Pc and LAP is pulmonary venoocclusive disease. This disease is characterized by fibrotic obstruction of pulmonary veins leading to an increased Pc, hence to hydrostatic edema, in the face of a normal LAP; in this disorder, PAOP may be either normal or elevated, depending on the site of venous obstruction with respect to the location of point J (69,70). In the adult respiratory distress syndrome (ARDS), it has been suggested that increased venous resistances contribute to the often associated pulmonary hypertension, thus adding a hydrostatic component to permeablity edema (68,71). This component is all the more important in presence of abnormally high capillary permeability, because the classical Starling equation implies a greater sensitivity of transvascular fluid flux to changes in hydrostatic pressure, as experimentally verified (72). The analysis of the postocclusion pulmonary artery pressure profile theoretically permits an estimation of Pc distinct from PAOP (68,71). In principle, this profile presents an initial segment , during the course of which pressure falls rapidly, an inflection point, and a final segment of slow, approximately monoexponential decay (Fig. 3). The initial segment corresponds to rapid equilibration of the pressure in the occluded artery with that in capillary bed. The final segment represents progressive emptying of the compliant capillary bed through the resistance of pulmonary veins. Pc may be calculated by backextrapolation of the final segment to the moment of occlusion. This interpretation of the postocclusion pressure profile has been validated in animal studies (73). The method has been used to infer the site of action of inhaled nitric oxide (NO) in ARDS patients, with the conclusion that this therapy led to preferential venous vasodilation and thus to reduced filtration pressure and edema formation (71). Clinical implementation of this technique is not easy. Pressure tracings devoid of respiratory artifacts are required, only obtained with reasonable adequacy in conditions of controlled mechanical ventilation. Even then, the inflection point as well as the time of occlusion needed for backextrapolation are imprecisely defined. Cardiac Output
A full discussion of the pathophysiological determinants of cardiac output (CO) is outside the scope of this review. Here, we shall only delve on the often neglected difficulty of determining whether the observed value of CO reflects a diminished cardiovascular reserve or a normal adaptation to the prevailing conditions. In healthy subjects, the basal CO varies according to age (Fig. 4) and body size (75). The latter
714
Perret et al.
Figure 3 Estimation of effective hydrostatic capillary pressure from the analysis of the pressure transient following occlusion of the pulmonary artery. (From Ref. 41, with permission.)
factor is usually taken into account by normalization to body surface area (BSA), i.e., the computation of cardiac index (CI), a method which has been recently criticized based on the fact that CI appeared inversely correlated to BSA in a large sample of healthy adults (76). The potential inaccuracies of BSA estimates in the intensive care setting should also be mentioned. Reflecting this state of affairs, the admitted normal range of basal CI is wide (2.8 to 3.8 L ⋅ min⫺1 ⋅ m⫺2). In critically ill patients, the difficulty of gauging the value of CO is compounded by the fact that basal conditions seldom apply, due to the multiplicity of factors which affect metabolic demand, thus inducing cardiovascular adaptation. For instance, although it is reasonable to assume that the ‘‘adequate’’ CO should be higher in presence of anxiety, fever, or treatment with beta-adrenergic agents, there are very few data on which to found quantitative predictions. In practice, one is often reduced to conjectures. For instance, based on limited data on the effect of cooling in febrile critically ill patients (77), one might assume a 10% change of CI per degree Celsius. Simultaneous consideration of variables derived from the oximetry of mixed venous blood (below), as well as patient age, somewhat facilitates the assessment of CO. As an example, a CI of 3 L ⋅ min⫺1 ⋅ m⫺2 with a C(a-v)O 2 of 32 mL O 2 /L may be indicative of a high output state if measured in a 75-year-old, hypothermic (34°C) woman. This same value of 3 L ⋅ min⫺ 1 ⋅ m⫺2 may also correspond to an indequate adaptation of cardiac output to metabolic demand if observed in a febrile (40°C) 40-year-old man, especially in
Invasive and Noninvasive Assessment
715
Figure 4 Resting cardiac output as a function of age in healthy humans. (From Ref. 75, with permission.)
presence of a C(a-v)O 2 ⬎ 45 mL O 2 /L; in such conditions, a concomitant left ventricular dysfunction should be suspected. Mixed Venous O 2 Saturation
Based on Fick’s equation, and ignoring dissolved oxygen, the mixed venous O 2 saturation (SvO2 ) may be expressed as: SvO 2 ⫽ SaO 2 ⫺ VO 2 /(Hb ⋅ 1.34 ⋅ CO)
(1)
where SaO 2 , VO 2 , and Hb are arterial O 2 saturation, O 2 uptake, and blood concentration of hemoglobin, respectively. From this equation, it is evident that a decrease in the SvO 2 may result from (1) arterial hypoxemia, whose effect may be exaggerated by a shift to the right of the HbO 2 dissociation curve; (2) an increased (VO 2 ); (3) a decreased cardiac output; and (4) a decreased hemoglobin level. As a rule, the presence of any of these mechanisms entails compensatory phenomena which tend to preserve O 2 transport. Thus, an abnormally low Hb level or arterial PO 2 is usually accompanied by an increased CO. Therefore, SvO 2 is difficult to interpret without considering the context in which the measurement is taken. A value of SvO 2 ⬍ 60% usually indicates abnormally high oxygen extraction; a SvO 2 ⬍ 40% indicates either acute tissue hypoxia or long term adaptation to a chronically low cardiac output, as for example in mitral stenosis (54).
716
Perret et al. B. Derived Variables
It is standard practice to compute several so-called derived variables, using formulas which variously combine the primary measurements described above. While the numbers so obtained may be helpful, they add no fundamentally new information. Due to cumulation of measurement error, they are inherently imprecise. Most importantly, the assumptions on which these computations are based are not necessarily valid, potentially leading the naive observer to significant interpretation mistakes. Variables Calculated from Pressures and CO
Vascular resistances are calculated as the inflow-outflow pressure difference divided by blood flow. The inflow (Pin) and outflow pressures (Pout) are respectively mean BP and RAP in the case of systemic vascular resistance (SVR), and mean PAP and PAOP in that of pulmonary vascular resistance (PVR), with the denominator being in both cases CO, or CI if indexing to body size is desired. Although indexing is often recommended, it is not essential in our view. If pressures are in mm Hg and CO in L⋅ min⫺1 , a multiplication factor of 80 is necessary to express vascular resistances in coherent c.g.s units (dyne ⋅ sec ⋅ cm⫺5). The normal ranges for SVR and PVR are 700 to 1600 and 20 to 130 dynes ⋅ sec ⋅ cm⫺5, respectively (46). It is erroneous to equate changes in vascular resistance with changes in the tone or total cross-sectional area of resistance vessels (78). This interpretation implicitely assumes a circuit with a linear pressure-flow relationship which intercepts the pressure axis at the value of Pout (Fig. 5, line a). However, most vascular beds
Figure 5 Circulatory pressure-flow relationship. See text for explanations.
Invasive and Noninvasive Assessment
717
rather behave as described by line b; i.e., the zero-flow intercept (PI ) is above Pout (76). PI is regarded as the critical closing pressure, reflecting the fact that microvessels require a positive transmural pressure to remain open. An increase in vascular tone may be reflected as a shift form line b to line c, which has a higher slope (reduced cross-sectional area of resistance vessels) and zero intercept (increased closing pressure). In such conditions, the VR calculated from single measurements of Pin, Pout, and blood flow, i.e., the slope of line OA, has no unambiguous physiologic interpretation. While it does increase with vascular tone if blood flow remains constant (lines OB vs. OA), it may not change or even decrease with a concomitant elevation of blood flow (lines OC and OD vs. OA). These considerations are not entirely academic, as the closing pressures in the total systemic circulation may range from 15 to 40 mm Hg (79,80)—i.e., significantly higher than RAP. In the pulmonary circulation, the relationship of PI to LAP is highly dependent on alveolar pressure and volume status. In particular, in zones I and II (see below), PI is essentially determined by alveolar pressure and thus exceeds LAP. Another mistake commonly made at the bedside is to equate SVR or PVR with left or right ventricular afterload, respectively. This oversimplification ignores the fundamental influence of blood flow pulsatility (arterial impedance) and ventricular geometry (Laplace law) on afterload, defined as systolic wall stress (81). The knowldege of CO, mean BP, and pressures measured with the PAC allows the computation of left and right ventricular stroke work, according to standard formulas (41,82). In our experience, this computation provides little clinically useful information. Variables Calculated from the Oximetry of Mixed Venous and Arterial Blood
The arteriovenous oxygen difference (C(a-v)O 2 ) is the difference in the O 2 content of arterial and mixed venous blood. It normally ranges from 30 to 55 mL O 2 per liter of blood. In a healthy individual doing muscular exercise, the response to increased O 2 requirements consists of a curvilinear increase in both C(a-v) and cardiac output (83). In sepsis and septic shock, by contrast, the increase in metabolic requirements is covered solely by the elevation of cardiac output, whereas peripheral oxygen extraction and C(a-v)O 2 are usually decreased (84). In low-CO syndromes, oxygen demand is satisfied by an augmentation of peripheral extraction, which entails an increased C(a-v)O 2 (85). Oxygen extraction (ERO 2 ) is calculated as the ratio of arteriovenous O 2 difference to arterial oxygen content, and is expressed in percent. The normal range is 22% to 33%. Oxygen extraction conveys similar information, and is interpreted along the same lines as C(a-v)O 2. Oxygen delivery (or transport) (DO 2 ) designates the quantity of oxygen leaving the left ventricle per unit of time. It is generally indexed to the body surface area and expressed in ml O 2 ⋅ min⫺1 ⋅ m⫺2. The adequacy of DO 2 depends on (1) the adaptation of the alveolar ventilation to metabolic requirements, 2) the efficiency of pulmonary gas exchange, (3) the carrying capacity of blood for O 2, a function of Hb level and affinity for O 2 (P50 ), and (4) the adaptation of cardiac output to
718
Perret et al.
metabolic requirements. The strategy of achieving a preset supranormal O2 with fluid loading followed by increasing doses of a beta-adrenergic agonist, originally advocated in high-risk surgical patients (86, 87), has not lived up to these expectations in other studies (88,89). This complicated controversy is outside the scope of the present review. Oxygen uptake (VO 2 ) may be computed as the product of CO and C(a-v)O 2 (reverse Fick method), but this calculation is of limited interest for several reasons. It is particularly imprecise due to the acccumulation of measurement errors. Furthermore, the steady-state conditions required for its validity are not necessarily met in the critical-care setting. Finally, reverse Fick VO 2 is mathematically coupled to DO 2 since the same value of CO is being used for the computation of both, potentially introducing a spurious VO 2 /DO 2 dependence (autocorrelation). The preferred method for the evaluation of VO 2 is indirect calorimetry (90,91), a method relatively easy to use at the bedside. It is expressed in mL O 2 /min, and is generally indexed to the body surface area.
C. Essential Role of Cardiopulmonary Interactions in the Interpretation of PAC Data
Implications of a Nonatmospheric Intrathoracic Pressure
The pressures measured with a PAC may be dramatically influenced by the fluctuations in intrathoracic pressure (ITP) induced by respiration. The catheter measures an intravascular or intracavitary pressure, relative to atmosphere. However, the interpretation of hemodynamic data requires thinking in terms of transmural pressure, which designates the difference between pressures on either side of the wall. The extramural pressure is not known, but is least influenced by respiratory efforts at the end of expiration. For this reason, it is generally considered that measurements should be taken at this instant of the respiratory cycle (41,50,64). The readings so obtained may be good approximations to transmural pressure if ITP is close to atmospheric, as normally occurs at the end of a passive exhalation. However, this is often not the case in dyspneic patients with labored breathing, in whom recruitment of expiratory muscles can lead to markedly postive end-expiratory ITP and consequently to large overestimation of ventricular filling pressures. Unfortunately, there is no general solution to this problem. Although changes in esophageal pressure (Pes) track changes in ITP, the absolute values of both may differ substantially (92). Furthermore, Pes is not easily measured at the bedside, especially in dyspneic nonintubated patients. In this situation, it has been recently proposed to take vascular pressure readings as the mean of end-expiratory and nadir-inspiratory values (93). Alternatively, if the patient is on mechanical ventilation, brief muscle relaxation may be justified for the purpose of obtaining measurements in the absence of respiratory muscle activity (94). Even with muscle relaxation, end-expiratory ITP may be above atmospheric pressure if PEEP is applied. Assuming that the compliances of the lung (CL ) and
Invasive and Noninvasive Assessment
719
chest wall (CW ) are in series and homogeneous, changes in alveolar pressure (∆PA ) translates into changes in ITP (∆PITP ) according to (41,50): ∆PITP /∆PA ⫽ 1/(1 ⫹ CW /CL )
(2)
CW /CL is not generally known with precision, and the validity of the underlying assumptions is rather approximate. Nevertheless, the above relationship is helpful for making rough predictions. For instance, it implies that, in normal conditions (CL ⫽ CW ⫽ 0.2 L/cm H2 O), approximately 50% of positive airway pressure is translated into positive changes in ITP. It can also be appreciated that the transmission ratio increases with increased CL and/or low CW . In acute lung injury, the low CL should limit the transmission of airway pressure, although the heterogeneity of the lung characteristic of this condition makes such a prediction hazardous in the individual patient. A better appreciation of the effects of PEEP may be gained by recording the intramural vascular pressures, in particular the PAOP, during a brief (⬍ 15 sec) disconnection from the ventilator: the nadir of the generated tracing represents left atrial transmural pressure (Fig. 6) (95). The ‘‘nadir PAOP’’ method is not yet universally accepted. One obvious limitation is the necessity of complete muscle relaxation in order to avoid artifacts due the patient’s breathing; another is that the nadir cannot be obtained in the presence of airway obstruction, because of delayed emptying of the lung following disconnection. It is unusual to apply high levels of PEEP in presence of airway obstruction. In such conditions however, there may exist an intrinsic PEEP (auto-PEEP) which has the same effects as an external PEEP and must prompt the same correction when estimating transmural pressures (96,97). It is worth noting that the transmission ratio of intrinsic PEEP to intrathoracic pressure may be especially high in patients with chronic obstructive pulmonary disease, who have emphysema and increased lung compliance. In presence of high PEEP and unstable hemodynamic conditions, the estimation of preload with a direct measurement of ventricular volumes may be desirable (see below, complementary role of echocardiography). In such conditions, the thermodilution measurement of right ventricular ejection fraction and end-diastolic vol-
Figure 6 Measurement of nadir pulmonary artery occlusion pressure. (From Ref. 41, with permission; Courtesy of G. Bernardin, M.D.)
720
Perret et al.
ume has been reported as useful (98), although one may question its validity unless tricuspid regurgitation can be excluded. Zoning
While alveolar pressure usually has a uniform distribution throughout the lung, intravascular pulmonary pressures are regionally influenced by the vertical hydrostatic gradient (apicocaudal in the erect, and anteroposterior in the supine position). This leads to the classical concept of vascular zones, defined according to the relative values of pulmonary arterial, alveolar and venous pressures. If the tip of a SwanGanz catheter is located in zone I or II, in which alveolar pressure exceeds venous pressure, PAOP is a reflection of the former rather than the latter. The reason is that the static column of fluid depicted in Figure 1 is interrupted by compression of the microvessels. In practice, this artifact is not very common, although it might occur more frequently when patients with ARDS are managed in the prone position. Even if the parenchyma at the level of the tip of the catheter is in zone II or I, the more dependent parts of the area subtended by the occluded vessel may be in zone III (i.e., venous pressure ⬎ alveolar), in which case a continuous path of static fluid still exists to point J (50). Furthermore, balloon flotation generally leads the catheter into a zone III at the time of insertion. Errors in the measurement of PAOP related to non–zone III conditions may be suspected with hypovolemia or when alveolar pressure is above atmospheric at the end of expiration (external or intrinsic PEEP), all conditions whereby zones I and II may extend at the expense of zone III. The clinician may be alerted to this possibility by one or more of the following observations (11,41). 1. During mechanical inflation with positive pressure, wide inspiratory increases of PAOP are observed, of about the same magnitude as the swings in Paw, and clearly wider than the respiratory changes seen on the PAP and RAP pressure traces. In zone III conditions, by contrast, the inspiratory augmentation of Paw should be incompletely transmitted to all three vascular pressures (Eq. 2). 2. A change in PEEP translates into a change in PAOP of the same magnitude; in zone III conditions, PAOP should change less than PEEP. 3. Despite proper damping of the catheter-transducer system and lack of overwedging on balloon inflation, ‘‘a’’ and ‘‘v’’ waves may not be detectable on the PAOP trace, suggesting lack of continuity between the occluded artery and the LA. D. Interpretation of Pressure Waveforms
The information content of pressure waveforms that may be recorded from the lumen of the PAC is briefly outlined here. A more complete description may be found in many textbooks (41,54,99), as well as in one excellent article (100). An absolute prerequisite to retrieve this information is an optimal frequency response of the catheter-transducer system (41,50).
Invasive and Noninvasive Assessment
721
Pulmonary Artery Pressure
The normal PAP waveform has a distinctly arterial pulse appearance, with a dicrotic notch located at approximately one-third of total pulse amplitude above end-diastolic pressure. Artifacts may be generated in the form of a protosystolic rapid and ample biphasic fluctuation produced by movement of the catheter tip (whip artifact) (101). Also, the waveform may be blurred by wide respiratory fluctuations, especially in presence of tachypnea and/or tachycardia, as well as by oscillations related to an underdamped catheter-transducer system. Abnormal waveforms can be seen whenever a giant v-wave-transmitted retrograde is superimposed on the diastolic descent, leading to an abnormally high dicrotic notch (102). In massive pulmonary embolism, one frequently observes a PAP wavefrom strikingly similar to a ventricular tracing (ventricularization) with a rapid end-systolic descent and a hardly visible or absent dicrotic notch (103). This morphology is almost pathognomonic for proximal obstruction pulmonary arteries; it is explained by the loss of arterial distensibility secondary to pulmonary hypertension, and by an accentuation of reflected pressure waves. Pulmonary Artery Occlusion Pressure
The normal PAOP waveform is characterized by ‘‘a’’ and ‘‘v’’ waves of low amplitude (a few mm Hg), the former related to atrial contraction and the latter to passive filling of the atrium followed by opening of the mitral valve. The ‘‘a’’ wave occurs approximately 160 msec after the electrocardiographic P, a delay related in part to the time needed for retrograde conduction of the pressure pulse in the fluid filled catheter from the LA, across the pulmonary circulation, to the catheter tip (100). For the same reason, the peak of the ‘‘v’’ wave occurs after the electrocardiographic T. Even with flawless technical conditions, the ‘‘a’’ and ‘‘v’’ waves are not always clearly seen on the PAOP trace. Artifacts can be generated by the whip phenomenon, as on the PAP waveform. If the catheter tip is too peripheral, balloon inflation is sometimes associated with a progressive rise of the measured pressure above the level of PAP. This phenomenon (overwedge) is explained by formation at the catheter tip of a small pocket of fluid isolated from the arterial lumen, due to balloon expansion in a too narrow vessel (41). The pressure measured inside this pocket progressively equilibrates with that of the pressurized infusion used for continuous flushing of the distal lumen. Observation of an overwedge mandates repositioning of the catheter. Finally, the inflated balloon may fail to achieve complete occlusion if the catheter tip is too proximal. In this case, a damped PA waveform may be observed. The principal abnormal waveform consists of a pathological giant ‘‘v’’ wave which is differentiated from its normal counterpart by an amplitude in excess of 10 mm Hg (41,54,99). The giant ‘‘v’’ wave is symetrical, without a dicrotic notch. Especially with tachycardia and/or wide respiratory variations, it is important to avoid confusion with a PA waveform and the consequent erroneous conclusion of incomplete occlusion. The classical cause of a giant ‘‘v’’ wave is mitral regurgitation, but this feature may occur in all situations characterized by a distended and
722
Perret et al.
non compliant left atrium (i.e., left ventricular failure from any cause), even with a competent mitral valve (99,104,105). The giant ‘‘v’’ wave observed in acute ventricular septal defect (complicating myocardial infarction) is explained by the increased pulmonary blood flow and increased venous return to the LA (106). In myocardial ischemia, giant ‘‘v’’ waves may rapidly occur and disappear, with associated fluctuations in the mean value of PAOP, an instability related to a time varying dysfunction of a papillary muscle (107). The magnitude of mitral regurgitation bears little relationship to the amplitude of the giant ‘‘v’’ wave. Right Atrial Pressure
The ‘‘a’’ and ‘‘v’’ waves are practically always recognized on the normal RAP waveform. The P-a interval is shorter than on the PAOP trace, due to the lack of a retrograde transmission delay (⬃ 80 msec) (100). The ‘‘v’’ wave is preceded and followed respectively by the ‘‘x’’ and the ‘‘y’’ descent, of approximately equal, low amplitude (a few mm Hg). Several types of abnormal waveforms may be distinguished. Tricuspid regurgitation translates into a systolic rise of RAP, which in severe instances becomes difficult to differentiate from the profile in the right ventricle. The amplitude of the regurgitant wave is enhanced during spontaneous inspiration, as expected from the phasic enhancement of venous return (100). Whenever diastolic expansion of the right ventricle is limited, either by a thickened pericardium (constrictive pericarditis), or by a structural defect (restrictive cardiomyopathy) or, more commonly, by reduced myocardial distensibility secondary to ischemia or to an acute dilation of the ventricle beyond its limit of elasticity (RV infarction, acute cor pulmonale), a deep ‘‘y’’ descent may be observed on the RAP waveform (41,108). This feature corresponds to the early diastolic dip of the dip and plateau pattern described in these circumstances on the RV pressure trace. It may be obscured by concomitant tricuspid regurgitation. The hallmark of cardiac tamponade consists in abnormally high and equalized RAP and PAOP, both being equilibrated with pericardial pressure (109,110). The RAP waveform is characterized by a deep ‘‘x’’ descent corresponding to a transient decrease in the volume enclosed within the tense pericardium during ventricular systole. The ‘‘y’’ descent is usually absent. This characteristic morphology is less easily seen on PAOP tracing, due to damping of left atrial pressure waves as they travel backward through the pulmonary vascular bed. The RAP waveform may contribute to the differential diagnosis of tachycardias. Atrial flutter can be recognized as a mechanical activity at an approximate rate of 300 per minute. For the diagnosis of tachycardias with prolonged QRS, it is useful to look for high-amplitude waves peaking slightly after the electrocardiographic R, which indicate atrial contraction against a closed tricuspid valve (cannon waves). Marked beat-to-beat variations in the amplitude of cannon waves reflect an atrioventricular dissociation and constitute a valid argument for the presence of ventricular tachycardia (100). Cannon waves of constant amplitude may be seen in AV nodal reentrant tachycardia (111).
Invasive and Noninvasive Assessment
723
IV. Echocardiography: A Complementary Role Among several very promising options, echocardiography has become an invaluable diagnostic tool that allows rapid assessment of cardiocirculatory function and provides hemodynamic data that can influence decision making. The introduction in ICU of transthoracic echocardiography (TTE) in the early 1980s had a significant impact on the care of critically ill patients. However, numerous restrictions on the imaging ability of (TTE) became rapidly evident, mostly related to suboptimal ultrasound windows. In contrast, transesophageal echocardiography (TEE), which is now widely available to intensivists, provides high-quality images and allows examination of deep cardiovascular structures that are inacessible via the transthoracic approach (112,113). Recent technical advances include several developments in hardware as well as in software, among them, the introduction of high-frequency transducers, biplane and multiplane probes, automatic blood-myocardium border detection, wall motion analysis, and 3D echocardiography (114). Most recently, the Tissue Doppler Imaging (TDI), a novel method for the online color-coding of myocardial velocity, has been developed. TDI coupled with conventional 2D echocardiography reflects alterations in regional and global LV contractility (115). In clinical practice, common indications for urgent cardiac investigations in critically ill patients include the assessment of LV and RV function, the determination of cardiac output and filling status, and PAP measurement. Traditionally, this information has been obtained with the PAC. At present, it can also be conveyed by echocardiography with minimal delays and without invasive vascular access. Furthermore, the latter method provides original data regarding cardiac anatomy and morphology, valvular function and pericardial abnormalities. A. Echocardiographic Quantification of LV Function
Quantification of LV function is an essential step in the investigation of acute cardiocirculatory or respiratory failure. Echocardiography—and particularly TEE—has proved of great interest in these settings because of its portability and relative noninvasiveness. LV Volumes and Ejection Fraction
Several investigators have validated the use of single plane and more recently biplane and multiplane TEE for determining LV volumes and calculating ejection fractions. The traditional approach used manual tracing of the endocardial borders from stop-frame images. Aside from potential underestimation of LV volume (116,117), this offline method is not suited to the requirements of intensive care. Online estimate of LV cross-sectional area or volume has taken large benefit from the new method of automated border detection (ABD). ABD uses backscatter data to differentiate between tissue and blood ultrasound densities (118,119). Several experimental and clinical studies have demonstrated a linear relationship between changes in LV cross sectional areas and changes in LV volume in physiological conditions (120). This relationship may break down in presence of significant wall
724
Perret et al.
motion abnormalities or aneurysms. Nevertheless, even in such cases, area measurements remain well suited to estimate serial volume changes over time (Fig. 7). Using this technique during cardiac surgery, Cheung et al. were able to reliably predict rapid changes in preload in patients with both normal and abnormal LV function (121). The ABD technique has been used to estimate LV stroke volume and cardiac output with acceptable accuracy in comparison with the conventional thermodilution method (122,123). However, the relatively wide limits of agreement observed and the high proportion of non usable measurements preclude clinical application in the present state of technology. Pressure-Volume and Pressure-Area Relationships
Analysis of pressure-volume relationships during rapid changes of pre- or afterload provides indices of LV contractility (end-systolic elastance, E’es) which are approximately load independent (124–127). In clinical practice, it is difficult to induce the required changes of loading conditions. Furthermore, pressure-volume analysis is limited by the technical difficulty of measuring both high-fidelity LVP and LV volume online. The online measurement of LV volume is now possible with ABD. Applying this concept to patients undergoing coronary artery bypass surgery, Gorc-
Figure 7 Stop-frame of a short-axis automatic boundary-detected image (top) with the online instantaneous cavity area graph (below) during rapid volume infusion, demonstrating a rapid and subsequent increase in LV area.
Invasive and Noninvasive Assessment
725
san et al. could show that E’es decreased immediately after bypass, whereas variations observed in stroke volume, cardiac output, or fractional area change were not systematic (128). A wider clinical application of this approach remains speculative at present. B. Cardiac Filling Status
The determination of RV and LV preload is important in presence of circulatory failure or unexplained hypotension. As stated above, preload is imperfectly estimated by the measurement of pressures. 2D echocardiography provides direct estimations of volumes. Furthermore, Doppler examination gives indirect clues on the state of ventricular distension. Reliable estimates of actual LV volume can be produced using geometric models such as area-length or Simpson’s rule methods. Because of the close linear relationship between LV area and volume, demonstrated both in animal (129) and human studies (120), it appears more practical to use modifications of areas for the detection of preload changes and for the prediction of hypovolemia (130,131), which can reliably be obtained online with TEE combined with ABD, as stated above. Pulse-wave Doppler examination infers the state of cardiac filling from the analysis of either the mitral or, more recently, the pulmonary venous flow patterns. As expected, these patterns largely depend on the degree of ventricular distension. Figure 8 demonstrates the normal profiles of mitral and pulmonary venous flows. Contrary to initial assumptions, analysis of mitral flow alone is not sufficient and needs to be combined with that of pulmonary venous flow (132–134). Qualitative information on the state of cardiac filling is easily obtained by simple inspection of these profiles (Fig. 8). C. Pulmonary Artery Pressure
Continuous-wave Doppler measurements of peak velocity in the tricuspid regurgitation jet has been used for a long time to estimate the systolic pressure gradient between the RV and RA using a modified Bernouilli equation (135,136). Addition of the estimated or measured RAP provides a reliable estimate of RV systolic pressure which, in the absence of pulmonary stenosis, is equal to PA systolic pressure. When tricuspid regurgitation is absent or difficult to record, or when a marked elevation of jugular venous pressure hampers the estimation of RV pressure, the qualitative assessment of pulmonary flow by pulse-wave Doppler may be useful to detect PHT (137). The estimation of diastolic PAP is also possible when a pulmonary valvular regurgitation can be recorded, which is rarely the case in critical-care patients. D. Cardiac Output
Estimates of cardiac output by Doppler echocardiography using both pulsed-wave and continuous-wave Doppler formats were first validated with the transthoracic approach (138–142). Theoretically, the Doppler measurement of blood flow may
726
Perret et al.
Figure 8 The upper tracings depict normal transmitral (TMF) and pulmonary venous (PVF) flow patterns, in relation to the ECG and left ventricular pressure (LVP). Positive signs denote antegrade flow to the left ventricle (TMF) and the left atrium (PVF). The normal PVF pattern is triphasic showing dominant systolic forward flow (S), early diastolic forward flow (D) concomitant to the E wave of TMF, and late diastolic flow reversal during atrial contraction (Ap) corresponding to Am wave of TMF. Variables that can be measured on PVF and TMF tracings include peak flow velocities and velocity-time integrals (VTI) of each phase. The systolic fraction of PVF is calculated using the following formula: SF ⫽ S / (S ⫹ D), using either peak velocities or VTI. The lower tracings depict the flow patterns observed in hypovolemia and hypervolemia. Hypovolemia is characterized by a largely predominant systolic PVF (i.e., S ⬎⬎ D), and a short duration, small velocity of the Ap-wave on PVF. Hypervolemia is characterized by a shift from predominant systolic to predominant early diastolic PVF, and by an Ap-wave duration superior to the Am-wave duration. These alterations of PVF are relatively specific of changes in volemic status. The patterns of TMF in hypervolemia may be characterized by increased E/Am ratio, resulting from a shift of flow velocities toward early diastole. By contrast, hypovolemia can be associated with an inverted E/Am ratio, with a predominant late diastolic filling. Compared to those of PVF, these modifications of TMF are less specific of changes in volemia.
be performed at multiple sites within the heart and great vessels. In clinical practice, the most promising approach uses the transgastric window to align the Doppler beam with the LV outflow tract. Katz et al. obtained adequate data in 50 of 57 attempted examinations (88%) (143). A close correlation of Doppler estimates with thermodilution measurements could be demonstrated. These results were later confirmed by
Invasive and Noninvasive Assessment
727
Stoddard et al. (144) and recently improved using bi- and multiplane TEE probes (145–147). In the present state of technology, these TEE methods do not replace thermodilution, although they may be of interest when the PAC is contraindicated or when particular conditions make the invasive measurement unreliable (i.e., severe tricuspid regurgitation). In selected patients, TEE may obviate the need for the invasive measurement of CO. E. Specific Indications of Echocardiography in the ICU
In various clinical conditions, echocardiography provides more appropriate, specific, and rapidly available informations compared with the PAC. Echocardiography is essential for evaluating suspected complications of acute myocardial infarction. Correctable causes of cardiogenic shock such as mitral regurgitation, septal or free wall ruptures, pseudoaneurysms, or right ventricular involvement may be reliably and rapidly detected. The best technique to diagnose compressive pericardial effusions and cardiac tamponade is 2D echocardiography. The transthoracic approach is sufficient in ⬎ 90% of patients. The most reliable predictor of hemodynamically significant heart compression in the demonstration of right atrial and right ventricular collapse (148). Soon after cardiac surgery, TEE is more powerful than TTE for the detection of regional tamponade due to pericardial blood clots (149,150). TEE appears to be of particular value in the setting of thoracic trauma, providing advantages over the computerised tomography (CT) scan of the thorax: less time delay, no need for transportation, and ability to perform the investigation during surgery. In addition to the evaluation of hemodynamic status, TEE safely and promptly provides information on mediastinal structures (151,152). In acute pulmonary embolism with the thrombus located in the main or right pulmonary artery, TEE can clarify the diagnosis within a few minutes without further procedures requiring transportation (153). Unfortunately, this occurrence is fairly rare, and conventional diagnostic techniques must generally be used. Until recently, no reliable criteria were available to evaluate the cardiac performance of potential heart donors, sometimes leading to the exclusion of brain-death donors exhibiting severe chest trauma, prolonged hypotension, cardiac arrest, and use of high-dose catecholamines. Echocardiography, and especially TEE, constitutes an alternative to direct surgical inspection to detect nonsuitable hearts (154,155). F. Advantages of Echocardiography in the ICU
Feasibility
In sedated patients and in the hands of an experienced physician, TEE can be considered as a minimally invasive technique. Its contraindications are few, being restricted to esophageal and gastroduodenal bleeding, as well as esophageal stricture. Over a 2year period, Khoury et al. reported a 100% feasibility among 77 critically ill patients, including 41 who did not require mechanical ventilation (156).
728
Perret et al. Safety
Complications of TEE are most frequent in outpatients, probably due to the stress response that awake or minimally sedated subjects experience while swallowing the probe. In critically ill sedated patients, complications from the insertion and use of the TEE probe are infrequent (156–158), and the associated incidence of bacteremia, with or without antibiotic treatment, has been evaluated at 1.4% (159). Impact on Management
There is no demonstration that the use of TEE improves survival in critically ill patients. However, numerous anecdotes and clinical studies suggest that TEE has a definite role in diagnosis and management. Table 1 summarizes the experience of several centers, demonstrating that TEE detected unexpected cardiovascular abnormalities in 25% to 59% of critically ill patients and influenced therapeutic decisions or indications for surgery in 8% to 48% (156–158,160–166). In addition, although difficult to quantify, the lack of pathological findings by TEE cannot be ignored since it provides the clinician with significant information concerning the normality of cardiac structures, function, and hemodynamics. V.
Changing Strategy
Considering the potential benefits of echocardiography in the care of critically ill patients, one may wonder why it is not of more general use in the ICU. There are several explanations. First, echocardiography was developed in the cardiology laboratory, and its use at the bedside is relatively recent, essentially related to the development of the transesophageal approach. Second, echocardiography was not considered adequate for frequently repeated examinations, a condition regarded as essential for guiding therapy. Third, its introduction in the ICU supposed special
Table 1 Impact of TTE on Therapeutic Management Authors Pavlides et al. (160) Font et al. (161) Chenzbraun et al. (162) Oh et al. (158) Pearson et al. (157) Hwang et al. (163) Vignon et al. (164) Khoury et al. (156) Heidenreich et al. (165) Alam (166)
Number of TEE Examinations
Unexpected/additional findings (%)
Change in therapy/ surgery (%)
86 112 113 51 62 78 98 77 61 121
— 32 45 59 44 50 — — 28 32
24 — 8 24 — 18 36 48 20 22
Invasive and Noninvasive Assessment
729
technical skills and training which were not part of standard critical care education programs. The current practice is rapidly evolving toward a new strategy which would optimally combine the benefits of the PAC with those of echocardiography. In our view, echocardiography represents a major diagnostic tool which, in a number of situations observed in intensive care, provides rapid and accurate information, frequently sufficient to initiate therapy. A good example is the possibility of ruling out a cardiogenic nature of shock by the demonstration of normal cardiac function in a hypotensive patient. Accordingly, it seems reasonable to perform echocardiography in priority whenever the cause of a circulatory or respiratory failure has not been elucidated by routine examination. On the other hand, the use of the PAC is justified in several conditions: (1) unavailability of echocardiography; (2) poor quality of TTE imaging and contraindications for TEE; and (3) insufficient training for accurate interpretation of echocardiographic data. In fact, the PAC will not generally be used as a diagnostic tool but as an appropriate means to obtain frequent evaluations of the hemodynamic profile for guiding therapy. The fact that measurements with the PAC can be repeated ad libitum or even obtained continuously with new technological developments (167) confers to this technique a considerable advantage over echocardiography which—even with the best operator—is generally not suitable for monitoring due to the discomfort that TEE imposes on concious patients. Thus, it is hardly imaginable to use echocardiography for gauging the immediate effects of all changes in ventilator settings. Furthermore, unexpected variations observed on profiles routinely obtained with the PAC may allow the detection of important events, which would otherwise have gone unnoticed. A case in point is the sudden development of acute mitral regurgitation due to papillary dysfunction secondary to silent myocardial ischemia, or a brutal drop in CO and/or SvO 2 in presence of unrecognized bleeding. Of note, the respective indications for echocardiographic and invasive hemodynamic investigations are likely to vary according to the echocardiographic skills locally available at the bedside. Although intensivists will generally not be fully trained in echocardiography, one can expect that they should master specific aspects of this technique (168). In that respect, education should be facilitated by the ability of videorecording the examinations for subsequent validation with a senior echocardiographist. In the years to come, the curricula of critical care physicians will likely include training in both invasive and non invasive hemodynamic monitoring. In summary, we have outlined the changes in strategy for hemodynamic investigation and monitoring which are likely to take place in the near future of critical care. The respective roles of noninvasive and invasive means will probably evolve with technological developments, but it is highly implausible that the former will soon entirely replace the latter. This trend has two kinds of implications. First, it should be taken into account when designing studies aimed at evaluating the PAC. Second, the curricula for professional training in critical care should be reconsidered. Physicians should not only improve their knowledge of the PAC, but also acquire specific elements of echocardiography, which would endow them with the capacity to reliably draw basic conclusions in specific circumstances.
730
Perret et al. References
1. Forsmann W. Die Sondierung des rechten Herzens. Berlin Klin Wochenschr 1929; 8:2085– 2087. 2. Cournand AF, Ranges HS. Catheterization of the right auricle in man. Proc Soc Exp Biol Med 1941; 46:462-466. 3. Richards DW. Cardiac output by the catheterization technique in various conditions. Fed Proc 1945; 4:215–220. 4. Dexter L. Studies of congenital heart diseases. II. The pressure and oxygen content of blood in the right auricle, right ventricle, and pulmonary artery in control patients, with observations on the oxygen saturation and source of pulmonary ‘‘capillary blood.’’ J Clin Invest 1947; 26:554–560. 5. Lategola M, Rahn H. A self-guiding catheter for cardiac and pulmonary arterial catheterization and occlusion. Proc Soc Exp Biol Med 1953; 84:667–668. 6. Dotter CT, Straube KR. Flow guided cardiac catheterization. Am J Roentgenol Radium Ther Nucl Med 1962; 88:27–30. 7. Bradley RD. Diagnostic right heart catheterization with miniature catheters in severely ill patients. Lancet 1964; 2:941–942. 8. Swan HJC, Ganz W, Forrester JS, Marcus H, Diamond G, Chonette D. Catheterization of the heart in man with the use of a flow-directed balloon-tipped catheter. N Engl J Med 1970; 283:447–451. 9. Forrester JS, Diamond GA, Swan HJC. Correlative classification of clinical and hemodynamic function after acute myocardial infarction. Am J Cardiol 1977; 39:137–145. 10. Weil MH, Henning RJ. New concepts in the diagnosis and fluid treatment of circulatory shock. Anesth Analg 1979; 58:124–132. 11. Marini JJ. Hemodynamic monitoring with the pulmonary artery catheter. Crit Care Clin 1986; 2:551–572. 12. Matthay MA, Chatterjee K. Bedside catheterization of the pulmonary artery: risks compared with benefits. Ann Intern Med 1988; 109:826–834. 13. Robin ED. The cult of the Swan-Ganz catheter. Overuse and abuse of pulmonary flow catheters. Ann Intern Med 1985; 103:445–449. 14. Robin ED. Death by pulmonary artery flow-directed catheter. Time for a moratorium? Chest 1987; 92:727–731. 15. Gore JM, Goldberg RJ, Spodick DH, Alpert JS, Dalen JE. A community-wide assessment of the use of pulmonary artery catheters in patients with acute myocardial infarction. Chest 1987; 92:721–727. 16. Zion MM, Balkin J, Rosenmann D, Goldbourt U, Reicher-Reiss H, Kaplinsky E, Behar S. Use of pulmonary artery catheters in patients with acute myocardial infarction. Analysis of experience in 5,841 patients in the SPRINT Registry. Chest 1990; 98:1331–1335. 17. Greenland P, Reicher-Reiss H, Goldbourt U, Behar S. In-hospital and 1-year mortality in 1,524 women after myocardial infarction. Comparison with 4,315 men. Circulation 1991; 83:484–491. 18. Tuman KJ, McCarthy RJ, Spiess BD, DaValle M, Hompland SJ, Dabir R, Ivankovich AD. Effect of pulmonary artery catheterization on outcome in patients undergoing coronary artery surgery. Anesthesiology 1989; 70:199–206. 19. Swan HJ, Ganz W. Complications with flow-directed balloon-tipped catheters [letter]. Ann Intern Med 1979; 91:494. 20. Shah KB, Rao TL, Laughlin S, El-Etr AA. A review of pulmonary artery catheterization in 6,245 patients. Anesthesiology 1984; 61:271–275. 21. Connors AF Jr, Speroff T, Dawson NV, Thomas C, Harrell FE, Jr., Wagner D, Desbiens N, Goldman L, Wu AW. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA 1996; 276:889–897. 22. Dalen JE, Bone RC. Is it time to pull the pulmonary artery catheter? [Editorial.] JAMA 1996; 276:916-918. 23. Lewis RP. Effectiveness of right heart catheterization: time for a randomized trial [letter]. JAMA 1997; 277:109.
Invasive and Noninvasive Assessment
731
24. Soni N. Swan song for the Swan-Ganz catheter? [Editorial.] BMJ 1996; 313:763–764. 25. Lazarus R. Pulmonary artery catheterisation. Proposed moratorium on use of pulmonary artery catheters is premature [letter]. BMJ 1996; 313:1328. 26. Dexter TJ. Pulmonary artery catheterisation. Catheterisation is useful when used by experienced clinicians [letter]. BMJ 1996; 313:1328. 27. Boyd O. Effectiveness of right heart catheterization: time for a randomized trial [letter]. JAMA 1997; 277:110–111; discussion 113–114. 28. Mueller HS, Chatterjee K, Davis KB, Fifer MA, Franklin C, Greenberg MA, Labovitz AJ, Shah PK, Tuman KJ. ACC expert consensus document. Present use of bedside right heart catheterization in patients with cardiac disease. J Am Coll Cardiol 1998; 32:840– 864. 29. Iberti TJ, Fischer EP, Leibowitz AB, Panacek EA, Albertson TE, Silverstein JH. A multicenter study of physicians’ knowledge of the pulmonary artery catheter. JAMA 1990; 264:2928–2932. 30. Gnaegi A, Feihl F, Perret C. Intensive care physicians’ insufficient knowledge of rightheart catheterization at the bedside: time to act? Crit Care Med 1997; 25:213–220. 31. Anonymous. Pulmonary artery catheter consensus conference: consensus statement. Crit Care Med 1997; 25:910–925. 32. Anonymous Pulmonary artery catheter consensus conference, Chicago, December 6–8, 1996. New Horizons 1997; 5:173–296. 33. Chernow B. Pulmonary artery flotation catheters. A statement by the American College of Chest Physicians and the American Thoracic Society [Editorial.] Chest 1997; 111:261– 262. 34. Spodick DH. The Swanz-Ganz catheter: requesting scientific trials is not an ‘‘assault.’’ Chest 1999; 115:857–858. 35. Layon AJ. The pulmonary artery catheter: nonexistential entity or occasionally useful tool? Chest 1999; 115:859–862. 36. Trottier SJ, Taylor RW. Physicians’ attitudes toward and knowledge of the pulmonary artery catheter: Society of Critical Care Medicine membership survey. New Horizons 1997; 5:201–206. 37. Guyatt G, Ontario Intensive Care Study Group. A randomized control trial of right heart catheterization in critically ill patients. J Intens Care Med 1991; 6:91–95. 38. Papadakos PJ, Vender JS. Training requirements for pulmonary artery catheter utilization in adult patients. New Horizons 1997; 5:287–291. 39. Vincent JL, Dhainaut JF, Perret C, Suter P. Is the pulmonary artery catheter misused? A European view. Crit Care Med 1998; 26:1283–1287. 40. Sprung CL. The Pulmonary Artery Catheter. Methodology and Clinical Applications, 2nd ed. Closter, NJ Critical Care Research Associates, 1993. 41. Perret C, Tagan D, Feihl F, Marini JJ. The Pulmonary Artery Catheter in Critical Care. Oxford: Blackwell Science, 1996. 42. Tobin MJ. Principles and Practice of Intensive Care Monitoring. New York: McGrawHill, 1997. 43. Magder S. More respect for the CVP [Editorial]. Intens Care Med 1998; 24:651–653. 44. Lopez-Sendon J, Coma-Canella I, Gamallo C. Sensitivity and specificity of hemodynamic criteria in the diagnosis of acute right ventricular infarction. Circulation 1981; 64:515– 525. 45. Herve´ P, Petitpretz P, Simonneau G, Salmeron S, Laine JF, Duroux P. The mechanisms of abnormal gas exchange in acute massive pulmonary embolism. Am Rev Respir Dis 1983; 128:1101. 46. Davidson CJ, Fishman RF, Bonow RO. Cardiac catheterization. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: W.B. Saunders, 1997: 177–203. 47. Fishman AP. Pulmonary circulation. In: Fishman A, ed. Handbook of Physiology: The Respiratory System. Baltimore: Williams and Wilkins, 1985:93–167. 48. McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol 1971; 28:288–294. 49. Falicov RE, Resnekov L. Relationship of the pulmonary artery diastolic pressure to left
732
50. 51. 52. 53. 54. 55. 56.
57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
Perret et al. ventricular end-diastolic and mean filling pressure in patients with and without left ventricular dysfunction. Circulation 1970; 42:65–73. O’Quin R, Marini JJ. Pulmonary artery occlusion pressure: clinical physiology, measurement and interpretation. Am Rev Respir Dis 1983; 128:319–326. Pagel PS, Grossman W, Haering JM, Warltier DC. Left ventricular diastolic function in the normal and diseased heart. Perspectives for the anesthesiologist (first of two parts). Anesthesiology 1993; 79:836–854. Pagel PS, Grossman W, Haering JM, Warltier DC. Left ventricular diastolic function in the normal and diseased heart. Perspectives for the anesthesiologist (second of two parts). Anesthesiology 1993; 79:1104–1120. Rahimtoola SH, Ehsani A, Sinno MZ, Loeb HS, Rosen KM, Gunnar RM. Left atrial transport function in myocardial infarction. Am J Med 1975; 59:686–694. Grossman W. Profiles in valvular heart disease. In: Grossman W , ed. Cardiac Catheterization, Angiography, and Interventions, 4th ed. Philadelphia: Lea & Febiger, 1991: 557– 581. Nakano T, Mayumi H, Hisahara M, Yasui H, Tokunaga K. The relationship between functional class, pulmonary artery pressure and size in left atrial myxoma. Cardiovas Surg 1996; 4:320–323. Eicher JC, de Nadai L, Falcon-Eicher S, Lefez C, Andre F, Fabre JL, Tatou E, Jeannin L, David M. Unexplained pulmonary edema: demonstration of obstruction to pulmonary venous return by transesophageal echocardiography. A propos of 4 cases. Arch Mal Coeur Vaisseaux 1997; 90:67–74. Leeman M, Lejeune P, Closset J, Vachie´ry JL, Me´lot C, Naeije R. Nature of pulmonary hypertension in canine oleic acid pulmonary edema. J Appl Physiol 1990; 69:293–298. Fang K, Krahmer RL, Rypins EB, Law WR. Starling resistor effects on pulmonary artery occlusion pressure in endotoxin shock provide inaccuracies in left ventricular compliance assessments. Crit Care Med 1996; 24:1618–1625. Butler BD, Drake RE, Hills BA. Effect of bronchial blood flow on pulmonary artery wedge pressure with pulmonary embolism. Crit Care Med 1986; 14:495–498. Me´lot C, Delcroix M, Closset J, Vanderhoeft P, Lejeune P, Leeman M, Naeije R. Starling resistor vs. distensible vessel models for embolic pulmonary hypertension. Am J Physiol 1995; 268:H817-H827. Crexells C, Chatterjee K, Forrester JS, Dikshit K, Swan HJC. Optimal level of filling pressure in the left side of the heart in acute myocardial infarction. N Engl J Med 1973; 289:1263–1266. Sibbald WJ, Driedger AA. Right ventricular function in acute disease states: pathophysiologic considerations. Crit Care Med 1983; 11:339–345. Raper R, Sibbald WJ. Misled by the wedge? The Swan-Ganz catheter and left ventricular preload. Chest 1986; 89:427–434. Leatherman JW, Marini JJ. Pulmonary artery catheterization: interpretation of pressure recordings. In: Tobin MJ, ed. Principles and Practice of Intensive Care Monitoring. New York: McGraw-Hill, 1997:821–836. Fein AM, Goldberg SK, Walkenstein MD, Dershaw B, Braitman L, Lippman ML. Is pulmonary artery catheterization necessary for the diagnosis of pulmonary edema? Am Rev Respir Dis 1984; 129:1006–1009. McHugh TJ, Forrester JS, Adler L, Zion D, Swan HJ. Pulmonary vascular congestion in acute myocardial infarction: hemodynamic and radiologic correlations. Ann Intern Med 1972; 76:29–33. Gaar KA Jr, Taylor AE, Owens LJ, Guyton AC. Pulmonary capillary pressure and filtration coefficient in the isolated perfused lung. Am J Physiol 1967; 213:910–914. Collee GG, Lynch KE, Hill RD, Zapol WM. Bedside measurement of pulmonary capillary pressure in patients with acute respiratory failure. Anesthesiology 1987; 66:614–620. Anonymous. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 48–1993. A 27-year-old woman with mediastinal lymphadenopathy and relentless cor pulmonale. N Engl J Med 1993; 329:1720–1728. Palmer SM, Robinson LJ, Wang A, Gossage JR, Bashore T, Tapson VF. Massive pulmo-
Invasive and Noninvasive Assessment
71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92.
733
nary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest 1998; 113:237–240. Cope DK, Grimbert F, Downey JM, Taylor AE. Pulmonary capillary pressure: a review. Crit Care Med 1992; 20:1043–1056. Patterson CE, Barnard JW, Lafuze JE, Hull MT, Baldwin SJ, Rhoades RA. The role of activation of neutrophils and microvascular pressure in acute pulmonary edema. Am Rev Respir Dis 1989; 140:1052–1062. Hakim TS, Kelly S. Occlusion pressures vs. micropipette pressures in the pulmonary circulation. J Appl Physiol 1989; 67:1277–1285. Rossetti M, Guenard H, Gabinski C. Effects of nitric oxide inhalation on pulmonary serial vascular resistances in ARDS. Am J Respir Crit Care Med 1996; 154:1375–1381. Guyton AC, Jones CE, Coleman TG. Circulatory physiology : cardiac output and its regulation. Philadelphia: WB. Saunders, 1973. Turner ST, Reilly SL. Fallacy of indexing renal and systemic hemodynamic measurements for body surface area. Am J Physiol 1995; 268:R978-R988. Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R, Schmidt GA, Wood LDH. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med 1995; 151:10–14. Nelson LD, Snyder JV. Technical problems in data acquisition. In: Snyder JV, Pinsky MR, eds. Oxygen Transport in the Critically Ill. Chicago: Year Book, 1987:205–234. Sylvester JT, Gilbert RD, Traystman RJ, Permutt S. Effects of hypoxia on the closing pressure of the canine systemic arterial circulation. Circ Res 1981; 49:980–987. Scharf SM. Flow through collapsible Starling resistors. In: Scharf SM , ed. Cardiopulmonary Physiology in Critical Care. New York: Marcel Dekker, 1992:25–29. Opie LH. Mechanisms of cardiac contraction and relaxation. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: W.B. Saunders, 1997: 360–393. Yang S, Bentivoglio LG, Maranhao V, Goldberg H. From Cardiac Catheterization Data to Hemodynamic Parameters, 2nd ed. Philadelphia: F.A. Davis, 1978. Astrand PO, Cuddy TE, Saltin B, Stenberg J. Cardiac output during submaximal and maximal work. J Appl Physiol 1964; 19:268–274. Rackow EC, Astiz ME, Weil MH. Cellular oxygen metabolism during sepsis and shock. The relationship of oxygen consumption to oxygen delivery. JAMA 1988; 259:1989-1993. Mohsenifar Z, Amin D, Jasper AC, Shah PK, Koener SK. Dependence of oxygen consumption on oxygen delivery in patients with chronic congestive heart failure. Chest 1987; 92: 447–450. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176–1186. Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993; 270:2699–2707. Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330: 1717–1722. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R, for the SvO 2 Collaborative Group. A trial of goal-oriented hemodynamic therapy in critically ill patients SvO 2. N Engl J Med 1995; 333:1025–1032. Takala J, Keina¨nen O, Va¨isa¨nen P, Kari A. Measurement of gas exchange in intensive care: laboratory and clinical validation of a new device. Crit Care Med 1989; 17:1041– 1047. Chiole´ro R, Mavrocordatos P, Bracco D, Schutz Y, Cayeux C, Revelly JP. O 2 consumption by the Fick method. Methodologic factors. Am J Respir Crit Care Med 1994; 149:1118– 1122. Marini JJ, O’Quin R, Culver BH, Butler J. Estimation of transmural cardiac pressures during ventilation with PEEP. J Appl Physiol 1982; 53:384–391.
734
Perret et al.
93. Hoyt JD, Leatherman JW. Interpretation of the pulmonary artery occlusion pressure in mechanically ventilated patients with large respiratory excursions in intrathoracic pressure. Intensive Care Med 1997; 23:1125-1131. 94. Schuster DP, Seeman MD. Temporary muscle paralysis for accurate measurement of pulmonary artery occlusion pressure. Chest 1983; 84:593–597. 95. Pinsky M, Vincent JL, De Smet JM. Estimating left ventricular filling pressure during positive end-expiratory pressure in humans. Am Rev Respir Dis 1991; 143:25–31. 96. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982; 126:166–170. 97. Pinsky MR. Through the past darkly: ventilatory management of patients with chronic obstructive pulmonary disease. Crit Care Med 1994; 22:1714–1716. 98. Yu M, Takiguchi S, Takanishi D, Myers S, McNamara JJ. Evaluation of the clinical usefulness of thermodilution volumetric catheter. Crit Care Med 1995; 23:681–686. 99. Sharkey SW. A guide to interpretation of hemodynamic data in the coronary care unit. Philadelphia: Lippincott-Raven, 1997. 100. Sharkey SW. Beyond the wedge: clinical physiology and the Swan-Ganz catheter. Am J Med 1987; 83:111–120. 101. Bashein G. Another source of artifact in the pulmonary artery pressure waveform. Anesthesiology 1988; 68:310. 102. Grose R, Strain J, Cohen MV. Pulmonary arterial V waves in mitral regurgitation: clinical and experimental observations. Circulation 1984; 69:214–222. 103. Nakayama Y, Nakanishi N, Sugimachi M, Takaki H, Kyotani S, Satoh T, Okano Y, Kunieda T, Sunagawa K. Characteristics of pulmonary artery pressure waveform for differential diagnosis of chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol 1997; 29:1311–1316. 104. Pichard AD, Kay R, Smith H, Rentrop P, Holt J, Gorlin R. Large V waves in the pulmonary wedge pressure tracing in the absence of mitral regurgitation. Am J Cardiol 1982; 50: 1044–1050. 105. Fuchs RM, Heuser RR, Yin FCP, Brinker JA. Limitations of pulmonary wedge V waves in diagnosing mitral regurgitation. Am J Cardiol 1982; 49:849–854. 106. Drobac M, Schwartz L, Scully HE, Bentley-Taylor MM. Giant left atrial V-waves in postmyocardial infarction ventricular septal defect. Ann Thorac Surg 1979; 27:347-349. 107. Messineo FC, Hager WD. Hemodynamic complications of acute myocardial infarction. Hosp Pract 1989; 24:147–166. 108. Hancock EW. On the elastic and rigid forms of constrictive pericarditis. Am Heart J 1980; 100:917–923. 109. Shabetai R, Fowler NO, Guntheroth WG. The hemodynamics of cardiac tamponade and constrictive pericarditis. Am J Cardiol 1970; 26:480–489. 110. Ameli S, Shah PK. Cardiac tamponade : pathophysiology, diagnosis, and management. Cardiol Clin 1991; 9:665–674. 111. Gu¨rsoy S, Steurer G, Brugada J, Andries E, Brugada P. Brief report: the hemodynamic mechanism of pounding in the neck in atrioventricular nodal reentrant tachycardia. N Engl J Med 1992; 327:772–774. 112. Porembka DT, Hoit BD. Transesophageal echocardiography in the intensive care patient. Crit Care Med 1991; 19:826–835. 113. Foster E, Schiller NB. Transesophageal echocardiography in the critical care patient. Cardiol Clin 1993; 11:489–503. 114. Andel H, Huemer G, Wolrab C, Tschernich H, Weber T, Zimpfer M. Transesophageal echocardiography in anesthesia and intensive care: current situation—indications—future trends. Acta Anaesthesiol Scand Suppl 1997; 111:267–269. 115. Gorcsan J, III, Strum DP, Mandarino WA, Gulati VK, Pinsky MR. Quantitative assessment of alterations in regional left ventricular contractility with color-coded tissue Doppler echocardiography. Comparison with sonomicrometry and pressure-volume relations. Circulation 1997; 95:2423–2433. 116. Smith MD, MacPhail B, Harrison MR, Lenhoff SJ, DeMaria AN. Value and limitations of transesophageal echocardiography in determination of left ventricular volumes and ejection fraction. J Am Coll Cardiol 1992; 19:1213–1222.
Invasive and Noninvasive Assessment
735
117. Hozumi T, Shakudo M, Shah PM. Quantitation of left ventricular volumes and ejection fraction by biplane transesophageal echocardiography. Am J Cardiol 1993; 72:356–359. 118. Perez JE, Waggoner AD, Barzilai B, Melton HE Jr, Miller JG, Sobel BE. On-line assessment of ventricular function by automatic boundary detection and ultrasonic backscatter imaging. J Am Coll Cardiol 1992; 19:313–320. 119. Vandenberg BF, Rath LS, Stuhlmuller P, Melton HE Jr, Skorton DJ. Estimation of left ventricular cavity area with an on-line, semiautomated echocardiographic edge detection system. Circulation 1992; 86:159–166. 120. Gorcsan J, III, Gasior TA, Mandarino WA, Deneault LG, Hattler BG, Pinsky MR. Online estimation of changes in left ventricular stroke volume by transesophageal echocardiographic automated border detection in patients undergoing coronary artery bypass grafting. Am J Cardiol 1993; 72:721–727. 121. Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA. Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventricular function. Anesthesiology 1994; 81:376-387. 122. Katz WE, Gasior TA, Reddy SC, Gorcsan J III. Utility and limitations of biplane transesophageal echocardiographic automated border detection for estimation of left ventricular stroke volume and cardiac output. Am Heart J 1994; 128:389–396. 123. Pinto FJ, Siegel LC, Chenzbraun A, Schnittger I. On-line estimation of cardiac output with a new automated border detection system using transesophageal echocardiography: a preliminary comparison with thermodilution. J Cardiothorac Vasc Anesth 1994; 8:625– 630. 124. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973; 32:314–322. 125. Suga H, Sagawa K. Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 1974; 35:117–126. 126. Glower DD, Spratt JA, Snow ND, Kabas JS, Davis JW, Olsen CO, Tyson GS, Sabiston DC Jr, Rankin JS. Linearity of the Frank-Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 1985; 71:994–1009. 127. Little WC, Cheng CP, Peterson T, Vinten-Johansen J. Response of the left ventricular endsystolic pressure-volume relation in conscious dogs to a wide range of contractile states. Circulation 1988; 78:736–745. 128. Gorcsan J III, Gasior TA, Mandarino WA, Deneault LG, Hattler BG, Pinsky MR. Assessment of the immediate effects of cardiopulmonary bypass on left ventricular performance by on-line pressure-area relations. Circulation 1994; 89:180–190. 129. Gorcsan J III, Morita S, Mandarino WA, Deneault LG, Kawai A, Kormos RL, Griffith BP, Pinsky MR. Two-dimensional echocardiographic automated border detection accurately reflects changes in left ventricular volume. J Am Soc Echocardiogr 1993; 6:482–489. 130. Reich DL, Konstadt SN, Nejat M, Abrams HP, Bucek J. Intraoperative transesophageal echocardiography for the detection of cardiac preload changes induced by transfusion and phlebotomy in pediatric patients. Anesthesiology 1993; 79:10–15. 131. Leung JM, Levine EH. Left ventricular end-systolic cavity obliteration as an estimate of intraoperative hypovolemia. Anesthesiology 1994; 81:1102-1109. 132. Kuecherer HF, Foster E. Hemodynamics by transesophageal echocardiography. Cardiol Clin 1993; 11:475–487. 133. Appleton CP. Doppler assessment of left ventricular diastolic function: the refinements continue [editorial]. J Am Coll Cardiol 1993; 21:1697–1700. 134. Poelaert J, Schmidt C, Colardyn F. Transoesophageal echocardiography in the critically ill. Anaesthesia 1998; 53:55–68. 135. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 1984; 70:657–662. 136. Currie PJ, Seward JB, Chan KL, Fyfe DA, Hagler DJ, Mair DD, Reeder GS, Nishimura RA, Tajik AJ. Continuous wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol 1985; 6: 750–756. 137. Dabestani A, Mahan G, Gardin JM, Takenaka K, Burn C, Allfie A, Henry WL. Evaluation
736
138. 139.
140. 141.
142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153.
154. 155.
Perret et al. of pulmonary artery pressure and resistance by pulsed Doppler echocardiography. Am J Cardiol 1987; 59:662–668. Nishimura RA, Callahan MJ, Schaff HV, Ilstrup DM, Miller FA, Tajik AJ. Noninvasive measurement of cardiac output by continuous-wave Doppler echocardiography: initial experience and review of the literature. Mayo Clin Proc 1984; 59:484–489. Stewart WJ, Jiang L, Mich R, Pandian N, Guerrero JL, Weyman AE. Variable effects of changes in flow rate through the aortic, pulmonary and mitral valves on valve area and flow velocity: impact on quantitative Doppler flow calculations. J Am Coll Cardiol 1985; 6:653–662. Dittmann H, Voelker W, Karsch KR, Seipel L. Influence of sampling site and flow area on cardiac output measurements by Doppler echocardiography. J Am Coll Cardiol 1987; 10:818–823. Bouchard A, Blumlein S, Schiller NB, Schlitt S, Byrd BFD, Ports T, Chatterjee K. Measurement of left ventricular stroke volume using continuous wave Doppler echocardiography of the ascending aorta and M-mode echocardiography of the aortic valve. J Am Coll Cardiol 1987; 9:75–83. Hoit BD, Rashwan M, Watt C, Sahn DJ, Bhargava V. Calculating cardiac output from transmitral volume flow using Doppler and M-mode echocardiography. Am J Cardiol 1988; 62:131–135. Katz WE, Gasior TA, Quinlan JJ, Gorcsan J III. Transgastric continuous-wave Doppler to determine cardiac output. Am J Cardiol 1993; 71:853–857. Stoddard MF, Prince CR, Ammash N, Goad JL, Vogel RL. Pulsed Doppler transesophageal echocardiographic determination of cardiac output in human beings: comparison with thermodilution technique. Am Heart J 1993; 126:956-962. Darmon PL, Hillel Z, Mogtader A, Mindich B, Thys D. Cardiac output by transesophageal echocardiography using continuous-wave Doppler across the aortic valve. Anesthesiology 1994; 80:796–805. Feinberg MS, Hopkins WE, Davila-Roman VG, Barzilai B. Multiplane transesophageal echocardiographic Doppler imaging accurately determines cardiac output measurements in critically ill patients. Chest 1995; 107:769–773. Descorps-Declere A, Smail N, Vigue B, Duranteau J, Mimoz O, Edouard A, Samii K. Transgastric, pulsed Doppler echocardiographic determination of cardiac output. Intens Care Med 1996; 22:34–38. Singh S, Wann LS, Schuchard GH, Klopfenstein HS, Leimgruber PP, Keelan MH Jr, Brooks HL. Right ventricular and right atrial collapse in patients with cardiac tamponade— a combined echocardiographic and hemodynamic study. Circulation 1984; 70:966–971. Beppu S, Tanaka N, Nakatani S, Ikegami K, Kumon K, Miyatake K. Pericardial clot after open heart surgery: its specific localization and haemodynamics. Eur Heart J 1993; 14: 230–234. Kochar GS, Jacobs LE, Kotler MN. Right atrial compression in postoperative cardiac patients: detection by transesophageal echocardiography. J Am Coll Cardiol 1990; 16:511– 516. Catoire P, Orliaguet G, Liu N, Delaunay L, Guerrini P, Beydon L, Bonnet F. Systematic transesophageal echocardiography for detection of mediastinal lesions in patients with multiple injuries. J Trauma 1995; 38:96–102. Vignon P, Rambaud G, Francois B, Preux PM, Lang RM, Gastinne H. Quantification of traumatic hemomediastinum using transesophageal echocardiography: impact on patient management. Chest 1998; 113:1475–1480. Vieillard-Baron A, Qanadli SD, Antakly Y, Fourme T, Loubieres Y, Jardin F, Dubourg O. Transesophageal echocardiography for the diagnosis of pulmonary embolism with acute cor pulmonale: a comparison with radiological procedures. Intens Care Med 1998; 24: 429–433. Gilbert EM, Krueger SK, Murray JL, Renlund DG, O’Connell JB, Gay WA, Bristow MR. Echocardiographic evaluation of potential cardiac transplant donors. J Thorac Cardiovasc Surg 1988; 95:1003–1007. Stoddard MF, Longaker RA. The role of transesophageal echocardiography in cardiac donor screening. Am Heart J 1993; 125:1676–1681.
Invasive and Noninvasive Assessment
737
156. Khoury AF, Afridi I, Quinones MA, Zoghbi WA. Transesophageal echocardiography in critically ill patients: feasibility, safety, and impact on management. Am Heart J 1994; 127:1363–1371. 157. Pearson AC, Castello R, Labovitz AJ. Safety and utility of transesophageal echocardiography in the critically ill patient. Am Heart J 1990; 119:1083–1089. 158. Oh JK, Seward JB, Khandheria BK, Gersh BJ, McGregor CG, Freeman WK, Sinak LJ, Tajik AJ. Transesophageal echocardiography in critically ill patients. Am J Cardiol 1990; 66:1492–1495. 159. Mentec H, Vignon P, Terre S, Cholley B, Roupie E, Legrand P, Lemaire F, Brun-Buisson C. Frequency of bacteremia associated with transesophageal echocardiography in intensive care unit patients: a prospective study of 139 patients. Crit Care Med 1995; 23:1194–1199. 160. Pavlides GS, Hauser AM, Stewart JR, O’Neill WW, Timmis GC. Contribution of transesophageal echocardiography to patient diagnosis and treatment: a prospective analysis. Am Heart J 1990; 120:910–914. 161. Font VE, Obarski TP, Klein AL, Bartlett JC, Nemec JJ, Stewart WJ, Salcedo EE. Transesophageal echocardiography in the critical care unit. Cleve Clin J Med 1991; 58:315– 322. 162. Chenzbraun A, Pinto FJ, Schnittger I. Transesophageal echocardiography in the intensive care unit: impact on diagnosis and decision-making. Clin Cardiol 1994; 17:438–444. 163. Hwang JJ, Shyu KG, Chen JJ, Tseng YZ, Kuan P, Lien WP. Usefulness of transesophageal echocardiography in the treatment of critically ill patients. Chest 1993; 104:861–866. 164. Vignon P, Mentec H, Terre´ S, Gastinne H, Ghe´ret P, Lemaire F. Diagnostic accuracy and therapeutic impact of transthoracic and transesophageal echocardiography in mechanically ventilated patients in the ICU. Chest 1994; 106:1829–1834. 165. Heidenreich PA, Stainback RF, Redberg RF, Schiller NB, Cohen NH, Foster E. Transesophageal echocardiography predicts mortality in critically ill patients with unexplained hypotension. J Am Coll Cardiol 1995; 26:152–158. 166. Alam M. Transesophageal echocardiography in critical care units: Henry Ford Hospital experience and review of the literature. Prog Cardiovasc Dis 1996; 38:315–328. [Review.] 167. Burchell SA, Yu M, Takiguchi SA, Ohta RM, Myers SA. Evaluation of a continuous cardiac output and mixed venous oxygen saturation catheter in critically ill surgical patients. Crit Care Med 1997; 25:388–391. 168. Benjamin E, Griffin K, Leibowitz AB, Manasia A, Oropello JM, Geoffroy V, DelGiudice R, Hufanda J, Rosen S. Goal-directed transesophageal echocardiography performed by intensivists to assess left ventricular function: comparison with pulmonary artery catheterization. J Cardiothorac Vasc Anesth 1998; 12:10–15.
28 Heart–Lung Interactions in Sepsis
SHELDON MAGDER McGill University Health Center Montreal, Quebec, Canada
I.
Definition of Sepsis
Sepsis is a generalized inflammatory response which is a result of exposure to an infectious agent. The agents can be viral, bacterial, fungal, or protozoal. For the purpose of studies, a consensus has been reached on the definition of sepsis. It is defined as being present when an infection is present or suspected and two or more of the following are present: heart rate ⬎90 beats/min; respiratory rate ⬎ 20 breaths/ minute or PaCO2 ⬍ 32 torr; white blood cell count ⬎ 12,000 cells/mm2 or ⬍ 4000 cells/mm2 or ⬎ 10% immature (band) forms; temperature ⬎ 38°C or ⬍ 36°C (79). A generalized inflammatory response can also occur without an inciting infectious agent and the term that is used for this is systemic inflammatory response syndrome (SIRS) (79). Causes include pancreatitis, trauma and bypass surgery (43). Sepsis is an increasingly important problem in hospitalized patients. Reasons for the increase include an aging population, increase use of immunosuppressive therapy, increase use of indwelling catheters, and the greater survival of chronically ill patients. Sepsis causes dysfunction of multiple organs and the cardiac and pulmonary systems are very commonly affected. The effect of sepsis on these systems and their interaction is the subject of the chapter. The generalized inflammatory state of sepsis is triggered by exposure to an inciting agent which acts as an inducer and turns on the immune cascade. The in739
740
Magder
ducers can be non-infectious, including complement products and antibodies to CD14, but are most often the byproducts of infectious agents, including endotoxin, from gram-negative organisms; enterotoxin and toxic shock syndrome toxin from gram-positive organisms; and cell components from mycobacteria. The bestworked-out process is that which occurs with exposure to gram-negative bacteria. The lipopolysaccharide coat (LPS) of these bacteria, called endotoxin, triggers the process. As so eloquently said by Lewis Thomas, quoted by R. Ulevitch (1): ‘‘It is the information carried by the bacteria that we cannot abide. The Gram-negative bacteria are the best examples of this. They display lipopolysaccharide endotoxin in their walls, and these macromolecules are read by our tissues as the very worst of bad news. When we sense lipopolysaccharide, we are likely to turn on every defence at our disposal. . . .’’ LPS can be isolated and injected into animals or even humans (2) to determine the mechanism of septic shock. This experimental approach also allows the precise time of the inciting event. LPS itself is not intrinsically toxic, but functions as a warning signal to the host to synthesize a plethora of pro-inflammatory substances. Although LPS can directly activate compliment and start the immune cascade (2), the more important mechanism of activation by LPS is probably through the binding of LPS with an LPS binding protein (LPB) which acts as an opsonin and presents LPS to both a cell membrane form and a soluble form of CD14 (3,4). When LPS binds to membrane CD14, monocytes/ macrophages/polymorphonuclear leukocytes/ lymphocytes are activated and the soluble receptor activates endothelial/epithelial cells. The receptors responsible for this activation have recently been identified as members of the Toll family which are characterized by leucine-rich repeats (1). Mutations in these receptors in mice make them resistant to endotoxin. These receptors also transduce the actions of Il-1 and activate NF-KB, a nuclear binding factor. Besides there being an inflammatory cascade, it is becoming increasing apparent that there is also an anti-inflammatory cascade which is necessary to regulate and eventually turn off the pro-inflammatory process (5–8). The time course and relative magnitudes of the these two events are crucial, for if the anti-inflammatory component is insufficient, the inflammatory process will be uncontrolled and multisystem organ damage will be increased. On the other hand, if the anti-inflammatory process is excessive, the host response to the invading antigens will be inadequate and the infectious process will be uncontrolled. Gram-positive bacteria and gram-negative organisms are equally effective in triggering the inflammatory response and also act through cell membrane proteins such as exotoxin (9,10). Viral and fungal organisms can trigger the process through reactions of their proteins with immune cells. These presumably act as an antigenic stimulus which begins the response from immunomodulatory cells and also activates complement. An early part of the process is the release of tumor necrosis factor alpha (TNFα), which triggers the inflammatory cascade by releasing other cytokines (10– 12). There is also activation of procoagulant and anticoagulant pathways (13). The inflammatory cytokines, in turn, trigger the release of a large number of modulators of the immune system. These include the leukotrines, prostaglandins, platelet activating factor (PAF), complement products (14,15), nitric oxide (NO) (16), and oxy-
Heart-Lung Interactions in Sepsis
741
gen radicals. These affect the production of adhesion molecules (17) and nuclear binding proteins (18), which trigger the production of mediators of the inflammatory process. These mediators cause cell injury and dysfunction of multiple organs including failure of the respiratory system, failure of cardiovascular homeostasis, renal failure, hepatic failure, failure of regulation of thrombolytic and thrombotic mechanisms, and altered neurological function. Two major organ systems involved in the injury of sepsis are the pulmonary and cardiovascular system, and the consequence of these injuries is amplified by the interaction of these two systems. This will be discussed next.
II. Cardiovascular and Pulmonary Responses to Sepsis The cardiovascular response to sepsis is most often characterized by an increase in cardiac output and decrease in blood pressure, which means that systemic vascular resistance is decreased (19–21). The increase in cardiac output is found in both survivors and nonsurvivors (10,22,23). An increased heart rate and low systemic vascular resistance predict a worse outcome (20). The time course of events in human endotoxemia was well described by Suffredini et al., who gave a small dose of endotoxin to normal human volunteers (24). By 30 min, there was an increase in cardiac output but no change in blood pressure. After 60 min, the blood pressure fell and there was a further increase in cardiac output. The characteristic fall of systemic vascular resistance was present by 60 min. In the late stage of sepsis, particularly in patients with a vulnerable premorbid cardiac status, the cardiac output can decrease instead of increasing, and the fall in arterial pressure is more severe. These patients develop a more severe metabolic acidemia and are particularly difficult to treat. If volume reserves are not adequate, cardiac output will be low even in patients with normal cardiovascular function and in the original descriptions of the septic syndrome, increased cardiac output was only evident after volume resuscitation (19). Despite the increase in cardiac output, cardiovascular injury in sepsis is manifest by a decrease in overall function and cardiac dilatation (23,25). Thus, if maximum cardiac function is studied, for example, by examining the contractile response of an isolated papillary muscle or the response to volume infusion (25), depression of cardiac function is evident. However, in the clinical situation, maximal function of the heart is not what matters. Maximal function is only significant when examing maximal aerobic performance. What is important clinically is whether the cardiac output is adequate for the metabolic needs. The actual cardiac output, rather than the maximal cardiac output, is dependent upon the potential reserves of the heart, the degree of neural humeral stimulation and the interaction with the circuit. Thus, in vivo, cardiac output can be increased even though peak function is decreased. Interestingly, patients who have dilated hearts with sepsis have a better outcome than patients whose hearts do not dilate (10,23). In septic patients, there is a loss of vascular tone with a consequent fall in blood pressure. Not only is blood pressure decreased, but the responsiveness to
742
Magder
catecholamines is also decreased (26–32). This is evident in animals within the first hour of exposure to endotoxin. The mechanism for this is still unknown. Nitric oxide synthase inhibitors restore responsiveness, even in animals which do not have a large iNOS induction (26). Prostaglandin inhibitors do not correct the hypotension (33,34). There does not seem to be a problem with receptor affinity (35) which presumably means that there is a defect in cell signaling, but specific defects have not been established. Tissue perfusion is also affected by microvascular abnormalities including decreased capillary density (36), decreased microvascular perfusion (37), and decreased endothelial-dependent vasodilatation. Another important part of the cardiovascular response is an increase in capillary permeability which leads to increased interstitial fluid (14,15,38,39). This is a major factor in the pulmonary injury, for increased interstitial edema in the lungs impairs gas exchange and results in hypoxemia. The inflammatory process activates neutrophils and thrombotic mechanisms which leads to plugging of the pulmonary vasculature (40). In conjunction with vasoactive agents, such as thromboxane A2 and endothelin (41–43), there is an increase in pulmonary arterial pressure (44). Pulmonary vasoconstriction and obstruction leads to maldistribution of pulmonary blood flow relative to ventilation. This leads to both hypoxemia and, very commonly, increased physiological dead space. Sepsis also alters oxidative metabolism which leads to increased lactic acid production (45). Whether this is due to a mismatch between oxygen delivery to the tissues and tissue oxygen needs (i.e., anemia, hypoxia, and stagnant hypoxia) or abnormal mitochondrial function (i.e., cytopathic hypoxia) is still debated (46), but the net result is an increase in acidemia. The increased acidosis, as well as increased carbon dioxide production from increased oxygen consumption, increases respiratory drive (47,48). There is also an important direct effect of endotoxin on the respiratory center, which produces an increase in ventilation with increases in both respiratory rate and volume. Thus, sepsis is an important differential diagnosis in a patient with respiratory alkalosis. The increase in pulmonary interstitial edema decreases lung compliance (49) and increases airway resistance (50), which means that pleural pressure swings must be larger to maintain adequate ventilation. Respiratory muscle work is thus increased, and this increase in energy demands for each breath which is compounded by the overall increase in total ventilatory requirements. Consequently, the need for respiratory muscle blood flow is greatly increased (51). If the flow cannot meet the needs of the working muscle, respiratory muscle failure will occur. In this chapter I will review the impact of the interaction of changes in cardiovascular function on pulmonary function and the impact of changes in pulmonary function on cardiovascular function.
III. Mechanism of High Cardiac Output The characteristic cardiovascular observation in sepsis is a rise in cardiac output, fall in blood pressure and low systemic vascular resistance (19,21,52). The cardiac output can rise to ⬎ 10 L/min. To understand the possible mechanisms for this
Heart-Lung Interactions in Sepsis
743
marked increase in cardiac output, it is necessary to review the principles of the control of cardiac output. These are reviewed in detail in Chapter 5, but a number of points need to be re-emphasized. As discussed in Chapter 5, the circulation can be considered to be composed of an arterial resistance in series with capillaries, in series with a large venous compliant region, which drains through a venous resistance back to the heart. The normal total blood volume is ⬃ 5.5 L for a 70-kg man, and ⬃ 70% of this volume is in small venules and veins, which comprise the largest part of the compliance of the circulation. Only 30% of the total blood volume distends the walls of the vessels and produces pressure (53). The volume that produces pressure in vessels is called stressed volume and the volume which does not distend vessels, but is necessary to fill vessels so that they are round, is called unstressed volume. Total volume for total pressure is called capacitance, whereas the change in volume for change in pressure is called compliance (53). In a 70-kg man, the stressed volume is ⬃ 1.3 L and the pressure in the compliant region is ⬃ 8 mm Hg (54). When there is no flow in the system, the pressure is the same in all vessels and equal to the pressure in the compliant region. Flow begins when the outflow pressure from the compliant region is less than the pressure in the compliant veins. The blood that empties from the veins is pumped back to the compliant region in the veins and venules by the heart. It needs to be appreciated that this outflow from the compliant venules and veins is not determined by the arterial pressure or inflow. This is because the volume in the compliant region is very large relative to the volume in the heart and arteries. In Chapter 5 this is referred to as the ‘‘bathtub’’ analogy. When a bathtub is filled, the water flowing out of it is not affected over the short run by turning off the inflow. The outflow is dependent upon the height of the water in the tub and the drainage characteristics of the tub. The inflow only affects the outflow by raising the level of fluid in the tub, and since the surface is so large, this takes time to occur. Similarly, arterial pressure and inflow to the compliant veins have little effect on the outflow from the small veins and venules. The only way arterial pressure affects the outflow from the compliant region is by affecting the afterload on the left ventricle which affects the pumping ability of the heart. Based on this analysis, how then does cardiac output reach such high levels during sepsis? An initial thought might be that the marked decrease in arterial resistance that occurs in sepsis (55) results in a decrease in afterload on the heart and contributes to the increase in cardiac output. This is unlikely to be the explanation. First, for this to be the mechanism, there would have to be a decrease in right atrial pressure to allow an increase in venous return. This is because the way a decrease in afterload improves cardiac output is by improving cardiac function. This shifts the cardiac function curve upward so that there is a higher cardiac output at any given right atrial pressure. The left and then right atrial pressure falls, which increases the gradient for venous return. However, what is usually observed in sepsis is that right atrial pressure does not change, or more often increases in septic patients with an increased cardiac output (24,44). In these patients, the increase in cardiac output cannot be simply related to the decrease in afterload. Second, although the systemic vascular resistance goes down in sepsis, pulmonary vascular resistance goes up
744
Magder
(20,44) and this is the load faced by the right ventricle. This will actually shift the cardiac function curve downward and result in a higher right atrial pressure and lower cardiac output. Since the left ventricle can only pump out what the right ventricle gives it, an increase in left ventricular function from a decrease in afterload on the left heart, combined with decreased right ventricular function from increased afterload on the right heart, will not increase cardiac output. Third, a change in cardiac function can only increase cardiac output if the right atrial pressure starts above the venous collapse pressure. As discussed above, the heart increases cardiac output by lowering right atrial, and the maximum effect occurs with venous collapse which occurs when the transmural pressure of the large veins is less than the surrounding pressure. If the right atrial pressure is not very high to begin with, then a pure increase in cardiac function can only produce a small increase in cardiac output. It next may be considered that perhaps cardiac contractility is increased in sepsis and this results in increased cardiac output and blood flow. As in the discussion above on the effect of afterload, this can only increase cardiac output by decreasing right atrial pressure, which is usually not observed. It would also require a very high initial right atrial pressure which is usually not observed. Furthermore, cardiac function is usually decreased in sepsis rather than increased. (Note, one must distinguish cardiac output, i.e., a specific value, from cardiac function, which represents a set of values for a given heart rate, contractility, and afterload.) Thus, the increase in cardiac output in sepsis must be due to a substantial increase in the factors which affect venous return, and the increase in cardiac output occurs because the heart responds to this increase in filling through the Frank-Starling mechanism or through an increase in contractility from circulating catecholamines. Venous return is determined by stressed volume, venous compliance, venous resistance, and right atrial pressure. As already discussed, the right atrial pressure is regulated by the heart. Since another hallmark of sepsis is increased capillary filtration, sepsis is most often associated with a fall in stressed volume. Furthermore, in sepsis there is a loss of venous tone which increases capacitance, and this will also decrease stressed volume by shifting stressed volume to unstressed volume (56). Clinicians usually compensate for this by giving exogenous volume during resuscitation, and in a porcine model of sepsis we found that when we gave more resuscitation volume than necessary (56) to maintain right atrial pressure constant, we produced an increase in cardiac output. Suffredini et al. in their studies of human endotoxemia also found that cardiac output rose more in endotoxic subjects when they infused volume (24). Of importance, however, they found that the cardiac output increased even without fluid resuscitation; therefore, volume infusion is not necessary for the increase in venous return and cardiac output of sepsis. This point should be kept in mind by clinicians. When one sees an unexpected increase in cardiac output in a patient, even without a fall in blood pressure, early sepsis should be considered. An increase in venous return and cardiac output could theoretically also be due to a decrease in venous compliance. This would result in a higher venous pressure for a given volume which would increase venous outflow. We found that the compliance
Heart-Lung Interactions in Sepsis
745
of the splanchnic bed decreased with endotoxemia in dogs and speculated that this was due to edema in the splanchnic region (57). This could contribute to the increase in cardiac output, but probably requires very severe edema. Although it has not been well established experimentally, the most likely factor to explain the large increase in venous return in sepsis is a decrease in venous resistance. The reason why this has probably not been shown experimentally in animal models is that most animal models do not have a high cardiac output during sepsis. However, without changes in stressed vascular volume, venous compliance or right atrial pressure, there is really no other possible mechanism for the large increase in cardiac output other than a large decrease in venous resistance. In our own studies, we were unable to show a significant decrease in resistance in the overall group of animals, but the animals that manifested the largest increases in cardiac output had a fall in venous resistance. A possible location for the decrease in venous resistance is a potential sphincterlike mechanism in the venous drainage of the splanchnic bed. There might also be a generalized decrease in venous tone. Besides arising from a decrease in venous tone, an effective decrease in venous resistance could occur by the redistribution of blood flow from the compliant splanchnic to the non splanchnic, noncompliant beds of the periphery and muscles (58). Cardiac output increases with this mechanism because the shift in the fraction of blood flow to the noncompliant beds increases the venous pressure in that region which then results in an increase in outflow. We examined this possibility in septic dogs and found no change in distribution of flow (57). Even though these animals do not develop a high output state, further calculations based on the two compartment model showed ⬎ 90% of the flow would have had to go to the muscle bed to increase cardiac output to the levels seen in sepsis, and this has never been documented in any animal studies in which the distribution of blood flow in sepsis has been examined. A large increase in circuit function, i.e., increase in venous return curve, results in a large increase in the filling pressure of the heart. Circuit function also improves during normal exercise, but in exercise, improved circuit function is matched by an increase in cardiac function, and right atrial pressure does not change (59) (Fig. 1). However, in sepsis, local rather than central mechanisms alter circuit function and produce venodilatation and there is no coordination between cardiac function and circuit function. There is often a large increase in right atrial pressure in sepsis, because heart function does not increase to match circuit function. The increased filling of the heart can lead to a limitation of cardiac filling by the pericardium or the cardiac cytoskeleton. This produces an apparent compliance problem in the heart or ‘‘diastolic dysfunction.’’ In reality, this decrease in compliance is due to contractile function which is inadequate to match the increase in venous return and the heart fails to keep up with the return. Thus, diastolic volume is on the steep part of the passive filling curve of the heart. It does not mean that there is actually diastolic dysfunction, but this also still could be present. We attempted to determine if venous resistance is decreased in sepsis by studying a porcine model of endotoxemia. In these studies, pigs were given 20 µg of endotoxin over a 2-hour period (56). They developed hypotension after 90 min and
746
Magder
Figure 1 Comparison of the changes in cardiac and circuit function with exercise and sepsis. Cardiac output starts at (a) at the intersection of the cardiac function and circuit function. A decrease in venous resistance (c) or a decrease in incapacitance and increase in MCFP (d), combined with an increase in cardiac function, leads to a rise in cardiac output (Q) and no change in right atrial pressure (Pra) (b). In sepsis the same change in venous resistance (c) or change in mean circulatory filling pressure from either volume or capacitance change (d) leads to either a small change or no change in cardiac output (Q) and increase in Pra (∆pra) (b). There is no change in Pra during exercise because the change in cardiac function is matched to the change in circuit function, whereas Pra rises in sepsis because of the lack of this matching.
had a small increase in cardiac output and thus a fall in systemic vascular resistance. Unfortunately, like most animal models, the increase in cardiac output was only very modest. However, the model still gave some insight into the processes involved in sepsis. In these studies, we transiently arrested the circulation by inflating a balloon in the right atrium so that we could measure mean circulatory filling pressure (MCFP) and obtain venous return curves. We also measured total blood volume with a dye dilution technique and gave volume boluses so that we could construct the pressure-volume relationship of the vasculature and measure vascular compliance and capacitance. In our initial studies, we gave sufficient volume to try to keep right atrial pressure between 3 and 4 mm Hg so that we could control the outflow pressure for venous return. We found that within 2 hours of endotoxemia, the pressure-volume curve of the vasculature was shifted to the right, indicating an increase in unstressed volume and thus an increase in capacitance (Fig. 2). However, the volume we used for resuscitation was in excess of needs, so that stressed volume increased and MCFP rose. This shifted the venous return curve in parallel to the right and there was no change in the slope, i.e., the venous resistance. Cardiac function remained the same or tended to increase so that the increase in venous return resulted in a greater preload. The cardiac output thus increased simply due to the volume given. We next reasoned that if we had not given the volume to maintain right atrial pressure constant, MCFP would have fallen because of the increase in
Heart-Lung Interactions in Sepsis
747
Figure 2 Pressure volume and cardiac function and venous return curves in volume-resuscitated (left) and non-volume-resuscitated (right) animals. The upper part of the figure shows the pressure-volume relationship as given by the mean circulatory filling pressure (MCFP) plotted against volume. The dotted lines represent the septic conditions. In septic animals, the capacitance curve shifted to the right, but MCFP rose because of the volume given. The bottom part of the figure shows the venous return and cardiac function curves (Q ⫽ flow; Pra ⫽ right atrial pressure). The increase in MCFP shifted the venous return curve to the right. There was slight or no change in the cardiac function so that both Pra and Q rose. In the non-volume-resuscitated animals, the capacitance increased less than in volume-resuscitated animals, but MCFP still fell. In the bottom part of the figure, the venous return curve shifted to the left and there was a surprisingly marked decrease in cardiac function so that Q fell with little change in Pra. (From Ref. 56.)
capacitance. The venous return curve would then have shifted to the left, and cardiac output should have fallen markedly. We therefore studied another set of animals, which did not receive volume resuscitation. As before, capacitance increased, but not as much as in the volume resuscitated animals. There was a tendency for venous resistance to increase but, most importantly and unexpectedly, there was a marked flattening of the cardiac function curve. The interaction of the circuit function and decrease in cardiac function resulted in no change in right atrial pressure even though the animals were not given volume. A likely explanation for the marked fall in cardiac function was that these animals had a greater fall in blood pressure than occurred in volume resuscitated animals and this could have compromised coronary flow. There likely was also a greater neurohumeral response to the larger fall in arterial pressure. Thus, adequate volume resuscitation resulted in prevention of cardiac depression by a mechanism which was not simply due to the mechanical filling of vascular structures.
748
Magder
We next hypothesized that the depression in cardiac function in the non-volume-resuscitated group was because of the neuro humeral responses and increased catecholamine release (33). To test this, we performed spinal section at the level of the second cervical vertebra to eliminate sympathetic activation and again gave endotoxin. To our surprise the increase in venous resistance with the administration of endotoxin was even greater than what we saw in nonsympathectomized animals, and the cardiac output was lower (Fig. 3). We had predicted exactly the opposite— a fall in venous resistance without activation of neurosympathetic pathways. We measured serum levels of endothelin in these animals (33,60) and found it to be markedly elevated, which suggests that it could be a possible cause of the increase in venous resistance. However, there would also have to be something that prevented this vasoconstriction in the intact animals. We speculated that spinal section results in the loss of the normal β-adrenergic tone which could be important because βagonists decrease venous resistance (61,62). Thus, if there is no β-adrenergic activity, vasoconstrictor forces are not balanced by vasodilating forces, and a mixed adrenergic agonist results in constriction. From these studies, it is clear that adequate volume resuscitation is essential for the maintenance of normal vascular function, and a certain amount of adrenergic activity is also beneficial. These studies also indicate that the role of volume is not simply to act in a mechanical way by filling the compliant veins or providing preload to the heart, but volume also seems to act by creating a stabler neuro humeral balance within the cardiovascular system. A. Effect of Septic Lungs on Cardiovascular Function
A marked decrease in the resistance to venous return results in much larger swings in cardiac output with the changes in pleural pressure. This is because the steeper
Figure 3 Venous return curves (left) and cardiac function curves at baseline (control, 䊊 —), after spinal section (■ -----) and after endotoxin infusion (䉲 and ⋅ ⋅ ⋅). There was a small increase in MCFP with spinal section (x intercept). When endotoxin was infused, venous resistance (slope of venous return curve) increased and there was a further small increase in MCFP. The cardiac output was significantly decreased (∗). The cardiac function curves are shown on the right side. There was no change in cardiac function in the three conditions. (From Ref. 33.)
Heart-Lung Interactions in Sepsis
749
the slope of the venous return curve, the greater the effect of a change in position of the cardiac function curve. An increase in pleural pressure shifts the cardiac function curve to the right (63) and a decrease in pleural pressure shifts the cardiac function curve to the left. In the spontaneously breathing patient who uses negative pleural pressure to expand the lungs, a decrease in lung compliance, or increase in respiratory airway resistance with sepsis, will mean that a larger fall in pleural pressure is required for any given change in lung volume. This will result in a greater shift in the position of the cardiac function curve relative to the venous return curve with each breath. When this is combined with the steeper slope of the venous return curve, the fluctuations in cardiac output will be further increased (Fig. 4). Very often, septic patients also have recruitment of abdominal muscles and forced expiration which result in a rise in pleural pressure during the expiratory phase of respiration. This causes a shift in the cardiac function curve to the right and there can be then an even larger swing between end inspiration and end expiration with very large phasic changes in the stroke volume. These changes in cardiac output with the respiratory cycle only occur when the venous return curve intersects the as-
Figure 4 Effect of a change in slope on the respiratory interactions of cardiac function and venous return. A decrease in pleural pressure (Ppl) shifts the cardiac function curve to the left (— — —) relative to the venous return curve, and an increase in pleural pressure shifts the cardiac function ( -----) to the right of the venous return curve. With the initial venous resistance, the decrease in Ppl produces a small increase in cardiac output (A → B), and an increase in Ppl produces a decrease in cardiac output (A → C). When venous resistance is decreased, a decrease in Ppl produces a larger increase in cardiac output (A′ → B′) and an increase in Ppl produces a large decrease (A′ → C′) so that the total respiratory change (⇒) is much larger with a low RVR than a high RVR.
750
Magder
cending part of the cardiac function curve. When it intersects the flat part of the cardiac function curve, there are fluctuations in the right atrial pressure and transmural pressure of the right heart but no change in cardiac output (Fig. 5). When the patient goes into respiratory failure and positive pressure ventilation is begun, there is a decrease in the gradient for venous return. Once again, this effect will be greater in patients with a low venous resistance and steeper slope to the venous return curve. This increase in pleural pressure needs to be compensated for by an increase in stressed vascular volume which increases MCFP. Stressed volume can be increased through the patient’s own reflex mechanisms if there is a sufficient volume reserve in the region of the venous capacitance. However, if catecholamine levels are already increased, then some unstressed volume may already have been recruited. Stressed volume can also be augmented by the administration of volume to the patient, as is common clinical practice. In both cases, an increase in MCFP by an increase in stressed volume results in an increase in the upstream capillary pressure. In septic patients with leaky capillaries, this increase in volume often has only a transient benefit, for the increase in capillary pressure means that capillary hydrostatic pressure is increased and this increases capillary filtration and volume loss. Thus, the need for a higher MCFP to maintain cardiac output in sepsis and the
Figure 5 Significance of the plateau of the cardiac function curve. In A, a shift in the venous return curve from a → b produces a small increase in cardiac output but further shifts from b → c and c → d produce no further change in cardiac output, although the right atrial pressure (Pra) rises. In B the significance of this is shown for changes in cardiac function. An increase in afterload, as occurs with a rise in pulmonary pressures, depresses the cardiac function curve (a → b). If the venous return curve intersects the ascending part of the cardiac function curve, a shift to the right of the venous return curve can compensate for the afterload. However, when the venous return curve intersects the plateau of the cardiac function curve, an increase in afterload will result in a decrease in cardiac output (a → b) which cannot be compensated by change in the venous return curve. Only an increase in contractility (b → a) or (a → c) can increase cardiac output.
Heart-Lung Interactions in Sepsis
751
consequent increase in capillary pressure means that the volume requirements can be expected to increase in septic patients who are mechanically ventilated. When administering volume to septic patients, it is important to consider whether the heart is functioning on the flat part of the cardiac function curve. Once the plateau of the cardiac function curve is reached, further volume loading does not increase cardiac output (Fig. 5). This point must be kept in mind, for too often septic patients are infused with large volumes for resuscitation which only increases right atrial pressure and does not change cardiac output. For a dramatic example, see Taveira da Silva et al. (64). The rise in venous pressures results in a rise in capillary pressure, which rapidly dissipates the fluid into the interstitial space, and the patients become severely edematous without any benefit to their cardiovascular system. A common observation in septic patients is an increase in pulmonary artery pressure (20,44). This increases the afterload on the right ventricle. The presence of increased afterload on the right ventricle means that more preload is needed for a given level of contractility to maintain the same cardiac output. If the heart is already functioning on the flat part of the cardiac function curve, an increase in preload will not increase cardiac output, and cardiac output will fall when the afterload is increased, unless there is also a compensatory increase in contractility. Thus, fluid administration will not increase cardiac output, and attempts to increase cardiac output by giving more fluid will simply overdistend the right heart. This will decrease coronary flow, distort the left ventricle (65,66) and decrease overall cardiac function. When contractility cannot be increased, cardiac output can only be increased by decreasing pulmonary artery pressure (Fig. 5). The right atrial pressure is often increased in septic patients because of the infusion of exogenous volume as part of the resuscitation and by volume retention by the kidneys. This provides a greater preload to increase cardiac output by the Frank-Starling mechanism. The rise in venous volume, however, leads to a rise in pressure in the venous compliant region and a rise in hydrostatic pressure in the upstream capillaries, which is the pressure that determines capillary filtration. Thus, when the venous return curve intersects the plateau of the right heart function curve, further volume loading only increases capillary leak and does not change cardiac output. It also compromises left heart function (65). It is thus important at the bedside to determine if the heart will respond to further increases in preload, i.e., is on the ascending portion of the cardiac function curve. This can be assessed by rapidly (i.e., ⬍ 10 min) infusing a bolus of fluid sufficient to raise the right atrial pressure by approximately 2 mm Hg and then determining whether cardiac output increased. If it did, this indicates that the patient is volume sensitive and further volume loading will increase, or at least maintain, cardiac output, if this is desired. If there was no increase in cardiac output, further volume loading will not be of help. Pulmonary artery pressure can be increased because of an increase in pulmonary vascular resistance or because of an increase in the critical closing pressure in the pulmonary vasculature (67). Although this has not been studied extensively, we found that the increase of pulmonary artery pressure in septic pigs was largely due
752
Magder
to an increase in the critical closing pressure (56). The importance of this is that when pulmonary artery pressure is increased due to an increase in critical closing pressure, changes in flow will have a smaller effect on pulmonary artery pressure than occurs when pulmonary vascular resistance is increased. B. Effects of the Septic Heart on the Lungs
One of the major effects of sepsis on the cardiovascular system is a decrease in cardiac function (68). When this is combined with increased venous return, an increase in the filling pressures of the heart results. Both ventricles are affected with a similar direction and pattern of dysfunction (69). Characteristically, there is dilatation of the ventricles and a fall in ejection fraction and rise in heart rate (10,22). The ejection fraction and end-diastolic volume return to normal with recovery. Interestingly, nonsurvivors do not have as much dilatation of their left ventricle as survivors. No good explanation has been given for this, but one possibility is that the nonsurvivors have more severe right heart dysfunction which limits the volume which gets to the left ventricle. There thus can be no left side failure without right sided success. A rise in left atrial pressure with left ventricular dysfunction results in a rise in pulmonary capillary pressure. This has a major impact on the lungs in sepsis because capillary permeability is usually increased. This means that a given change in hydrostatic pressure has a much greater impact on the net filtration by the pulmonary capillaries. The net efflux of fluid is made even worse by the decrease in oncotic pressure, which occurs because of a decrease in albumin as part of the acute phase reaction. An important part of managing septic patients is thus to keep the pulmonary capillary pressures low so that pulmonary edema is minimized, while still maintaining adequate cardiac preload to maintain cardiac output. Whether because of inadequate oxygen delivery, effective systemic shunts or decreased mitochondrial function and impaired oxygen extraction, sepsis is characterized by signs of tissue hypoxemia including increased lactate and acidemia (46,70). The hypermetabolic state associated with sepsis also increases oxygen consumption, which increases carbon dioxide production. This results in a considerable increase in the load on the respiratory system (51,71,72). In addition, endotoxin has a direct effect on the respiratory center and increases the drive to breathe. This increased work by the respiratory muscles requires increased blood flow to provide adequate oxygen delivery, and this occurs through vasodilatation of the vessels in the respiratory muscles (73). However, when cardiac output cannot be increased to meet the needs of the muscles, and the blood pressure is already low, respiratory muscle blood flow becomes limited. When the respiratory muscle blood cannot match the metabolic needs of the tissue, respiratory muscles fail, and in nonventilated patients, respiratory muscle failure is the most common cause of death in severe sepsis (51). This can occur without a warning rise in PCO2. As the respiratory muscles fail, PO2 usually falls too because of alveolar collapse and ventilation/perfusion mismatching. Hypoxemia combined with decreased blood flow leads to further impairment of cardiovascular function, which leads to a further decrease in oxygen
Heart-Lung Interactions in Sepsis
753
delivery and worsening of the gas exchange. This positive feedback means that patients can deteriorate very rapidly. It also seems that sepsis directly impairs the function of the respiratory muscles and fatigue develops more rapidly than in normal muscles, which further compounds the problem (74). The clinical implication of this is that intubation and ventilatory support should not be delayed in a septic patient with low blood pressure, decreased sensorium, and high ventilatory rate who still has a normal or low PCO2. The severity of the septic state should dictate the need for intubation and not the arterial blood gases. It has been shown that ventilatory support of septic animals increases blood flow to other vital organs, including the brain (73). This was initially thought to be because the working respiratory muscles during sepsis steal blood from other vital organs. Artificial ventilation and paralysis was then thought to decrease the respiratory work, decrease respiratory muscle blood flow, and leave more blood flow available for other organs (73). Further studies, however, suggest that part of the redistribution of blood flow away from the nonrespiratory muscles and vital organs is because of increased afferent activity from the nerves in the working muscle (71,75) (see Chapter 15). This increase in afferent activity is due to mechanical and chemical signals in the muscle and leads to an increased drive to breathe as well as increased sympathetic activation (76,77). This increased sympathetic activity then decreases blood flow to the kidney, splanchnic bed, and even the brain. The reduction of the respiratory effort results in a decrease in this signal and less redistribution of flow away from these vital organs.
C. Implications for Treatment
Fluid Management
One of the commonest manifestations of sepsis is an increase in the alveolar-arterial oxygen gradient due to pulmonary edema which is due to increased capillary leak. Because the pulmonary edema is due to increased leak, it is more sensitive to pulmonary capillary hydrostatic pressures than under normal conditions. Thus, careful regulation of volume status and avoidance of high pulmonary capillary wedge pressures can reduce lung edema. Protection of the lungs has to be balanced with the need to maintain adequate preload for cardiac output, especially considering that the cardiac function is decreased. However, as discussed above, once the cardiac function curve intersects the plateau of the venous return curve, further volume loading will not increase cardiac output and will only increase capillary pressures and worsen pulmonary edema. Since blood pressure is approximately equal to the cardiac output times the systemic vascular resistance (see Chapter 5), the hypotension of sepsis can be corrected by increasing cardiac output or increasing the systemic vascular resistance. Volume infusion increases the blood pressure by increasing cardiac output, whereas norepinephrine increases blood pressure by raising arterial resistance as well as cardiac output (78). The consequences of raising the blood pressure by volume infusion and increasing cardiac output versus raising systemic vascular resistance are, how-
754
Magder
Figure 6 Different effects on the pressure profile of the vasculature from changes in systemic pressure with volume (fluid) vs. norepinephrine. Systemic pressures are shown starting from the aorta and going to the right atrium (Ra). The pressure at the capillaries is marked with a dotted line. Both fluid and norepinephrine increase the arterial pressure. With fluid, the pressure is increased throughout the vasculature and therefore also rises at the capillary level. With norepinephrine, arterial resistance is increased which results in a greater fall in pressure in the systemic arteries so that the capillary pressure is either unchanged or even possibly decreased compared to baseline.
ever, very different (Fig. 6). When the blood pressure is increased by raising cardiac output alone, the pressure rises throughout the vascular network, including the capillaries. This will increase capillary filtration and contribute to the very large volumes that are often infused in septic patients. If used to excess, marked peripheral and pulmonary edema result. On the other hand, increasing the blood pressure by increasing systemic vascular resistance results in an increase in the resistance proximal to the capillaries. If this is not matched by a proportionately greater increase in venous resistance, capillary hydrostatic pressure and capillary filtration will decrease. This will tend to decrease fluid needs and decrease the development of peripheral and pulmonary edema. Pharmacological Agents Norepinephrine
Norepinephrine, which has both α- and β-agonist properties, has multiple cardiovascular effects which make it a very effective drug for the treatment of the hypotension of sepsis (26). Its α agonist activity results in an increase in arterial resistance which restores arterial pressure. As discussed above, increasing arterial pressure by increasing arterial resistance, can potentially decrease capillary pressure and decrease capil-
Heart-Lung Interactions in Sepsis
755
lary filtration (26). Of importance, norepinephrine has little effect on the pulmonary arteries and therefore does not increase right ventricular load. Stimulation of αadrenergic receptors also causes constriction of capacitance vessels, which increases stressed volume by the recruitment of unstressed volume (79). The action of norepinephrine on β-adrenergic receptors increases cardiac contractility and thereby helps the heart adapt to the increase in venous return (62) that comes from the decrease in capacitance. Beta-adrenergic agonists decrease the resistance to venous return, whereas α-adrenergic agonists increase the resistance to venous return (80). Norepinephrine appears to give a balanced effect with either no change, or even a decrease, in venous resistance. The net effect of norepinephrine on cardiac and circuit function is usually a rise in cardiac output and blood pressure with no change in right atrial pressure. Norepinephrine is much more effective in septic shock than in cardiogenic shock because the primary problem in septic shock is a loss of vascular tone which is restored by norepinephrine. In contrast, in cardiogenic shock, systemic vascular resistance is already high and the capacitance vessels are constricted. Thus, the administration of norepinephrine results in little further recruitment of capacitance volume and may just increase venous resistance. There is little increase in cardiac inotrope in the failing heart, and the further increase in systemic vascular resistance increases the afterload on an already poorly functioning ventricle which makes cardiac function worse. Thus, norepinephrine is far less effective when cardiogenic shock is present. Typical doses in septic patients are 6 to 20 µg/min. Higher doses are often used to maintain blood pressure, but when doses ⬎ 60 to 70 µg/min are necessary, other drugs should be considered. Phenylephrine
Phenylephrine is a pure α-agonist. It might thus seem to be a potentially effective agent to counteract the loss of arterial tone in sepsis. The problems with this agent are that it does not significantly increase cardiac contractility and it stimulates αreceptors on veins but has no β-activity to counteract this constriction. The extent of the rise in the resistance to venous return is dependent upon the ability of the baroreceptor to modulate the response (80). A rise in venous resistance will decrease cardiac output and increase capillary leak. Thus, this is not an ideal first line agent for the treatment of sepsis. An advantage of phenylephrine over norepinephrine is that it can be given through a peripheral line and is therefore an excellent drug for rapid resuscitation. The doses of boluses range from 100 to 1000 µg and the infusion rate is 20 to 200 µg/min. Dopamine
Dopamine is still one of the most popular agents for resuscitating septic patients (81). Dopamine in low doses (⬍ 2.5 µg/kg/min) stimulates dopaminergic receptors. In the kidney, this increases renal blood flow and produces naturesis. This is particularly effective in patients who have adequate volume reserves. Dopamine is often combined with norepinephrine to maintain a naturesis (82,83). At doses of 2.5 to 10 µg/kg/min, dopamine has primarily β-agonist properties and thus functions like dobutamine. Above 10 µg/kg/min, dopamine has primarily
756
Magder
α-agonist properties and has effects which are between those of norepinephrine and phenylephrine (84). Because its effects are variable, I personally prefer to use norepinephrine for vasoconstriction with some contractility actions and use dobutamine or milrinone, a phosphodiesterase inhibitor for cardiac stimulation. Dobutamine
Because cardiac function is decreased in sepsis, it might seem worthwhile to increase cardiac function with a β-agonist such as dobutamine (85–88). In fact, the β-agonist isoproterenol was one of the earliest catecholamines used in septic patients (89). The problem with dobutamine is that it decreases systemic vascular resistance. If the infusion fails to increase the cardiac output, this will decrease blood pressure further and potentially worsen cardiac function because coronary flow will be compromised. This is especially a concern when the load on the right ventricle is increased, although in some patients, dobutamine may decrease pulmonary vascular resistance and therefore decrease the load on the right heart. Thus, although the effects of dobutamine may be helpful in some patients, it must be used very cautiously, and vasopressors should be available to counteract the significant hypertension. The usual dosage range is from 2.5 to 20 µg/kg/min. A possible problem with increasing cardiac output with an agent such as dobutamine is that this can result in an increase in pulmonary shunt and worsen oxygenation. Other side effects of dobutamine include tachycardia, atrial and ventricular arrhythmias, and an increase in oxygen consumption. Adrenaline
Adrenaline has mixed α- and β-agonist properties, especially β 2 . It thus provides a little more inotropic effects than norepinephrine. However, the effects of epinephrine are very dose dependent. In lower doses (2 to 20 µg/min) it has a greater β-agonist effect, but in higher doses the α properties increase in prominence. It thus has a more variable response, somewhat like dopamine, but is less predictable. When tapering this drug, as well as dopamine, there is often a fall in blood pressure because the α effect is lost and the β effects predominate, which can make withdrawal difficult. Thus, norepinephrine is generally easier to titrate than epinephrine, although the impact of a dose of epinephrine is often greater than that of norepinephrine. Milrinone
Milrinone is a phosphodiesterase inhibitor. It acts by decreasing the breakdown of cyclic adenosine monophosphate (AMP) which increases inotrope. The mechanism of increased inotrope action with stimulation of β-receptors is also by an increase in cyclic AMP. Thus, the effects of milrinone are additive to those of β adrenergic drug, for the β-agonist increases cyclic AMP by a receptor-dependent mechanism and milrinone decreases the breakdown of cAMP. The actions of milrinone are much like those of dobutamine, except that it seems to have a greater dilating effect on pulmonary vessels and less effect on heart rate. A disadvantage of milrinone over dobutamine is that it has a longer half-life, and if it results is worsening hypertension, the effect will be present for 2 to 4 hours.
Heart-Lung Interactions in Sepsis
757
Milrinone is given with a loading dose of 0.05 µg/kg over 10 min and then 0.1– 0.5 µg/kg/min. In hypotensive patients, half this dose is often given to start. Nitric Oxide Synthase Inhibitors
There was recently a lot of interest in the effect of blocking nitric oxide synthase (NOS) by increasing blood pressure in septic humans and animals (90–93). The reasoning was based on a large amount of experimental evidence in rats and mice which showed that there is an inducible form of NOS which is expressed in large amounts in the septic animals (32,94). This isoform of NOS produces large amounts of nitric oxide, which is known to be a vascular vasodilator. Subsequently, NOS inhibitors were found to increase blood pressure in many species as well as humans (95). Based on these studies, a large double-blind randomized clinical trial was started to compare the addition of the NOS inhibitor L-nitro-mono methylarginine (LNMMA) to conventional therapy alone. The study was stopped because there was no benefit, or even perhaps a worse outcome, in patients treated with a NOS inhibitor. An important problem with this approach is that iNOS does not appear to play a large role in species of a higher order than rats and mice (96). Blocking NOS results in blockade of the normal constitutive NOS which include endothelial NOS (ecNOS) and neuronal NOS (nNOS). This results in interference with the normal matching of flow to tissue metabolic needs. Inhibition of NOS also results in an increase in the resistance to venous return which decreases cardiac output (97). It also seems to have a direct depressive effect on cardiac function (56). Finally, nitric oxide reduces the production of adhesion molecules by the endothelial membrane (39). Thus, total blockade of NOS may result in an upregulation of adhesions molecules and increased neutrophil attachment to the vessel walls with a consequent increase in inflammatory response (98). Thus, ironically, it might be better to actually slightly increase the amount of nitric oxide. D. Positive-Pressure Ventilation
Since respiratory muscle failure is a common endpoint in septic patients, it is often necessary to support these patients with mechanical ventilation. This results in an increase in intrathoracic pressure. The consequences of this have been covered elsewhere in this chapter, but a few points will be reviewed here. When intrathoracic pressure is increased, the pressure in the capacitant region of the vasculature must rise to maintain the gradient for venous return. Thus, vascular volume needs to be increased when a patient is ventilated with positive pressures. A rise in pressure in the capacitant region results in a rise in pressure in the upstream areas, including the capillaries. This will tend to increase capillary leak. Thus, high intrathoracic pressure should be avoided if possible and may be one of the factors which resulted in the improvement of outcome with the low tidal volume in the recent NIH-supported trial of low versus high tidal volumes in critically ill patients (99). On the positive side, by decreasing the gradient for venous return, the increase in intrathoracic pressure may help decompress an overdistended right ventricle. This could result in less interference of the right ventricle with the left ventricle and
758
Magder
may result in improvement in hemodynamic function (65). Furthermore, the positive pressure may help improve left ventricular ejection (100). Finally, artificially supporting the ventilatory muscles could result in decreased afferent activity and less sympathetic activation as well as less energy consumption by the respiratory muscles which improves the overall balance between energy needs and oxygen consumption (101,102). IV. Summary Sepsis has many effects on the cardiovascular and respiratory systems. The important interaction between these two systems can amplify the harmful effects of sepsis. The interactions of these two systems can be further worsened by the therapies that are used in the treatment of sepsis. Thus, careful consideration of the cardiovascular and respiratory effects of the treatment, as well as their interactions, must be taken into account before considering any therapy for the treatment of septic patients. References 1. Ulevitch RJ. Endotoxin opens the Tollgates to innate immunity. Nature Med 1999; 5:144– 145. 2. Danner RL, Joiner KA, Parillo JE. Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-Lipid X. J Clin Invest 1987, 80:605–612. 3. Raetz CRH, Ulevitch RJ, Wright SD, Sibley CH, Ding A, Nathan CF. Gram-negative endotoxin: an extraordinary lipid with profound effects on eukaryotic signal transduction. FASEB J 1991; 5:2652–2660. 4. Mukaida N, Ishikawa Y, Ikeda N, Fujioka N, Watanabe S, Kuno K, Matsushima K. Novel insight into molecular mechanism of endotoxin shock: biochemical analysis of LPS receptor signaling in a cell-free system targeting NF-kB and regulation of cytokine production/ action through b2 integrin in vivo. J Leukoc Biol 1996; 59:145–151. 5. Ertel W, Kremer J, Kenney J. Down-regulation of proinflammatory cytokine release in whole blood from septic patients. Blood 1995; 85:1341–1347. 6. Hensler T, Heidecke CD, Hecker H. Increased susceptibility to postoperative sepsis in patients with imparied monocyte IL-12 production. J Immunol 1998; 161: 2655–2659. 7. Marie C, Muret J, Fitting C. Reduced ex vivo interleukin-8 production by neutrophils in septic and nonseptic systemic inflammatory response syndrome. Blood 1998; 91:3439– 3446. 8. Van der Poll T, de Waal Malefyt R, Coyle SM, Lowry SF. Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10, and IL-13. J Infect Dis 1997; 175: 118–122. 9. Natanson C, Danner RL, Elin RJ, Hosseini JM, Peart KW, Banks SM, MacVittie TJ, Walker RI, Parrillo JE. Role of endotoxemia in cardiovascular dysfunction and mortality. J Clin Invest 1989; 83:243–251. 10. Parillo JE. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113:227–242. 11. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993; 328:1471– 1477. 12. Rackow EC, Astiz ME. Mechanisms and management of septic shock. Crit Care Clin 1993; 9:219–237. 13. Ziegler EJ. Tumor necrosis factor in humans. N Engl J Med 1988; 318(23):1533–1535.
Heart-Lung Interactions in Sepsis
759
14. Kurose I, Kubes P, Wolf R, Anderson DC, Paulson J, Miyasaka M, Granger DN. Inhbition of nitric oxide production: mechanisms of vascular albumin leakage. Circ Res 1993; 73: 164–171. 15. Kurose I, Wolf R, Grisham MB, Yee Aw T, Specian RD, Granger DN. Microvascular responses to inhibition of nitric oxide production: role of active oxidants. Circ Res 1995; 76:30–39. 16. Busse R, Mulsch A. Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett 1990; 265:133–136. 17. Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 1993; 92:1866–1874. 18. Bohrer H, Qiu F, Zimmermann T, Zhang Y, Jllmer T, Mannel D, Bottiger DM, Stern DM, Waldherr R, Saeger H-D, Ziegler R, Bierhaus A, Martin F, Nawroth PP. Role of NFkB in the mortality of sepsis. J Clin Invest 1997; 100:972–985. 19. Duff JH, Groves AC, McLean APH, LaPointe R, MacLean LD. Defective oxygen consumption in septic shock. Surg Gynecol Obstet 1969; 128:1051–1060. 20. Parker MM, Shelhamer JH, Natanson C, Alling DW, Parillo JE. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med 1987; 15:923–929. 21. Wilson RF, Thal AP, Kindling PH, Grifka T, Akerman E. Hemodynamic measurements in septic shock. Arch Surg 1969; 1965:121–129. 22. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984; 100:483–490. 23. Parker MM, Suffredini AF, Natanson C, Ognibene P, Shelhamer JH, Parillo JE. Responses of left ventricular function in survivors and nonsurvivors of septic shock. J Crit Care 1989; 4:19–25. 24. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. New Engl J Med 1989; 321:280–287. 25. Ognibene FP, Parker MM, Natanson C, Shelhamer JH, Parrillo JE. Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 1988; 93:903–910. 26. Datta P, Magder S. Hemodynamic response to norepinephrine with and without inhibition of nitric oxide synthase in porcine endotoxemia. Am J Respir Crit Care Med. 1999; 160: 1987–1993. 27. Fleming I, Julou-Schaeffer G, Gray GA, Parratt JR, Stoclet JC. Evidence that an Larginine/nitric oxide dependent elevation of tissue cyclic GMP content is involved in depression of vascular reactivity by endotoxin. Br J Pharmacol 1991; 103:1047–1052. 28. Gray GA, Schott C, Julou-Schaeffer G, Fleming I, Parratt JR, Stoclet JC. An investigation of the effect of inhibitors of the L-arginine pathway on endotoxin-induced vascular hyporeactivity in vivo. Br J Pharmacol 1991; 103:1218–1224. 29. Gray GA, Schott C, Julou-Schaeffer G, Fleming I, Parratt JR, Stoclet JC. The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. Br J Pharmacol 1991; 103:1218–1224. 30. Nava E, Palmer MJ, Moncada S. Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet 1991; 338:1555–1557. 31. Nava E, Palmer RMJ, Moncada S. The role of ntiric oxide in endotoxic shock: effects of NG- monomethyl-L-arginine. J Cardiovasc Pharmacol 1992; 20:S132–S134. 32. Szabo C. Alterations in nitric oxide production in various forms of circulatory shock. New Horiz 1995; 3:2–32. 33. Rastegarpanah M, Magder S. Role of sympathetic pathways in the vascular response to sepsis. J Crit Care 1998; 13:169–176. 34. Yamamoto S, Burman HP, O’Donnell CP, Cahill PA, Robotham JL. Endothelin causes portal and pulmonary hypertension in porcine endotoxemic shock. Am J Physiol 1997; 272:H1239–H1249.
760
Magder
35. Suba EA, McKenna TM, Williams TJ. In vivo and in vitro effects of endotoxin on vascular responsiveness to norephinephrine and signal transduction in the rat. Circ Shock 1992; 36: 127–133. 36. Farquhar I, Martin CM, Lam C, Potter R, Ellis CG, Sibbald WJ. Decreased capillary density in vivo in bowel mucosa of rats with normotensive sepsis. J Surg Res 1996; 61:190–196. 37. Lam C, Tyml K, Martin C, Sibbald W. Microvascular perfusion is impaired in a rat model of normotensive sepsis. J Clin Invest. 1994; 94:2077–2083. 38. Brigham KL, Bowers RE, Haynes J. Increased sheep lung vascular permeability caused by Escherichia coli endotoxin. Circ Res 1979; 45:292–297. 39. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992; 31:H611–H615. 40. Sessler CN, Bloomfield GL, Fowler AA. Current concepts of sepsis and acute lung injury. Clin Chest Med 1996; 17:213–235. 41. Owada A, Tomita K, Terada Y, Sakamoto H, Nonoguchi H, Marumo F. Endothelin (ET)-3 stimulates cyclic guanosine 3′,5′-monophosphate production via ETB receptor by producing nitric oxide in isolated rat glomerulus, and in cultured rat mesangial cells. J Clin Invest 1994; 93:556–563. 42. Sugiura M, Inagami T, Kon V. Endotoxin stimulates endothelin-release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun 1989; 161(3): 1220–1227. 43. Voerman HJ, Stehouwer CDA, van Kamp GJ, Strack van Schijndel RJM. Groeneveld ABJ, Thijs LG. Plasma endothelin levels are increased during septic shock. Crit Care Med. 1992; 20:1097–1101. 44. Shoemaker WC, Appel PL, Bishop MH. Temporal patterns of blood volume, hemodynamics, and oxygen transport in pathogenesis and therapy of postoperative adult respiratory distress syndrome. New Horiz 1993; 1:522–537. 45. Parillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993; 328:1471–1477. 46. Schwartz DR, Malhotra A, Fink MP. Cytopathic hypoxia in sepsis: an overview. Sepsis 1998; 2:279–289. 47. Hussain SNA, Abdul-Hussain MN, El-Dwairi Q. Exhaled nitric oxide as a marker for serum nitric oxide concentration in acute endotoxemia. J Crit Care 1996; 11: 167–175. 48. Hussain SNA, Graham R, Rutledge F, Roussos C. Respiratory muscle energetics during endotoxic shock in dogs. J Appl Physiol 1986; 60:486–493. 49. Bates DV. Syndromes of respiratory failure. In: Respiratory Function in Disease, edited by D.V. Bates. Philadelphia: W.B. Saunders Company, 1989, p. 382–386. 50. Marini JJ. Lung mechanics in the adult respiratory distress syndrome. Clin Chest Med 1990; 11:673–690. 51. Hussain SNA, Simkus G, Roussos C. Respiratory muscle fatigue: a cause of ventilatory failure in septic shock. J Appl Physiol 1985; 58:2033–2040. 52. Reemtsma K, Hottinger GC, Degraff AC, Jr, Creech O Jr. The estimation of hepatic blood flow using indocyanine green. Surg Gynecol Obstet 1960; 3:353–356. 53. Rothe CF. Reflex control of veins and vascular capacitance. Physiol Rev 1983; 63(4): 1281–1295. 54. Magder S, De Varennes B. Clinical death and the measurement of stressed vascular volume. Crit Care Med 1998; 26:1061–1064. 55. Hermreck AS, Thal AP. Mechanisms for the high circulatory requirements in sepsis and septic shock. Ann Surg 1969; 170:677–695. 56. Magder S, Vanelli G. Circuit factors in the high cardiac output of sepsis. J Crit Care 1996; 111:155–166. 57. Magder S, Quinn R. Endotoxin and the mechanical properties of the canine peripheral circulation. J Crit Care 1991; 6:81–88. 58. Caldini P, Permutt S, Waddell JA, Riley RL. Effect of epinephrine on pressure, flow, and volume relationships in the systemic circulation of dogs. Circ Res 1974; 34:606–623. 59. Notarius CF, Levy RD, Tully A, Fitchett D, Magder S. Cardiac vs. noncardiac limits to exercise following heart transplantation. Am Heart J 1998; 135: 339–348. 60. Magder S, Javeshghani D, Cernacek P, Giaid A. Differential expression of endothelin in endotoxic pigs—a possible hormonal role. Am J Respir Crit Care Med 1997; 155(4):A930.
Heart-Lung Interactions in Sepsis
761
61. Deschamps A, Magder S. Effects of heat stress on vascular capacitance. Am J Physiol 1994; 266:H2122-H2129. 62. Green JF. Mechanism of action of isoproterenol on venous return. Am J Physiol 1977; 232(2):H152–H156. 63. Guyton AC, Jones CE, Coleman TG. Circulatory Physiology: Cardiac Output and Its Regulation. Philadelphia: W.B. Saunders, 1973. 64. Taveira da Silva AM, Kaulbach FS, Chuidian FS, Lambert DR, Suffredini AF, Danner RL. Brief report: shock and multiple-organ dysfunction after self-administration of salmonella endotoxin. N Engl J Med 1993; 328:1457–1460. 65. Atherton JJ, Moore TD, Lele SS, Thomson HL, Galbrath AJ, Belenkie I, Tyberg JV, Frenneaux MP. Diastolic ventricular interaction in chronic heart failure. Lancet 1997; 349: 1720–1724. 66. Atherton JJ, Thomson HL, Moore TD, Wright KN, Muehle GWF, Fitzpatrick LE, Frenneaux MP. Diastolic ventricular interaction. A possible mechanism for abnormal vascular responses during volume unloading in heart failure. Circulation 1997; 96:4273–4279. 67. Mitzner W. Resistance of pulmonary circulation. Clin Chest Med 1983; 4(2):127–137. 68. Parillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W. 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 1985; 76:1539–1553. 69. Parker MM, McCarthy KE, Ognibene FP, Parillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 1990; 97:126–131. 70. Brealey D, Singer M. Tissue oxygenation in sepsis. Sepsis 1998; 2:291–302. 71. Hussain S, Chatillon A, Comtois A, Roussos C, Magder S. The chemical activation of thin-fiber phrenic afferents: cardiovascular responses. J Appl Physiol 1991; 70:77–86. 72. Hussain SNA, Magder S. Respiratory muscle function in shock and infection. Semin in Respir Med 1991; 12:287–297. 73. Hussain SNA, Roussos C. Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs. J Appl Physiol 1985; 59:1802–1808. 74. Boczkowski J, Dureuil B, Brauger C, Aubier, M. Effects of sepsis on diaphragmatic function in rats. Am Rev Resp Dis 138, 260–265. 1988. (GENERIC) Ref Type: Journal (Full). 75. Hussain SNA, Chatillon A, Comtois A, Roussos C, Magder S. Chemical activation of thinfiber phrenic afferents. 2. The cardiovascular responses. J Appl Physiol 1991; 70:159– 167. 76. Teitelbaum J, Borel CO, Magder S, Traystman RJ, and Hussain SNA. Effect of selective diaphragmatic paralysis on the inspiratory motor drive. J Appl Physiol 1993; 74:2261– 2268. 77. Teitelbaum JS, Magder SA, Roussos C, Hussain SNA. Effects of diaphragmatic ischemia on the inspiratory motor drive. J Appl Physiol 1992; 72:447–454. 78. Walker G, Pfeilschifter J, Kunz D. Mechanisms of suppression of inducible nitric-oxide synthase (iNOS) expression in interferon (IFN)-y-stimulated RAW 264.7 cells by dexamethasone. J Biol Chem 1996; 271:16679–16687. 79. Deschamps A, Magder S. Baroreflex control of regional capacitance and blood flow distribution with or without alpha adrenergic blockade. J Appl Physiol 1992;l 263:H1755– H1763. 80. Appleton C, Olajos M, Morkin E, Goldman S. Alpha-1 adrenergic control of the venous circulation in intact dogs. J Pharmacol Exp Ther 1985; 233:729–734. 81. Wenzel RP. Anti-endotoxin monoclonal antibodies—a second look. N Engl J Med 1992; 326:1151–1153. 82. Desjars P, Pinaud M, Bugnon D, Tasseau F. Norepinephrine therapy has no deleterious renal effects in human septic shock. Crit Care Med 1989; 17:426. 83. Schaer GL, Fink MP, Parrillo JE. Norepinephrine alone versus norepinephrine plus lowdose dopamine: Enhanced renal blood flow with combination pressor therapy. Crit Care Med 1985; 13:492–496. 84. Goldberg LI. Cardiovascular and renal actions of dopamine: Potential clinical applications. Pharmacol Rev 1972; 24:1–29.
762
Magder
85. Hannemann L, Reinhart K, Grenzer O, Meier-Hellmann A, Bredle DL. Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake in septic shock. Crit Care Med 1995; 23:1962–1970. 86. Kilbourn RG, Cromeens DM, Chelley FD, Griffith OW. NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemia dogs. Crit Care Med 1994; 22:1835–1839. 87. Ruffolo RR Jr. Messick K. Effects of dopamine, (⫾)-dobutamine and the (⫹) and (⫺)enantiomers of dobutamine on cardiac function in pithed rats. J Pharmacol Exp Ther 1985; 235:558–565. 88. Vincent JL, Van der Linden P, Domb M, Bleic S, Azimi G, Bernard A. Dopamine compared with dobutamine in experimental septic shock: relevance of fluid administration. Anesth Analg 1987; 66:565–571. 89. MacLean LD, Mulligan WG, McLean APH, Duff JH. Patterns of septic shock in man–A detailed study of 56 patients. Ann Surg 1967; 166:543–562. 90. Kilbourn R, Gross S, Jubran A, Adams J, Griffith O, Levi R, Lodata R. NG-methyl-Larginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA. 1990; 87:3629–3632. 91. Pastor C, Teisseire B, Vicaut E, Payen D. Effects of L-arginine and L-nitroarginine treatment on blood pressure and cardiac output in a rabbit endotoxin shock model. Crit Care Med 1994; 22:465–469. 92. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991; 338:1557–1558. 93. Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol 1990; 182:591– 595. 94. Hom GJ, Grant SK, Wolfe G, Bach TJ, MacIntyre DE, Hutchinson NI. Lipopolysaccharideinduced hypotensiona nd vascular hyporeactivity in the rat: Tissue analysis of nitric oxide synthase mRNA and protein expression in the presence and absence of dexamethason, N00G-monomethyl-L-arginine or indomethacin. JPET 1995; 272:452–459. 95. Petros AJ, Hewlett AM, Bogle RG, Pearson JD. L-arginine-induced hypotension. Lancet 1991; 337:1044–1045. 96. Mehta S, Javeshghani D, Datta P, Levy RD, Magder S. Porcine endotoxaemic shock is associated with increased expired nitric oxide. Crit Care Med 1999; 27:385–393. 97. Magder S, Kabsele K. Evidence for constitutive release of nitric oxide in the venous circuit of pigs. J Cardiovasc Pharmacol 1998; 32:366–372. 98. Chollet-Martin C, Gatecel C, Keermarrec N, Gougerot-Posicalo MA, Payen D. Alveolar neutrophil functions and cytokine levels during nitric oxide inhalation in ARDS patients. Am J Respir Crit Care Med 1996; 153:985–990. 99. Amata MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347–354. 100. Pinksy MR, Summer WR, Wise RA, Permutt S, Bromberger-Barnea B. Augmentation of cardiac function by elevation of intrathoracic pressure. J Appl Physiol Respir Environ Exercise Physiol 1983; 54:950–955. 101. Aubier M, Trippenbach T, Roussos C. Respiratory muscle fatigue during cardiogenic shock. J of Appl Physiol Respir, Environ Exericse Physiol 1981; 51:499–508. 102. Viires N, Sillye G, Aubier M, Rassidakis A, Roussos C. Regional blood flow distribution in dog during induced hypotension and low cardiac output. Spontaneous breathing versus artificial ventilation. J Clin Invest 1983; 72:935–947.
29 Nitric Oxide and Cardiopulmonary Failure in Sepsis
RUBIN COHEN Long Island Jewish Medical Center New Hyde Park, New York
I.
Introduction
Over the last two decades nitric oxide (NO), a gas once regarded as a product of smog and an environmental irritant, has emerged as one of the most important molecules in biology. This L-arginine-derived product is found in serum, saliva, urine, and exhaled breath. It is recognized as the perfect cell-to-cell messenger since it is so lipophilic and readily diffuses across membranes. Moreover, through activation of guanylate cyclase and resultant cyclic guanosine monophospahate (cGMP) production, NO participates in the regulation of systemic and pulmonary vascular resistances (1), adhesion of platelets and neutrophils (2), and contraction of multiple organs including the heart, stomach, intestines, and uterus. It regulates transcription factor activation, translation of mRNAs controlling iron metabolism, glycolysis, mitochondrial electron transport, and protein acylation. On the one hand, excessive production of NO appears to contribute to the hypotension in septic shock and causes tissue damage in many chronic inflammatory diseases such as arthritis, glomerulonephritis, and diabetes (3). On the other hand, NO is effective in bacterial killing (4), downregulates the immune response (5), decreases oxidant injury, and protects cells against cytokine-induced injury and apoptosis (6). Thus NO, one of the simplest biosynthetic molecules, appears be both beneficial and toxic. The aim of this chapter
763
764
Cohen
is to shed insight into the confusing and often contradictory roles of NO in sepsis and in sepsis-induced myocardial dysfunction. II. Nitric Oxide Synthases NO is synthesized in mammalian cells by a family of three nitric oxide synthases (NOS), each a product of a different gene, that share 55% amino acid homology with particularly strong sequence conservation noted in regions of the proteins importantly involved in catalysis. The first NOS was described in neuronal tissue (nNOS, or NOS1). Later, another isoform was isolated in large vessels and endothelial cells (eNOS, or NOS3 ). These are calcium and calmodulin dependent and are constitutively expressed in mammals. The third isoform, iNOS or NOS2, was initially isolated in macrophages. It is produced following its induction by immunologic and inflammatory stimuli, and is calcium and calmodulin independent. However, it is now recognized that the level of gene expression of eNOS and nNOS may be ‘‘induced’’ under different physiological conditions (for example hemodynamic shear stress or nerve injury) and, conversely, that iNOS may function as a ‘‘constitutive’’ enzyme under physiological conditions in some cells (3). All three enzymes have now been isolated in several cell types, and all have been isolated from the myocardium including from myocytes, conduction tissue, and coronary vasculature (7). Nitric oxide synthases can also be characterized as low versus high output. Because activity of eNOS is triggered by calcium-elevating agonists, its effect is transient (minutes). Hence this enzyme is mostly involved in homeostatic processes such as moment-to-moment blood pressure regulation. In contrast, iNOS is a highoutput enzyme, its expression often linked to infection or inflammation, and it is generally geared toward host defense. Largely because iNOS is independent of calcium-elevating agonists, its activity is sustained and can last for days (3). This NO production via iNOS has been implicated in hypotension and myocardial dysfunction associated with septic shock. In spite of their differences, all NOS isoforms contain a heme moiety (protoporphyrine IX) and share a similar catalytic scheme. This involves the five-electron oxidation of the terminal guanido nitrogen of the of the amino acid L-arginine to form NO plus L-citrulline. The reaction is quite complex and involves oxygen, NADPH (both as cosubstrates), and redox cofactors flavin adenine dinucleotide, flavin mononucleotide, calmodulin, and tetrahydrobiopterin (8). III. Nitric Oxide in Septic Shock: Effects on Hemodynamics Several lines of evidence suggest that excess production of NO is involved in the pathogenesis of septic shock. NO lowers blood pressure in sepsis (9–11), blocks response to pressors (12), influences the distribution of the circulation (13) , and interferes with cellular respiration (14,15). Lipopolysaccharide (LPS) as well as IL1β, IL-2, tumor necrosis factor alpha (TNFα), and interferon-gamma (IFNγ) have
NO and Cardiopulmonary Failure in Sepsis
765
been shown to increase NO production in vitro via the induction of iNOS (8,16). Furthermore, septic shock is associated with increased production of NO, usually assessed as nitrite and nitrate, the stable end products of NO oxidation (17,18). In support of this concept, nonselective NOS inhibitors (agents which inhibit mostly eNOS) were found to increase mean arterial pressure (MAP) and systemic vascular resistance (SVR) in humans with sepsis and in animal models of septic shock (19–21). However, determining whether NOS inhibition reduces tissue injury or increases survival in sepsis has been more difficult. While studies in rodents have reported increased survival (22,23), these data have not always been reproducible in higher-order mammals (24). Additionally, administration of NOS inhibitors in septic shock has frequently resulted in decreased cardiac output (CO) (25–27), decreased venous return (28), decreased blood flow to peripheral organs (29), decreased oxygen delivery (30), and increased activation of intravascular coagulation (31). Kilbourne and colleagues (32) criticized some of the studies in which the administration of NOS inhibitors resulted in decreased CO for the following reasons: First, the use of anesthesia may have contributed to myocardial dysfunction. Second, in models in which short time courses are used, iNOS expression and related effects cannot be expected. Third, these authors postulate that the use of endotoxin to mimic sepsis syndrome may induce parallel NO-independent pathways. Fourth, the administration of LPS in some models resulted in an immediate drop in CO, thereby not reproducing hyperdynamic human septic shock. Finally, since eNOS plays a crucial role in the maintenance of basal coronary flow, and NO inhibits platelet adhesion, it is reasonable to assume that eNOS inhibition can result in myocardial ischemia and result in myocardial dysfunction. All such potentially adverse effects would be more pronounced under conditions of septic shock. In accordance with the final point, Wright et al. noted increased mortality following N ω-methyl-L-arginine (LNMMA), given either before or after endotoxin to anesthetized septic rabbits. Based on ECG criteria that showed evidence of ischemia, these authors concluded that NO inhibition resulted in coronary ischemia (33). However, ECG criteria are not a sensitive method for detecting ischemia, and moreover, it was not clear whether the ECG changes were due to the fall of blood pressure or were the cause of it. To address the issue of myocardial ischemia following NOS inhibition, Cohen et al. (34) assessed coronary vasoconstriction or myocardial ischemia following administration of the non selective NOS inhibitor N G-nitro-L-arginine (L-NAME) in a canine model of septic shock. This NOS inhibitor inhibits mostly eNOS. In this study, L-NAME was administered when the animal was in shock (about 2 hours after endotoxin infusion). L-NAME increased MAP and SVR without a significant drop in CO. Furthermore, these investigators found no evidence of increased left ventricular afterload or decreased contractility following administration of LNAME. In a subsequent study, Cohen et al. administered large doses of L-NAME (300 mg/kg) to normal dogs and again did not detect evidence myocardial ischemia (35). Cobb et al. (36) addressed concerns over the potentially harmful hemodynamic effects of NOS inhibition, the possible confounding effects of general anesthesia,
766
Cohen
and the paucity of survival data in higher-order mammals. These authors used an awake canine model to determine whether NOS inhibition reverses hypotension and improves survival after endotoxin challenge. The hemodynamic effects of a bolus injection followed by a 22-hour infusion of N ω-amino-L-arginine (L-NAA) was assessed in both control (normal saline) and endotoxemic animals. In both groups LNAA increased MAP and SVR, but also increased PVR and decreased CO, oxygen delivery and consumption, and arterial pH. Furthermore, NOS inhibition did not improve endotoxin-induced myocardial depression as measured by radionuclidedetermined left ventricular ejection fraction. More worrisome was the fact that LNAA increased mortality in dogs even at doses that did not significantly increase MAP. Moreover, L-NAA at higher doses caused muscular rigidity and seizurelike activity, and this led to its withdrawal from further experiments. This group of investigators next studied L-NMMA. This agent was thought to be more appropriate in septic shock since it inhibits both the constitutive and inducible isoforms of NOS. L-NMMA was administered as a bolus followed by a 22-hour infusion to awake dogs. L-NMMA increased MAP, SVR, and PVR and decreased CO and oxygen delivery in endotoxemic animals. The increase in MPAP was more pronounced in endotoxic than control animals. However, L-NMMA did not increase survival times, and once again at highest doses it decreased survival. Of note this decreased survival was not explained by differences in endotoxin or TNFα levels (37). Another trial examined the effect of NOS inhibition on survival and the use of NOS inhibitors along with conventional pressors (38). A low dose of L-NMMA (1 mg/kg/h) was studied since this was the only dose that demonstrated a possible beneficial trend. Sepsis was induced not with lipopolysaccharide (LPS), but with an E. coli–infected fibrin clot placed into the peritoneal cavity. The time of L-NMMA administration was chosen to coincide with the presence of established shock. LNMMA significantly increased SVRI and MAP, and when combined with epinephrine, produced mainly additive effects. In this study, L-NMMA preserved cardiac performance better than the single infusion of epinephrine that was administered, but once again NOS inhibition did not improve survival. Kilbourn et al. (39) confirmed the decrease in CO, following L-NMMA administration in endotoxemic dogs. The administration of dobutamine restored CO prompting these investigators to suggest that the combination of a NOS inhibition and dobutamine is of therapeutic value. However, this study did not evaluate survival nor did it examine organ function. To address the issue of decreased CO and increased MPAP and PVR following NOS inhibition, Cohen et al. (40) administered L-NAME, a highly selective eNOS inhibitor, as a bolus (15 mg/kg) to endotoxemic swine. To simulate a clinical scenario, these authors used a minimally invasive, nonanesthetized, sedated swine model of septic shock. L-NAME was administered only after the MAP had dropped by 30 mm Hg from baseline or decreased to ⬍ 60 mm Hg. For comparison, a group of pigs received the same dose of endotoxin, but were resuscitated with normal saline sufficient to maintain pulmonary artery occlusion pressure (PAOP) no more than 1.5 times baseline. This fluid infusion maintained CO and produced a normody-
NO and Cardiopulmonary Failure in Sepsis
767
namic model of endotoxic shock. Right ventricular volume and ejection fraction were determined via a rapid thermistor pulmonary artery catheter. Left ventricular volumes and ejection fraction were studied echocardiographically. Furthermore, these authors assessed gastric pCO2 tonometrically as an index of gastric mucosal perfusion. L-NAME administration restored MAP to baseline value, but also resulted in worsening pulmonary hypertension, increased right ventricular volumes, and decreased CO compared to the saline treated group. The decrease in CO was due to increased right ventricular overload and there was no evidence of left ventricular dysfunction. L-NAME also resulted in increased mortality due to severe pulmonary hypertension and right ventricular failure. Moreover, the restoration of MAP following L-NAME did not correct gastric mucosal acidosis, indicating ongoing gastric mucosal ischemia in spite of normalization of MAP in the endotoxic animals. A study by Strand et al. (41) was one of the few that showed improved survival in a pig model of abdominal sepsis using the NOS inhibitor L-NMMA which maintained MAP without aggravating tissue oxygenation. Furthermore, CO, SVR, and urine production were well maintained during treatment. However, others have questioned the relevance of survival at 9 hours (the end point in this study) in anesthetized pigs without antibiotics to the clinical setting, where a full complement of supportive care would be available (42). Since endotoxin induces pulmonary hypertension, some authors have suggested the inhalation of NO gas to improve pulmonary hemodynamics. Inhaled NO had been reported to act as a selective pulmonary vasodilator without causing systemic vasodilatation (43). Beneficial effects of NO have also been documented in patients with chronic obstructive pulmonary disease, congenital heart failure, and pulmonary arterial hypertension (44–46). Ogura and colleagues (47) studied the effects of inhaled NO on pulmonary function in endotoxemic swine using the multiple inert-gas technique. These authors concluded that inhaled NO improves LPS-induced ventilation-perfusion mismatching by decreasing shunt fraction and, by decreasing pulmonary edema and redistributing blood flow from true shunt to the ventilated area. Offner et al. (48) administered inhaled NO to endotoxemic swine and studied the effects on RV function. In this study, LPS caused pulmonary hypertension, RV dysfunction, and increased RV end-diastolic volume. Inhaled NO decreased MPAP, increased RV ejection fraction, and improved oxygen delivery without adverse effects. Fierobe and coauthors (49) administered inhaled NO to patients in severe adult respiratory distress syndrome (ARDS). These authors demonstrated that NO inhalation improved arterial oxygenation and decreased RV loading conditions. Klemm et al. (50) took this concept one step further and combined NOS inhibition to elevate MAP and SVR with inhaled NO to improve pulmonary hemodynamics in a model of porcine endotoxemia. In this study, swine were given a continuous infusion of L-NMMA at a dose of 0.1 mg/kg/min with NO inhalation at 50 ppm. The animals were followed for 3 hours. Animals that were infused with LPS alone had a 58% mortality, while those infused with LPS and treated with L-NMMA alone had a 63% mortality. Interestingly, the group that received LPS and given both LNMMA and NO gas had no mortality. NO inhalation appeared to prevent the rise
768
Cohen
in MPAP and PVR as well as alterations in gas exchange, while L-NMMA prevented the fall in MAP. Similarly, Offner et al. (51) concluded that inhaled NO reversed pulmonary hypertension which followed L-NAME treatment during endotoxemia in swine, and suggested that NO inhalation may be a useful adjunct to NOS inhibition in the treatment of endotoxemia. Weitzberg et al. also studied the combined effect of NO inhalation and L-NNA in a model of porcine endotoxin shock. These investigators concluded that the addition of inhaled NO did indeed reduce MPAP, but the combination of the NOS inhibitor and NO gas did not improve CO or systemic and renal vascular resistance (52). Hinder et al. (53) investigated the role of NO in LPS-associated pulmonary edema in awake, spontaneously breathing, chronically instrumented sheep observed for 28 hours. Endotoxemia resulted in pulmonary edema, which was aggravated by the NOS inhibitor L-NAME. The inhalation of NO normalized pulmonary arterial pressure and ameliorated pulmonary edema. Interestingly, these investigators noted a trend for lower SVR in the group that received L-NAME and NO than in the group that received L-NAME only. While the difference was not statistically significant, this raises the issue that inhaled NO may have a vasodilating effect on the circulation. This is in contrast with the generally held view that NO is a highly selective pulmonary vasodilator that does not elicit systemic effects due to its scavenging by hemoglobin. However, Stamler and co-workers (54) proposed that hemoglobin is S-nitrosylated (S-nitrosylation is the attachment or transfer of NO⫹ to sulfhydryl groups) in the lung when red blood cells are oxygenated, and that NO is then released during arterial-venous transit to improve microcirculatory blood flow, particularly under hypoxic conditions. Furthermore, Stamler et al. showed that NO could adduct with albumin (55) in the form of stable nitrosothiols, which then circulate or diffuse to remote sites and release bioactive NO. This protection of NO by erythrocytes and other proteins has significant implications. First, the half-life of NO would be greatly prolonged (the half life of NO in water is ⬃ 3 sec), and secondly NO may have effects far away from its site of production. The vasodilatory effect of NO gas may have been masked in some studies since endogenous production of S-nitrosothiols can be inhibited by NOS inhibition (56). While the notion of NO forming stable adducts with thiol groups on proteins and having a hormonelike action remains highly speculative, it is nevertheless quite intriguing. Nitric oxide synthase inhibition was also administered to humans in septic shock. Lorente et al. (57) administered the non selective NOS inhibitor L-N ω-nitroL-arginine (L-NNA) to septic patients in hyperdynamic shock (20 mg/kg IV bolus). L-NNA increased MAP, SVR, MPAP, and PVR. The increase in MAP was reversed with L-arginine. Furthermore, L-arginine caused transient hypotension when given to another group of septic patients. The authors concluded that NO plays a role in the regulation of systemic and pulmonary tone in human septic shock. Petros et al. (21) reached similar conclusions when they administered L-NMMA to septic patients. Additionally, there are several case reports where non selective NOS inhibitors were administered in patients with septic shock unresponsive to usual pressors. In
NO and Cardiopulmonary Failure in Sepsis
769
these instances, NOS inhibition raised MAP and SVR, but did not affect mortality (58,59). In a more recent report, L-NMMA was administered to two patients to manage sepsis-induced hypotension refractory to the usual pressor agents. MAP was raised to nearly normal levels following L-NMMA infusion. However, both patients died suddenly, their deaths attributed to LV failure. While the authors had no evidence to implicate L-NMMA, they nevertheless urged ‘‘extreme caution’’ when using NOS inhibitors to treat hypotension (60). A multicenter trial using L-NMMA in the treatment of sepsis-induced hypotension in humans reported encouraging results, albeit without change in morality, in a Phase II trial (61). This agent was titrated to maintain MAP ⱖ 70 mm Hg, and the investigators noted a transient decrease in CO which on occasions required dobutamine support. NOS inhibition was followed by an increase in MPAP, but there were no reports of hemodynamic collapse due to right ventricular failure. However, the Phase III multicenter trial was terminated early on the advice of the study’s independent data safety monitoring board due to serious adverse outcomes in the L-NMMA group. A. Targeting iNOS in Sepsis
The major critique regarding many of the earlier studies is the use of nonselective NOS inhibitors. These primarily target the constitutive isoform (eNOS), and have little or no effect on iNOS. This eNOS inhibition may cause further harm since it is postulated that suppression of constitutively produced NO leads to loss of normal NO-mediated vasoregulatory and immunomodulatory functions. Szabo et al. (62) demonstrated that endotoxic shock causes induction of iNOS in multiple organs. Liu et al. provided direct molecular evidence for iNOS production in endotoxemia by detecting iNOS mRNA 4 hours after endotoxin administration in multiple organs in rats (63). In a subsequent study, Liu et al. demonstrated downregulation of eNOS mRNA in multiple organs of endotoxemic rats, and concurrent upregulation of iNOS mRNA (64). Bateson et al. (65) detected increases in iNOS mRNA in the rat left ventricle within 30 min following endotoxin administration. Robinson and colleagues showed that endotoxemia led to both iNOS gene transcription and calcium-independent NOS enzyme activity in the rat myocardium (66). These data would indicate that iNOS activation is important in sepsis and that therapy should be directed at excess NO production in sepsis by selectively inhibiting iNOS. The role of iNOS in endotoxemia was further defined with the use of iNOS knockout mice. These mice are phenotypically and histologically indistinguishable from their normal counterparts. In one study (67), serum nitrate and nitrite were elevated only in the wild-type animals following lipopolysaccharide (LPS) infusion. Furthermore, endotoxin caused shock and death in wild-type mice (iNOS ⫹/⫹), while the fall in MAP was markedly attenuated and early death averted in the knockout mice (iNOS ⫺/⫺). Thus, the lack of iNOS protected these animals from LPSinduced cardiovascular collapse. The blood pressure response to endotoxemia in heterozygote mice (iNOS ⫹/⫺) was intermediate between that of the wild type and
770
Cohen
the iNOS deficient. All the heterozygotes survived the endotoxin infusion, but had a 30% decline in blood pressure. This implies that pharmacological inhibition of iNOS may provide a degree of protection against endotoxin-induced hypotension even if such agents did not inhibit iNOS completely. In the same study (67), elevation of serum lactate dehydrogenase and liver enzymes occurred in the iNOS ⫹/⫹ and the iNOS ⫺/⫺ mice indicating similar damage to hepatocyte in both groups. In further experiments, iNOS-/- mice primed with P. acnes and then challenged with LPS died quickly. These results may be clinically relevant insofar as it mimics localized, indolent, or partially controlled infections from which microbes or their products spill abruptly into the circulation. The vulnerability of iNOS⫺/⫺ mice in this setting suggests that routes other than iNOS may be involved in LPS-associated death. Moreover, the iNOS-deficient mice died from inocula of L. monocytogenes that were 10-fold lower than those needed to kill normal mice, suggesting that iNOS is important to host defenses. In the study by Wei et al. (68), iNOS deficiency was also shown to be protective from intraperitoneal LPS administration in iNOS knockout mice. However, a study by Laubach and colleagues (69) found no protection from death in similar, but independently generated, knockout mice. The reasons for these differences are unknown, but certain conclusions are clear. There is a role for iNOS in endotoxininduced cardiovascular collapse. To that effect, other studies have also connected iNOS with LPS-induced lung damage (70,71). However, iNOS activation and subsequent production of iNOS cannot explain all aspects of LPS-associated mortality. At the same time, iNOS appears to be critical to host defenses especially against intracellular pathogens. This was confirmed by other studies in knockout mice which showed that iNOS is critical for survival in such infections as tuberculosis, leishmaniasis, and toxoplasmosis (72). B. Nitric Oxide Synthases: Defining the Target
All NOS isoforms can be inhibited with N G-substituted L-arginine analogs, and most of these show selectivity toward the constitutive isoforms. For example, L-NNA and its prodrug L-NAME have very low potency for iNOS, making them poor choices for iNOS inhibition (73). There are also differences in these inhibitors’ mode of action owing to their chemical structure. For example, L-NAME inhibits the enzyme’s mediated consumption of NADPH by interrupting electron flux immediately before reduction of the heme iron on the NOS, whereas L-NMMA uncouples NADPH oxidation from catalytic activity. Consequently, L-NAME is a slowly reversible competitive agonist of L-arginine, whereas L-NMMA is an alternative substrate, an inactivator of the enzyme, which produces a time-dependent loss of NOS activity (74). L-NMMA also inhibits both isoforms equally and was thus considered a better choice; however, experimental data have not borne this out. Attention has now shifted to the use of highly more selective iNOS inhibitors. Those that have been primarily studied are: Aminoguanidine, the S-alkyl isothioureas, especially Smethylisothiourea (SMT), L-Canavanine, and the highly selective iNOS inhibitor N-(3-(aminomethyl)benzyl)-acetamide (1400W).
NO and Cardiopulmonary Failure in Sepsis
771
Aminoguanidine has shown beneficial effects in some experimental models of shock, although the doses required to elicit effective iNOS inhibition in vivo can be quite high (400 mg/kg/day range). Aminoguanidine has been shown to restore contractile response in vascular tissues of animals treated with endotoxin (75). Wu and colleagues (76) compared the effects of aminoguanidine and L-NAME on endotoxin-induced multiple organ dysfunction in the rat. In the sham-operated rats, only L-NAME administration resulted in increase in MAP. Both agents resulted in increased MAP in endotoxemic rats, but only aminoguanidine inhibited the plasma nitrite increase caused by endotoxin. Furthermore, only aminoguanidine attenuated the renal, liver, and pancreatic dysfunction caused by endotoxemia. SMT was found to be at least 10 to 30-fold more potent an inhibitor of iNOS in immunostimulated cultured macrophages and vascular smooth muscle cells than L-NMMA. SMT also protected the endotoxemic rats from circulatory failure and organ dysfunction and increased their survival. Furthermore, SMT and L-NMMA produced similar increases in blood pressure in normal rats (77). Thus, SMT does likely inhibits eNOS as well. Aranow et al. (78) evaluated the effects on survival of NO blocking strategies comparing L-NAME and SMT. Rats were made endotoxemic by intraperitoneal implantation of viable E. coli and were treated with IV ampicillin. Only SMT prolonged survival in this model of gram-negative sepsis. In another study, Rossellet et al. (79) administered low (0.1 mg/kg/hr) or high (1 mg/kg/hr) doses of SMT to endotoxemic rats and compared these two doses to norepinephrine. While norepinephrine increased MAP and reduced the endotoxin-induced fall in CO, it did not affect lactic acidosis, organ dysfunction, or lactate accumulation. Both doses of SMT reduced signs of renal, but not liver dysfunction and both doses increased MAP. In another study that used rodents, the two selective iNOS inhibitors SMT and aminoguanidine ameliorated LPS-induced intestinal hypermeability (80). Vos et al. (81) showed increased NO production in livers of rats given LPS. These investigators also measured the effects of the two NOS inhibitors L-NAME (nonselective) and SMT (selective) on systemic and portal pressures, and LPS-induced liver damage. In endotoxemic rats, liver damage increased after L-NAME treatment, but liver damage did not worsen following SMT. Both agents lowered NO levels to a similar extent, and SMT had a greater effect on hemodynamics than L-NAME. The authors proposed that decreased hepatic perfusion following L-NAME may be the reason for increased hepatic damage with this agent. Alternatively, the authors postulated that since LPS causes the production of reactive oxygen intermediates (ROI) and since L-NAME had been shown to increase ROI in another study (82), increased oxidative stress may be another pathway by which L-NAME contributes to organ dysfunction. Similarly, SMT may be beneficial because it decreases oxidative stress due to its thiol group. Cohen et al. (83) investigated the effects of SMT in a swine model of endotoxemic shock and compared the effects of SMT to LNAME and phenylephrine. Animals were resuscitated with either agent when the MAP had dropped 30 mm Hg from baseline or was ⱕ 60 mm Hg. The drugs were infused and titrated to increase MAP by no more than 20 mm Hg. All three drugs increased MAP to the desired
772
Cohen
range, but L-NAME had more detrimental effects on right and left ventricular function, while only SMT appeared to improve LV function. Furthermore, SMT and phenylephrine corrected gastric mucosal acidosis and restored gastric pCO 2 to baseline, while L-NAME did not (Fig. 1). Once again, this indicated ongoing gastric mucosal ischemia in spite of correction of MAP. In another study, Saetre et al. showed that aminoethyl-isothiourea improved liver circulation and oxygen metabolism in a porcine model of endotoxemia (84). The pharmacological use of some of the isothioureas has been limited by poor tissue intake and instability in vivo. In addition, some of the bisisothioureas show significant acute toxicity, perhaps due to ion channel interference. Garvey et al. addressed the problem of toxicity by designing an analog of acetamidine named 1400W. This compound is reported to be relatively nontoxic and to inhibit iNOS
Figure 1 Gastric pCO 2 vs time in three groups of pigs. All groups received LPS and normal saline to maintain PAOP 1–2 times baseline. LPS caused hypotension and an increase in gastric pCO2. When MAP became ⱕ60 mm Hg (usually by 2 hours), L-NAME or SMT was administered to elevate MAP by no more than 20 mm Hg. The third group received saline only. For the same elevation in blood pressure, SMT corrected gastric mucosal pCO2, while L-NAME did not. Legend: ‘‘a’’ indicates significance to baseline value in the same group; ‘‘b’’ indicates significance to LPS/saline group at same time period.
NO and Cardiopulmonary Failure in Sepsis
773
5000-fold more effectively than eNOS and 200-fold more effectively than nNOS. In one study, the infusion of 1400W 2 hours after the injection of endotoxin attenuated the hypotension in the rat. However, 1400W did not affect endotoxin-induced renal, liver, or pancreatic injury (85). L-Canavanine has been shown to be effective in rodent models of sepsis. LCanavanine restored blood pressure, while L-NAME resulted in an initial elevation in MAP followed by hemodynamic collapse and death (86). L-Canavanine has also been reported to improve organ function and tissue ATP levels in endotoxemia (87), and it improved venous return in another study (88). Thus, these data support a role for iNOS and the use of iNOS-selective inhibitors in endotoxin-induced shock. C. Other Methods of Nitric Oxide Blockade
There are other approaches to inhibit NO synthesis apart from NOS inhibitors that generally interact within the active site of the enzyme. Nitric oxide synthases are tetrahydrobiopterin (BH4)-dependent enzymes (89), and the activity of newly synthesized enzyme depends on this cofactor. Since eNOS has a tightly bound cofactor, inhibiting BH4 would result in inhibiting iNOS. The main problem is that BH4 inhibitors would have to be administered prior to iNOS induction. The administration of L-arginine has been shown to cause vasodilatation in experimental models of septic shock. In a study of patients with septic shock, the administration of L-arginine led to further vasodilatation (57). Many cells, when stimulated with cytokines, are able to activate enzymes that increase the transport of L-arginine (90) or support additional L-arginine production (91). These data suggest that arginine depletion may constitute an approach to limiting NO synthesis. Decreasing L-arginine in parenteral or enteral nutrition formulae may be one approach to limit L-arginine concentration. However, arginine has been shown in animal studies to increase wound healing and to augment the immune system. Indeed, specialized nutritional formulae contain increased L-arginine content. Nonetheless, to date none of the specialized nutritional formulations have been shown to affect outcome in septic patients (92). Hemoglobin (Hgb) is a very effective NO scavenger (93). Pyridoxylated hemoglobin polyoxyethylene conjugate (PHP) has been used to decrease NO availability. PHP has been shown to improve myocardial contractility (94), increase urine flow (95), and increase MAP in septic sheep (96). However, the use of cross linked Hgb in septic rats resulted in higher mortality when compared to SMT septic rats (78). Finally, the majority of NO effects appear to be mediated primarily by the activation of guanylyl cyclase (3), resulting in cGMP increase. The intracellular effects of cGMP are achieved by the regulation of protein kinases, gated ion channels, and nucleotide phosphodiesterases. Each of these cGMP targets represent an expanding family of regulatory proteins; each is a potential target for therapeutic intervention (97). Therefore, this area is under intense study. Methylene Blue, an inhibitor of guanylyl cyclase, had demonstrated a pressor action in an animal model of septic shock. Methylene Blue did not affect CO in that study, but it may have
774
Cohen
selectively increased mesenteric blood flow at low doses. Higher doses resulted in worsening hypotension and myocardial depression (98). IV. Nitric Oxide in the Normal Heart Several groups have investigated the role of constitutively expressed NO in cardiac myocytes preparations or isolated papillary muscles. NO appears to exert both negative chronotropic and inotropic effects on the heart (99–101). Balligrand and colleagues demonstrated that intramyocyte produced NO produced by activated eNOS in myocytes was responsible for a reduction of the inotropic response to β-adrenergic stimulation (102). Whereas the actions of endothelium-derived NO on myocyte function are well established and include various physiological processes such as regulation of vascular tone and inhibition of platelet aggregation, the relevance of cardiomyocyte-derived NO is still debated (103). Gauthier et al. shed some light on the role of cardiomyocyte-derived NO. These investigators provided evidence for the functional expression of a third βadrenoreceptor subtype, β 3, in the human ventricle. In contrast to β 1 and β 2 adrenoceptors, β 3 stimulation mediates a decrease in cardiac contractility (104). This negative inotropic effect of the β 3 receptors appears to be mediated by NO (105). In endomyocardial biopsies, these investigators demonstrated that the decrease in contractility was inhibited by the two constitutive NOS inhibitors L-NMMA and LNAME. Furthermore, the effects of NOS inhibitors was reversed by L-arginine. Moreover, the actions of a β 3-adrenoceptors agonist were associated with parallel increases in the production of NO and intracellular cGMP; suggesting that β 3-adrenoceptor agonists increase NO production through direct activation of eNOS. These authors postulate that a balance exists between positive inotropic effects of catecholamines (through β 1 and β 2) and negative effects of NO (through β 3 ) on the heart. The molecular mechanisms by which NO induces myocardial depression have not been fully resolved, but may be related to stimulation of cGMP-dependent protein kinases which decrease calcium current through regulation of L-type calcium channels (106,107). NO may also decrease cardiac myofilament sensitivity to calcium, possibly through phophorylation of troponin I (108) and the activation of cGMP-stimulated phosphodiesterases, which decrease cAMP levels (109). Alternatively, NO may regulate cardiac function in a cGMP-independent manner through covalent modifications of key proteins such as cytochrome c oxidase (110), creatine phosphokinase (111), or L-type calcium channels (112). It should be noted, however, that the relative importance of each pathway as well as the effect on contractility may be profoundly influenced by parameters such as the experimental preparation, species, and region of the heart studied, as well as the concentration of NO or cGMP generated (105). V.
Nitric Oxide and the Heart in Endotoxemia
Myocardial performance is an important contributing factor to the outcome of shock, and the potential existence of a myocardial depressant factor in sepsis has been
NO and Cardiopulmonary Failure in Sepsis
775
proposed. The large amount of in vitro data demonstrate the cardiodepressive effects of TNF and IL-1, alone or in combination, and it has been postulated that these cytokines are myocardial depressant factors (113). However, the ability of cardiac cells to express NO, the discovery that cytokines and LPS lead to myocardial NO production in large amounts, and the fact that NO has negative inotropic action on the myocardium, all led to the hypothesis that NO causes myocardial dysfunction in sepsis. Notwithstanding the effects of NO on the heart, early (minutes) myocardial dysfunction in sepsis cannot be accounted for by NO production through iNOS activation. While iNOS mRNA has been demonstrated in the rat myocardium as early as 20 minutes following LPS administration (114), it would take at least another 2 hours for the protein to be translated. Finkel et al. noted depression of contractility within five minutes of exposure of isolated hamster myocytes to cytokines (115). The reasons for early myocardial depression in endotoxemia are not fully identified. However, possible mechanisms include rapid stimulation of NO from constitutive sources, or the production of the highly toxic radical peroxynitrite. Other investigators have proposed that TNFα causes early sepsis-induced myocardial depression via NO-independent mechanisms. TNFα is produced in the heart during sepsis by resident macrophages (116). The mechanism of TNFα-induced myocardial depression is thought to be the production of sphingolipid metabolites which occurs minutes following TNFα administration. Spingolipids are stress-induced second messengers that participate in intracellular signal transduction after TNFα has bound to its receptor. These have been shown to block calcium transients in the sacroplasmic reticulum thus depressing contractility. Blockade of sphingosine production abolished TNFα-induced myocardial contractile dysfunction, while sphingosine administration induced contractile depression in a dose-dependent manner (117). Thus, early myocardial depression may be NO independent, while NO may bring about depression at later a stage (hours). Finkel and colleagues demonstrated that NOS inhibition prevented the myocardial depressive effects of either TNFα or IL-1 in vitro (115). Balligand et al. (118) demonstrated that rat ventricular myocytes preincubated with endotoxin-activated rat macrophages showed reduced response to isoproternol. In this study, LNMMA completely restored the reduced response to baseline levels. Furthermore, release of NO by the myocytes in response to the activated medium was detected. Simmons et al. (119) found that cytokines induce L-arginine transporter systems in cardiac myocytes to support the increased L-arginine demand of iNOS. Similar to expression of iNOS in vascular smooth muscle, cardiac myocytes iNOS is mediated by activation of tyrosine kinase, and it can be inhibited by glucocorticoids. Expression of myocardial iNOS can also be suppressed by protein kinase C inhibitors and by agents that increase intracellular cAMP levels (120–122). Similarly, other investigators have implicated NO in sepsis induced myocardial dysfunction in vitro (123–126). Since NO has been shown to exacerbate myocardial contractility in endotoxemia, NOS inhibition would be expected to improve contractility in vivo. However, this has not been readily demonstrated. Using a swine model of endotoxemia, Her-
776
Cohen
bertson et al. (127) found that L-NNA improved myocardial contractility as assessed using the slope of the end-systolic pressure-volume relationship (Emax). However, L-NNA raised pulmonary arterial pressure and resulted in an overall drop in CO. Kaszaki et al. (128) used similar techniques to assess left ventricular contractility in endotoxemic dogs, and reached similar conclusions: that while L-NNA improves left ventricular contractility, its overall effects on CO were detrimental likely due to the effects of NO inhibition on MPAP, (see Cohen et al. [40]). These studies illustrate the complexity of investigating the myocardial effects of NO in whole animals. The mechanisms by which NOS inhibitors influence CO are multifactorial and represent the sum of actions on preload, afterload, and contractile functions, all of which are altered in sepsis. The role of NO in cardiac dysfunction in septic shock remains controversial as other studies have been unable to attribute myocardial depression to NO in animal models. Klabunde and Coston (129) measured left ventricular developed pressure (LVDP) via the Langendorff technique and established decreased LVDP 6 hours following endotoxin administration. This decrease in LVDP did not change following administration of either the nonselective L-NNA or the selective aminoguanidine. Similar results were obtained in another rat model whereupon neither LNMMA nor SMT improved endotoxin-induced decrease in LVDP (130). Toth et al. (131) also found no improvement in guinea pig isolated myocyte contractility following L-NAME administration. Hock et al. concluded that NO is not responsible for the depressed cardiac function after LPS administration in their rat model (132). Paradoxically, Ishihara et al. (133) evaluated the effect of NO inhalation on left ventricular contractility as assessed by measuring Emax in endotoxic pigs. NO inhalation maintained left ventricular function and prevented its impairment. Similar protective effects of inhaled NO in an animal model of myocardial ischemia-reperfusion have also been reported (134). Zhang and coworkers (135) studied the effects of the NO donor 3-morpholinosydnonimine (SIN-1) on oxygen availability and regional blood flow in anesthetized, mechanically ventilated dogs. These animals received E. Coli endotoxin and saline infusion to maintain PAOP. The administration of SIN-1 increased cardiac index and superior mesenteric blood flow without deleterious consequences on MAP. These data would then support the notion that NO is essential to maintain organ flow and to preserve LV function in endotoxic shock. Cohen et al. (135a) attempted to correlate myocardial dysfunction and myocardial NO levels in a model of rat endotoxemia. These investigators used isolated papillary muscle removed at different time periods to assess changes in contractility as an index of myocardial function. Following injection of LPS, contractility was impaired at 16 hours, with recovery to baseline levels occurring at 48 hours. Pretreatment of animals with SMT (SMT/LPS group) 30 min prior to the injection of LPS restored contractility to control levels at 16 hours when compared with the group that received LPS alone. However, pretreatment with L-NAME (L-NAME/LPS group) resulted in worsening myocardial contractility and even increased mortality (Fig. 2). Myocardial NO levels were found to be significantly elevated at 16 hours following LPS injection, and levels decreased with SMT (SMT/LPS group) and decreased
NO and Cardiopulmonary Failure in Sepsis
777
Figure 2 Peak tension in rat papillary muscle was assessed ex vivo at different time periods following LPS administration. LPS caused a decrease in peak tension by 16 hours, while pretreatment with L-NAME decreased peak tension even more. SMT returned function to baseline levels by 16 hours. By 48 hours, the peak tension in the LPS group has recovered to baseline, while the L-NAME group remained depressed. Legend: * indicates significance to baseline value; ⫹ indicates significance to SMT/LPS group at same time period.
even further with L-NAME (L-NAME/LPS) pretreatment at 16 hours (Fig. 3) Moreover, myocardial NO levels at 48 hours (when contractility had recovered to baseline levels) remained elevated in both the SMT/LPS and the LPS groups despite a return to function. These investigators concluded that NO myocardial levels did not correlate with endotoxin-induced myocardial dysfunction or recovery. The basis for the conflicting outcomes in these experiments is not fully known. As usual, the reasons may relate to the use of different animal models, different methods of assessing myocardial function, and the timing of the administration of NOS inhibitors and the doses used. One must also remember that while in vitro studies have demonstrated the capability of endogenously produced NO to suppress myocardial contractility in response to cytokines, these preparations are artificial. Many factors that can be controlled in assays, cannot be duplicated in vivo. In some cases the concentrations of cytokines and NO and the time of exposure to these
778
Cohen
Figure 3 Nitrite/nitrate (NOx) levels were assessed in left ventricular tissue in the rats as above. LPS caused an increase in NOx levels by 4 hours, this increase was more pronounced by 16 hours and levels remained elevated at 48 hours. Pretreatment with SMT caused a decrease in NOx levels. L-NAME caused a further in NOx levels, but also caused worsening contractility (see Fig. 2). By 48 hours NOx levels remained elevated in spite of return of contractility to baseline (see Fig. 2). Legend: * indicates significance to baseline; ⫹ indicated significance to L-NAME group at same time period.
agents do not reflect the in vivo situation. Moreover, important endogenous inhibitors of iNOS expression (for example, glucocorticoids which block iNOS transcription) are not present in the assays. Furthermore, it is unlikely that myocardial depression in sepsis is due to one factor, rather; it is probably linked to altered production of several different factors such as NO, endothelin-1, bradykinin, and adrenergic mediators; the reader is referred to the review of Corda et al. regarding this topic (103). However, the basis for the contradictory data is that NO is essentially a cellular signal molecule that has a wide range of effects. To better understand this concept, a review of the molecular biology of NO is necessary.
NO and Cardiopulmonary Failure in Sepsis
779
VI. Nitric Oxide: Not Just an Endothelial-Derived Relaxing Factor Apart from dilating blood vessels in sepsis, NO has multiple other actions. Its production decreases platelet aggregation and leukocyte adhesion, provides antimicrobial effects, and may scavenge peroxide (136). However, the most influential role that NO likely plays in biological systems is its ability to react with oxygen, superoxide, and transition metals. This is possible because NO is a free radical species as it contains an odd number of electrons. NO is then able exert diverse activities as well as opposing effects within the same biological systems. This expression of a wide variety of effects is achieved through the interactions of NO with targets (such as proteins) via redox additive chemistry. Both covalent modification of proteins and oxidation events that do not involve attachment of the NO group can be used as signaling mechanisms (137). In biological systems metal- and thiol-containing proteins serve as major signaling proteins—for example, ion channels, receptor enzymes, and transcription factors. These proteins contain transition metals and thiols strategically located at either allosteric or active sites. Accordingly, metal- and thiol-containing proteins serve as major target sites for NO. When NO interacts with the prosthetic iron or thiol groups in these proteins, it can form complexes that activate or inactivate target enzymes. In fact, it is through this process that NO activates one of its main target enzymes, soluble guanylate cyclase, which increases cellular cGMP concentrations. The heme-dependent activation of this enzyme by NO results in vasorelaxation in the vasculature and neurotransmission in the CNS. The inhibition or activation of enzymes is believed to be the mechanism by which cytokine-generated NO can inhibit the growth of target cells, whether they be invading microorganisms, tumor cells, or lymphocytes. This capacity of NO to alter enzymatic activity becomes important in regulating cellular function. How or whether these reactions proceed may depend not only on the availability of NO, but also the cellular conditions such as oxidative stress or thiol availability. For instance N-nitrosation of DNA and covalent modifications of tyrosine residues by NO, both potential mechanisms of toxicity, are more likely to occur under conditions of oxidative stress. Thus NO may have both protective and detrimental effects depending on its concentration as well as the tissue milieu (137,138). The confusion concerning NO’s involvement in tissue injury is further complicated by its multifaceted and often paradoxical action in various cytotoxic mechanisms. NO itself is not a powerful cytotoxic agent; however, it can render cells susceptible to other cytotoxic agents such as heavy metals. Yet, NO has been shown to be protective against an array of agents that induce oxidative stress, such as hydrogen peroxide (H2O2 ), alkyl peroxide, and superoxide (see discussion below). NO reacts with some redox metal complexes, yet its reactivity varies from complex to complex. NO can react with oxygen to form a variety of different reactive intermediates that are associated with cellular damage. However, NO can also neutralize oxidants associated with oxidative stress and abate ROI-mediated toxicity (139). The
780
Cohen
complexity of this situation is perhaps best illustrated by the action of NO with the superoxide radical (O 2⫺ ). Under inflammatory conditions such as sepsis, cells release oxidants such hydrogen peroxide that reacts with metals to form the powerful hydroxyl radical, and superoxide. Indeed, following endotoxin administration, a rapid (minutes to 2 or 3 hours) increase in the formation of the superoxide radical and peroxide has been demonstrated (140,141). While these radicals are as an essential part of the host’s defense system as they are toxic to pathogens, and serve as signaling agents, they also damage nearby cells. Mechanisms of cellular injury include oxidation of DNA, proteins, and lipids, all of which can ultimately result in cell death. Oxidative stress, defined as production of ROIs beyond the capacity of cellular antioxidant systems, would be especially toxic to the myocardium due to its dependence on aerobic metabolism (142). It is well established that NO can combine with superoxide to form the potent oxidant peroxynitrite (ONOO⫺ ): O 2⫺ ⫹ NO→ ONOO ⫺
(1)
Peroxynitrite reacts with and damages many important biological molecules including lipids, thiols, and nucleic acids by a number of mechanisms. One such mechanism, nitration of tyrosine residues leading to protein modification, has received particular attention (143). This led Beckman (144) to suggest that in vivo oxidative tissue damage is more likely to occur with the formation of peroxynitrite than with superoxide production alone. However, under physiological conditions, there are factors that limit the contribution of peroxynitrite formation and hence its toxicity. Indeed, there are two major determinants of peroxynitrite formation that must be considered. The first is the relative amounts of NO and superoxide produced, the second is the biological reaction of these radicals with other biological components, which may limit the availability of NO and superoxide and therefore decrease the amount of peroxynitrite formed. Under normal physiological conditions, superoxide levels are minute (nanomolar range). This is due to the very short half-life of superoxide and its dismutation by the abundant enzyme superoxide dismutase (SOD). In fact very small amounts of SOD will effectively compete with NO for superoxide. Moreover, just as SOD reduces availability of superoxide, the reaction of NO with heme proteins reduces NO concentration. In fact the reaction of NO with oxyhemoglobin is the major consumption mechanism for NO (144). Thus, in normal physiological situations, peroxynitrite production is insignificant. However, in situations where SOD concentration is decreased, or superoxide production is increased, and especially if NO levels are increased, formation of peroxynitrite may proceed with subsequent tissue damage. One such situation may be immune cells which when activated produce large quantities of superoxide through NADPH oxidase or xanthine oxidase (145). At the same time, NO production in these cells is increased through iNOS induction, thereby promoting peroxynitrite formation and tissue damage.
NO and Cardiopulmonary Failure in Sepsis
781
However, excess NO may also limit peroxynitrite reactivity in some biological circumstances by the following reaction that results in the production of nitrogen dioxide (NO2 ) (146,147). ONOO⫺ ⫹ NO → NO 2 ⫹ NO 2⫺
(2)
Investigators have found that maximum tissue oxidation via peroxynitrite occurred when the rate of production of superoxide and NO are equivalent (148). Additionally, when NO is in excess, the oxidation mediated by peroxynitrite appears to be dramatically decreased (149). Therefore, under certain conditions, NO combines with superoxide to form peroxynitrite and potentially increases cellular oxidative burden; however, if NO is present in excess, it may then react with the formed peroxynitrite, effectively behaving as a peroxynitrite scavenger, and suppressing oxidation (Eq. 2). Though the peroxynitrite-mediated oxidation is reduced by NO, other reactive nitrogen species such as nitrogen dioxide are created (139), see Eq. 2 above. Nitrogen dioxide may in turn rapidly react with NO to form the nitrosating species N 2O 3 . Thus, NO can lessen peroxynitrite-mediated oxidative stress, and may protect cells against oxidant injury. Likewise, different studies have shown NO can be protective in other ways: It protects against cytotoxicity of oxidants and peroxide (150); it protects the pulmonary endothelium (151); in animal models NO has been shown to be protective not only in sepsis (152), but also in ischemia-reperfusion (153) and traumatic shock (154). Thus, a balance exists in the NO chemistry between oxidative stress (mediated by ROI) and nitrosative stress (mediated by reactive nitrogen intermediates RNI). These include not only NO, but also species resulting from NO’s rapid oxidation, reduction, or adduction in physiologic milieu, such as NO2 , NO2⫺, N2 O 3, N2 O4, and S-nitrosothiols (139). To complicate matters further, accumulating evidence suggests that RNI posses biologically important antimicrobial activity and are an important part of the host’s response to infection or injury. Therefore, tissue damage may be the price to pay for equipping the host’s cells with the ability to employ NO against viruses, mycobacteria, protozoa, and helminths (72). The majority of the studies discussed were performed in vitro, so one needs to ask about peroxynitrite in vivo. Peroxynitrite production has been shown to be associated in cytokine-induced myocardial dysfunction (assessed echocardiographically) in dogs (155). Peroxynitrite formation was also increased within the human myocardium in patients with sepsis and viral myocarditis (156). Furthermore, peroxynitrite was increased in bronchial tissue of asthmatics (157), and was implicated in bronchiolitis obliterans in human transplanted lungs (158). It should be noted that while increased tissue peroxynitrite appears to correlate with pathology, it is difficult to ascertain a causative effect based solely on morphological findings. Furthermore, the short lifetime (1.9 sec) and the high doses of peroxynitrite required for tissue damage in vivo have led other investigators to question its role. Pou et al. (159), using electron spin resonance spectroscopy, showed that although peroxynitrite can decompose to form other oxidative radicals, the yield was only 1% to 4%. Further evidence has emerged which suggests that peroxynitrite may possess a physiological role not unlike NO (160).
782
Cohen
In addition to superoxide dismutase, the myocardium also expresses other antioxidant enzymes such as glutathione peroxidase (GPX) and catalase. Interestingly, these are heme proteins and therefore can become targets for NO. GPX is one of the major cystolic antioxidant enzymes present in myocytes that detoxifies hydrogen peroxide (H2 O2 ), phospholipid hydroperoxide and hydroperoxides using reduced glutathione as a specific hydrogen ion donor: H2 O 2 ⫹ 2 GSH → 2 H2 O ⫹ GSSG
(3)
where GSH is reduced glutathione and GSSG is oxidized glutathione. Reduced glutathione is then regenerated by glutathione reductase (161). Cowan et al. showed increased GPX gene transcription and mRNA expression in cultured ventricular myocytes in response to oxidative stress (162), a potentially protective mechanism. One study showed that NO inactivates GPX which may explain the cytotoxic effect of NO (163). Recently, it has been demonstrated that iNOS induction decreases GPX activity. Moreover, in the same study, increased NO concentrations using an NO donor decreased GPX activity as well (164). Thus decreased GPX activity via NO may account for increased hydrogen peroxide and oxidative cellular damage. On the other hand, Dengim and coworkers (165) have shown that NO prevents peroxide mediated cellular injury. Furthermore, this study suggested that NO must be present simultaneously with peroxide to exert its protective effect. Kuo et al. demonstrated that cytokine-induced NO production may be protective in the setting of oxidative stress by regulating glutathione synthesis in hepatocytes (166). The toxicity of NO is then dependent on the chemistry it undergoes in a given biological circumstance. Reactions of NO may be toxic or protective, depending on the nature of the insult. In systems where toxicity is due chiefly to ROI, NO may act as a chain breaker and thus limit damage. In systems where toxicity originates from NO synthesis, the reactions with ROI may be deleterious by promoting nitrosation reactions leading to depletion of energy stores, and disruption of cellular function. In this manner, NO can potentially have paradoxical effects on any reaction that is under redox control (137). VII. Regulation of iNOS Inducible NOS is subject predominantly to transcriptional regulation (3). The molecular basis for induction of iNOS is complex and only partially understood. Many different agents up- or down-regulate iNOS, which would be expected, since iNOS gene expression must be tightly controlled as it can have detrimental effects. It is not surprising then that multiple positive and negative regulatory elements, responsive to numerous transcription factors, have been identified in the iNOS promoter. One such transcription factor is the ubiquitous nuclear factor kappa beta (NF-κβ). NF-κβ is a heterodimeric family of transcription factors whose activity is regulated by an inhibitor subunit Iκ-β, which binds to the NF-κβ nuclear localization sequence and sequesters the complex in the cytoplasm. Activators of NF-κβ are
NO and Cardiopulmonary Failure in Sepsis
783
multiple and include LPS and TNFα. These cause phophorylation of Iκ-β on serine 32 and serine 36 by Iκ-β kinase. This in turn leads to ubiquination of Iκ-β and its proteolytic degradation in the proteasome. The destruction of Iκ-β permits nuclear translocation of the NF-κβ complex and transcriptional activity of the NF-κβ responsive genes. These include iNOS, IL-1, IL-6, IL-2, and IL-8, as well as adhesion molecules (ICAM and E-selectins), TNF, lipo-oxygenase, and cyclo-oxygenase-2. Thus, NF-κβ encodes many of the proteins involved in inflammation (167). Indeed, NF-κβ inhibition increased MAP in a rat model of sepsis (168). Peng et al. (169) demonstrated that NO decreases NF-κβ synthesis by stabilizing Iκ-β. Thus, NO appears to negatively regulate its own induction as well as the induction of multiple factors in the inflammatory response by downregulating the action NF-κβ through the activation of its inhibitor Iκ-β. These investigators extended their findings in a later study and showed that inducible NO acts as an inhibitor of vascular inflammation (170). While the actions of LPS appear to depend on NF-κB activation, IFNγ (along with interferon regulatory factor 1) has direct action on the iNOS promoter-enhancer region, resulting in synergistic iNOS induction (171,172). Inhibitors of iNOS transcription include transforming growth factor β in rat vascular smooth muscle (173) and Fe3⫹ in macrophages (174). Interestingly, cellular Fe both regulates and is regulated by iNOS and serves as NO’s most important target (3). It should also be noted the effective signal for iNOS activation varies from cell to cell. For example murine macrophages respond highly to a combination of LPS and IFNγ, while smooth muscle cells respond to IL-1, while hepatocytes respond vigorously to a combination of LPS, TNF, and IFNγ (136). Modification of iNOS activity through recombinant DNA technology would be another approach to therapy.
VIII. Summary Understandably, the sometimes divergent actions exhibited by NO in septic shock have led to confusion. Although the toxic effects of NO appear to correlate roughly with higher concentrations, NO delivery may be protective in some instances. While smaller amounts of NO appear to have homoeostatic functions, inhibiting further NO synthesis may alleviate tissue damage in other conditions. NO has beneficial effects through its modulation of the inflammatory response and its antimicrobial actions, but contributes to organ dysfunction in sepsis. Is NO harmful in sepsis, or is it beneficial? The answer appears to be yes to both. The actions of NO in cardiopulmonary failure in sepsis are directed by the unique chemistry of NO in biological systems. Where, when, and how much NO is present or is being produced under a given circumstance determines its biological response. It should be appreciated that NO production through iNOS activation in sepsis is part of an adaptive response to infection and inflammation. Vasodilatation in sepsis may be viewed as an adaptive response aimed at maximizing tissue perfusion. There appears to be little doubt that NO contributes to sepsis-induced hypotension, and clearly excessive vasodilatation leads to vascular collapse and death. However,
784
Cohen
the use of nonselective NOS inhibitors, while correcting blood pressure, causes more harm than good. At the present time, there appears to be little role for these inhibitors in sepsis, and while selective inhibition seems to be more promising, further studies are essential especially in higher order mammals and eventually in humans. Thus, the initial excitement that NO inhibition in septic shock would be a new therapeutic strategy has unfortunately proved to be too simplistic an approach to a very complex clinical problem. Nonetheless, NO remains an extremely attractive therapeutic target in sepsis. Future research and clinical trials will hopefully define the clinical situations in which NO modulation, rather than inhibition, will be of therapeutic value.
References 1. Stamler JS, Loh EL, Roddy M-A, Currie KE, Creager MA. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994; 89:2035– 2040. 2. Lowenstein CL, Dinerman JL, Solomon HS. Nitric oxide: A physiologic messenger. Ann Intern Med 1994; 120:227–237. 3. Nathan C and Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994; 78: 915–918. 4. Fortier AH, Polsinelli T, Green SJ, Nacy CA. Activation of macrophages for destruction of Francisella tularensis: identification of cytokines, effector cells, and effector molecules. Infect Immun 1992; 60:817–825. 5. Peng H-B, Libby P, Liao JK. Induction and stabilization of IκBα by nitric oxide mediates inhibition of NF-κB. J Biol Chem 1995; 270:14214–14219. 6. Wink DA, Hanbauer I, Laval F, Cook JA, Krishna MC, Mitchell JB. Nitric oxide protects against the cytotoxic effects of reactive oxygen species. Ann NY Acad Sci 1994; 738: 265–278. 7. Pannas D, Khadour FH, Szabo C, Schulz R. Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism. Am J Physiol 1998; 275:H1016–H1023. 8. Michel T, Feron O. Nitric oxide synthases: which, where, how and why. J Clin Invest 1997; 100:2146–2152. 9. Killbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF. N G-methylL-arginine inhibits tumor necrosis factor–induced hypotension: implication for involvement of nitric oxide. Proc Natl Acad Sci USA 1990; 87:3629–3632. 10. Moncada S. The L-arginine nitric oxide pathway. Acta Physiol Scand 1992; 145:201– 227. 11. Gomez-Jimenez, Sagado A, Mourelle M, Martin MC, Segura RM, Peracaula R, Moncada S. L-arginine: Nitric oxide pathway in endotoxemia and human septic shock. Crit Care Med 1995; 23:253–258. 12. Hollenberg SM, Cunnion RE, Zimmerberg J. Nitric oxide synthase responsiveness reverses arteriolar hyporesponsiveness to catecholamines in septic rats. Am J physiol 1993; 254: H660–H663. 13. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109–142. 14. Stuher DJ, Nathan CF. Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med 1989; 169:1543–1555. 15. Hibbs J Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for L-arginine deaminase and imino nitrogen oxidation to nitrite. Science 1987; 235:473–476. 16. Stuehr DJ, Marletta MA. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci USA 1985; 82:7738–7742.
NO and Cardiopulmonary Failure in Sepsis
785
17. Ochoa JB, Udekwu AO, Billiar TR, Curran RD, Cerra FB, Simmons RL, Peitzman AB. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991; 214:621– 626. 18. Lai CS, Komorov AM. Spintrapping of nitric oxide produced in vivo in septic-shock mice. FEBS Lett 1994; 345:120–124. 19. Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 1990; 172:1132–1138. 20. Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo Eur J Phamacol 1990; 182:591– 595. 21. Petros A, Lamb G, Leone A, Moncada S, Bennett D, Valance P. Effects of nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 1994; 28:34–39. 22. Teale Dm, Atkinson AM. Inhibition of nitric oxide synthase improves survival in a murine peritonitis model of sepsis that is not cured by antibiotics alone. J Antimicrob Chemother 1992; 30:839–842. 23. Rees DD, Monkhouse JE, Moncada S. N G-monomethyl-L-arginine HCl (L-NMMA: 546C88) improves survival in a conscious instrumented mouse model of endotoxin shock. Endothelium 1995; 3:S116. Abstract 460. 24. Evans T, Carpenter A, Silva A, Cohen J. Inhibition of nitric oxide synthase in experimental gram-negative sepsis. J Infect Dis 1994; 169:343–349. 25. Lorente JA, Landin L, Renes E, Pablo R, Jorge P, Rodena E, Liste D. Role of nitric oxide in the hemodynamic changes of sepsis. Crit Care Med 1993; 21:759–767. 26. Robertson FM, Offner PJ, Ciceri DP, Becker WK, Pruitt BA Jr. Detrimental effects of nitric oxide synthase inhibition in septic shock. Arch Surg 1994; 129:149–156. 27. Klabunde RE, Ritger RC. N G-monomethyl L-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Commun 1991; 178:1135–1140. 28. Saetre T, Smith AO, Schola T, Carlson H, Nordsletten L, Fahlstrom E, Aasen AO. Nitric oxide synthase inhibition reduces venous return in porcine endotoxemia. Am J Physiol 1996; 271:H1325–H1332. 29. Offner PJ, Robertson FM, Pruitt BA Jr. Effects of nitric oxide synthase inhibition on regional blood flow in a porcine model of endotoxic shock. J Trauma Injury Infect Crit Care 1995; 39:338–343. 30. Statman R, Cheng W, Cunningham JN, Henderson JL, Damiani P, Siconolfi A, Rogers D, Horovitz JH. Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. J Surg Res 1994; 57:93–98. 31. Jourdain M, Tournoys A, Leroy X, Mangalaboyi J, Fourrier F, Goudemand J, Gosselin B, Vallet B, Chopin C. Effects of N ω-nitro-L-arginine methyl ester on the endotoxin-induced disseminated intravascular coagulation in porcine septic shock. Crit Care Med 1997; 25: 452–459. 32. Kilbourne RG, Szabo C, Traber D. Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies. Shock 1997; 7:235–246. 33. Wright CE, Rees DD, Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 1992; 26:48–57. 34. Cohen RI, Huberfeld S, Genovese J, Steinberg HN, Scharf SM. A comparison between the effects of nitric oxide synthase inhibition and fluid resuscitation on myocardial function and metabolism in endotoxemic dogs. J Crit Care 1996; 11:27–36. 35. Cohen RI, Chen L, Scharf SM. The effects of high dose N G-nitro-L-arginine -methyl ester on myocardial blood flow and left ventricular function in dogs. J Crit Care 1996; 11:206– 213. 36. Cobb PJ, Natans on C, Hoffman WD, Lodato RF, Banks S, Kev CA, Solomon MA, Clin RJ, Hassan JM, Danger RL. N ω-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 1992; 176:1175–1182. 37. Cobb PJ, Natans on C, Caseate AM, William D, Hoffman WD, Kev C, Banks S, Cornea
786
38.
39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.
Cohen R, Levi R, Clin R, Hassan J, Danger RL. Differential hemodynamic effects of L-NMMA in endotoxemic and normal dogs. Am J Physiol 1995; 268:H1634–H1642. Freeman BD, Zeni F, Banks SM, Eichacker PQ, Bacher JD, Garvey Ep, Tuttle JV, Jurgensen BS, Natanson C, Danner RL. Response of the septic vasculature to prolonged vasopressor therapy with N ω-monomethyl-L-arginine and epinephrine in canines. Crit Care Med 1998; 26:877–885. Kilbourn RG, Gromeens DM, Chelly FD, Griffith OW. N G-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs. Crit Care Med 1994; 22:1835-1840. Cohen RI, Shapir Y, Chen L, Scharf SM. Right ventricular overload causes the decrease in cardiac output after nitric oxide synthesis inhibition in endotoxemia. Crit Care Med 1998; 26:738-747. Strand AO, Leone AM, Giercksky K-E, Skovlund E, Kirkeboen KA. N G-monomethyl-Larginine improves survival in a pig model of abdominal sepsis. Crit Care Med 1998; 26: 1490–1499. Freeman BD, Cobb JP. Nitric oxide synthase as a therapeutic target in sepsis—more questions than answers? Crit Care Med 1998; 26:1469–1470. Frostell C, Frattacci MD, Wain JC, Jones R, Zopol WM. Inhaled nitric oxide. A selective vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1992; 83:2038– 2047. Adatia I, Thompson J, Landberg M, Wessel DL. Inhaled nitric oxide in chronic lung disease. Lancet 1993; 341:307–308. Roberts JD, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation 1993; 87:447–453. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan At, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338:1173–1174. Ogura H, Cioffi WG, Offner PJ, Jordan BS, Johnson AA, Pruitt BA. Effect of inhaled nitric oxide on pulmonary function after sepsis in a swine model. Surgery 1994; 116:313– 321. Offner PJ, Ogura H, Jordan BS, Pruitt BA, Cioffi WG. Effects of inhaled nitric oxide on right ventricular function in endotoxic shock. J Trauma 1995; 39:179–186. Fierobe L, Brunet F, Dhainaut J-F, Monchi M, Belghith M, Mira J-P, Dall’ava-Santucci J, Dinh-Xuan TA. Effects of inhaled nitric oxide on right ventricular function in adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151(5):1414–1419. Klemm P, Thiemermann C, Winklmaier G, Martorana PA, Henning R. Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxic shock. Br J Pharmacol 1995; 114:363–368. Offner PJ, Ogura H, Jordan BS, Pruitt BA, Cioffi WG. Cardiopulmonary effects of combined nitric oxide inhibition and inhaled nitric oxide in porcine endotoxic shock. J Trauma 1996; 41:641–646. Weitzberg E, Rudehill A, Modin A, Lundberg JM. Effect of combined nitric oxide inhalation and N G-nitro-L-arginine infusion in porcine endotoxic shock. Crit care Med 1995; 23: 909–918. Hinder F, Stubbe HD, Aken HV, Waurick R, Booke M, Meyer J. Role of nitric oxide in sepsis-associated pulmonary edema. Am J Respir Crit Care Med 1999; 159:252–257. Stamler JS, Jia L, Eu JP, Mcmahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulation by S-nitroso-hemoglobin in the physiological oxygen gradient. Science 1997; 276:2034–2038. Keaney JF Jr, Simon DI, Stamler JS, Jaraki Q, Scharfstein J, Vita JA, Losealgo J. NO forms an adduct with serum albumin that has endothelium-derived relaxing factr-like properties. J Clin Invest 1993; 91:1582–1589. Jia L, Bonaventura C, Bonaventura A, Stamler JS. S-nitrosohemoglobin—a dynamic activity of blood involved in vascular control. Nature 1996; 380:221–226. Lorente JA, Landin L, De Pablo R, Renes E, Liste D. L-arginine pathway in the sepsis syndrome. Crit Care Med 1993: 21:1287–1295.
NO and Cardiopulmonary Failure in Sepsis
787
58. Lin PJ, Chang C-H, Chang J-P. Reversal of refractory hypotension in septic shock by inhibitor of nitric oxide synthase. Chest 1994;106:626–629. 59. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991; 338:1557–1558. 60. Locker GJ, Burgmann H, Staudinger T, Knapps S, Laczikas F, Fras M. Fatal cardiac side effecsts of L-NMMA? Crit Care Med 1996; 24:1930. 61. Grover R, Bakker J, Mcluckie A, Anderson J, LeGall J-R. The nitric oxide synthase inhibitor 546C88 promotes the resolution of shock in patients with severe sepsis. The Seventh World Congress of Intensive and Critical Care Medicine, Ottawa, Canada, June 29–July 3, 1997. 62. Szabo CS, Mitchell JA, Thiemermann C, Vane JR. Nitric oxide mediated hyporeactivity to norepinephrine precedes nitric oxide synthase induction in endotoxin shock. Br J Pharmacol 1993; 108:786–792. 63. Liu SF, Adock I, Old R, Barnes PJ, Evans TW. Lipopolysaccharide treatment in vivo induces widespread tissue expression of inducible nitric oxide synthase mRNA. Biochem Biophys Res Commun 1993; 196:1208–1213. 64. Liu SF, Adock IM, Old RW, Barnes PJ, Evans TW. Differential regulation of the constitutive and inducible nitric oxide synthase mRNA by lipopolysaccharide treatment in vivo in the rat. Crit Care Med 1996; 24:1219–1225. 65. Bateson An, Jakiwczyk OM, Schulz R. Rapid increase in inducible nitric oxide synthase gene expression in the heart during endotoxemia. Eur J Pharmacol 1996; 303:141–144. 66. Robinson NM, Westmore KR, Martin JF, Emson P, Charles IG: Inducible nitric oxide synthase transcription and protein activity in the rat heart during endotoxaemia. Biochem Biophys Res Commun 1997; 231:211–216. 67. MacMicking JD, Nathan C, Hom G, Chatrain N, Fletcher DS, Trumbauer M, Stevens K, Xie Q-W, Sokol K, Huthchinson N, Cen H, Mudgett JS. Altered response to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995; 81:641–650. 68. Wei X, Charles IG, Smih A, Ure J, Feng GJ, Huang FF, Xu D, Muller W, Moncada S, Liew FX. Altered immune responses in mice lacking inducible nitric oxidesynthase. Nature 1995; 375:408–411. 69. Laubach VE, Shesely EG, Smithies O, Sherman PA. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA 1995; 92:10688–10692. 70. Li XY, Donaldson K, MacNee W. Lipopolysaccharide-induced alveolar epithelial permeability. Am J Repir Crit Care Med 1998; 157:1027–1033. 71. Katsuya M, Nishina K, Tamada M, Takao Y, Maekawa N, Obara H. Aminoguanididne attenuates endotoxin-induced acute lung injury in rabbits. Crit Care Med 1198; 26:905– 911. 72. Fang FC. Mechanism of nitric oxide-related antimicrobial activity. J Clin Invest 1997; 99: 2818–2825. 73. Babu BR, Griffith OW: Design of isoform-selecive inhibitors of nitric oxide synthase. Curr Opin Chem Biol 1998; 2:491–500. 74. Olken N, Marletta M. N G-methyl-L-arginine functions as an alternative substrate and mechanism-based inhibitor of nitric oxide sythase. Biochemistry 1995; 32:9677–9685. 75. Griffiths M, Messent M, MacAllister R, Evans T. Aminoguanidine selectively inhibits inducible nitric oxide synthase. Br J Pharmacol 1993; 110:963–968. 76. Wu C-C, Ruetten H, Thiemermann C. Comparison of the effects of aminoguanidine and N ω-nitro-L-arginine methyl ester on the multiple organ dysfunction caused by endotoxemia in the rat. Eur J Phamacol 1996; 300:99–104. 77. Szabo C, Southan G, Thiemermann C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci USA 1994; 91:12472–12476. 78. Aranow JS, Zhuang J, Wang H, Larkin V, Smith M, Fink MP. A selective inhibitor of inducible nitric oxide synthase prolongs survival in a rat model of bacterial peritonitis: a comparison with two nonselective strategies. Shock 1996; 5:116–121.
788
Cohen
79. Rosselet A, Feihl F, Markert M, Gnaegi A, Perret C, Liaudet L. Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am J Respir Crit Care Med 1998; 157:162–170. 80. Unno N, Wang H, Menconi M, Tytgat S, Larkin V, Smith M, Morin M, Chavez A, Hodin R, Fink MP. Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in the rats. Gastroenterology 1997; 113:1246–1257. 81. Vos TA, Gouw A, Klok P, Havinga R, Goor HV, Huitema S, Roelofsen H, Kuipers F, Jansen P, Moshage H. Differential effects of nitric oxide synthase inhibitors on endotoxininduced liver damage in rats. Gastroenterology 1997; 113:1323–1333. 82. Bautista AP, Spitzer JJ. Inhibition of nitric oxide formation in vivo enhances superoxide release by the perfused liver. Am J physiol 1994; 266:G783–G788. 83. Cohen RI, Shapir Y, Davis A, Loona R, Scharf SM. Comparison between selective and nonselective nitric oxide synthase inhibition and phenylephrine in normal and endotoxic swine. Crit Care Med 2000; 28:3257–3267. 84. Saetre T, Gundersen Y, Thiemermann C, Lilleaasen P, Aasen A. Aminoethyl-isothiourea, a selective inhibitor of inducible nitric oxide synthase activity, improves liver circulation and oxygen metabolism in a porcine model of endotoxemia. Shock 1998; 9:109–115. 85. Wray GM, Millar CG, Hinds CJ, Thiemermann C. Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/ dysfunction, caused by endotoxin. Shock 1998; 9:329–335. 86. Teale DM, Atkinson AM. L-canavanine restores blood pressure in a rat model of endotoxic shock. Eur J Pharmacol 1994; 271:87–92. 87. Liaudet L, Fishman D, Markert M, Perret C, Feihl F. L-canavanine improves organ function and tissue adenosine triphosphate levels in rodent endotoxemia. Am J Respir Crit Care Med 1997; 155:1643–1648. 88. Fishman D, Liaudet L, Lazor R, Perret C, Feihl F. L-canavanine, an inhibitor of inducible nitric oxide synthase, improves venous return in endotoxemic rats. Crit Care Med 1997; 25:469–475. 89. Stuehr D, Griffith OW. Mammalian nitric oxide synthases. Adv Enzymol 1992; 65:287– 346. 90. Nussler A, Biliar T, Liu Z, Morris S. Co-induction of nitric oxide synthase and argininosuccinate synthases in murine macrophage cell line. J Biol Chem 1994; 269:1257–1261. 91. Hattori Y, Campbell E, Gross S. Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle: role in the regeneration of arginine for nitric oxide synthesis. J Biol Chem 1994; 269:9405–9408. 92. Heyland DK, Cook DJ, Guyatt G. Does the formulation of enteral feeding products influence infectious morbidity and mortality rates in the critically ill patient? A critical review of the evidence. Crit Care Med 1994; 22:1192–1202. 93. Stamler JS, Gow AJ. Reactions betwen nitric oxide and haemoglobin under physiological conditions. Nature 1998; 391:169–173. 94. Bone H, Schenarts P, Mcguire R, Cindrick L Fisher S, Booke M. Modified hemoglobin causes a redistribution of blood in the myocardium during ovine sepsis. Crit Care Med 1996; 24:A99. 95. Hinder F, Brooke M, Traber L, Matsumoto N, Nishida K, Rogers S. Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically elevated atrial naturiuretic peptide. Crit Care Med 1996; 24:131–136. 96. Bone H, Brooke M, Traber L, Spaulding T, Traber D. Nitric oxide synthase inhibition versus nitric oxide scavanging in sepsis. Circulation 1995; 92:I–46. 97. Herald HH, Schidt W, Urlich W. NO at work. Cell 1994; 78:919–925. 98. Zhang H, Rogiers P, Preiser J-C, Spapen H, Manikis P, Metz G, Vincent J-L. Effects of methylene blue on oxygen availability and regional blood flow during endotoxic shock. Crit Care Med 1995; 23:1711–1721. 99. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of Ca⫹⫹ independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992; 105:575– 580. 100. Kelly, RA, Balligand J-L, Smith TW. Nitric oxide and cardiac function. Circ Res 1996; 79:363–380.
NO and Cardiopulmonary Failure in Sepsis
789
101. Balligand J-L, Cannon PJ. Nitric oxide and cardiac muscle. Autocrine and paracrine influences. Arterioscler Thromb Vasc Biol 1997; 17:24–35. 102. Balligand J-L, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signalling system. Proc Natl Acad Sci USA 1993; 90:347–351. 103. Corda S, Mebazaa A, Tavernier B, Ayed MB, Payen D. Paracrine regulation of cardiac myocytes in normal and septic hearts. J Crit Care 1998; 13:39–47. 104. Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H. Functional β 3-adrenoceptor in the human heart. J Clin Invest 1996; 98:556–562. 105. Gauthier C, Leblais V, Kobzik L, Trochu J-N, Khandoudi N, Bril A, Balligand J-L, Le Marec H. The negative inotropic effect of β 3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest 1998; 102: 1377–1384. 106. Mery PF, Lohmann SM, Walter U, Fischmeister R. Ca⫹⫹ current is regulated by cGMPdependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci USA 1991; 88:1197–1201. 107. Wahler GM, Dollinger SJ. Nitric oxide donor SIN-1 inhibits mammalian cardiac calcium current through cGMP-dependent protein kinases. Am J Physiol 1995; 268:C45-C54. 108. Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG. 8-bromo-cGMP reduces the myofilament response to calcium in intact cardiac myocytes. Circ Res 1994; 74:970– 978. 109. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75:725–748. 110. Torres J, Darley-Usmar V, Wilson MT. Inhibition of cytochrome c oxidase turnover by nitric oxide: mechanism and implications for control of respiration. Biochem J 1995; 212: 169–173. 111. Gross WL, Bak MI, Ingwall JS, Kelly RA, Balligand J-L, Smith TW. Nitric oxide regulates rat heart contractile reserve by reversible post-translational modification of creatine kinase. Proc Natl Acad Sci USA. 1996; 93:5604–5609. 112. Campbell DL, Stamler JS, Strauss HC. Redox modulation of the L-type cacium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols. J Gen Physiol 1996; 108:277–293. 113. Cunnion RE, Parrillo JE. Myocardial dysfunction in sepsis. Crit Care Clin 1989; 5:99– 118. 114. Liu SF, Barnes PJ, Evans TW. Time course and cellular localization of lipopolysaccharideinduced inducible nitric oxide synthase messanger RNA expression in the rat in vivo. Crit Care Med 1997; 25:512–518. 115. Finkel TH, Oddis TD, Jacob SC, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257:387–389. 116. Gurevitch J, Dfrolkis I, Yuhas Y, Paz M, Masta R, Yakirevich V. Tumor necrosis factoralpha is released from isolated heart undergiong ischemia and reperfusion. J Am Coll Cardiol 1996; 28:247–252. 117. Oral H, Dorn GW, Mann DL. Sphingosine mediates the immediate negaive inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem 1997; 272:4836–4842. 118. Balligand J-L, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthaesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993; 91:2314–2319. 119. Simmons W, Closs E, Cunningham J, Smith T, Kelly R. Cytokines and insulin induce cationic amino acid transporter (CAT) expression in cardiac myocytes: regulation of Larginine transport and no production of CAT-1, CAT-2A, and CAT-2B. J Biol Chem 1996; 271:11694–11702. 120. Mckenna T, Li S, Tao S. PKC mediates LPS- and phorbol-induced cardiac cell nitric oxide synthase activity and hypocontractility. Am J Physiol 1995; 269:H1891–H1898. 121. Singh K, Balligand J-L, Fischer T, Smith T, Kelly R. regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvacsular endothelial cells: role of extra-
790
122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 135a. 136. 137. 138. 139. 140. 141. 142. 143.
Cohen cellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT 1 alpha. J biol Chem 1996; 271:1111–1117. Lapointe M, Sitkins J. Mechanisms of interleukin-1 beta regulation of nitric oxide synthase in cardiac myocytes. Hypertension 1996; 27:709–714. Brady AJB, Poole-Wilson PA, Harding SE, Waren JB. Nitric oxide– production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992; 263: H1963–H1966. Kinugawa K, Takahasi T, Kohmoto O, Yao A, Aovagi T, Momomura S, Hirata Y, Serizawa T. Nitric oxide–mediated effects of interleukin-6 on [Ca2⫹ ] i and cell contraction in cultured chick ventricular myocytes. Circ Res 1994; 75:285–295. Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993; 265:H176–H182. Schulz R, Panas DL, Catena R, Moncada S, Olley PM, Lopaschuk GD. The role of nitric oxide in cardiac depression induced by interleukin-1β and tumor nacrosis factor-α. Br J Pharmacol 1995; 114:27–34. Herbertson MJ, Werner HA, Waley KR. Nitric oxide synthase inhibition partially prevents decreased LV contractility during endotoxemia. Am J Phsiol 1996; 270:H1979–H1984. Kaszaki J, Wolford A, Bari F, Boros M, Parratt J, Nagy S. Effect of nitric oxide synthase inhibition on myocardial contractility in anesthetized normal and endotoxemic dogs. Shock 1996; 4:279–285. Klabunde RE, Coston AF. nitric oxide synthase inhibition does not prevent cardiac depression in endotoxic shock. Shock 1995; 3:73–78. Meng X, Ao L, Brown JM, Fullerton DA, Banerjee A, Harken AH. Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock. Shock 1997; 7:111–118. Toth I, Heard S. Nitric oxide does not mediate lipopolysaccharide induced myocardial depression in guinea pigs. Crit Care Med 1997; 25:684–688. Hoch CE, Yin K, Yue G, Wong PY. Effects of inhibition of nitric oxide synthase by aminoguanidine in acute endotoxemia. Am J Physiol 1997; 272:H843–H850. Ishihara S, Ward JA, Tasaki O, Pruitt BA Jr , Goodwin CW Jr. Mozingo DW, Cioffi WG Jr. Inhaled nitric oxide prevents left ventricular impairement during endotoxemia. J Appl Physiol 1998; 85:2018–2024. Weyrich AS, Xin-liang M, Buerke M, Murohara T, Armstead VE, Lefer AM, Nicolas JM, Thomas AP, Lefer D. Physiological concentrations of nitric oxide do not elicit an acute negative inotropic effect in unstimulated cardiac muscle. Circ Res 1994; 75:692–700. Zhang H, Rogiers P, Friedman G, Preiser J-C, Spapen H, Buurman WA, Vincent J-L. Effects of nitric oxide donor SIN-1 in oxygen availability and regional blood flow during endotoxic shock. Arch Surg 1996; 131:767–774. Afulukwe IF, Cohen RI, Zeballos GA, Iqbal M, Scharf SM. Selective NOS inhibition restores myocardial contractility in endotoxemic rats; however myocardial NO content does not correlate with myocardial dysfunction. Am J Resp Crit Care Med 2000; 162:21–26. Billiar TR. Nitric oxide; novel biology with clinical relevance. Ann Surg 1995; 221:339– 349. Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 1994; 78:931–936. Kronke K-D, Fehsel K, Bachofen-Kolk V. Nitric oxide: Cytotoxicity versus cytoprotection—how, why, when, and where? Nitric Oxide Biol Chem 1997; 1:107–120. Wink DA, Mitchell JB. Chemical biology of nitric oxide insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Rad Biol Med 1998; 25:434–456. Deming RH, Lalonde PR, Ryan P, Zhu D, Liu Y. Endotoxemia produces an increase in arterial but not venous lipid peroxides in sheep. J Appl Physiol 1988; 64:592–598. Minamiya Y, Abo S, Kiamura M, Keiichi I, Kimura Y, Tozawa K, Saito S. Endotoxininduced hydrogen peroxide production in intact pulmonary circulation of rat. Am J Respir Crit Care Med. 1995; 152:348–354. Goode HF, Webster NR. Free radicals and antioxidants in sepsis. Crit Care Med 1993; 21:1770–1776. Szabo C, Zingarelli B, Salzman A. Role of poly-ADP ribosyltransferase activation in the
NO and Cardiopulmonary Failure in Sepsis
144. 145. 146. 147. 148. 149. 150.
151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164.
791
vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res 1996; 78:1051–1063. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol 1996; 271:C1524–C1437. Packer MA, Scarlett JL, Martin SW. Peroxynitrite: A biolgically significant oxidant. Gen Phamacol 1998; 31:179–186. Koppenol WH. Moreno JL, Pryor WA, Ischiropoulus H, Beckman JS. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol 1992; 5:834– 842. Miles AM, Bohle DS, Glassbrenner PA, Hansert B, Wink DA, Grisham MB. Modulation of superoxide-dependent oxidation and hydroxylation reactons by nitric oxide. J Biol Chem 1996; 271:40–47. Radi R, Beckman JS, Brush KM, Freeman BA. Peroxynitrite oxidation of sulfhydryls: the cytotoxic potential of superoxide and nitric oxide. J Biol Chem 119; 266:4244–4250. Clancy RM, Leszczynska-Piziak J, Abramson SB. Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on NADPH oxidase. J Clin Invest 1992; 90:1116–1121. Wink DA, Cook JA, Pacelli R, DeGraff W, Gamson J, Liembman J, Krishna M, Mitchell JB. The effect of various nitric-oxide donor agents on hydrogen peroxide-mediated toxicity: A direct correlation between nitric oxide formation and protection. Arch Biochem Biophys 1996; 331:241–248. Chang J, Rao N, Markewitz BA, Hoidal JR, Michael JR. Nitric oxide donor prevents hydrogen peroxide mediated endothelial cell injury. Am J Physiol 1996; 270:L9231–L940. Boughton-Smith NK, Hutcheson IR, Deakin AM, Whittle BJR, Moncada S. Protective effect of S-nitroso-N-acetyl-penicillamine in endotoxin-induced acute intestinal damage in the rat. Eur J Pharmacol 1990; 191:485–488. Kubes P. Ischemia-reperfusion in feline small intestines: a role for nitric oxide. Am J Physiol 1993; 264:G142–G149. Christopher TA, Ma X, Lefer AM. Beneficial actions of S-nitroso-N-acetylpenicillamine, a nitric oxide donor, in murine traumatic shock. Shock 1994; 1:19–24. Oyama J-I, Shimokawa H, Mommii H, Cheng X-S, Fukuyama N, Arai Y, Egashira K, Nakazawa H, Takeshita A. Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardail dysfunction in dogs in vivo. J Clin Invest 1998; 101:2207–2214. Kooy NW, Lewis SJ, Royall JA, Ye YZ, Kelly DR, Beckman JS. Extensive tyrosine nitration in human myocardial inflammation: evidence for the presence of peroxynitrite. Crit Care Med 1997; 25:812–819. Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. Increased formation of the potent oxidant peroxynirite in the airways of asthmatic patients is associzted with the induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J 1998; 12:929–937. Mason NA, Springall DR, Pomerance A, Evans TJ, Yacoub MH, Polak JM. Expression of inducible nitric oxide synthase and formation of peroxynitite in posttransplant obliterative bronchiolitis. J Heart Lung Trans 1998; 17:710–714. Pou Y, Nguyen SY, Gladwell T. Does peroxynitrite generate hydroxyl radical? Biochim Biophys Acta 1995; 244:62–68. Taprey M, Beckman JS, Ischiropoulos H. Peroxynitrite stimulates vascular smooth muscle cell cGMP synthesis. FEBS Lett 1995; 354:314–318. Thompson JA, Hell ML. The oxygen free radical system: a fundemental mechanism in the production of myocardial necrosis. Prog Cardiovasc Dis 1986; 28:449–462. Cowan DB, Weisel RD, Williams WG, Mickle DA. The regulation of glutathione peroxidase gene expression by oxygen tension in cultured human cardiomyocytes. J Mol Cell Cardiol 1992; 24:423-433. Asahi M, Fujii J, Suzuki K, Seo HG, Kuzuya T, Hori M, Tada M, Fujii S, Taniguchi N. Inactivation of glutathione peroxidase by nitric oxide; implications for cytotoxicity. J Biol Chem 1995; 270:21035–21039. Igarashi J, Nishida M, Hoshida S, Yamashita N, Kosaka H, Hori M, Kuzuya T, Tada M. Inducible nitric oxide synthase augments injury elicited by oxidative stress in rat cardiac myocytes. Am J Physiol 1998; 274:C245.
792
Cohen
165. Degnim AC, Morrow SE, Ku J, Zar HA, Nakayama DK. Nitric oxide inhibits peroxidemediated endothelial toxicity. J Surg Res 1998; 75:127–134. 166. Kuo PC, Slivka A. Nitric oxide decreases oxidant-mediated hepatocyte injury. J Surg Res 1994; 56:594–600. 167. Baldwin AS. The NF-κB and IκB proteins; new discoveries and insights. Annu Rev Immunol 1996; 14:640–681. 168. Liu SF, Ye X, Malik AB. In vivo inhibition of nuclear factor-κB activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J Immunol 1997; 159:3976–3983. 169. Peng HB, Libby P, Liao JK. Induction and stabilization of IκBα by nitric oxide mediates inhibition of NF-κB. J Biolol Chem 1995; 270:14214–14219. 170. Peng HB, Spiecker M, Liao JK. Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation. J Immunol 1998; 161:1970–1976. 171. Kamijo R, Harada H, Matsuyama T, Rosland M, Gerecitano J, Shapiro D, Le J, Im KS, Kimura T, Green S, Mark TW, Taniguchi T, Vilcek J. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 1994; 263:1612–1615. 172. Martin E, Nathan C, Xie, Q-W. Role of interferon regulator facor 1 (IRF-1) in induction of nitric oxide synthase. J Exp Med 1994; 180:977–984. 173. Perrella JA, Yoshizumi M, Fen Z, Tsai JC, Hsieh C-M, Kourembanas S, Lee M-E. Transforming growth factor-β1, but not dexamethasone, down regulates nitric oxide synthase mRNA after its induction by interleukin-1β in rat smooth muscle cells. J Biol Chem 1994; 269:14595–14600. 174. Weiss G, Werner-Felmayer G, Werner ER, Grunwald K, Wachter H, Hentze MW. Iron regulates nitric xide synthase activity by controlling nuclear transcription. J Exp Med 1994; 180:969–976.
30 Databases and Outcomes in Cardiopulmonary Care
ALAN S. MULTZ and CORRADO P. MARINI Long Island Jewish Medical Center New Hyde Park, New York
I.
Introduction
Critical care is a complex subspecialty consuming a large proportion of health care dollars in the United States (1,2). As technology improves and more expensive lifesustaining treatments become available, critical care physicians will be required to justify the use of such measures through performance improvement programs as well as prospective outcomes data. Recently, controversy has risen regarding the appropriate use of right heart catheters as well as the role of weaning protocols to shorten mechanical ventilation (3–8). Additional political areas of controversy include triage criteria for admission to the ICU to optimize the use of limited resources, end-of-life issues, and the use of protocols and guidelines in the treatment of critically ill patients to increase clinical effectiveness. Escalating costs and the lack of rigorous prospective data demonstrating benefits for some of the treatments that we do fuel these controversies. Clearly, in the face of increasing costs and decreasing resources, critical care as a specialty in medicine will continue to grow through the use of databases and outcomes reports. Specialists will be required to document effectiveness. If we agree to take this initiative ourselves, we may remain free from regulatory governmental agencies while remaining on the cutting edge in both science and clinical medicine. 793
794
Multz and Marini II. Databases
A database is a mechanism by which data can be organized, subsequently studied, and from which inferences can be made. Databases should be flexible, relational, and easy to administer. Operational databases are used in many areas of the hospital and create a record for each observation. This type of database contains repeated measurements of the same variable in the form of data points. This is in contrast to analytical databases, which have the ability to integrate many different variables of interest and create a record for each patient event. Analytic databases frequently contain a single measurement of a particular variable. It is possible using a powerful enough database to take operational data and convert them into analytic data. An ideal database for critical care medicine would be able to easily integrate the barriers that exist to the effective and direct flow of data from operational databases into analytic ones. Table 1 contains a complete list of the contents that would be desirable in a database to be used for critical care. The list shown in Table 1 is much more comprehensive than that which is provided by the federal government database, which retrieves information from patients with Medicare, Medicaid, and private insurers. Despite the many limitations of state and government databases, these databases have generated the ‘‘outcome’’ information available today in critical care (9,10). This is necessary in order to meet the demands required by continuous quality improvement (CQI). Most of the discharge data that we have available are obtained from the use of ICD-9-CM codes (International Classification of Diseases, Ninth Revision, Clinical Modification). Inherent to using ICD-9-CM codes is the question, ‘‘Do the codes accurately reflect the actual disease and illness?’’ At our institution, as a part of CQI, we reviewed 100 charts of patients with a discharge diagnosis of pneumonia. As part of our review, we also examined all of the chest radiographs that were taken upon admission and during the subsequent hospitalization. We found that 10% of the patients had a normal radiograph throughout the hospitalization and one-third of the patients actually had congestive heart failure. This point is quite important, as administrative decisions may be made based on point epidemiologic studies that use ICD-9-CM codes. The limitations of information derived by ICD-9-CM codes can be appreciated in the following example. A health care system decides to investigate whether a chronic ventilatory unit is needed in their system. They decide to review all of the tracheostomy patients to come to this programmatic decision. This type of point survey may be triggered by identification of a rise in the number of patients with ICD-9-CM codes for tracheostomy. What this type of investigation fails to do, is take into account the reason for tracheostomy. A tracheostomy for thyroid or laryngeal cancer has a different prognosis and implication from a tracheostomy performed for chronic ventilatory failure. We believe that databases should include a glossary of defined medical terms to provide meaningful comparative analysis. In the absence of defined terminology, comparison of performance cannot be made accurately. An example of the impact
Databases and Outcomes in Cardiopulmonary Care Table 1
795
Suggested Variables for a Critical Care Database
Demographics Medical Record No. Date of birth Social Security No. Name Address Phone No. Sex Ethnicity Admission data Admit date Discharge (D/C) date ICU admit date ICU D/C date Ventilator start date Ventilator end date Reason for intubation Referred by Transfer from ICU arrival condition Primary diagnosis Secondary diagnosis Hospital D/C status ICU D/C status Insurance data Height Weight Admitting service Internist/surgeon Consultants Medicolegal issues Complications ICU D/C condition Functional D/C status Critical care services Radiology data X-ray type Location Interpretation
Medication data Medication Strength Route Frequency Start date Stop date
Digoxin level Lactate Fibrinogen Fibrin split products Urine lytes Urinalysis Other studies
Hemodynamics Date Time Systolic BP Diastolic BP Pulmonary artery BP Central venous pressure Wedge pressure Cardiac output Heart rate
Respiratory Date Time Hemoglobin Cardiac output PH PaO 2 PaCO 2 Base excess Saturation FIO 2 Ventilator settings PEEP level I: E ratio Plateau pressure
Microbiology Date Time Procedure Culture site Organize Sensitivities Gram stain Laboratory Date Complete blood count Electrolytes PT/PTT Liver functions Blood gas CPK-isoenzymes Amylase Calcium Magnesium Phosphorous Vancomycin level Gentamicin level
Procedures Physician Procedure No. of attempts Location Start date Stop date Complications Survival date apache ii score Pittsburgh brain injury TISS score Glasgow coma scale SAPS II score Progress data
796
Multz and Marini
of this lack of a well-defined glossary on CQI can be appreciated by the following example concerning catheter infections. A health care system consisting of several institutions wants to monitor catheter infection in their system since these events increase ICU costs. What is a catheter infection? Catheter colonization is defined as the presence of a positive culture of an intracutaneous segment and/or catheter tip in the absence of leukocytosis or fever. Catheter infection could be defined as a fever and/or leukocytosis, and a positive culture of an intracutaneous catheter segment and/or catheter tip. These two concepts are clearly different from a catheterrelated septicemia, which would include the same criteria to define a catheter infection plus a positive blood culture. In a practical sense, these terms are frequently interchanged due to lack of stringent criteria to define such events. This potentially leads to inaccurate epidemiologic data and possibly unnecessary CQI efforts. With the knowledge that the database must be both operational and analytic, it should also have a strict, universal system of defining medical diseases and complications. The database must be able to provide information on utilization, costs, clinical data, disease registries, and mortality. This type of strong database would enable us to conduct effective prospective and/or retrospective clinical research, perform CQI activities, and analyze clinical outcomes. Some examples of commercially available databases are ICU Assistant (version 1.2) and Project Impact. Tables 2 and 3 contain examples of reports that can be generated using an ICU database. It
Table 2 Summay Statistics by Diagnosis between 1997 and 1998 Time period
Number of patients Patient days Mean age Average LOS Average vent days Functional class apache ii score apache iii score Glascow coma scale TISS-78 TISS-28 SAPS Deaths Pred mortality (SAPS) Pred mortality (APII) Estimated mortality Actual mortality
1/1/98–12/31/98 (count)
1/1/97–12/31/97 (count)
62 291 (62) 73.56 (62) 4.69 (62) 3.57 (58) 5.2 (62) 11.9 (62) 44.05 (62) 15.0 (62) 38.08 (62) 34.87 (62) 26.79 (62) 1/62 9.44% (62) 21.32% (62) 1.61% (62) 1.61% (62)
54 320 (54) 74.43 (54) 5.93 (54) 4.67 (48) 4.3 (54) 13.78 (54) 50.94 (54) 14.74 (54) 39.69 (54) 33.94 (54) 28.69 (54) 3/54 12.47% (54) 28.92% (54) 7.41% (54) 5.56% (54)
Diagnosis: 441.4, Abdominal aortic aneurysm. Note: Values reflect the scores recorded during the first 24 hours after admission to the ICU.
Databases and Outcomes in Cardiopulmonary Care
797
Table 3 Summary of Catheter-Related Statistics (January 1, 1999, to February 28, 1999): Summary by Catheter Types (total patients ⫽ 57) Catheter type
No.
Catheter days
Catheter days (mean)
Arterial lines Percutaneous Cutdown
59 58 1
192 185 7
(3.25) (3.19) (7.0)
Central venous lines CVP Double lumen CVP Triple lumen CVP Hemodialysis
28 18 3 4 3
110 56 25 17 12
(3.93) (3.11) (8.33) (4.25) (4.0)
PA catheters Swan-Ganz catheter Oxymetric swan
37 36 1
66 62 4
(1.78) (1.72) (4.0)
0 0 0 124
0 0 0 368
(---) (---) (---) (6.46)
Transvenous pacemakers Transvenous PPM Temporary PPM Total
Positive cultures (catheter tip or ICS) No./Total
% Group
% Total
Arterial lines Percutaneous Cutdown
2/59 2/58 0/1
3.39 3.45 0.0
3.39 0.0
CVP lines CVP Double lumen CVP Triple lumen CVP Hemodialysis CVP (unspecified)
7/28 3/18 0/3 4/4 0/3 0/28
25.0 16.67 0.0 100.0 0.0 0.0
10.71 0.0 14.29 0.0 0.0
PA lines Swan-Ganz catheter Oxymetric Swan Pacemakers Transvenous PPM Temporary PPM Total
1/37 1/36 0/1 0/0 0/0 0/0 10/124
2.7 2.78 0.0 — — — 8.06
2.7 0.0 — —
798
Multz and Marini
Table 3 Continued Positive catheters per 100 catheter-days Arterial lines Percutaneous Cutdown
1.04 1.08 0.0
CVP lines CVP Double lumen CVP Triple lumen CVP Hemodialysis CVP (unspecified)
6.36 5.36 0.0 23.53 0.0 0.0
PA lines Swanz-Ganz catheter Oxymetric swan
1.52 1.61 0.0
Pacemakers Transvenous PPM Temporary PPM
— —
Total positive catheters/100 catheter-days ⫽ 8.06. Two patients had identical positive catheter and blood cultures for a catheter-related sepsis rate of 1.61 catheters/100 patient catheter-days. Five patients had catheter colonization for a catheter colonization rate of 4.03 catheters/100 patient catheter-days.
is easy to appreciate how powerful and valuable a good database can be to the performance of CQI, cost containment, and outcomes studies.
III. Outcomes Data and Scoring Systems Measuring outcomes in critical care is a difficult task. Clearly, we practice in a ‘‘high-mortality’’ area of the hospital. Yet mortality continues to be the easiest outcome for clinical research. Mortality can be assessed at various times and in various parts of the hospital. For instance, using 28-day survival versus hospital survival is one area of controversy. ICU mortality versus hospital mortality raises the question of issues like ICU discharge and triage, as well as differences in ICU organization. There has been an increased interest in looking at economic outcomes as part of database analysis. There are various areas that have been investigated, including ICU length of stay (LOS), hospital LOS, and ventilator days. These issues have been tied into issues surrounding ICU organization. The emergence of different scoring systems for risk prediction is being used more frequently in matters relating to both mortality and economic outcomes (11). Terms like cost-effectiveness, costminimization, cost-utility, and cost-benefit have entered into the picture (12).
Databases and Outcomes in Cardiopulmonary Care
799
The Acute Physiology and Chronic Health Evaluation (apache) scoring system emerged in 1985 (13,14). At that point in time, apache ii was introduced to help classify the severity of illness. Using easily obtainable variables, one is able to predict hospital mortality. apache ii can be used to evaluate both prospectively and retrospectively issues like treatment effectiveness and risk of death. This scoring system is also widely used as an admission criterion for clinical trials. Marsh et al. looked at apache ii as an indicator for both mortality and quality of care by using the standardized mortality ratio (SMR) to assess hospital’s performance. SMR is the ratio of actual mortality to predicted mortality. The rationale behind SMR is that if this ratio at your institution is ⬍ 1, a more favorable outcome than would have been predicted is being seen. The implication is that quality of care being delivered is ‘‘better’’ than the standard that might be expected for patient with the same severity of illness score. The authors found a different SMR for nonoperative patients at two different hospitals within the same institution (p ⫽ .014). Other than patients residing on the hepatology or hematology/oncology service, no other differences in SMR were observed between operative and nonoperative patients. The data are felt by the authors to possibly be related to an intrinsic weakness in the apache ii system for case mix data (15). The Mortality Prediction Model (MPM and MPM II ) is a different scoring system to aid in determining outcome and mortality (16–18). This system examines admission variables, which don’t necessarily require the patient to have been seen by the data collector at this time of admission, and permit a calculation of predicted mortality. This is the MPM 0. By expanding some of the variables contained in the MPM 0, one can also determine the MPM 24 and MPM 48, thus allowing repeated predictions of mortality over the initial 48 hours a patient’s illness. The apache iii Prognostic System was introduced in 1991 in an attempt to improve the risk prediction model of apache ii (19). This included a change in the weighting scale of certain variables and also sought to examine the impact of patient’s selection and timing of ICU admission to hospital outcome. Some investigators believe apache iii to be superior to its predecessor, apache ii; however, apache iii is a proprietary program and at the time of this publication, the equations used by apache iii to derive prognosis are not available without buying this expensive system. Other scoring systems available include the Therapeutic Intervention Scoring System (TISS 28 and TISS 76 ) (20,21), the Simplified Acute Physiology Score (SAPS and SAPS II) (22,23), and the Rapid Acute Physiology Score (RAPS). The prognostic accuracy of apache iii was evaluated prospectively in a large nonrandomized observational study. In this study, Zimmerman et al. showed a good correlation between predicted mortality and the actual hospital mortality (24). However, some disease-specific differences were observed, particularly with myocardial infarction, overdoses, and nonoperative trauma cases. Sirio et al. looked at the use of apache iii as a model for the Cleveland Health Quality Choice System (25). This was a retrospective cohort study that looked at mortality and compared it to calculated risk. This study showed that apache iii overestimated the risk of death. It also suggested that using scoring systems across a series of hospitals may be not be valid, as admission and discharge criteria may have geographic and political differences.
800
Multz and Marini
On the other hand, a decline in the SMR was noted over years, as well as a reduction on the length of stay. The data suggest that changes can occur and be sustained over time. A possible limitation of apache iii was discussed in this article namely failure to address functional status, mental health, or social support. A large focus of clinical research is on use scoring systems in the ICU. Studies have been done to look at comparison data between scoring systems, or look at the use of scoring systems in disease specific entities and assess reliability. LeGall et al. looked at using SAPS II and MPM II 24 in the setting of severe sepsis (26). They noted that in this subgroup, patients had a higher mortality rate that predicted from the scores when compared to all ICU patients. The authors proceeded to develop a customized scoring system for severe sepsis that improved the predictability of the models. Pittet et al. examined variables that could determine mortality of patients admitted to the ICU for bacteremic sepsis (27). In this study, apache ii score was found to be one of the best independent prognostic factors for outcome (odds ratio 1.13; 85% confidence intervals 1.08 to 1.17; P ⫽ .0016). Hamahata et al. compared apache ii against apache iii for mortality post-hepatectomy in patients with biliary tract carcinoma (28). They found that apache iii was more reliable as a predictor of postoperative mortality (P ⬍ .0001). Studies aimed at validating or comparing scoring systems are prevalent. Beck et al. evaluated apache ii and apache iii prospectively in a cohort of mixed medical and surgical ICU patients (29). They found that hospital mortality was higher than predicted by both scoring systems. The risk prediction for surgical patients and those with gastrointestinal disease was better with apache ii. Overall, there was no significant difference between the two scoring systems and in some disease-specific categories, apache iii performed worse. Nouira et al. prospectively compared four severity scoring systems in Tunisia (30): apache ii, MPM 0, MPM 24, and the SAPS II. They found that all but MPM 0 scoring systems tended to underestimate mortality rates in this country. Clearly, a mortality higher than predicted by these scoring systems may indicate a quality-of-care issue in Tunisia rather than a problem with the scoring systems themselves since scoring systems are known to over-, not underestimate mortality rate. Moreno et al. examined the differences between the SAPS II and MPM 0 model from the European Intensive Care Units Studies (euricus-1) group (31). In this study, both severity systems overestimated mortality. The conclusion was that neither of these severity scoring systems accurately predicted mortality in this large multicenter ICU database. Hence, one should interpret with caution conclusions drawn from data using these scoring systems. Most recently, Janssens et al. have done a prospective study comparing apache iii, SAPS II, and MPM II 0-72 (32). They looked at consecutive patients and first found no differences between any of the scoring systems with respect to ICU mortality. They also noted no differences in day-to-day changes between nonsurvivors and survivors out to day 6, suggesting that looking at daily severity scores did not improve the outcome prediction. In the United Kingdom, Pappachan et al. looked at the use of apache iii prospectively (33). They found that after performing a case mix adjustment, mortality was greater than predicted by the scoring system. The
Databases and Outcomes in Cardiopulmonary Care
801
authors felt this may be due to the inapplicability of this scoring system in the United Kingdom, or a poorer ICU performance than that in the United States. Ultimately, the goals of using databases and scoring systems are to make an impact upon medical care. That impact can be multifaceted as it could focus on costs, quality of life, and mortality. In 1995, Cohen et al. used information from the Statewide Planning and Cooperative System (sparcs) to retrospectively examine the impact of age on mechanical ventilation. They found that age had an important effect on mechanical ventilation, but that other factors were involved in outcome from ICU care. Esserman et al. also looked at the effectiveness of critical care by examining those patients in whom critical care was ineffective (34). They defined an entity called potentially ineffective care (PIC) and used the apache iii model for risk estimates. They found a large portion of resources devoted to the PCI category and suggested a change of focus to an assessment looking at ineffective care based on outcome and resource use. Outcome studies have been used to assess other aggressive kinds of therapies in high-mortality groups. Hamel et al. retrospectively examined both outcome and cost-effectiveness of initiating dialysis in critically ill patients (35). Both apache ii and TISS 28 scores were calculated in this cohort and used in determination of cost-effectiveness and outcome. They found that in patients with a poor prognosis, initiating and continuing hemodialysis was not a cost-effective measure. Another well-defined group of patients with poor outcomes is those who have received bone marrow transplantation and require mechanical ventilation (36–39). Paz et al. recently evaluated an educational program upon physicians regarding this issue to see if a change in ICU resource utilization would ensue (40). The authors found that physician education had a minimal impact upon physician practice and referral patterns, even in a group of patients with a known dismal outcome. The implication for the practices of critical care remains an endpoint for clinical studies. Multz et al. examined the effects of ICU organization on the practice of critical care (41). This study found a difference in both ICU (P ⬍ .0001) and hospital LOS (P ⬍ .008) with a closed ICU organization. In addition, a significant impact was noted on length of days of mechanical ventilation with a closed ICU (P ⬍ .0005). No mortality effect was firmly shown here, but the implication was more efficient care in the ICU setting. Cost-benefit resulted as a consequence of a closed unit model. Similarly, Bach et al. looked at outcome differences between critically ill patients managed by a university-based (UB) intensivist as compared to a community-based (CB) intensivist (42). These authors found a significant effect on mechanical ventilation (p⫽0.02), addressing advanced directives and end-of-life issues (P ⬍ .01) in the UB service. This study failed again to demonstrate an effect on mortality. Cost data were examined and a significant difference was noted between the UB and CB physician groups with respect to reimbursement, the UB group demonstrating the favorable financial profile (P ⫽ 0.03). One of the most influential factors in the outcome and resource utilization appears to be mechanical ventilation. Mechanical ventilation is such a strong variable that is has been shown to correlate with both hospital and ICU LOS and predict
802
Multz and Marini
ICU mortality (41). Therefore, a considerable amount of time and effort has been spent trying to address issues surrounding this ICU treatment. Time has been dedicated to matters like withdrawal of mechanical ventilation, trying to identify groups in whom this process should be avoided or withheld, and what is the best way to try to safely discontinue it. The impact of this treatment is broad based if we take into account associated costs. For example, nosocomial pneumonia is a significant cause of morbidity in this group of patients; there is the matter of sedation and/or paralysis; the problem of self-extubation; the longterm complications associated with tracheostomy or prolonged endotracheal intubation; and manpower concerns for respiratory therapy (43). The process of discontinuing mechanical ventilation begins with an assessment of ‘‘weanability.’’ Identification of validated weaning criteria to predict outcome from weaning has not been easy. The traditional weaning parameters suggested by Sahn and Lakshminarayan were minute ventilation and maximal inspiratory pressure (44). In 1991, Yang and Tobin suggested use of the ‘‘rapid shallow breathing index,’’ which was expressed as the ratio of the frequency of breathing to the tidal volume (f/V T ) (45). This study suggested that the rapid shallow breathing index was the best predictor of successful weaning (specificity of 0.64). The maximal inspiratory pressure (sensitivity of 1.0) and the rapid shallow breathing index (sensitivity of 0.97) were the best predictors of failure to wean. From weaning parameters, studies began to focus on the proper technique or mode with which to facilitate discontinuation of mechanical ventilation. Esteban performed a multicenter prospective, randomized trial on patients who were considered to be ready for weaning by their caretakers (5). They compared intermittent mandatory ventilation (IMV), pressure support ventilation (PSV), intermittent trials of spontaneous breathing conducted two or more times a day, and a once-a-day trial of spontaneous breathing. They found once-a-day spontaneous breathing trials to be superior to both IMV (P ⬍ .006) and PSV (P ⬍ .04) weaning. No significant differences were noted between once-a-day trials and multiple trials of spontaneous breathing. One must still be cautious in interpretation of studies involving weaning parameters and weaning techniques. For example, there is a subgroup of patients who require no weaning at all, like drug overdoses or the patient who presents in acute pulmonary edema that is successfully treated. Then there are the patients who may be deemed ‘‘unweanable’’ but who really are not, like those with neuromuscular disease. There is also the group of patients who meet ‘‘criteria,’’ but may not be good candidates for weaning, like those with severe acid-base disturbances or multiple organ dysfunction syndrome. So at this point, it is safe to say that some degree of individualization may still be necessary in approaching the weaning issue. Due to the way critical care services are organized in the United States, most of the intensive care units are directed by general internists in an open organizational format. There is potential to have a delay in weaning in hospitals with this structure for many possible reasons including lack of round-the-clock on-site supervision, oversedation, inappropriate use of neuromuscular blocking agents, or excessive caloric intake. Thus, there has been a push to create weaning protocols that are directed
Databases and Outcomes in Cardiopulmonary Care
803
under the auspices of nonphysician critical caregivers. Ely et al. conducted a randomized, controlled study performed by nurses and respiratory therapists to identify patients who were ready for weaning (6). Physicians were informed of their patient’s ‘‘weanability’’ and the intervention produced a decrease in the median number of says of mechanical ventilation (P ⫽ .003). Additionally, the complication rate was less in the intervention cohort (P ⫽ .001) as well as total critical care costs (P ⫽ .03). Their conclusion focused on a reduction in both the duration of mechanical ventilation and the associated costs of critical care in the setting of a reduced complication rate. Kollef et al. also did a randomized controlled trial of a protocol-directed weaning process where they compared the protocol to physician-directed weaning (7). They found a difference in time of mechanical ventilation in the protocol-directed group (median time 35 hours) versus the physician-directed weaning (median time 44 hours). A significant reduction in costs was noted as a result of this time difference. However, no differences in mortality, reintubation, or complications were noted between the groups. Most recently, Ely and coworkers prospectively evaluated the implementation of a therapist-driven weaning protocol without daily physician input (8). They demonstrated that this type of weaning strategy is feasible and effective. However, barriers to complete implementation were in part due to lack of physician compliance with the protocol and potential loss of autonomy in patient care. The process of implementing protocols has to be dynamic and should include review and CQI by all parties involved. The potential for better outcomes with significant savings in cost will warrant an examination of this process on a larger scale. Mechanical ventilation is such a common treatment in the critical care setting and it represents a prototype example of potential for improvement with proper administration and outcome measure assessment. As we stand at the crossroads of critical care practice, issues like use of protocols, the involvement of more nonphysician medical professionals in traditional physician roles, and reliance on interpretation of outcomes data will become a daily exercise. These issues will help shape the future of critical care and how ICU medicine is practiced.
References 1. 2. 3.
4. 5.
Henning RJ, McClish D, Daly B, Nearman J, Franklin C, Jackson D. Clinical characteristics and resource utilization of ICU patients: implications of organization of intensive care. Crit Care Med 1987; 15:264–269. Spivack D. The high cost of acute health care: a review of escalating costs and limitations of such exposure in intensive care units. Am Rev Respir Dis 1987; 136:1007–1011. Connors AF, Speroff T, Dawson NV, Thomas C, Harrell FE, Wagner D, Desbiens N, Goldman L, Wu A, Califf RM, Fulkerson WJ, Vidaillet H, Broste S, Bellamy P, Lynn J, Knaus WA. The effectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 1996; 276:889–897. Pulmonary Artery Catheter Consensus Conference Participants. Consensus statement. Crit Care Med 1997; 25:910–925. Esteban A, Frutos F, Tobin MJ, Alia I, Solsona JF, Valverdu I, Fernandez R, de la Cal
804
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
20. 21. 22. 23. 24. 25.
Multz and Marini MA, Benito S, Tomas R, Carriedo D, Macais S, Blanco J. A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med 1995; 332:345–350. Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, Johnson MM, Browder RW, Bowton DL, Haponik EF. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335:1684–1689. Kollef MH, Shapiro SD, Silver P, St John RE, Prentice D, Sauer S, Ahrens TS, Shannon W, Baker-Clinkscale D. A randomized, controlled trial of protocol-directed versus physiciandirected weaning from mechanical ventilation. Crit Care Med 1997; 25:567–574. Ely EW, Bennett PA, Bowton DL, Murphy SM, Florance AM, Haponik EF. Large-scale implementation of a respiratory therapist-driven protocol for ventilator weaning. Am J Respir Crit Care Med 1999; 159:439–446. Mitchell JB, Bubolz T, Paul JE, Pashos CL, Escarce JJ, Mulbaier LH, Wiesman JM, Young WW, Epstein RS, Javitt JC. Using Medicare claims for outcomes research. Med Care 1994; 32:JS38–JS51. Lave JR, Pashos CL, Anderson GF, Brailer D, Bubolz T, Conrad D, Freund DA, Fox SH, Keeler E, Lipscomb J, Luft HS, Provenzano P. Cost in medical care: using Medicare administrative data. Med Care 1994; 32:JS77–JS89. Curtis JR. The ‘‘patient-centered’’ outcomes of critical care: what are they and how should they be used? New Horiz 1998; 6:26–32. Rubenfeld GD. Cost-effectiveness considerations in critical care. New Horiz 1998; 6:33– 40. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. apache ii: a severity of disease classification system. Crit Care Med 1985; 13:818–829. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. An evaluation of outcome from intensive care in major medical centers. Ann Intern Med 1986; 104:410–418. Marsh HM, Krishan I, Naessons JM, Strickland RA, Gracey DR, Campion ME, Nobrega FT, Southorn PA, McMichan JC, Kelly MP. Assessment of prediction of mortality by using the apache ii scoring system in intensive care units. Mayo Clin Proc 1990; 65:1549–1557. Lemeshow S, Teres D, Pastides H, Avrunin JS, Steingrub, JS. A method for predicting survival and mortality of ICU patients using objectively derived weights. Crit Care Med 1985; 13:519–525. Lemeshow S, Teres D, Avrunin JS, Gage RW. Refining intensive care unit outcome prediction by using changing probabilities of mortality. Crit Care Med 1988; 16:470–477. Lemeshow S, Teres D, Klar J, Avrunin JS, Gehlbach SH, Rapoport J. Mortality probability models (MPM II ) based on an international cohort of intensive care unit patients. JAMA 1993; 270:2478–2486. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, Sirio CA, Murphy DJ, Lotring T, Damiano A, Harrell FE. The apache iii prognostic system: risk prediction of hospital mortality for critically ill hospitalized patients. Chest 1991; 100:1619– 1636. Cullen DJ, Civetta JM, Briggs BA, Ferrara LC. Therapeutic intervention scoring system. A method for quantitative comparison of patient care. Crit Care Med 1974; 2:57–60. Keene AR, Cullen DJ. Therapeutic intervention scoring system: update 1983. Crit Care Med 1983; 11:1–3. LeGall JR, Loriat P, Alperovitch A, Glaser D, Grathil C, Mathieu D, Mercier P, Thomas R, Villers D. A simplified physiology score for ICU patients. Crit Care Med 1984; 12:975– 977. LeGall JR, Lemeshow S, Saulnier F. A new simplified acute physiology score (SAPS II) based on a European/North American multi-center study. JAMA 1993; 270:2957–2963. Zimmerman JE, Wagner DP, Draper EA, Wright L, Alzola C, Knaus WA. Evaluation of acute physiology and chronic health evaluation. III. Predictions of hospital mortality in an individual database. Crit Care Med 1998; 26:1317–1326. Sirio CA, Shepardson LB, Rotandi AJ, Cooper GS, Angus DC, Harper DL, Rosenthal GE. Community-wide assessment of intensive care outcomes using a physiologically based prognostic measure. Implications for critical care delivery from Cleveland Health Quality Choice. Chest 1999; 115:793–801.
Databases and Outcomes in Cardiopulmonary Care 26. 27. 28. 29.
30. 31. 32. 33. 34. 35.
36. 37. 38. 39. 40. 41.
42. 43. 44. 45.
805
LeGall JR, Lemeshow S, Leleu G, Klar J, Huillard J, Rue M, Teres D, Artigas A. Customized probability models for early severe sepsis in adult intensive care patients. JAMA 1995; 273: 644–650. Pittet D, Thievent B, Wenzell RP, Li N, Auckenthaler R, Suter PM. Bedside prediction of mortality from bacteremic sepsis: a dynamic analysis of ICU patients. Am J Respir Crit Care Med 1996; 153:684–693. Hamahata N, Nagino M, Nimura Y. apache iii, unlike apache ii, predicts posthepatecomy mortality in patients with biliary tract carcinoma. Crit Care Med 1998; 26:1671–1676. Beck DH, Taylor BL, Millar B, Smith GB. Prediction of outcome from intensive care: a prospective cohort study comparing acute physiology and chronic health evaluation II and III prognostic systems in a United Kingdom intensive care unit. Crit Care Med 1997; 25: 9–15. Nouira S, Belghith M, Elatrous S, Jaafoura M, Ellouzi M, Boujdaria R, Gahbiche M, Bouchoucha S, Abroug F. Predictive value of scoring systems: comparison of four models in Tunisia adult intensive care units. Crit Care Med 1998; 26:852–859. Moreno R, Miranda DR, Fidler V, Van Schlifgaarde RV. Evaluation of two outcome prediction models on an independent database. Crit Care Med 1998; 26:50–61. Janssens U, Graf C, Graf J, Hanrath P. Comparison of different scoring systems (apache iii, SAPS II, MPM II0-72 ): value of daily measurement in 303 consecutive patients. Crit Care Med 1999; 27(suppl):A63. Pappachan JV, Millar B, Bennett ED, Smith GB. Comparison of outcome from intensive care admission after adjustment for case mix by the apache iii prognostic system. Chest 1999; 115:802–810. Esserman L, Bellacora J, Lenert L. Potentially ineffective care. A new outcome to assess the limits of critical care. JAMA 1995; 274:1544–1551. Hamel MB, Phillips RS, Davis RB, Desbiens N, Connors AF, Teno JM, Wenger N, Lynn J, Wu AW, Fulkerson W, Tsevat J. Outcomes and cost-effectiveness of initiating dialysis and continuing aggressive care in seriously ill hospitalized adults. Ann Intern Med 1997; 127:195–202. Crawford SW, Schwartz DA, Petersen FB, Clark JG. Mechanical ventilation after marrow transplantation: risk factors and clinical outcome. Am Rev Respir Dis 1988; 137:682-687. Crawford SW, Petersen FB. Long-term survival from respiratory failure after marrow transplantation. Am Rev Respir Dis 1992; 145:510–514. Paz HL, Crilley P, Weinar M, Brodsky I. Outcomes of patients requiring ICU admission following bone marrow transplantation. Chest 1993; 104:527–531. Crawford SW. Using outcomes research to improve the management of blood and marrow transplant recipients in the intensive care unit. New Horiz 1998; 6:69–74. Paz HL, Garland A, Weinar M, Crilley P, Brodsky I. Effect of clinical outcomes data on intensive care unit utilization by bone marrow transplant recipients. Crit Care Med 1998; 26:66–70. Multz AS, Chalfin DB, Samson IM, Dantzker DR, Fein AM, Steinberg HN, Niederman MS, Scharf SM. A ‘‘closed’’ medical intensive care unit (MICU) improves resource utilization when compared with an ‘‘open’’ MICU. Am J Respir Crit Care Med 1998; 157:1468– 1473. Bach PB, Carson SS, Leff A. Outcomes and resource utilization for patients with prolonged critical illness managed by university-based or community-based subspecialists. Am J Respir Crit Care Med 1998; 158:1410–1415. Kollef MH, Horst HM Prang L, Brock WA. Reducing the duration of mechanical ventilation. Three examples of change in the intensive care unit. New Horiz 1998; 6:52-60. Sahn SA, Lakshminarayan S. Bedside criteria for discontinuation of mechanical ventilation. Chest 1973; 63:1002–1005. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning form mechanical ventilation. N Engl J Med 1991; 324:1445-1450.
31 Mechanical Ventilation with PEEP
HENRY E. FESSLER Johns Hopkins Medical Institutions Baltimore, Maryland
I.
Introduction
The good air goes in. The bad air comes out. The blood goes around and around. For readers in a hurry, this summary may suffice. Mechanical ventilation with PEEP is a broad topic which has been the subject of extensive animal and clinical research in the decade since the first edition of this text. Many of the relevant basic concepts of heart-lung interaction are covered in detail in other chapters of this edition. This chapter will attempt to integrate basic mechanisms into the global effects of PEEP, and relate these concepts to patient care. In the past decade, there have been several new approaches to the delivery of mechanical ventilation such as inverse-ratio ventilation and partial liquid ventilation in acute respiratory distress syndrome (ARDS). There have also been further clinical insights into PEEP, such as appreciation of the prevalence and importance of auto-PEEP, and the use of PEEP in obstructive lung disease. The very purpose and goal of PEEP are changing. Typically, it has been used sparingly to minimize oxygen requirements in diffuse lung injury. Now it is now being advocated in more generous quantities to reduce lung injury associated with mechanical ventilation (1–3) and even to reduce inflammation (4). 807
808
Fessler
We will begin by revisiting and reviewing a few concepts of how the respiratory and circulatory systems act and interact. These concepts are rooted in physical laws, and form a relatively unchanging paradigm with which to interpret observations. We will next integrate newer data which illuminate the complexity of these interactions or, occasionally, shift the paradigm. We will focus on mechanical effects, which have been studied in greatest detail. Finally, we will apply these concepts to some of the recent changes in the clinical application of mechanical ventilation and PEEP. This last goal will be the most ephemeral. Clinical care continually evolves, and it is likely that some of the techniques discussed will never come into widespread practice. Others will fall out of favor as data and experience prove them unhelpful. Nevertheless, we will attempt to describe the cardiovascular consequences of PEEP as currently practiced, and perhaps as it will be used in the decade to come.
II. History of MV and PEEP The widespread use of mechanical ventilation and PEEP during surgery or respiratory failure is a modern development with ancient origins. Artificial respiration is described in Genesis 2:7, ‘‘And the Lord God formed man of the dust of the ground, and breathed into his nostrils the breath of life, and man became a living soul.’’ More prosaically, Andreas Vesalius ventilated a pig through a tracheostomy. He describes some early cardiopulmonary interactions from the experiment in 1543: ‘‘For when the lung, long flaccid, has collapsed, the beat of the heart and arteries appears wavy, creepy, twisting, but when the lung is inflated, it becomes strong again and swift and displays wondrous variations’’ (5). In 1667 Hooke used a bellows to ventilate a dog. In addition, by making numerous incisions on the visceral pleural surface he was able to keep the animal alive with a continuous flow of air into the trachea, demonstrating that the air rather than the movement of the lungs was essential (6). Human application did not progress substantially until the adoption of surgical anesthesia beginning in the latter half of the 19th century. Surgery was typically performed in a spontaneously breathing patient. This limited the development of thoracic surgery, since a unilateral pneumothorax via a large thoracotomy was poorly tolerated. An early attempt to overcome this problem was to enclose both the surgeon and the patient, except for his head, in a chamber which would be negatively pressurized. This still required the patient to inspire, was hot and cramped, and impeded communication (7). Practical application of mechanical ventilation awaited a suitable interface between the ventilator and patient. Early endotracheal tubes were metal, placed blindly, and were sealed to the airway with pharyngeal packing. The interface was simplified by the invention of flexible endotracheal tubes which sealed with an inflatable balloon and by the modern laryngoscope (8). However, positive-pressure ventilation was adopted only slowly, in part because of the perceived difficulty of reliably and safely intubating patients and concerns about overdistending their lungs.
Mechanical Ventilation with PEEP
809
Pump or bellows devices for manually inflating and deflating the lungs were available in the late 1800s. The Drager Pulmotor was a manual device for ventilating through a tight-fitting face mask. It was widely used by rescue squads, but not for hospital care. The first commercial automatic positive-pressure ventilators were introduced in the 1940s, based on the Spiropulsator designed by Crafoord (9). Practical tank ventilators (‘‘iron lungs’’) were manufactured by Drinker in 1928 (10) and modified by Emerson. While widely used internationally during the polio epidemics of the 1950s, the limitations of negative-pressure ventilation included hypoventilation, retained secretions, and poor access for nursing care. Bennett et al. modified the tank ventilator with a device to provide positive pressure through a tracheostomy during inspiration (11). It was soon recognized that the tank was superfluous, and adequate tidal volumes could be delivered for long periods through an endotracheal tube or tracheostomy outside of the operating theater. Positive end-expiratory pressure was first used in the form of CPAP by Poulton in 1936 (12) and Alvin Barach in 1938 (13), who advocated its use for pulmonary edema. Only recently have potential benefits of this simple therapy been appreciated (14). Extensive but classified investigation of the cardiovascular effects of PEEP was stimulated by the requirements of high-altitude aviation during World War II. Because of engineering limitations, airplane cockpits could not be pressurized. Although pilots could breathe supplemental oxygen, at altitudes in excess of 40,000 feet, they risked disorientation or syncope from hypoxemia. This was responsible for many deaths during test flights. It was demonstrated that breathing oxygen through a face mask under positive pressure could reverse hypoxemia (15). At ambient barometric pressure at 40,000 feet on 100% oxygen, alveolar PO 2 is only 56 mm Hg. This is increases by 7 mm Hg for every 10 cm H 2 O CPAP. However, it quickly became apparent that high levels of CPAP also caused syncope from hypotension. The cause of this was explored by Cournand (16). He reasoned it was due to decreased venous return brought about by the high pressures within the thorax, a conclusion which remains valid 50 years later. This problem was not fully solved until cockpits themselves were pressurized. Recognition of the deleterious effects of positive airway pressure on cardiac output inhibited the use of PEEP in clinical care. Its beneficial effects on oxygenation in normal subjects were reported in 1959 (17). The widespread use of PEEP and CPAP awaited reports of their use in the management of ARDS by Ashbaugh in 1967 (18), in respiratory distress syndrome of the newborn by Gregory in 1971 (19), and in similar reports that quickly followed (20,21).
III. Basic Concepts A. Control of Cardiac Output
Analysis of cardiac output is rendered much simpler (and this book rendered unnecessary) if one ignores the act of breathing. Cardiac output is then determined only by a relatively limited number of factors: (1) the ability of each ventricle to generate pressure; (2) the pressure within the systemic and pulmonary circulation driving
810
Fessler
blood back to the respective atrium; (3) the downstream pressures opposing cardiac ejection and venous return; and (4) the resistances for cardiac output and venous return. Of course, each of these factors is subject to numerous influences. These include changes in neural tone, local or systemic vasoactive mediators, posture, muscle tone, or cardiac perfusion. Furthermore, the cyclic nature of blood flow means that change in any one of these factors can alter all of the others. For the purpose of understanding heart-lung interactions during PEEP, it is expedient to focus on the factors directly determining venous return. Venous return is quite sensitive to the relatively small pressure changes generated by ventilation. Also, although respiration affects myriad determinants of blood flow, ultimately these effects can be condensed to their impact on the few determinants of venous return. These factors are discussed in detail in Chapter 5. B. Stresses on the Circulation by Respiration
Fundamentally, ventilation only adds a single detail to the simple mechanical system described above: lung volume increases. During spontaneous breathing, this is accomplished through inspiratory muscle activation which lowers pleural pressure. During positive-pressure mechanical ventilation in a patient making no respiratory efforts, this is accompanied by an increase in pleural pressure. In both cases, alveolar pressure rises relative to pleural pressure; in the former alveolar pressure remains near atmospheric, while in the latter it is increased. In both cases, abdominal pressure rises as the diaphragm descends; in the former transdiaphragmatic pressure rises, while in the latter it does not. Thus, inspiration, whether spontaneous or mechanical, causes four basic mechanical stresses on the circulation. It increases the stress on alveolar blood vessels. It increases the stress on abdominal blood vessels. It may increase or decrease the stress on one ventricle through distention of the other. It may increase or decrease the stress on the surface of the heart. A theoretical discussion of these stresses is the subject of a recent review (22) and of several chapters in this text. These stresses are further simplified by limiting consideration to steady-state effects. Since ventilation is phasic, it causes transient cardiovascular changes within each respiratory cycle. These give rise to numerous interesting clinical signs such as paradoxical pulse or Kussmaul’s sign, as discussed in Chapters 10 and 33. However, beyond their diagnostic value and physiologic interest, these transient effects have little impact on the patient. Of greater importance are effects leading to a sustained change in cardiac output or its distribution. In this regard, compared to spontaneous breathing, the most profound effect of mechanical ventilation is the elevation of mean pleural pressure. This is further increased by PEEP, accompanied by an increase in mean lung volume. IV. Effects of PEEP A. PEEP and the Determinants of Venous Return
It has been recognized for over 50 years that PEEP decreases cardiac output, yet the primary cause of this decrease has been the topic of great debate. PEEP increases
Mechanical Ventilation with PEEP
811
right atrial pressure. The most proximate cause of this is the direct transmission of increased pleural pressure surrounding the right atrium. Many investigators have concluded that this increase in right atrial pressure is the major reason cardiac output falls; i.e., venous return falls because the downstream pressure for venous flow has risen (16,23). However, implicit in that conclusion is the assumption that the upstream pressure to venous return, mean systemic pressure (PMS ), is unchanged, or at least rises less than does right atrial pressure. There are good reasons to question that assumption. It has been shown that hypotension or sympathetic stimulation increases PMS (24–26). A fall in arterial pressure such as accompanies PEEP would increase sympathetic tone, and would have similar effects. Circulating catecholamines, released in response to hypotension, also decrease systemic vascular capacitance (27–29). PEEP increases abdominal pressure by displacing the diaphragm downward. This increased stress on abdominal vessels would decrease their unstressed volume and increase PMS . Finally, PEEP translocates blood volume from the heart and pulmonary circulation into the systemic circulation (23). Like a transfusion, this would also increase PMS . Scharf and colleagues examined cardiovascular effects of PEEP in anesthetized, paralyzed dogs (30). Their preparation allowed PEEP to be applied either with its associated increase in lung volume or, by pressurizing the pleural space by the same amount as the PEEP, at unchanged lung volume. They plotted the cardiac output at different levels of PEEP against the concurrent right atrial pressure in the format of venous return curves. Their plots differed from typical canine venous return relations (31). They were quite curvilinear, and the extrapolated zero-flow intercept exceeded 20 mm Hg. The relation obtained at constant lung volume (when pleural pressure was higher for equal PEEP) lay to the right of the one obtained at increased lung volume. From these findings, Scharf et al. inferred that PEEP increased PMS; that is, the single relationship plotted at different levels of PEEP was actually composed of points on separate, parallel venous return curves. They attributed the greater rightward shift when lung volume was kept constant to greater displacement of the diaphragm and higher abdominal pressure. In further studies, they compared the roles of abdominal pressure changes and sympathetically mediated venoconstriction during PEEP (32). They varied the magnitude of PEEP’s effect on abdominal pressure by either binding or widely opening the abdomen. They also ablated α-adrenergic reflexes with phenoxybenzamine. They found no effect of abdominal binding on the change in cardiac output caused by PEEP, suggesting that stress on the surface of abdominal vessels was of little importance. In contrast, the PEEP-induced fall in cardiac output was much greater in the presence of α-adrenergic blockade. Based on these inferences, Fessler et al. more explicitly measured the effects of PEEP on PMS (33). PMS was measured as the right atrial pressure during a brief period of ventricular fibrillation. This may underestimate PMS because there has not been complete pressure equilibration throughout the systemic circulation, but that error is likely to be small. They found that PEEP elevated PMS ; surprisingly, it elevated it by the same amount as it did PRA ; that is, the pressure gradient driving venous return was unaltered. Confirming the inferences of Scharf et al., PMS rose
812
Fessler
similarly when the abdomen was open, closed, or tightly bound. The increase in PMS was attenuated somewhat after carotid sinus denervation and reduced by about 50% when sympathetic reflexes were eliminated by total spinal anesthesia (with a continuous infusion of epinephrine to maintain arterial pressure at its off-PEEP level). This supported the important role of reflex changes in the circulation in response to PEEP. However, PMS rose significantly on PEEP even during spinal anesthesia. It was speculated that the transfer of blood from the central to the peripheral circulation was responsible for this rise. The equal increases in both PMS and PRA have since been shown in humans during the brief periods of ventricular fibrillation accompanying electrophysiologic testing (34). Although PMS and PRA rose equally in the canine studies, cardiac output nonetheless fell. By basic principles, this implies a change in the conducting properties of veins. Fessler et al. studied this issue by applying 10 mm Hg PEEP in a closedchest canine right heart bypass preparation to compare venous return curves on and off PEEP (35). The systemic venous return from the inferior and superior venae cavae (IVC and SVC) were separated, because it was anticipated that mechanical and reflex effects might differ in these beds. They found that PEEP had several effects on the venous return curves. The zero-flow intercept, approximating PMS , was increased similarly in the two venous circuits. The slope of the curve decreased significantly (resistance increased) only in the SVC. The downstream pressure below which flow became maximal, termed PCRIT , increased in both SVC and IVC, and tended to increase to a greater extent in the IVC (Fig. 1). A total venous return curve was obtained by summing the venous return from the IVC and SVC (Fig. 2). In canine studies in which the venous return curve was estimated from two-point measurements, Nanas and Magder found qualitatively similar effects of PEEP: Venous return fell despite no change in the PMS-PRA driving pressure, and venous resistance therefore rose (36). In the studies of Fessler et al., 10 mm Hg PEEP decreased total venous return by about 40% even when the downstream pressure for venous return was kept constant and subatmospheric. This illustrates the potential for PEEP to decrease cardiac output even independent of any increase in right atrial pressure it might cause. Total venous resistance, measured as the flow-weighted average of the SVC and IVC resistances, increased by 15%. The disproportionate fall in flow suggests there was also a decrease in the pressure gradient driving flow. How can this be reconciled with evidence that PMS and PRA rose equally? If right atrial pressure were below PCRIT, a condition termed a ‘‘vascular waterfall’’ is said to exist. This term was first applied to blood flow through the pulmonary circulation when alveolar pressure exceeded left atrial pressure (37). The waterfall analogy refers to the dissociation of flow from left atrial pressure, much the way that flow over a falls is independent of its height or conditions downstream. Under these circumstances, the effective downstream pressure for flow is PCRIT , not PRA . If PEEP were to elevate PCRIT in some parts of the circulation in excess of PRA , then the effective pressure gradient for venous flow from those regions could fall despite an unaltered (PMS-PRA ) difference.
Mechanical Ventilation with PEEP
813
(a)
(b) Figure 1 (a) Venous return from the inferior vena cava (VRivc) versus the downstream pressure in the IVC (Pivc) plotted as a venous return curve. Squares ⫽ no PEEP, circles ⫽ 10 mm Hg PEEP; mean of eight canine experiments. (From Ref. 35.) (b) Venous return from the superior vena cava (VRsvc) versus the downstream pressure in the SVC (Psvc) plotted as a venous return curve. Squares ⫽ no PEEP, circles ⫽ 10 mm Hg PEEP; mean of eight canine experiments. (From Ref. 35.)
814
Fessler
Figure 2 Total venous return curve obtained by summing the flows from the data in Figure 1 at 1 mm Hg intervals, plotted against right atrial pressure. (From Ref. 35.)
If such a vascular waterfall were present, one may find a discontinuity of intravascular pressure somewhere between the locus of PMS and the right atrium. Pressures upstream of the discontinuity would be determined by pressure-flow relations between PMS and PCRIT . Pressures downstream would be determined by flow, PRA , and the resistance downstream from the locus of PCRIT . There would be a sudden change in pressure across a short length of vessel that spans the site of the vascular waterfall. To explore for this phenomenon, Fessler et al. measured the intravascular pressure through catheters withdrawn in 1-cm increments from the right atrium up the SVC and down the IVC in intact anesthetized dogs (38). Measurements were made with and without 10 mm Hg PEEP. They were also made in four positions in order to vary regional lung volume: supine, prone, left and right lateral decubitus. Off PEEP in the left lateral decubitus position, a sudden change in pressure at a discrete site in the IVC was seen in only one of 10 animals. However, on PEEP a fall in pressure of up to 4 to 5 mm Hg was found over a 1 to 2-cm length of the intrathoracic IVC in 9 of 10 animals (Fig. 3). In the right lateral decubitus position, only one animal showed a localized pressure drop (2 mm Hg) with or without PEEP (Fig. 4). In supine and prone positions, the effects of PEEP were less consistent, and such a pressure drop was never observed in the SVC. When the pressure drop was present on PEEP, it could be eliminated by volume-loading the animal to raise intravascular pressure, and then reproduced by increasing PEEP to raise extravascular pressure (Fig. 5). These findings suggest that the intrathoracic IVC is being compressed by lungs hyperinflated with PEEP. Since nondependent lungs are more inflated than dependent lungs, this effect on the IVC would be more pronounced when the right lung was nondependent. Supporting this interpretation, the pressure drop did not appear if
Mechanical Ventilation with PEEP
815
Figure 3 Longitudinal distribution of pressure in the SVC and IVC in the left lateral decubitus position. Distance is in centimeters cephalad (positive values) and caudad (negative values) from the right atrium, which is indicated by 0. Each symbol represents the same animal. Top panel ⫽ no PEEP; bottom panel ⫽ 10 mm Hg PEEP. (From Ref. 38.)
PEEP was applied with inflation of the right lower lobe prevented by intrabronchial occlusion. Although flow was not measured in these studies, the pressures upstream of the site of sudden pressure drop were shown to be dissociated from right atrial pressure. In the left lateral decubitus position on PEEP, right atrial pressure could be elevated without raising pressures in the IVC just upstream of the site of presumed compression. Once PCRIT was exceeded, both right atrial and upstream pressures rose together. Returning to the waterfall analogy, this corresponds to raising the base of the falls. Pressures upstream are not affected until the base rises above the lip of the falls.
816
Fessler
Figure 4 See legend to Figure 3. Right lateral decubitus position. Top panel ⫽ no PEEP; bottom panel ⫽ 10 mm Hg PEEP. (From Ref. 38.)
For this phenomenon to occur, PEEP not only must elevate pressure on the surface of the IVC, but must elevate it by more than it does the pressure on the surface of the right atrium. Finally, magnetic resonance imaging was used to visualize the IVC, which was shown to be widely patent off PEEP and compressed by surrounding lung on PEEP. An increase of effective downstream pressure of only a few mm Hg may not seem large. However, it can have a dramatic effect on flow because of the very low resistance of the venous circulation, whose total driving pressure is normally only about 5 mm Hg. Other investigators have compared the effects of PEEP applied to the right lung or left lung alone, or to both lungs, using a dual-lumen endotracheal tube in supine dogs. These studies have demonstrated the greatest fall in cardiac output
Mechanical Ventilation with PEEP
817
Figure 5 Longitudinal distribution of pressure in the SVC and IVC in a single animal in the left lateral decubitus position, plotted as in Figures 3 and 4. When euvolemic (right atrial pressure about 1 mm Hg on no PEEP), the addition of 10 mm Hg PEEP introduces a sudden pressure drop in the IVC. Volume-loading the animal raised all intravascular pressures and eliminated the gradient along the IVC. Raising PEEP reproduced the sudden pressure drop at the same location.
when PEEP is applied to both lungs (39,40). Cardiac output also falls when PEEP is applied to the right lung alone, but generally to a lesser degree. PEEP applied only to the left lung causes little or no change in cardiac output. In a study by Veddeng et al., right and left PEEP increased pericardial pressure similarly. This suggests that other factors, such as the direct compression of the IVC, may have caused the greater fall in output during right PEEP compared to left PEEP. To summarize the effects of PEEP on the venous circulation, it has been shown to elevate right atrial pressure but also to elevate PMS by about the same amount. Thus, the pressure gradient driving venous return is unchanged. Venous return falls because of increased venous resistance and possibly due to elevation of pressure surrounding portions of the venous system in excess of right atrial pressure.
818
Fessler
While demonstrable in dogs, it remains uncertain to what extent these phenomena occur when PEEP is applied in humans. The canine IVC has a long intrathoracic course, unlike in the human, and runs between the right lower and cardiac lobe. The latter has no counterpart in man. The focal compression of the IVC requires lung hyperinflation, which occurs predictably in anesthetized dogs with normal lungs. In humans in whom PEEP is applied, lung compliance and end-expiratory lung volume are typically reduced. In that case, PEEP would merely restore lung volume toward normal. In patients requiring PEEP, there is also variation in intravascular volume status, vascular tone, sympathetic responsivity, exogenous catecholamines, and drugs with autonomic effects. These differences will likely alter the extent to which PEEP can elevate PMS , and make it difficult to generalize from the canine findings. However, the potential for PEEP to compress the IVC in humans is suggested by findings in another hyperinflated state, emphysema. Nakhjavan et al. angiographically demonstrated occlusion of the IVC at the level of the diaphragm during inspiration in 6 of 15 hyperinflated emphysema patients. They also showed that respiratory changes in right atrial pressure were dissociated from pressure in the IVC measured upstream from the occlusive site (41). Finally, a steplike change in pressure in the IVC of a few mm Hg was found by catheter pullback in some emphysema patients undergoing right heart catheterization prior to lung volume reduction surgery (personal communications, Dr. Steven Scharf). Several studies have suggested that PEEP or CPAP has less deleterious effects on cardiac output, or can even increase output, in patients with left ventricular failure (42–44). PEEP decreases both LV preload and afterload (see below). A failing ventricle is less sensitive to preload reduction and more sensitive to afterload reduction (45). Therefore, these differential effects of PEEP on ventricular loading have been suggested as the explanation for its more salutary effects in heart failure. However, in intact animals and patients, failing hearts are coupled to circulations. One may speculate that the different effects of PEEP in heart failure are attributable to different effects on the peripheral circulation. Since the venous return curves on and off PEEP intersect each other, PEEP could have different effects on venous return depending on whether baseline right atrial pressure was high or low. At constant right atrial pressure, i.e., independent of PEEP’s effect on the heart, venous return must fall if PEEP is applied when right atrial pressure is low because of the decrease in maximal flow. At high PRA , venous return could rise because of the increase in mean systemic pressure. The possible PEEP-induced change in venous return at constant right atrial pressure is shown by the vertical difference between the venous return curves with and without PEEP shown in Figure 2. This difference is plotted in Figure 6. B. Right Ventricular Emptying
The change in PRA caused by PEEP is due to both increases in the pressure on the surface of the RV and changes in its transmural pressure. One mechanism whereby
Mechanical Ventilation with PEEP
819
Figure 6 Change in venous return which would occur if PEEP were applied at constant right atrial pressure. This plot is the vertical distance between the venous return curves on and off PEEP shown in Figure 2.
PEEP can increase RV transmural pressure is by impairing RV ejection. Pulmonary vascular resistance (PVR) is related to lung volume in a bimodal fashion. Resistance is minimal near functional residual capacity. At lower volumes, resistance rises (46). This is believed to be due to kinking and tortuosity of vessels. At lung volumes above FRC, resistance rises again. This is due both to lengthening of pulmonary vessels and to the elevation of alveolar pressure relative to pulmonary artery and left atrial pressure (47). This expands zone II regions of the lung (48), where alveolar pressure is the effective pressure against which the RV ejects. The decrease in venous return accompanying PEEP would tend to make the RV smaller. The greater impediment to RV ejection would tend to make the RV larger. Moreover, the magnitude of this latter effect will vary, depending on how much of the lung is in zone II, how sensitive the RV is to changes in its afterload (49), and the range of lung volume over which PEEP is acting (46). Therefore, it should be no surprise that both animal and human studies document the RV getting smaller, larger, or staying the same size on PEEP (40,49–54). In general, if volume loading is used to restore cardiac output to its levels off PEEP, then the RV is larger on PEEP. In patients, the effects of PEEP on RV diastolic volume have been quite unpredictable (54,55). The failing, or ischemic, ventricle is more sensitive to an increase in afterload than is a normal ventricle. Schulman and colleagues applied up to 20 cmH 2 O to dogs before and after infarcting much of the RV by right coronary artery occlusion. Using thermodilution techniques, they found that PEEP caused dilatation of the RV only after RV infarction. In addition, PEEP after infarction decreased RV blood flow further, perhaps by increasing wall stress and decreasing arterial pressure (49).
820
Fessler C. Left Ventricular Filling
Any decrease in right ventricular inflow must, within a few heart beats, result in decreased inflow to the left ventricle. However, in addition to this passive, series effect, PEEP may have more direct effects on LV filling. The diastolic volume of the LV is determined by its transmural pressure and compliance. These may be altered by changes in the deformability of the lung surrounding the heart, shifts of the interventricular septum, changes in the shape of the LV cavity from nonuniform pressures surrounding it, and intrinsic changes in the elastic properties of myocardium (56). These factors have been difficult to tease apart, because of complex interaction between cardiac and lung volume. Takata and Robotham showed that off PEEP in euvolemic pigs, the pericardium is under stress (57). However, they found that that the lungs progressively constrain the heart (transpericardial pressure approaches zero) as PEEP is increased. With volume loading, on the other hand, transpericardial pressure remains positive up to 20 cmH 2 O PEEP. In animals, PEEP causes flattening of the left ventricle, which is greatest at the free wall (53,58,59). In humans, it increases the radius of curvature of the septum (60,61). PEEP has been shown in some studies to decrease LV compliance (62,63), which may be due to changes in LV conformation or increased rigidity of the distended surrounding lung (63). Others have failed to find reduced LV compliance during PEEP (64), or have shown it only when RV dilatation was exaggerated by high levels of PEEP and RV ischemia (49). Veddeng et al. compared the effects on cardiac output and ventricular dimensions of PEEP applied to both lungs or right or left lung alone in anesthetized dogs. They found that 20 cmH 2 O PEEP applied selectively to the left lung caused the greatest diastolic deformation of the left ventricle, but did not decrease cardiac output at all (40). This suggests that these changes in LV conformation, while of mechanistic interest, ultimately have little impact on cardiac output with PEEP. D. Left Ventricular Emptying
Afterload
The effect of increased pleural pressure on LV afterload is described in detail elsewhere in this volume. In brief, increased pleural pressure, at constant arterial pressure, decreases the force necessary to eject blood from the LV in a manner exactly analogous to decreased arterial pressure, at constant pleural pressure (65–67). In addition to this mechanism, PEEP also commonly decreases arterial pressure. Thus, LV afterload inevitably falls. Since, as discussed above, PEEP generally decreases LV filling, the accompanying decrease in LV afterload does not necessarily translate into increased cardiac output. However, the failing heart is more sensitive to decreased afterload than is the normal heart. It is also less sensitive to decreased preload (45). Therefore, in a manner analogous to the effects of vasodilators in congestive heart failure, cardiac output could rise when PEEP is applied to patients with poor myocardial function.
Mechanical Ventilation with PEEP
821
Mathru et al. found that the addition of 5 cmH 2 O PEEP to intermittent mandatory ventilation decreased cardiac index in eight patients with a mean LV ejection fraction of 0.68, but increased cardiac index in 12 patients with a mean ejection fraction of 0.34 (44). Additional studies have been performed using CPAP in spontaneously breathing subjects. Bradley et al. applied 5 cmH 2 O CPAP via a nasal mask to 22 patients with LV ejection fraction ⬍0.45. Patients (n⫽11) with a pulmonary capillary wedge pressure ⬎ 16 mm Hg increased cardiac index an average of 17%. Patients with lower wedge pressure decreased cardiac index an average of 8% (68). Similarly, Genovese et al. found that CPAP decreased cardiac index in lightly sedated normovolemic pigs. However, when the animals were volume loaded with hetastarch (which both caused hypervolemia and impaired LV function), cardiac index rose with 5 cmH 2 O CPAP (69). These studies are supportive of the concept that elevated pleural pressure mechanically decreases both afterload and preload, and effects on steady-state output are merely the balance between those two factors. However, this interpretation is likely to be overly simplistic. First, 5 cmH 2 O CPAP would be expected to increase cardiac surface pressure by only about 2 mm Hg. This is a trivial decrease in LV afterload. Indeed, in hypervolemic pigs, 5 cmH 2 O CPAP actually decreased intrapericardial pressure (70). This was also found in hypervolemic dogs with acute lung injury (71). The authors speculated that this may have been due to a small reduction in cardiac volume over a volume range near the pericardium’s elastic limit. Secondly, Genovese et al. also demonstrated that the cardiac index, which increased on 5 cmH 2 O CPAP in pigs with pacing-induced heart failure, increased still further when CPAP was removed. This was associated with decreased systemic vascular resistance. They suggested that CPAP may induce poorly understood reflex vasodilation in patients with congestive heart failure, rather than straightforward mechanical effects (72). Contractility
Perhaps no other area has generated more controversy in this field than the question of whether PEEP impairs myocardial function. This arose in part from difficulty in defining myocardial function and, once defined, difficulty in measuring it. One commonly used estimate of myocardial function is the Starling relationship, the relationship between filling pressure of a ventricle and cardiac output. For both RV and LV, the end-diastolic pressure (measured relative to ambient pressure) rises with PEEP, and cardiac output falls. At first glance, this suggests depression of a cardiac function curve. However, this is obviously misleading. The Starling relationship describes a relationship between the ventricular preload and output. Preload is end-diastolic volume, which is directly related to transmural pressure. PEEP elevates the pressure on the ventricular surface. Therefore, at a minimum, it is necessary to measure the pressure surrounding the ventricle. This has been done in many studies by estimating pleural pressure from esophageal pressure. However, Smiseth and Veddeng found that changes in esophageal during PEEP underestimated pressure changes on the
822
Fessler
lateral ventricular surfaces by about 35% (73). Wallis et al. used a balloon in the left or right ventricle during cardiac arrest to estimate the influence of lung inflation on cardiac pressure in the absence of any secondary change in heart volume. The change in pressure in the balloon is the best estimate of the change in mean surface pressure around the heart. They found that PEEP increased that pressure in a complex fashion that varied with cardiac volume and chest wall compliance (74). Thus, esophageal pressure may be quite inadequate as a representation of the pressure on the cardiac surface. Marini et al. also found in supine dogs that PEEP elevated the heart by up to 1.3 cm (75). If vascular pressure is recorded with a fluid-filled catheter and external transducer, elevation of the heart would cause an overestimation of intravascular pressure. An underestimation of pressure surrounding the heart or overestimation of the pressure within the heart could lead to the mistaken conclusion that PEEP depressed the Starling function. Since cardiac surface pressure may vary at different loci on PEEP, and since a mean surface pressure cannot be estimated except during cardiac standstill (74), a more attractive approach is to examine the relationship between end-diastolic cardiac volumes and output on PEEP. This has been attempted in animal and human studies, measuring cardiac volumes with thermodilution, sonomicrometer crystals, echocardiography, or nuclear angiography (49,52,59–62,64,76). In general, these studies have failed to demonstrate a decrease in LV function by these techniques. However, many of the techniques suffer their own limitations. Nuclear radiographic or thermodilution volumes have limited precision, and estimates of volume from reconstructed two-dimensional images cannot account for the shape changes caused by PEEP. The use of the Starling relation to describe myocardial function, even if technically perfect, is an imperfect index of intrinsic myocardial function. The Starling curve slope can be depressed by external loading conditions, such as increased afterload, with no change in the ability of myocardium to contract. Since PEEP changes afterload of both the RV and LV, this may lead to false inferences about its effects. Other indices of ventricular function, such the peak rate of pressure development or velocity of fiber shortening, suffer the same sensitivity to external loading conditions. A preferable index of intrinsic myocardial function is the ventricular endsystolic pressure/volume relationship, as proposed by Sagawa and colleagues. Briefly, instantaneous ventricular pressure and volume are plotted against each other as a redundant loop. When preload is suddenly reduced, these loops spiral laterally to smaller volumes and lower pressures with successive contractions. From each heart beat, the point of maximal elastance (pressure/volume) is measured. These points determine a line, which is the limit of the envelope of maximal elastance attainable by the ventricle in its contractile state. The parameters of that line, its slope and intercept, can be used to define myocardial contractility. This has been shown to be quite independent of preload and afterload, and to respond in predictable fashion to interventions such as ischemia, betaadrenergic blockade, or catecholamines (77,78).
Mechanical Ventilation with PEEP
823
In vivo and clinical estimates of instantaneous ventricular volume have been obtained using echocardiography or conductance catheters. Pressure measurements suffer from the same inaccuracies in estimating the surface pressure around the ventricle. However, errors in estimating the surface pressure would be more likely to affect the intercept of a ventricular end-systolic pressure/volume curve, rather than its slope. In animal studies (59,79) the slope is not altered by PEEP, which supports the conclusion that contractility is unchanged. Some very ingenious studies avoided all the problems in measuring changes in surface pressure or volume on PEEP while searching for a circulating factor that might depress myocardial function. Manny et al. used blood from support dogs to perfuse the coronary circulation of recipient isolated hearts at constant flow (80). When the support animals were placed on PEEP, myocardial function as measured by isovolemic developed pressure was depressed in the isolated hearts. Preventing the fall in cardiac output in the support animals by volume loading during PEEP did not prevent the myocardial depression. Off PEEP, decreasing the cardiac output by hemorrhage to levels similar to those seen on PEEP actually increased contractility in the isolated hearts. Lung stretch was apparently necessary for this cardiodepressive effect of PEEP, since there was no change in contractility when end-expiratory airway and pleural pressures were increased equally. In similar studies, plasma from dogs was used to superfuse isolated rat papillary muscle preparations. Tension that developed during field stimulation fell when the dogs were placed on PEEP. As in the experiments of Manny et al., the fall in papillary muscle contractile force occurred even when cardiac output in the dogs was maintained at baseline levels by volume infusion during PEEP (81). These studies provide convincing evidence that an unidentified cardiodepressive substance is released by PEEP. It remains uncertain why this effect is not apparent in intact animals or humans, but may be due to reflex or mechanical effects that obscure it. E. Myocardial Blood Flow
Numerous studies have documented that PEEP decreases left ventricular blood flow. In an isolated heart-lung preparation, elevated pressure on the surface of the heart decreased coronary flow at constant myocardial workload. At high cardiac surface pressures, myocardial dysfunction and evidence of ischemia were observed (82). In isolated perfused hearts, elevation of cardiac surface pressure shifted coronary pressure-flow relationships suggesting an increase in the downstream pressure for coronary flow (83). In vivo, PEEP increases the pressure on the surface of the heart. It also often decreases arterial pressure, the upstream pressure for coronary flow. However, since PEEP decreases cardiac output and LV afterload, major determinants of myocardial oxygen consumption, it is not apparent that the decrease in blood flow is deleterious rather than physiologic. Although several studies have addressed this question, it cannot be definitively answered. Several studies have indicated that PEEP has disadvantageous effects on
824
Fessler
the relationship between cardiac work and perfusion. In early studies, Tucker and Murray found that PEEP decreased the coronary sinus blood oxygen content and increased the trans-coronary oxygen content difference in dogs (84). Manny et al. found that PEEP and hemorrhage to equal cardiac outputs both decreased myocardial blood flow, but that PEEP caused a selective decrease in subendocardial flow (85). Jacobs and Venus found that 15 cmH 2 O PEEP decreased myocardial blood flow when volume infusion was used to keep cardiac output and arterial pressure constant. Even in animals in which the chest wall was widely resected to minimize changes in cardiac surface pressure, myocardial blood flow fell while cardiac output remained constant. These authors hypothesized a reflex coronary vasoconstriction (86). Following coronary bypass surgery, Tittley et al. found that about half of patients decreased cardiac lactate utilization (suggesting a shift to anaerobic metabolism) on 15 cmH 2 O PEEP (87). In contrast, Fewell et al. found that 12 cmH 2 O PEEP in dogs decreased cardiac output but not myocardial blood flow or its subendocardial/subepicardial distribution (50). Dorinsky et al. found that 14 and 25 cmH 2 O PEEP decreased coronary flow, but that the decrease in flow was proportionate to the decrease in cardiac output under all conditions (88). Hevroy et al. found the decrease in myocardial blood flow on 15 cmH 2 O PEEP closely correlated to the decrease in myocardial oxygen consumption. This relationship was maintained when cardiac contractility was pharmacologically varied, and suggests the change in blood flow was physiologic (89). Flow to the interventricular septum was studied by Zwissler et al. in dogs with oleic acid lung injury. They found that flow was well maintained on up to 20 cmH 2 O PEEP (with volume loading) and that the ratio of septal flow to cardiac output increased on PEEP (90). In humans, elevation of pleural pressure by the Valsalva maneuver can relieve angina (91), but of course this does not increase lung volume as does PEEP. The disparate finding in these studies likely reflects the range of methodologies. Flows were measured with microspheres, indicator dilution, or probes, each with different precision. Animal studies were open or closed chest, with or without volume loading, with or without lung injury, and used different levels of PEEP. No firm conclusion can be reached about the effects of PEEP on coronary perfusion in vivo, except that they are not overwhelmingly obvious. F. Splanchnic and Hepatic Blood Flow
The effects of PEEP on the splanchnic circulation is important for several reasons. This bed is the site of much of the unstressed volume of the circulation, and plays an active role in the vascular response to hemodynamic stress and the control of venous return. In critically ill patients in whom PEEP is commonly used, impaired mesenteric perfusion has been suggested as a contributor to multisystem organ failure. Hepatic dysfunction is also common in these patients, and increases sensitivity to endotoxin. Since lung expansion increases abdominal pressure, PEEP may affect the abdominal circulation in ways distinct from its effects on other portions of the vasculature.
Mechanical Ventilation with PEEP
825
Early studies noted that PEEP decreased hepatic arterial flow. Manny et al. found that 15 cmH 2 O PEEP reduced cardiac output by one-third, but reduced hepatic arterial flow by half. More significantly, hemorrhage to a similar level of cardiac output did not reduce hepatic flow, suggesting a specific effect of PEEP. With the exception of the stomach, intestinal flow was not reduced by PEEP, which implies portal flow was preserved (85). Love et al. used intravital microscopy to measure mesenteric arteriolar flow in rats. They found PEEP decreased flow, and flow remained 45% below baseline even after cardiac output had been restored with volume infusion (92). In contrast, others have found decreases in hepatic arterial and/or portal flow simply proportional to the fall in cardiac output (88,93,94). Both Bredenberg et al. (93) and Matushak et al. (95) found that restoration of cardiac output to baseline with volume infusion on PEEP also restored hepatic flow. This suggests there was no specific effect of PEEP beyond its generalized decrease in cardiac output. Matushak et al. (95) also found no effect of PEEP on hepatic clearance of indocyanine green. In patients undergoing cholecystectomy or hepatic surgery, proportional decreases in portal flow and cardiac output were found (96). In patients undergoing a variety of abdominal surgeries, 15 cmH 2 O PEEP did not change transsplanchnic lactate concentrations, suggesting there was no significant gut ischemia (97). Despite the paucity of evidence that the decrease in mesenteric blood flow on PEEP is of any functional significance, several authors have reported it may be ameliorated by enteral feeding (98,99) or vasopressors (100–102). The effects of PEEP on hepatic arterial and portal pressure-flow relations were studied in pigs by Brienza et al. (103). In the portal system, they found that PEEP between 5 and 15 cmH 2 O increased the portal venous resistance. The backpressure to portal flow was always equal to hepatic venous pressure; i.e., a vascular waterfall was not operational in the portal system on PEEP. In the hepatic artery, PEEP increased arterial resistance. In addition, the hepatic artery stop-flow pressure always exceeded hepatic venous pressure, and increased with each increment in PEEP. This suggests a critical closing pressure of the arteries which varies with pressures downstream, as has been described in the coronary circulation (104). Changes in blood flow to a region are not necessarily correlated with changes in blood volume, which also depend on vascular compliance and inflow and outflow resistances. Risoe et al. estimated changes in liver and spleen volume from sonomicrometer dimensions in dogs (105). They found PEEP increased liver volume, which they attributed to passive congestion. Hepatic pressure-volume relations indicated decreased compliance. There was also an increase in liver unstressed volume. Spleen volume decreased. The spleen is an important vascular volume reservoir in dogs, and this likely reflected active contraction. Summing the changes in the two organs, they calculated a net increase in blood volume of 4 mL/kg body weight at 15 cmH 2 O PEEP. Similarly, in humans, using technetium-labeled red cells, CPAP breathing at 10 to 12 cmH 2 O caused an increase in blood volume in the intestines and liver, but not the limbs (106).
826
Fessler V.
Clinical Issues
A. Auto-PEEP
Since the first edition of this text, there has come a greater appreciation of the prevalence and effects of what has been called ‘‘auto-PEEP,’’ ‘‘occult PEEP,’’ or ‘‘intrinsic PEEP.’’ These terms refer to an alveolar pressure that remains above proximal airway pressure at the end of tidal expiration. The hemodynamic effects of this phenomenon were described in three patients with obstructive airway disease on mechanical ventilation with no applied PEEP whose alveolar pressure was estimated at 10 to 26 cmH 2 O. When disconnected from mechanical ventilation, blood pressure increased (107). Auto-PEEP can occur through three basic mechanisms. First, some airways may be completely closed at the end of tidal expiration, with an elevated alveolar pressure. This occurs with bronchospasm or mucus plugging. The lungs of patients dying of asthma, for example, remain hyperinflated even when excised from the chest (108). Second, slowly emptying but patent airways may not have time to reach their static equilibrium lung volume before the next inspiration. This can occur in any state of flow limitation, and is referred to as dynamic hyperinflation. Since the conditions causing pathologic flow limitation and those causing airway closure are frequently identical, lungs that are dynamically hyperinflated could still be hyperinflated (with occluded airways) after a prolonged expiration. Thirdly, in both ambulatory (109) and intubated (110) patients with obstructive airway disease, expiratory muscle recruitment during tidal breathing has been shown to elevate alveolar pressure. This mechanism would increase pleural pressure but not lung volume. Auto-PEEP has been recognized as a characteristic feature of severe obstructive lung disease even in ambulatory patients (111). It increases with the hyperventilation of exercise and can artifactually elevate pulmonary capillary wedge pressure in severely obstructed patients (112,113). Unlike PEEP applied extrinsically to hypoxic patients with diffuse lung injury, auto-PEEP occurs in patients with normal or increased lung compliance. Therefore, it can cause greater increases in lung volume and pleural pressure than would an equal elevation in alveolar pressure in a patient with ARDS. However, its hemodynamic effects are generally well tolerated in spontaneously breathing patients. Despite elevated pleural pressure during expiration, venous return can be sustained during the vigorous inspiratory efforts. In patients on positive-pressure ventilation, in contrast, the hemodynamic effects of auto-PEEP can be devastating. Tuxen and Lane demonstrated the increase in end-expiratory lung volume and hypotension which can be induced by alteration of respiratory pattern in ventilated patients. They showed that end-expiratory lung volume increased with increased respiratory rate at constant tidal volume, increased tidal volume at constant respiratory rate, or increased inspiratory time at constant volume and rate. In these patients with obstructive lung disease, esophageal and central venous pressures rose and arterial pressure fell with hyperinflation (114). The phenomenon of auto-PEEP went unrecognized for so long because it is not directly detectable by conventional monitoring of proximal airway pressure. During expiration, the airway manometer is opened to ambient pressure, while alve-
Mechanical Ventilation with PEEP
827
olar pressure may be elevated upstream of a high resistance or fully occluded airways. Auto-PEEP may be suspected by the presence of expiratory airflow or wheezes which are only interrupted by the next ventilator-delivered breath. It may be detected and quantified by several methods. If the ventilator expiratory port is occluded just prior to an inspiration, all airway pressures will equilibrate and will be detected by the manometer (107). This will measure an average alveolar pressure, with the contribution of all patent lung units weighted in proportion to their fractional compliance (much like mean systemic pressure). This method will not detect pressure in lung regions whose airways are completely closed at end expiration. In a spontaneously breathing patient with auto-PEEP, pleural pressure must decrease isometrically to lower alveolar pressure to ambient before inspiration can begin. Therefore, one may measure the fall in esophageal pressure that occurs prior to inspiratory flow. That change in pressure will equal the level of auto-PEEP. Likewise, in a passively ventilated patient one may record the increase in airway pressure that precedes inspiratory flow. However, these techniques will measure the lowest regional alveolar pressure, since flow will begin into that region prior to other regions. Auto-PEEP occurs most commonly in patients with pathologic airflow limitation. The condition of flow limitation in the airways is analogous to that of a vascular waterfall in the blood vessels. That is, elevation of pressure downstream of a site of flow limitation should have no effect on flow until a critical pressure is exceeded. This was studied by Ranieri et al., who added extrinsic PEEP to patients with autoPEEP (115). They showed no effects on expiratory flow, end-expiratory lung volume, or cardiac index until applied PEEP exceeded about 85% of the measured auto-PEEP, suggesting a critical pressure at a flow-limiting segment was exceeded. Thus, somewhat paradoxically, while patients with airway obstruction may be hemodynamically more sensitive to the effects of auto-PEEP because of their compliant lungs, they are less sensitive to applied PEEP. B. Inverse-Ratio Ventilation (IRV)
Ventilation in which inspiration is more prolonged than expiration has been advocated in the management of ARDS (116,118). Purported benefits of IRV include improved gas exchange and lower peak airway pressure. Since oxygenation often improves, PEEP may be reduced. However, the conditions of IRV, with short expiratory time, are those which would favor the development of auto-PEEP. It is also more difficult to check for auto-PEEP during brief expirations. Thus, it is possible that IRV merely substitutes auto-PEEP for PEEP. Evidence for this was shown by Cole et al., who compared IRV and conventional ventilation with PEEP in 10 patients with ARDS. In each patient, PEEP was adjusted on conventional ventilation to match the end-expiratory lung volume measured on IRV. At an I :E ratio of 1: 2, an average of 13 cmH 2 O PEEP was necessary to achieve the same lung volume (measured by inductance plethysmography) as was present during IRV at a ratio of 4:1. At equal lung volumes, there was no difference in shunt or cardiac output (119). Similarly, at constant total PEEP (applied plus auto-PEEP), Mercat et al. found no difference in oxygenation but decreased cardiac
828
Fessler
index and oxygen delivery on IRV (120). These studies suggest that IRV substitutes auto-PEEP, which is difficult to measure, for applied PEEP, which is more obvious. This may provide some false reassurance, but no special hemodynamic advantage. C. Partial Liquid Ventilation
The use of liquid perflurocarbon compounds with high gas solubility as adjuncts to mechanical ventilation in ARDS is undergoing clinical trials. These compounds have been described as ‘‘liquid PEEP,’’ warranting a discussion of the cardiovascular effects of this intervention. Perflurocarbons are carbon chain compounds in which fluorine is substituted for hydrogen. They have physical properties that make them attractive for ventilatory support. They have a high solubility for oxygen and carbon dioxide. They are immiscible with aqueous solutions, poorly soluble in lipids, and relatively biologically inert. They have a low vapor pressure, which retards evaporation, and a high density, which provides a PEEP-like effect in proportion to their hydrostatic depth. They have low surface tension and a high spreading coefficient, which aids their distribution in the lung and reduces the contribution of surface forces to lung recoil (121,122). Tidal ventilation with industrial perflurocarbons has been studied experimentally since the first reports of Clark and Gollan in 1966 (123). However, tidal breathing of liquids (total liquid ventilation) suffers several technical and physiologic limitations. Specialized equipment is required to oxygenate the compound and pump it into and out of the lungs. Very large volumes are required for continuous ventilation, unless the compound is recirculated. Because of its viscosity, expiratory flows are low and respiratory rate is limited. In addition, because of diffusion limitation of gas exchange within the fluid, CO 2 elimination is maximal at respiratory rates of only 4 to 6. This often results in severe respiratory acidosis (124,125). For these reasons, tidal ventilation with perflurocarbon compounds never advanced clinically beyond small descriptive trials (126). In 1991, Fuhrman et al. described what has come to be called partial liquid ventilation (PLV) (127). During PLV, the lungs are partially or fully filled with perflurocarbon. Tidal ventilation then occurs with gas. The lungs serve as the mixing chamber between gas and liquid. Gas ventilation allows the use of standard clinical ventilators and typical settings, and these can achieve normocapnia. A sterile compound, perflubron, has been commercially developed for PLV. In addition to the physical qualities listed above, perflubron is radio-opaque due to the presence of a bromine atom. Beneficial effects on gas exchange and improved lung compliance have been demonstrated in a variety of animal models of lung injury (128–133). Proposed mechanisms of the improved gas exchange include enhanced removal of alveolar exudate, replacement of oxygen-poor serum in alveoli with oxygen-rich perflubron (decreased shunt), redistribution of blood flow to better-ventilated lung (V/Q matching), a tamponadelike effect suggested to decrease alveolar edema, the PEEP-like
Mechanical Ventilation with PEEP
829
action of opening atelectatic lung regions, or anti-inflammatory activity which has been shown in vitro in perflubron-exposed macrophages (134). In addition to the extensive animal studies, several small clinical series have recently been published (135–138). Filling the lung with saline decreases the gravitational distribution of pulmonary blood flow (48). In preliminary studies, this has also been shown to occur during PLV (139). Since perflubron is twice the density of saline, one would anticipate an even greater redistribution; filling the lungs with perflubron could reverse the normal pattern of flow to one favoring the least dependent lung regions. However, the redistribution of blood flow during PLV in dogs with oleic acid lung injury was no greater than in gas-ventilated, injured lungs in one study using PET scanning (140). The degree to which PLV redistributes blood flow is important in regard to its mechanism of improved oxygenation. In ARDS, most of the ventilation goes to non dependent lung. This is also the case during PLV. Thus, even if the compound did not carry oxygen, it could improve V/Q matching and arterial PaO 2 if it directed blood flow to ventilated lung regions. This mechanism would apply, for example, if PLV were performed with mercury instead of perflubron. In animal studies, oxygenation can be supported by high-frequency oscillation during PLV (141). The mechanisms proposed for gas transport during oscillation (such as facilitated diffusion and Taylor dispersion) would be ineffective in a medium approximately 100-fold more viscous and thousands of times denser than gas. It therefore does not seem likely that oscillation could effectively re oxygenate pools of perflubron in distal, dependent lung regions. It follows that the improvement in oxygenation during oscillation with PLV may be attributable largely to the redistribution of blood flow to ventilated ventral lung. However, the PaO 2 during PLV has also been shown to be strongly dependent on tidal volume (132), unlike during gas ventilation in ARDS (142,143). While this appears to conflict with the efficacy of high-frequency oscillation, it suggests that physical mixing of gas and perflubron also contributes to gas exchange. Total liquid ventilation (tidal breathing with perflurocarbon) has been shown in some studies to decrease cardiac output, increase pulmonary vascular resistance, and cause metabolic acidosis (144,145). However, unlike TLV or PEEP, PLV has been notably devoid of systemic hemodynamic consequences. With fill volumes up to 30 mL/kg, approximating normal FRC, PLV has not been shown to alter right atrial pressure, pulmonary capillary wedge pressure, arterial pressure, or thermodilution cardiac output in most animal studies (129,132,133,146). Systematic studies in humans have not been performed. Since many patients who are candidates for PLV will also have pulmonary artery catheters in place, one question of clinical importance is the effect of PLV on the accuracy of clinical hemodynamic measures. One anticipates that PEEP elevates the pressure on the cardiac surface, and factors that into one’s interpretation of a pulmonary capillary wedge pressure measured at the bedside. During PLV, the extent to which pressure on the cardiac surface changes is unknown. Furthermore, the use of the capillary wedge pressure to estimate left atrial pressure presumes there is a continuous channel of blood from the catheter tip to the left atrium. That is
830
Fessler
usually the case when a PAC is inserted, but may no longer be true when the airspaces are filled with dense fluid. We recently investigated the accuracy of the PAC in a group of six sheep with normal lungs and closed chest weighing 25 to 50 kg (147). Pressure in the pericardium was measured with a flat, air-filled balloon. Pulmonary capillary wedge pressure was compared to pressure measured directly by a left atrial catheter. We found close agreement between wedged and left atrial pressures when the lungs were gas-filled, or filled with 10 mL/kg or 30 mL/kg perflubron. This indicates vascular continuity through at least some pathways between the PAC and the left atrium. In addition, there was no significant change in pericardial pressure when the lungs were filled with perflubron. While this may seem surprising, we believe the explanation is as follows: If the perflubron merely displaces gas, then there is no difference in lung volume when the lung is filled with liquid. If lung volume is unchanged, so is chest wall volume. Since chest wall compliance would not have changed, mean pleural pressure must be unchanged. For every increase in pleural pressure in dependent regions due to the weight of the lung, there must be a decrease in pleural pressure in nondependent regions to keep the mean pressure constant. Somewhere in the middle, apparently at about the level of the heart, pleural pressure changes very little. Thus, despite extremely high alveolar pressure in dependent alveoli (40 cmH 2 O in a lung of 20 cm depth, for example), ‘‘liquid PEEP’’ has minimal systemic hemodynamic effects compared to ‘‘gas PEEP.’’ VI. Summary In the past decade, enormous progress has been made in understanding the cardiovascular effects of PEEP. Nevertheless, the questions have expanded at least as fast as the answers. PEEP in patients with airway obstruction is more common than was ever suspected. The effects of PEEP on both the heart and vasculature are more complex than previously imagined. PEEP is being applied in new ways and for new purposes. The ‘‘wondrous’’ heart-lung interactions observed by Vesalius are extending to the level of cellular function and gene regulation. We can only look forward with restless anticipation to the next decade. References 1. Corbridge TC, Wood LDH, Crawford GP, Chudoba M, Yanos J, Sznajder JI. Adverse effects of large tidal volume and low PEEP in canine acid aspiration. Am Rev Respir Dis 1990; 142:311–315. 2. Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema. Am Rev Respir Dis 1988; 137:1159–1164. 3. Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347– 354. 4. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fox m-RNA expression in an isolated rate lung model. J Clin Invest 1997; 99:944–952.
Mechanical Ventilation with PEEP
831
5. Vesalius A. De Humani Corporis Fabrica Libra Septem. Basel, 1555. 6. Hooke R. An account of an experiment made by M. Hook of preserving animals alive by blowing through their lungs with a bellows. Phil Trans R Soc Lond 1667; 2:539–540. 7. Morch ET. History of mechanical ventilation. In: Kirby R, Smith R, Desautels D, eds. Mechanical Ventilation. New York: Churchill Livingstone, 1985. 8. Jackson C. The technique of insertion of intratracheal insufflation tubes. Surg Gynecol Obstet 1913; 17:507–509. 9. Crafoord C. Some aspects of the development of intrathoracic surgery. Surg Gynecol Obstet 1949; 89:629–637. 10. Drinker IA, Shaw LA. An apparatus for the prolonged administration of artificial respiration. J Clin Invest 1929; 7:229–247. 11. Bennett VR, Bower AG, Dillon JB, Axelrod B. Investigation on the care and treatment of poliomyelitis patients. Ann West Med Surg 1950; 4:561–582. 12. Poulton PE. Left-sided heart failure with pulmonary edema; its treatment with the ‘‘pulmonary plus pressure machine.’’ Lancet 1936; 2:981–983. 13. Barach AL, Martin J, Eckman M. Positive pressure respiration and its application in the treatment of acute pulmonary edema. Ann Intern Med 1938; 12:754. 14. Bersten AD, Holt AW, Bedig AE, Skowronski GA, Baggoley CJ. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med 1991; 325:1825–1830. 15. Barach AL, Fenn WO, Ferns EB, Schmidt CF. The physiology of pressure breathing. J Aviation Med 1947; 18:73–87. 16. Cournand A, Motley HL, Werko L, Richards DW. Physiological studies of the effects of intermittent positive pressure breathing on cardiac output in man. Am J Physiol 1948; 152: 162–174. 17. Frumin MJ, Bergman NA, Holaday DA, Rackow H, Salanitre E. Aleolar-arterial O 2 differences during artifical respiration in man. J Appl Physiol 1959; 14:694–700. 18. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2:319–323. 19. Gregory GA, Kitterman JA, Phibbs RH. Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. N Engl J Med 1971; 284:1333– 1340. 20. Falke KJ, Pontoppidan H, Kumar A, Leith DE, Geffin B, Laver MB. Ventilation with endexpiratory pressure in acute lung disease. J Clin Invest 1972; 51:2315–2323. 21. Kumar A, Falke KJ, Geffin B, et al. Continuous positive-pressure ventilation in acute respiratory failure. N Engl J Med 1970; 283:1430–1436. 22. Fessler HE, Permutt S. Interaction between the circulatory and ventilatory pump. In: Roussos C, ed. The Thorax, 2nd ed. New York: Marcel Dekker, 1995:1621–1640. 23. Braunwald E, Binton JT, Morgan WL, Sarnoff SJ. Alterations in central blood volume and cardiac output induced by positive pressure breathing and counteracted by metaraminol (aramine). Circ Res 1957; 5:670–675. 24. Greene AS, Shoukas AA. Changes in canine cardiac function and venous return curves by the carotid baroreflex. Am J Respir Crit Care Med 1986; 251:H288-H296. 25. Brunner MJ, Shoukas AA, MacAnespie CL. The effect of the carotid sinus baroreceptor reflex on blood flow and volume redistribution in the total systemic vascular bed of the dog. Circ Res 1981; 48:274–285. 26. Bower EA, O’Donnell CP. Mean circulatory filling pressure during splanchnic nerve stimulation and whole-body hypoxia in the anaesthetized cat. J Physiol 1991; 432:543–556. 27. Mitzner W, Goldberg H. Effects of epinephrine on resistive and compliant properties of the canine vasculature. J Appl Physiol 1975; 39:272–280. 28. Greenway CV, Seaman KL, Innes IR. Norepinephrine on venous compliance and unstressed volume in cat liver. Am J Physiol 1985; 248:H468-H476. 29. Bennett TD, Wyss CR, Scher AM. Changes in vascular capacity in awake dogs in response to carotid sinus occlusion and administration of catecholamines. Circ Res 1984; 55:440– 453. 30. Scharf SM, Caldini P, Ingram RH. Cardiovascular effects of increasing airway pressure in the dog. Am J Physiol 1977; 232:H35-H43.
832
Fessler
31. Guyton AC. Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev 1955; 35:123–129. 32. Scharf SM, Ingram RH. Influence of abdominal pressure and sympathetic vasoconstriction on the cardiovascular response to positive end-expiratory pressure. Am Rev Respir Dis 1977; 116:661–670. 33. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of positive end-expiratory pressure on the gradient for venous return. Am Rev Respir Dis 1991; 143:19–24. 34. Beloucif S, Bizot J, Leenhardt A, Payen D. PEEP increases mean systemic pressure in humans. Am J Respir Crit Care Med 1995; 151:A708. Abstract. 35. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of positive end-expiratory pressure on the canine venous return curve. Am Rev Respir Dis 1992; 146:4–10. 36. Nanas S, Magder S. Adaptions of the peripheral circulation to PEEP. Am Rev Respir Dis 1992; 146:688–693. 37. Permutt S, Bromberger-Barnea B, Bane HN. Alveolar pressure, pulmonary venous pressure, and the vascular waterfall. Med Thorac 1962; 19:239–260. 38. Fessler HE, Brower RG, Shapiro EP, Permutt S. Effects of positive end-expiratory pressure and body position on pressure in the thoracic great veins. Am Rev Respir Dis 1993; 148: 1657–1664. 39. Marini JJ, Culver B, Butler J. Mechanical effect of lung distention with positive pressure on cardiac function. Am Rev Respir Dis 1981; 124:382–386. 40. Veddeng OJ, Myhre ESP, Risoe C, Smiseth OA. Selective positive end-expiratory pressure and intracardiac dimensions in dogs. J Appl Physiol 1992; 73:2016–2020. 41. Nakhjavan FK, Palmer WHJ, McGregor M. Influence of respiration on venous return in pulmonary emphysema. Circulation 1966; 33:8–16. 42. Ra¨sa¨nen J, Va¨isa¨nen IT, Heikkila¨ J, Nikki P. Acute myocardial infarction complicated by left ventricular dysfunction and respiratory failure. Chest 1985; 8:158–162. 43. Grace MP, Greenbaum DM. Cardiac performance in response to PEEP in patients with cardiac dysfunction. Crit Care Med 1982; 10:358–360. 44. Mathru M, Rao TLK, Ed-Etr AA, Pifarre R. Hemodynamic response to changes in ventilatory patterns in patients with normal and poor left ventricular reserve. Crit Care Med 1982; 10:423–426. 45. Pouleur H, Covell JW, Ross J. Effects of nitroprusside on venous return and central blood volume in the absence and presence of acute heart failure. Circulation 1980; 61:328– 337. 46. Burton AC, Patel DJ. Effect on pulmonary vascular resistance of inflation of the rabbit lungs. J Appl Physiol 1958; 12:239–246. 47. Whittenberger JL, McGregor M, Berflund E, Borst HG. Influence of state of inflation of the lung on pulmonary vascular resistance. J Appl Physiol 1960; 15:878–882. 48. West JB, Dollery CT, Matthews ME, Zardini P. Distribution of blood flow and ventilation in saline-filled lung. J Appl Physiol 1965; 20:1107–1117. 49. Schulman DS, Biondi JW, Zohgbi S, Cecchetti A, Zaret BL, Soufer R. Left ventricular diastolic function during positive end-expiratory pressure. Am Rev Respir Dis 1992; 145: 515–521. 50. Fewell JE, Abendschein DR, Carlson CJ, Murray JF, Rapaport E. Continuous positivepressure ventilation decreases right and left ventricular end-diastolic volumes in the dog. Circ Res 1980; 46:125–132. 51. Mitaka C, Nagura T, Sakanishi N, Tsunoda Y, Amaha K. Two-dimensional echocardiographic evaluation of inferior vena cava, right ventricle, and left ventricle during positivepressure ventilation with varying levels of positive end-expiratory pressure. Crit Care Med 1989; 17:205–210. 52. Huemer G, Kolev N, Kurz A, Zimpfer M. Influence of positive end-expiratory pressure on right and left ventricular performance assessed by Doppler two-dimensional echocardiography. Chest 1994; 106:67–73. 53. Cassidy S, Mitchell JH, Johnson RL. Dimensional analysis of right and left ventricles during positive-pressure ventilation in dogs. Am J Physiol 1982; 242:H549-H556. 54. Neidhart PP, Suter PM. Changes of right ventricular function with positive end-expiratory pressure (PEEP) in man. Inten Care Med 1988; 14:471–473.
Mechanical Ventilation with PEEP
833
55. Pinsky MR, Desmet J, Vincent JL. Effect of positive end-expiratory pressure on right ventricular function in humans. Am Rev Respir Dis 1992; 146:681–687. 56. Santamore WP, Heckman JL, Bove AA. Right and left ventricular pressure-volume response to respiratory maneuvers. J Appl Physiol Respir Environ Exercise Physiol 1984; 57:1520–1527. 57. Takata M, Robotham JL. Ventricular external constraint by lung and pericardium during positive end-expiratory pressure. Am Rev Respir Dis 1991; 143:872–875. 58. Cassidy S, Ramanathan M. Dimenstional analysis of the left ventricle during PEEP: relative septal and lateral wall displacements. Am J Physiol 1984; 246:H792-H805. 59. Johnston WE, Vinten-Johansen J, Santamore WP, Case LD, Little WC. Mechanism of reduced cardiac output during positive end-expiratory pressure in the dog. Am Rev Respir Dis 1989; 140:1257–1264. 60. Cassidy S, Eschenbacher WL, Robertson CH, Nixon JV, Blomquist G, Johnson R. Cardiovascular effects of positive-pressure ventilation in normal subjects. J Appl Physiol 1979; 47:453–461. 61. Jardin F, Farcot J, Boisante L, Curien N, Margairaz A, Bourdaris J. Influence of positive end-expiratory pressure on left ventricular performance. N Engl J Med 1981; 304:387–392. 62. Haynes JB, Carson SD, Whitney WP, Zerbe GO, Hyers TM, Steele P. Positive end-expiratory pressure shifts left ventricular diastolic pressure-area curves. J Appl Physiol 1980; 48:670–676. 63. Lloyd TC. Mechanical cardiopulmonary interdependence. J Appl Physiol 1982; 52:333– 339. 64. Fewell JE, Abendschein DR, Carlson CJ, Rapaport E, Murray JF. Continuous positivepressure ventilation does not alter ventricular pressure-volume relationship. Am J Physiol 1981; 240:H821-H826. 65. Pinsky MR, Matuschak GM, Klain M. Determinants of cardiac augmentation by elevations in intrathoracic pressure. Am J Respir Crit Care Med 1985; 58:1189–1198. 66. Pinsky MR, Summer WR, Wise RA, Permutt S, Bromberger-Barnea B. Augmentation of cardiac function by elevation of intrathoracic pressure. J Appl Physiol 1983; 54:950–955. 67. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of systolic and diastolic positive pleural pressure pulses with altered cardiac contractility. J Appl Physiol 1992; 73:498–505. 68. Bradley TD, Holloway RM, McLaughlin PR, Ross BL, Walters J, Liu PP. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992; 145:377–382. 69. Genovese J, Moskowitz M, Tarasiuk A, Graver LM, Scharf SM. Effects of continuous positive airway pressure on cardiac output in normal and hypervolemic unanesthetized pigs. Am J Respir Crit Care Med 1994; 150:752–758. 70. Huberfeld S, Genovese J, Tarasiuk A, Scharf SM. Effect of CPAP on pericardial pressure and respiratory system mechanics in pigs. Am J Respir Crit Care Med 1995; 152:142– 147. 71. Cabrera MR, Nakamura GE, Montague DA, Cole RP. Effect of airway pressure on pericardial pressure. Am Rev Respir Dis 1989; 140:659–667. 72. Genovese J, Huberfeld S, Tarasiuk A, Moskowitz M, Scharf SM. Effects of CPAP on cardiac output in pigs with pacing-induced congestive heart failure. Am J Respir Crit Care Med 1995; 152:1847–1853. 73. Smiseth OA, Veddeng OJ. A comparison of changes in esophageal pressure and regional juxtacardiac pressures. J Appl Physiol 1990; 69:1053–1057. 74. Wallis TW, Robotham J, Compean R, Kindred M. Mechanical heart-lung interactions with positive end-expiratory pressure. J Appl Physiol 1983; 54:1039–1047. 75. Marini JJ, O’Quin R, Culver B, Butler J. Estimation of transmural cardiac pressure during ventilation with PEEP. J Appl Physiol 1982; 53:384–391. 76. Calvin JE, Driedger AA, Sibbald WJ. Positive end-expiratory pressure (PEEP) does not depress left ventricular function in patients with pulmonary edema. Am Rev Respir Dis 1981; 124:121–128. 77. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973; 32:314–322.
834
Fessler
78. Sagawa K. Editorial. The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use. Circulation 1981; 63:1223–1227. 79. Crottogini AJ, Willshaw P, Barra JG, Breithart GJ, Pichel RH. End-systolic pressure-volume relationships in dogs during ventilation with PEEP. Am J Physiol 1988; 254:H664H670. 80. Manny J, Grindlinger GA, Mathe AA, Hechtman HB. Positive end-expiratory pressure, lung stretch, and decreased myocardial contractility. Surgery 1978; 84:127–133. 81. Grindlinger GA, Manny J, Justice R, Dunham B, Shepro D, Hechtman HB. Presence of negative inotropic agents in canine plasma during positive end-expiratory pressure. Circ Res 1979; 45:460–467. 82. Fessler HE, Brower RG, Wise RA, Permutt S. Positive pleural pressure decreases coronary perfusion. Am J Physiol 1990; 258:H814-H820. 83. Satoh S, Watanabe J, Keitoku M, Itoh N, Maruyama Y, Takishima T. Influences of pressure surrounding the heart and intracardiac pressure on the diastolic coronary pressure-flow relation in excised canine heart. Circ Res 1988; 63:788–797. 84. Tucker HJ, Murray JF. Effects of end-expiratory pressure on organ blood flow in normal and diseased dogs. J Appl Physiol 1973; 39:573–577. 85. Manny J, Justice R, Hechtman HB. Abnormalities in organ blood flow and its distribution during positive end-expiratory pressure. Surgery 1979; 85:425–432. 86. Jacobs HK, Venus B. Left ventricular regional myocardial blood flows during controlled positive pressure ventilation and positive end-expiratory pressure in dogs. Crit Care Med 1983; 11:872–875. 87. Tittley JG, Fremes SE, Weisel RD, et al. Hemodynamic and myocardial metabolic consequences of PEEP. Chest 1985; 88:496–502. 88. Dorinsky PM, Hamlin RL, Gadek JE. Alterations in regional blood flow during positive end-expiratory pressure ventilation. Crit Care Med 1987; 15:106–113. 89. Hevroy O, Grundnes O, Bjertnaes L, Ole D. Myocardial blood flow and oxygen consumption during positive end-expiratory pressure ventilation at different levels of cardiac inotropy and frequency. Crit Care Med 1989; 17:48–52. 90. Zwissler B, Schosser R, Schwickert C, et al. Perfusion of the interventricular septum during ventilation with positive end-expiratory pressure. Crit Care Med 1991; 19:1414–1424. 91. Levin HJ, McIntyre KM, Glovsky MM. Relief of angina pectoris by the Valsalva maneuver. N Engl J Med 1966; 275:487–489. 92. Love R, Choe E, Lippton H, Flint L, Steinberg S. Positive end-expiratory pressure decreases mesenteric blood flow despite normalization of cardiac output. J Trauma 1995; 39:195–199. 93. Bredenberg CE, Paskanik AM. Relation of portal hemodynamics to cardiac output during mechanical ventilation with PEEP. Ann Surg 1983; 198:218–222. 94. Beyer J, Beckenlechner P, Messmer K. The influence of PEEP ventilation on organ blood flow and peripheral oxygen delivery. Intens Care Med 1982; 8:75–80. 95. Matuschak GM, Pinsky MR, Rogers RM. Effects of positive end-expiratory pressure on hepatic blood flow and performance. J Appl Physiol 1987; 62:1377–1383. 96. Winso O, Biber B, Gustavsson B, Holm C, Milson I, Niemand D. Portal blood flow in man during graded positive end-expiratory pressure ventilation. Intens Care Med 1986; 12:80–85. 97. Berendes E, Lippert G, Loick HM, Brussel T. Effects of positive end-expiratory pressure ventilation on splanchnic oxygenation in humans. J Cardiothoracic Vasc Anesth 1996; 10: 598–602. 98. Purcell PN, Branson RD, Hurst JM, Davis K, Johnson DJ. Gut feeding and hepatic hemodynamics during PEEP ventilation for acute lung injury. J Surg Res 1992; 53:335–341. 99. Purcell PN, Davis K, Branson RD, Johnson DJ. Continuous duodenal feeding restores gut blood flow and increases gut oxygen utilization during PEEP ventilation for lung injury. Am J Surg 1993; 165:188–193. 100. Steinberg S, Azar G, Love R, Lee R, Choe E, Flint L. Dopexamine prevents depression of mesenteric blood flow caused by positive end-expiratory pressure in rats. Surgery 1996; 120:597–601. 101. Johnson DJ, Johannigman JA, Branson RD, Davis K Jr, Hurst JM. The effect of low dose
Mechanical Ventilation with PEEP
102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125.
835
dopamine on gut hemodynamics during PEEP ventilation for acute lung injury. J Surg Res 1991; 50:344–349. Azar G, Love R, Choe E, Flint L, Steinberg S. Neither dopamine nor dobutamine reverses the depression in mesenteric blood flow caused by positive end-expiratory pressure. J Trauma 1996; 40:679–685. Brienza N, Revelly J, Ayuse T, Robotham JL. Effects of PEEP on liver arterial and venous blood flows. Am J Respir Crit Care Med 1995; 152:504–510. Bellamy RF, Lowensohn HS, Ehrlich W, Baer RW. Effect of coronary sinus occlusion on coronary pressure-flow relations. Am J Physiol 1980; H57-H64. Risoe C, Hall C, Smiseth OA. Splanchnic vascular capacitance and positive end-expiratory pressure in dogs. J Appl Physiol 1991; 70:818–824. Peters J, Hecker B, Neuser D, Schaden W. Regional blood volume distribution during positive and negative airway pressure breathing in supine humans. J Appl Physiol 1993; 75:1740–1747. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982; 126:166–170. Dunnill MS. The pathology of asthma. Ciba Foundation Study Group 1971; 38:35–46. Ninane V, Yernault J-C, de Troyer A. Intrinsic PEEP in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 148:1037–1042. Lessard MR, Lofaso F, Brochard L. Expiratory muscle activity increases intrinsic positive end-expiratory pressure independently of dynamic hyperinflation in mechanically ventilated patients. Am J Respir Crit Care Med 1995; 151:562–569. Aldrich TK, Hendler JM, Vizioli LD, Park M, Multz AS, Shapiro SM. Intrinsic positive end-expiratory pressure in ambulatory patients with airways obstruction. Am Rev Respir Dis 1999; 147:845–849. Babb TG, Viggiano R, Hurley B, Staats B, Rodarte JR. Effect of mild-to-moderate airflow limitation on exercise capacity. J Appl Physiol 1991; 70:223–230. Rice DL, Awe RJ, Gaasch WH, Alexander JK, Jenkins DE. Wedge pressure measurements in obstructive pulmonary disease. Chest 1974; 66:628–632. Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressures, and circulation in mechanical ventilation of patients with severe air-flow obstruction. Am Rev Respir Dis 1987; 136:872–879. Ranieri VM, Giuliana R, Cinnella G, et al. Physiologic effects of positive end-expiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis 1993; 147:5–13. Marcy TW, Marini JJ. Inverse ratio ventilation in ARDS: rationale and implementation. Chest 1991; 100:494–504. Gurevitch MJ, VanDyke J, Young ES, Jackson K. Improved oxygenation and lower peak airway pressure in severe adult respiratory distress syndrome: treatment with inverse ratio ventilation. Chest 1986; 89:211–213. Tharratt RS, Allen RP, Albertson TE. Pressure controlled inverse ratio ventilation in severe adult respiratory failure. Chest 1988; 94:755–762. Cole AGH, Weller SF, Sykes MK. Inverse ratio ventilation compared with PEEP in adult respiratory failure. Intens Care Med 1984; 10:227–232. Mercat A, Titiriga M, Anguel N, Richard C, Teboul JL. Inverse ratio ventilation (I/E ⫽ 2/1) in acute respiratory distress syndrome: a six-hour controlled study. Am J Respir Crit Care Med 1997; 155:1637–1642. Weis CM, Wolfson MR, Shaffer TH. Liquid-assisted ventilation: physiology and clinical application. Ann Med 1997; 29:509–517. Degraeuwe PLJ, Vos GD, Blanco CE. Perfluorochemical liquid ventilation: from the animal laboratory to the intensive care unit. Int J Artif Organs 1995; 18:674–683. Clark LC, Gollan F. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science 1996; 152:1755–1756. Tuazon JG, Modell J, Hood CI, Swenson EW. Pulmonary function after ventilation with fluorocarbon liquid (Caroxin-D). Anesthesiology 1973; 38:134–140. Modell J, Newby EJ, Ruiz BC. Long-term survival of dogs after breathing oxygenated fluorocarbon liquid. Fed Proc 1970; 29:1731–1736.
836
Fessler
126. Greenspan JS, Wolfson MR, Rubenstein SD, Shaffer TH. Liquid ventilation of human preterm neonates. J Pediatr 1990; 117:106–111. 127. Fuhrman BP, Paczan PR, DeFrancisis M. Perfluorocarbon-associated gas exchange. Crit Care Med 1991; 19:712–722. 128. Curtis SE, Peek JT, Kelly DR. Partial liquid breathing with perflubron improves arterial oxygenation in acute canine lung injury. J Appl Physiol 1993; 75:2696–2702. 129. Overbeck MC, Pranikoff T, Yadao BS, Hirschl RB. Efficacy of perfluorocarbon partial liquid ventilation in a large animal model of acute respiratory failure. Crit Care Med 1996; 24:1208–1214. 130. Leach CL, Fuhrman BP, Morin FC, Rath MG. Perfluorocarbon-associated gas exchange (partial liquid ventilation) in respiratory distress syndrome: a prospective, randomized, controlled study. Crit Care Med 1993; 21:1270–1278. 131. Tutuncu AS, Faithfull NS, Lachmann B. Comparison of ventilatory support with intratracheal perfluorocarbon administration and conventional mechanical ventilation in animals with acute respiratory failure. Am Rev Respir Dis 1993; 148:785–792. 132. Parent AC, Overbeck MC, Hirschl RB. Oxygen dynamics during partial liquid ventilation in a sheep model of severe respiratory failure. Surgery 1997; 121:327. 133. Nesti FD, Fuhrman BP, Steinhorn DM, et al. Perfluorocarbon-associated gas exchange in gastric aspiration. Crit Care Med 1994; 22:1445–1452. 134. Smith TM, Steinhorn DM, Thusu K, Fuhrman BP, Dandona P. A liquid perfluorochemical decreases the in vitro production of reactive oxygen species by alveolar macrophages. Crit Care Med 1995; 23:1533–1539. 135. Pranikoff T, Gauger PG, Hirschl RB. Partial liquid ventilation in newborn patients with congenital diaphragmatic hernia. J Pediatr Surg 1996; 31:613–618. 136. Leach CL, Greenspan JS, Rubenstein SD, et al. Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome. N Engl J Med 1996; 335: 761–767. 137. Gauger PG, Pranikoff T, Schreiner RJ, Moler FW, Hirschl RB. Initial experience with partial liquid ventilation in pediatric patients with the acute respiratory distress syndrome. Crit Care Med 1996; 24:16–22. 138. Hirschl RB, Pranikoff T, Wise C, et al. Initial experience with partial liquid ventilation in adult patients with the acute respiratory distress syndrome. JAMA 1996; 275:383–389. 139. Cox PN, Morris KP, Fmdova H, Mazer D, McKerlie C. Partial liquid ventilation (PLV) redistributes pulmonary blood flow away from dependent lung regions. Am J Respir Crit Care Med 1998; 157:A462. Abstract. 140. Gauger PG, Overbeck MC, Koeppe RA, et al. Distribution of pulmonary blood flow and total lung water during partial liquid ventilation in acute lung injury. Surgery 1997; 122: 313–323. 141. Sukumar M, Bommaraju M, Fisher JE, et al. High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange. J Appl Physiol 1998; 84: 327–334. 142. Leatherman JW, Lari RL, Iber C, Ney AL. Tidal volume reduction in ARDS. Effect on cardiac output and arterial oxygenation. Chest 1991; 99:1227–1231. 143. Kiiski R, Takala J, Kari A, Milic-Emili J. Effect of tidal volume on gas exchange and oxygen transport in the adult respiratory distress syndrome. Am Rev Respir Dis 1992; 146: 1131–1135. 144. Lowe CA, Shaffer TH. Pulmonary vascular resistance in the fluorocarbon-filled lung. J Appl Physiol 1986; 60:154–159. 145. Lowe CA, Tuma RF, Sivieri EM, Shaffer TH. Liquid ventilation: cardiovascular adjustments with secondary hyperlactatemia and acidosis. J Appl Physiol Respir Environ Exercise Physiol 1979; 47:1051–1057. 146. Houmes RJM, Verbrugge SJC, Hendrik ER, Lachmann B. Hemodynamic effects of partial liquid ventilation with perfluorocarbon in acute lung injury. Intens Care Med 1995; 21: 966–972. 147. Fessler HE, Pearse D. Accuracy of hemodynamic measurements during partial liquid ventilation with perflubron. Am J Resp Crit Care Med 2000; 162:1372–1376.
32 Cardiocirculatory Management in Acute Lung Injury and ARDS
RENE´ GUST
DANIEL P. SCHUSTER
University of Heidelberg Heidelberg, Germany
Washington University School of Medicine St. Louis, Missouri
I.
Introduction
The optimal treatment of any critically ill patient always involves therapies aimed at controlling the source of the acute insult while providing the best supportive care to maintain organ function and homeostasis. Although it may be difficult to quantify the relative benefit of any particular supportive measure (e.g., the optimal treatment of infections, a shift from parenteral to enteral nutrition, suctioning of respiratory secretions, stress ulcer and deep venous thrombosis prophylaxis, etc.), few would disagree that it is precisely the effectiveness of these measures that frequently determines outcome. Recent evidence (1–3) suggests that mortality in the acute respiratory distress syndrome (ARDS) has fallen significantly over the last decade, particularly among the subset of patients with sepsis-related ARDS (1–3) despite the fact that no specific therapy (4–10) has been proven effective in any large, randomized, prospective study. Therefore this improvement, if real, can only be attributed to better overall supportive care. Despite the fact that acute lung injury (ALI) and ARDS have been recognized as a distinct clinical entity for ⬎30 years, many—if not most—aspects of their management have been—and still are—controversial. What has emerged is some broad consensus on general issues: e.g. mechanical ventilatory support should in837
838
Gust and Schuster
clude lower tidal volumes, some amount of positive end-expiratory pressure necessary to maintain oxygenation, a willingness to allow hypercapnia to develop if airway pressures are high, and the use of inverse-ratio ventilation or other, similar modes to salvage oxygenation when necessary. Among other supportive therapies in ALI and ARDS, cardiocirculatory management, especially proper fluid management and support of systemic perfusion, has been the focus of debate for a long time. The controversies surrounding hemodynamic management in ALI/ARDS concern not only the impact of restrictive fluid strategy or supranormal oxygen delivery on clinical outcome, but also which endpoints to follow in clinical practice and which strategy to use to achieve the desired goal. For instance, in a septic hypotensive patient with respiratory failure, clinicians in the ICU often face the dilemma of trying to balance the potential benefits of intravascular volume expansion on reversing shock and improving organ perfusion against the potential deleterious effect of causing or worsening pulmonary edema. Furthermore, even if a negative fluid strategy is pursued, it is often difficult to achieve this goal in individual patients because of the demands associated with nutrition, antibiotics, and so forth. The justification for restricting fluid administration in ALI/ARDS, or more directly, for actively trying to lower pulmonary capillary pressures is based on the familiar Starling equation. This equation predicts that whenever the permeability of the alveolocapillary membrane increases, pulmonary edema develops at lower pulmonary capillary pressures than otherwise. Thus, the theoretical benefit of reducing pulmonary capillary pressures is enhanced, not reduced, whenever membrane permeability is increased as in ALI or ARDS. Furthermore, an extensive animal experimental experience (11–23) supports the theoretical therapeutic benefit of reducing hydrostatic pressures during ALI, including the use of diuretics to specifically reduce the amount of pulmonary edema, quantified as extravascular lung water. Theory and experimental studies are also supported by clinical data (24–31) although most clinical studies have been either very small or observational in design. Even so, in general, outcome has been better when fluid management has been restricted in patients with ARDS. This chapter first addresses the pathophysiology of ALI/ARDS relevant to cardiocirculatory management. Then, the relationship between oxygen delivery and consumption is examined. Next, studies which support treatments directed toward actively reducing pulmonary capillary pressures (Pc) will be reviewed, including a discussion of the limitations and risks of restrictive fluid management in critically ill patients. Finally, we present our overall approach to the cardiocirculatory management of ALI/ARDS.
II. Optimizing Substrate Delivery Inherent to the topic of cardiocirculatory management in ALI and ARDS is the notion of balance—in this case, the balance between the need to maintain cellular metabolism and function on the one hand, and the presumed value of minimizing
Acute Lung Injury and ARDS
839
pulmonary edema accumulation by reducing pulmonary capillary pressures on the other hand. This latter point will be discussed in detail in later sections. While the need to maintain cellular metabolism and function is obvious, the best method to do so is not. In general terms, one could alter the overall delivery of substrates to peripheral tissues, could alter the overall composition of substrates delivered, or both. Other than ensuring adequate amounts of oxygen and glucose, however, little is known about how (or even whether) to alter available substrates for tissue metabolism in the acute setting. Therefore, in general, the problem is usually framed in terms of managing overall oxygen delivery. Since the value of achieving maximum oxygen saturation of hemoglobin can be assumed, the problem reduces to how best to ensure the appropriate cardiac output.* The issues then are: What is the appropriate target cardiac output?, and What is the best means of achieving that target? Since oxygen consumption must be in some sense dependent on oxygen delivery, the relationship between oxygen consumption and delivery has been used as one way of evaluating answers to these questions. While recognizing that the sum of all such relations at the microscopic level must ultimately yield a global value for the relationship between consumption and delivery, it is not the case that these global values will always be appropriately representative of events taking place in individual organs or tissues. With this caveat in mind, however, the global relationship between oxygen consumption and delivery can be schematized as shown in Figure 1. In this figure, note that there is a range of values for oxygen delivery (DO 2 ) for which oxygen consumption (VO 2 ) is stable. The mechanism for this stability is the steady increase in oxygen extraction from blood delivered to the tissues, as quantified by the oxygen extraction ratio, O 2 ER. At some point, even in normal subjects, the tissues are unable to extract any additional oxygen from blood. Below this point, referred to as the critical DO 2 , any further reduction in O 2 delivery will result in a reduction in O 2 consumption. In other words, below the critical DO 2 , oxygen consumption becomes dependent upon oxygen delivery. Presumably, similar types of relationships could be derived for other critical substrates. Given such a normal relationship, i.e., one in which VO 2 becomes independent of DO 2 above a certain critical value for DO 2 , it is obvious that there is little value, at least acutely, to increase DO 2 substantially above the critical DO 2 . The normal value for DO 2 is about 15 mL/kg/min and for O 2 ER, about 0.25. The normal value for the critical DO 2 is about 5 mL/kg/min, and for the critical O 2 ER, about 0.6. Thus, there is normally a significant physiologic reserve before any decrease in DO 2 will fall below the critical value. These basic concepts were dramatically challenged by Danek et al. (32) when they reported that VO 2 was dependent on DO 2 at all levels of DO 2 in a group of
* We will ignore, for the purposes of this discussion, any controversy about the optimal hemoglobin mass.
840
Gust and Schuster
Figure 1 (a) Hypothesized relationship between DO 2 and VO 2 in normal (solid line) and pathologic (dashed line) states. The ‘‘critical’’ DO 2 indicates the point as which VO 2 decreases as DO 2 decreases in the normal state. In the pathologic state, VO 2 is dependent on DO 2 throughout the entire range shown. (b) Hypothesized relationship between DO 2 and the oxygen extraction ratio (O 2 ER). The ‘‘critical’’ O 2 ER is the O 2 ER at the critical DO 2 . Normally, as DO 2 falls below the critical DO 2 and the O 2 ER increases, but not enough to maintain VO 2 . In the pathologic state, O 2 ER barely increases at all. (From Ref. 41.)
patients with ARDS, including those values for DO 2 typically above the critical DO 2 . Accordingly, the VO 2-DO 2 relationship would look like that shown by the dashed line in Figure 1; i.e., in this case, there was a pathologic dependence of VO 2 on DO 2 . The implications of such a relationship were immediately apparent. If the observations of Danek et al. (32) were true, what in fact was the proper DO 2 ? Would it be possible that at supranormal values for DO 2 , the relationship between DO 2 and VO 2 would plateau, as in the normal state? The potential importance of this latter possibility was underscored by reports from Shoemaker et al. (33) that the outcome of patients with spontaneously ‘‘supranormal’’ values for DO 2 had a better outcome on average than patients with lesser values. Subsequently, this same group reported that patients treated to bring DO 2 to higher-than-normal values also had a better outcome than patients not so treated (34,35). Although additional reports
Acute Lung Injury and ARDS
841
substantiating the Shoemaker studies about the effects of treating patients to achieve a higher DO 2 were sparse, many other studies confirmed the basic observation that in sepsis or ARDS, VO 2 appeared to be dependent on DO 2 over the entire observed range of values for DO 2 (36–40). Russell (41), among others (42), has critically reviewed these reports and has astutely pointed out several crucial methodologic errors that have cast doubt on the validity of the proposed pathologic relationship between DO 2 and VO 2 in sepsis and ARDS. For one, many observations were made over extended periods of time, allowing for the possibility that increases in observed DO 2 were simply a response to increased oxygen demand. Another problem is the result of mathematical coupling of shared measurement error, which occurs because in all the above studies, VO 2 was calculated from the well-known Fick relationship, which includes measurements of cardiac output and arterial oxygen content, both variables used to calculate DO 2 . Therefore, since an error in cardiac output, for instance, will propagate to the calculation of both DO 2 and VO 2 , the two variables will appear to be related when in fact they may not be. Ultimately, this issue was resolved when several groups failed to observe a pathologic dependence of VO 2 on DO 2 when both variables were measured independently of one another (Table 1). Several groups have tried to confirm the reports by Shoemaker and colleagues that outcome can be improved by increasing DO 2 to supranormal levels (34,35). As reviewed by Russell (41), the results and interpretation of these studies has been controversial (Table 2). The largest such study (43), involving a prospective randomized trial in a generalized ICU patient population, failed to identify any favorable effect of such an approach to supportive management. Several smaller trials, however, did identify favorable effects of treating patients to achieve supranormal DO 2 , especially when the effort was made prophylactically—i.e., prior to the clinical onset of shock or ARDS (Table 2).
Table 1 Studies in Which Independent Measurements of Oxygen Consumption and Oxygen Delivery Failed to Show any Pathologic Dependence Between the Two Variables (88–94) No. patients
Means of DO 2 manipulation
88 89 90 91 92
9 10 14 14 19
PEEP Dobutamine Dobutamine RBCT Life support discontinued
93 94
17 17
Dobutamine MAST ⫹ dobutamine
Reference
Source: Ref. 41.
Controls ALI Septic shock Sepsis: normal and high lactacte ARDS: normal and high lactate Dying patients: septic and nonseptic ARDS Sepsis: normal and high lactate
842
Gust and Schuster
Table 2 Randomized Controlled Trials of Supranormal Versus Normal Oxygen Delivery in Critically Ill Patients (34,35,43,95–100)
Reference 95 96 34 97 35 98 43 99 100
100
Patient type Septic shock Surgical Surgical ARDS Trauma Critical Critical Critical Critical, pHi normal Critical, pHi low
No. patients 51
Mortality (%) Controls
Interventions
72
50
107 88 100 67 67 503 109 141
22 28 48 44 34 48.4 34 53
6 4 60 24 34 48.6 54 28
119
37
36
P ns ⬍.05 ⬍.05 ns ns ns ns ns ⬍.05
ns
Source: Ref. 41.
Even if it were true that increasing DO 2 to supranormal levels was valuable, the question would remain as to how best to achieve this goal. In almost all cases, the primary method that has been used has been first to attempt to increase cardiac output by increasing cardiac filling pressures. But this might not always be possible or even such a good idea. The use of intravascular volume expansion as the means of improving cardiac performance is simply a clinical application of Starling’s law of the heart, which relates stroke output to ‘‘preload.’’ Occlusion pressure is used as the principal index of preload, despite the enormous difficulty in accurately measuring—not to mention interpreting—occlusion pressures in the usual clinical situation (44–47). Equally problematic is what endpoint occlusion pressure should be targeted to achieve optimal cardiac performance. Specific guidelines are lacking in the clinical literature, but our group has observed that many physicians attempt to maintain the occlusion pressure between 14 and 18 mm Hg. The justification for these specific pressure endpoints is obscure. Perhaps the observation that cardiac output is frequently optimized in patients with acute myocardial infarction when the occlusion pressure reaches this level has been instrumental in forming this opinion (48). Furthermore, our group believes a bias exists that, all other variables being equal, it is ‘‘better’’ (i.e., the risk-benefit ratio is more favorable) to increase cardiac output by intravascular volume expansion than with inotropic or vasoactive drugs. However, many patients with sepsis and other noncardiogenic forms of shock achieve maximal cardiac performance at much lower filling pressures (49) or at least fail to improve cardiac performance with volume expansion (50). Finally, as reviewed by Russell
Acute Lung Injury and ARDS
843
(41), there is evidence that one of the most common ways to increase intravascular volume, namely via red blood cell transfusion, may even be deleterious to outcome. Thus, if these latter studies are representative of the hemodynamic circumstances of most ARDS patients, and if exacerbating extravascular lung water accumulation or delaying its resolution does affect outcome (see following sections), then the result of these clinical strategies that seek to routinely increase the occlusion pressure to between 14 and 18 mm Hg would be to increase the risks associated with pulmonary edema without gaining any additional benefit from improved cardiac performance. In contrast, as discussed below, currently available data suggest that diuresis/ fluid restriction in euvolemic (and certainly in hypervolemic) ARDS patients can be accomplished without clinically important deterioration in either cardiac or renal function. Thus, in many patients, it may be possible to shorten the duration of pulmonary edema without compromising perfusion.
III. Theoretical Basis for Fluid Restriction in ALI/ARDS The American Thoracic Society and the European Society of Intensive Care Medicine recommended in their consensus conference on ARDS in 1992 that ALI should be defined as a ‘‘syndrome of inflammation and increasing permeability that is associated with a constellation of clinical, radiologic, and physiologic abnormalities that cannot be explained by, but may coexist with, left atrial or pulmonary capillary hypertension,’’ and that ARDS should be defined simply as a more severe form of ALI (51,52). Although these definitions are widely accepted, they are, by the very nature of a consensus conference, a compromise and are still a controversial topic. We prefer a more meaningful definition of ALI and ARDS, which incorporates the typical histopathologic correlate of ALI and ARDS—i.e., ‘‘diffuse alveolar damage.’’ We believe that an ‘‘acute lung injury’’ is present whenever characteristic pathologic abnormalities in the lungs’ normal underlying structure result in a deterioration of normal lung function. ‘‘ARDS,’’ however, should be considered a specific form of lung injury (not just the most severe clinical manifestation of ALI), one with diverse causes, characterized pathologically by diffuse alveolar damage and pathophysiologically by a breakdown in both the barrier and gas exchange functions of the lung, resulting in proteinaceous alveolar edema and hypoxemia (1). Although controversy may surround the definition of ALI and ARDS, it is clear at the very least ALI/ARDS is associated with an increased permeability of the alveolocapillary membrane, which in turn leads to the development of pulmonary edema at otherwise normal pulmonary capillary pressures. The theoretical basis for attempting to achieve a negative fluid balance in pulmonary edema by restricting fluids or administering diuretics is centered around the familiar Starling equation (53,54). For a simple, two-compartment model of tissue in which vascular and extravascular compartments are separated by a semipermeable membrane, this equation expresses how fluid flux across this barrier depends on the relationships between hydrostatic pressure and oncotic pressure on either side
844
Gust and Schuster
of the membrane, and on the permeability characteristics of the membrane itself. A common modification is to add the influence of lymphatic flow (and other mechanisms for resolution) on the accumulation of fluid in the extravascular compartment: EVLW ⫽ K fc ([Pc ⫺ Pi ] ⫺ σ[Π c ⫺ Π i ]) ⫺ lymph flow where EVLW is extravascular lung water, K fc is the hydraulic coefficient, Pc and Pi are capillary and interstitial hydrostatic pressures, σ is the protein reflection coefficient, and Π c and Π i are capillary and interstitial oncotic pressures. Despite general familiarity with the concepts represented by this equation, it is still useful to make several important points. First, at best, the equation is a model of fluid accumulation in the interstitium. Accordingly, the Starling equation is most appropriate as a model for the development of interstitial edema. In the lung, especially, the onset of alveolar edema is a function of a different set of less well understood factors that result in the all-or-none development of alveolar edema (53–56). Furthermore, the capacity of the perivascular interstitium depends on the degree of lung inflation (which can increase the capacity 20-fold); the presence or absence of ventilation; the time for the accumulation of fluid; the integrity of the alveolar epithelium; and the interstitial compliance and pressure gradients, which favor filtration and clearance toward the hilum (57). In addition, it is now clear that the distribution and clearance of fluid from the airspace in the edematous lung depend on factors such as the compliance of the interstitium and the active sodium transport by the lung epithelium (56,57). Although interstitial edema is presumably a necessary antecedent to the development of alveolar edema, it is not at all clear that once alveolar edema has developed, further accumulation of that edema is accurately described by the Starling equation. Furthermore, the factors controlling the resolution of alveolar edema are almost certainly different than those factors controlling its onset (56,58). The Starling equation predicts, assuming all other factors remain unchanged, that any increase in pulmonary capillary pressure will be followed by an increase in fluid flux into the extravascular compartment. However, other factors in the Starling equation do not remain unchanged, constituting the so-called ‘‘safety factors’’ against the development of significant organ edema (e.g., the dilution of extravascular proteins and the reduction in extravascular oncotic pressures as edema develops) (53–55). Nevertheless, there is a physiologic limit to how much the other forces can change in response to a step change in pulmonary capillary pressure. As a result, clinically important alveolar edema will almost always develop whenever the pulmonary capillary pressure increases to ⬎20 to 23 mm Hg. Whenever the permeability of the alveolocapillary membrane increases (increased K fc , decreased σ), these safety factors become less efficient. Thus, pulmonary edema develops at a lower pulmonary capillary pressure for two reasons: decreased membrane integrity, and reduced effects of the safety factors. Also, when membrane permeability is abnormal, the rate of increase in edema is greater for any given change in pulmonary capillary pressure than when membrane function is normal. Thus, the theoretical benefit of reducing pulmonary capillary pressures is enhanced, not reduced, whenever membrane permeability is increased.
Acute Lung Injury and ARDS
845
IV. Experimental Evidence Supporting Active Reduction of Pc in ALI/ARDS The theoretical sensitivity of the lung to hydrostatic stress when membrane permeability is abnormal has been demonstrated experimentally in numerous acute lung injury models (11–14,16,18–23,59). For instance, after oleic acid administration, Prewitt et al. (13) showed that decreasing left atrial pressures by only 4 mm Hg (either by controlled hemorrhage or nitroprusside) resulted in a 25% to 32% reduction in extravascular lung water accumulation during the first 4 hours of injury. Likewise, using an in situ, perfused, dog lung preparation, Huchon et al. (12) showed that significantly more edema accumulated after the same dose of injurious agent in animals maintained with ‘‘high’’ left atrial pressures (⬃18 mg Hg) than in those animals with pressures kept at 0 mm Hg. Using positron emission tomography to measure lung water concentrations before and after oleic acid injury, as well as the pulmonary transcapillary escape rate for gallium-68-labeled transferrin (an index of vascular permeability), Schuster and Haller (60) showed that changes in lung water accumulation correlated well (r 2 ⫽ .73) with hydrostatic pressure and pulmonary transcapillary escape rate combined, but not with either variable alone. However, the influence of the hydrostatic pressure was the more important variable. The most common method of reducing Pc clinically is to administer a diuretic, such as furosemide. This maneuver is associated with reductions in extravascular lung water after experimental lung injury (11,16). However, Ali et al. (61) speculated that furosemide might also have vasoactive effects that reduced shunt and extravascular lung water in injured regions. In subsequent studies (62), this same group showed in a lobar model of oleic acid injury that furosemide decreased shunt even though perfusion to the injured lobe increased, while extravascular lung water was unchanged compared with a control group. These data suggested that furosemide caused the preferential perfusion of nonflooded lung units. Ali et al. (62) showed in an isolated, perfused lung model that furosemide caused a parallel downward shift in the pulmonary arterial pressure-cardiac output relationship, resulting in a lower ‘‘effective downstream pressure,’’ while for any given driving pressure, blood flow to the isolated lobe increased. These effects were inversely proportional to the amount of edema present. They are consistent with vasodilatation of a portion of the pulmonary vascular bed acting as a Starling resistor. Stevens et al. (63) also confirmed that furosemide vasodilates pulmonary vessels, in addition to a bronchodilating effect. However, Rusch et al. (64) found that 24 hours after oleic acid edema, furosemide failed to improve either oxygenation or extravascular lung water, unlike its apparent salutary effect in the first few hours after oleic acid injury. Although active diuresis is the only currently available way to reduce pulmonary capillary pressures clinically, other approaches may be possible. For instance, the fact that pulmonary capillary pressures are often significantly higher than pulmonary wedge pressures (i.e., higher than left atrial pressure) in ARDS (65), suggests that pulmonary venoconstriction may add to the hydrostatic stress of acute lung injury. Thromboxane, a metabolic product of arachidonic acid metabolism, is a known potent venoconstrictor, and thromboxane levels in blood and lung lavage
846
Gust and Schuster
fluid are known to be elevated in both experimental and clinical forms of lung injury (66,67). Thus, a plausible hypothesis is that thromboxane contributes to pulmonary capillary hypertension in ALI/ARDS, which in turn contributes to the hydrostatic stress that can exacerbate pulmonary edema. As an example of how important pulmonary venoconstriction might be to the pathogenesis of ALI/ARDS, we tested the hypothesis in a recent study that pulmonary edema accumulation during a 24- to 28-hr period of observation after acute lung injury (induced by intravenous oleic acid) would be less in dogs treated with a nonspecific cyclo-oxygenase inhibitor, or with a specific thromboxane receptor blocker (both of which would block thromboxane effects), than in a group of dogs injured with OA alone (68). We found that after 24 to 28 hr, pulmonary edema accumulation was significantly less in the thromboxane receptor blocking group than in the meclofenamate group, with a similar trend for reduction compared to the placebo group (P ⫽ 0.12) (Fig. 2). The only significant correlation with the development of pulmonary edema was with the integral of pulmonary pressures over the 24- to 28-hr time period (i.e., the period of exposure to elevated pulmonary pressures) (Fig. 3). Data such as these suggest that thromboxane inhibition could reduce edema accumulation in acute lung injury but that this effect depends on reductions in Pc. If thromboxane inhibition is accompanied by increases in Pc because of simultaneous
Figure 2 Change in lung water concentration (LWC) between baseline and 24 to 28 hr after the onset of experimentally induced acute lung injury, in three experimental groups: group P—placebo (injury only); group M—treated with meclofenamate after injury; group O—treated with the thromboxane receptor blocker ONO3708 prior to and after injury. Dashed line ⫽ mean values; horizontal line in each box is the median value. *Group M is significantly different from group O. (From Ref. 103.)
Acute Lung Injury and ARDS
847
Figure 3 Examples of pulmonary artery diastolic (PAD) or pulmonary capillary wedge pressure (PCWP) plots as a function of time in individual animals from the same study as in Figure 2 (103). (A) Animal treated with meclofenamate. (B) Placebo-treated animal. Note obvious marked increase in PA pressures in the meclofenamate-treated animal, representing significant additional hydrostatic stress to the injured alveolocapillary membrane.
inhibition of vasodilatation (e.g., prostacyclin inhibition with a non specific cyclooxygenase inhibitor), then the net effect on pulmonary edema accumulation could be an actual increase. The data also suggest that these changes in Pc are, in general, significantly more important than any local change in rPBF on edema accumulation. Other maneuvers that reduce either perfusion or hydrostatic pressures to injured lung regions, such as regional hypoxic ventilation, stellate ganglion ablation, or α-adrenergic blockade, are also associated with reduced extravascular lung water accumulation experimentally (69–72). Conversely, interventions that increase perfusion or hydrostatic pressures are associated with increased extravascular lung water, even when occlusion pressure is kept constant (73). In such experiments, it is difficult to distinguish between the potential effects of changes in Pc per se, and changes in regional perfusion per se, because the two are linked, as follows. The pulmonary capillary pressure (Pc) is related to pulmonary resistances by the so-called Gaar equation (53): Pc ⫽ Pv ⫹ Rv/(Ra ⫹ Rv) ∗ (Pa ⫺ Pv) Under normal circumstances, it is usually accepted that ⬃40% of the total pulmonary vascular resistance is in the venous compartment. It is possible by simple algebraic manipulation to rearrange the Gaar equation so that: Pc ⫽ Pv ⫹ Rv ∗ rPBF Thus, theoretically, Pc could decrease with either venous vasodilation or decrease in rPBF, even when Rv is constant. Nevertheless, the various experimental studies (11–16,18–23,60,74) lead to the general conclusion that reduced capillary pressures and/or reduced perfusion to acutely injured lung units results in reduced extravascular lung water accumulation, but that the impact of a reduction in Pc is probably more potent than the impact of a
Fluid Balance and Patient Outcome in Pulmonary Edema (24–29,49,50,101) (Source: Ref. 102.) Design
24
Effect of diuretics, dialysis, and PEEP on compliance and urinary output
Not controlled; prospective series of patients with ARDS. Evaluation of response to therapeutic intervention
12 ARDS patients
25
Effect of edema reduction on PEEP requirements, PCWP, and outcome
Not randomized; comparative study of aggressive diuretic therapy in ARDS with high-dose furosemide
15 ARDS patients who underwent aggressive diuresis compared with 10 ARDS patients with conventional fluid management
28
Effect of fluid balance on survival in ARDS
113 ARDS patients from medical (55%) and surgical (45%) ICUs
27
Effects of postoperative weight gain on outcome
Prospective data collection without standardization of fluid therapy. Comparison by survival. Comparison of outcome and APACHE-II scores according to weight changes
Patient population
48 consecutive patients admitted to SICU
Results 8 patients responded to diuretics; 2 responded to dialysis by improving static compliance, oxygenation, and urine output Aggressive diuresis group associated with a 4 ⫾ 2 kg wt loss, lower PEEP, lower PCWP, and 20% mortality compared with a 5 ⫾ 4 kg wt gain and 60% mortality Survivors lost weight and had significantly lower intakeoutput 29 patients (60%) gained ⱕ10% weight and had a 10% mortality; 16 (33%) with 11– 20% weight gain had a 19% mortality; all 3 (6%) with ⬎20% weight gain died
Conclusion
Comments
Improvement in pulmonary mechanics and gas exchange without impact on mortality
Small study (type II error)
Aggressive fluid managment associated with improved clinical outcome and no evidence of renal or other end-organ failure
Preliminary report (abstract)
Weight loss and negative fluid balance in ARDS associated with improved survival Significant morbidity associated with postoperative fluid overload
Retrospective analysis; lacking baseline data and severity of illness scores Retrospective analysis; not interventional trial
Gust and Schuster
Question addressed
Reference
848
Table 3
Not controlled series; hemodynamic measurements at baseline and after fluid loading
21 patients in hypovolemic or septic shock, with a baseline PCWP ⱕ 10 mm Hg
50
Evaluate left ventricular performance in response to volume infusions
Controlled study, comparing left ventricular complaince and contractility in sepsis with and without shock
14 ICU patients (controls), 21 patients with sepsis, 21 patients with septic shock
26
Evaluate safety and tolerance of a strategy of fluid restriction in critically ill patients based on EVLW measurments Evaluate whether a management strategy of lowering PCWP is associated with improved outcome
Prospective, randomized study comparing EVLW vs. PCWP endpoints
Evaluate whether a fluid management strategy that emphasized diuresis and fluid restriction can affect the resolution of EVLW and outcome implications
Randomized, controlled, prospective trial of fluid managment based on direct measurements of EVLW vs. PCWP management
25 patients randomized to EVLW protocol management; 23 patients routine managment; similar baseline characteristics 40 ARDS patients; 16 (40%) had a reduction of PCWP of ⱖ25% (group 1); 24 (60%) without PCWP reduction of at least 25% (group 2) 89 patients with pulmonary edema out of 101 patients who required PAX; 52 patients in EVLW gorup, 49 patients in PCWP group
29
101
Retrospective analysis of survival and ICU length of stay according to changes in PCWP
PCWP elevation to 12 mm Hg associated with increased CI, SVI, and LVSWI; subsequent elevations of PCWP without further hemodynamic improvement Significantly less improvement in contractility after volume infusion in sepsis and septic shock compared with controls Hemodynamic management based on EVLW was associated with less fluid adminsitration and improved outcome in ARDS 75% vs. 29% survival in favor of group 1 (P ⫽ .02); also, shorter ICU length of stay.
Patients managed in the EVLW group had no fluid gain and significantly reduced time on ventilator and in ICU (P ⬍ .05)
Optimum left-sided heart filling pressures during resuscitation not to exceed PCWP of 12 mm Hg
2 patients remained with a PCWP ⬍ 10 mm Hg in spite of 5–8 L of normal saline
Altered ventricular performance in septic patients
8/14 control patients were hypovolemic on average 1 of NS infused to achieve a PCWP increase of 2–3 mm Hg
Protocol of fluid restriction guided by EVLW safe and hastens the resolution of pulmonary edema
Small sample size to detect differences in mortality
Treatment of low-pressure pulmonary edema with reduction of PCWP is associated with increased survival
Retrospective study; groups unequal at baseline; lack of fluid balance data; not clear that groups were treated differently ‘‘Intention-to-treat’’ analysis; small sample size to detect difference in mortality. Applicability of EVLW measurement unclear
A lower positive fluid balance in patients with pulmonary edema regardless of cause is associated with reduced EVLW, ventilator, and ICU days
849
Effect of increasing filling pressures on cardiac performance
Acute Lung Injury and ARDS
40
850
Gust and Schuster
reduction in regional perfusion to an injured region in the absence of a comcomitant reduction in Pc.
V.
Clinical Evidence for the Value of Fluid Restriction in ALI/ ARDS
The above theory and experimental studies are also supported by clinical data. Although most such studies have either been small or observational in design, larger prospective and retrospective studies in medical and surgical ICUs have now provided additional evidence that a positive fluid balance is associated with worse outcomes and therapeutic efforts to achieve a negative fluid balance are associated with improved outcome (Table 3) (24,25,27,29–31,49,75). The largest prospective randomized trial on this topic was conducted by our group several years ago in which patients requiring pulmonary artery catheterization in the course of managing pulmonary edema were treated either by a protocol that emphasized fluid restriction and diuresis where possible, or by a treatment strategy that targeted ‘‘optimizing’’ the pulmonary artery occlusion pressure (PAOP) between 15 and 18 mm Hg (30,31). Of the 89 patients enrolled in the study, 50 had an initial wedge pressure ⬍18 mm Hg. There were 48 patients meeting formal criteria for ARDS or sepsis. The principal evidence that the groups were actually treated differently with respect to fluid management as a whole was the difference in cumulative intake versus output (I-O). As expected, cumulative I-O was less in the group managed with the restrictive fluid strategy. Moreover, the differences in fluid management were greatest in the subset of 50 patients with a wedge pressure ⬍18 mm Hg (mostly patients with ARDS or sepsis). The initial extravascular lung water (EVLW) (measured by the bedside double indicator dilution technique [76]) was not significantly different between the two study groups, but EVLW was significantly less at each time point after 24 hr in patients managed with diuresis/fluid restriction compared with the baseline value, which was not the case in the other set of patients (Fig. 4). Patients from the group managed with diuresis/fluid restriction also required mechanical ventilation and were in the ICU for a significantly shorter period of time than patients from the other group. The time required for mechanical ventilation in the subset of patients with ARDS was also shorter for those managed with diuresis/fluid restriction. Although ICU and hospital mortality were not different between the two management groups, the trends favored the group managed with diuresis and fluid restriction. Survivors (regardless of management group) had no net fluid gain on average, while nonsurvivors were characterized by positive rates of fluid gain. For patients with ⬎15% reduction in their EVLW and an underlying diagnosis of ARDS or sepsis, ventilator days and ICU days were less than those with ⬍15% reduction in EVLW. In studies of this sort, there is often a poor correlation between overall net intake versus output and the resolution of extravascular lung water. Actually, this
Acute Lung Injury and ARDS
851
Figure 4 Mean extravascular lung water (EVLW) after each time interval for 89 patients in pulmonary edema. Note statistically significant reduction in EVLW in the group treated by a protocol that emphasized fluid restriction and/or diuresis. (From Ref. 31.)
is not surprising as net intake-output represents the relative fluid balance from all body compartments and not just the lung. Fluid balance can be expected to affect pulmonary microvascular hydrostatic pressures (but not necessarily in a 1:1 ratio). As embodied in the Starling equation, many other factors also affect extravascular lung water, and, in any given patient, these other factors may overwhelm the potential beneficial effect of reducing hydrostatic pressures on extravascular lung water accumulation. It is perhaps more correct to think of fluid balance as an important permissive factor which can favorably affect extravascular lung water if hydrostatic pressures are reduced, and then only if other factors (e.g., magnitude of damage to the alveolocapillary membrane) are not greater in importance. The association between improved outcome and fluid balance in pulmonary edema also may be related to factors other than extravascular lung water reduction, including decreased gut edema with reduced bacterial translocation, improved gas exchange for reasons other than extravascular lung water reduction per se, or unknown reasons. Improved resolution of extravascular lung water itself might reduce ventilator days, thereby reducing the risks of infection, barotrauma, and oxygen toxicity associated with prolonged mechanical ventilation. VI. Other Clinical Approaches to Reducing Pc Another approach to reducing Pc in ARDS may be to use inhaled nitric oxide (iNO) (65,77–83). Recent data indicate that pulmonary capillary pressures are significantly higher than left atrial (i.e., wedge) pressures, implying a significant contribution of pulmonary venous resistance to overall pulmonary artery pressure in ARDS (Fig. 5).
852
Gust and Schuster
Figure 5 Mean pulmonary artery pressure (PAP), pulmonary capillary pressure (Pcap), and wedge pressure (WP) in seven patients with ARDS. (From Ref. 65.)
Interestingly, the primary effect of iNO may also be on pulmonary venous, not arterial, resistance (65). If true, then iNO would have an effect on pulmonary capillary pressures that would be similar to that seen after treating left atrial hypertension or with the use of thromboxane inhibitors in animals (see previous sections). Most studies have shown that iNO often (but not universally) improves oxygenation and lowers pulmonary arterial pressures in ARDS, presumably by vasodilating normally ventilated lung units and by altering the intrapulmonary distribution of blood flow. Not only might this improvement in gas exchange reduce the need for high airway pressures or FiO 2 s, along with their associated complications, but the reduction in pulmonary arterial pressure might also improve cardiac performance and increase tissue oxygen delivery. Interestingly, however, the reduction in pulmonary arterial pressure with iNO is generally modest (⬃10% to 15% on average) (65,77–83) (Fig. 6). More importantly, this change in right ventricular afterload is not associated with significant changes in cardiac output (Fig. 7). This observation is in contrast to the results with intravenously administered vasodilators, which not only lower mean pulmonary arterial pressures about as much as iNO, but also lower mean systemic blood pressure and increase cardiac output (78,79,82). Accordingly, it seems reasonable to conclude that pulmonary arterial hypertension is not a major limiting factor for an adequate cardiac output in ARDS. Other treatments directed toward reducing pulmonary capillary pressures (say with thromboxane receptor antagonists) may be of benefit. Inhibitors of eicosanoid formation or action have been used in several clinical studies of acute lung injury in humans. The largest relevant clinical study involving eicosanoid inhibition was that recently reported by Bernard et al. (66). Ibuprofen was used as the inhibitor agent, and the study focused on patients with sepsis, not ARDS per se. By standard ARDS criteria, only 30% of patients had ARDS, and no secondary analysis of this
Acute Lung Injury and ARDS
853
Figure 6 Mean reduction in pulmonary artery pressure (PAP), pulmonary capillary pressure (Pcap), and wedge pressure (WP) in response to inhaled NO (second bar in each group) in seven patients with ARDS. (From ref. 65.) Note that the reduction in pulmonary artery pressure is virtually entirely explained by the reduction in pulmonary capillary pressure, implying a reduction in pulmonary venous resistance.
Figure 7 Average reduction in pulmonary artery pressures (PAP) (statistically significant) and lack of significant change in cardiac output (c.o.) in response to inhaled nitric oxide. Total N ⫽ 141 patients. (From Refs. 65,77,78,81,82,104.)
854
Gust and Schuster
subset was reported. Overall, the use of ibuprofen, which as just noted would be expected to inhibit both vasodilator and vasoconstrictor prostanoids, had no effect on patient outcome. The available literature on the role of thromboxane per se in ARDS is sparse, but nevertheless provocative. Thromboxane synthesis remains elevated for at least 44 hours after the onset of sepsis, the most common risk factor for the development of ARDS (66,67). Supporting data have previously been reported by Reines et al. with elevated plasma levels for at least 72 hours after the onset of sepsis (67). More specifically, in ARDS, Deby-Dupont et al. (84) also reported that plasma thromboxane levels in ARDS patients were elevated for several days after the onset of the illness. There have been a few reports of the effects of thromboxane inhibition in ARDS, involving small numbers of patients. Slotman et al. (85) and Yu et al. (86) both reported on the use of ketoconozole (an inhibitor of thromboxane) in septic surgical patients. Both groups reported a reduction in the incidence of ARDS in the treatment group. Reines et al. (67) and Leeman et al. (87) studied the use of the thromboxane synthesis inhibitor dazoxiben in a small group of ARDS patients. Neither study reported any changes in hemodynamics or other outcomes, but these were very acute studies in which in some cases only one dose of drug was given. The effect on EVLW per se was never measured, and the effect on pulmonary capillary pressures—as opposed to pulmonary wedge pressures (which are a measure of left atrial pressure)—was also not measured. Thus, it is impossible to conclude from these early exploratory studies that thromboxane receptor inhibition will not have a favorable effect on the course of pulmonary edema.
VII. Summary and Management Recommendations Pulmonary hypertension is common in ARDS, but its underlying cause is undoubtedly multifactorial. There is good reason to believe that when pulmonary hypertension is due to left atrial hypertension or pulmonary venoconstriction, treatment with fluid restriction, diuretics, or possibly iNO should have a favorable effect on pulmonary edema accumulation and outcome. In contrast, there is little evidence that pulmonary arterial hypertension per se in ARDS affects cardiac performance, and no evidence that its treatment will alter outcome. On the other hand, pulmonary edema is exacerbated unnecessarily when pulmonary capillary pressures are higher than required to maintain cardiac filling. There is evidence that pulmonary venoconstriction is frequently present in ARDS. Thus, any intervention that could markedly reduce pulmonary venous hypertension might reduce the ongoing formation of pulmonary edema or hasten its resolution. The ultimate impact of shortening the duration of pulmonary edema could be less time on mechanical ventilation, with a reduced chance of associated complications such as nosocomial pneumonia or barotrauma, less time in the ICU or hospital, and possibly reduced mortality.
Acute Lung Injury and ARDS
855
While on balance a strategy of relative or absolute fluid restriction may improve outcome overall for patients with ARDS, the individual patient can certainly be harmed if such therapy results in vital organ hypoperfusion. Clinical and even invasive monitoring of organ function and hemodynamics, and the willingness to adjust therapy as necessary to maintain adequate perfusion, must be part of the therapeutic plan. With this caveat in mind, available data suggest that diuresis/fluid restriction in euvolemic (and certainly in hypervolemic) ARDS patients can be accomplished without clinically important deterioration in either cardiac or renal function. Other interventions (such as inhaled NO or thromboxane inhibition per se) have not been tested specifically for this purpose. Although as reviewed, there appears to be little factual support for the idea that systemic perfusion should be treated to achieve ‘‘supra normal’’ levels, still unanswered is whether systemic perfusion, when treated at all, should be principally maintained by adjustments in volume status or by the use of inotropes and vasodilators. Likewise, the endpoint for determining ‘‘adequate’’ perfusion, as judged primarily from hemodynamic data, is unknown. Clinical trials of different endpoints, with different therapeutic strategies, are needed. Thus, as in other aspects of care for patients with ALI/ARDS, the avialable evidence (as opposed to opinion) only supports relatively broad statements about proper cardiocirculatory management: patients who have an increased DO 2 relative to normal values (especially septic ARDS patients) have a better prognosis than those who do not, but therapeutically driving DO 2 to supranormal values does not appear to alter outcome. Patients with a low DO 2 , especially if low because of a depressed cardiac output, have an especially poor prognosis, and early volume resuscitation is entirely appropriate for such patients. Although restoration of end-organ function (urine output, mental status, myocardial function) is the goal of treatment, in the absence of these clinical targets, the marker of ‘‘adequate’’ fluid therapy is unclear. However, we believe that there is no evidence that continued fluid resuscitation is valuable once a cardiac filling pressure of 12 to 15 mm Hg is achieved. Indeed, if end-organ function is not an issue, as is often true in many ARDS patients, then we believe the balance of benefit shifts to making efforts to actively reduce Pc, first by reducing left atrial (i.e., wedge pressure) as much as possible consistent with continued adequate peripheral perfusion, and someday, perhaps, by specifically inhibiting pulmonary venoconstriction. References 1. Schuster DP. What is acute lung injury? What is ARDS? Chest 1995; 107:1721–1726. 2. Kollef MH, Schuster DP. The acute respiratory distress syndrome. N Engl J Med 1995; 332:27–37. 3. Hudson LD. New therapies for ARDS. Chest 1995; 108:79S–91S. 4. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. JAMA 1979; 242:2193–2196. 5. Bernard GR, Luce JM, Sprung CL, et al. High dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987; 317:1565–1570. 6. Holzapfel L, Robert D, Perrin F, Gaussorgues P, Giudicelli DP. Comparison of high frequency jet ventilation to conventional ventilation in adults with respiratory distress syndrome. Intens Care Med 1987; 22:61–68.
856
Gust and Schuster
7. Morris AH, Menlove RL, Rollins RJ, Wallace CJ, Beck E. A controlled clinical trial of a new 3-step therapy that includes extracorporeal CO 2 removal for ARDS. Trans Am Soc Artif 1988; 11:48–53. 8. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO 2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994; 149:295–305. 9. Jepsen S, Herlevsen P, Bud MI, Knudsen P, Klaussen NO. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome. A prospective, randomized, placebo-controlled study. Crit Care Med 1992; 20:918–923. 10. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized Phase II trial. Crit Care Med 1998; 26:15–23. 11. Chernicki JAW, Wood LDH. Effect of furosemide in canine low-pressure pulmonary edema. J Clin Invest 1979; 64:1494–1504. 12. Huchon GJ, Hopewell PC, Murray JF. Interactions between permeability and hydrostatic pressure in perfused dogs’ lungs. J Appl Physiol 1981; 50:905–911. 13. Prewitt RM, McCarthy J, Wood LDH. Treatment of acute low pressure edema in dogs. Relative effects of hydrostatic and oncotic pressure, nitroprusside, and end-expiratory pressure. J Clin Invest 1981; 67:409–418. 14. Winn R, Stothert J, Nadir B, Hildebrandt J. Lung fluid balance, vascular permeability, and gas exchange after acid aspiration in awake goats. J Appl Physiol 1984; 56:979–985. 15. Molloy WD, Lee KY, Girling L, Prewitt RM. Treatment of canine permeability pulmonary edema: short-term effects of dobutamine, furosemide, and hydralazine. Circulation 1985; 72:1365–1371. 16. Sivak ED, Tita J, Meden G, et al. Effects of furosemide versus isolated ultrafiltration on extravascular lung water in oleic acid-induced pulmonary edema. Crit Care Med 1986; 14:48–51. 17. Schuster DP, Haller J. Regional pulmonary blood flow during acute pulmonary edema: a PET study. J Appl Physiol 1990; 69:353–361. 18. Berner ME, Teague WG, Scheerer RG, Bland RD. Furosemide reduces lung fluid filtration in lambs with lung microvascular injury from air emboli. J Appl Physiol 1989; 67:1990– 1996. 19. Zucker AR, Sznajder JI, Becker CJ, Berger S, Wood LDH. The pathophysiology and treatment of canine kerosene pulmonary injury: effects of plasmapheresis and positive endexpiratory pressure. J Crit Care 1989; 4:184–193. 20. Sznajder JI, Zucker AR, Wood LDH. The effects of plasmapheresis and hemofiltration on canine acid aspiration pulmonary edema. Am Rev Respir Dis 1986; 134:222–228. 21. Allen SJ, Drake RE, Katz J, Gabel JC, Laine GA. Lowered pulmonary arterial pressure prevents edema after endotoxin in sheep. J Appl Physiol 1987; 63:1008–1001. 22. Long R, Breen PH, Mayers I, Wood LDH. Treatment of canine aspiration pneumonitis: fluid volume reduction vs. fluid volume expansion. J Appl Physiol 1988; 65:1736– 1744. 23. Townsley MI, Lim EH, Sahawneh TM, Song W. Interaction of chemical and high vascular pressure injury in isolated canine lung. J Appl Physiol 1990; 69:1647–1664. 24. Bone RC. Treatment of adult respiratory distress syndrome with diuretics, dialysis, and positive end-expiratory pressure. Crit Care Med 1978; 6:136–139. 25. Costello JL, Dorinsky PM, Gadek JE. Edema reduction improves clinical abnormalities in ARDS: a clinical trial of aggressive diuretic therapy. Am Rev Respir Dis 1987; 135: A9. 26. Eisenberg PR, Hansbrough JR, Anderson D, Schuster DP. A prospective study of lung water measurements during patient management in an intensive care unit. Am Rev Respir Dis 1987; 136:662–668. 27. Lowell JA, Schifferdecker C, Driscoll DF, Benotti PN, Bistrain BR. Postoperative fluid overload: not a benign problem. Crit Care Med 1990; 18:728–733. 28. Simmons RS, Berdine GG, Seidenfeld JJ, et al. Fluid balance and the adult respiratory distress syndrome. Am Rev Respir Dis 1987; 135:924–929. 29. Humphrey H, Hall J, Sznajder I, Silverstein M, Wood L. Improved survival in ARDS
Acute Lung Injury and ARDS
30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
857
patients associated with a reduction in pulmonary capillary wedge pressure. Chest 1990; 97:1176–1180. Schuller D, Mitchell JP, Calandrino FS, Schuster DP. Fluid balance during pulmonary edema. Is fluid gain a marker or a cause of poor outcome? [See comments.] Chest 1991; 100:1068–1075. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. [See comments.] Am Rev of Respir Dis 1992; 145:990–998. Danek SJ, Lynch JP, Weg JG, Dantzker DR. The dependence of oxygen uptake on oxygen delivery in the adult respiratory distress syndrome. Am Rev Respir Dis 1980; 122:387– 395. Bland RD, Shoemaker WC, Abraham E, Cobo JC. Hemodynamic and oxygen transport patterns in surviving and nonsurviving postoperative patients. Crit Care Med 1985; 13: 85–90. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal value of survivors as therapetuic goals in high-risk surgical patients. Chest 1988; 94: 1176–1186. Fleming A, Bishop M, Shoemaker W, et al. Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 1992; 127:1175–1181. Kaufman BS, Rackow EC, Galk JL. The relationship between oxygen delivery and consumption during fluid resuscitation of hypovolemic and septic shock. Chest 1984; 85:336– 340. Astiz ME, Rackow EC, Falk JL, Kaufman BS, Weil MH. Oxygen delivery and consumption in patients with hyperdynamic septic shock. Crit Care Med 1987; 15:26–28. Fenwick JC, Dodek PM, Ronco JJ, Phang PT, Wiggs BR, Russell JA. Increased concentrations of plasma lactate predict pathologic dependence of oxygen consumption on oxygen delivery in patients with adult respiratory distress syndrome. J Crit Care 1990; 5:81–86. Vincent JL, Roman A, DeBacker D, Kahn RJ. Oxygen uptake/supply dependency. Effects of short-term dobutamine infusion. Am Rev Respir Dis 1990; 142:2–7. Bihari D, Smithies M, Gimson A, Tinker J. The effects of vasodilation with prostacyclin on oxygen delivery and uptake in critically ill patients. N Engl J Med 1987; 317:397–403. Russell JA. Fluid strategy in ARDS: the concept of maintaining peripheral perfusion. In: Burchardi H, ed. Current Topics in Intensive Care, Vol. 4. London: W.B. Saunders, 1997: 17–42. Hayes M, Watson D. Oxygen transport. In: Evans TW, Hinds CJ, eds. Recent Advances in Critical Care Medicine, Vol. 4. New York: Churchill Livingstone, 1996:91–109. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995; 333:1025–1032. O’Quin R, Marini JJ. Pulmonary artery occlusion pressure: clinical physiology, measurement, and interpretation. Am Rev Respir Dis 1983; 128:319–328. Goldenheim PD, Kazemi H. Cardiopulmonary monitoring of critically ill patients (Part 1). N Engl J Med 1984; 311:717–720. Schuster DP, Seeman MD. Temporary muscle paralysis for accurate measurement of pulmonary artery occlusion pressure. Chest 1983; 84:593–597. Wiedemann HP, Matthay MA, Matthay RA. Cardiovascular-pulmonary monitoring in the intensive care unit (Part 1). Chest 1984; 85:537–549. Crexells C, Chatterjee K, Forrester JS, et al. Optimal level of filling pressure in the left side of the heart in acute myocardial infarction. N Engl J Med 1973; 289:1263–1266. Packman MI, Rackow EC. Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic shock. Crit Care Med 1983; 11:165–168. Ognibene FP, Parker MM, Natanson C, et al. Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 1988; 93:903– 910. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818–824. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus
858
53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76.
Gust and Schuster Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. The Consensus Committee. Intens Care Med 1994; 20:225–232. Schuster DP. Pulmonary edema. In: Fishman AP, ed. Pulmonary Diseases and Disorders, 3rd ed., Vol. 1. Philadelphia: McGraw Hill, 1996:1331–1356. Schuster DP. Pulmonary edema. In: Rippe J, Irwin R, Cerra F, eds. Intensive Care Medicine. New York: Lippincott-Raven, 1997:576–580. Matthay MA. Pathophysiology of pulmonary edema. Clin Chest Med 1985; 6:301– 312. Matthay MA, Folkesson HG, Campagna A, Kheradmand F. Alveolar epithelial barrier and acute lung injury. New Horizons 1993; 1:613–622. Zwinkler MP, Peters TM, Michel RP. Effects of pulmonary fibrosis on the distribution of edema: computed tomographic scanning and morphology. Am J Respir Crit Care Med 1994; 149:1266–1275. Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 1990; 142:1250–1257. Molloy WD, Lee KY, Girling L, Prewitt RM. Treatment of canine permeability pulmonary edema: short-term effects of dobutamine, furosemide, and hydralazine. Circulation 1985; 72:1365–1371. Schuster DP, Haller J. A quantitative correlation of extravascular lung water accumulation with vascular permeability and hydrostatic pressure measurements: a positron emission tomography study. J Crit Care 1990; 5:161–168. Ali J, Unruh H, Skoog C, et al. The effect of lung edema on pulmonary vasoactivity of furosemide. J Surg Res 1983; 35:383–390. Ali J, Wood LDH. Pulmonary vascular effects of furosemide on gas exchange in pulmonary edema. J Appl Physiol 1984; 57:160–167. Stevens EL, Uyehara CfT, Southgate WM, et al. Furosemide differentially relaxes airway and vascular smooth muscle in fetal, newborn, and adult guinea pigs. Am Rev Respir Dis 1992; 146:1192–1197. Rusch VW, Artman L, Cheney FW. Effect of furosemide on fully established low pressure pulmonary edema. J Surg Res 1986; 41:141–145. Rossetti M, Guenard H, Gabinski C. Effects of nitric oxide inhalation on pulmonary serial vascular resistances in ARDS. Am J Respir Crit Care Med 1996; 154:1375–1381. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997; 336:912–918. Reines HD, Halushka PV, Olanoff LS, Hunt PS. Dazoxiben in human sepsis and adult respiratory distress syndrome. Clin Pharmacol Ther 1985; 37:391–395. Schuster DP, Stephenson AH, Holmberg S, Sandiford P. Effect of eicosanoid inhibition on the development of pulmonary edema after acute lung injury. J Appl Physiol 1996; 80: 915–923. Cheney FW, Bishop MJ, Chi EY, et al. Effect of regional alveolar hypoxia on permeability pulmonary edema formation in dogs. J Appl Physiol 1987; 62:1690–1697. Bishop MJ, Boatman ES, Webster R, et al. Effects of lobar pulmonary blood flow on the evolution of oleic acid lung injury in dogs. J Surg Res 1986; 41:394–400. Dauber IM, Weil JV. Lung injury edema in dogs. Influence of sympathetic ablation. J Clin Invest 1993; 72:1977–1986. Leeman M, Closset J, Vachiery J, et al. Sino-aortic deafferentation reduces intrapulmonary shunt in dogs with oleic acid lung injury. J Appl Physiol 1989; 67:833–838. Hasinoff I, Ducas J, Prewitt RM. Increased cardiac output increases lung water in canine permeability pulmonary edema. J Crit Care 1988; 3:225–231. Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 1994; 149:245–260. Eisenberg PR, Hansbrough JR, Anderson D, Schuster DP. A prospective study of lung water measurements during patient management in an intensive care unit. Am Rev Respir Dis 1987; 136:662–668. Schuster DP. The evaluation of pulmonary edema by measuring lung water. In: Tobin MJ, ed. Principles and Practice of Intensive Care Monitoring. New York: McGraw Hill, 1997: 1136–1160.
Acute Lung Injury and ARDS
859
77. Rossaint R, Falke KF, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328:399–405. 78. Zwissler B, Kemming G, Habler O, et al. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. Am J Respir Crit Care Med 1996; 154:1671– 1677. 79. Walmrath D, Hossein-Ardeschir G, Grimminger F, Seeger W. Synergism of alveolar endotoxin ‘‘priming’’ and intravascular exotoxin challenge in lung injury. Am J Respir Crit Care Med 1996; 154:460–468. 80. Rossaint R, Slama K, Steudel W, et al. Effects of inhaled nitric oxide on right ventricular function in severe acute respiratory distress syndrome. Intens Care Med 1994; 21:197– 203. 81. Rossaint R, Gerlach H, Schmidt-Ruhnke H, et al. Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 1995; 107:1107–1115. 82. Fierobe L, Brunet F, Dhainaut J, et al. Effect of inhaled nitric oxide on right ventricular function in adult respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151: 1414–1419. 83. Puybasset L, Rouby J, Mourgeon E, et al. Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure. Am J Respir Crit Care Med 1995; 152: 318–328. 84. Deby-Dupont G, Braun M, Lamy M, et al. Thromboxane and prostacyclin release in adult respiratory distress syndrome. Intens Care Med 1987; 13:167–174. 85. Slotman G, Burchard K, D’Arezzo A, Gann D. Ketoconazole prevents acute respiratory failure in critically ill surgery patients. J Trauma 1988; 28:648–654. 86. Yu M, Tomasa G. A double blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care Med 1993; 21:1635–1642. 87. Leeman M, Boeynaems JM, Degaute JP, Vincent J, Kahn R. Administration of dazoxiben, a selective thromboxane synthetase inhibitor, in the adult respiratory distress syndrome. Chest 1985; 87:726–730. 88. Carlile PV, Gray BA. Effect of opposite changes in cardiac output and arterial PO 2 on the relationship between mixed venous PO 2 and oxygen transport. Am Rev Respir Dis 1989; 140:891–898. 89. Manthous CA, Shumacker PT, Pohlman A, et al. Absence of supply dependence of oxygen consumption in patients with septic shock. J Crit Care 1993; 8:203–211. 90. Ronco JJ, Fenwick J, Wiggs BR, Phang PT, Russell JA, Tweeddale MG. Oxygen consumption is independent of increases in oxygen delivery by dobutamine in septic patients who have normal or increased plasma lactate. Am Rev Respir Dis 1993; 147:25–31. 91. Ronco JJ, Phang PT, Walley KR, Wiggs B, Fenwick JC, Russell JA. Oxygen consumption is independent of changes in oxygen delivery in severe adult respiratory distress syndrome. Am Rev Respir Dis 1991; 143:1267–1273. 92. Ronco JJ, Fenwick JC, Tweeddale MG, et al. Identification of the critical oxygen delivery for anaerobic metalolism in critically ill septic and nonseptic humans. JAMA 1993; 270: 1724–1730. 93. Phang PT, Cunningham KF, Ronco JJ, Wiggs BR, Russell JA. Mathematical coupling explains dependence of oxygen consumption on oxygen delivery in ARDS. Am J Respir Dis Crit Care Med 1994; 50:318–323. 94. Mira JP, Gabre JE, Baigorri F, et al. Lack of oxygen supply dependency in patients with severe sepsis. A study of oxygen delivery increased by military antishock trouser and dobutamine. Chest 1994; 106:1524–1531. 95. Tuchschmidt J, Fried J, Astiz M, Rackow E. Elevation of cardiac output and oxygen delivery improves outcome n septic shock. Chest 1992; 102:216–220. 96. Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993; 270:2699–2707. 97. Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Chest 1989; 96: 114–119.
860
Gust and Schuster
98. Yu M, Levy MM, Smith P, Takiguchi SA, Miyasaki A, Myers SA. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study. Crit Care Med 1993; 21:830–838. 99. Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330: 1717–1722. 100. Guttierez G, Palizas F, Doglio G, et al. Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 1992; 339:195–199. 101. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis 1992; 145:990–998. 102. Schuller D, Schuster DP. Fluid management in pulmonary edema. In: Kuehn CA, ed. Current Opinion in Critical Care, Vol. 2. Philadelphia: Current Science, 1996:1–7. 103. Schuster DP, Stephenson AH, Holmberg S, Sandiford P. Effect of eicosanoid inhibition on the development of pulmonary edema after acute lung injury. J Appl Physiol 1996; 80: 915–923. 104. Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 153:991–996.
33 Diagnostic Information from the Respiratory Variations in Central Hemodynamics Pressures
SHELDON MAGDER McGill University Health Center Montreal, Quebec, Canada
I.
Introduction
Central hemodynamic pressures, including central venous pressure (CVP), right atrial pressure (Pra), and pulmonary capillary wedge pressure (Pcw), are very useful for determining the appropriate vascular volume for cardiac output, the management of pulmonary edema, and the diagnosis of cardiac pathophysiology. Besides the simple magnitude of the pressure, there is a lot of important clinical information available from the actual pattern of pressure variation which occurs during a respiratory cycle, as well as the waveform of the pressure fluctuations that occur during the cardiac cycle. In this chapter, the basic principles of measurement will first be reviewed and then the effects of changes in pleural pressure and abdominal pressure, as well as the fluctuations of the wave pattern in the cardiac cycle will be reviewed.
II. Principles of Pressure Measurements A. Basic Principles
Although pressures are regularly measured by clinicians, basic principles are often not appreciated. This was well exemplified by Courtois et al., who gave two problems to 10 cardiologists and 8 out of 10 got the answer to the first problem, but not 861
862
Magder
a single one got the second answer correct! The problems are illustrated in Figure 1, but the correct answer is only given at the end of this section on measurement principles. A force is defined as a mass times acceleration in a given direction. The force of a 1-kg mass with an acceleration of one m/sec 2 gives 1 Newton (N). When examining the force acting over the surface of a curved structure, force is given per crosssectional area which is pressure. Pressures have traditionally been given in units of cmH 2 O or mm Hg, which are both length terms, and have no obvious force units. The force component comes from the force of gravity that acts upon the mass of the liquid. Since mass is density times volume, and volume is related to the third power of length (L) and pressure is force per cross-sectional area (i.e., L 2 ), pressure is proportional to the height (i.e., L) of the liquid. The density of blood is close to the density of water which is 1 and therefore the clinical assessment of jugular venous pressure at the bedside can be given in cmH 2O. However, the value displayed on most electronic monitors is mm Hg. It is therefore necessary to be able to convert cmH 2 O to mm Hg. Since mass is density times volume and mercury is 13.6 times as dense as water, the height of a column of mercury produces 13.6 times the pressure as the height of a column of water. Thus, 10 mm Hg ⫽ 13.6 cmH 2 O and 10 cmH 2 O is ⬃ 7.4 mm Hg. The reason for using mm Hg instead of cmH 2 O for vascular measurements is that a much smaller column is then needed to measure pressure. For example, if a water column is used to measure the normal arterial pressure of 120 mm Hg, the column would have to be 160 cm high and would obviously be very awkward. On the other hand, pulmonary measurements are usually made in cmH 2 O, because the numbers are much smaller. If these pressures were measured with a mercury column, one would have to use a magnifying glass to observe the changes in pressure. The problem with measuring pressures with units based on the height of a column of fluid and the effect of gravity on this column is that the force of gravity varies inversely with distance from the center of the earth. This means that the force of a column of water on the top of Mount Everest is less than at sea level. The difference is small but the measurement still lacks precision, and physicists, who control the standards of measurement, prefer absolute pressures which are based on known forces. The force produced by 1 kg with an acceleration of 1 m/sec 2 is 1 N and the pressure from a N/m 2 is a Pascal. A pressure of 100 mm Hg at sea level is 7.4 kPa. Two important principles must be kept in mind when interpreting hydrostatic pressures: (1) They are relative to an arbitrary reference point which is set by the person doing the measurement. (2) the value that is important is the pressure difference acting across the wall of the vessel. This is called the transmural pressure and is given by the difference between the inside pressure and outside pressure of the elastic structure. B. Pressures Are Relative to an Arbitrary Reference Point
The basic principle that needs to be considered when making hydrostatic measurements is that fluids tend to seek their own level. Thus, when a water monometer is
Respiratory Variations
(a) Figure 1
(b)
Two questions posed to 10 cardiologists. Their responses are listed at the bottom. The correct answer is in the text. (From ref. 7.)
863
864
Magder
used to measure the pressure in a container, the pressure in the container pushes the water in the monometer up to the same height as the fluid in the tank (Fig. 2a). The measurement is made by reading the value on the manometer or transducer, or an amplifier connected to a pressure transducer which is placed at a fixed position relative to the patient’s heart. This means that if the position of the bottom has changed, the water will reach a different level on the manometer and a different value will be obtained (Fig 2b), even though the conditions of the tank have not changed. Furthermore, it does not matter whether the tubing connected to the manometer is open to the top or bottom of the container, as long as the tubing is fluid filled. This is because even when the tubing opens to the top of the tank, the column of fluid in the tubing still provides a force per cross-sectional area which pushes up the fluid in the manometer or creates a ‘‘weight’’ on the transducer and the fluid is ‘‘pushed’’ to the same height as in the tank. The consequence of this principle is that if the pressure transducer is mounted on a column that moves independently of the patient’s bed, changes in bed position change the measured pressure. For example, raising a bed by 10 cm will raise the recorded pressure by 7.4 mm Hg. It should thus be apparent that it is very important to standardize the reference position for pressure measurements. In physiological measurements, the position that is used is the mid point of the right atrium, for this is the point where blood returning to the heart meets the pumping action of the heart. Early cadaveric studies showed that the midpoint of the right atrium is found in most people as being ⬃ 5 cm below the sternal angle, or the Angle of Louis. Thus, the usual reference point for jugular venous distension on clinical exam is from the sternal angle (4). The right atrial pressure or central venous pressure can then be obtained by adding 5 cmH2O to this measurement, and this value can be converted to mm Hg by dividing
(a)
(b)
Figure 2 Pressures are relative to an arbitrary reference point. (a) The tubing is open to the bottom of the tank which is filled to 20 cm. The pressure is 20 cmH 2O and the water manometer is also filled to the 20 cm mark. (b) Tubing is connected to the top of the same tank as in (a) and the pressure transducer is also level to the top of the tank. The water manometer is only filled at the bottom and reads zero, and so does the pressure transducer with stopcock A or B open.
Respiratory Variations
(a)
865
(b)
Figure 3 Comparison of the (a) sternal angle versus midaxillary line for the hemodynamic reference point. In the supine position, the two are close although usually the midaxillary is slightly lower. However, when the patient is tilted (b), the reference point along the midaxillary are very different from 5 cm below the sternal angle. The midaxillary position should only be used in the supine position. (From Ref. 7.)
by 1.36 (Fig. 3a). Fortuitously, the right atrium remains approximately 5 cm vertically below the sternal angle even when the trunk of the body is angled up to 60°. Thus, the sternal angle can be used to level the pressure transducer, even in patients who are not lying supine. This is done by using a leveling device and setting the point where the transducer is open to air 5 cm below the level of the sternal angle. An important advantage to this approach is that the transducer can be re-leveled when the patient’s body position is changed and patients can be nursed up to an angle of 60° off the horizontal position of the bed. This is useful when nasogastric feedings are being used, when patients are in pulmonary edema, or when there is a lot of thoracic bleeding. The disadvantage to this approach is that it requires greater education of the staff and needs to be checked regularly, for changes in the patient’s position in the bed change the measurement. Another approach to leveling the transducer is to set it at the level of the midthoracic position (Fig. 3b) (12). The advantage to this approach is that it is easy to standardize. The disadvantage is that it should only be used when the patient is in the supine position. There will also be greater variation among patients because of differences in the anterior-posterior diameter of the chest which will then affect the relative position of the right atrium to the midchest position (7). It is very important to have a fixed way of referencing transducers, for once the reference level is established, the most useful information comes from the trend of the changes in pressure. For example, if a rise in Pcw is well tolerated and associated with an increase in cardiac output and no worsening of gas exchange, then this is clearly a positive outcome. On the other hand, if the increase in Pcw is associated with pink froth coming out of the endotracheal tube and worsening gas exchange, then clearly, for that patient, this is not a desirable value. The importance of a reference point for pressure measurement is only true when using fluid-filled measuring systems. This is because air has a negligible weight and therefore the column of air on the transducer has no measurable effect. This is why the level of the transducer is not an issue for respiratory measurements.
866
Magder
However, the position of the transducer is important when patients are ventilated with liquid hydrocarbons, for the fluid in the lung creates a hydrostatic gradient. The pressure at the surface, however, is not affected unless the tubing connected to the transducer is filled with fluid. We can now go over the example in Figure 1. In the first example, the transducer was 10 cm below the surface, therefore the height of the column of fluid above the transducer was 10 cmH2O. In the second example, even though the end of the tubing is at the bottom of the container and is below the transducer, only the water above the transducer provides a force on the transducer and the pressure is still 10 cmH 2 O. C. Transmural Pressure
As already stated, the pressure that is important in the mechanical analysis of an elastic structure is the pressure difference between the inside and outside of the structure. This is the force that distends the walls of vessels and also is the major outward force which drives the filtration of fluid from the capillaries. The pressure surrounding extrathoracic vessels is atmospheric pressure, and measuring devices are referenced to atmosphere as the zero reference point. However, it should be appreciated that an arterial pressure measured in the brachial artery of 120 mmHg at an atmospheric pressure of 760 mm Hg is, in reality, 880 mm Hg (i.e., 880–760 ⫽ 120 mm Hg). The importance of the concept of transmural pressure becomes significant when making hemodynamic pressure measurements in intrathoracic vessels, for they are surrounded by pleural pressure which changes during the ventilatory cycle. Ideally, measurements of intrathoracic vascular pressure should be referenced to the pleural pressure, but this is a difficult task to perform and, furthermore, the pleural pressure is not uniform throughout the thoracic cavity (1,5). Thus, for simplicity, measuring devices are referenced relative to atmosphere, but this creates an important artifactual illusion about what is actually happening in the vessel. For example, if pleural pressure falls with inspiration, and the atrial pressure signal on the monitor does not change relative to atmosphere, the right atrial pressure has actually increased because the outside fell and the inside pressure did not change (Fig. 4). If the pressure transducer had been referenced to the pleural space, the rise in pressure would have been seen. Thus, the failure to observe a change in pressure is simply a result of the reference system. Similarly, left atrial pressure, relative to atmosphere, always falls with spontaneous inspiration, but when the fall in left atrial pressure is compared to the fall in pleural pressure, left atrial pressure usually falls less. Therefore, left atrial transmural pressure actually rises on inspiration. The observation of a fall in left atrial pressure relative to atmosphere lead Sharpey-Schaffer to try to explain why there was decreased filling of the left heart during inspiration when, in fact, the pressure was rising and he needed to explain why there was increased filling (23). Since it is not feasible to obtain the pressure outside the heart in patients, intrathoracic pressures are measured at end expiration (or just before inspiration), for at this point, pleural pressure is closest to atmospheric pressure.
Respiratory Variations
867
Figure 4 Concept of transmural pressure. The figure shows a fluid-filled sphere inside a box. An observer outside the box notes that the pressure transiently falls as would occur during an inspiration (A). However, the pressure inside the box also fell (B) and fell more than in the sphere. This caused fluid to move into the sphere so that an observer inside the box would actually see a rise in pressure (C). This is the true increase in transmural pressure. This can be obtained from the pressure in A minus the pressure in B.
Figure 5 The effect of a forced expiration on cardiac filling pressures measured relative to atmosphere. The top shows the central venous pressure. The black bar marks the inspiratory phase. Following inspiration, there is a marked rise in pressure which continuously decreases during the expiratory phase due to a prolonged forced expiration. The bottom part of the figure shows a wedge pressure tracing. The deep y descents indicate the inspiratory phase. Following inspiration, there is a progressive increase in the pressure due to forced expiration. In both these tracings, the true transmural pressure is very difficult to obtain.
868
Magder
There is an important caution that must be considered. If the patient has a forced expiration, intrathoracic pressure can be considerably elevated at end expiration, and intrathoracic vascular pressures do not give a good estimate of transmural pressure. Forced expiration is very common in critically ill patients and, if not considered, this can lead to very significant errors in judgment and management of patients (Fig. 5).
D. Coupled Versus Uncoupled Pericardial Constraint
A series of experiments by Takata and coworkers (28) evaluated an important factor in the production of cardiac pressure waves and that is whether there is ‘‘coupled’’ cardiac constraint or ‘‘uncoupled’’ constraint (Fig. 6). Coupled constraint means that changes in the pressure or volume in one chamber affects all chambers. The situation where this is clearest is cardiac tamponade, for the fluid in the pericardium distributes pressures to all cardiac chambers. In uncoupled constraint, there is still interaction between right and left sides of the heart but it is less marked as is typical in pericardiac constriction. In this condition, there is more marked interaction between the atria and ventricles.
Figure 6 Concept of coupled versus uncoupled pericardial constraint. Epe, the elastance of the pericardium; Epe rv elastance of the right ventricle; Epe lv, the elastance of the left ventricle; Erv f, elastance of the right ventricular free wall; Es, elastance of the septum; Elvf, elastance of the left ventricle; Ppe, pericardial pressure; Ppe rv, pericardial pressure over the right ventricle; Tpelv, pressure over the left ventricle; Prv, pressure in the right ventricle; Tlv, pressure in the left ventricle; Vrvf, volume of the right ventricle; Vs, volume of the septum; Vvf, the volume of the left ventricle. (From Ref. 25.)
Respiratory Variations
869
III. Diagnostic Uses of Respiratory Variations in Central Hemodynamics A. Use of the Inspiratory Variation in Pra to Predict the Response to a Fluid Challenge
The hemodynamic effects of the swings in pleural pressure on central hemodynamics are covered elsewhere and the cardiac function–venous return relationship is discussed in Chapter 5, but a few basic principles need to be reviewed. At end expiration, pleural pressure is slightly negative relative to atmosphere, and the cardiac function curve is shifted to the left relative to the venous return curve. With a spontaneous breath, the cardiac function curve shifts more to the left, and with positive pressure inspiration, the cardiac function curve shifts to the right (Fig. 7). The venous
Figure 7 Respiratory pattern of right atrial pressure predicts the response to a fluid challenge. The top left-hand side shows the condition where the venous return curve intersects the ascending part of the cardiac function curve. The right-hand side shows the condition where the venous return curve intersects the plateau of the cardiac function curve. When the venous return curve intersects the ascending part of the cardiac function curve, right atrial pressure falls with a breath. In these patients, volume loading will increase cardiac output. However, when the venous return curve intersects the plateau of the cardiac function curve (top right), an inspiration does not change right atrial pressure. In these patients, volume loading will not increase cardiac output. This prediction was tested in 33 patients as shown in the bottom graph (⫹ve Resp). Most patients who had no fall in right atrial pressure (⫹RVSP) had an increase in cardiac output with fluid challenge (∆L/min), whereas those with no respiratory variation (⫺ve Resp) had no change in cardiac output. (From Ref. 13.)
870
Magder
return curve is most often depicted as intersecting the ascending part of the cardiac function curve. Therefore, a shift to the left of the cardiac function curve relative to the venous return curve results in an increase in cardiac output and a decrease in the Pra until the cardiac function curve intersects the flat part of the venous return curve (i.e., Pra is less than pleural pressure). After that, further decreases in pleural pressure do not increase cardiac output, although they still result in a fall in Pra. Medical students are taught to use the inspiratory fall in CVP to distinguish jugular vein pulsations from carotid artery pulsations (4). The opposite occurs with positivepressure ventilation: the rise in pleural pressure with positive-pressure ventilation shifts the cardiac function curve to the right and results in a fall in cardiac output with a rise in Pra. The cardiac function curve has a plateau which is produced most often by pericardial constraint, but is even present at high ventricular volumes when the pericardium is absent, because of restrictions from the cardiac cytoskeleton. Occasionally, mediastinal structures can also limit the filling of the heart and produce a plateau of the cardiac function curve (5). When the venous return curve intersects the plateau of the cardiac function curve, the effects of changes in pleural pressure are very different from those seen when the venous return curve intersects the ascending part of the cardiac function curve. When the plateau of the cardiac function curve is intersected, the inspiratory fall in pleural pressure produces no change in cardiac output and no change in Pra. Thus, observations of the changes in Pra during the respiratory cycle can be used to determine if the heart is functioning on the plateau of the cardiac function curve or on the ascending part of the cardiac function curve. This allows one to predict potential response to a fluid challenge (13). An inspiratory fall in Pra indicates that the venous return curve intersects the ascending part of the cardiac function curve. In the ascending part of the cardiac function curve, an increase in preload results in an increase in cardiac output. Thus, these patients should respond to a fluid challenge. However, the actual change in cardiac output cannot be predicted because the patient might be close to the plateau of the cardiac function curve in which case there will only be a limited benefit. If there is no fall in Pra with inspiration, this implies that the venous return curve intersects the plateau of the cardiac function curve. On this part of the cardiac function curve, increases in preload do not result in a change in cardiac output, and therefore volume loading, which shifts the venous return curve to the right, will not increase cardiac output. The increase in right-side pressure may actually distort the left ventricle and lower cardiac output (3). We tested this prospectively in a series of ICU patients and found that the predictions worked very well (13). It was particularly useful in the group with no respiratory variation. Out of the 11 patients in that group, only one had a response to a fluid challenge, and when we reviewed the records, this was most likely because the patient did not have an adequate inspiratory effort to produce a large enough change in pleural pressure to observe a respiratory fall in Pra. Most of the patients with a respiratory variation in central venous pressure had a response to fluid challenge, but not all of these patients, as would be expected, since some might have been close to the plateau of their cardiac function curve. For the test to be accurate,
Respiratory Variations
871
there has to be an adequate inspiratory effort which produces enough of a change in pleural pressure to affect Pra. One can assess the adequacy of the fall in pleural pressure by observing the inspiratory fall in Pcw. For the inspiratory effort to be adequate, we require that the Pcw fall by at least 2 mm Hg with each breath. The left atrial pressure always falls with the fall in pleural pressure in contrast to the Pra. This is because both the upstream pressure, or vascular reservoir, for the left atrium, and the left atrium are in the pleural cavity and exposed to the change in pleural pressure. Thus, the change in pleural pressure affects upstream and downstream chambers equally. On the other hand, the right heart is in the pleural cavity and Pra is affected by changes in pleural pressure, whereas the venous reservoir feeding the right atrium, i.e., the venous capacitance, is surrounded by atmospheric pressure and does not change during the respiratory cycle. In some cases, the pressure in the abdominal venous reservoir may actually rise due to the descent of the diaphragm and an increase in abdominal pressure. Therefore the gradient for venous return changes on the right side during the respiratory cycle, whereas it does not initially change on the left side. When using this test, one must also be cautious to distinguish an increase in the y descent (which is discussed below) from a true fall in the baseline of the Pra tracing. We used the base of the a wave to measure Pra as the best reflection of right ventricular preload. B. Respiratory Swings and PEEP
Mechanically ventilated patients who trigger the ventilator still have a fall in pleural pressure at the onset of inspiration. It might seem possible that this could be used to predict the response of cardiac output to an increase in pleural pressure. As already discussed, a fall in Pra with a fall in pleural pressure indicates that the patient’s venous return curve intersects the ascending part of the cardiac function curve. When the pleural pressure is increased by the positive pressure inspiration, the cardiac function curve is shifted to the right, which should always result, in these patients, in a decrease in cardiac output (Fig. 8a). On the other hand, if the patient has no inspiratory fall in Pra on the triggered component of the breath, this should indicate that the venous return curve intersects the plateau of the cardiac function curve, and an increase in pleural pressure should not produce a fall in cardiac output until the cardiac function curve is shifted far enough to the right to cause the venous return curve to intersect the ascending part of the cardiac function curve (Fig. 8b). The theory thus predicts that this test should be most useful in patients with an inspiratory fall in Pra, for it would predict that cardiac output will always fall when PEEP is applied to these patients. We tested this in a group of ICU patients and, although the general pattern followed the prediction, the predictive value was poor for individual patients. There are a number of reasons for the failure of the test to predict the response of cardiac output to the application of PEEP which provide insight into the physiological response to PEEP. In the study, PEEP was increased in steps and then withdrawn. The heart rate and cardiac output tended to be higher at the end of the PEEP trial, indicating activation of cardiovascular reflexes which changed cardiovascular function (11,16). Furthermore, the application of PEEP can result in
872
Magder
Figure 8 Interaction of the cardiac function and venous return curves during PEEP. PEEP shifts the cardiac function curve to the right and results in a fall in cardiac output and rise in right atrial pressure (Pra) when the venous return curve intersects the ascending part of the cardiac function curve (Q ⫽ flow which is cardiac output or venous return) . However, when the venous return curve intersects the flat part of the cardiac function curve, some levels of PEEP will not decrease cardiac output or change Pra (A and B), although when sufficiently large, the PEEP will decrease cardiac output and raise right atrial pressure (C).
an increase in abdominal pressure as well as recruitment of abdominal muscles. This can result in a shift in the position of the venous return curve to the right, which will further confuse the results. The prediction of the change in cardiac output in response to a fluid challenge has only been studied with an inspiratory fall in pleural pressure. The use of the converse, that is, a rise in Pra with a positive increase in pleural pressure, is probably not helpful. A lack of change in Pra with a positive-pressure breath should predict the lack of response to a fluid challenge, but this pattern does not occur very often. This may be because even a patient whose heart is functioning on the flat part of the function curve at end expiration can have a rise in Pra when the cardiac function curve is shifted enough to the right. Thus, two factors are acting—the initial position of the intersection of the cardiac function curve and venous return curve, and the magnitude of the change in pleural pressure. Furthermore, the descent of the diaphragm and a consequent rise in abdominal pressure could shift the venous return curve to the right which would increase Pra even in patients whose hearts are functioning on the flat part of the cardiac function curve. C. Diagnostic Use of Respiratory Variations in Systolic Arterial Pressure
Variations in systolic arterial pressure during the ventilatory cycle of mechanically ventilated patients have also been used to predict the response to a fluid challenge (19–21). In this test, the baseline of the arterial pressure is first established by an apnea of 5 sec. During inspiration with a ventilator, the increase in the pressure in the chest decreases the gradient for venous return to the right heart and thus de-
Respiratory Variations
873
creases right-sided stroke volume. After a few beats, the decrease in output from the right heart results in a decrease in stroke volume from the left heart. This results in a decrease in the systolic arterial pressure which has been called the delta down (dDOWN) relative to the apnea breath (Fig. 9). During inspiration, the positive pressure in the chest is transmitted to the ventricles. This decreases the afterload on the left ventricle, and increases emptying from the pulmonary veins. Together, these changes increase the left-sided stroke volume and arterial pressure. There are also cyclic changes in the stroke volumes of the two ventricles produced by the variation in the right-sided stroke volume which is then transmitted to the left ventricle and produces a variation in the left ventricular stroke volume. These result in a delta up (dUP) relative to the apnea baseline. The normal dDOWN is 5 to 6 mm Hg and the normal dUP is 2 to 4 mm Hg. Together these produce a normal systolic pressure variation (SPV) during the mechanical ventilatory cycle of 8 to 10 mm Hg. The magnitude of SPV has been shown to be a sensitive indicator of the adequacy of ventricular preload (6,18,19,22). The dDOWN is particularly sensitive to hypovolemia, and when fluids are administered, the dDOWN decreases. In patients with congestive heart failure or volume excess, there is almost no dDOWN. The explanation for this is much the same as previously discussed with the respiratory variations in Pra. When the venous return curve intersects the plateau of the cardiac function curve, it is possible for there to be a rightward shift of the cardiac function curve due to an increase in pleural pressure without a change in Pra or stroke volume. However, in the same way that the predictive value of the rise in Pra with an increase in pleural pressure is limited by the magnitude of the pleural pressure swing and how close the intersection of the venous return curve and cardiac function curve is to the plateau of the cardiac function curve, even in a well-filled patient, a large enough change in pleural pressure could increase dDOWN by shifting the cardiac function curve sufficiently to the right. The converse, though, is less likely. That is, a patient with a small or no dDOWN and a sufficiently large change in pleural pressure is unlikely to have a change in cardiac
Figure 9 Use of the respiratory variations in arterial pressure to predict the response to fluid challenge. Up ⫽ the early inspiratory increase in arterial pressure; Down ⫽ later inspiratory decrease in artery pressure in ventilated patient. Changes are in comparison to a short apneic period (see text for discussion). (From Ref. 19.)
874
Magder
output with volume loading. dDOWN can also be affected by transient effects on the emptying of the pulmonary veins and the afterload reducing effect of the positive pleural pressure which may contribute to fluctuations in SPV, even in patients who are on the flat part of the cardiac function curve. Furthermore, there is the possibility that in some patients, recruitment of abdominal venous blood by the descent of the diaphragm could increase right-sided transmural filling pressure, distend the right ventricular and decrease left ventricular stroke volume and blood pressure (3) . This will be especially true in patients with a complete cardiac constraint (28).
IV. Change in Abdominal Pressure A. Hepato-jugular Reflux
The hepato-jugular reflux (HJR) refers to the rise in CVP that occurs when pressure is applied to the abdomen (9,10). Although it is called a hepato-jugular reflux, it is not necessary to press over the liver. A continuous force of 20 mm Hg is applied to the abdomen and the patient must be told not to contract the abdominal muscles. The normal response is a rise in CVP which lasts ⬍ 10 sec (9). A more persistent rise in CVP implies a limitation of cardiac filling or a limitation of cardiac reserves and is particularly sensitive to right ventricular dysfunction (9), although it is also affected by left ventricular dysfunction (10). The mechanism is as follows. The large venous capacitance is in the splanchnic bed. The application of pressure over the abdomen raises the pressure in splanchnic vessels. This shifts the venous return curve to the right and the venous return curve intersects the cardiac function curve at a higher cardiac output and Pra. The actual amount of fluid mobilized is dependent upon the pressure and volume of the abdominal cavity, and if the volume is not high, the increase of abdominal pressure may simply collapse the vena cava and produce the equivalent of West zone II or even zone I in the abdominal cavity (24–28) and there will be no change in the rate at emptying of blood from the abdomen. This is because there will be an effective increase in venous resistance or change in the plateau of the venous return curve. However, assuming there is adequate blood volume in the abdomen to allow recruitment, this results in an increase in cardiac preload. If the cardiac function curve is normal and there are cardiac reserves, the increase in preload from recruitment of abdominal blood increases cardiac output and, consequently, blood pressure. The cardiovascular system then readjusts within 10 to 15 sec, possibly due to a baroreceptor-mediated process in response to the increase in arterial pressure. The consequent improvement in cardiac function brings the Pra down again. However, if the heart is operating on the plateau of the cardiac function curve, then the rise in Pra is greater. This is because the diastolic compliance is very low when the cardiac function curve is flat, and small changes in volume produce very large changes in pressure. The reflex adjustments then may not be sufficient to regulate the cardiac function sufficiently to bring Pra back down. This will especially be the case if cardiac function is depressed. Furthermore, patients with compromised cardiac function will tend to have more fluid retention and more recruitable volume from the abdominal
Respiratory Variations
875
cavity. Thus, persistent elevation of CVP with the HJR (i.e., ⬎ 10 sec) indicates a limitation of cardiac reserves. B. Kussmaule’s Sign
Kussmaule’s sign refers to the lack of change, or increase, in CVP or Pra with inspiration (17). The most common pattern of respiratory variation in the jugular venous pressure is a fall in pressure with inspiration. This occurs because pleural pressure surrounds the heart, and the fall in pleural pressure with inspiration is transmitted to the cardiac structures. As discussed above, this can be graphically demonstrated by the leftward shift of the cardiac function curve relative to the venous return curve (Fig. 7). However, as also noted above, when the venous return curve intersects the plateau of the cardiac function curve, inspiration does not result in a fall in CVP (Fig. 7). A rise in CVP can occur with inspiration when the descending diaphragm raises abdominal pressure which compresses the compliant splanchnic vessels (27). The inspiratory action of the diaphragm thus acts like the hand of the physician performing an HJR maneuver. The increase in pressure on splanchnic vessels shifts the venous return curve to the right which increases CVP. The increase in CVP can be further affected by the rise in pulmonary vascular resistance which always occurs on inspiration (14). A rise in pulmonary vascular resistance increases right ventricular afterload. This decreases ventricular emptying, which further increases the filling pressure of the right ventricle and may also contribute to Kussmaule’s sign. Kussmaule’s sign is primarily seen in patients with uncoupled pericardial constraint (24,25) and therefore is most often seen with constrictive pericarditis or patients without a fully effective pericardial cavity as in a postoperative cardiac surgery patient. Under these conditions, there is less transmission of the rise in right-side pressures to the left heart than occurs with coupled constraint because only the elastance of the right heart accepts the enhanced venous return (25). When Kussmaule’s sign is present, it indicates that there is a limitation of right ventricular filling and further volume loading will not increase cardiac output. V.
Information from the Hemodynamic Waveforms
A. General Principles
Central venous pressures are characterized by three positive deflexions called the a, c and v waves, and two negative deflections called the x and y descents (Fig. 10). These waves provide useful diagnostic information. The magnitude of a pressure wave is determined by the change in volume and the compliance of the elastic structure that contains the fluid. This includes the cardiac chambers, the pericardium, and their interactions (24,25). It should also be appreciated, as discussed above, that the pressure waves observed on an electronic monitor are relative to the reference value which was established during the leveling and zeroing of the transducer. The a wave is produced by atrial contractions just prior to ventricular excitation. This contraction gives the final stretch to the ventricular muscle to optimize ventricular preload. Following relaxation of the atrial contraction, there is a fall in
876
Magder
Figure 10 The basic waveform of the atrial tracing. See text for details.
pressure as the atrium relaxes, called the x descent. At the beginning of systole, the rise in ventricular pressures force the atrioventricular valves backward and they bulge into the atria. There is also a deceleration of venous flow into the atria because of closure of the atrioventricular valve. These two forces together produce the c wave, which is usually small and often below the frequency response of recording systems. The beginning of the c wave can thus be used to mark the beginning of systole, and the nadir between the a and c gives the ventricular preload is called the z part (12). In practice, the fidelity of most systems is not sufficient to identify this point, and the base of the a wave gives a good measures of ventricular preload. This wave is followed by a second negative-pressure called the x descent (12). During ventricular systole, blood continues to return to the atrium and the pressure rises because the atrioventricular valve is closed. This produces the v wave. If there is any leak from the ventricle to the atrium because of an incompetent atrioventricular valve, this greatly increases the v wave and it peaks earlier. At the end of systole, the ventricular pressure rapidly falls, and when it falls to the pressure in the atria, the atrioventricular valves open and atrial volume empties into the ventricles. This results in a sudden fall in atrial pressure and this is called the y descent. During the early phase of diastole, the atrium rapidly fills and the pressure again rises to the volume which gives the pressure at the base of the a wave. B. a Wave
Since the a wave is produced by contraction of the atrium at the end of diastole, it is only present when atrial contraction is present. This point can be used to determine if the atrium is actually contracting and whether atrial contractions are appropriately timed to ventricular contractions; in other words, it can be used to determine whether there is atrioventricular dissociation. As with all waves, the magnitude of the a wave depends upon the compliance of the elastic structure and the volume transferred into it. A large a wave thus indicates that there is either a large volume transferred or the atrial compliance is low. Decreased atrial compliance can occur because the atrium starts with a large volume and is on the steep part of its pressure volume curve or because of interactions with the other cardiac chambers and the pericaridum
Respiratory Variations
877
(25). However, the pressure wave also requires a competent contractile force so that the absence of a large a wave does not rule out decreased atrial compliance. When atrial flutter is present, a waves are evident at a frequency of 300 beats/ min and this can be used to identify this rhythm and differentiate it from other superventricular rhythms (Fig. 11). In atrial fibrillation, there is no well-organized atrial contraction and there is thus a loss of the a wave, although sometimes small fluctuations can be seen on the atrial pressure tracing because there are still some small contractions occurring in the atrial muscle. Furthermore, the c wave can sometimes be confused with an a wave and thus it might appear that there is an a wave in a patient with atrial fibrillation even though there is no real atrial contraction. The a wave is markedly increased when the atrium contracts against the closed atrioventricular valve. This occurs when there is atrioventricular dissociation and the cannon a waves which are produced are diagnostic of this condition. This phenomenon is frequently seen in patients who have ventricular pacemakers. The cannon a waves interfere with the normal venous return and contribute to the decrease in cardiac output in these patients. The typical pattern is that of ‘‘cannon’’ a waves of varying magnitude which depend upon the timing of the atrial contraction relative to ventricular contraction. The blood pressure will tend to be smaller when there is a cannon a wave and larger when there is no cannon a wave. When this is observed in a patient with an external pacemaker and a low blood pressure, it is worth turning the pacemaker off, or the rate down, to see if the patient’s underlying intrinsic rate is sufficient, for this may allow an increase in blood pressure and cardiac output because of better coordination of the cardiac function and venous return. C. v Wave
When a large v wave is present, insufficiency of the atrioventricular valve should be considered. Generally, v waves are wider and have smaller amplitude in the right heart and are taller and thinner in the left heart. An extreme example is shown in Figure 12, in which case the v wave is very similar to the pulmonary pressure. The difference is the slower upstroke of the v wave and the secondary peak from the v wave on the pulmonary arterial pressure tracing. This is because the compliance of the great veins and right atrium is much larger than that of the left atrium and pulmonary veins so that
Figure 11 An example of flutter waves on a central venous pressure tracing. The dots represent the timing of the atrial flutter waves on the pressure tracing. These can be mapped through the tracing.
878
Magder
Figure 12 Marked v wave with severe tricuspid regurgitation. The left-hand side shows a pulmonary artery pressure tracing (PAP), and the right-hand side the wedge pressure (Pcw). The v wave is of equal magnitude to the PAP. However, the upstroke is slower and the v wave pressure is narrower.
the same change in volume produces a smaller change in pressure on the right side. Large v waves do not necessarily, though, indicate that atrioventricular regurgitation is present. This is because the pressure-volume curve of the atrium is curvilinear, and at larger atrial volumes the compliance is very small. Under this condition, small changes in volume produce large changes in pressure. Thus, large v waves in the Pcw are often present when left-sided filling pressures are high and the left atrium is distended even when there is no mitral regurgitation. The v wave in these cases should decrease with diuresis. An example is shown in Figure 13. Another
Figure 13 An example of the effect of diuresis on v waves. The upper tracing (Pra) shows the pulmonary capillary wedge tracing of the patient who is volume loaded. The tracing shows very marked a and v waves. Pressures are 0 to 60 mm Hg. The bottom tracing shows the pulmonary artery pressures and Pcw following diuresis (Post). The P is markedly decreased, and there are no longer any v waves.
Respiratory Variations
879
Figure 14 An example of marked v waves on a right atrial pressure tracing. The left-hand side of the figure shows the pulmonary artery pressure (PAP) tracing for this patient, and the right-hand side shows the right atrial pressure tracing (Pra) with marked v waves. This pattern would make the insertion of a Swan-Ganz catheter very difficult because the Pra tracing looks almost identical to the right ventricular pressure. Note how the v waves are much wider than those seen in the wedge tracing in Figures 12 and 13.
example where this can occur is in patients with a ruptured ventricular septum following a myocardial infarction and who have a left-to-right shunt (8). The increase in flow through the pulmonary circuit with decreased left ventricular function results in a markedly elevated left atrial pressure and is frequently associated with a large v wave, even without mitral regurgitation. On the right side, an important clinical point is that large v waves may make the atrial pressure tracing look like a ventricular tracing. This can make the insertion of a flotation catheter under pressure guidance very difficult when this is not considered (Fig. 14). D. Y Descent
The y descent provides a lot of very useful clinical information (31). With the onset of a spontaneous inspiration, the y descent usually increases and this can be used as an indicator of the inspiratory phase of the ventilatory cycle. The increase in the y descent occurs because, during inspiration, pleural pressure falls, which means that the pressure outside the heart falls. The fall in pressure outside the heart is then transmitted to the inside of the heart. The impact of this is greatest at the beginning of diastole because the heart is at its lowest volume and is at its most compliant stage. This allows more of the pleural pressure to be transmitted to the heart. Thus, the nadir of the y descent is very much affected by the pleural pressure around the heart. During the next part of diastole, when the atrium and ventricles rapidly fill, the pressure in these chambers rises. The increase in pressure is further augmented by the fact that the atrioventricular compliance decreases as the volume increases because of the curvilinear shape of the pressure-volume curve. When positivepressure ventilation is present, the opposite occurs. The y descent decreases with inspiration because the outside of the heart becomes more positive. The y descent can be increased when the baseline atrial pressure is high, because there is a potential for greater atrial emptying at the start of diastole. This is usually said to indicate a restrictive pattern of ventricular filling. This is seen well
880
Magder
in modeling studies on coupled versus uncoupled pericardial constraints (25). In uncoupled constraint, the y descent is increased and ventricular filling is mainly diastolic. This is because during systole, the Pra is not affected by the change in right ventricular volume. Thus, the x descent is diminished and Pra can only fall when the tricuspid valve opens. However, a prominent y descent is not present in patients with cardiac restriction when ventricular rejection is reduced and the end systolic volume remains high. This is because the reduced ejection means that ventricular pressure does not fall very much at the end of systole, and there is a reduced gradient from the atrium to ventricle at the start of diastole. Thus, the absence of a large y descent does not rule out a restrictive filling pattern (31). A very useful diagnostic point is that the presence of a y descent generally rules out cardiac tamponade. This is because in cardiac tamponade, the whole heart is surrounded by pericardial fluid at an increased pressure (i.e., marked coupled constraint). This pericardial pressure limits the volume changes in the whole cardiac fossa. Thus, during systole, when the ventricles eject, the atria fill, and the total volume of the pericardial sac and heart remains relatively constant and there are no large x or y descents. For a y descent to be present, the pressure in the ventricle must be able to fall below the basal atrial level at the start of diastole. An important exception to this clinical rule occurs in patients who have tamponade following cardiac surgery. In these patients, the fluid usually does not surround the whole heart. More often there is a localized clot which compresses the superior vena cava, atria, ventricle, or pulmonary outflow tract. In these cases, the y descent may still be present, even though the heart is effectively tamponaded and the patient will only improve if the chest is opened. They actually have uncoupled constraint.
VI. Summary Careful observation of the respiratory pattern in central hemodynamic pressures can provide useful information about the interaction of the heart and circuit. Examination of the individual wave patterns in the atrial pressure tracing also gives insight into the coordination of contractions of the atria and ventricles and how the heart is being affected by the surrounding pleural pressure. The respiratory patterns of central hemodynamic pressure also provide a wonderful example of the clinical usefulness of applied physiology.
References 1. 2.
Agostoni E, Mead J. Statics of the respiratory system. In: Fenn WO, Rahn H. eds. Respiration. Washington. American Physiological Society, 1964;387–409. Anzueto A, Lodato R, Lorente J, Holzapfel L, Grover R, Takala J. Multicenter placebocontrolled, double-blind trial of the nitric oxide synthase inhibitor 546C88 in patients with septic shock: acute hemodynamic effects. Am J Respir Crit Care Med Abstract. 155: A263.
Respiratory Variations 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
881
Atherton JJ, Moore TD, Lele SS, Thomson HL, Galbrath AJ, Belenkie I, Tyberg JV, Frenneaux MP. Diastolic ventricular interaction in chronic heart failure. Lancet 1997; 349:1720– 1724. Bickley LS, Hoekelman RA. Bates’ Guide to Physical Examination and History Taking. Philadelphia: Lippincott, 1999;299–303. Bishop VS, Horwitz LD, Stone HL, Stegall HF, and Engelken EJ. Left ventricular internal diameter and cardiac function in conscious dogs. Journal of Applied Physiology 1969; 27(5): 619–623. Coriat P, Vrillon M, Perel A, Baron JF, LeBret F, Saada M, and Vlars P. A comparison of systolic blood pressure variations and echocardiographic estimates of end-diastolic left ventricular size in patients after aortic surgery. Anesth Analg 1994; 78:46–53. Courtois M. Fattal PG, Kovacs SJ, Tiefenbrunn AJ, Ludbrook PA. Anatomically and physiologically based reference level for measurement of intracardiac pressures. Circulation 1995; 92:1994–2000. Drobac M, Schwartz C, Scully HE, Bentley-Taylor MM. Giant left atrial v-waves in post myocardial infarction ventricular septal defect. Ann Thorac Surg. 1979; 27:347–349. Ducas J, Magder SA, McGregor M. Hepatojugular reflux: a re-evaluation. Clin Invest Med 1983; 6:42. Abstract. Ewy GA. The abdomino-jugular test: technique and hemodynamic correlates. Ann Intern Med 1980; 109:456. Fessler HE, Brower RG, Wise RA, Permutt S. Effects of positive end-expiratory pressure on the gradient for venous return. Am Rev Respir Dis 1992; 146:4–10. Lodato RF. Use of the pulmonary artery catheter. Semin Respir Crit Care Med 1999; 20: 29–42. Magder SA, Georgiadis G, Tuck C. Respiratory variations in right atrial pressure predict response to fluid challenge. 1992; J Crit Care 7:76–85. Mitzner W. Resistance of pulmonary circulation. Clin Chest Med 1983; 4(2):127–137. Mukaida N, Ishikawa Y, Ikeda N, Fujioka N, Watanabe S, Kuno K, Matsushima K. Novel insight into molecular mechanism of endotoxin shock: biochemical analysis of LPS receptor signaling in a cell-free system targeting NF-kB and regulation of cytokine production/action through b2 integrin in vivo. J Leuk Biol 1996; 59:145–151. Nanas S, Magder S. Adaptations of the peripheral circulation to PEEP. Am Rev Respir Dis 1992; 146:688–693. O’Rourke RA. The measurement of systemic blood pressure; normal and abnormal pulsations of the arteries and veins. In: Hurst JW, The Heart. Schlant RC, Rackley CE, Sonnenblick EH, Kass Wenger N, eds. New York: McGraw-Hill, 1990;158–160. Ornstein E, Eidelman LA, Drenger B, Elami A, Pizov R. Systolic pressure variation predicts the response to acute blood loss. J Clin Anesth 1998;10:137–140. Perel A, Pizov R, Cotev S. Systolic blood pressure variation is a sensitive indicator of hypovelemia in ventilated dogs subjected to graded hemorrhage. Anesthesiology 1987;67: 498–502. Perel A. Assessing fluid responsiveness by the systolic pressure variation in mechanically ventilated patients. Anesthesiology 1998;89:1310–1312. Perel A, Pizov R, Cotev S. Systolic blood pressure variation is a sensitive indicator of hypovolemia in ventilated dogs subjected to graded hemorrhage. Anesthesiology 1987;67: 498–502. Rooke GA, Schwid HA, Shapira Y. The effect of graded hemorrhage and intravascular volume replacement on systolic pressure variation in humans during mechanical and spontaneous ventilation. Anesth Analg 1995; 80:925–932. Sharpey-Schaffer EP. Effects of respiratory acts on the circulation. In: Dowpey H, ed. Handbook of Physiology, Section 2. Washington; American Physiological Society, 1965;1875. Takata M, Beloucif S, Shimada M, Robotham JL. Superior and inferior vena caval flows during respiration: pathogenesis of Kussmaul’s sign. Am J Physiol 1990; 262:H763-H770. Takata M, Harasawa Y, Beloucif S, Robotham JL. Coupled vs. uncoupled pericardial constraint: effects on cardiac chamber interactions. J Appl Physiol 1997; 83:1799–1813. Takata M, Mitzner W, Robotham JL. Influence of the pericardium on ventricular loading during respiration. J Appl Physiol 1990; 68:1640–1650.
882 27. 28. 29. 30.
31.
Magder Takata M, Robotham JL. Effects of inspiratory diaphragmatic descent on inferior vena caval venous return. J Appl Physiol 1992; 72:597–607. Takata M, Wise RA, Robotham JL. Effects of abdominal pressure on venous return: abdominal vascular zone conditions. J Appl Physiol 1990; 69:1961–1972. Werle JM, Cosby RS, Wiggers CJ. Observations on hemorrhagic hypotension and hemorrhagic shock. Am J Physiol 1942; 136:401–420. Yamanaka N, Takaya Y, Oriyama T, Furukawa K, Tanaka T, Tanaka T, Ichikawa N, Yasui C, Ando T, Yamanaka J, Kuroda N, Ko M, Takada M. Imakita M, Kitayama Y, Ikamoto E, Sasaki S, Nakagaki I, Hori S, Ito T. Hepatoprotective effect of a nonselective endothelin receptor antagonist (TAK-044) in the transplanted liver. J Surg Res 1997:70:156–160. Magder S, Erice F, Lagonidis D. Determination of the y descent and its usefulness as a predictor of ventricular filling. J Intensive Care Med 2000; 15:262–269.
34 Abdominal-Circulatory Interactions
PETER GOLDBERG McGill University Royal Victoria Hospital Montre´al, Que´bec, Canada
I.
Introduction
Whereas the impact of changes in intrathoracic pressure on circulatory physiology has been studied extensively and disseminated widely into the clinical setting, the same cannot be said of the effect of intra-abdominal pressure on the circulation. Yet the clinical conditions in which such an impact could be expected are varied and commonly encountered. Clinical conditions such as weaning from mechanical ventilation, marked abdominal ascites, the development of the ‘‘abdominal compartment syndrome,’’ the performance of laparoscopic surgery, and the application of antishock trousers may all induce significant interactions between the increase in intra-abdominal pressure and both systemic and regional hemodynamics. The goal of this chapter is to examine the relationship between intra-abdominal pressure and cardiovascular function. I will first review the animal data and then place those data in the clinical context. II. Animal Data A. Central Hemodynamics
While several studies (1–5) have demonstrated a fall in cardiac output when intraabdominal pressure (Pab) is increased, the physiological basis for the decline in 883
884
Goldberg
cardiac output continues to be the subject of debate. Kashtan (2) concluded that the decline in heart function was due to an increase in systemic vascular resistance (SVR) induced, directly or indirectly, by the increase in abdominal pressure. He and his colleagues examined the impact of increasing abdominal pressure to 40 mm Hg on ventricular function in dogs. Although pleural pressure rose concomitantly with Pab, transmural right atrial pressure (Pra tm ) nevertheless rose as cardiac output fell, which suggests that right ventricular performance declined. They then went on to demonstrate a downward and rightward shift in the left ventricular function curve when Pab was increased to 40 mm Hg. Given the accompanying significant increase in SVR, the authors attributed the fall in left ventricular function to an increase in afterload. In a more recent study, Ridings and colleagues (3) observed similar changes in both cardiac output and right- and left-sided cardiac pressures when Pab was augmented by 25 mm Hg in a swine model of the abdominal compartment syndrome (ACS). However, unlike the findings reported by Kashton (2), both (Pra tm ) and transmural pulmonary capillary wedge pressure (PCWP tm ) actually fell, albeit not statistically, despite significant increases in both right atrial pressure (Pra) and pulmonary capillary wedge pressure (PCWP) relative to atmosphere. Bloomfield and co workers (1) confirmed many of the same findings in their swine model of ACS in which Pab was also raised to 25 mm Hg above baseline. However, by subjecting their animals to sternotomy and pleuropericardotomy they were able to eliminate the confounding influence of changes in intrathoracic pressure and thereby eliminate the significant increases in Pra, PCWP, and pulmonary arterial pressure that developed in the cohort animals that had remained closed-chested. They demonstrated that regardless of the animal preparation cardiac output decreased as SVR increased. Taken together, these data suggest that the fall in cardiac output that accompanies an increase in Pab is due to both a fall in venous return and a concomitant increase in SVR. In an earlier study Robotham et al. (5) found that increasing abdominal pressures not only resulted in a fall in cardiac output because of the increase in left ventricular afterload but also redistributed that lower output. In 10 open-chested dogs they documented that an increase in Pab of approximately 10 cmH 2O resulted in a relative increase in cephalad blood flow but decreased abdominal blood flows. Along this same theme, Bloomfield and coworkers (1) found a significant increase in intracranial pressure when Pab was augmented in the swine model of ACS cited above (1) and also that the rise was eliminated completely when the increase in intrathoracic pressure was reversed. Parenthetically, Robotham also demonstrated (5) that an increase in left atrial pressure associated with an increase in Pab could be completely inhibited by preventing the cephalad movement of the diaphragm. This suggests that the fall in cardiac output can be explained, in part, by compressive effects of the diaphragm on the heart. In the study cited above, Kashtan and coworkers (2) investigated the effects of increased Pab on venous return. In that set of experiments, they set intra-abdominal pressure at five different levels between 0 and 40 mm Hg. They found that both mean systemic pressure (Pms) and venous resistance (Rv) increased as abdominal
Abdominal-Circulatory Interactions
885
pressure rose. However, due to the antithetical effects that these two trends impose on venous return, and hence on cardiac output, their net impact depended on the premorbid volume status of the animals. Increased Rv predominated in animals with a low Pra (hypovolemic) whereas the increase in Pms predominated in animals with a high Pra (hypervolemic). The authors concluded that although Pms may rise as splanchnic veins and venules are compressed, that increase may be more than offset in animals which are hypo- or even normovolemic by the accompanying increase in Rv due to the compression and collapse of the intra-abdominal vena cava. The authors therefore inferred that it is the balance between the levels of Pab and Pra (volume status) that is critical in determining the net impact of the former on venous return. To more fully explore that interaction, Takata et al. (6) modeled the abdominal vasculature in much the same manner that West and colleagues had proposed for the lung (7). The former suggested that vascular zone conditions exist in the abdomen and that a vascular waterfall, as proposed by Permutt and Riley (8), could develop depending on the particular set of values for Pab, the pressure within the abdominal inferior vena cava Pivc at the level of the diaphragm, and Pc. Pc reflects the influence of the vessel wall tone on the collapse state, that is, the critical transmural closing pressure of the vessel at the vascular waterfall. The concept of Pc had gained currency in an earlier study in which Lloyd (9) demonstrated that net flow in the IVC would always be forward unless Pivc was 5 cmH 2O or more below Pab. He concluded, therefore, that the inferior vena cava (IVC) does not act as a pure Starling resistor but rather that the IVC possesses a tethering open capacity or Pc. Figure 1 illustrates the model of the IVC circulation upon which Takata and colleagues based their model. In this model, an upstream extra-abdominal vascular compartment surrounded by atmospheric pressure flows into a downstream abdomi-
Figure 1 Schematic illustration of model of IVC circulation.
886
Goldberg
nal compartment which, surrounded by Pab, empties, in turn, into the thoracic IVC. If Pivc ⬎ Pab ⫹ Pc where the IVC crosses the diaphragm into the thorax, then zone 3 conditions pertain and Pivc acts as the effective backpressure (Pb) to IVC flow. If however, Pivc ⬍ Pab ⫹ Pc, then zone 2 conditions exist such that Pab⫹Pc serves as the effective back pressure to IVC flow as a vascular waterfall is developed. Figure 2 illustrates the variable effects that changes in Pab would have on IVC flow into the thorax and upon IVC blood volume for any given zonal conditions within the abdomen as predicted by this model. If Pab were to increase such that
Figure 2 Schematic illustrations showing changes in blood volumes in IVC circulation with an increase in abdominal pressure with a pure zone 3 abdomen (A), a pure zone 2 abdomen (B), and a transition from zone 3 to zone 2 abdomen (C). ∆Pab, step increase in Pab to achieve a new steady state.
Abdominal-Circulatory Interactions
887
zone 3 conditions (Pivc ⱖ Pab ⫹ Pc) were to remain unchanged, IVC blood flow into the thorax would increase while IVC blood volume within the extra-abdominal compartment (Vu) would remain unchanged thereby yielding an overall decrease in total IVC blood volume (Vivc). If zone 2 conditions were to remain unchanged after an increase in Pab, IVC flow into the thorax would transiently decrease and IVC blood volume in the downstream abdominal compartment (Vd) would remain the same whereas the upstream IVC compartment would increase, leading to an overall increase in IVC blood volume. Lastly, if the increase in Pab were to cause a transition from zone 3 to zone 2, then IVC flow would transiently increase and then fall, trapping blood in the extra-abdominal compartment. The overall net effect on Vivc, therefore, could be variable depending on the baseline values for Pivc, Pab, and Pc, and the change in Pab. In a series of imaginative experiments these authors tested their model by variously altering Pivc, baseline Pab, and by transiently increasing Pab through bilateral phrenic nerve stimulation. Figure 3 depicts the changes in IVC flow at various levels of Pab with Pivc held constant. In panel A, baseline Pab is considerably smaller than Pivc (zone 3) and the transient increase in Pab of approximately 4.6 mm Hg induced by phrenic nerve stimulation fails to induce a zonal change. As predicted by the model, IVC blood flow increases as represented by a steep change
Figure 3 Typical changes in Pab, Vres, and Pfv during phrenic nerve stimulation in series 1 experiments. From A to E, baseline Pab was progressively elevated while Pivc was maintained constant. Slope of change in Vres reflects thoracic IVC flow rate. In A with baseline Pab much smaller than Pivc (zone 3 abdomen), increase in Pab produced a steady rise in Vres, reflecting an increase in IVC venous flow throughout diaphragmatic construction. In E with baseline Pab much greater than Pivc (zone 2 abdomen), increase in Pab produced a steady fall in Vres, reflecting a decrease in IVC venous flow. Intermediate stages between these two extremes reflect patterns of IVC venous return, with increases for much of diaphragmatic contraction (B), increases and then slowly declines (C), or increases briefly but then declines during the rest of the diaphragmatic contractin (D).
888
Goldberg
in the slope of Vres (blood volume in the reservoir in the circuit). In panel E in which zone 2 conditions prevail at baseline, the transient increase in Pab is accompanied by a fall in IVC flow. Panels B through D reflect various conditions in which zone 3 switches to zone 2 during phrenic nerve stimulation such that IVC flow increases for much of diaphragmatic contraction and then plateaus (panel B), increases and then slowly tapers off (panel C), or increases briefly before declining during the remainder of diaphragmatic contraction (panel D). The authors then proceeded to substantiate the second prediction of their model, that a vascular waterfall could develop within the abdomen at the thoracic inlet of the IVC. Figure 4 graphically depicts their results. By applying variable amounts of Pab (levels a–e) at different levels of Pivc, the authors determined the critical pressure within the inferior vena cava (Pivc crit ) for each level of imposed Pab at which that increase would continue to be reflected upstream in femoral venous pressure (Pfv)—i.e., the absence of a vascular waterfall. These results convincingly demonstrate that a vascular waterfall develops in their animal model and that the critical pressure at which the waterfall develops is directly dependent on the relative levels of Pivc and Pab. Using this model of abdominal vascular zone conditions, this same group of investigators (10) set out to delineate the source of the changes in IVC blood flow that accompany an increase in Pab, and to isolate the effects of a rise in Pab from those of a fall in intrathoracic pressure on IVC blood flow. In this set of experiments Pab was increased by only 6 mm Hg as open-chested dogs rendered apneic underwent electrocardiogram-triggered phrenic nerve stimulation and diaphragmatic
Figure 4 Representative plot of Pfv vs. Pivc at different levels of Pab in series 2 experiments. Letters a–e represent different levels of Pab, with (a) the highest and (e) the lowest. Critical value of Pivc above which Pfv started to rise (Pivccrit ) decreased as Pab decreased from (a) to (e).
Abdominal-Circulatory Interactions
889
decent. They were successful, in the first instance, in confirming their previous findings that baseline volume status determines, in large part, the change in IVC flow at the diaphragm as Pab is increased. In the second, they were able to demonstrate that the increase in IVC flow that occurs in the hypervolemic animals (Pra ⬎ 8 mm Hg) is due completely to an increase in splanchnic blood flow and that non splanchnic flow actually decreases under those conditions. Contrarily, hypovolemic dogs (Pra ⬍ 5 mm Hg) subjected to the same increase in Pab (abdominal zone 2) demonstrated a biphasic response. While intrathoracic IVC flow increased initially, it fell back to baseline by the second heart beat and then fell below baseline by the third beat. These changes were due almost exclusively to the accompanying changes in the splanchnic blood flow. Furthermore, they interpreted the inverse relationship they had observed between splanchnic and nonsplanchnic blood flow to be due to a common downstream venous pressure that both circulations must share and that those different responses to increases in Pab reflect regional variability in venous resistance. The authors also concluded that the increase in intrathoracic IVC flow could only be due to the increase in Pab and not to any concomitant fall in intrathoracic pressure because these dogs were studied open-chested. Finally, Takata and Robotham (10) completed this set of experiments by demonstrating that even in circumstances in which Pab does not rise during diaphragmatic descent as, for example, in the eviscerated animal, IVC blood flow would still increase. They inferred that the observed increase in blood flow under those circumstances was due to the increase in focal contact stress over the liver such that the counterforce to hepatic displacement during diaphragmatic descent would be the extrusion of splanchnic blood into the IVC, a finding that appeared to confirm an earlier study by Decramer and colleagues which documented marked regional variability in intra-abdominal pressures in the non-fluid-filled abdomen (11). Takata and colleagues (12) then applied their model of the abdominal vascular waterfall to explain the pathophysiology of Kussmaul’s sign and in so doing emphasized the very critical role that increases in abdominal pressure have on the generation of pressures within the heart chambers and upon intrathoracic blood flow. Two groups of closed-chested dogs, one rendered hypovolemic (Pra ⬍ 2 mm Hg) and the other hypervolemic (Pra ⬎ 6.5 mm Hg) were subjected to phrenic nerve stimulation. However, while all animals were subjected to the same fall in esophageal pressure (Pes) during phrenic nerve stimulation, one set of measurements were made with an open airway, thereby allowing for diaphragmatic descent and a change in lung volume, whereas the second set was made with an occluded airway (Mueller maneuver; MM), thereby precluding any changes in either lung volume or diaphragmatic position. In the hypervolemic animals in which lung volume was permitted to change, diaphragmatic descent increased Pab, and Pra increased coincident with the fall in Pes (Kussmaul’s sign). In contrast, Pra did not increase in animals subjected to the MM. Furthermore, whereas IVC flow increased equally in all the hypervolemic animals, regardless of the patency of their airway, superior vena cava blood flow (Qsvc) fell with the open airway during phrenic nerve stimulation, but actually rose during MM. With hypovolemia, however, phrenic nerve stimulation applied to the
890
Goldberg
open airway caused an initial increase in both IVC flow and in Qsvc and failed to induce a Kussmaul’s sign, changes which were accompanied by an increase in the gradient between Pra and Pivc. These latter findings are consistent with the development of a vascular waterfall between the Pivc and Pra. Takata and colleagues explained their findings as follows (12): In the hypervolemic animals in which abdominal zone 3 conditions prevail, the increase in Pab through diaphragmatic descent propels blood back into the central compartment from the volume-charged splanchnic circulation and results in a Kussmaul sign. The fall in Qsvc derives from the rise in Pra and the consequential fall in driving pressure between the SVC and the right atrium. The central role of Pab in the development of the Kussmaul sign is suggested by the failure of an equivalent fall in Pes in the absence of diaphragmatic descent to generate the Kussmaul. In the hypovolemic state, the increase in Pab during diaphragmatic descent is deemed responsible for the creation of the vascular waterfall. After an initial rise in IVC flow, the latter falls significantly below baseline by the third heart beat (transition zone 3 to zone 2) while the gradient between Pra and Pivc, absent in the hypervolemic state, widens as the vascular waterfall becomes effective at the thoracic inlet (Fig. 5). In a very recent study, Kitano and coworkers (13) reexamined the influence of abdominal pressure on steady-state cardiac performance. They both confirmed Kashton’s original findings (2) and, by employing their model of abdominal vascular zones, elaborated upon them. They demonstrated, as did Kashton, (2), that biventricular dysfunction develops at rather high abdominal pressures (30 mm Hg) and that the right ventricle was more depressed than the left ventricle. They attributed this
Figure 5 Effects of increased Pab (䉱) on inferior vena cava pressure (Pivc; 䊐) and Pra (䊊). Data are presented as means ⫾ SE; n ⫽ 7 animals. Pivc increased in parallel with Pab, but Pra showed significant difference with Pivc (†P ⬍ .01 by one-way ANOVA with Sheffe´s test) when Pab was ⬎15 mm Hg. PP 7.5, PP 15, PP 30, abdominal pressure of 7.5, 15, 30 mm Hg, respectively.
Abdominal-Circulatory Interactions
891
to the increased afterload which confronts both ventricles. However, they also examined the graded effects of incremental increases in Pab on cardiac output. As Pab was augmented, cardiac output exhibited biphasic changes. It increased at lower levels, then returned to baseline as the levels were increased, and then decreased at ⬎30 mm Hg (Table 1). At lower levels of abdominal pressure (7.5 mmHg) Pra was still higher than Pab, and zone 3 conditions prevailed such that the increase in Pab resulted in an increase in venous return, an increase in both Pra tm and PCWP tm , and an increase in cardiac output. At higher levels of Pab where abdominal pressure exceeded Pra, zone 2 abdominal vascular conditions were created such that venous return fell and caused the cardiac output to decrease toward baseline values. At still higher levels of Pab, venous return fell still further and that, combined with the increase in afterload, resulted in a significant drop in cardiac output. B. Regional Hemodynamics
Whereas increased Pab can adversely affect organ function through its negative impact on cardiac output, that increase may also have independent and direct effects on intra-abdominal organ performance. Harman and colleagues (14) examined the consequences of increased Pab on renal function by measuring cardiac output, renal blood flow, glomerular filtration rate, and urine output in dogs subjected to increasing levels of intra-abdominal pressures. At 20 mm Hg, both renal blood flow and glomerular filtration rate were decreased to ⬍ 25% of baseline. At 40 mm Hg, three dogs were rendered anuric whereas the renal blood flow decreased in the remaining animals and glomerular filtration rate decreased to 7% of baseline whereas cardiac output fell to only 40% of baseline. Furthermore, restoration of cardiac output back to baseline through the use of volume expansion failed to normalize either renal blood flow or glomerular filtration rate, both of which returned to only 25% of the baseline value. Renal vascular resistance was calculated to have risen fivefold at an intra-abdominal pressure of 20 mm Hg, 15 times the simultaneously calculated systemic vascular resistance. These authors concluded that the impairment in renal func-
Table 1
Results of Series 1 Baseline
CO, mL/min Pla, mm Hg Pra, mm Hg Ppe, mm Hg Paw, mm Hg
1052 7.1 5.5 1.4 4.5
⫾ ⫾ ⫾ ⫾ ⫾
55 0.3 0.2 0.2 0.4
PP7.5 1107 9.7 8.2 3.3 4.7
⫾ ⫾ ⫾ ⫾ ⫾
60 0.4* 0.4* 0.2* 0.3
PP15 1023 10.6 9.7 4.7 6.3
⫾ ⫾ ⫾ ⫾ ⫾
60 0.5* 0.5* 0.2* 0.4*
PP30 804 9.6 9.4 5.4 8.1
⫾ ⫾ ⫾ ⫾ ⫾
40* 0.5* 0.6* 0.6* 0.6*
Values are means ⫾ SE; n ⫽ 7 swine. PP7.5, PP15, PP30, abdominal pressure of 7.5, 15, 30 mm Hg, respectively; CO, cardiac output; Pla, left atrial pressure; Pra, right atrial pressure; Ppe, pericardiac pressure; Paw, airway pressure. *Significant difference, compared with baseline, by one-way ANOVA for repeated measures with Scheffe´s test, P ⬍ .01.
892
Goldberg
tion was partially mediated centrally through a fall in cardiac output but primarily through local compressive effects. In this same regard, Diebel and coworkers (15) examined the effects of increased Pab on regional visceral perfusion within the abdomen. Using a swine model of ACS these investigators demonstrated that despite the stability of both cardiac output and mean arterial pressure, both superior mesenteric and intestinal mucosal blood flows decreased significantly at a Pab of 20 mm Hg. Furthermore, using a similar experimental model, they described (16) a significant fall in both hepatic arterial and microvascular blood flows at a Pab of just 10 mm Hg while the fall in portal venous flow achieved significance at Pab of 20 mm Hg despite the stability, once again, of both cardiac output and arterial pressure. Finally, they confirmed (17) that despite keeping central hemodynamics constant, rectus sheath blood flow decreased at all levels of increased Pab as it was increased sequentially by 10 mm Hg steps to a maximum of 40 mm Hg.
III. Human Data A. Weaning from Mechanical Ventilation
From what has been said previously, it would be expected that the change in abdominal pressures produced during spontaneous breathing can significantly influence cardio pulmonary function in humans. That such is the case was illustrated by Lemaire and colleagues (18). They examined 15 patients with chronic obstructive pulmonary disease (COPD) who had been ventilated for cardiopulmonary decompensation. During repeated failures at weaning from mechanical ventilation, these patients had exhibited significant increases in both their PCWPtm (from 7.5 to 24.5 mm Hg) and Pratm (from 3 to 15 mm Hg) and in their right and left ventricular end-diastolic volumes while biventricular systolic function remained unchanged. After shedding a mean of 5 kg body weight, eight of those patients ultimately underwent successful weaning trials during which time their PCWP measurements remained well within the normal range. The authors implicated several possible contributing factors to explain their observations, including recurrent cardiac ischemia, ventricular interdependence, and the effect of the documented increases in levels of circulating cathecholamines on left ventricular afterload. The authors inferred, however, that it was the significant diuresis that had transpired between the unsuccessful and successful weaning trials that was primarily responsible for that success. And given that temporal relationship, the authors concluded that it had been the physiological changes that ensue when switching from positive pressure (artificial) to negative (spontaneous) ventilation and, in particular, the resultant increase in venous return to the right side of the heart that had been responsible for those earlier weaning failures. To a large extent, the authors were correct. Diuresis was crucial in facilitating weaning from mechanical ventilation. However, it was Permutt (19), in his accompanying editorial, who incisively articulated the critical findings of this study and attributed both success and failure to the changes in Pab that had occurred during the weaning trials. His first astute observation was that during the failed weaning at-
Abdominal-Circulatory Interactions
893
tempts Pratm rose more than the concomitant fall in pleural pressure that accompanied spontaneous inspiration; that is, Pra rose relative to atmosphere. Permutt suggested that it was the increase in abdominal pressure which resulted from diaphragmatic descent that must have been responsible for these findings. In fact, Permutt (19) concluded, much as Takata and Robotham were to later demonstrate experimentally (10,12), that both the increase in preload and afterload observed in this study were due to the rise in transdiaphragmatic pressure, due primarily to the increase in Pab and not to the fall in pleural pressure. Such changes would not have been expected to occur when these patients were ventilated because the rise in abdominal pressure would have been accompanied by a near-parallel increase in pleural pressures with little change resulting in transdiaphragmatic pressure. While the 5-kg diuresis that had transpired between weaning attempts was undoubtedly critical for the ultimate weaning success, it is likely that it was the diuresis-induced decompression of the splanchnic circulation and the resultant decrease in splanchnic abdominal blood flow into the thoracic cavity during spontaneous inspiration that were responsible for these transient changes in Pra and PCWP. While the bulk of the experimental data on this subject focus on the effects of diaphragmatic descent during inspiration on Pab and its impact on venous return, little attention has been addressed to the consequences of an increase in Pab which results from forced expiration. There are considerable data (20) that during loaded breathing and during exercise, subjects actively recruit their expiratory muscles. Clearly, this increase in Pab differs fundamentally with that which occurs during diaphragmatic descent in that transdiaphragmatic pressure may remain unaltered as Pab is transmitted unaltered across the diaphragm. In their recent study, Gorini and coworkers (21) were able to confirm this phenomenon. After inducing bronchoconstriction in 14 stable COPD patients they noted an increase of approximately 4 cmH 2O in gastric pressures due to expiratory muscle recruitment. But they also documented a near-identical increase in intrinsic PEEP (PEEPi), thereby implying near complete transmission of the increase in Pab to the pleural space which thereby left expiratory transdiaphragmatic pressure unchanged. Notwithstanding these findings, this issue of expiratory increases in Pab and its effect on intrathoracic IVC flow deserves further consideration given the possible time delay that has been reported to occur in the transmission of the increase in Pab to the pleural space due to the presence of postinspiratory muscle diaphragmatic activity (22). B. Ascites
The clinical importance of abdominal-cardiac interactions may be greatest in the setting of two clinical conditions, one rather common, the other less so. The clinical approach to the cirrhotic patient with tense ascites suffering either from respiratory impairment or from significant discomfort has been the subject of controversy for several years, and only recently has some degree of consensus been reached. Until the 1950’s large-volume paracenteses were commonly practiced. During the ensuing decade a variety of anecdotal reports were published linking that practice with unacceptable side-effects including hepatic failure, renal failure, hypotension, hypona-
894
Goldberg
tremia, and bacterial peritonitis (23). In response to those reports the practice of simple sodium restriction combined with diuretic use gained favour and remained the preferred treatment for this condition until only recently. Given those anecdotal reports, Knauer and Lowe (24) carried out one of the earliest hemodynamic studies detailing the sequential changes accompanying parcentesis. They demonstrated, as one would have expected, that decompression of the distended abdomen resulted in a progressive lowering of Pab and, in turn, in a progressive dimunition in inferior vena caval pressures. But somewhat surprisingly, they also documented an increase in stroke volume which reached significance after the removal of just 250 mL. Stroke volume then began to fall and returned to baseline after the removal of 1.5 L. Contrarily, SVR fell and reached significance somewhat earlier than did the increase in stroke volume. Because these investigators did not measure cardiac chamber pressures or volumes, no inferences could be made regarding cardiac function; that is, given the data, no conclusion could be reached as to whether the early increase in cardiac output was due entirely to the fall in SVR or whether an increase in venous return secondary to decompression of the inferior vena cava and/or of the right atrium could be implicated. Approximately 10 years later, Guazzi and colleagues (25) studied 21 men with Laennec’s cirrhosis and tense ascites. They collected hemodynamic data, measured sequentially, after the removal of 1-L aliquots of ascitic fluid with a minimum of 5 L and a maximum of 8 L removed in total. As Knauer and Lowe (24) had previously shown, these investigators documented a gradual decrease in both abdominal and inferior vena caval pressures, the former falling from a baseline of 18 mm Hg to 10 mm Hg, a stepwise fall in SVR, and a rise in stroke volume with no change in mean arterial pressure. However, unlike the previous studies, Guazzi and colleagues (25) documented that those changes were accompanied by a fall in the mean Pra, which was both progressive and significant, and described, in fact, a relationship between mean Pra and right ventricular stroke work that was inversely proportional. Both mean pulmonary arterial and PCWP remained unchanged throughout the course of the study. The authors concluded that the increase in cardiac output was due to an increase in venous return which had been previously impeded by an increase in juxtacardiac pressure, the latter a result of the intrathoracic transmission of an increased Pab. Removal of that fluid and the resultant fall in abdominal and juxtacardiac pressures resulted in a fall in right-sided pressures and led, in turn, to an increase in right ventricular output. Contrarily, Savino et al. (26) concluded that the increase in stroke volume that they also documented upon the aspiration of ascitic fluid was due not to the decrease in Pra, but rather to the accompanying significant decrease in SVR. They studied 25 patients in whom intra-abdominal pressures were 25 cmH 2O, measured via the transvesical technique with the use of a transurethral catheter (v.i.). Approximately 3 hours after the paracenteses during which Pab fell from a mean of 33 to 19 cmH 2O, stroke volume increased significantly and SVR fell, whereas neither Pra nor PCWP changed. They ascribed the accompanying improvement in both glomerular and tubular renal function to the relief in the increased Pab rather than to the increase in cardiac output.
Abdominal-Circulatory Interactions
895
More recently, Pozzi and colleagues (27) catalogued the immediate and longer-term hemodynamic consequences and the accompanying hormonal changes in 12 cirrhotic patients with tense ascites who were undergoing large volume paracentesis. All patients had been admitted 5 days prior to paracentesis during which time diuretics had been withheld and a low daily intake of sodium prescribed. Cardiac function was assessed echocardiographically. Hemodynamics were measured via a Swan-Ganz catheter. An average of 10 L of ascitic fluid was drained over ⬃ 1 hour at a rate of ⬃ 250 mL/min. As expected, intra-abdominal pressure fell from a baseline of 17 mm Hg to 2 mm Hg. Furthermore, intra-thoracic pressure as measured by a fluid-filled esophageal catheter fell significantly. They also documented a significant increase in stroke volume index while SVR fell significantly. Although Pra declined significantly, Pra tm remained unchanged, leading the authors to implicate the removal of a mechanical obstruction to venous return as responsible for the rise in cardiac output. Additionally, Pozzi and colleagues (27) performed sequential radioimmunoassay measurements of both plasma aldosterone and renin activity and of plasma atrial natriuretic peptide (ANP) concentration throughout the period of paracenteses, and at 24 and 48 hours and at 6 days following their completion. While both plasma renin activity and aldosterone concentrations were markedly elevated at baseline, both fell significantly during the paracenteses, whereas ANP was elevated at baseline and rose significantly following paracenteses. The findings had been documented several years earlier by Salerno et al. (28). It may well be that this change in the humoral profile, rather than the relief of a purely mechanical mechanism, is responsible, at least in part, for the fall in SVR. Whereas most of the hemodynamic changes described were salutary, mean arterial pressure nevertheless fell significantly. Whereas cardiac index had been noted to be modestly elevated at baseline, it clearly could not increase adequately to offset the concomitant fall in SVR. In this regard, Van Obbergh and colleagues (29) recently documented depressed myocardial function in a rat model of biliary cirrhosis, due to both a fall in coronary artery perfusion pressure and decreased myocardial contractility, both of which could be reversed, in whole or in part, by nitric oxide synthase inhibition. Several other reports, however, have failed to confirm either the hemodynamic or the hormonal changes described above. One such report is that of Peltekian and colleagues (30), who did not find any change in cardiac output as measured by radionuclide angiography following paracentesis. Furthermore, they were unable to document any changes in levels of plasma renin activity, concentrations of plasma aldosterone, or ANP levels in 12 patients with cirrhosis and tense ascites subjected to 5-L paracenteses. Finally, although a review of the therapeutic options in this condition is beyond the purview of this article, it would be inappropriate to leave the reader with the impression that large-volume paracentesis alone is the therapy of choice in the management of tense ascites. Indeed, there still remains considerable controversy concerning the appropriate management of this condition. In particular, there is debate
896
Goldberg
over the use of intravenous albumin following large-volume paracentesis, a topic exhaustively reviewed by Gines and Arroyo (31). They concluded that despite the immediate improvement in systemic hemodynamics during paracentesis, the infusion of approximately 6 to 8 g of albumin per liter of ascitic fluid removed prevents the fall in effective circulating volume that occurs ⬃ 12 to 24 hours following ascitic fluid removal. Another therapeutic tool commonly used in the management of patients with cirrhotic liver disease is the transjugular intrahepatic portosystemic stent shunt (TIPSS). This radiological interventional procedure is used in the treatment of recurrent esophageal hemorrhage and refractory ascites. As with paracentesis, TIPSS has been shown to have significant hemodynamic implications, although results of studies have not been uniform. Stanley and colleagues (32) studied 11 patients undergoing this procedure. Accompanying the anticipated fall in the portoatrial gradient, Pra, PCWP, stroke volume, and mean pulmonary arterial pressure all rose while SVR fell. Van de Linden et al. (33) studied 16 patients and also observed increases in Pra, PCWP, mean pulmonary arterial pressure, and cardiac output, although the change in this last was accounted for completely by an increase in heart rate. SVR also fell significantly. An added contribution of this second study (33) was the observation that when the shunt was transiently obstructed, mean pulmonary arterial pressure fell somewhat but remained increased despite the return of all other hemodynamic variables back to baseline. The authors concluded that in addition to the obvious circulatory changes induced by the TIPSS, the release of humoral factor(s), such as endothelin and norepinephrine, both of which have been shown to be elevated in advanced cirrhotic liver disease (34,35), may well be responsible for the generation of increased pulmonary vascular resistance following this procedure. Similar to the animal data outlined above there appear to be effects of increased Pab on regional hemodynamics in patients with cirrhotic liver disease such that changing Pab may carry significant therapeutic implications. Luca and colleagues (36) addressed this issue by reversibly increasing Pab by 10 mm Hg in 14 cirrhotic patients with portal hypertension. That intervention increased both free hepatic (FHVP) and portal venous pressures which yielded a hepatic venous pressure gradient that remained constant, on the one hand, but an elevation in the Pra-FHVP gradient, on the other. The authors (36) confirmed the findings of several other studies—albeit in reverse—that in this patient population, an increase in Pab induces a fall in cardiac output and an increase in SVR and mean arterial pressure. Perhaps more importantly, the increase in Pab was associated with a decrease in hepatic blood flow and by a commensurate increase of ⬃ 20% in azygos blood flow. The latter is an index of gastroesophageal collateral blood flow. Furthermore, these changes were reversed when Pab was returned to baseline. The authors could only speculate as to the mechanisms underlying these changes but suggested that the increase in Pab may have increased hepatic vascular resistance due to direct hepatic compression and/or may have exercised differential effects on resistance to blood flow through the IVC as opposed to the portocollateral vessels.
Abdominal-Circulatory Interactions
897
These changes in splanchnic hemodynamics may well provide the pathophysiologic basis for the report by Kravetz and colleagues (37) who documented that large-volume paracentesis is associated with a significant fall in measurements of variceal size including intravariceal pressure, variceal diameter, and variceal wall tension. Since all of these variables carry significant implications for the risk of esophageal variceal hemorrhage, this report suggests that paracentesis may be advisable for the treatment and prevention of esophageal variceal rupture. In summary, the decrease in Pab that results from large-volume paracentesis leads to a decrease in intrathoracic and juxtacardiac pressures which permits an increase in venous return and cardiac output. Coincident with these changes, systemic vascular resistance falls significantly, either by direct mechanical effects as suggested by Kashton and coworkers (2) or through a decline in the circulating levels of vasoconstricting agents such as aldosterone, plasma renin, and angiotensin. Although baseline cardiac function is elevated in these subjects, the fall in SVR appears to dominate such that mean arterial pressure is decreased. Finally, the increase in Pab appears to result in an increase in portocollateral blood flow such that the relief of that pressure results in a decrease in variceal size, pressure, and wall tension. C. Abdominal Compartment Syndrome
The second clinical condition in which Pab plays a pivotal role is the abdominal compartment syndrome (ACS), which is encountered in a variety of clinical settings including intra- and retroperitoneal hemorrhage, ischemic bowel, acute bowel obstruction, abdominal and pelvic trauma, and abdominal closure under excessive tension. Although ACS can be said to exist in a variety of clinical conditions in which Pab is increased, including ascites and pregnancy, its use is usually confined to those conditions in which that pressure rises acutely. Indeed, the usual clinical scenario is that of a critically injured patient who has suffered severe abdominal and/or pelvic trauma. In that clinical context, the patient often receives aggressive fluid resuscitation which places his intestine at high risk for the development of massive bowel edema. The abdominal compartment may be further compromised by the presence of a retroperitoneal hematoma, by the use of perihepatic packings as an adjunct to the management of severe liver injuries, or by the use of such packings to control abdominal and pelvic hemorrhage in the coagulopathic patient. Whereas normal Pab is zero to subatmospheric (14,38), the level of Pab measured in the various reports of this condition has been quite variable. It also appears that its deleterious consequences appear gradually as Pab is raised (39). Despite the lack of a standard definition in the literature, Mayberry (40) has recently proposed the following diagnostic criteria for this syndrome: (1) Pab ⱖ25 mm Hg or 30 cmH2 O (bladder pressure v.i.); (2) One or more of the following: oliguria, increased peak airway pressure, hypoxia, decreased cardiac output, acidosis, hypotension; and (3) clinical improvement following adominal decompression. Although recognized relatively uncommonly in the clinical setting, the syndrome has proven to be somewhat more frequent when studied in a systematic fash-
898
Goldberg
ion. In their recent prospective examination, Sugrue and colleagues (39) measured Pab in 263 patients who had undergone intraperitoneal abdominal surgery. Based on a critical level of 18 mm Hg or greater, these investigators diagnosed ACS in approximately 40% of their subjects. Furthermore, these authors were able to convincingly demonstrate an independent relationship between the increase in Pab and the development of renal failure. The level of Pab ranked fourth behind hypotension, sepsis, and age ⬎ 60 years as an independent risk factor for the development of post-operative renal insufficiency which usually occurred 1 to 2 days following the onset of the increased Pab. They also described a dose effect in that the incidence of renal failure doubled as Pab rose from 18 to 25 mm Hg. The impact of the increase in Pab on hemodynamics in this clinical setting and its response to surgical decompression has been well characterized. Cullen and colleagues (41) studied six patients in whom Pab was severely increased to a mean of 51 cm H 2O due to a variety of medical, surgical, and traumatic insults. The first crucial observation to be noted from this study is that despite markedly elevated filling pressures (Pra ⫽ 22 mm Hg; PCWP ⫽ 25 mm Hg), all six patients responded to a volume challenge with significant increases in both their cardiac output and blood pressure. Secondly, four of the patients subjected to surgical decompression demonstrated significant falls in those filling pressures accompanied by significant increases in both cardiac output and hourly urine output. These results are quite compatible with the animal data discussed above in that the increased Pab, by exerting a tamponadelike effect on the heart, elevates filling pressures relative to atmosphere which may be mistakenly interpreted for cardiac dysfunction when in fact there is a decrease in ventricular transmural pressures. Evidence that the latter was in fact the case in these six patients was the finding obtained through gated blood pool scanning of normal left ventricular ejection fractions and normal calculated left ventricular end-diastolic volumes. Further evidence of this tamponadelike effect in ACS was reported by Chang and coworkers (42) who described the hemodynamic course and visceral perfusion in 11 consecutive patients undergoing surgical decompression following a clinical diagnosis of ACS. The Pab was ⬎25 mm Hg. Following decompression from a mean of 49 to 19 mm Hg, right ventricular end-diastolic volume index rose significantly as did stroke volume, while neither Pra nor PCWP, both elevated prior to depression, changed. The authors were able to describe an inverse relationship between both right- and left-sided filling pressures and cardiac index prior to decompression, and both of these pressures had a positive relationship with Pab. Furthermore, and in keeping with this tamponadelike effect, there was no correlation between Pra and right ventricular end-diastolic volume index. Evidence of improved tissue perfusion following abdominal decompression was deduced from both the decrease in base deficit and the increase in pHi, which was measured tonometrically. In summary, the implications of ACS are twofold. Firstly, abdominal decompression can result in significant improvements in systemic and regional perfusion marked by increases in stroke volume, urine output, and splanchnic perfusion. Moreover, it appears that significant elevation in Pab is not uncommon and that paracentesis should be undertaken if the increase in Pab is associated with evidence of visceral
Abdominal-Circulatory Interactions
899
hypoperfusion. Secondly, hemodynamic monitoring carried out in this setting must be interpreted cautiously, given the poor and, in some studies, inverse relationship between Pra and PCWP and cardiac index. Because of the significant influence that Pab may have on the measurements of cardiac filling pressure, some estimation of its impact should be attempted either through its indirect measurement (v.i.) or through the measurement of intrathoracic pressures. Another potential solution is the assessment of right ventricular end-diastolic volumes through the use of the volumetric hemodynamic catheter (42). D. Laparoscopic Surgery
During the past several years, laparoscopic surgery has markedly expanded beyond its initial application to gynecological procedures and has moved widely into the general surgery sphere. With this technique, intra-abdominal insufflation is carried out, usually with CO 2 , to a pressure of ⬃ 14 to 15 mm Hg (43,44). Despite these seemingly very modest elevations in Pab, significant hemodynamic changes have been described in a variety of human studies. Myre and coworkers (43) followed the hemodynamic and echocardiographic course of seven patients who did not have any clinical history of cardiac disease and were undergoing laparoscopic cholecystectomy. Pab was raised to 15 mm Hg with CO 2 insufflation and measurements were made after a steady state was achieved (10 min). Under these conditions, Pra and PCWP both increased significantly despite the lack of any change in the left ventricular end-diastolic volume, as measured via transesophageal echocardiography. Neither cardiac index nor heart rate increased. Finally, both mean arterial pressure and systemic vascular resistance increased. These findings, within the limits of the techniques used, are compatible with the notion that an the increase in abdominal pressure is responsible, through direct transmission, for the increase in PCWP. Addressing this same question, but in patients with preexisting cardiac dysfunction, Gebhardt and coworkers (44) studied 15 patients in whom Pab had been increased to 14 mm Hg through CO 2 insufflation. In addition to Swan-Ganz catheterization, all patients were fitted with an intra esophageal catheter to measure intrathoracic pressure changes. With the increase in Pab, Pra rose significantly, but this was accompanied by a relatively greater increase in esophageal pressure so that calculated Pra tm actually fell and continued to fall throughout the period of insufflation, and returned to baseline immediately after abdominal decompression. Cardiac output fell significantly within 10 min of the increase in Pab, and returned to baseline by 30 min. The restoration in cardiac output could be accounted for by a compensatory increase in heart rate. Stroke volume, on the other hand, fell continuously throughout the procedure. Systemic vascular resistance rose immediately and significantly upon insufflation but returned to baseline after ⬃ 60 min despite the continued period of insufflation. It is apparent that in this latter study, the rise in Pra was due to the direct transmission of the increase in Pab to the juxtacardiac space. Whether or not IVC flow was also decreased, as the authors suggest, which would help explain the fall in Pra tm , can only be speculated upon. Why the Pra tm continues to fall throughout the
900
Goldberg
procedure is not entirely clear but its immediate return to baseline upon abdominal decompression argues strongly for a mechanical cause. The increase in systemic vascular resistance, similar to the data reported in animals reviewed above, may be due to mechanical compression of the vasculature but could also be due to the effects of elevated levels of vasopressin and catecholamines that are reported to increase immediately after the induction of CO 2 pneumoperitoneum (45). It appears, therefore, that even in the presence of the apparently modest increases in Pab that accompany laparascopic surgery, there are clinically significant effects on both Pra and PCWP accompanied, at least in some instances, by a fall in stroke volume and an increase in systemic vascular resistance. The implications of these studies are twofold. Firstly, similar to that mentioned in the context of ACS, both right- and left-sided pressure measurements are potentially very misleading as accurate gauges of their respective volumes in this clinical setting. Secondly, notwithstanding the study reported by Gebhardt et al. (44) in which only 1 of 15 patients had to be converted to an open procedure due to hemodynamic instability, these circulatory changes could be of clinical concern in patients with preoperative cardiac dysfunction. E.
Measurement of Intra-Abdominal Pressure
In order to allow for the accurate assessment of Pab, both direct and indirect methods of measurement have been suggested. Other than the continuous measurement of Pab during laparascopic surgery by the intraperitoneal catheter attached to the automatic electronic insufflator, direct measurements are rarely performed in the clinical setting because of the potential complications of both hemorrhage and infection. Although several studies have pointed to the inhomogeneity of pressures within the abdominal cavity (11) Kron and colleagues (46) were nevertheless able to demonstrate a close correlation between urinary bladder and intra-abdominal pressures. This method can conveniently be used clinically in that virtually all these patients are fitted with Foley catheters. With this method ⬃ 50 to 100 cc sterile fluid is injected into the bladder through the catheter after which the tubing of the urinary drainage bag is cross-clamped just distal to the culture aspiration port. After a continuous column of fluid is established between the bladder and the cross-clamp, a transduction system is established via the aspiration port, using the symphysis pubis as the reference level. Alternatively, the urinary drainage tubing is raised above the bed, perpendicular to the patient, and the pressure is measured in cmH 2 O above the symphysis pubis. Using an animal model in which abdominal pressures were varied between 10 and 70 mm Hg, Iberti and coworkers (47) confirmed the reliability of this method by demonstrating the close correlation between bladder pressure and Pab. The latter was measured directly through the percutaneous placement of an intraperitoneal catheter. Another convenient portal to the abdominal compartment is through a nasogastric (NG) tube which, like the Foley catheter, is used almost ubiquitously in such critically ill patients. In its most simple application, the nasogastric tube is filled with ⬃ 100 cc of fluid and, similar to the method described for the urinary drainage system,
Abdominal-Circulatory Interactions
901
is raised perpendicular to the patient. The height of the column of water, relative to the midaxillary line, is then measured (38). Alternatively, a transduction system can be affixed to the aspiration port of the NG tube, allowing the bedside monitor to display the pressure in mm Hg, once again using the midaxillary line or a point 5 cmH 2 O below the sternal angle as the zero position (48). Finally, balloons can be inserted into the stomach for the expressed purpose of measuring gastric pressure, but the added invasiveness of this procedure makes it less attractive. In this regard, however, there are commercially available NG tubes, affixed with balloons, which permit the use of this technology in the absence of any added patient manipulation (49). Lastly, it has been suggested that in animals, IVC pressure measured transfemorally correlates directly with Pab (38). Although no human corroborative data exist, those findings must be contrasted with those of Ho and coworkers (50) who demonstrated a close correlation in humans between IVC pressure, measured transfemorally and Pra, at Pab levels between 5 and 25 cmH 2 O. IV. Summary The impact of intra-abdominal events on hemodynamic stability can express itself in a variety of common clinical conditions which range from the transition from mechanical to spontaneous ventilation, the development of ascites, the abdominal compartment syndrome, and the performance of laparoscopic surgery. Models of intra-abdominal blood flow which incorporate concepts of vascular zone conditions which are analogous to those previously proposed for the lung, have been advanced and corroborated experimentally. These models can be most helpful when trying to place the antithetical trends that an increase in Pab can exert on IVC blood flow, on the one hand, and on IVC collapse and the development of a vascular waterfall at the abdominal-thoracic interface, on the other hand. Finally, the influence of Pab on both right- and left-sided cardiac pressures is crucial in permitting the fundamental understanding of the physiological effects of Pab on those pressures. But also, more practically, it allows for the appropriate clinical choices to be made in patients with increased Pab, especially at a time when the measurement of hemodynamic variables in the critically ill patient has been questioned. References 1. 2. 3. 4.
Bloomfield GL, Ridings PC, Blocher CR, Mamarou A, Sugerman HJ. A proposed relationship between increased intra-abdominal, intrathoracic, and intracranial pressure. Crit Care Med 1997; 25:496–503. Kashtan J, Green JF, Parsons EQ, Holcroft JW. Hemodynamic effects of increased abdominal pressure. J Surg Res 1981; 30:249–255. Ridings PC, Bloomfield GL, Blocher CR, Sugerman HJ. Cardiopulmonary effects of raised intra-abdominal pressure before and after intravascular volume expansion. J Trauma Injury Infect and Crit Care 1995; 39:1071–1075. Bloomfield GL, Blocher CR, Fakhry IF, Sica DA, Sugerman HJ. Elevated intra-abdominal pressure increases plasma renin activity and aldosterone levels. J Trauma Injury Infect and Crit Care 1997; 42:997–1005.
902 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
Goldberg Robotham JL, Wise RA, Bromberger-Barnea B. Effects of changes in abdominal pressure on left ventricular performance and regional blood flow. Crit Care Clin 1985; 13:803–809. Takata M, Wise RA, Robothom JL. Effects of abdominal pressure on venous return: abdominal vascular zone conditions. J Appl Physiol 1990; 69:1961–1972. West J, Dollery C, Naimark A. Distribution of blood flow inosolated lung: relation to vascular and alveolar pressures. J Appl Physiol 1964; 19:713–724. Permutt S, Riley RL. Hemodynamics of collapsible vessels with tone; the vascular waterfall. J Appl Physiol 1963; 18:932 Lloyd TC. Effect of inspiration on inferior vena caval blood flow in dogs. J Appl Physiol 1983; 55:1701–1706. Takata M, Robotham JL. Effects of inspiratory diaphragmatic descent on inferior vena caval venous return. J Appl Physiol 1992; 72:597–607. Decramer M, De Troyer A, Kelly S, Zocchi L, Macklem PT. Regional differences in abdominal pressure swings in dogs. J Appl Physiol 1984; 57:1682–1687. Takata M, Beloucif S, Shimada M, Robotham JL. Superior and inferior vena caval flows during respiration: pathogenesis of Kussmaul’s sign. Am J Physiol 1990; 262:H763–H770 Kitano Y, Takata M, Sasaki N, Zhang Q, Yamamoto S, Miyasaka K. Influence of increased abdominal pressure on steady-state cardiac performance. J Appl Physiol 1999; 86:1651–1656. Harman PK, Kron IL, McLachlan HD, Freedlender AE, Nolan SP. Elevated intra-abdominal pressure and renal function. Ann Surg 1982; 196:594–597. Diebel LN, Dulchavsky SA, Wilson RF. Effect of increased intra-abdominal pressure on mesenteric arterial and intestinal mucosal blood flow. J Trauma 1992; 33:45–49. Diebel LN, Wilson RF, Dulchavsky SA, Saxe J. Effect of increased intra-abdominal pressure on hepatic artery, portal venous, and hepatic microcirculatory blood flow. J Trauma 1992; 33:279–283. Diebel L, Saxe J, Dulchavsky S. Effect of intra-abdominal pressure on abdominal wall blood flow. Am Surg 1992; 58:573–575. Lemaire F, Teboul J-L, Cinotti L, Giotto G, Abrouk F, Steg G, Macquin-Mavier I, Zapol WM. Acute left ventricular dysfunction during unsucessful weaning from mechanical ventilation. Anesthesiology 1988; 69:171–179. Permutt S. Circulatory effects of weaning from mechanical ventilation: the importance of transdiaphragmatic pressure. Anesthesiology 1988; 69:157–160. Yan S, Sliwinski P, Gauthier AP, Lichros I, Zakynthinos S, Macklem PT. Effect of global inspiratory muscle fatigue on ventilatory and respiratory muscle responses to CO 2. J Appl Physiol 1993; 75:1371–1377. Gorini M, Misuri G, Duranti R, Iandelli I, Mancini M, Scano G. Abdominal muscle recruitment and PEEPi during bronchoconstriction in chronic obstructive pulmonary disease. Thorax 1997; 52:355–361. Easton PA, Katagiri M, Kieser TM, Platt RS. Postinspiratory activity of costal and crural diaphragm. J Appl Physiol 1999; 87:582–589. Kellerman PS, Linas SL. Large-volume paracentesis in treatment of ascites. Ann Intern Med 1990; 112:889–891. Knauer CM, Lowe HM. Hemodynamics in the cirrhotic patient during paracentesis. N Engl J Med 1967; 276:491–496. Guazzi MPA, Magrini F, Fiorentini C, Olivari MT. Negative influences of ascites on the cardiac function of cirrhotic patients. Am J Med 1975; 59:165–170. Savino JA, Cerabona T, Agarwal N, Byrne D. Manipulation of ascitic fluid pressure in cirrhotics to optimize hemodynamic and renal function. Ann Surg 1988; 208:504–511. Pozzi M, Osculati G, Boari G, Serboli P, Colombo P, Lambrughi C, De Ceglia S, Roffi L, Piperno A, Cusa EN. Time course of circulatory and humoral effects of rapid total paracentesis in cirrhotic patients with tense, refractory ascites. Gastroenterology 1994; 106:709–719. Salerno F, Badalamenti S, Lorenzano E, Incerti P, Dioguardi N. Atrial natriuretic factor in cirrhotic patients with tense ascites. Effect of large-volume paracentesis. Gastroenterology 1990; 98:1063–1070. Van Obbergh L, Vallieres Y, Blaise G. Cardiac modifications occurring in the ascitic rat with biliary cirrhosis are nitric oxide related. J Hepatol 1996; 24:747–752. Peltekian KM, Wong F, Liu PP, Logan AG, Sherman M, Blendis LM. Cardiovascular, renal
Abdominal-Circulatory Interactions
31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.
903
and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. 1997; 3:399. Gines P, Arroyo V. Paracentesis in the management of cirrhotic ascites. J Hepatol 1993; 17:S14–S18 Stanley AJ, Redhead DN, Bouchier IA, Hayes PC. Acute effects of transjugular intrahepatic portosystemic stent-shunt (TIPSS) procedure on renal blood flow and cardiopulmonary hemodynamics in cirrhosis. Am J Gastroenterol 1998; 93:2463–2468. Van der Linden P, Le Moine O, Ghysels M, Ortinez M, Deviere J. Pulmonary hypertension after transjugular intrahepatic portosystemic shunt: effects on right ventricular function. Hepatology 1996; 23:982–987. Uchihara M, Izumi N, Sato C, Marumo F. Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis. Hepatology 1992; 16:95–99. Asbert M, Gines A, Gines P, Jimenez W, Claria J, Salo J, Arroyo V. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993; 104:1485–1491. Luca A, Cirera I, Garcia-Pagan JC, Feu F, Pizcueta P, Bosch J, Rodes J. Hemodynamic effects of acute changes in intra-abdominal pressure in patients with cirrhosis. Gastroenterology 1993; 104:222–227. Kravetz D, Romero G, Argonz J, Fuevara M, Abecasis R, Bildozola M, Valero J, Terg R. Total volume paracentesis decreases variceal pressure, size, and variceal wall tension in cirrhotic patients. Hepatology 1997; 25:59–62. Schein M, Wittmann DH, Aprahamian CC, Condon RE. The abdominal compartment syndrome: the physiological and clinical consequences of elevated intra-abdominal pressure. J Am College Surg 1995; 180:745–753. Sugrue M, Jones F, Deane SA, Bishop G, Bauman A, Hillman K. Intra-abdominal hypertension is an independent cause of postoperative renal impairment. Arch Surg 1999; 134:1082– 1085. Mayberry JC. Prevention of the abdominal compartment syndrome. Lancet 1999; 354:1749. Cullen DJ, Coyle JP, Teplick R, Long MC. Cardiovascular, pulmonary, and renal effects of massively increased intra-abdominal pressure in critically ill patients. Crit Care Med 1989; 17:118–121. Chang MC, Miller PR, D’Agostino R Jr, Meredith JW. Effects of abdominal decompression on cardiopulmonary function and visceral perfusion in patients with intra-abdominal hypertension. J Trauma 1998; 44:440–445. Myre K, Buanes T, Smith G, Stokland O. Simultaneous hemodynamic and echocardiographic changes during abdominal gas insufflation. Surg Laparosc Endosc 1997; 7:415– 419. Gebhardt H, Bautz A, Ross M, Loose D, Wulf H, Schaube H. Pathophysiological and clinical aspects of the CO 2 pnheumoperitoneum (CO 2-PP). Surg Endosc 1997; 11:864–867. Mikami O, Fujise K, Matsumoto S, Ashida M, Matsuda T. High intra-abdominal pressure increases plasma catecholamine concentrations during pneumoperitoneum for laparoscopic procedures. Arch Surg 1998; 133:39–43. Kron IL, Harman PK, Nolan SP. The measurement of intra-abdominal pressure as a criterion for abdominal re-exploration. Ann Surg 1984; 199:28–30. Iberti TJKKM, Gentill DRHS, Benjamin E. A simple technique to accurately determine intra-abdominal pressure. Crit Care Med 1987; 15:1140–1142. Reader C, Angel M, Mobeireek A, Turner J, Miller DL, Milic-Emili J, Zidulka A. Non invasive measurement of maximal transdiaphragmatic pressure (PdiMAX). Am Rev Respir Dis 1990; 141:A578-A579. Abstract. Goldberg P, Reissmann H, Maltais F, Ranieri M, Gottfried SB. Efficacy of noninvasive CPAP in COPD with acute respiratory failure. Eur Respir J 1995; 8:1894–1900. Ho KM, Joynt GM, Tan P. A comparison of central venous pressure and common iliac venous pressure in critically ill mechanically ventilated patients. Crit Care Med 1998; 26: 461–464.
35 Inhaled Nitric Oxide and Acute Lung Injury
DIDIER PAYEN McGill University Royal Victoria Hospital Montreal, Quebec, Canada
I.
Introduction
Since the 1980s the scientific and medical saga of nitric oxide (NO) has exploded in many directions because of the ubiquity of NO in biological systems. The present review will be focused on inhaled NO as a potential therapy for patients suffering from acute lung injury (ALI). The discovery of NO initially as the molecular compound corresponding to endothelial-derived relaxing factor (1,2) stimulated tremendous interests in experimental and clinical research. Among these, the inhalation of NO is one of the most interesting fields because of its potential application as a therapy for various diseases in adult and infants (3–5). Although none of the published trials on the use of inhaled NO in adult ALI have demonstrated a positive impact on outcome, it remains one the most exciting topics in ALI. Since the first clinical paper published on inhaled NO in ARDS patients (6) in 1993, a tremendous amount of knowledge has been published on inhaled NO concerning the dose effects, the toxicity, the effects on gas exchange, the interactions with coagulation, inflammatory network, immune defense, and metabolism. This chapter will summarize the most relevant results for clinicians related to acute lung injury in adults. However, before discussing the effects on the lung, some important points on the chemistry of NO will be reviewed. II. NO: A Gas The discovery of NO has been a major advance in medical science for several reasons. First, NO seems to be a simple chemical molecule, but with very complex 905
906
Payen
interactions related to its radical structure. Second, except for oxygen, NO is the first ubiquitous and biologically active gas. Third, as a gas, it can be delivered by inhalation. Fourth, its short half-life and diffusion properties to the adjacent cells makes it the first cross-talk agent of such a type. Fifth, its relatively selective vasodilatation for the pulmonary vessels during inhalation, offers an elegant solution to treat pulmonary diseases (such as hypertension, intrapulmonary shunt) since the systemic side of the circulation is not hemodynamically modified. The NO system includes interactions with substrate, cofactors, enzymes, metabolic ways, biological effects, toxicity, or harmful effects. NO is synthesized by an enzyme called nitric oxide synthase (NOS) (7). NOS exists in three isoforms named for the tissues in which they were first cloned and characterized: endothelial NOS (eNOS or NOS3), neuronal NOS (nNOS or NOS1), and macrophage-inducible NOS (iNOS or NOS2). These enzymes are heme-containing enzymes and catalyze the NADPH⫺- and O 2-dependent five-electron oxidation of L-arginine to NO and citrulline. Because of their ubiquitous expression, the NOS enzymes have a great diversity of physiological effects (7). Exogenous NO given by inhalation has been shown to have similar effects to those observed for endogenous NO, in addition to its complex interaction with the endogenous NO system. The uptake of inhaled NO by the lung, can have extrapulmonary effects in addition to its relaxing effect on pulmonary smooth muscle cells. It has been shown that inhaled NO fractions taken up by the lung approximates 70% of the inhaled fraction and 100% of the NO fraction reaching the alveolar space (8). Although the metabolism of exogenous NO is not clearly understood, it might be similar to the metabolism of endogenous NO (5). Briefly, NO diffuses passively through the alveolocapillary membrane toward the bloodstream. Then several interactions can then occur with molecules normally present in the blood. A. Interaction with Hemoglobin
Interaction with hemoglobin operates at three levels: the heme, and the α and the β chains of globin. NO binds to intracellular iron and heme-containing proteins, especially hemoglobin (Hb). NO reacts rapidly both with Fe 2⫹ and Fe 3⫹ to form nitrosyl-Hb, and this reaction limits the vasodilating effect of NO (9–11). Methemoglobin is formed when the heme iron is oxidized from Fe 2⫹ to Fe 3⫹ and NO 3 is released (12). Most of the methemoglobin is reduced back to Fe 2⫹ Hb by NADHcytochrome b5/cytochrome b5 methemoglobin reductase. In addition, reduced glutathione can reduce methemoglobin (5). The binding of NO to the β globin chain has been shown recently to occur via transnitrosation reactions with the sulfhydryl (SH) group to form S-nitrosohemoglobin (13). This reaction might be an important step for distribution of NO within the systemic circulation, and that may assist the tissue oxygenation. A dynamic cycle exists in which hemoglobin is S-nitrosylated in the lung when red blood cells are oxygenated, and the NO group is released during arterial-venous transit. These findings highlight newly discovered allosteric and electronic properties of hemoglobin that appear to be involved in the control of blood pressure and which may facilitate efficient delivery of oxygen to tissues (13).
Inhaled NO and Acute Lung Injury
907
The NO fixation in Hb α subunit has been shown to increase the hemoglobin P50 in a dose-dependent manner. Such a P50 increase facilitates oxygen diffusion to the tissue and by this mechanism, nitrates or NO donors can facilitate tissue oxygenation independently from the hemodynamic effect of NO (14). Although these effects of NO via Hb have not been proven in clinical situations, such as the application during inhaled NO, the possibility of their occurring is potentially an important additional mechanism by which NO can affect gas exchange. B. Interaction with Thiols
As mentioned above for Hb, these interactions are of major importance. NO can nitrosylate thiol groups (SH) to form S-nitrosothiols. Considering the distribution of such thiol groups in biology, one can imagine the large interactions with various proteins such bioamines (15,16), albumin, and Hb (13,14). We and others have demonstrated that serotonin (16) and angiotensin II (15) have different in vivo properties after nitrosylation and/or nitrosation. These effects may participate in the observed modifications in cardiovascular status in acute inflammation and septic shock (17). C. Interaction with DNA
These interactions of NO might be of importance during long-term administration of NO. NO can promote the formation of mutagenic nitrosamines (18) or radical nitrogen oxide species (as ONOO⫺ ) and inhibit enzymatic system necessary to repair DNA lesions (19). The role of NO in carcinogenesis is probably multidimensional. Tissues exposed for prolonged durations at high concentrations of NO with or without inflammation but in association with release of reactive oxygen species may accumulate mutations. However, as a tumor develops, NO can regulate the tumor cell growth, limit the local inflammation and the metastases, and promote apoptosis of tumor cells (20). D. Interaction with Oxygen Derivatives
These interactions are the most common in biological systems. First, NO in the gaseous phase can react with molecular oxygen to form NO 2 with a relatively slow reaction (5). In aqueous solution, NO 2 gives equal molar concentrations of NO 2 ⫺ and NO 3⫺. The final step of NO metabolism in vivo is NO 3 , which is eliminated in urine. Urinary NO 3 thus corresponds to the global metabolism of NO plus NO production by the kidney. NO interacts with reactive oxygen species (ROS) such as superoxide anion O 2 ⫺. This rapid reaction forms peroxynitrite (ONOO⫺) which is highly reactive with biological structures. Normally, ROS are scavenged and transformed by endogenous systems such as superoxide dismutase and the formation of ONOO⫺ is minimal. However, during acute inflammation with elevated concentrations of O 2 ⫺ or OH⫺, the scavenging systems cannot contain this ROS storm, and a lot of ONOO⫺ is formed. This molecule is known to have cytotoxic effects such as oxidation, peroxidation, and nitration of biologically important molecules. The classic and important
908
Payen
reaction caused by ONOO⫺ is the nitration of tyrosine and the formation of nitrotyrosine, which inhibits tyrosine phosphorylation (20,21). Nitrotyrosine has been detected in many acutely inflammed human tissues such as the lung, the skeletal muscle, and the heart. The net effect of these combinations between oxygen derivatives and NO is not always certain. Although the toxicity of ONOO⫺ is well proven, it has also been shown that ONOO⫺ is able to improve the post ischemic-reperfusion injury (22). In addition, ONOO⫺ formation has been suggested to be less damaging than O 2 ⫺, because the alternative metabolic pathways of O2–can be involved in more widespread effects. Whatever the origin of ROS, NO might play a role in scavenging ROS (22,23) in addition to its normal effect on ROS production (see below). E.
Mechanism of Vascular Actions of Inhaled NO
Most of the cardiovascular effects of NO are mediated by cyclic GMP (cGMP) release (24). cGMP results from the activation of the soluble adenylate cyclase by NO, which then transforms GTP to cyclic GMP. The physiologic actions of cGMP are regulated or controlled by its hydrolysis to GMP by a family of cyclic nucleotide phosphodiesterase isozymes, of which the types 1 and 5 hydrolyze cGMP. Type 1 phosphodiesterase also catalyzes the hydrolysis of cAMP in several tissues such as the brain, heart, lung, and testis. On the other hand, type 5 is cGMP specific with a high affinity for cGMP and can be inhibited by inhibitors like zaprinast (25,26) and dipyridamole (27).
III. NO: A ‘‘Selective’’ Pulmonary Vasodilator Since NO inhalation does not decrease normal pulmonary pressure, and only reduces vasoconstriction-induced pulmonary hypertension, NO might be considered more as an inhibitor or antivasoconstrictor rather than a pure and direct vasodilating agent (28–30). In this respect, it differs from nitroprusside, an NO donor. It was initially reported in animal models that pulmonary hypertension induced by different mechanisms (28,29) might be reversed by inhaled NO, without any detectable hemodynamic changes on the systemic side of the circulation. Consequently, the authors called NO a ‘‘selective pulmonary vasodilating agent.’’ As an example, alveolar hypoxia (29), thomboxane A 2 (31), and angiotensin II (32) induce pulmonary vasoconstriction which is totally reversed by NO inhalation. Based on this, the clinical situations with constricted pulmonary vessels became potential indications for inhaled NO. Inhaled NO selectively vasodilates pulmonary vessels and produces no systemic-induced hypotension. Inhaled NO thus can improve the right coronary perfusion pressure by decreasing right-sided pressures while maintaining perfusion pressure and thus improve the function of an ischemic compromised right ventricule (33). However, improvement in right ventricular function in association with an impaired left ventricular function may precipitate left ventricular failure (34) because the sudden increase in venous return to the LV overloads the ventricle.
Inhaled NO and Acute Lung Injury
909
This has been shown in patients (34) and has to be kept in mind before using inhaled NO. It is important to analyze the longitudinal effects of inhaled NO within the pulmonary vasculature. A differential modification of arterial and venous vascular tone can have a large influence on hydrostatic fluid exchange within the alveolocapillary barrier, especially when there is an increase in vascular permeability. Predominant pulmonary venoconstriction increases the hydrostatic filtration pressure and promotes edema formation. Selective vasodilatation acting on arterial tone may reduce the edema formation. It appears that inhaled NO at 5, 20, and 80 ppm decreases arterial, microvascular, and venous resistances to the same extent in an isolated rabbit lung model (35). This result has been confirmed in vivo in a feline model using X-ray television (36). After induction of hypoxic vasoconstriction by lobar anoxia, NO inhalation dilated smaller constricted and larger nonconstricted arteries, as well as veins. It can then be concluded that NO inhalation vasodilates similarly pulmonary arteries and veins. The selective pulmonary vasodilatation of inhaled NO depends on the delivery to ventilated areas where the inhaled NO is taken up. Furthermore, the intrapulmonary distribution of blood flow and the ventilation (Va/Q distribution) is a major determinant of oxygenation. In physiological conditions well-ventilated areas are well perfused. The oxygen shunt fraction of pulmonary blood flow is then mainly extrapulmonary and ⬍8% of total flow (37). Local alveolar hypoxia (38) or low mixed venous oxygen tension (39) induces a local hypoxic vasoconstriction that redistributes blood flow to lung regions with better ventilation and lower local vascular resistance. This helps preserve arterial PaO 2 better than is the case in the absence of hypoxic vasoconstriction (40,41). It has been proposed that inhaled NO amplifies such a mechanism of flow redistribution toward well-ventilated areas, thus improving gas exchange and particularly oxygenation. This has been demonstrated in lung injury models with VA/Q mismatch. These models have confirmed this theory and have demonstrated the beneficial effect of inhaled NO for reducing VA/Q mismatch and improving PaO 2 (42). However, a limitation to this theory has also been emphasized by Hopkins and coworkers (42). In a dog model of lung areas with low VA/ Q zones, inhaled NO increased the oxygen shunt from local blood flow and thus worsened venous admixture.
IV. NO Inhalation Impact on Bronchial Tree and Surfactant Although it has been demonstrated in animal models that inhaled NO decreases airway resistances after induced-bronchoconstriction in guinea pig (43) or in other animal species (44–46), this has not been confirmed in human acute lung injury. Surfactant is synthesized by type 2 alveolar epithelial cells and affects lung mechanics by reducing surface tension and has antimicrobial function (47). It appears that exposure of surfactant to NO ex vivo is not associated with changes in surface activity. However, in vivo, inhaled NO is associated with high inspired oxygen fractions which significantly reduce the minimum surface tension of surfactant
910
Payen
recovered by bronchoalveolar lavage. An inhibition of surfactant protein A lipid aggregation has been also shown (48), and there may also be a decrease in the gene expression of surfactant protein A.
V.
Inhaled NO in Acute Lung Injury
A. Administration (49–51)
Since the start of the application of inhaled NO therapy, many different administration systems have been used and developed. One can divide such systems in two main types: those delivering NO upstream from the ventilator, and those delivering NO downstream from the ventilator, the latter being delivered as a continuous or intermittent flow. When NO is added before the ventilator, a stable concentration is achieved, but the prolonged mixing time increases the risk of NO 2 formation. This approach is not recommended for clinical use (52). Delivery of NO with a continuous flow directly injected into the inspiratory limb may lead to poor mixing. Thus it has been suggested that high peaks of fractional NO might be delivered as a ‘‘bolus’’ to the patient (51). Thus, triggered systems have been developed to synchronize the NO delivery to the inspiratory phase. A valve linked to insuflation pressure or flow (53) opens and allows the flow of NO gas that is adapted to obtain the desired fraction. Although evidence for better mixing has not been demonstrated, these systems have the advantage of reducing costs since NO is not lost during the expiration phase (53) and therefore less NO is required. Environmental consequences of inhaled NO have also been explored especially because of the need to protect health care workers. After a fatal accident in Bristol (54), it has been proposed to use soda lime on the expiratory circuit to scavenge NO 2 . It seems that soda lime containing potassium permanganate (KMnO 4 ) removes 80% of both NO and NO 2 . Soda lime can also be used to eliminate any risk of NO contamination by NO 2 . On the other hand, the reality of a leak of NO or NO 2 into the ICU room during NO inhalation therapy with no specific precautions has been discussed. It seems that such a risk is negligible at the therapeutically used fraction of NO (55). Because of the potential toxicity of NO, monitoring of the delivered NO fraction has been recommended in many countries (52). Initially, the devices were derived from industrial use. They have been considerably improved to adapt to the medical use with a reasonable price. Two major principles are currently used: chemiluminescence and the electrochemical sensors (56). Both of these techniques are suitable for routine clinical use since the combination of an alarm containing delivery system with a monitoring system makes the NO delivery safe. Since NO is taken up by the lung and has extrapulmonary effects, it might be possible to use the uptake of NO by the lung as a parameter to monitor patients. In one study, after a breath hold of 11 sec, only 1 ppm of the 40 ppm inhaled was expired (57). Since the uptake from airways is negligible because of poor water solubility of NO, the uptake can be assumed to occur mainly at the alveolar level. Based on this analysis, in healthy
Inhaled NO and Acute Lung Injury
911
volunteers, 90% of inhaled NO is taken up from the alveolar space (57). In patients with an acute lung injury, an average of 70% of the inhaled NO fraction is taken up, but with large variations related to alveolar dead space (8). The greater the alveolar dead space, the smaller the total amount of NO retained by the lung. The major point is that the uptake of NO from ventilated and perfused alveoli is nearly 100% in both healthy volunteers and patients with ALI. Consequently, the risk of NO or NO 2 accumulation in such areas of the lung is small. Approximately, 70% of NO taken up is transformed into nitrates (NO 3 ), whereas the metabolic routes for the remaining 30% are not clearly established. As mentioned before, these are numerous possibilities for combinations of NO with other biochemical compounds which may account for some extrapulmonary effects of inhaled NO (58,59). B. Doses of Inhaled NO
The dose-response curve of inhaled NO needs to be considered. Two major effects have been evaluated for this purpose: the increase in PaO 2 and the decrease in pulmonary arterial pressure (Pap). Studies have used large ranges of inhaled fractional NO from parts per billion (ppb) to the parts per million (ppm). The first report on the beneficial effect of NO on PaO 2 in patients in ARDS was by Rossaint et al., who used two fractions of inhaled NO—18 and 36 ppm (6). Since there was no differences between these two concentrations, the same group and others explored lower doses (60,61). The maximal effect on PaO 2 and decrease in pulmonary pressure can be obtained with an NO fraction ⬍1 to 2 ppm, without further effects ⬎5 ppm. In healthy volunteers NO produced in the upper airways is autoinhaled at low concentrations (50 to 100 ppb) (62). Intubation interrupts this physiologic NO inhalation, which suggests that low dose of inhaled NO could also be considered as a replacement therapy. There is now a consensus that inhaled NO ⬎10 ppm is not advantageous for ALI patients. Interestingly, a reduction in mean pulmonary artery pressure is not necessary to obtain an improvement in PaO 2 during NO inhalation. Thus, the redistribution of pulmonary blood flow is essential for the required effect of inhaled NO on oxygenation, since a redistribution of flow can take place within the pulmonary circulation without an overall reduction in pulmonary vascular resistance. In most ALI patients, maximal oxygenation improvement occurs with 10 ppm inhaled and although there are large inter-individual variations. It is thus important to perform an individual dose-response curve in each patient before setting NO level. C. Responders/Nonresponders
Despite a logical and well-established mechanism for improvement in oxygenation, not all ALI patients respond to inhaled NO. An expert conference gave a definition of responders. For most of the authors, a patient is considered as a responder if the PaO 2 increases during NO inhalation by at least 20% from the preinhalation value. Based on this, various studies have found that ⬃60% of ALI patients are responders (63–65). Various parameters have been investigated to explain why some patients do not respond. The stage of the disease might be important since lesions can be
912
Payen
fixed and the vessels may have little reactivity (5). In addition, when dead space is large, NO reaches only a few alveoli and may not have a significant effect. Therefore, alveolar recruitment with higher levels of PEEP may augment the effect of inhaled NO (66). D. Therapeutic Associations
Based on the mechanism of hypoxia in ALI patients and of the benefit of NO inhalation on gas exchange, inhaled NO is expected to redistribute pulmonary blood flow toward aerated lung zones with inhaled NO. It thus appears logical to combine pharmacologic agents that reinforce the vasoconstriction in poorly ventilated zones with inhaled NO. Such an approach has been developed in France with bismesylate of almitrine (67,68). Although almitrine has been used for many years in COPD patients, it has also been used to reduce VA/Q mismatch in ARDS patients or ALI animals (69,70). The first cases reported associating almitrine and inhaled NO (67) showed a spectacular effect on PaO 2 . This approach has been tested in larger series of ALI patients by several groups (68,71–73) with excellent effects on PaO 2 . It is frequently possible to reduce FiO 2 and the PEEP level with this therapeutic combination. The fraction of responders with one or both of the drugs was larger than that reported with inhaled NO alone and approximated 80% (72,73). The use of all the possible interventions to support ALI patients (74) reduced the number of patients with persistant severe hypoxia. Such a strategy may include extravascular lung water reduction, alveolar recruitment, reduction of pulmonary blood flow, prone position, inhaled NO, almitrine, and thoracic drainage of gas and effusions. In this respect, inhaled NO can be considered as an additional measure to correct hypoxia but not as a fundamental curative therapy. No other drugs have been used successfully in such a combination (75). VI. Extra-Gas Exchange Effects Since inhaled NO is taken up by the lung (8), extrapulmonary effects may occur. Two major subjects have been investigated in experimental and clinical literature, and concern effects on platelets (59,76,77) and anti-inflammatory effects (22,58,78– 83). The modulation of platelet aggregation by NO is well known (84) and could have a significant impact on ALI because of the presence of microthrombi, vascular obstructions, and activation of platelets aggregation in these patients (80). Thus, inhaled NO might limit pulmonary vascular obstruction. However, this effect has not been demonstrated in clinical conditions and remains only an experimental concept. Furthermore, the downside is a potential enhanced risk of bleeding. However, no reports of hemorrhagic complications during NO inhalation have been published. The cellular inflammatory mechanisms occurring during ALI involve various types of cells. Among these, polymorphonuclear cells (PMN) play an important role (85,86). Inhaled NO may reduce pulmonary lesions during oxidative injury (78). In addition, NO reduces the rolling and the activation of PMN in different models (58,87). This may occur in ARDS patients inhaling NO at 10 ppm. PMNs from
Inhaled NO and Acute Lung Injury
913
bronchoalveolar lavage fluid after NO inhalation have been shown to produce less reactive oxygen species, cytokines and β 2 integrins compared to control patients with ARDS (79). This anti-inflammatory effect has been confirmed in lung transplantation (88) and ischemia/reperfusion injury (58). Interestingly, because of its uptake in the lung, NO may act on distant lesions. Recently, Fox Robichaud et al. demonstrated that inhaled NO may reduce gut ischemia-reperfusion injury with a reduction in white cells rolling and a better-preserved microcirculatory regional blood (58,89). Although such an effect has not been shown in humans, it means that an important impact of inhaled NO may act as a lung and extralung antiinflammatory agent.
VII. Clinical Trials on Inhaled NO in Adult ARDS Troncy et al. carried out the first single-center randomized clinical trial on inhaled NO in 30 ARDS patients. They evaluated lung function, morbidity, and mortality (90), and concluded that inhaled NO improves gas exchange but does not affect mortality (90). Their observations have been confirmed by the most recent multicenter trials (63–65). Except for an improvement in PaO 2 , all these trials failed to observe any positive effect on mechanical ventilation duration and mortality. Most of the deaths were due to a multiple-organ dysfunction syndrome. The second trial was a Phase II trial performed in the United States (63). Thirty centers were enrolled to collect data on 177 ALI patients with nonseptic etiologies, within 72 hours of the onset of ARDS. Randomization allows comparison of inhaled NO at different fractions (from 1.25 to 80 ppm) with nitrogen as a placebo. Based on an increase of at least 20% of the baseline PaO 2 , the proportion of responders was ⬇60%. Interestingly, PaO 2 improved in 24% of the control patients treated with nitrogen. There were no differences among the pooled inhaled NO groups and placebo groups in relation to mortality, the number of days alive and off mechanical ventilation, or the number of days alive meeting oxygenation criteria for extubation. Based on the trends, the authors suggested that 5 ppm might be an adequate fraction to be tested in future trials. No apparent differences in the number or type of adverse events were observed among patients receiving inhaled NO compared with placebo. Very recently, a European Phase II/III trial has been published. It included 43 centers and 268 patients with early ARDS (64). Only the NO responders were randomized to after testing different fractions (2, 10, 40 ppm) of inhaled NO. Inhaled NO was given to the lowest effective dose for up to 30 days. The primary endpoint was reversal of ALI. The frequency of reversal of ALI was not different in inhaled NO group (61%) and controls (54%), whereas development of severe ARDS was lower in the inhaled NO group (2.2% vs. 10.3% in control group; P ⬍ .05). The mortality at 30 days did not differ significantly (44% with inhaled NO vs. 40% in control patients). Inhaled NO did not increase the reversal of ALI nor change the survival rate. A second Phase III trial has been completed in France (65) in 27 centers. The primary goal was to reduce the duration of mechanical ventilation (MV). The sur-
914
Payen
vival rate at day 28 and prevention of worsening of ARDS were the secondary endpoints. After 24 hours of therapeutic optimization, ARDS patients (Murray score 2–3) were randomized to receive either 10 ppm of NO in nitrogen or placebo (nitrogen alone). Discontinuation of NO was decided when PaO 2 /FiO 2 was ⬎250 for 4 hours, with a PEEP ⱕ 10 cmH 2 O. A shift from gas A to gas B was scheduled when Murray score reached 4. Two hundred and three patients were enrolled. The proportion of patients weaned from inhaled therapy tended to be significant (P ⬍ .07) between NO group and the control group. The number of days alive and off the ventilator within the 28-day period (median 12 [inhaled NO] vs. 13.5 days [placebo]) did not differ between the two groups. The percentages of patients alive and off ventilator at day 28 day were also not different (31.6 [inhaled NO] and 34.3 [placebo]). Kaplan-Meier survival curves were not different for time evolution and for final mortality rate (day 28) (49% [inhaled NO] and 43.8% [placebo]). The proportion of patients discharged from hospital during the survey period (90 days) was similar within the two groups (54 [inhaled NO] and 50.5% [placebo]). No differences in organ failure were observed between the two groups, and no adverse effects were noted. Again, in ARDS patients (Murray score 2–3), 10 ppm of NO did not modify either duration of mechanical ventilation or 28-day mortality. In conclusion, inhaled NO in ALI/ARDS does not change outcome or the morbidity (63–65). There is no evidence for the translation of the known physiologic benefit on oxygenation to clinical benefit. The results of these three adult studies need to be contrasted to three large pediatric primary pulmonary hypertension of the newborn (PPHN) trials (91–93) where inhaled NO has been demonstrated to decrease the use of extracorporeal membrane oxygenation. Such a difference in benefits may result from the impact of the comorbidity that is low in pediatric patients and high in adults. In addition, the pediatric reports were in PPHN a relatively homogenous disease compared to the large list of diseases able to induce adult ARDS. Also, the heterogeneity of the adult patients population is high and the signal-tonoise ratio is too weak to detect benefit (94).
References 1. 2. 3. 4. 5. 6. 7.
Palmer R, Ferrige A, Moncada S. Nitric oxide release acounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327:524–526. Ignarro L, Buga G, Wood K, Byrns R, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987; 84:9265–9269. Hart CM. Nitric oxide in adult lung disease. Chest 1999; 115:1407–1417. Greene JH, Klinger JR. The efficacy of inhaled nitric oxide in the treatment of acute respiratory distress syndrome. An evidence-based medicine approach. Crit Care Clin 1998; 14: 387–409. Steudel W, Hurford WE, Zapol WM. Inhaled nitric oxide: basic biology and clinical applications. Anesthesiology 1999; 91:1090–1121. Rossaint R, Falke K, Lopez F, Slama K, Pison U, Zapol W. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328:399–405. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 1997; 48:489–509.
Inhaled NO and Acute Lung Injury 8. 9. 10. 11. 12. 13. 14. 15.
16. 17. 18. 19. 20. 21.
22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
915
Westfelt UN, Lundin S, Stenqvist O. Uptake of inhaled nitric oxide in acute lung injury. Acta Anaesthesiol Scand 1997; 41:818–823. Cooper CE. Nitric oxide and iron proteins. Biochim Biophys Acta 1999; 1411:290–309. Henry Y, Guissani A. Interactions of nitric oxide with hemoproteins: roles of nitric oxide in mitochondria. Cell Mol Life Sci 1999; 55:1003–1014. Hanson ES, Leibold EA. Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species. Gene Express 1999; 7:367–376. Tabrizi-Fard MA, Lee WI, Fung HL. Differential interactions of nitric oxide donors with rat oxyhemoglobin. Biochem Pharmacol 1999; 58:671–674. Jia L, Bonaventura C, Bonaventura J, Stamler J. S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 1996; 380:221–226. Kosaka H, Seiyama A. Elevation of oxygen release by nitroglycerin without an increase in blood flow in the hepatic microcirculation. Nature Med 1997; 3:456–459. Ducrocq C, Dendane M, Laprevote O, Serani L, Das BC, Bouchemal-Chibani N, Doan BT, Gillet B, Karim A, Carayon A, Payen D. Chemical modifications of the vasoconstrictor peptide angiotensin II by nitrogen oxides (NO, HNO2, HOONO)—evaluation by mass spectrometry. Eur J Biochem 1998; 253:146–153. Blanchard B, Dendane M, Gallard JF, Houee-Levin C, Karim A, Payen D, Launay JM, Ducrocq C. Oxidation, nitrosation, and nitration of serotonin by nitric oxide-derived nitrogen oxides: biological implications in the rat vascular system. Nitric Oxide 1997; 1:442–452. Payen D, Bernard C, Beloucif S. Nitric oxide in sepsis. Clin Chest Med 1996; 17:333–350. Tamir S, deRojas-Walker T, Wishnok JS, Tannenbaum SR. DNA damage and genotoxicity by nitric oxide. Methods Enzymol 1996; 269:230–243. Lepoivre M, Fieschi F, Coves J, Thelander L, Fontecave M. Inactivation of ribonucleotide reductase by nitric oxide. Biochem Biophys Res Commun 1991; 179:442–448. Wink DA, Vodovotz Y, Cook JA, Krishna MC, Kim S, Coffin D, DeGraff W, Deluca AM, Liebmann J, Mitchell JB. The role of nitric oxide chemistry in cancer treatment. Biochemistry (Mosc) 1998; 63:802–809. Dijkstra G, Moshage H, van Dullemen HM, de Jager-Krikken A, Tiebosch AT, Kleibeuker JH, Jansen PL, van Goor H. Expression of nitric oxide synthases and formation of nitrotyrosine and reactive oxygen species in inflammatory bowel disease. J Pathol 1998; 186:416– 421. Lefer DJ, Scalia R, Campbell B, Nossuli T, Hayward R, Salamon M, Grayson J, Lefer AM. Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemiareperfusion injury in rats. J Clin Invest 1997; 99:684–91. Isobe M, Katsuramaki T, Hirata K, Kimura H, Nagayama M, Matsuno T. Beneficial effects of inducible nitric oxide synthase inhibitor on reperfusion injury in the pig liver. Transplantation 1999; 68:803–813. Lane P, Gross SS. Cell signaling by nitric oxide. Semin Nephrol 1999; 19:215–229. Ichinose F, Adrie C, Hurford WE, Bloch KD, Zapol WM. Selective pulmonary vasodilation induced by aerosolized zaprinast. Anesthesiology 1998; 88:410–416. McMahon TJ, Ignarro LJ, Kadowitz PJ. Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed. J Appl Physiol 1993; 74:1704–1711. Ivy DD, Ziegler JW, Kinsella JP, Wiggins JW, Abman SH. Hemodynamic effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Chest 1998; 114:17S. Fratacci MD, Frostell CG, Chen TY, Wain JC Jr, Robinson DR, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology 1991; 75:990–999. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction [published erratum appears in Circulation 1991; 84(5):2212]. Circulation 1991; 83:2038–2047. Bigatello L, Hurford W, Kacmarek R, Roberts J, Zapol W. Prolonged inhalation of low concentrations of nitric oxide in patients with severe ARDS. Anesthesiology 1994; 80:761– 770. Aizawa H, Inoue H, Nakano H, Matsumoto K, Yoshida M, Fukuyama S, Koto H, Hara N. Effects of thromboxane A 2 antagonist on airway hyperresponsiveness, exhaled nitric oxide,
916
32. 33. 34.
35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
53.
Payen and induced sputum eosinophils in asthmatics. Prostaglandins Leukot Essent Fatty Acids 1998; 59:185–190. Frank DU, Horstman DJ, Rich GF. The effect of prolonged inhaled nitric oxide on pulmonary vasoconstriction in rats. Anesth Analg 1998; 87:1285–1290. Gatecel C, Mebazaa A, Kong R, Guinard N, Kermarrec N, Mateo J, Payen D. Inhaled nitric oxide improves hepatic tissue oxygenation in right ventricular failure: value of hepatic venous oxygen saturation monitoring [see comments]. Anesthesiology 1995; 82:588–590. Hare JM, Shernan SK, Body SC, Graydon E, Colucci WS, Couper GS. Influence of inhaled nitric oxide on systemic flow and ventricular filling pressure in patients receiving mechanical circulatory assistance [published erratum appears in Circulation 1997; 96(3):1065] [see comments]. Circulation 1997; 95:2250–2253. Lindeborg DM, Kavanagh BP, Van Meurs K, Pearl RG. Inhaled nitric oxide does not alter the longitudinal distribution of pulmonary vascular resistance. J Appl Physiol 1995; 78: 341–348. Shirai M, Shimouchi A, Kawaguchi AT, Sunagawa K, Ninomiya I. Inhaled nitric oxide: diameter response patterns in feline small pulmonary arteries and veins. Am J Physiol 1996; 270:H974–H980. West J, Wagner P. Ventilation-perfusion relationship. In: Crystal R, West J, eds. The Lung: Scientific Foundations. New York: Raven Press, 1991:1289–1306. Archer S, Huang J, Henry T, Peterson D, Weir E. A redox-based O 2 sensor in rat pulmonary vasculature. Circ Res 1993; 73:1100–1112. Payen D, Carli P, Brun-Buisson C, Huet Y, Teisseire B, Lemaire F. Lower body positive pressure versus dopamine during PEEP ventilation. J Appl Physiol 1985; 58:77–82. Marshall C, Marshall B. Site and sensitivity for stimulation of hypoxic pulmonary vasoconstriction. J Appl Physiol 1983; 55:711–716. Marshall B, Marshall C, Frasch F, Hanson C. Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. Intens Care Med 1994; 20:291– 297. Hopkins SR, Johnson EC, Richardson RS, Wagner H, De Rosa M, Wagner PD. Effects of inhaled nitric oxide on gas exchange in lungs with shunt or poorly ventilated areas. Am J Respir Crit Care Med 1997; 156:484–491. Dupuy P, Shore S, Drazen J, Frostell C, Hill W, Zapol W. Bronchodilator action of inhaled nitric oxide in guinea pigs. J Clin Invest 1992; 90:421–428. Hogman M, Wei SZ, Frostell C, Arnberg H, Hedenstierna G. Effects of inhaled nitric oxide on methacholine-induced bronchoconstriction: a concentration response study in rabbits. Eur Respir J 1994; 7:698–702. Hogman M, Frostell CG, Hedenstrom H, Hedenstierna G. Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis 1993; 148:1474–1478. Hogman M, Frostell C, Arnberg H, Hedenstierna G. Inhalation of nitric oxide modulates methacholine-induced bronchoconstriction in the rabbit [see comments]. Eur Respir J 1993; 6:177–180. Hallman M, Bry K. Nitric oxide and lung surfactant. Semin Perinatol 1996; 20:173–185. Ayad O, Wong HR. Nitric oxide decreases surfactant protein A gene expression in H441 cells. Crit Care Med 1998; 26: 1277–1282. Kirmse M, Hess D, Fujino Y, Kacmarek RM, Hurford WE. Delivery of inhaled nitric oxide using the Ohmeda INOvent Delivery System. Chest 1998; 113:1650–1657. Kakuya F, Takase M, Ishii N, Kajino M, Hayashi T, Miyamoto K, Muraki S, Iwamoto J, Okuno A. Inhaled nitric oxide therapy via nasopharyngeal tube in an infant with end-stage pulmonary hypertension. Acta Paediatr Jpn 1998; 40:155–158. Francoe M, Troncy E, Blaise G. Inhaled nitric oxide: technical aspects of administration and monitoring. Crit Care Med 1998; 26:782–796. Cuthbertson BH, Dellinger P, Dyar OJ, Evans TE, Higenbottam T, Latimer R, Payen D, Stott SA, Webster NR, Young JD. UK guidelines for the use of inhaled nitric oxide therapy in adult ICUs. American-European Consensus Conference on ALI/ARDS. Intens Care Med 1997; 23:1212–1218. Sieffert E, Ducros L, Losser M, Payen D. Inhaled nitric oxide fractions is influenced by both the site and the mode of administration. J Clin Monitoring 1999; 1–9.
Inhaled NO and Acute Lung Injury 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.
64. 65. 66.
67. 68. 69. 70. 71. 72. 73. 74.
917
Clutton-Brock J. Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anesthesia. Br J Anaest 1967; 39:388–392. Mourgeon E, Levesque E, Duveau C, Law-Koune JD, Charbit B, Ternissien E, Coriat P, Rouby JJ. Factors influencing indoor concentrations of nitric oxide in a Parisian intensive care unit. Am J Respir Crit Care Med 1997; 156:1692–1695. Ducros L, Thomazeau L, Payen D. Monitoring of Expired Nitric Oxide. In: Principles and Practice of Intensive Care Monitoring, M Tobin, ed. 1998:707–717. Borland CD, Higenbottam TW. A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide. Eur Respir J 1989; 2:56–63. Fox-Robichaud A, Payne D, Hasan SU, Ostrovsky L, Fairhead T, Reinhardt P, Kubes P. Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds. J Clin Invest 1998; 101:2497–2505. Kermarrec N, Zunic P, Beloucif S, Benessiano J, Drouet L, Payen D. Impact of inhaled nitric oxide on platelet aggregation and fibrinolysis in rats with endotoxic lung injury. Role of cyclic guanosine 5′-monophosphate. Am J Respir Crit Care Med 1998; 158:833–839. Gerlach H, Rossaint R, Pappert D, Falke KJ. Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome [see comments]. Eur J Clin Invest 1993; 23:499–502. Puybasset L, Rouby J, Mourgeon E, Stewart T, Cluzel P, Arthaud M, Poe`te P, Bodin L, Korinek A, Viars P. Inhaled nitric oxide in acute respiratory failure: dose-response curves. Intens Care Med 1994; 20:319–327. Gerlach H, Rossaint R, Pappert D, Knorr M, Falke KJ. Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx [see comments]. Lancet 1994; 343: 518–519. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P. 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 [see comments]. Crit Care Med 1998; 26:15–23. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intens Care Med 1999; 25:911–919. Payen D, Vallet B, Geno, A. Results of the French prospective multicentric randomized double blind placebo controlled trial on inhaled nitric oxide in ARDS. Intens Care Med 1999; 25:S166 (Abstr 647). Puybasset L, Rouby J, Mourgeon E, Cluzel P, Souhil Z, Law-Koune J, Stewart T, Devilliers C, Lu Q, Roche S, Kalfon P, Vicaut E, Viars E. Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure. Am J Respir Crit Care Med 1995; 152: 318–328. Payen DM, Gatecel C, Plaisance P. Almitrine effect on nitric oxide inhalation in adult respiratory distress syndrome [letter]. Lancet 1993; 341:1664. Wysocki M, Delclaux C, Roupie E, Langeron O, Liu N, Herman B, Lemaire F, Brochard L. Additive effect on gas exchange of inhaled nitric oxide and intravenous almitrine bismesylate in the adult respiratory distress syndrome. Intens Care Med 1994; 20:254–259. Reyes A, Roca J, Rodriguez-Roisin R, Torres A, Ussetti P, Wagner PD. Effect of almitrine on ventilation-perfusion distribution in adult respiratory distress syndrome. Am Rev Respir Dis 1988; 137:1062–1067. Romaldini H, Rodriguez-Roisin R, Wagner P, West J. Enhancement of hypoxic pulmonary vasoconstriction by almitrine in the dog. Am Rev Respir Dis 1983; 128:288–293. Jolliet P, Bulpa P, Ritz M, Ricou B, Lopez J, Chevrolet JC. Additive beneficial effects of the prone position, nitric oxide, and almitrine bismesylate on gas exchange and oxygen transport in acute respiratory distress syndrome. Crit Care Med 1997; 25:786–794. Gallart L, Lu Q, Puybasset L, Umamaheswara Rao GS, Coriat P, Rouby JJ. Intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158:1770–1777. Payen D, Muret J, Beloucif S, Gatecel C, Kermarrec N, Guinard N, Mateo J. Inhaled nitric oxide, almitrine infusion, or their coadministration as a treatment of severe hypoxemic focal lung lesions. Anesthesiology 1998; 89:1157–1165. Guinard N, Beloucif S, Gatecel C, Mateo J, Payen D. Interest of a therapeutic optimization strategy in severe ARDS [see comments]. Chest 1997; 111:1000–1007.
918 75.
76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94.
Payen Papazian L, Bregeon F, Gaillat F, Kaphan E, Thirion X, Saux P, Badier M, Gregoire R, Gouin F, Jammes Y, Auffray JP. Does norepinephrine modify the effects of inhaled nitric oxide in septic patients with acute respiratory distress syndrome? Anesthesiology 1998; 89: 1089–1098. Ho¨gman M, Frostell C, Arnberg H, Hedenstierna G. Bleeding time prolongation and NO inhalation. Lancet 1993; 341:1664–1665. Ho¨gman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G. Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiol Scand 1994; 151:125–129. Kavanagh BP, Mouchawar A, Goldsmith J, Pearl RG. Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury. J Appl Physiol 1994; 76:1324–1329. Chollet-Martin S, Gatecel C, Kermarrec N, Gougerot-Pocidalo MA, Payen DM. Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation. Am J Respir Crit Care Med 1996; 153:985–990. Kermarrec N, Chollet-Martin S, Beloucif S, Faivre V, Gougerot-Pocidalo MA, Payen DM. Alveolar neutrophil oxidative burst and beta 2 integrin expression in experimental acute pulmonary inflammation are not modified by inhaled nitric oxide. Shock 1998; 10:129–134. Lefer A. Cytoprotective actions of nitric oxide and NO-donors in ischaemia-reperfusion of coronary and splanchnic circulations. 1991. Nossuli TO, Hayward R, Jensen D, Scalia R, Lefer AM. Mechanisms of cardioprotection by peroxynitrite in myocardial ischemia and reperfusion injury. Am J Physiol 1998; 275: H509–H519. Nossuli TO, Hayward R, Scalia R, Lefer AM. Peroxynitrite reduces myocardial infarct size and preserves coronary endothelium after ischemia and reperfusion in cats. Circulation 1997; 96:2317–2324. Radomski MW, Palmer RM, Moncada S. Modulation of platelet aggregation by an Larginine–nitric oxide pathway. Trends Pharmacol Sci 1991; 12:87–88. Hogg JC. The traffic of polymorphonuclear leukocytes through pulmonary microvessels in health and disease. AJR 1994; 163:769–775. Windsor AC, Mullen PG, Fowler AA, Sugerman HJ. Role of the neutrophil in adult respiratory distress syndrome. Br J Surg 1993; 80:10–17. Kubes P, Kanwar S, Niu XF, Gaboury JP. Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells. FASEB J 1993; 7:1293–1299. Murakami S, Bacha EA, Mazmanian GM, Detruit H, Chapelier A, Dartevelle P, Herve P. Effects of various timings and concentrations of inhaled nitric oxide in lung ischemiareperfusion. Am J Respir Crit Care Med 1997; 156:454–458. Kubes P, Payne D, Grisham MB, Jourd-Heuil D, Fox-Robichaud A. Inhaled NO impacts vascular but not extravascular compartments in postischemic peripheral organs. Am J Physiol 1999; 277:H676–H682. Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med 1998; 157:1483–1488. Roberts J Jr, Fineman JR, Morin FR, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heymann MA, Zapol WM. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336:605–610. Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW, Stark AR, Kourembanas S. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1997; 100:e7. NINO Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure [published erratum appears in N Engl J Med 1997; 337(6):434]. J Pediatr 1997; 130:597–604. Payen DM. Is nitric oxide inhalation a ‘‘cosmetic’’ therapy in acute respiratory distress syndrome? [editorial; comment]. Am J Respir Crit Care Med 1998; 157:1361–1362.
36 Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn Basis for Evolving Therapeutic Guidelines
DENNIS DAVIDSON Schneider Children’s Hospital Long Island Jewish Medical Center New Hyde Park, New York
I.
Introduction
These are exciting times for investigators who have been involved in bringing nitric oxide (NO) from the laboratory bench to the bedside. The inhaled form of nitric oxide (I-NO) is used in critically ill newborns with persistent pulmonary hypertension (PPHN) as a selective pulmonary vasodilator to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO). There are approximately 10,000 newborns born in the United States annually, with a variety of underlying causes of pulmonary hypertension, who are potential beneficiaries of this novel therapy (1). So, it is fitting to the celebrate contributions by a large number and variety of scientists, epitomized by the 1998 Nobel Prize winners Drs. Furchgott, Ignarro, and Murad. In addition, it is now pleasing to have proof that extracorporeal membrane saves newborns with PPHN (2), yet this highly invasive therapy can be circumvented by I-NO for many newborns (3–5). The use of inhaled nitric oxide has been widespread throughout the United States, independent of FDA approval (December 1999). The aim of this chapter is to face these realities and provide the scientific background for evolving clinical guidelines so that I-NO is used effectively, safely, and as an adjunct to other therapy, 919
920
Davidson
tailored to the newborn’s underlying cardiopulmonary pathophysiology. A corollary aim is to consider what additional investigations we need for the future.
II. PPHN Pathophysiology: Basic and Clinical A. Disorders Underlying PPHN
Persistent pulmonary hypertension of the newborn (PPHN) can be defined as a group of acute disorders causing respiratory failure characterized by systemic hypoxemia, extrapulmonary shunting of venous blood, and evidence of elevated pulmonary artery pressure in the absence of congenital heart disease. PPHN is much more common in term and postterm infants than preterm infants. The incidences of the underlying disorders, exclusive of lung hypoplasia (e.g., congenital diaphragmatic hernia), are shown in Table 1 (6). There is little difference in the incidence of these disorders when comparing near-term and term infants with severe hypoxemic respiratory failure, from any cause, to PPHN; this is because 78% of the former category will have signs of PPHN by echocardiography (3). Only a minority (10% to 20%) of PPHN patients have the ‘‘idiopathic’’ form of PPHN, with solely pulmonary vascular disease, as initially described by Gersony et al. in 1969 (7). Usually a careful history, physical exam, chest X-ray, complete blood count, arterial blood gases, and blood culture point to the correct underlying disorder by 24 hours after birth (6). Color Doppler echocardiography plays a principal role in diagnostic and therapeutic management of infants with PPHN; its first role is to rule out masquerading cyanotic congenital heart disease such as anomalous pulmonary venous return (8) and acute myocardial injury such as papillary muscle dysfunction (9). Fatal forms of idiopathic PPHN may be a result of congenital abnormalities of the pulmonary vasculature, e.g., alveolar capillary dysplasia and pulmonary veno-occlusive disease (10). These rare disorders are usually identified only after lung biopsy or on autopsy, usually after prolonged therapy, which may include ECMO for refractory pulmonary hypertension. Alveolar capillary dysplasia may be
Table 1 Diagnoses Underlying PPHN* Diagnosis Meconium aspiration syndrome Sepsis Idiopathic Respiratory distress syndrome Other (aspiration, perinatal distress)
Incidence† (%) 53 26 21 11 19
*Excluding lung hypoplasia (e.g., congenital diaphragmatic hernia). †Patients may have ⬎1 diagnosis. Source: Ref. 6.
Persistent Pulmonary Hypertension in Newborn
921
suspected when there are other congenital anomalies, especially in the gastrointestinal tract or genitourinary tract (11,12). B. Experimental Models
An understanding of the mechanisms resulting in the normally high fetal pulmonary vascular resistance and the normal circulatory adjustments at birth is important in understanding the development and treatment of PPHN. At birth there is a 10-fold increase in pulmonary blood flow, maintenance of systemic arterial pressure, and functional followed by anatomical closure of the ductus arteriosus and foramen ovale (13,14). Systemic arterial pressure is maintained by cord clamping and the release of vasoactive substances, such as catecholamines and angiotensin II (15). The drop in pulmonary vascular resistance occurs with gaseous distension of alveoli as fetal lung fluid is removed. The retractile surface tension forces in the newly inflated airways dilates extra-alveolar arterioles (16,17). Relief of hypoxic pulmonary vasoconstriction is the other predominant mechanism for the drop in pulmonary vascular resistance, since fetal PaO2 is in the range of 20 to 30 torr (13). The role of vasoactive substances in the drop of pulmonary vascular resistance is less clear. Prostacyclin inhibition is associated with an increase in fetal pulmonary vascular resistance in acute fetal preparations (18). However, prostacyclin inhibition with indomethacin only causes mild elevation in pulmonary artery pressure upon delivery of newborn lambs (19). Within the last decade, the role of endogenous nitric oxide during fetal development and the circulatory adjustments has received increased attention (20), as summarized below. A pivotal development in research examining the pathogenesis of PPHN came from histologic studies of the pulmonary vasculature of newborns who died within several days of birth from meconium aspiration syndrome (21,22). The finding of abnormal extension of pulmonary arteriolar smooth muscle extending to the level of the acinus could only be explained by a stimulus occurring in fetal life. As a result, investigators attempted to create a variety of chronic conditions in experimental fetal animals, particularly sheep, that could lead to precocious muscularization of the fetal pulmonary vasculature (22). These models included chronic intrauterine hypoxia by hyperbaric hypoxia or embolization of the placenta, ductal constriction or ligation, chronic nitric oxide synthase blockade, and second-trimester creation of a congenital diaphragmatic hernia. The most successful and best-studied model is the fetal ductal ligation model which produces an idiopathic-type PPHN disorder upon delivery (24,25). The increase in fetal pulmonary blood flow against high resistance, with this in utero surgical intervention, leads to increased vascular shear stress followed by precocious pulmonary arteriolar muscularization. After birth there is pulmonary hypertension, severe right-to-left shunting at the foramen ovale, and the need for high levels of FIO 2 and mechanical ventilation. Selective vasodilation with I-NO in this model will lead to survival up to 24 hours (24,25). Experimental alveolar hypoxia and group B streptococcal sepsis, but not meconium aspiration, produce acute models of pulmonary hypertension. These have
922
Davidson
been useful models because of their clinical relevance and for examining the acute pulmonary hypertensive effects of mediators such as thromboxane during sepsis (26). A conclusion that the clinician can derive from these models is that when one is using I-NO for PPHN, even if one must resort to ECMO, the underlying disorder, such as regression of smooth muscle hypertrophy or eradication of infection, must be reversed before withdrawal of therapy. This helps explain the clinical observations, for example, that patients with idiopathic PPHN require 3 to 7 days of I-NO or ECMO support before pulmonary hypertension is reduced so that conventional ventilation alone can be resumed (6). A summary of the pathophysiologic mechanisms in PPHN is shown in Table 2. Over the past decade there has been increasing evidence that the NO-cyclic GMP transduction pathway plays a role in the normal circulatory adjustments at birth and the development of persistent pulmonary hypertension (20). The first report that nitric oxide, also known as endothelium-derived relaxing factor (EDRF), is physiologically present in the perinatal circulation, was described at the Society of Pediatric Research meetings at 1989 (27). At the time, inhaled nitric oxide was being used experimentally in adults with emphysema and pulmonary hypertension (28). The public suggestion, that I-NO could also be used for PPHN, was met with great skepticism and concern. This reaction was appropriate considering that before 1987 and the identification of EDRF as NO, nitric oxide was known as an air pollutant and a chemical that could cause severe airway inflammation (29,30). Further work in perinatal animals indicated that nitric oxide may play an important role in the control of fetal pulmonary vascular resistance, the increase in pulmonary blood flow a birth, and postnatal control of pulmonary vascular resistance, counterbalancing vasoconstrictor effects (31,32). In 1993 inhaled nitric oxide was shown to reduce pulmonary vascular resistance due to acute alveolar hypoxia with and without hypercarbia (33). The reduction in pulmonary vascular resistance was near maximal at 20 ppm, however a small but significant further effect was observed up to 80 ppm. Those dose-related findings were similar to results from
Table 2 Pathophysiology of PPHN Under- or overinflation of the lung Lung hypoplasia Hypoxic pulmonary vasoconstriction Myocardial dyskinesia or depressed contractility Pulmonary arteriolar smooth muscle hypertrophy/extension Pulmonary vascular constriction or ↑ reactivity secondary to: ↑ vasoconstriction production (TBX, LT, PAF, ET) ↓ vasodilator production (PGI 2, NO) ↓ smooth muscle guanylate cyclase activity TBX, Thromboxane; LT, peptidoleukotrienes; PAF, platelet activating factor; ET, endothelin 1; PGI 2 prostacyclin; PGI 2, NO, nitric oxide.
Persistent Pulmonary Hypertension in Newborn
923
human PPHN clinical trial data which showed little advantage for oxygenation by going above 20 ppm of I-NO (3,6). Detailed reviews of nitric oxide research in experimental models of PPHN, in different stages of development or under differing experimental conditions, have been the subject of several reviews including a previous chapter from Lung Biology in Health and Disease (20). However, two relatively new approaches that could lead to widespread clinical testing involve cyclic GMP phosphodiesterase inhibitors and superoxide dismutase (Fig. 1). Superoxide dismutase may theoretically reduce airway inflammation by preventing the combination of oxygen free radicals with nitric oxide to yield peroxynitrite (34). It is also theoretically possible that lower doses of I-NO maybe necessary if the short life of nitric oxide (seconds) is prolonged by impeding oxygen free radical reactions. However, recent work suggests that SOD may actually enhance the conversion of an intermediate in the L-arginine pathway,
Figure 1 Mechanism of action and metabolic fate of inhaled nitric oxide. New avenues of preclinical research that may lead to the use of lower I-NO concentrations include superoxide dismutase (SOD) and cyclic-GMP-specific phosphodiesterase inhibitors (PDEI).
924
Davidson
such as nitroxyl (HNO) to NO, as opposed to protecting NO once it is formed (35). Increasing the potency of inhaled nitric oxide, using cyclic GMP phosphodiesterase inhibition, has been demonstrated in the ductal ligation model of PPHN (23) and newborns during the postoperative period of congenital heart surgery (36). Lowdose nitric oxide may also be beneficial in preventing chronic lung disease, since nitric oxide prevents neutrophil adhesion in the pulmonary microvasculature (37). Clinical Presentation
By history, most patients with PPHN are born to mothers with antenatal and intrapartum risk factors. PPHN occurs much more frequently in the term infant than preterm infant. About 60% of PPHN patients are born by cesarean section. The 5-min Apgar scores in general are mildly depressed 7 ⫾ 2 (mean ⫾ SD). There is no predisposition by gender. The majority of patients are born outside tertiary medical centers where support has been usually started with oxygen, mechanical ventilation, induction of alkalosis, paralysis, sedation, nonspecific vasodilators, and pressors (6). On physical exam, signs of tachypnea, retractions, and cyanosis are nonspecific. The abdomen may appear scaphoid and the heart sounds may be shifted with congenital diaphragmatic hernia. When there is thoracic dystrophy or renal dysgenesis, the chest may appear small or ‘‘bell-shaped’’ on X-ray and the face may appear to have been compressed (Potter’s syndrome). Rarely, one will be able to detect differential cyanosis; only 9% of PPHN patients, moderately ill at about 1 day of age, will have a preductal versus postductal saturation of ⬎10% (6). Initially, laboratory data must be used to rule out hypoxemia, acidosis, polycythemia, hypoglycemia, or hypocalcemia, which can aggravate pulmonary hypertension or impair myocardial contractility. The chest X-ray may vary from clear lung fields (idiopathic PPHN) to bilateral consolidation (acute respiratory distress syndrome or pneumonia). Congenital diaphragmatic hernia must be differentiated from other thoracic surgical lesions such as the cystic adenoid malformation–lung sequestration spectrum. A homogeneous poorly aerated lung may suggest the need for exogenous surfactant administration (38) or an increase in mean airway pressure or a trial of high-frequency oscillation (39). The echocardiogram plays an important role in the diagnosis and treatment of PPHN. Structural congenital heart disease such as total anomalous pulmonary venous return, isolated congenital tricuspid valve dysplasia, or transposition of the great vessels can masquerade as PPHN (8). Ischemic myocardial necrosis and papillary muscle dysfunction associated with severe tricuspid or mitral insufficiency may also be seen on echocardiogram (9). The classic echocardiographic features (Fig. 2) associated with PPHN are right-to-left or bidirectional ductal and foramen ovale shunts, a regurgitant tricuspid jet in about 70% of the cases, from which systolic pulmonary artery pressure can be estimated (Bernoulli’s equation), and posterior systolic bowing of the interventricular septum (6). Poor cardiac contractility and low cardiac output may be ominous signs. The diagnosis of PPHN is usually made between 12 and 24 hours after birth. One measure of the seriousness of the underlying disease is the oxygenation index (OI),
Persistent Pulmonary Hypertension in Newborn
925
Figure 2 Persistent pulmonary hypertension of the newborn. Arrows depict abnormal circulatory patterns, including right-to-left shunting of venous blood at the ductus arteriosus (DA) and foramen ovale (FO) due to a marked elevation in pulmonary vascular resistance (PVR). There can also be tricuspid insufficiency and systolic bowing of the ventricular septum from right to left. (From Ref. 42.)
OI ⫽
Paw (cmH 2 0) ⫻ FIO 2 ⫻ 100% postductal PaO 2 (torr)
where Paw ⫽ mean airway pressure, FiO 2 ⫽ fractional inspired O 2 and PaO 2 ⫽ arterial oxygen partial pressure. The OI is probably the most common measure used because it includes work by the ventilator (Paw). Based on recent prospective data, one can estimate the need for ECMO at the time one is considering I-NO therapy. OIs of 24 and 44 are associated with an ECMO rate of 36% and 64%, respectively (3,5). These estimates are close to former retrospective studies before 1996 that projected the need for ECMO at 50% and 80% when the OIs were 25 and 40, respectively (40,41). III. Development of Inhaled Nitric Oxide for PPHN The development of inhaled nitric oxide from the laboratory bench to the bedside has been previously described in detail (42,43). Because of its high affinity for hemoglobin and short half-life, inhaled nitric oxide can be used as a selective pulmonary vasodilator, a major advantage over intravenous vasodilators such as tolazoline, prostacyclin, or nitroprusside (44–46). I-NO acutely improves oxygenation in
926
Davidson
PPHN, principally by two mechanisms: reversal of extrapulmonary right-to-left shunts, and improvement in ventilation perfusion matching (3,47,48). Other mechanisms by which I-NO could gradually improve oxygenation may be related to decreased pulmonary microvascular pressure and hydrostatic edema, as well as decreased neutrophil and platelet adhesion to the pulmonary microvasculature which result in less permeability edema (37). In 1992, prior to the widespread use of I-NO, the mortality and morbidity associated with PPHN provided ample reason for testing new therapy (49). At about this time period, the following outcome data were collected retrospectively to assist in the development of a clinical trial (6): In early-detected, moderately severe PPHN, the rate of death was 8%, ECMO was 36%, neurologic sequelae was 25%, and bronchopulmonary dysplasia was 5%. Nerve deafness both static and progressive also appeared to be increased in incidence in PPHN patients, possibly related to hyperventilation (50,51). Most PPHN patients required hyperoxia exposure (FIO 2 0.6 to 1.0) for 3 to 4 days and have severe lability in oxygenation. The usual need for mechanical ventilation was 7 ⫾ 3 days (mean ⫾ SD), supplemental oxygen 10 ⫾ 5 days, and hospitalization 18 ⫾ 5 days. Clinical research during this time period was confounded by the considerable lack of knowledge on the benefits and risks of so-called conventional therapy—e.g., hyperventilation (chronic lung disease and deafness), paralytic agents, and intravenous vasodilators (52). In addition, surfactant (53) and high-frequency ventilatory rescue (54) were becoming standard rescue therapy without definite evidence of outcome benefit or safety. The initial clinical studies by Roberts et al. (55) and Kinsella et al. (56), published in 1992, were small series which showed that I-NO markedly improved oxygenation in PPHN patients who were ECMO candidates. Subsequent studies demonstrated that concentrations of I-NO as low as 5 to 6 ppm appeared to be as effective as larger doses based on acute improvement in oxygenation and the need for ECMO appeared to decrease (57). Throughout the United States, the temptation to treat PPHN with I-NO was great and the FDA permitted many small local studies, as investigators jumped on the bandwagon. However, the call for multicentered clinical trials was heeded just in time before concerns regarding the placebo treated infants could gain ground (58). An initial concern for trial design was whether a sustained improvement in oxygenation or hard-outcome endpoints such as death or ECMO would be acceptable for the primary endpoint of clinical trials. Consensus from a combined NIH, FDA, and investigator meeting in 1994 was for a reduction in hardoutcome endpoints, such as death and/or ECMO. A concern was whether patients who met standardized ECMO criteria were in fact saved from death and long-term sequelae by ECMO (59,60). Fortunately, it became known, after the major North American trials of I-NO were completed, that ECMO does save lives without an increase in neurologic morbidity based on an adequately designed, prospective clinical trial by the U.K. Collaborative ECMO Trial Group (2). IV. Clinical Trials: Efficacy There have been four large, multicentered, placebo-controlled, double-masked, randomized clinical trials in North America without crossover therapy (3–6). Only one
Persistent Pulmonary Hypertension in Newborn
927
of these trials had a primary focus on dose response (6). A review of smaller, singlecentered trials completed before 1997 has been previously published (61). The first pivotal trial was published in 1997 and entitled Inhaled Nitric Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory Failure (3). It was supported by the Canadian Medical Research Council and the National Institute of Child Health and Human Development (3). Hypoxic respiratory failure was defined as an oxygenation index of at least 25 on two measurements made at least 15 min apart. Echocardiographic evidence for pulmonary hypertension was not required. Infants had to be eligible for ECMO, which meant that they were ⱖ34 weeks gestation. Pretreatment with surfactant and concomitant ventilation with high frequency oscillation was permitted. The primary outcome endpoint was a reduction in death and/or ECMO. At baseline, infants (N ⫽ 235) were a mean 1.7 days old and critically ill with a mean oxygenation index of 45. Seventy-eight percent of the infants had evidence of pulmonary hypertension. The I-NO group received 20 ppm with the possibility of an 80 ppm trial if an acute increase in PaO2 ⱖ 20 torr did not occur in 30 min. Very few responders were seen at 80 ppm. Although I-NO did not reduce mortality, the principal finding was that death and/or ECMO were reduced from 64% to 46% with I-NO. The trial was not designed to focus on early treatment as soon as the diagnosis was made, and when the OI was lower (less exposure to barotrauma and hyperoxia), which would have included a much broader population seen in most NICUs. In addition, the trial was not designed to study potential additive, efficacious, or adverse effects of surfactant and high-frequency ventilation. A second, strongly supportive clinical trial was also published simultaneously in 1997 and entitled Inhaled Nitric Oxide and Persistent Pulmonary Hypertension of the Newborn, by Roberts et al. (4). Term infants with PPHN having a postductal PaO 2 of ⱕ 55 torr for at least 30 min, while on conventional ventilation and FIO2 1.0, were enrolled. The primary outcome measure was improved systemic oxygenation. Patients (N ⫽ 58) had a mean OI of 46, but the exact time of baseline measurements was not given. The I-NO group received 80 ppm and then the dose was reduced progressively if treatment was successful. Treatment success was defined as a PaO 2 ⱖ55 mm Hg or OI decrease to ⱕ40 with no systemic hypotension (mean systemic blood pressure ⬍40 torr) within 20 min. A majority of the I-NO patients had a marked improvement in oxygenation. The median dose of I-NO was decreased to 20 ppm or less by 2 days. The need for ECMO was reduced from 71% in the control group to 40% in the I-NO group (P ⫽ .02). The numbers of deaths in each group were similar. Although a reduction in ECMO was not declared a primary outcome endpoint at the start of the trial, statistical purists might have trouble with the posthoc analysis of a reduction in ECMO. However, most neonatologists accept that this trial demonstrated a reduction in ECMO by I-NO, since the need for ECMO is almost always based on oxygenation criteria. The third major multicenter clinical trial, published in 1998, was entitled Inhaled Nitric Oxide for the Early Treatment of Persistent Pulmonary Hypertension of the Term Newborn: A Randomized, Double-Masked, Placebo-Controlled, DoseResponse, Multicenter Study, by Davidson et al: (5). Term infants with PPHN were enrolled as rapidly as possible. Previous administration of surfactant and concomi-
928
Davidson
tant high-frequency ventilation were not permitted because it was felt that these were unproven rescue therapies that could confound efficacy and safety interpretation (62,63). Patients received I-NO (0, 5, 20, or 80 ppm) at a constant dose until failure or success criteria were met. The primary endpoint for the trial was the development of at least one PPHN major sequelae (death, use of ECMO, neurologic sequelae or bronchopulmonary dysplasia). Secondary endpoints included a sustained improvement in oxygenation for up to 24 hours or treatment failure defined as a PaO2 ⬍40 torr for ⬎ 30 min or refractory hypotension (mean systemic arterial pressure ⬍35 torr). The baseline oxygenation index was 24 ⫾ 9 at 25 ⫾ 17 hours (mean ⫾ SD). The study was halted at N ⫽ 155 (320 planned) because of slowing enrollment. Enrollment problems could be ascribed to growing use of surfactant, high-frequency ventilation, and I-NO, as well as changing referral patterns due to economics (64). As a result, the study was underpowered to determine outcome. There was a trend toward a reduction in ECMO (34% placebo, 22% pooled I-NO group; P ⫽ .12). A statistically significant improvement in oxygenation both acute and sustained was demonstrated that was not dose related. This trial provided important dose related safety data, particularly with regard to nitrogen dioxide, methemoglobinemia, and withdrawal of I-NO. In addition, this study provided a strong rationale for attempts by others to examine early treatment of PPHN with I-NO. The last controlled multicenter trial, which became the second pivotal trial for FDA approval, was coordinated by Clark et al. (5). Patients ⱖ34 weeks’ gestation who had severe PPHN or hypoxemic respiratory failure were enrolled (OI ⱖ 25; n ⫽ 248). High-frequency oscillatory ventilation and surfactant were encouraged at baseline, at least theoretically, to optimize lung recruitment prior to randomization. The baseline oxygenation index was 41 ⫾ 21 at the age of enrollment 28 ⫾ 17 hours after birth. Therefore, these infants had severe PPHN, at or near ECMO criteria (like the ninos study), but were treated relatively early. The I-NO treatment group received 20 ppm but the patients had to be reduced to 5 ppm within 24 hours. Like all other studies there was an acute improvement in oxygenation. Survival was the same in both treatment aims but the need for ECMO was significantly lower, 64% and 38%, in the control and I-NO group, respectively. In addition the incidence of BPD was lower in the I-NO group and perhaps this secondary finding was the result of lower FIO2 and ventilator requirements. In this study, the control group had a relatively high rate of BPD (20%) because patients with congenital diaphragmatic hernia were included in the analysis. The principal outcome benefit based on the two pivotal trials leading to FDA approval is shown in Table 3. The results demonstrate that I-NO reduces ECMO by about one-third. It should be noted that this analysis excludes patients with congenital diaphragmatic hernia. On the other hand, in highly experienced hands, and in combination with other adjuncts to conventional ventilation, the need for ECMO has dropped (65) even further than predicted from the pivotal trials (3,5). It is also of interest that while the optimum starting dose is still not known based on outcome (3,5,66), a dose response was uncovered in treatment successes as they weaned off I-NO therapy (after 81 ⫾ 59 hours) between 1, 4, and 16 ppm;
Persistent Pulmonary Hypertension in Newborn
929
Table 3 Pivotal Efficacy Trial Results of I-NO for Severe PPHN or Hypoxemic Respiratory Failure: Near-Term and Term Infants
ninos (N ⫽ 235) Control I-NO Clark et al. (N ⫽ 248) Control I-NO
Death or ECMO
Death
ECMO
64% 46%*
17% 14%
55% 39%*
66% 40%*
11% 8%
64% 38%*
*Statistically significant P ⱕ .01.
there was dose-related hypoxemia when each of these doses of I-NO was discontinued (67). Studies in experimental animals suggest that 20 ppm is a reasonable starting dose (33). However, a sustained improvement in oxygenation for 24 hours in moderately ill (mean OI ⫽ 25) infants with PPHN was similar whether 5, 20, or 80 ppm dose was used. A safe but effective starting dose of 20 ppm appears to be reasonable. The use of I-NO is not approved for use in newborns ⬍34 weeks. No appreciable short-term or outcome benefit was observed in two clinical trials involving premature infants with severe hypoxemic respiratory failure (68,69). A major safety concern was that nitric oxide could potentially depress platelet adhesiveness, leading to intraventricular hemorrhage, however, this did not occur. Neither study focused on the rare premature infant with PPHN who has relatively clear lung fields and echocardiograms demonstrating significant extrapulmonary right-to-left shunting. It could be argued that inhaled nitric oxide should be used for this rare idiopathic form of PPHN in premature infants. However, it is suggested that I-NO be used only after the echocardiogram is analyzed and only if a high oxygenation index (⬎15) persists after conventional lung recruitment strategies fails, until further studies are available. V.
Safety Considerations
Other than methemoglobinemia and elevated inspired NO2 levels when I-NO is used at 80 ppm, there was no apparent adverse effects of I-NO in the multicenter clinical trials (3–6). However, there are several clarifications required by this statement. First we do not have good information regarding the use of I-NO beyond the usual course of treatment which is 81 ⫾ 59 hours (6), particularly its effect on lung function (70). In addition, there still may not be an adequate cumulative sample size to uncover certain serious adverse events of low frequency, and long-term follow-up studies need careful review. Finally, there may be new safety concerns that develop when inhaled nitric oxide use becomes widespread and away from the immediate safety net of ECMO (67).
930
Davidson
Nitrogen dioxide (NO 2 ) levels are proportional to the second power of the inspired NO concentration and to the first power of the inspired oxygen concentration (71). In particular, the dose of I-NO and the volume of the inspiratory line distal to the entry site of the stock NO gas in nitrogen, including the humidifier, must be kept to a minimum. It is theoretically possible that higher levels of NO 2 may be found in the lungs of infants who receive NO with high-frequency ventilation, an area that needs further investigation (72). Only one study has systematically examined dose-related effects of I-NO on inspired NO2 levels using a conventional ventilator and electrochemical measuring techniques (6). Figure 3 demonstrates the INO at 80 ppm could result in NO 2 levels above safety standards—i.e., ⬎ 3 ppm exposure of NO 2 for ⬎ 8 hours (73). In Figure 3, the apparent decline in NO 2 levels several hours after starting I-NO at 80 ppm is because the trial mandated a lowering of the treatment gas concentration if the NO 2 level was ⬎3 ppm or the methemoglobin was elevated (methemoglobinemia is a common side effect at I-NO 80 ppm). Note that NO 2 values remained at a low level when I-NO of ⱕ20 ppm was used. In fact, part of the elevated NO 2 levels that were observed may be somewhat artificial because the electrochemical techniques overestimate NO 2 levels because of NO 2 formation in the sampling circuit (74). NO 2 at low doses and NO and peroxynitrite have been implicated in the development of lung injury in experimental animals; however, pulmonary toxicity in human newborns exposed to I-NO ⬍ 10 days has not been documented (5). Methemoglobin production as a function of I-NO dose has been studied systematically in only one study, as shown in Figure 4 (5). The study design mandated a reduction in the fixed treatment gas concentration if the methemoglobin levels rose ⬎ 7%. Upon completion of the study, it was noted that one-third
Figure 3 Inspired NO 2 levels at baseline and during the administration of treatment gases (control ⫽ 0 ppm of I-NO, NO ⫽ 5, 20, or 80 ppm) for up to 12 hours in term infants with PPHN. For one-third of the patients in the 80 ppm group, reductions in treatment gas concentrations were mandated by protocol because of methemoglobinemia at a median of 8 hours. (From Ref. 6.)
Persistent Pulmonary Hypertension in Newborn
931
Figure 4 Methemoglobin levels at baseline and during the administration of treatment gases (control ⫽ 0 ppm of I-NO) for up to 2 days in term infants with PPHN. All study sites used the same co-oximetry equipment for measuring methemoglobin. If methemoglobin levels increased above 7%, investigators were permitted to reduce the treatment gas by specific decrements. (From Ref. 6.)
of the patients in the 80 ppm group developed methemoglobin levels ⬎7% at a median of 8 hours after starting the treatment gas. The apparent reduction in methemoglobin levels for this group, after 10 hours, was due to the required reduction in study gas concentration once 7% methemoglobin was reached. Methemoglobin levels generally remained at clinically insignificant levels (⬍2%) if I-NO was used at ⱕ20 ppm. Bleeding complications secondary to a reduction in platelet adhesiveness and platelet aggregation, resulting in increased bleeding time (75,76), have not been observed in neonatal clinical trials involving near-term and term infants. Clinical trials in term and preterm newborns showed no increased incidence of intracranial hemorrhage as a result of I-NO at ⱕ20 ppm (3,5,68,69). Since patients with severe PPHN have about a 12% rate of severe neurodevelopmental disability, as well as increased incidence of reactive airway disease and slow growth (77), it will be of great interest to determine if I-NO has a beneficial long-term outcome effect. Preliminary findings from one large controlled study (5,78) indicate that there are no 1-year neurodevelopmental or medical (and specifically pulmonary) complications from the use of I-NO for the early treatment of moderately severe PPHN in term infants. Finally, there is one important safety issue that may become important as INO therapy use becomes more available—the hidden mortality and morbidity associated with withdrawal of I-NO on or before transport to ECMO centers. It has been previously shown (before the I-NO era), that there is a hidden mortality rate associated with extracorporeal membrane oxygenation due to a failure to transfer PPHN patients at an appropriate time (79). For treatment failures, patients at or near ECMO criteria, discontinuing I-NO could lead to life-threatening hypoxemia, based on
932
Davidson
unique data from a randomized, controlled, double-masked multicenter clinical trial (67) (Fig. 5). Therefore even if there did not seem to be any apparent effect of INO after ⬎4 hours of therapy, it may be detrimental to stop I-NO immediately prior to transport. On the one hand, it is now known that for treatment successes (infants who have been treated with I-NO resulting in a sustained reduction in OI ⬍10), either a slow wean in I-NO dose down to 1 ppm or an increase in FIO 2 can prevent acute hypoxemia when I-NO is discontinued (67,80) (Fig. 6). An example of withdrawal from I-NO after treatment failure is seen in Figure 7. This moderately ill newborn with meconium aspiration, on conventional ventilation, had an early response to a treatment gas (subsequently unmasked as 5 ppm INO) based on the drop in OI. After 12 hours, the oxygenation status began to worsen and the infant had to be taken off I-NO when treatment failure criteria were met (PaO 2 ⬍ 40 torr for ⱖ30 min). An appreciable worsening in oxygenation, above an OI of 40 occurred, was reversed partially by high-frequency conventional ventilation and surfactant until the patient reached an ECMO center. Had the patient been on high-frequency oscillatory ventilation and inhaled nitric oxide (39) and still deteriorated, one would have probably seen an even greater increase in OI, after switching the patient to conventional ventilation for transport.
Figure 5 Percent change in oxygenation index on withdrawal of placebo or nitric oxide study gas (initial dose of 5, 20, or 80 ppm) in PPHN patients declared treatment failures. Patients met treatment failure criteria when the PaO 2 was ⬍40 mm Hg for 30 min and/or mean systemic arterial pressure was ⬍35 mm Hg. At the final step in this masked withdrawal protocol, patients were at 0, 1, 4, or 16 ppm. Oxygenation was assessed at the start and 30 min after the end of the withdrawal protocol. (From Ref. 67).
Persistent Pulmonary Hypertension in Newborn
933
Figure 6 Changes in PaO 2 (no ventilator changes) 30 min after cessation of inhaled nitric oxide treatment gas (masked) in patients with PPHN treated successfully. Treatment success criteria were defined as FIO 2 ⬍0.6, mean airway pressure ⬍10 cmH2O, and a postductal PaO 2 ⱖ60 mmHg. (From Ref. 67.)
Although transport systems with inhaled nitric oxide may prevent severe hypoxemia before ECMO (81), consensus is needed as to when PPHN patients on INO should be transferred. Based on the one study (67), it has been suggested that deterioration in OI to ⬎30 on I-NO should be one of the factors leading to the decision to transfer for possible ECMO. Dipyridamole has been used to attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease (36). However, dipyridamole is not specific for the pulmonary circulation and therefore it can be potentially hazardous to a PPHN patient if there is underlying sepsis or hypotension. Furthermore, interference with platelet function before going on to ECMO could result in safety issues related to hemorrhage. The problem of late transfer to ECMO centers was recognized almost a decade ago prior to the development of inhaled nitric oxide for PPHN (79). It is likely that the increasing use of I-NO at non-ECMO centers will raise this important safety issue again. VI. Disease-Related Responses to I-NO With the completion of most major trials and the widespread use of I-NO, attention is starting to focus on predicting response, particularly which infants will become treatment failures and require ECMO. To some degree, predicting response may
934
Davidson
change over time with the increasing acceptance of adjunctive therapy such as surfactant, high-frequency ventilation, as well as modifications of conventional ventilatory techniques. But this issue will always be important because most newborns with PPHN are born and initially managed at non-ECMO centers. Even when there may be an early initial response to I-NO, this may not be predictive of the need for ECMO as exemplified in Figure 7. Based on recent clinical trials, some answers regarding prediction of successful therapy are starting to emerge. First, congenital diaphragmatic hernia is still a serious problem for which I-NO therapy has a limited value. The largest trial to address this issue was published in 1997 by the NICHD Neonatal Research Network and the Canadian I-NO Study Group (ninos) (82). This project evaluated I-NO for hypoxic respiratory failure in infants with congenital diaphragmatic hernia and whether death and/or ECMO could be reduced. This was a particularly difficult study to perform because the incidence of congenital diaphragmatic hernia is one in every 3000 to 4000 deliveries. The infants are usually extremely ill because of lung hypoplasia, possible surfactant deficiency, pulmonary hypertension, and sometimes left ventricular underdevelopment. In this study the baseline OI was about 45. The median age for starting I-NO was about 12 hours after birth. I-NO did not
Figure 7 Time course of change in oxygenation index for a 12-hour-old term infant with meconium aspiration syndrome and PPHN. The patient was treated with conventional ventilation and a treatment gas; later unmasking revealed I-NO at 5 ppm. There was an initial significant reduction in oxygenation index. However, after 12 hours of therapy, a deterioration in oxygenation index, followed by severe rebound off nitric oxide, occurred prior to transport for ECMO.
Persistent Pulmonary Hypertension in Newborn
935
produce an improvement in oxygenation or reduction in death and/or ECMO (82% control, 96% I-NO). Although the trial was small (N ⫽ 53), the trial did have sufficient power to reject a 25% reduction in primary outcome. Although the ninos trial found no benefit of I-NO therapy for congenital diaphragmatic hernia (CDH), there have been case reports form individual centers suggesting that early I-NO therapy combined with optimal lung recruitment strategies may result in a marked improvement in oxygenation for the infants (57). If such a positive response is observed, the patient can be non emergently placed on ECMO or the hernia repair can be delayed for about a week when rebound pulmonary hypertension after surgical repair may be less problematic (83). An example of such a successful case in which surgery was delayed 7 days and ECMO could be avoided, is depicted in Figure 8. The combination of I-NO and HFOV produced a marked improvement in oxygenation. However, these isolated case reports are most likely to be the exception rather than the rule and the neonatologist must be aware that the use of I-NO for CDH at a non-ECMO center may involve considerable risk. Some centers have also found that I-NO is useful in helping CDH patients wean off ECMO if the run becomes prolonged (several weeks) and the apparent risks outweigh the benefits, even if there was no previous response to I-NO before ECMO (84). In spite of apparent successes in treating some CDH patients with I-NO, the overall mortality rate (85) for correctable lesions is about 58%, but this value is probably the high range because it is based on data up to 1995 and data are only
Figure 8 Oxygenation index after birth in a term infant with congenital diaphragmatic hernia and severe persistent pulmonary hypertension. There was no initial improvement with I-NO. After adding high-frequency oscillatory ventilation there was improvement followed by deterioration until an optimal strategy was found 6 to 10 hours after birth. By 11 hours the combination of I-NO and HFOV substantially reduced the risk for ECMO (using historical criteria). Late surgical repair was successful at 5 days of age.
936
Davidson
from ECMO centers. Still, it is recommended that all patients with an antenatal diagnosis of CDH be born in an ECMO center. Another new area for investigation is the perioperative use of I-NO for CDH patients who have received ECMO and are undergoing a late repair. We recently had an infant with CDH who required a long ECMO run but still had systemic levels of pulmonary hypertension on moderately low ventilatory support after ECMO and before repair (Fig. 9). In order to prevent a pulmonary hypertensive crisis either during or after repair, we measured tricuspid insufficiency jet velocity as an index of pulmonary artery pressure and found a submaximal dose of I-NO (10 ppm) which profoundly lowered pulmonary artery pressure. Patients with certain diagnoses of PPHN (other than CDH) may have a better outcome using optimal lung recruitment combined with I-NO therapy. This was demonstrated in an important study entitled A Randomized, Multicenter Trial of Inhaled Nitric Oxide and High Frequency Oscillatory Ventilation in Severe Persistent Pulmonary Hypertension of the Newborn, by Kinsella et al. (39). This was a multicenter trial with 205 newborns that were stratified by predominant disease category underlying PPHN. Patients were then assigned to high-frequency oscillatory ventilation or conventional ventilation combined with inhaled nitric oxide. An acute improvement in PaO 2 determined whether a patient was kept on the initial therapy or crossed over to the other therapy. After the first crossover all subsequent nonresponders received high frequency oscillatory ventilation with I-NO. These patients
Figure 9 Reduction in pulmonary hypertension by I-NO during the late repair of a term infant with congenital diaphragmatic hernia. Initially there was no reduction in pulmonary artery pressure with I-NO at 20 ppm. After ECMO, pulmonary hypertension persisted (day 17) on low ventilator requirements but now I-NO reduced pulmonary hypertension (tricuspid regurgitant jet on ECHO) in a dose-dependent fashion (10 ppm, maximum response) before surgical repair on day 19.
Persistent Pulmonary Hypertension in Newborn
937
were treated relatively early, about 25 hours after birth, yet they were severely ill with baseline oxygenation indices averaging about 48. Sixty percent responded— that is, no death and/or need for ECMO. Statistically significant benefit was observed for the respiratory distress and meconium aspiration syndrome patients when the combination of HVOF and I-NO therapy was used. Although criticized because of crossover methodology, this study suggested an important clinical principle; inflate the lung optimally, then selectively dilate the pulmonary circulation and for the best results tailor therapy to the underlying disorder. However, non-ECMO centers have to be cautious if the patient has an initial improvement in oxygenation on I-NO and HFOV and then fails; HFOV is generally not available on transport, and the additive effect of HFOV and I-NO could be lost before the baby can receive ECMO. We still do not know whether we can predict outcome with more reliability when we start inhaled nitric oxide for PPHN at or below an oxygenation index of 25 and within the first 12 hours of life. We need to know if an acute increase in PaO 2 with inhaled nitric oxide on conventional ventilation is predictive of outcome. We need to know if clear lung fields versus bilaterally opacified lungs on the baseline chest X-ray is predictive of outcome. One way to get these answers may be to combine data from the four major randomized, masked, noncrossover multicentered trials and the I-NO registry.
VII. Conclusion Inhaled nitric oxide is a selective pulmonary vasodilator, which serves as a useful adjunct to current respiratory therapies for near-term, term and postterm infants with hypoxemic respiratory failure and persistent pulmonary hypertension of the newborn. Specifically, I-NO appears to reduce the need for ECMO in some patients. The greatest success likely will be observed (65) in NICUs with large experiences, familiarity with combining I-NO and high-frequency oscillatory ventilation, availability of serial echocardiography, personnel who can provide round-theclock meticulous care, and the ECMO safety net. Now that there is a consensus among neonatologists that there is objective evidence that ECMO saves lives and may improve long-term outcome (2), the claim that I-NO therapy reduces ECMO can be seen as an important advance. It is likely that there are other important benefits related to I-NO therapy which are difficult to measure—for example, the usefulness of sustaining oxygenation as a bridge to ECMO and the effect of a sustained improvement in oxygenation leading to less reliance on potentially hazardous therapy such as hyperventilation and hypocarbia, paralytic agents, and nonspecific vasodilators requiring counterbalance by pressors. We must be cautious about using inhaled nitric oxide in an overly zealous fashion. We still do not know whether I-NO has a benefit when it is started at an OI ⬍25. We do not know if there are short- and long-term adverse effects if we use I-NO beyond 7 to 10 days. In addition, we must be cautious about the use of inhaled nitric oxide giving a sense of false security at non-ECMO centers. Availabil-
938
Davidson
ity of I-NO for transport and guidelines for establishing when a patient should be moved to an ECMO center must be established at all non-ECMO centers. Future studies are needed in a number of areas. Using data from the large masked multicentered trials and the I-NO registry, we have the opportunity to better define predictors of the need for ECMO (e.g., acute changes in oxygenation, chest X-ray, or underlying diagnoses). Further basic research is needed to determine whether I-NO therapy can be safely and selectively enhanced by phosphodiesterase inhibitors (86), superoxide dismutase (87), surfactant, or perfluorocarbon liquid. The results of new research efforts and long-term follow-up from the major clinical trials need careful evaluation. With the recent approval of I-NO for the treatment of near-term and term infants with hypoxemic respiratory failure or PPHN, we need to pause momentarily to translate today’s clinical trial findings into practice guidelines. Table 4 provides suggested guidelines based on the background and evidence for the effective and safe use of inhaled nitric oxide therapy, described in this chapter. Until further re-
Table 4 Suggested Guidelines for I-NO Therapy in the Newborn Indications PPHN or hypoxemic respiratory failure, ⱖ 34 weeks gestational age OI ⱖ 15, reversible pulmonary disorder Echocardiogram that shows no evidence of congenital heart disease (CHD) Contraindications Ductal-dependent CHD with R → L shunting or pulmonary venous obstruction High baseline methemoglobin (⬎5%) levels Dose Start at 20 ppm with optimal lung inflation strategies and cardiovascular support ⬎20 ppm rarely needed Lower dose (1–5 ppm steps) after a sustained improvement in oxygenation (24–48 hours) to 5 ppm Serial echocardiograms useful (tricuspid regurgitant jet) Duration Usually 2–6 days, experience ⱖ7 days is limited Precautions Does not reduce need for ECMO with CDH, may stabilize before cannulation Keep MetHgb ⬍5% by reducing I-NO, check q4 hours then q12 when stable Keep NO 2 ⬍0.5 ppm by reducing I-NO, minimize dead space on inspiratory side Additive effect on oxygenation with I-NO and HFOV may be lost if I-NO and conventional ventilation used on transport Phosphodiesterase inhibition of cGMP (safety unproven) Discontinuation Treatment successes on I-NO (OI ⬍ 10, ⱖ4 hours, usually 2–6 days of I-NO): wean gradually to 1 ppm then 0 ppm to avoid hypoxemia Treatment failure on I-NO at non-ECMO center (OI ⬎30, 1⬎ I-NO trial hours ⬍6): transport on I-NO; discontinuation may be life-threatening even if no apparent benefit
Persistent Pulmonary Hypertension in Newborn
939
search is performed, it is hoped that these recommendations will be useful to the neonatologist at the bedside.
Acknowledgement This chapter is dedicated to Diane, Ryan, Kate, Eric, Julie, and David Davidson.
References 1. 2. 3. 4.
5.
6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Linde-Zwirble WT, Angus DC, Clermont G, Roberts MS, Coleman MB, Newbold RC, Goldstein M, Pinsky MR. Diagnoses associated with the delivery of mechanical ventilation in the newborn. Pediatr Res 1997; 41:202A. UK Collaborative ECMO Trial Group. UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348:75–82. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336:597–604. Roberts JD, Fineman JR, Morin III FC, Shaul PW, Rimer S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Hemann MA, Zapol WM, Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336:605–610. Clark RH, Kueser TJ, Walker MW, Southgate M, Huckaby JL, Perez JA, Roy BJ, Keszler M, Kinsella JP, Clinical Inhaled Nitric Oxide Research Group. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000; 342:469– 474. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang CT, I-NO/PPHN Study Group. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics 1998; 101:325–334. Gersony WM, Duc GV, Sinclair JC. ‘PFC’ syndrome (persistence of the fetal circulation). Circulation 1969; 40(suppl 3):87. Abstract. Long WA. Structural cardiovascular abnormalities presenting as persistent pulmonary hypertension of the newborn. Clin-Perinatol 1984; 11:601–626. Donnelly WH. Ischemic myocardial necrosis and papillary muscle dysfunction in infants and children. Am J Cardiovasc Pathol 1987; 1:173–188. Steinhorn RH, Cox PN, Fineman JR, Finer NN, Rosenberg EM, Silver MM, Tyebkhan J, Zwass MS, Marin FC 3rd. Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia. J Pediatr 1997; 130:417–422. Vassal HB, Malone M, Petros AJ, Winter RM. Familial persistent pulmonary hypertension of the newborn resulting form misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia). J Med Genet 1998; 35:58–60. Cullinane C, Cox PN, Silver MM. Persistent pulmonary hypertension of the newborn due to alveolar capillary dysplasia. Pediatr Pathol 1992; 12:499–514. Cassin S, Dawes GS, Mott JC, Ross BB, Strang LB. Vascular resistance of the foetal and newly ventilated lung of the lamb. J Physiol 1964; 171:61–79. Heymann MA, Soifer SJ. Control of fetal and neonatal pulmonary circulation. In: Weir EK, Reeves JT, eds. Pulmonary Vascular Physiology and Pathophysiology. New York: Marcel Dekker, 1989:33–50. Davidson D. Circulating vasoactive substances and the hemodynamic adjustments at birth in lambs. J Appl Physiol 1987; 63:676–684. Enhorning G, Adams FH, Norman A. Effect of lung expansion on the fetal lamb circulation. Acta Paediatr Scand 1966; 55:441–451.
940 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.
Davidson Walker AM, Ritchie BC, Adamson TM, Maloney JE. Effects of changing lung liquid volume on the pulmonary circulation of fetal lambs. J Appl Physiol 1988; 64:61–67. Leffler CW, Tyler TL, Cassin S. Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats. Am J Physiol 1978; 234:H346-H351. Davidson D. Pulmonary hemodynamics at birth: Effect of acute cyclo-oxygenase inhibition in lambs. J Appl Physiol 1988; 64:1676–1682. Roberts JD, Kinsella JP, Abman SH. Inhaled nitric oxide in neonatal pulmonary hypertension and severe respiratory distress syndrome: experimental and clinical studies. In: Zapol WM, Block KD, eds. Nitric Oxide and the Lung. New York: Marcel Dekker, 1997; 333–357. Murphy J, Vawter G, Reid L. Pulmonary vascular disease in fatal meconium aspiration. J Pediatr 1984; 104:758–762. Haworth SG. Pulmonary vascular remodeling in neonatal pulmonary hypertension: state of the art. Chest 1988; 93:133S. Steinhorn RH, Morin FC, Fineman JR. Models of persistent pulmonary hypertension of the newborn (PPHN) and the role of cyclic guanosine monophosphate in pulmonary vasorelaxation. Semin Perinatol 1997; 21:393–408. Zayek M, Cleveland D, Morin FC. Treatment of persistent pulmonary hypertension of the newborn lamb by inhaled NO. J Pediatr 1993; 122:743–750. Zayek M, Wild L, Roberts JD, Cleveland D, Morin FC. Effect of NO on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension. J Pediatr 1993; 123:947–952. Truog WE, Sorensen GK, Standaert TA, Redding GJ. Effects of thromboxane inhibitor, dazmegrel (UK 38,485), on pulmonary gas exchange and hemodynamics in neonatal sepsis. Pediatr Res 1986; 20:481–486. Davidson D, Eldemerdash A. Endothelium-derived relaxing factor: presence in pulmonary and systemic arteries of the newborn guinea pig. Pediatr Res 1990; 27:128–132. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan At, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991; 338:1173–1174. Epler GR. Silo-fillers disease: a new perspective. Mayo Clin Proc 1989; 64:368–370. Frampton MW, Morrow PE, Cox C, Gibb FR, Speers DM, Utell MJ. Effects of nitrogen dioxide exposure on pulmonary function and airway reactivity in normal humans. Am Rev Respir Dis 1991; 143:522–527. Davidson D, Eldemerdash A. Endothelium-derived relaxing factor: evidence that it regulates pulmonary vascular resistance in the isolated neonatal guinea pig lung. Pediatr Res 1991; 29:538–542. Abman SH, Chatfield BA, Hall SL, McMurtly IF. Role of endothelium-derived relaxing factor during transition of the pulmonary circulation at birth. Am J Physiol 1990; 259: H1921-H1927. Roberts JF, Chen T, Kawar N, Wain J, Dupuy P, Shimouchi A, Block K, Polaner D, Zapol WM. Inhaled NO reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circ Res 1993; 72:246–254. Robbins CG, Horowitz S, Merritt TA, Kheiter A, Tierney J, Narula P, Davis JM. Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia. Am J Physiol 1997; 272:L903-L907. Hobbs AJ, Fokuto JM, Ignarro LJ. Formation of free nitric oxide from l-arginine by nitric oxide synthase: direct enhancement of generators by superoxide dismutase. Proc Natl Acad Sci USA 1994; 91:10992–10996. Ivy DD, Kinsella JP, Ziegler JW, Abman SH. Dipyridamole attenuates rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease. J Thorac Cardiovasc Surg 1988; 115:875–882. Kinsella JP, Parker TA, Galan H, Sheridan BC, Halbower AC, Abman SH. Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease. Pediatr Res 1997; 41:457–463. Lotze A, Mitchell BR, Bolas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr 1998; 132:40–47.
Persistent Pulmonary Hypertension in Newborn 39.
40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61.
941
Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, Redding, GJ, deLemos RA, Sardesai S, McCornin DC, Moreland SG, Cotter GR, Abman SH. Randomized, multicenter trial of inhaled nitric oxide and high frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 1997; 131:55–62. Ichiba S, Bartlett RH. Current status of extracorporeal membrane oxygenation for severe respiratory failure. Artif Organs 1996; 20:120–123. Schumacher RE, Roloff DW, Chapman R, Snedecor S, Bartlett RH. Extracorporeal membrane oxygenation in term newborns. A prospective cost benefit analysis. ASAIO-J 1993; 39:873–879. Davidson D. Nitric oxide from bench to bedside: a perinatal perspective. Part I. Int J OB Anesth 1996; 5:181–188. Davidson D. Nitric oxide from bench to bedside: A perinatal perspective–Part II. Int J OB Anesth 1996; 5:244–253. Ichinose F, Horford WE, Zapol WM. Evaluation of inhaled nitric oxide in experimental models of lung injury. In: Zapol WM, Bloch KD, eds. Nitric Oxide and the Lung. New York: Marcel Dekker, 1997:333–357. Goetzman B, Sunshine P, Johnson J, Wennberg RP, Hackel A, Merten DF, Bartoletti AL, Silverman NH. Neonatal hypoxia and vasospasm: response to tolazoline. J Pediatr 1996; 89:617-621. Stevenson D, Kastings D, Darnall RA, Ariagno RL, Johnson JD, Malachowski N, Beets Cl, Sunshine B. Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr 1979; 95:595–599. Roze´ JC, Storme L, Zupan V, Morville P, Dinh-Xuan AT, Mercier JC. Echocardiographic investigation of inhaled nitric oxide in newborns with severe hypoxemia. Lancet 1994; 344: 303–305. Ochikubo CG, Waffarn F, Turbow R, Kanakriyeh M. Echocardiographic evidence of improved hemodynamics during inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatr Cardiol 1997; 18:282–287. Weigel TJ, Hageman JR. National survey of diagnosis and management of persistent pulmonary hypertension of the newborn. J Perinatol 1990; 10:369–375. Bifano EM, Pfannenstiel A. Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatrics 1988; 81:657–661. Hendricks-Munoz KD, Walton JP. Hearing loss in infants with persistent fetal circulation. Pediatrics 1988; 20:147–150. Sahni R, Wung JT, James LS. Controversies in management of persistent pulmonary hypertension of the newborn. Pediatrics 1994; 94:307–309. Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996; 97:48–52. Clark RH, Yoder BA, Sell MS. Prospective randomized comparison of high-frequency oscillaiton and conventional ventilaiton in candidates for extracorporeal membrane oxygenation. J Pediatr 1994; 124:447–454. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:818–819. Kinsella JP, Neish SR, Schaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:819–820. Kinsella JP, Neish SR, Ivy DD, Schaffer E, Abman SH. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr 1993; 123:103–108. Davidson D. NO bandwagon, yet: inhaled nitric oxide (NO) for neonatal pulmonary hypertension. Am Rev Respir Dis 1993; 147:1078–1079. Short BL, Miller MK, Anderson KD. Extracorporeal membrane oxygenation in the management of respiratory failure in the newborn. Clin Perinatol 1987; 14:737–748. Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76:488–494. Finer NN, Barrington KJ. Nitric oxide in respiratory failure in the newborn infant. Semin Perinatol 1997; 21:426–440.
942 62. 63. 64. 65. 66. 67. 68.
69. 70. 71. 72. 73. 74.
75. 76. 77. 78.
79. 80. 81. 82. 83.
Davidson Wiswell TE, Graziani LJ, Kornhauser MS, Cullen J, Merton DA, McKee L, Spitzer AR. High frequency jet ventilation in the early management of respiratory distress syndrome is associated with a greater risk of adverse outcomes. Pediatrics 1996; 98:1035–1043. Auten RL, Notler RH, Kendig JJJW, Davis JM, Shapiro DL. Surfactant treatment of fullterm newborns with respiratory failure. Pediatrics 1991; 887:101–107. Stark AR, Davidson D. Inhaled nitric oxide for persistent pulmonary hypertension of the newborn: implications and strategy for future ‘‘high-tech’’ neonatal clinical trials. Pediatrics 1995; 96:1147–1151. Kennaugh JM, Kinsella JP, Abman SH, Hernandez JA, Moreland SG, Rosenberg AA. Impact of new treatments for neonatal pulmonary hypertension on extracorporeal membrane oxygenation use and outcome. J Perinatol 1997; 17:366–369. Finer NN, Etches PC, Kamstra B, Tierney AJ, Peliowski A, Ryan CA. Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response. J Pediatr 1994; 124:302–308. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Straube R, Rhines J, Chang CT, INO/PPHN Study Group. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999; 104:231–236. Kinsella JP, Walsh WF, Bose CL, Gerstmann DR, Labella JJ, Sardesai S, Walsh-Sukys MC, McCaffrey MJ, Cornfield DN, Bhutani VK, Cutler GR, Baier M, Abman SH. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet 1999; 354:1066–1071. Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. Lancet 1999; 354:1066–1071. Hallman M. Molecular interactions between nitric oxide and lung surfactant. Biol Neonate 1997; 71:44–48. Foubert L, Flemking B, Latimer R, Jonas M, Oduro A, Borland C, Higenbottam T. Safety guidelines for use of nitric oxide. Lancet 1992; 339:1615–1616. Shibata Y, Okamoto K, Kokita I, Kikuta K, Sato T. The safety of a nitric oxide inhalation system with high frequency ventilation. Acta Paediatr Jpn 1997; 39:176–180. Centers for Disease Control. Recommendations for occupational safety and health standards. MMWR 1988; 37:21. Sokol GM, Van Meura KP, Thorn WJ. Limitations in nitrogen dioxide measurement with commercially available analyzers. Paper presented at 12th Annual Children’s National Medical Center Symposium on ECMO and Advanced Therapies for Respiratory Failure, Keystone, CO, 1996. Abstract 71. Cheung PY, Salas E, Schulz, R, Radomski MW. Nitric oxide and platelet function: implications for neonatology. Semin Perinatol 1997; 21:409–417. George TN, Johnson KJ, Bates JN, Segar JL. The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates. J Pediatr 1998; 132;731–734. Rosenberg AA, Kennaugh JM, Moreland SG, Fashaw JM, Hale KA, Torielli FM, Abman SH, Kinsella JP. Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J Pediatr 1997; 131:70–75. Lipkin P, Davidson D, Spivak L, Straube R, Rhines J, Chang CT, I-NO/PPHN Study Group. One year neurodevelopmental and medical outcomes of persistent pulmonary hypertension of the newborn (PPHN) in a placebo controlled trial of inhaled nitric oxide. Pediatr Res 1999; 45:248a. Boedy RF, Howell CG, Kanto WP. Hidden mortality rate associated with extracorporeal membrane oxygenation. J Pediatr 1990; 117:462–464. Aly H, Sahni R, Wong JT. Weaning strategy with inhaled nitric oxide treatment in persistent pulmonary hypertension of the newborn. Arch Dis Child 1997; 76:F118-F122. Kinsella JP, Schmidt JM, Abman SH. Inhaled nitric oxide treatment for stabilization and emergency medical transport of critically ill newborns and infants. Pediatrics 1995; 95:773– 776. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99:838-845. Wung JT, Sahni R, Moffitt ST, Lipsitz E, Stolar CJ. Congenital diaphragmatic hernia: sur-
Persistent Pulmonary Hypertension in Newborn
84. 85. 86. 87.
943
vival treated with very delayed surgery, spontaneous respiration and no chest tube. J Pediatr Surg 1995; 30:406–409. Karamanoukian HL, Glick PL, Zayek M, Steinhorn RH, Swass MS, Fineman JR, Morin FC. Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios. Pediatrics 1994; 94:715–718. Neonatal ECMO Registry of the Extracorporeal Life Support Organization (ELSO). Ann Arbor, MI, July 1995. Dukarm RC, Russell JA, Morin FC III, Perry BJ, Steinhorn RH. The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. Am J Respir Crit Care Med 1999; 160:858–865. Robbins CG, Horowitz S, Merritt TA, Kheiter A, Tierney J, Narula P, Davis JM. Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia. Am J Physiol 1997; 272:L903–L907.
Index
abdomen, 12, 34 zonal vascular conditions in, 886 abdominal compartment syndrome, 897 abdominal muscles, 39–40 acetylcholine, 428, 448, 568 acid injury, 382 acidosis, 578, 644 metabolic, 662 acoustic stimulus, 617 acute lung injury, 6, 186, 203–205, 367, 379, 837, 905 and nitric oxide, 910–912 adenoidal hypertrophy, 642 adenosine, 59, 131, 411 in obstructive sleep apnea, 570 adenosine diphosphate, 131, 219–221 adenosine triphosphate, 59, 113, 131, 219–221, 319 ADH (see antidiuretic hormone) adhesion molecules, 486, 741 ADP (see denosine diphosphate) adrenaline, 756 adrenergic neurons, central, 149 adrenoreceptors, 774 adult respiratory distress syndrome, 438– 439, 713, 827, 829, 837, 905 aerobic glycolysis, 221 afferent hypothesis, 421 after-discharge, in ventilatory control, 512
afterload, 100, 743, 819, 891 left ventricular, 26, 263, 526, 532, 562, 588, 622, 632, 644, 653, 717, 820– 821, 873, 892 right ventricular, 191, 527, 622, 632, 689, 717, 751, 852, 875 ventricular, 297–301 airflow obstruction, in exercise, 246 air trapping, 188 airway disease, 24–28 alae nasi, 411, 414 albumin, 907 alcohol, 553 aldosterone, 435, 895 ALI (see acute lung injury) almitrine, 912 alpha adrenergic agents, and venous return, 106 alpha adrenergic blockade, 623, 847 alpha adrenoreceptors, 618 alpha-1-antitrypsin deficiency, 20 alphaxolone/alphadolone, 631 altitude, Cheyne-Stokes Respiration and, 594 alveolar-arterial oxygen gradient, in sepsis, 753 alveolar-capillary dysplasia, 920 alveolar fluid clearance, 374–376 alveolar inflammatory cells, 191
945
946 alveolar neutrophils, 371 alveolar rupture, 438 alveolar space, 362 alveolar vessels, 193 amiloride, 372, 375 aminoguanidine, 770 aminophyllin, 570 amygdala, 151 anaerobic glycolysis, 224–225 anaerobic threshold, 224, 243–244 anaphylaxis, 110 anemia, 110 angiotensin, 897 angiotensin 1, 435 angiotensin 2, 433, 435, 907, 921 angiotensin converting enzyme, 433, 435 angle of Louis, 864 anorexigens, 447, 450, 466 pulmonary hypertension in, 467–468 anterior horn cell, 410 antidiuretic hormone, 191, 427, 433 and PEEP, 435 antishock trousers, 883 anti-TNF antibodies, 486 A1 noradrenergic nerve, 620 aortic bodies, 161 aortic depressor nerve, 148, 634 aortic regurgitation, 711 APACHE (Acute Physiology and Chronic Health Evaluation), 799 Apgar score, 924 apneas, obstructive vs. non-obstructive, 628–631 apnea–hypopnea index, 553, 557, 642 apnea termination, 616 apneic threshold, 591 apoptosis, 452, 589, 763 appositional force, 37 aquiporins, 362, 376–378 arachadonic acid, 427, 845 ARDS (see adult respiratory distress syndrome) arginine vasopressin, 621 arousal, and sleep apnea, 562, 592, 602, 617 arousal index, 513 arousal response, 616 arterio-venous oxygen difference, 717 arterio-venous shunt, 129–130
Index ascites, cardiovascular effects of, 893–897 asphyxia, 602 aspirin, 431–432 asthma, 6, 191, 201, 826 asthmatics, 781 asynchronous breathing, 664 atelectasis, 652, 695 ATP (see adenosine triphosphate) atrial baffles, 301–302 atrial fibrillation, 298 atrial flutter, 722 atrial natriuretic factor, 191, 262, 435 atrial natriuretic peptide, 568, 603, 895 atrial stiffness, 297 atrial stretch receptors, 436 atriopeptins, 427, 433, 435–436, 439 atrioventricular interaction, 267–270, 300 automated border detection, 723 autonomic function, 526 autonomic imbalance, 499 autonomic nervous system, 145, 555, 616 autoregulation, of diaphragm blood flow, 64 a waves, 721, 875, 877 baroreceptors, 148, 155–161, 200, 556, 561, 610, 874 afferents, 502 sensitivity in CHF, 500 baroreflex, 149–152 dysfunction, 565 gain, 500 interactions with chemoreflex, 391–392 barotrauma, 439, 854, 927 benzodiazepines, 422, 513 beri-beri, 110 Bernoulli’s equation, 725, 924 beta adrenergic agonists and alveolar fluid clearance, 374–375 and venous return, 106 beta adrenergic block, 532, 615 beta adrenergic receptor, 748, 756 beta-1 receptor, 374 myocardial Bezold–Jarisch reflex, 391 biplane angiography, 283 bleomycin, 376 blinking capillary model (microcirculation), 135
Index blood flow fractal models, 137–140 heterogeneous models, 144 network models, 136–137 to respiratory muscles, 57–62 blood pressure, in sepsis, 741 blood volume, 94, 543, 646 Bochdalek, foramen of, 35 body mass index, 553 body surface area, 714 Bohr effect, 122, 223, 239 Botzinger complex, 151 bradycardia, 390, 560 bradykinin, 411, 415, 437, 778 brain natriuretic peptide, 436 brainstem, 581 breath holding, 562 bronchiolitis obliterans, 781 broncho-alveolar lavage, 913 bronchoconstriction, 24, 893 bronchopulmonary dysplasia (BPD), 928 bronchospasm, 201, 826 bulbis cordis, 72 cachexia, and respiratory muscles, 41 caffeine, 454 calcium channels, L-type, 321 calcium-induced calcium release, 454 calcium, intracellular, 319, 330–331 cannon waves, 722 capacitance, 98, 105 systemic vascular, 811 venous, 104, 871 capillaries, axial oxygen gradient in, 120– 121 capillary filtration, 744 pO2, 123, 129 recruitment, 236–238 transit time, 136 capillary barrier, 125 capsaicin, 411, 415 carbaminohemoglobin, 122 carbon dioxide production, 219 recruitment threshold, 657 as vasodilator, 131 carbon monoxide diffusing capacity, 520 cardiac asthma, 520
947 cardiac cycle specific increases in intrathoracic pressure, 207–208 via jet ventilation, 302 cardiac dysfunction, 502 cardiac function, 101, 555 in sepsis, 747 cardiac function curve, 109, 744, 750, 870 cardiac index, 491, 661, 687, 714, 827, 895 cardiac ischemia, 892 cardiac massage, 302 cardiac output, 6, 71, 93–94, 107, 192, 221, 265, 396, 498, 571, 534, 555, 582, 599, 617, 635, 646, 652, 683, 706, 749, 765, 852, 865 in ARDS, 839 control of, 95–97, 809–810 by echocardiography, 726 in exercise, 248–250 and intra-abdominal pressure, 883–891 by pulmonary artery catheters, 713– 715 in sepsis, 481, 741 cardiac sympathetic activity, 390 cardiac tamponade, 204, 265, 685, 722, 868, 880 cardiac volume, 188 cardiodynamic stimulation to ventilation, 241 cardiomyopathy, 84, 509 restrictive, 722 carina, 13 carotid body, 161, 390, 499 denervation of, 618 carotid chemoreceptors, 502, 526 carotid sinus, 148, 391 nerve of, 620 pressure in and venous return, 106 catalase, 318, 782 catecholamines, 488, 498, 554, 632, 750, 811, 892, 921 and congestive heart failure, 439 and continuous positive airway pressure, 399 and sepsis, 489–490, 742 and sleep apnea, 602 catheter infections, 796 cellular respiration, 221–225 central apnea, 161, 590
948 central pattern generator, 2, 409 central tendon, diaphragm, 38 ceramide, 491 cerebral cortex, 409 c-fibers, 521 C-fos, 152, 170, 619 cGMP (see cyclic guanosine 3′ 5′-monophosphate) cGMP phosphodiesterase, 774 chamber area, left ventricular, 304 chemiluminescence, for measuring NO, 910 chemoreceptors, 161–172, 499, 502, 561, 590, 616, 629 gain of, 592 peripheral, 595 (see also carotid body) responsiveness, 659 chemoreflex, 390–392, 630 hypothesis in sleep apnea, 656 chest wall, 13 Cheyne-Stokes respiration, 208, 499, 506–512, 589–600 CHF (see congestive heart failure) chloride channels, 328 chronic obstructive pulmonary disease, 6, 206–207, 248, 265, 408, 451, 580, 767, 826, 892, 912 circulation time, 597 cirrhosis, 894 clinical death, 98 coenzymes, mitochondrial, 225 coherence, 500 compliance abdominal, 37 arterial, 94–95 chest wall, 719, 830 left ventricular, 527, 632, 711, 820 lung, 719, 742, 749, 828 splanchnic bed, 744 venous, 94–95 ventricular, 71, 646 compound action potential, 42 computed tomography, 13, 727 helical/spiral, 287–288 high resolution, 283 high speed, 281–283 C1 adrenergic area, 620 congenital diaphragmatic hernia (CDH), 920 congestion, pulmonary, 594
Index congestive heart failure, 3, 208, 435, 439, 519, 578, 588, 594 and apneas, 635–637 chemosensitivity in , 499–502 mortality, 501 respiratory function in, 520–521 constrictive pericarditis, 265, 722 continuous positive airway pressure, 191, 199, 399, 519, 521, 530, 551, 564, 580, 821 baroreceptors in, 589 cardiac output in, 534–535 and Cheyne-Stokes respiration, 597 and CHF, 205, 514, 532–534 myocardial blood flow in, 539–540 vasodilation in, 542 ventricular afterload in, 535 continuum mechanics, 293 contractility cardiac, 100–101, 588, 625, 632, 744, 751, 773, 821–822, 895 diaphragm, 662 contraction, isovolumic, 73 contraction time, 41 control of breathing, 408–421 conus, 72 convection, microcirculatory, 117 convective acceleration, 18 COPD (see chronic obstructive pulmonary disease) coronary artery disease, 588 and weaning, 185 coronary blood flow, 624, 625, 635, 747, 751 in apneas, 623 and cardiac surface pressure, 528 and PEEP, 529 right ventricular, 192 in sepsis, 487 coronary perfusion pressure, 201 coronary vascular resistance, 623, 635 coronary vasodilator reserve, 635 cor pulmonale, 194, 197, 581, 628, 644, 687, 719, 722 cortical arousals, 559 cost-effectiveness, 798 cough, 39, 409 cough syncope, 17 CPAP (see continuous positive airway pressure)
Index creatine phosphokinase, 774 critical capillary pO2 , 229–236 critical coronary stenosis, 625, 635 cross-talk gain, 527 CT (see computed tomography) c wave, 875 cyanide, 335 cyclic adenosine monophosphate (cAMP), 908, 374, 376, 756 cyclic guanosine 3′ 5′-monophosphate (cGMP), 437, 763, 908, 922 cyclopiazonic acid, 454, 463 cyclo-oxygenase, 318, 411, 783 inhibition of, 190 cystic fibrosis, 463 cytochrome methemoglobin reductase, 906 cytochrome c oxidase, 774 cytochrome oxidase, 335 databases, 794–798 dazoxiben, 854 dDOWN, 873 dead space, 407, 503, 652 ventilation of, 654, 665 defense reaction, hypertension as, 567 diaphragm, 13, 26, 34–36, 408, 411, 660 blood flow to, 407 costal, 36–37 crural, 36 ischemia of, 415 O2 consumption of, 407 paralyzed, 247 ischemia of, 415 diastolic function, right ventricular, 67– 69 dihydrocodein, 502 dihydropyridine, 50 diffusion, 113 facilitated, 829 limitation of, 115 diltiazem, 454 dip and plateau, 266 2,3, diphosphglycerate, 122 dipyridamole, 908, 833 diving reflex, 390, 560 DNA and nitric oxide, 907 dobutamine, 756 dopamine, 755 dorsal respiratory group, 408
949 dp/dt ventricular, 76 airway occlusion pressure, 659 ductal ligation, 434 ductus arteriosus, 434 patent, 448 dUP, 873 duty cycle, 54 dynamic hyperinflation, 188 dynamic spatial reconstruction, 284–285, 295 dynamics, respiratory system, 16–20 dysautonomia, 190 dyspnea, 247, 250, 502 echocardiogram, in PPHN, 924 echocardiography color doppler, 920 in ICU, 723–729 in sleep apnea, 642 echo planar imaging, 289 ECMO (see extracorporeal membrane oxygenation) edema, 87 alveolar, 844 hemorrhagic, 367 interstitial, 844, 520 leg in sleep apnea, 645 effective downstream pressure, 845 Eisenmenger syndrome, 449, 463 ejection fraction, 302, 752 left ventricular, 481, 486, 488, 491, 499, 505, 511, 535, 594, 599, 602, 645, 697, 767 right ventricular, 76, 645, 687, 719, 767 elastance, 10, 73 end-systolic, 724 lung, 29, 666 right ventricular, 85 time varying, 75 elastic recoil lung, 26, 246–247, 681 pericardial, 262 electromyogram, 51 electron beam CT, 284–287 emphysema, 26, 203, 247, 248, 690, 818, 922 bullus, 29 end-capillary pO2, 236 end-diastolic volume, 752
950 end-diastolic volume index, 489 left ventricular, 481 right ventricular, 197, 767 end-ejection, 76 end-inspiratory volume, 24 endorphin, 51 endothelial cells, 479 pulmonary, 131, 190 endothelial cell junctions, 362 endothelial dysfunction, 449, 568 endothelial injury, 370 endothelin, 106, 262, 318, 321, 333, 433, 439, 449, 451, 503, 568, 742, 778, 896 endothelium, 503 in hypoxic pulmonary vasoconstriction, 338 endothelium derived relaxing factor, 321, 451, 462, 922 endotoxic shock, 532 endotoxin, 130, 367, 376, 379, 437, 439, 482, 483–484, 740, 824 endotracheal tube, 407–408 end-systolic volume index, 489 English bulldog, apneas in, 614 enterotoxin, 740, 765 eosinophila-myalgia syndrome, 450 epicardium, 258 epinephrine, 557 ergoreceptors, 411, 505 erythrocytes, O2 uptake in, 124 Eschrichia coli, 483 peritonitis model, 484 essential pulmonary hypertension, 203 excitation-contraction coupling, 452–456 exercise in CHF, 502 femoral venous lactate, 234–236 femoral venous pCO2, 227 femoral venous pH, 227 femoral venous pO2, 230 hyperpnea in, 504 induced pulmonary hypertension, 694 limitation in lung disease, 245–251 mean response time, 243 near syncope in, 250 and pulmonary vascular disease, 249 and respiratory muscles, 39 exotoxin, 376
Index extra-alveolar vessels, 193, 438, 522 extracorporeal membrane oxygenation, 919 extraction pressure, 125 failure left heart, 581 right heart, 580, 644, 692 familial platelet storage pool disease, 450 fast Fourier transform, 51, 289 fatigue, respiratory muscle, 48–56 central, 664 high frequency, 663 low frequency, 663 transmission, 664 fenfluramine, 448 on pulmonary smooth muscle cells, 467–468 fetal lung, 434 FEV1 (see forced expired volume in one second) fiber types, diaphragm, 40 fibrinogen, 450 fibrinolytic activity, and pulmonary hypertension, 450 fibrinopeptide A, and pulmonary hypertension, 450 Fick’s law, 113–114, 236–237 filtration coefficient, 364 flow limitation, 682 fluid balance, lung, 22 fluid challenge, 869–871 fluid management in sepsis, 753–754 Fontan procedure, 301 foramen ovale, 434, 921 force, definition of, 862 forced expired volume in one second, 580, 654, 690 force-frequency relationship, 41–42 force-velocity relation, 47–48 fragmentation, sleep, 615 Frank-Starling curve, 100 Frank-Starling mechanism, 262, 481, 697, 751 FRC (see functional residual capacity) free wall, right ventricular, 81–82, 192 frequency response, 720 functional residual capacity, 24, 193, 510, 580, 591, 597, 685
Index Gaar equation, 847 GABA (see gamma aminobutyric acid) gain, systolic, 84 gamma aminobutyric acid, 149–165 gamma motoneurons, 410 ganglionic blockade, 561, 632 gasping reflex, 148 gastric mucosal ischemia, 767 gastrocnemius, 411 genioglossus, 414 gigantocellular vasodepressor region, 152 glossopharyngeal nerve, 162 1-glutamate, 148 glutathione peroxidase, 782 glycine spinal sympathetic interneurons, 149 Golgi tendon organs, 51, 410 gram negative organisms, 740 granulocyte colony stimulating factor, 486 Group I -IV afferent fibers, 410–411, 414 growth factors, 428, 449 guanylate cyclase, 763, 775 Hageman factor, 437 Haldane effect, 243, 656 heart block, 560, 588 heart failure, 7, 263, 394, 552 critical capillary pO2 in, 232–236 heart rate, 100, 555, 615 variability in, 394, 499 hemoglobin, 122, 438, 773, 839, 925 and nitric oxide, 906–907 Henry’s law, 120 hepatic blood flow, and PEEP, 824–825 hepatic cirrhosis, 439 hepatic dysfunction, 824 hepatojugular reflux, 874–875 Herpes simplex, and pulmonary hypertension, 450 Herring-Breuer reflex, 2 hexamethonium, 616, 632, 635 hiccups, 409 high energy phosphate compounds, 219– 220, 488, 505 high frequency jet ventilation, 205 high frequency oscillation, 829, 927 histamine, 131, 427, 433 HIV infection, 450
951 Hoover’s sign, 37, 661 host factors in sepsis, 486 hydrogen ions, as vasodilator, 131 hydrothorax, 695 6-hydroxydopamine, 618 hypercapnia, 389, 390, 579, 616, 632, 644 mechanisms in COPD, 653–655 with oxygen in COPD, 656 permissive, 439, 838 and respiratory muscles, 39, 62 and sympathetic neurons, 155 Hyperinflation, 60, 660–661, 689, 826 dynamic, 681 release of humoral substances in, 429– 432 hyperoxia, 376, 500, 504, 562, 625, 927 hyperphosphatemia, and diaphragm, 662 hypersomnolance, 590 hypertension, 395, 616, 644 and sleep apnea, 552–554 hypertrophy, left ventricular, 552 hyperventilation, and mediator release, 431–432 hypoplasia, lung, 920 hypoplastic left heart, 301 hypotension, 61, 110, 745, 826 hypothalamic-preoptic regions, 151 hypothalamic stress hormones, 153–155 hypothalamus, 409 hypoventilation, 115–116, 654 hypovolemia, 203, 873 hypoxemia, 220, 247–248, 390 in COPD, 652–653 tissue, 752 hypoxia, 3, 62, 317–323, 389, 616 and CHF, 510 continuous, 618 cytopathic, 742 episodic, 618–622 and sleep apnea, 561–563, 588 stagnant, 742 and sympathetic neurons, 153 hypoxic contraction early, 318 late, 321–322 hypoxic drive and CHF, 500 and pressor response, 625
952 hypoxic pulmonary vasoconstriction, 433, 458–462, 921 hypoxic relaxation, 319–321 ibuprofen, 852 ICAM (intercellular adhesion molecule), 783 ICD-9 (international classification of diseases), 794 idiopathic dilated cardiomyopathy, 394 impedance aortic input, 200 arterial, 717 pulmonary input, 191 indomethacin, 434, 921 infarction, right ventricular, 722 inferior vena cava flow, 889 in COPD, 685 pressure, 885 inorganic phosphate, 221 inosital 1,4,5-triphosphate induced calcium release, 454–456 inspiratory muscle resistive breathing, 683 insulin, 553 interaction, systolic ventricular, 77–86 intercostal muscles, 38–39 interdependence heart-lung, 685 ventricular, 4, 69–72, 86–87, 194–195, 263, 526, 892 and apneas, 637 interferon-gamma, 764 interleukins, 427 IL-1, 437, 486, 740, 775, 783 IL-1β, 764 IL-2, 764, 783 IL-6, 783 IL-8, 783 interleukin-1 receptor antagonists, 481 intermittent mandatory ventilation, 205, 802, 821 interosseous muscles, 39 interstitial fibrosis, 201, 463 interstitial space, 362 intestinal mucosal blood flow, 892 intestinal polypeptide, 557 intimal fibrosis, 449
Index intimal proliferation, 449 intra-alveolar vessels, 522 intra-aortic balloon pump, 303 intracranial hemorrhage, 931 intrathoracic pressure (see pressure, intrathoracic) inverse ratio ventilation, 204, 827–828, 838 ischemia-reperfusion injury, 908 ischemia, right ventricular, 527 isometric contraction, 666 jet ventilation, 532 Kaplan Meier curves, 914 K-complexes, 393 ketoconozole, 854 Konno-Mead diagram, 34 Krogh cylinder models, 114 Krogh model, of O2 transport, 117–120 Kussmaul’s sign, 5, 266, 273–275, 810, 875, 889 kyphoscoliosus, 247 lactate, 59, 219, 502, 752 production, 488 lactic acid, 131, 185, 226, 411, 415, 504, 742, 771 lactic acidosis, 220–223, 240 and dyspnea, 250 laparoscopic surgery, and abdominal pressure, 899–900 LaPlace equation, 191, 199 law, 660, 717 relationship, 10 in diaphragm, 47 L-arginine, 763, 773, 906, 923 laryngeal edema, 201 lateral tegmental field, 149, 170 L-canavanine, 770 L-citrulline, 764, 906 left atrial stretch receptors, 409 left ventricle, 20, 298 to body weight ratio, 618 diastolic function, 644 dysfunction, 500, 752, 767, 874 failure, 520, 908 filling pressure, 706
Index [left ventricle] function curve, 884 hypertrophy, 695 mass index, 642 performance in COPD, 695–699 posterior wall, 642 stroke work, 622 systolic pressure of, 79 volume, 511, 594, 767 lethal corners, 120 levator costae, 38 length–tension relationship, 44–47 leukotrienes, 433, 740 lipid peroxidation, 434 lipopolysaccharide, 437, 740, 764 lipoxygenase (lipo-oxygenase), 320, 783 liquid ventilation, 829 liver blood flow, 196 L-NAA (N ω-amino-L-arginine), 766 L-NAME (N G-nitro-L-arginine), 765 L-MMA (N ω-methyl-L-arginine), 491– 492, 757, 765 locus ceruleus, 153 L-type calcium channels, 319, 325, 774 lung-ear circulation time (LECT), 510, 597 lung inflation, 370, 390, 542 on left ventricle, 302 reflexes, 630 lung injury, 828 lung volume in CHF, 521 and diaphragm, 37 hemodynamic effects, 189–195 and pulmonary hemodynamics, 694 reduction, 27–29, 689 lung water, 843 extravascular, 843, 850 lymphatic vessels, 362 lymph flow, 367 lymph/plasma protein concentration ratio, 365 lymphocytes, 479 macrophages, 479 magnetic resonance imaging, 288–294 magnetic resonance spectroscopy, 487 MAP II kinase, 456 maximum expiratory flow curve, 17
953 maximum inspiratory pressure–flow curve, 47 mean circulatory filling pressure, 96, 625 mean inspiratory flow, 655 mechanical heart–lung interactions, 195, 528 mechanical ventilation (see ventilation, mechanical) mechanoreceptors, 502, 630 meclofenamate, 846 medial hypertrophy, 449, 452, 456, 462 mediastinum, 13 medulla, 51, 146–170, 499, 500 mesothelial cells, 262 metalloendoprotease, 437 metanephrine, urinary and CPAP, 558 methemoglobin, 906 methemoglobinemia, 929 methemoglobin reductase, 906 methylene blue, 773 microcirculation, pulmonary, 711 microneurography, 394, 554 microvascular flow, 130–132 milrinone, 756 miniature pigs, apneas in, 614 mitochondria, 113 pO2 in, 236 respiration in, 221–223 mitral regurgitation, 603, 711, 721 mitral stenosis, 448, 715 mixed venous O2 content, 706 mixed venous pO2 , 652, 909 mixed venous saturation, and pulmonary artery catheters, 715 monocytes, 479 Morgagni, foramen of, 35 mortality, 798 from COPD, 651 and pulmonary artery catheters, 707 motor unit, 42–43 MRI (see magnetic resonance imaging) MSNA (see muscle sympathetic nerve activity) mucous plugging, 826 Mueller maneuver, 189, 306–308, 389, 391, 525, 562, 584–585, 628, 695, 889 multiple sleep latency test, 508, 514 muscle fatigue, 249
954 muscle pump, 265 muscle spindles, 247, 410, 419 muscle sympathetic nerve activity, 394, 555, 558, 560, 588, 618, 632 muscles, respiratory, 12 expiratory, 44 failure of, 406 force–velocity relations, 16, 44, 47 inspiratory, 44 Mustard procedure, 301 myocardial blood flow, 299, 302 and PEEP, 823–824 myocardial catechols, 532 myocardial depression, in septic shock, 487 myocardial dysfunction, 481 myocardial fibrosis, 644 myocardial function, regional, 625, 635 myocardial infarction, 394, 500, 552 myocardial injury, 920 myocardial ischemia, 635, 729 and PEEP, 205, 529 in sleep apnea, 635 and weaning, 185 myocardial lactate, in septic shock, 487 myocardial magnetic resonance imaging, 291–294 myocardial necrosis, 532 myocardial oxygen consumption, 488 myocardial oxygen demand, 588 myocytes, cardiac, 774 myofibroblasts, 449 myogenic theory, 131 myoglobin, facilitated O2 diffusion by, 114, 125 myosin light chain kinase, 453 NADH oxidase, 318 nadir wedge method, 187 Na-K-ATPase (see sodium potassium ATPase) natriuretic peptide receptors, 437 necrotizing arteritis, 449 nerve of Hering, 162 neurokinins, 427 neuropathy, peripheral, 556 neutrophils, 479, 486 New York Heart Association Functional Class, 497
Index Newton, 862 nifedipine, 448, 454 nitric oxide, 3, 58, 131, 190, 318, 332, 428, 434, 439, 449, 460, 503, 713 clinical trials in ARDS, 913–914 inhaled, 767, 851 administration of, 910 myocardial, 776 in sepsis, 490–492, 740 nitric oxide synthase, 148, 318, 434, 763, 906 inducible, 437, 440, 451, 491, 769– 770, 783 inhibitors, 106, 490, 568, 742, 756 in pulmonary hypertension, 468–471 nitrogen dioxide, 781, 928 nitroprusside, 374, 566 nitrosative stress, 781 nitrosohemoglobin, 906 nitrotyrosine, 908 nitroxyl, 924 NMDA receptors, 155 NO (see nitric oxide) nodose ganglion, 148 nonadrenergic, noncholinergic autonomic endings, 191 non-rapid eye movement sleep, 393, 507, 558, 615, 623, 646 and CHF, 509 norepinephrine, 106–107, 191, 394, 428, 433, 513–514, 532, 554, 556, 588, 602, 754, 771, 896 noscioreceptors, 411 NTS (see nucleus of solitary tract) nuclear factor kappa beta (NF-KB), 740, 782 nuclear magnetic resonance, 288 nucleus ambiguus, 151–170 nucleus of solitary tract (nucleus tractus solitarius), 146–170, 409, 619 obesity, 553, 563, 580, 644 obliques, internal and external, 39 obstructive apneas, 614 left heart function in, 624–625 neurocirculatory events in, 559–561 obstructive lung disease, and respiratory muscles, 46–47
Index obstructive sleep apnea, 208, 507 on left ventricle, 581–589 on right ventricle, 578–581 O2 consumption (see oxygen consumption) oleic acid, 367, 382 opioids, 422, 427 O2 pulse (see oxygen pulse) organ dysfunction, 479 overlap syndrome, 580 overwedging, of pulmonary artery catheter, 710 oxidant injury, 763 oxidative phosphorylation, 336, 462 oxidative stress, 779, 781 oxygen in Cheyne–Stokes respiration, 595 free radicals, 50, 663, 741 oxygenation index (OI), 924–925 oxygen consumption, 219–221, 265, 603, 838, 839 maximal, 502 oxygen delivery, 6, 560, 752, 827, 834, 906 cellular, 488 consumption relationships, 127 in ARDS, 839 index, 491 peripheral, 661, 717 oxygen extraction, 488, 717, 839 oxygen pulse, 248, 685, 697 oxygen, response in COPD, 655–658 oxygen sensing, 335–338, 460 oxygen transport lung, 115 peripheral tissues, 114–117 oxygen uptake, 718 oxyhemoglobin dissociation curve, 123, 238 oxyhemoglobin saturation, 579 oxymyoglobin, 219 oxytocin, 153 papillary dysfunction, 729 papillary muscles, 774 paracentesis, 896 paradoxical breathing, 664 paragigantocellular region, 155 paraquate, 434
955 parasternal muscles, 411 parasympathetic block, 615 parasympathetic efferents, 634 parenchymal emphysema, 438 parietal pericardium, 258 parietal pleura, 13, 38 partial liquid ventilation, 828–830 Pascal, 862 PCO2, gastric, 767, 772 Pendelluft, 671 perflubron, 828 perflurocarbon, 828 periaqueductal gray, 155 pericardial anatomy, 258 pericardial constraint, 259, 267–270, 868, 875 coupled vs. uncoupled, 267 volume elastance, 270 pericardial constriction, 868 pericardial disease, 265–267 pericardial fluid, 259, 262 pericardial restraint, 189 pericardial sac, 295 pericardial space, 258 pericardiectomy, 262 pericarditis, constrictive, 72 pericardium, 86, 192, 820 and interdependence, 68–71 periodic breathing, 595 perivascular cuffs, 365 permissive hypercapnia, 205 peroneal nerve, 554 peroxynitrite, 434, 780, 907 petrosal ganglion, 148, 153 pharyngeal caliber, in Cheyne–Stokes Respiration, 597 phenoxybenzamine, 811 phentolamine, 448, 623 phenylephrine, 500, 755, 772 phenyltheophyllin, 570 phonation, 409 phosphate, 415 phosphocreatine, 219, 223–224, 319 phosphodiesterase, 756, 908, 923 phospholipases, 428 photoplethysmography, 559 phrenic arteries, 57, 412 phrenic nerves, 37, 411, 412 stimulation of, 887
956 phrenic veins, 57 Pickwickian syndrome, 641, 644 plasminogen activator, 433 platelet activating factor, 427, 433, 740 platelet derived growth factors, 456 pleural space, 13 plexiform lesions, 449, 450, 462, 470 pliometric contraction, 666 pneumomediastinum, 438 pneumopericardium, 438 pneumoperitoneum, 438 pneumothorax, 438 Poiseuille’s law, 110 polymorphonuclear leukocytes, 912 polysomnography, 208, 513 P.1 (see pressure, airway occlusion) pons, 146, 173, 409 pontine parabrachial complex, 155 portal hypertension, 439 positive end-expiratory pressure (PEEP): 4, 26, 60. 186–189, 264, 309, 519, 527–530, 673, 711, 718, 912 auto (see intrinsic) cardiodepressor substances in, 823 history of, 808-809 hormonal effects, 433 intrinsic, 206, 406, 408, 669, 719, 692, 826–827, 893 liquid, 828 and respiratory swings in venous pressure, 871–872 splanchnic blood flow in, 824–825 positive feedback interaction, 556–557 positive pressure ventilation, 186–188, 198, 264, 757 positron emission tomography, 280, 845 posture, 71 potassium, as vasodilator, 131 arterial, 504 potassium channels, 325–328, 455 and hypoxic pulmonary vasoconstriction, 458 potassium permanganate, 910 Potter’s syndrome, 924 power spectral content, 51 in analysis of heart rate, 499 PPHN (see pulmonary hypertension of the newborn)
Index preload, 262, 725, 839 left ventricular, 198–199, 263, 582, 637, 712, 821 recruitable stroke work, 76 right ventricular, 197, 684 pressor response, 616 pressure abdominal, 34, 196, 263, 671–672, 810, 824, 872 measurement of, 900–901 airway, 185–189 airway occlusion, 858 alveolar, 826 arterial, 823, 874, 921 respiratory variation in, 872–874 capillary, 845 on cardiac function, 525–526 cardiac surface, 528, 530, 537, 823 central venous, 103, 687, 861 critical closing, 717, 751 esophageal, 14, 189, 718, 822, 890 in failing heart, 524, 530 femoral venous, 888 hydrostatic, 364 interstitial, 438 intramuscular, 59 intrathoracic, 5, 34, 104, 195–202, 263, 302, 561–562, 579, 615, 623, 644, 681, 718 effects on venous return, 523–525 juxtacardiac, 23, 186–189 left atrial, 368, 710, 752, 845, 866, 884 transmural, 72 left ventricular end-diastolic, 109, 711 left ventricular filling, 186, 579, 594, 706 left ventricular transmural, 200, 628 liquid, 22, 259 mean arterial, 486, 765 mean circulatory, 522, 682, 746, 750 mean systemic, 884 osmotic, 364 pericardial, 68, 186–189, 264, 537, 830 pericardial surface, 258–261 pleural (see also pressure, intrathoracic), 13, 14, 22, 39, 97, 101, 185–189, 265, 748, 810, 826, 866, 884 portal venous, 896 positive airway, 188
Index [pressure] pulmonary artery, 94, 447, 559, 578, 682, 687, 707, 721, 766, 852, 911, 924 artifacts, 721 and sepsis, 742, 751 pulmonary artery occlusion, 101, 520, 528, 653, 707, 709, 710–713, 721, 766, 850 nadir, 719 pulmonary artery transmural, 192, 579, 684 pulmonary capillary, 711–713, 838 pulmonary capillary wedge, 448, 579, 687, 826, 861 pulmonary capillary wedge transmural, 884 pulmonary wedge, 845 right atrial, 94, 96–97, 102, 107, 192, 197, 262, 522, 625, 682, 709, 722. 743, 810, 861, 894 right atrial transmural, 646, 683, 884 right ventricular diastolic, 262, 687 surface, 259 systemic arterial, 188, 578 tracheal, 615 transdiaphragmatic, 41, 664, 810 transmural, 6, 9, 69, 525, 821, 866– 868 transpericardial, 263, 820, 538 transpulmonary, 193 wedge, 102, 706 pressure controlled ventilation, 204–205 pressure gradient, pleural, 15 pressure support ventilation, 802 pressure-time product, 406 pressure-volume curve chest wall, 11–13, 24 end-systolic, 776, 822 lung, 9–11 vasculature, 746 pressure-volume relation end-systolic, 73 of heart, 299, 545 primary pulmonary hypertension, 447, 450 of the newborn, 914 disorders underlying, 920–921 registry, 447, 462
957 propranolol, 375, 615 prostacyclin, 432–433, 451, 460, 847, 921 and pulmonary hypertension, 468–471 prostaglandins, 262, 429, 433 PGI2, 433, 740 proteases, 428 protein concentration, 372 protein kinase C, 319, 374, 775 proteoglycans, 450 pulmonary arterial hypertension, 767 pulmonary arteries distal, 322–323 proximal, 317–322 pulmonary artery blood flow, 81 pulmonary artery catheterization, 705 and partial liquid ventilation, 830 pulmonary artery endothelial cells, 329– 333 proliferation of, 470 pulmonary artery smooth muscle cells, 323–324, 452–453, 457, 464, 470 pulmonary edema, 199, 205, 507, 520, 768, 843 cardiogenic, 713, 753 high altitude, 370 high pressure, 365–367 permeability, 367–369 physiologic basis, 364–369 resolution, 371–374 structural basis, 362 pulmonary embolism, 203, 721 pulmonary fibrosis, 449 pulmonary hypertension, 767, 922 in apneas, 628 hyperkinetic, 448–449 obstructive, 449–450 passive, 448 precapillary vs. postcapillary, 709 thromboembolic, 449, 463 pulmonary reflexes, 521 pulmonary vascular remodeling, 456 pulmonary vascular resistance, 4, 21, 188, 191–194, 203, 447, 452, 689, 710, 716, 743, 766, 829, 875, 922 pulmonary vasoconstriction, 742 pulmonary vasodilation, 431 pulmonary veins, 449 pulmonary venoconstriction, 846, 909
958 pulmonary veno-occlusive disease, 450, 713, 920 pulsus paradoxus, 5, 26, 194, 199–200, 203, 266, 273–275, 527, 810 pump, ventilatory, 34 radionuclide ventriculography, 645 rapeseed oil, 450 rapid eye movement sleep, 393, 397, 507, 558, 614, 623 rapidly adapting receptors, 410, 521 reactive oxygen intermediates, 77 reactive oxygen species, 333, 907 rectus abdominus, 391 reflection coefficient, 364 relaxation time, 41 REM (see rapid eye movement sleep) renal blood flow, 891 renal vascular resistance, 891 renin, 192, 433, 439, 895 residual volume, 44, 580 resistance airway, 25, 520, 666, 681, 742 arterial, 743 chest wall, 16 venous, 745, 812, 884 to venous return, 97, 106, 625 respiratory exchange ratio, 241 respiratory muscles (see also muscles, respiratory) in COPD, 660–665 fatigue of, 412, 663–664 weakness of, 49 respiratory rate, 406–408 resting chemoreflex drive, 394 resuscitation, cardiopulmonary, 30 reversed pulsus paradoxus, 526 rib cage, 12, 34 right heart catheterization, 706, 793 right heart morphology in sleep apnea, 642–644 right ventricle, 580 dysfunction of, 767, 874 elastance of, 275 enlargement of, 645 filling, 196–198 function in COPD, 688–690 hypertrophy, 627, 642, 710 infarction of, 819
Index [right ventricle] ischemia, 820 stroke volume of, 622 stroke work of, 76, 894 sympathetic stimulation on, 73 systolic pressure of, 81 vagal stimulation on, 73 volume, 82, 767, 629 wall thickness, 643, 695 rostral ventrolateral medulla, 146, 170, 619 RV (see residual volume) RVLM (see rostral ventrolateral medulla) ryanodine, 50, 319, 324, 454 salmeterol, 375 SAPS (simplified acute physiology score), 799 sarcolemma, 41, 51 sarcoplasmic reticulum, 50, 319, 454 scalene muscles, 38–39 schistosomiasis, 450 scleroderma, 463 Senning procedure, 301 sepsis, 61, 110, 437, 481, 717, 837, 921 definition of, 739 outcomes in, 800 septic shock, 379, 479, 717, 773 septum, interventricular, 199, 582, 642, 820 and interdependence, 70–78, 82 serotonin, 149, 165, 427, 433, 449, 450, 907 shab subfamily, 326 Shaker subfamily, 326 shear stress, 131, 449 shock, 484, 842 short term potentiation (ventilatory control), 512 shunt, 116 Shy-Drager syndrome, 561 SIDS (see sudden infant death syndrome) signal transduction, 329–330 Simpson’s rule, 725 SIN-1 (3–morpholinosyndnonimine), 776 single photon emission computed tomography, 280 sinus arrhythmia, 190 sinus rhythm, 298
Index sleep, 392 sleep apnea, 6, 389, 393, 397 sleep deprivation, 566 sleep disordered breathing, 641 sleep fragmentation, 508 slowly adapting receptors, 410, 521 slow oxidative fibers, 40 slow twitch fibers, 40 small airways, 10, 520 smooth muscle, 453 smooth muscle cells, 449 SMR (standardized mortality ratio), 799 SMT (S-methylthiourea), 770 sneezing, 409 snoring, 552, 554, 642 soda lime, 910 sodium-potassium ATPase, 320, 371–374 sodium transport, alveolar, 374 spatial modulation of magnetization, 291 sphingomyelinase, 491 sphingosine, 491, 775 spinal injury, 110 spinal preganglionic neurons, 151 spindle organs, 51 spin-echo imaging, 284 spreading coefficient, 828 Staphylococcus aureus, 484 Starling equation, 364, 713, 838 Starling forces, 371 Starling resistor, 845, 885 Starling’s law, 520, 842 Starling’s mechanism, 580, 582, 821 status asthmaticus, 263, 265 stellate ganglion, 847 sternal angle, 864 stressed volume, 96–98, 743, 750 stretch receptors, lung, 247, 629 (see also slowly and rapidly adapting receptors) stroke, 552 stroke volume, 95, 241, 265, 302, 545, 555, 582, 599, 634, 635, 894 index, 489 with jet ventilation, 532 subcutaneous emphysema, 438 substance P, 411, 415, 418 sudden infant death syndrome, 6, 145– 173 pathology of, 167
959 superior mesentaric blood flow, 892 superior vena caval blood flow, 889 superoxide, 318, 907 superoxide dismutase, 318, 780, 782, 922 supraspinal neuronal circuits, 146 surface tension, 10, 369, 828, 909 surfactant, 11, 366, 374, 434, 438, 909, 927 protein A, 910 sympathetic afferent nerves, 409 sympathetic discharges, 147–148 sympathetic nerve activity, 414, 554, 562 cervical, 619 renal, 596, 629 sympathetic nervous system, 146–147, 526, 588 in hypertension, 556–557 in sleep apnea, 554–555 sympathetic network, brainstem, 148–155 sympathetic outflow, 505 sympathetic stimulation on RV, 73 sympathetic vasoconstriction, in sleep apnea, 390 sympathoadrenal function in CHF, 532 and CPAP, 540 systemic inflammatory response syndrome, 739 systemic vascular resistance, 534, 555, 716, 742, 765, 884, 894 systole, ventricular, 23 tachycardia, 396, 710 ventricular, 722 tamponade, cardiac, 72 tension-time index, 54, 59, 664 terbutaline, 374 tetanic contraction, 42 tetrodotoxin-sensitive Na⫹⫹ currents, 329 thalamus, 151 thalidomide, 440 thapsigargin, 319, 324, 454 theophyllin, 603 thin fiber afferents, 411, 421 thiols and nitric oxide, 909 third messenger, 152 thoracic cavity, 26 thoracic pump, 198 thoracoabdominal configuration, 46
960 thorax, 11, 14 thromboxane A2, 433, 449, 451–452, 742, 843, 908 thyrotoxicosis, 110 tight junctions, 382 time constant, 100 respiratory, 660 for venous return, 106 TISS (therapeutic intervention scoring system), 799 tissue doppler imaging, 723 tissue forces, 10 TLC (see total lung capacity) TNF-α (see tumor necrosis factor alpha) tonsillar hypertrophy, 642 total heart volume, 294–302 total lung capacity, 26, 37, 44 total peripheral resistance, 646 total work, myocardial, 299–300 toxic oil syndrome, 450 toxic shock syndrome, 740 tracheostomy, 557, 580 outcomes, 794 traction, on lung, 13 transcription factors, 466 transforming growth factor alpha (TGFα), 375 transjugular intrahepatic portosystemic stent shunt (TIPSS) transmural pressure (see pressure, transmural) transposition of great arteries, 301 transverse abdominus, 411 triangularis sterni, 40, 411 tricuspid regurgitation, 722 tropomyosin, 50 troponin I, 774 T tubular system, 50 tumor necrosis factor alpha, 376, 427, 437, 440, 486, 490, 740, 764, 775, 783 tumor necrosis factor specific antibodies, 481 twitch, 41 type 1 cells (alveolar), 373, 378 type 2 cells (alveolar), 372 -373, 376, 378 tyrosine hydroxylase, 619 ultrasound, 280 unstressed volume, 96–98, 197, 743
Index upper airway obstruction, 263, 614, 643 upper airways and Cheyne-Stokes respiration, 596 upper motor respiratory neurons, 409 urodilantin, 436 vagal afferent nerves, 409 vagotomy, 615, 630, 634 Valsalva maneuver, 189, 198, 306–308, 526, 696, 824 vanilylmandelic acid, urinary and CPAP, 558 vascular waterfall, 99, 827, 885 vasoactive intestinal peptide, 428, 437, 440 vasoconstriction, 616 pulmonary, 190, 193, 579, 909 vasodilation, 632, 773 vasopressin, 153 vasomotor center, 147 vena cava, 26 venous return, 4, 20, 72, 195–196, 263, 533–523, 555, 582, 625, 646, 743, 765, 872, 908 and COPD, 682–686 curve, 98–100, 103–110, 744, 812 and PEEP, 810–818 and periodic apneas, 625–628 ventilation coupling to gas exchange, 240–245 as exercise, 184–185 mechanical, 5, 30, 801 and cardiac ischemia, 541 history of, 808–809 ventilation induced lung injury, 438–439 ventilation–perfusion relationships, 25, 503, 652, 828, 909 in exercise, 220 ventilatory pump (see pump, ventilatory) ventral respiratory group, 408 ventricular ejection, 264, 686 ventricular interdependence (see interdependence, ventricular) ventricular septal defect, 448 ventricular tachycardia, 602 VIP (see vasoactive intestinal peptide) visceral pleura, 13 vocal cord paralysis, 201 voltage dependent calcium channels, 454 volutrauma, 439
Index
961
Von Willebrand factor, 450 Voronoi Tesallation algorithm, 133 V/Q (see ventilation-perfusion relationships) v waves, 721, 875, 877–879 giant, 710
[weaning from ventilation] trial, 667 witnessed apneas, 552 1400 W[N-(3-(aminomethy)benzyl)– acetamine], 770 work of breathing, 666
wall motion, 302 wall stress, 717 water channels, transcellular, 362, 377 water permeability, 377 wave speed, limitation of maximum expiratory flow by, 18–19 weaning from ventilation, 185, 199, 202– 203, 406, 421, 793, 802 and abdominal pressure, 892–893
xanthine, 434 x descent, 266, 270, 875 y descent, 266, 270, 875, 879 zaprinast, 908 zonal conditions, abdominal, 685, 886– 887 zone of apposition (diaphragm), 36–37 zones, lung, 720, 874
