Sepsis, Kidney And Multiple Organ Dysfunction: 3rd International Course on Critical Care Nephrology, Vicenza, June 2004 (Contributions to Nephrology)

Sepsis, Kidney and Multiple Organ Dysfunction

This book has been made possible by the generous support of

Contributions to Nephrology Vol. 144

Series Editor

Claudio Ronco

Vicenza

Proceedings of the Third International Course on Critical Care Nephrology Vicenza, June 1–4, 2004

Sepsis, Kidney and Multiple Organ Dysfunction Volume Editors

Claudio Ronco Vicenza Rinaldo Bellomo Melbourne Alessandra Brendolan Vicenza

55 figures, 7 in color, and 37 tables, 2004

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Contributions to Nephrology (Founded 1975 by Geoffrey M. Berlyne)

Claudio Ronco

Rinaldo Bellomo

Department of Nephrology St. Bortolo Hospital I-36100 Vicenza (Italy)

Intensive Care Unit Austin & Repatriation Medical Center Melbourne, Vic. 3084 (Australia)

Alessandra Brendolan Department of Nephrology St. Bortolo Hospital I-36100 Vicenza (Italy)

Library of Congress Cataloging-in-Publication Data A catalog record for this title is available from the Library of Congress

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2004 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0302–5144 ISBN 3–8055–7755–9

Contents

IX Preface Ronco, C. (Vicenza); Bellomo, R. (Melbourne); Brendolan, A. (Vicenza) Epidemiology and Pathogenesis of ARF, Sepsis and MOF 1 Acute Renal Failure in the Critically Ill: Impact on Morbidity and Mortality Hoste, E.A. (Gent); Kellum, J.A. (Pittsburgh, Pa.) 12 Acute Renal Failure in the Intensive Care Unit. Risk Factors Piccinni, P.; Carraro, R.; Ricci, Z. (Vicenza) 19 Pathophysiology of Ischemic Acute Renal Failure. Inflammation, Lung-Kidney Cross-Talk, and Biomarkers Bonventre, J.V. (Boston, Mass.) 31 Pathophysiology of Sepsis and Multiple Organ Failure: Pro- versus Anti-Inflammatory Aspects Pinsky, M.R. (Pittsburgh, Pa.) 44 Tropical Acute Renal Failure Barsoum, R.S. (Cairo) The Critically Ill Patients: Pathological Mechanisms 53 Mechanisms Underlying Combined Acute Renal Failure and Acute Lung Injury in the Intensive Care Unit Chien, C.-C.; King, L.S.; Rabb, H. (Baltimore, Md.)

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63 Cytokine Single Nucleotide Polymorphism. Role in Acute Renal Failure Liangos, O.; Balakrishnan, V.S.; Pereira, B.J.G.; Jaber, B.L. (Boston, Mass.) 76 Mechanisms of Immunodysregulation in Sepsis Cavaillon, J.-M.; Fitting, C.; Adib-Conquy, M. (Paris) Fluid, Electrolyte and Acid Base 94 Goals of Resuscitation from Circulatory Shock Pinsky, M.R. (Pittsburgh, Pa.) 105 Intravenous Fluids and Acid-Base Balance Bellomo, R.; Naka, T.; Baldwin, I. (Melbourne) 119 Glucose Control in the Critically Ill Schetz, M.; Van den Berghe, G. (Leuven) 132 Dysnatremias in the Critical Care Setting Moritz, M.L. (Pittsburgh, Pa.); Ayus, J.C. (San Antonio, Tex.) Pharmacological Issues in ARF and Sepsis 158 Rasburicase Therapy in Acute Hyperuricemic Renal Dysfunction Ronco, C. (Vicenza); Bellomo, R. (Melbourne); Inguaggiato, P. (Cuneo); Bonello, M.; Bordoni, V.; Salvatori, G.; D’Intini, V.; Ratanarat, R. (Vicenza) 166 Diuretics in Acute Renal Failure? Schetz, M. (Leuven) 182 How to Manage Vasopressors in Acute Renal Failure and Septic Shock Dan, M.; Rossi, S.; Callegarin, L.; Ronco, C. (Vicenza) Practical Aspects of CRRT 191 Management of Vascular Catheters for Acute Renal Replacement Therapy D’Intini, V.; Bonello, M.; Salvatori, G.; Ronco, C. (Vicenza) 203 Relationship between Blood Flow, Access Catheter and Circuit Failure during CRRT: A Practical Review Baldwin, I.; Bellomo, R. (Melbourne) Renal Replacement Therapy in the ICU: Consensus and Recommendations from ADQI 214 CRRT: Selection of Patients and Starting Criteria Palevsky, P.M. (Pittsburgh, Pa.)

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222 Fluid Composition for CRRT Leblanc, M. (Montreal) 228 Anticoagulation for Continuous Renal Replacement Therapy Davenport, A. (London) Which Treatment for ARF in ICU? 239 Peritoneal Dialysis in Acute Renal Failure of Adults: The Under-Utilized Modality Ash, S.R. (West Lafayette, Ind.) 255 Intermittent Hemodialysis for Acute Renal Failure Patients – An Update Lameire, N.; Van Biesen, W.; Vanholder, R.; Hoste, E. (Gent) 264 Continuous Renal Replacement Techniques Clark, W.R. (Lawrence, Mass./Indianapolis, Ind.); Ronco, C. (Vicenza) 278 Hybrid Renal Replacement Therapies for Critically Ill Patients Golper, T.A. (Nashville, Tenn.) 284 Pediatric Acute Renal Failure: Demographics and Treatment Goldstein, S.L. (Houston, Tex.) Technical Aspects of CRRT 291 Vascular Access for Extracorporeal Renal Replacement Therapy in the Intensive Care Unit Canaud, B.; Formet, C.; Raynal, N.; Amigues, L.; Klouche, K.; Leray-Moragues, H.; Béraud, J.-J. (Montpellier) 308 Anticoagulation in Continuous Renal Replacement Therapy Vargas Hein, O.; Kox, W.J.; Spies, C. (Berlin) 317 Replacement and Dialysate Fluids for Patients with Acute Renal Failure Treated by Continuous Veno-Venous Haemofiltration and/or Haemodiafiltration Davenport, A. (London) CRRT Information Technology 329 A Practical Tool for Determining the Adequacy of Renal Replacement Therapy in Acute Renal Failure Patients Pisitkun, T.; Tiranathanagul, K. (Bangkok); Poulin, S.; Bonello, M.; Salvatori, G.; D’Intini, V.; Ricci, Z. (Vicenza); Bellomo, R. (Melbourne); Ronco, C. (Vicenza)

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New Frontiers in the Management of ARF, MOF and Sepsis 350 How to Approach Sepsis Today? Vincent, J.-L. (Brussels) 362 High Volume Hemofiltration in Critically Ill Patients: Why,When and How? Tetta, C. (Bad Homburg); Bellomo, R. (Melbourne); Kellum, J. (Pittsburgh, Pa.); Ricci, Z. (Vicenza); Pohlmeier, R.; Passlick-Deetjen, J. (Bad Homburg); Ronco, C. (Vicenza) 376 Coupled Plasma Filtration Adsorption: Rationale,Technical Development and Early Clinical Experience Brendolan, A.; Ronco, C.; Ricci, Z.; Bordoni, V.; Bonello, M.; D’Intini, V. (Vicenza); Wratten, M.L. (Mirandola); Bellomo, R. (Melbourne) 387 Plasmapheresis in Sepsis Berlot, G. (Trieste); Di Capua, G. (Naples); Nosella, P.; Rocconi, S.; Thomann, C. (Trieste) 395 Author Index 396 Subject Index

Contents

VIII

Preface

Multiple epidemiological studies have established and continue to emphasize the fact that sepsis is the dominant syndrome in modern Intensive Care Units. Severe sepsis occurs in approximately 50 to 100 cases/100,000 people/ year and is the most common cause of death in intensive care patients. Severe sepsis and septic shock are now also the most common cause of kidney failure in intensive care and the most common cause of severe kidney failure requiring in general renal replacement therapy. This kind of kidney failure, however, is rarely seen in isolation. Most commonly, it occurs as part of a syndrome of multiple organ failure, where the kidney is one of several organ systems that become profoundly dysfunctional. In this setting, vasodilatory shock is frequent, mechanical ventilation is frequent and disorders of bone marrow function, acid-base balance, gastrointestinal activity and cerebral function are common. Thus, severe sepsis links kidney function, multiple organ function and patient outcome from the start to the end. The care of patients with severe sepsis and/or septic shock is complex and typically involves a multidisciplinary approach. Critical care specialists typically co-ordinate resuscitation, fluid administration, and mechanical ventilation. In conjuction with the nephrologist, they deal with issues of electrolyte and water balance, acid-base control and renal support. Increasingly, renal support focuses on complex approaches to extracorporeal therapy, which require the use of sorbents, high-volume plasma water exchange techniques and plasmafiltration or plasma exchange techniques. In conjunction with the infectious disease specialist, critical care physicians and nephrologists co-ordinate antibiotic or antifungal treatment. This requires important adjustments, which

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depend on renal function and the technique of renal support being applied. Accordingly, knowledge of pharmacokinetics and pharmacodynamics becomes essential. Finally, emerging evidence indicates that the resolution of the septic state and of multiorgan dysfunction might require optimization of the endocrine environment through replacement of glucocorticoids in patients with loss of adrenal functional reserve, the supplementation of vasopressin in selected patients with vasodilatory shock and, perhaps more importantly, the restoration of normoglycemia through aggressive insulin administration. The above considerations make it clear that for patients to receive optimal care, the treating physician needs a detailed working knowledge of multiple aspects of care so that appropriate multidisciplinary assistance is sought at the right time and new techniques of organ support are applied in a safe, timely and effective way. In the present book we have combined the contributions of experts in various fields to tackle some of the fundamental and complex aspects of patients care. First we have focussed on the epidemiology of acute renal failure in intensive care and on its role in determining outcome. We then present recent advances in the insight into the pathogenesis of ischemic renal failure and of sepsis and multiple organ failure. Because the immune response to infection is central in determining organ injury, the book then focuses on its role in determining renal and lung injury, on the role of immune mediators in inducing dysregulation of the immune response and on the role of genetics in determining such a response. We then move to the issue of fluid resuscitation, the goals of resuscitation, the importance of acid-base control and the issues that surround glucose control and sodium control in the ICU. Pharmacological aspects of care involving the use of common medications such as diuretics and vasopressors are analyzed and the possible role of uric acid modulation discussed. As extracorporeal therapies are being increasingly used in the care of these complex patients, we focus on important technical aspects of such therapies including vascular catheter management, control of circuit blood flow, anticoagulation, choice of replacement or dialysate fluids, the role of information technology and the selection of patients for treatment. As the choice of treatment modality remains controversial, we also discuss different approaches to renal support from intermittent dialysis to continuous therapies and hybrid techniques. Finally, we conclude with a description of advanced extracorporeal techniques of organ support and discuss their role in the management of sepsis and kidney failure in the context of an overall strategy of sepsis management. The aim of this book is to present all physicians involved in the care of critically ill patients with sepsis and kidney/multiorgan dysfunction with a practical and up-to-date summary of current knowledge and technology as well as a fundamental understanding of pathogenesis and likely future developments in this field. Our endeavour is part of a now long-standing and continuing effort

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to improve patient outcome through laboratory and clinical research, education and consensus development. Working on the development of the specialty of Critical Care Nephrology and of the Acute Dialysis Quality Initiative (ADQI), we hope to move steadily in the direction of improved outcomes for critically patients with kidney and multiorgan dysfunction. We hope this book will serve as a useful tool for consultation, reference and informative reading for all professionals involved in the care of critically ill patients and that it will represent yet another small step toward improving the standards of care for such patients worldwide. Claudio Ronco Rinaldo Bellomo Alessandra Brendolan

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Epidemiology and Pathogenesis of ARF, Sepsis and MOF Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 1–11

Acute Renal Failure in the Critically Ill: Impact on Morbidity and Mortality Eric A. Hostea, John A. Kellumb a

Intensive Care Unit, Ghent University Hospital, Gent, Belgium; The CRISMA Laboratory (Clinical Research, Investigation, and Systems Modeling of Acute Illness), Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA

b

The occurrence rate of acute renal failure (ARF) in critically ill patients varies in the literature between 1.1 and 31% according to the definition of ARF used and the patient population studied [1–3]. In critically ill patients more than 90% of ARF episodes are of ischemic or toxic etiology or a combination of both. However, numerous other etiologies of ARF have been identified. Examples include obstruction of the urine outflow tract, acute tubulointerstitial nephritis, acute glomerulonephritis, and atheroemboli [4–9]. The precise diagnosis of the etiology of ARF is not always obvious or easy to establish; some patients can therefore be misclassified. Furthermore, the spectrum of etiologies will be different, depending on the specific patient population studied. In turn, each etiology can be associated with a specific spectrum of comorbidities, and consequent impact on outcome. For example, the complications and prognosis of contrast media induced ARF are different from that of ischemic ARF in a patient with sepsis, or ARF caused by lupus nephritis. It is therefore not surprising that the mortality of critically ill patients with ARF as reported in recent trials varies between 28 and 82% [3, 10]. In contrast to the former dogma that patients die with and not because of ARF, there is now ample evidence that ARF is itself somehow associated with excess mortality, or in other words ARF has ‘attributable mortality’ [11]. This has been most convincingly demonstrated in patients with ARF requiring treatment with renal replacement therapy (RRT) [1, 12, 13], but also appears to be true for patients with the less severe form of contrast media-induced ARF [14]. ARF patients are amongst the sickest in the intensive care unit. Patients often develop ARF as a consequence of conditions which are themselves associated with high mortality,

e.g. sepsis, hypotension. Furthermore, ARF may result in a variety of complications that can, in turn, lead to comorbidity or organ dysfunction [12, 14], thus negatively impacting on patient outcomes in the ICU. In this review we will discuss many of the complications of ARF, and consider their potential impact on patient outcomes in the ICU. While numerous reviews have focused on the clinical effects of RRT, it is important to note that emerging evidence suggests that even when ARF does not result in RRT, there is a significant impact on mortality [15]. Thus, it is important to consider the possible mechanisms of attributable mortality with ARF even when RRT is not employed. It is this group with which we will concern ourselves.

Complications of ARF

Uremic retention products are compounds that under normal conditions are excreted by the healthy kidneys. Impaired clearance of these compounds, as in ARF, leads to higher concentrations. When these compounds interfere with organ function one speaks of ‘uremic toxins’. There are currently more than 90 uremic retention products described in the literature for patients with chronic uremia [16, 17]. Whether these compounds fulfill the definition of uremic toxin is less well established [18]. Furthermore, the role that any of these molecules plays in ARF is less certain. For example, while chronic exposure to molecules such as leptin and retinol binding protein is associated with loss of appetite and neuro-muscular symptoms, it is unknown if these toxicities occur in the acute setting where less time for accumulation has passed. Conversely, uremic toxicity might play an even larger role in acute disease. Indeed there is growing evidence that more intensive treatment of uremia, or a higher dose of RRT, improves survival [10, 19, 20]. Of course, earlier and more intensive RRT might also control blood volume, salt and acid-base variables more efficiently and this too could affect outcome. Because the literature on uremic toxicity in ARF is much less abundant than in chronic uremia, we will focus on the complications of acute renal failure, of which many are a result of uremic retention compounds and their effects on normal physiology. Volume Overload Salt and water retention result in volume overload, this can occur even early in the course of ARF. Volume overload is one of the main reasons for initiating RRT [5, 21, 22]. Patients with volume overload will develop edema, ascites, and pleural effusions. As a consequence of volume overload, cardiovascular complications, such as congestive heart failure, hypertension, and pulmonary edema

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may develop. Respiratory function can be impaired by pleural effusion, and pulmonary edema. That volume overload can lead to many untoward effects has been illustrated in colorectal surgery where a restrictive fluid therapy regimen lead to a significant reduction in comorbidity [23]. Another, less common, complication of volume overload is the development of an abdominal compartment syndrome (ACS) [24]. ACS is becoming more commonly recognized as a complication of volume resuscitation and capillary leak. It has been described in patients with multiple organ failure and burns [25]. Patients with ACS have an increased intra-abdominal pressure, resulting in a pro-inflammatory response, and a decreased preload, low cardiac output, hypotension, impaired oxygenation and oliguria [26]. ACS may reduce renal perfusion and further worsen ARF or delay recovery. Formation of edema may also result in delayed wound healing [27]. Cell swelling interferes with normal cellular function, the most prominent symptoms are neurologic: impaired consciousness to coma and death [28]. In summary, volume overload can cause a whole range of complications, and this may help explain why ARF patients with oliguria have a worse survival, compared to non-oliguric ARF patients [2, 4, 7, 29–34]. Acidosis The kidneys play an important role in preservation of the acid base homeostasis; this through excretion of non-volatile acids and control of cation/anion balance. When the glomerular filtration rate (GFR) declines, there is accumulation of organic anions, e.g. hyperphosphatemia, and other unmeasured anions [35]. Furthermore, there is decreased production of bicarbonate by the decreased proximal tubular reabsorption and regeneration. Another factor that is important in the pathogenesis of metabolic acidosis is the decreased buffering capacity, secondary to hypoalbuminemia [35]. Finally, many patients will also have non-renal reasons for acidosis leading to mixed disorders in acid base balance. Examples of non-renal etiologies of acidosis are lactic acidosis, respiratory acidosis induced by permissive hypercapnia ventilation strategies or, less frequently, keto-acidosis. Mild-to-moderate acidosis is therefore a common finding in patients with ARF [35, 36]. The effects of metabolic acidosis are diverse [37, 38]. Acidosis can lead to many untoward effects, especially of the cardiovascular system, and may be associated with decreased survival [34]. Blood pressure and cardiac output can be decreased [39, 40], as well as hepatic and renal blood flow [41]. The underlying mechanisms of these effects are uncertain. Decrease of the ␤-receptors on the cell surface of the heart can play a role [42], as well as an increase of inducible nitric oxide synthase (iNOS) which can lead to vasodilatation [43]. Furthermore, it has been demonstrated that hyperchloremic acidosis increases lung and intestinal injury and decrease gut barrier function [43–46].

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Acidosis has also many untoward effects on metabolism. Glucose metabolism is impaired by the induction of insulin resistance [47] and inhibition of anaerobic glycolysis. Furthermore, there is induction of protein breakdown and decreased muscle protein synthesis [48–54]. Hyperchloremic acidosis has proinflammatory effects documented in vitro and in animal models. HCl infusion increases the release of NO and increases the Il-6/Il-10 ratio. In addition, HCl increased NF-␬B DNA binding in LPS-stimulated RAW 264.7 cells [55]. Acidosis also induces hyperkalemia by a shift of intracellular potassium to the extracellular compartment [56]. Finally, acidosis has a negative impact on metabolism of the central nervous system, resulting in impaired consciousness and eventually coma. Immunological Function, Inflammation, and Infection Patients with ARF have a high incidence of infectious complications. In one recent study, the higher the preoperative creatinine, the higher was the incidence of infections in patients who underwent open-heart surgery [57]. Bloodstream infections had an almost 3 times higher occurrence rate in critically ill patients with ARF compared to patients without ARF [58]. Finally, the occurrence rate of serious infections or sepsis in ARF patients treated with RRT ranges from 15 to 58.5% [57, 59, 60]. Thus, immunosupression seems likely in patients with ARF [58]. In patients with chronic uremia there is ample evidence that there is a decreased immune response as seen with impaired phagocytic function of white blood cells taken from these patients [61–63]. The underlying mechanisms for these effects are believed to include malnutrition, uremic toxicity, iron overload, anemia, and incompatibility of the hemodialyzers. There is less data concerning the immune response in the setting of ARF; however, the causative factors held responsible for the decreased neutrophil function are also present in patients with ARF. It seems therefore plausible that the phagocytic function of polymorphonuclear cells in ARF patients is also impaired. Finally, ARF itself, can lead to a non-infectious, pro-inflammatory response with activation of lung macrophages, secretion of pro-inflammatory cytokines, and recruitment of neurtrophils and macrophages with resultant lung injury, as has been demonstrated in animal models of ischemia-reperfusion-induced ARF [64–68]. Electrolyte Disorders Hyponatremia is a common finding in patients with ARF [36]. Usually, hyponatremia is dilutional, either hypervolemic or euvolemic. Underlying mechanisms for dilutional hyponatremia can be decreased free water clearance (hypervolemic hyponatremia), and hyperosmolar dilution, e.g. as a resultant of administration of synthetic colloids, or hyperglycemia (either hypervolemic or

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euvolemic after redistribution of fluid from the intracellular to the extracellular compartment). Free water clearance can already be impaired in an early stage of ARF, before elevations of creatinine or blood urea nitrogen [69]. Hypovolemic hyponatremia can be the resultant of losses of hypertonic fluids, e.g. after excessive vomiting or diarrhea, or interstitial or ‘third space’ losses as in burns or muscle injury. Hyponatremia, especially, acute hyponatremia (duration less than 48 h), interferes with normal cell function. The hypotonic extracellular environment causes cell swelling, as the osmotic gradient causes redistribution of water from the extracellular to the intracellular compartment. Symptoms include a whole spectrum of primarily neurological symptoms from headache, lethargy to coma and even dead. The more rapid the onset of hyponatremia, the higher the likelihood of severe symptoms [70]. Like hyponatremia, hyperkalemia is a potentially life-threatening situation as it may be complicated by cardiac arrhythmias. Hyperkalemia is a common complication in patients with ARF. The kidneys play a pivotal role in potassium homeostasis; failure of the kidneys to excrete potassium may therefore result in hyperkalemia. Other common causes of hyperkalemia in ARF patients may be the increased release of potassium from the intracellular compartment, as in rhabdomyolis, tumor lysis syndrome, and hemolysis [71–74], and side effects of drugs (e.g. non-steroidal anti-inflammatory drugs and COX-2 inhibitors, trimethoprim/sulfamethoxazole, angiotensin receptor blockers, cyclosporin or tacrolimus [75–78], and heparin). Anemia Anemia is a consistent finding in ARF patients. Underlying mechanisms for anemia are decreased synthesis of red blood cells, increased destruction of red blood cells, and increased blood loss. ARF patients have inappropriate low levels of erythropoietin [79, 80]. The uremic state causes increased red blood cell fragility and destruction [81], and increased blood loss is aggravated by platelet dysfunction [82, 83]. Anemia may excacerbate cardiovascular disease. Although a hemoglobin level as low as 7 g/dl is well tolerated in a general intensive care population, and is even beneficial for the subgroups of patients who are younger, and less severely ill, higher hemoglobin levels are recommended for patients with ischemic heart disease [84, 85].

Drug Prescription

Adequate dosing of drugs is a challenge in patients with ARF, because the pharmocodynamics and pharmacokinetics of drugs may be altered at every

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level. Plasma levels can be lower as a result of decreased availability when given orally [86], or increased volume of distribution. Alternatively, plasma drug levels may be higher as a result of reduced albumin binding, decreased metabolism and/or decreased renal excretion [87]. Additionally, plasma levels of metabolites of drugs may be increased for the same reasons, and this may also result in increased toxicity. To complicate things even more, none of the variables mentioned above remains constant during the course of an ARF episode: GFR changes and RRT affects drug concentrations. The dosing of an exhaustive list of drugs is reviewed in ‘Drug prescribing in renal failure’, a publication by the American College of Physicians [88]. We will limit ourselves to the discussion of the particular aspects of drug dosing of 3 groups of drugs, these being the most commonly prescribed to critically ill patients with ARF: vaso-active agents, antimicrobial agents, and sedatives/ analgetics. Vaso-Active Agents The dose of vasopressor agents such as norepinephrine, epinephrine and dopamine, is prescribed according to their effect on blood pressure and cardiac output. There are no dosing restrictions for patients with renal insufficiency. However, for inotropic agents from the class of phosphodiesterase inhibitors, a dose reduction is recommended for patients with renal insufficiency. Clearance of dopamine, epinephrine, and norepinephrine is minimal, and clinically insignificant when continuous veno-venous hemodiafiltration is used as mode of RRT [89]. These data can probably be extrapolated to other forms of RRT currently used for critically ill patients with ARF. Antimicrobial Agents Almost all antimicrobial agents are eliminated by the kidneys. Adjustment of dose and/or interval between 2 doses should therefore always be considered in patients with ARF in order to prevent toxicity as a result of high plasma levels. Another consideration is the increase in distribution volume that ARF patients will have as a result of edema and low albumin levels. Underdosing of antimicrobial agents and, therefore, inefficient antimicrobial treatment, is also a potential hazard in patients with ARF. In general, the loading dose of antimicrobial agents should be higher while the dosing interval longer, compared to that given to patients without ARF. Sedatives and Analgetics Most opiates and the older sedatives from the class of the benzodiazepines (e.g. diazepam and lorazepam) are excreted via the urine. Decreased renal

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function will therefore lead to accumulation of the drug or its metabolites, of which some also have sedative properties (e.g. morphine-6-glucuronide, a metabolite of morphine). A dose reduction is therefore recommended for these drugs in patients with decreased kidney function. This problem exists to a much lesser extent for propofol and midazolam, drugs that have renal elimination of inactive metabolites, and remifentanyl, a recently developed opiate that is metabolized in plasma and tissues. Adequate dosing of drugs in order to become adequate drug levels is an important cornerstone of anti-infectious chemotherapy. Critically ill patients with ARF are at risk for both low and high drug levels of antimicrobial chemotherapeutic agents, and both are undesirable. High drug levels may result in drug toxicity, and low drug levels may result in inadequate eradication of the infectious process, but also increased antimicrobial resistance [90].

Conclusions

It is currently not known why, even in the absence of RRT, ARF leads to an increase in mortality in critically ill patients. However, given the number of major perturbations in physiology that result from renal dysfunction, it seems likely that the explanation is multifactorial. We do not know if correction of these abnormalities will reduce the attributable mortality of ARF or whether early RRT, or ‘renal support’ will improve outcome. We speculate that given the multiple effects of even early ARF, efforts to prevent its development or hasten its recovery will significantly improve survival in critically ill patients.

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Liaño F, Pascual J, the Madrid Acute Renal Failure Study Group: Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Kidney Int 1996;50:811–818. Liaño F, Junco E, Pascual J, Madero R, Verde E, the Madrid Acute Renal Failure Study Group: The spectrum of acute renal failure in the intensive care unit compared to that seen in other settings. Kidney Int 1998;53(suppl 66):S16–S24. Pascual J, Liaño F, the Madrid Acute Renal failure Study Group: Causes and prognosis of acute renal failure in the very old. J Am Geriatr Soc 1998;46:721–725. Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305–310. Kellum JA, Angus DC: Patients are dying of acute renal failure. Crit Care Med 2002;30:2156–2157. Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051–2058. Hoste EA, Lameire NH, Vanholder RC, Benoit DD, Decruyenaere JM, Colardyn FA: Acute renal failure in patients with sepsis in a surgical ICU: Predictive factors, incidence, comorbidity, and outcome. J Am Soc Nephrol 2003;14:1022–1030. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality: A cohort analysis. JAMA 1996;275:1489–1494. Hoste E, Clermont G, Kersten A, Venkataraman R, Kaldas H, Angus DC, Kellum JA: Clinical evaluation of the new RIFLE criteria for acute renal failure. Crit Care 2004; abstract for the 24th International Symposium on Intensive Care and Emergency Medicine, Brussels. Vanholder R, De Smet R: Pathophysiologic effects of uremic retention solutes. J Am Soc Nephrol 1999;10:1815–1823. Vanholder R, De Smet R, Glorieux G, Argiles A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jorres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W: Review on uremic toxins: Classification, concentration, and interindividual variability. Kidney Int 2003; 63:1934–1943. Vanholder R, Glorieux G, De Smet R, Lameire N: New insights in uremic toxins. Kidney Int Suppl 2003;84:S6–S10. Conger JD: A controlled evaluation of prophylactic dialysis in post-traumatic acute renal failure. J Trauma 1975;15:1056–1063. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effect of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure: A prospective randomized trial. Lancet 2000;356:26–30. Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MTA, Farkas A, Kaplan RM: For the Collaborative Group for the Treatment of ARF in the ICU: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60:1154–1163. Cole L, Bellomo R, Silvester W, Reeves JH: A prospective, multicenter study of the epidemiology, management, and outcome of severe acute renal failure in a ‘closed’ ICU system. Am J Respir Crit Care Med 2000;162:191–196. Brandstrup B, Tonnesen H, Beier-Holgersen R, Hjortso E, Ording H, Lindorff-Larsen K, Rasmussen MS, Lanng C, Wallin L, Iversen LH, Gramkow CS, Okholm M, Blemmer T, Svendsen PE, Rottensten HH, Thage B, Riis J, Jeppesen IS, Teilum D, Christensen AM, Graungaard B, Pott F: Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens: A randomized assessor-blinded multicenter trial. Ann Surg 2003;238:641–648. Morken J, West MA: Abdominal compartment syndrome in the intensive care unit. Curr Opin Crit Care 2001;7:268–274. Balogh Z, McKinley BA, Holcomb JB, Miller CC, Cocanour CS, Kozar RA, Valdivia A, Ware DN, Moore FA: Both primary and secondary abdominal compartment syndrome can be predicted early and are harbingers of multiple organ failure. J Trauma 2003;54:848–859; discussion 859–861. Rezende-Neto JB, Moore EE, Melo de Andrade MV, Teixeira MM, Lisboa FA, Arantes RM, de Souza DG, da Cunha-Melo JR: Systemic inflammatory response secondary to abdominal compartment syndrome: Stage for multiple organ failure. J Trauma 2002;53:1121–1128.

Hoste/Kellum

8

27 28

29 30

31

32 33 34

35

36 37 38

39 40 41 42 43

44

45 46 47 48 49 50 51

Teschan PE: Acute renal failure during the Korean War. Ren Fail 1992;14:237–239. Steele A, Gowrishankar M, Abrahamson S, Mazer CD, Feldman RD, Halperin ML: Postoperative hyponatremia despite near-isotonic saline infusion: A phenomenon of desalination. Ann Intern Med 1997;126:20–25. Mehta RL, Pascual MT, Gruta CG, Zhuang S, Chertow GM: Refining predictive models in critically ill patients with acute renal failure. J Am Soc Nephrol 2002;13:1350–1357. Guerin C, Girard R, Selli J-M, Perdrix J-P, Ayzac L: For the Rhone-Alpes Area Study Group on Acute Renal Failure: Initial versus delayed acute renal failure in the intensive care unit: A multicenter prospective epidemiological study. Am J Respir Crit Care Med 2000;161:872–879. Guerin C, Girard R, Selli JM, Ayzac L: Intermittent versus continuous renal replacement therapy for acute renal failure in intensive care units: Results from a multicenter prospective epidemiological survey. Intens Care Med 2002;28:1411–1418. Rasmussen HH, Pitt EA, Ibels LS, McNeil DR: Prediction of outcome in acute renal failure by discriminant analysis of clinical variables. Arch Intern Med 1985;145:2015–2018. Bullock ML, Umen AJ, Finkelstein M, Keane WF: The assessment of risk factors in 462 patients with acute renal failure. Am J Kidney Dis 1985;5:97–103. Chertow GM, Lazarus J, Paganini E, Allgren R, Lafayette R, Sayegh M: Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group. J Am Soc Nephrol 1998;9:692–698. Rocktaeschel J, Morimatsu H, Uchino S, Goldsmith D, Poustie S, Story D, Gutteridge G, Bellomo R: Acid-base status of critically ill patients with acute renal failure: Analysis based on Stewart-Figge methodology. Crit Care 2003;7:R60. Dolson GM: Electrolyte abnormalities before and after the onset of acute renal failure. Miner Electrolyte Metab 1991;17:133–140. Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. First of two parts. N Engl J Med 1998;338:26–34. Gunnerson KJ, Song M, Kellum JA: Influence of acid-base balance on patients with sepsis; in Vincent JL (ed): Yearbook of Intensive Care and Emergency Medicine 2004. Springer-Verlag, Berlin, 2004, pp 58–67. Weil MH, Houle DB, Brown EB Jr, Campbell GS, Heath C: Vasopressor agents: Influence of acidosis on cardiac and vascular responsiveness. Calif Med 1958;88:437–440. Kellum JA, Song M, Venkataraman R: Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest 2004;125:243–248. Bersentes TJ, Simmons DH: Effects of acute acidosis on renal hemodynamics. Am J Physiol 1967; 212:633–640. Marsh JD, Margolis TI, Kim D: Mechanism of diminished contractile response to catecholamines during acidosis. Am J Physiol 1988;254:H20–H27. Pedoto A, Caruso JE, Nandi J, Oler A, Hoffmann SP, Tassiopoulos AK, McGraw DJ, Camporesi EM, Hakim TS: Acidosis stimulates nitric oxide production and lung damage in rats. Am J Respir Crit Care Med 1999;159:397–402. Salzman AL, Wang H, Wollert PS, Vandermeer TJ, Compton CC, Denenberg AG, Fink MP: Endotoxin-induced ileal mucosal hyperpermeability in pigs: Role of tissue acidosis. Am J Physiol 1994;266:G633–G646. Unno N, Hodin RA, Fink MP: Acidic conditions exacerbate interferon-gamma-induced intestinal epithelial hyperpermeability: Role of peroxynitrous acid. Crit Care Med 1999;27:1429–1436. Pedoto A, Nandi J, Oler A, Camporesi EM, Hakim TS, Levine RA: Role of nitric oxide in acidosisinduced intestinal injury in anesthetized rats. J Lab Clin Med 2001;138:270–276. DeFronzo RA, Beckles AD: Glucose intolerance following chronic metabolic acidosis in man. Am J Physiol 1979;236:E328–E334. Mitch WE, Goldberg AL: Mechanisms of muscle wasting: The role of the ubiquitin-proteasome pathway. N Engl J Med 1996;335:1897–1905. Mitch WE: Mechanisms causing loss of muscle in acute uremia. Ren Fail 1996;18:389–394. Bailey JL, Mitch WE: Metabolic acidosis as a uremic toxin. Semin Nephrol 1996;16:160–166. Mitch WE: Metabolic acidosis stimulates protein metabolism in uremia. Miner Electrolyte Metab 1996;22:62–65.

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52 53 54

55

56 57 58

59 60

61 62

63 64

65 66

67

68 69 70 71

72 73 74 75 76

Bailey JL, England BK, Long RC, Mitch WE: Influence of acid loading, extracellular pH and uremia on intracellular pH in muscle. Miner Electrolyte Metab 1996;22:66–68. May RC, Bailey JL, Mitch WE, Masud T, England BK: Glucocorticoids and acidosis stimulate protein and amino acid catabolism in vivo. Kidney Int 1996;49:679–683. Isozaki U, Mitch WE, England BK, Price SR: Protein degradation and increased mRNAs encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3H1 myocytes require an interaction between glucocorticoids and acidification. Proc Natl Acad Sci USA 1996;93:1967–1971. Kellum JA, Song M, Li J: Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004; 286:R686–R692. Adrogue HJ, Madias NE: Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med 1981;71:456–467. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP: Renal dysfunction and serious infections after open-heart surgery. Kidney Int 2003;64:239–246. Hoste E, Blot S, Lameire N, Vanholder R, De Bacquer D, Colardyn F: Impact of nosocomial bloodstream infection on the outcome of critically ill patients with acute renal failure treated with renal replacement therapy. J Am Soc Nephrol 2004;15:454–462. Schiffl H, Lang SM, Konig A, Strasser T, Haider MC, Held E: Biocompatible membranes in acute renal failure: Prospective case-controlled study. Lancet 1994;344:570–572. Fiaccadori E, Lombardi M, Leonardi S, Rotelli CF, Tortorella G, Borghetti A: Prevalence and clinical outcome associated with preexisting malnutrition in acute renal failure: A prospective cohort study. J Am Soc Nephrol 1999;10:581–593. Vanholder R, Ringoir S: Infectious morbidity and defects of phagocytic function in end-stage renal disease: A review. J Am Soc Nephrol 1993;3:1541–1554. Vanholder R, De Smet R, Waterloos MA, Van Landschoot N, Vogeleere P, Hoste E, Ringoir S: Mechanisms of uremic inhibition of phagocyte reactive species production: Characterization of the role of p-cresol. Kidney Int 1995;47:510–517. Horl WH: Neutrophil function and infections in uremia. Am J Kidney Dis 1999;33:xlv–xlviii. Kramer AA, Postler G, Salhab KF, Mendez C, Carey LC, Rabb H: Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int 1999;55: 2362–2367. Rabb H, Chamoun F, Hotchkiss J: Molecular mechanisms underlying combined kidney-lung dysfunction during acute renal failure. Contrib Nephrol. Basel, Karger, 2001, pp 41–52. Donnahoo KK, Meldrum DR, Shenkar R, Chung CS, Abraham E, Harken AH: Early renal ischemia, with or without reperfusion, activates NFkappaB and increases TNF-alpha bioactivity in the kidney. J Urol 2000;163:1328–1332. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR: Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 1999;277:R922–R929. Donnahoo KK, Shames BD, Harken AH, Meldrum DR: Review article: The role of tumor necrosis factor in renal ischemia-reperfusion injury. J Urol 1999;162:196–203. Baek SM, Makabali GG, Brown RS, Shoemaker WC: Free-water clearance patterns as predictors and therapeutic guides in acute renal failure. Surgery 1975;77:632–640. Rose BD, Post TW: Hypoosmolal states-hyponatremia; in Post TW (ed): Clinical Physiology of Acid-Base and Electrolyte Disorders, ed 5. New York, McGraw-Hill, 2001, pp 696–745. Erek E, Sever MS, Serdengecti K, Vanholder R, Akoglu E, Yavuz M, Ergin H, Tekce M, Duman N, Lameire N: An overview of morbidity and mortality in patients with acute renal failure due to crush syndrome: The Marmara earthquake experience. Nephrol Dial Transplant 2002;17:33–40. Jeha S: Tumor lysis syndrome. Semin Hematol 2001;38:4–8. Arrambide K, Toto RD: Tumor lysis syndrome. Semin Nephrol 1993;13:273–280. Gloe D: Common reactions to transfusions. Heart Lung 1991;20:506–512. Harris RC Jr: Cyclooxygenase-2 inhibition and renal physiology. Am J Cardiol 2002;89:10D–17D. Wrenger E, Muller R, Moesenthin M, Welte T, Frolich JC, Neumann KH: Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: Analysis of 44 cases. BMJ 2003;327:147–149.

Hoste/Kellum

10

77 78 79 80 81 82 83 84

85

86

87 88

89

90

Kahan BD: Cyclosporine nephrotoxicity: Pathogenesis, prophylaxis, therapy, and prognosis. Am J Kidney Dis 1986;8:323–331. Hsu I, Wordell CJ: Hyperkalemia and high-dose trimethoprim/sulfamethoxazole. Ann Pharmacother 1995;29:427–429. Lipkin GW, Kendall RG, Russon LJ, Turney JH, Norfolk DR, Brownjohn AM: Erythropoietin deficiency in acute renal failure. Nephrol Dial Transplant 1990;5:920–922. Lipkin GW, Kendall R, Haggett P, Turney JH, Brownjohn AM: Erythropoietin in acute renal failure. Lancet 1989;i:1029. Nagano N, Koumegawa J, Arai H, Wada M, Kusaka M: Effect of recombinant human erythropoietin on new anaemic model rats induced by gentamicin. J Pharm Pharmacol 1990;42:758–762. Eknoyan G, Wacksman SJ, Glueck HI, Will JJ: Platelet function in renal failure. N Engl J Med 1969;280:677–681. Weigert AL, Schafer AI: Uremic bleeding: Pathogenesis and therapy. Am J Med Sci 1998;316: 94–104. Hébert PC, Yetisir E, Martin C, Blajchman MA, Wells G, Marshall J, Tweeddale M, Pagliarello G, Schweitzer I: The transfusion requirements in critical care investigators for the Canadian critical care trials group: Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? Crit Care Med 2001;29:227–233. Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E: Group TTRiCcIftCCCT: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–417. Craig RM, Murphy P, Gibson TP, Quintanilla A, Chao GC, Cochrane C, Patterson A, Atkinson AJ Jr: Kinetic analysis of D-xylose absorption in normal subjects and in patients with chronic renal failure. J Lab Clin Med 1983;101:496–506. Reidenberg MM: The biotransformation of drugs in renal failure. Am J Med 1977;62:482–485. Aronoff G, Berns J, Brier M, Golper T, Morrison G, Singer I, Swan SK, Bennet W: Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. Philadelphia, American College of Physicians, 1999. Bellomo R, McGrath B, Boyce N: Effect of continuous venovenous hemofiltration with dialysis on hormone and catecholamine clearance in critically ill patients with acute renal failure. Crit Care Med 1994;22:833–837. Pinder M, Bellomo R, Lipman J: Pharmacological principles of antibiotic prescription in the critically ill. Anaesth Intens Care 2002;30:134–144.

John A. Kellum, MD 608 Scaife Hall, The CRISMA Laboratory, Critical Care Medicine University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261 (USA) Tel. ⫹1 412 647 6966, Fax ⫹1 412 647 3791, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 12–18

Acute Renal Failure in the Intensive Care Unit Risk Factors

P. Piccinni, R. Carraro, Z. Ricci Department of Anesthesiology and ICU, St.Bortolo Hospital, Vicenza, Italy

Acute renal failure (ARF) is a common clinical event affecting 2–5% of hospitalized patients and up to 10–30% of those in intensive care units (ICU), depending on the population studied and the criteria used to define [1]. The mortality rate in ARF patients remains high [2] despite hemodialysis therapy and substantial improvement of dialysis techniques. Possible explanations for this finding include the fact that ICU patients today are older and more debilitated than previously, and that the same pathophysiologic factors involved in the development of ARF are also incriminated in the failure of other organs, so that ARF is often part of the multiple organ failure (MOF) syndrome. [3] Acute renal failure can be oliguric (urinary output, ⬍400 ml per day) or nonoliguric (⬎400 ml per day). Patients with nonoliguric acute renal failure have a better prognosis than those with oliguric renal failure, probably due in large measure to the decreased severity of the insult and the fact that many have drug-associated nephrotoxicity or interstitial nephritis. The percentage of patients with acute renal failure who require dialysis ranges from 20 to 60%. Among the subgroup of patients who survive initial dialysis, less than 25% require long-term dialysis, demonstrating the potential reversibility of the syndrome [3]. Brivet et al. [4], in a prospective, multicenter study, found seven predictive factors for severe ARF patients requiring ICU stay related to the acute clinical setting in which ARF occurred and three characteristics of ARF influenced the outcome of patients: (a) hospitalization before ICU admission or a delayed occurrence of ARF during ICU stay; (b) sepsis, and (c) oliguria. Levy et al. [5] on an objective to determine if the high mortality in ARF is explained by underlying illnesses in cohort analytic study, found that the

mortality in subjects without renal failure was 7%, compared with 34% in the corresponding index subjects with renal failure. In ICU some 75% of ARF is a consequence of surgery, often associated with sepsis. A small focus of fecal contamination in the abdomen in a patient with acute renal failure or multiple organ failure will prove fatal and, similarly, a segment of dead bowel also negates recovery. ARF remains an infrequent but major complication of surgery necessitating cardiopulmonary bypass (CPB): the likelihood of developing ARF after cardiac surgery depends on factors associated with poor cardiac performance (particularly when separating from CPB) and with the level of baseline renal insufficiency [6]. The outcome of patients with ARF complicating cardiac surgery was particularly poor in those with associated cardiovascular failure [7]. Risk factors for ARF in severe trauma increased by age, ISS ⬎17, the presence of hemoperitoneum, shock, hypotension, rhabdomyolysis with CPK ⬎10,000 IU/l, presence of acute lung injury requiring mechanical ventilation, and Glasgow Coma Score ⬍10 [8]. A renal injury by exotoxins (e.g. antibiotics, anesthetic agents, contrast media, diuretics) and endotoxins (e.g. myoglobin) may also be involved. In patients with prerenal azotemia renal injury is more likely to be caused by drugs that can alter intrarenal hemodynamics, such as NSAIDs, or reach high concentrations in renal tissue, such as aminoglycosides. Patients with preexisting renal insufficiency are predisposed to acute renal failure due to radiocontrast agents, aminoglycosides, atheroembolism and cardiovascular surgery. Patients with both renal insufficiency and diabetes mellitus are at particularly high risk for toxic reactions to radiocontrast agents. Patients with hyperbilirubinemia also appear to be predisposed to acute renal failure. Elderly patients are susceptible to many forms of acute renal failure because the aging kidney loses functional reserve and its ability to withstand acute insults is compromised [9]. Synergy between renal hypoperfusion and toxic insults from an increased renal concentration of toxins at a time when sodium reabsorption and urinary concentration are enhanced and the oxygen supply is reduced are shown in figure 1 [10]. Severe infection include a combination of factors such inadequate perfusion with consequent inadequate delivery of oxygen, the sepsis-endotoxin-cytokine mediator system and superimposed disseminated intravascular coagulation (malignant intravascular inflammation). In this condition, the hemodynamic of this kidneys is impaired even without systemic hypotension: this is nevertheless a common feature of SIRS even in presence of high cardiac output (hyperdynamic hypotension) and it is due to decrease of, resistances or decrease of critical closing pressure in the arterial circuit [11, 12].

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Medullary oxygen insufficiency

Precipitation of Tamm–Horsfall protein

↑ Delivery of Na to macula densa

NSAIDs

Release of prostanoids, adenosine, nitric oxide

↑ Medullary blood flow

Volume depletion Cortical vasoconstriction

↓ IGF-I

BJP

Tubular obstruction and damage

↓ mTAL transport Renal failure

Medullary oxygen sufficiency

Fig. 1. Probable mechanisms leading from medullary hypoxia to renal failure. From Brezis and Rosen [10], modified.

Recently, an original study is published on behalf of the SOFA group of the European Society of Intensive Care Medicine on objective to describe risk factors for the development of ARF in ICU, and the association of ARF with MOF and outcome using the sequential organ failure assessment (SOFA) score. Forty participating centers in 16 countries enrolled 1,411 patients and conclude that the most important risk factors for development of ARF present on admission were acute circulatory or respiratory failure; age more than 65 years, presence of infection, past history of chronic heart failure (CHF) lymphoma or leukemia, or cirrhosis. The presence of infection during the ICU stay increased the risk of death by all other factors, especially circulatory failure [13]. In other words, there are conditions favoring deterioration of factors that render the kidney susceptible to acute injury, like: high O2 consumption; counter current multiplier; high blood flow; unique glomerular structure; renal blood flow autoregulation. Systemic hypotension induces loss of autoregulatory flow and repetitive periods of low perfusion pressure may induce repetitive ischemia in a region of the kidney already prone to hypoxia such as the medulla of the thick ascending limb of Henle’s loop (mTAL), see fig. 2. Heterogeneity of intrarenal blood flow contributes to the pathophysiology of ischemic acute renal failure. An imbalance between the vasodilator nitric

Piccinni/Carraro/Ricci

14

Blood flow, 4.2ml/min/g

Macula densa

Cortical labyrinths

PO2, ~50 mm Hg

Medullary rays Outer Blood flow, medulla 1.9 ml/min/g

PO2, ~10–20 mm Hg

Inner medulla

Medullary thick ascending limbs

Cortex Renal vein

Renal artery

Fig. 2. Anatomical and physiologic features of the renal cortex and medulla. From Brezis and Rosen [10], modified.

oxide and the vasoconstrictor endothelin may also impair medullary blood flow and contribute to tubular-cell damage. In the outer medulla, where tubules have high oxygen requirements, ischemia causes swelling of tubular and endothelial cells as well as adherence of neutrophils to capillaries and venules. These changes lead to vascular congestion and decreased blood flow, tipping the tenuous balance between oxygenation and energy demand. This ‘medullary anginal syndrome’ is a possible cause of apoptosis for part of parenchyma which had not undergone previous necrosis, i.e. the infinite story in biology of programmed cell death [14]. Apoptosis is an evolutionarily conserved and highly regulated program of cell death, which plays an important role in both normal physiologic processes and, when accelerated, in disease states as well. Many reports on apoptosis have focused on the role of the executioner cysteine-aspartate proteases termed ‘caspases’ that are triggered in response to proapoptotic signals and that result in disassembly of the cell. Recent studies demonstrated the coexistence of multiple parallel apoptotic pathways; in mammalian cells, at least four distinct pathways exist. Knowledge of caspase regulation may allow manipulation of apoptosis. A key caspase involved in the apoptotic pathway is caspase. Inhibition of caspase-3 has been linked to prevention of apoptotic death in vitro, although certain stimuli can induce apoptosis by a caspase-3-independent pathway. A second area of apoptosis research focused on the antiapoptotic protein, BCL [15–17].

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Pathophysiology of Ischemic Acute Renal Failure

The pathophysiology of ischemic acute renal failure, because of prerenal azotemia, can be considered a preischemic state and prerenal azotemia and ischemia are common causes of acute renal failure. As in any cell, anoxia in kidney cells results in the depletion of energy stores, collapse of electrolyte gradients, disruption of the actin cytoskeleton, activation of phospholipases, and changes in gene expression. Renal hypoxia induces the loss of epithelial polarity along the proximal tubules and the selective induction of growthresponse genes with rapid DNA fragmentation (suggestive of apoptosis) along the medullary thick limbs. Ischemic injury to renal vessels increases renovascular reactivity and predisposes patients to secondary ischemic insults from hypotension during the recovery from acute renal failure. Ischemia induces the expression of histocompatibility antigens on renal tubular cells and of intercellular adhesion molecules on endothelial cells, which leads to the local aggregation of neutrophils and platelets. After ischemia, intrarenal congestion is prominent in the outer medulla because of regional hypoxia and because the vasa recta are easily compressed by surrounding tubular edema [18, 19].

Acute Morphologic Lesions in Tubules

Anoxic damage along the tubules is governed by the intrinsic vulnerability of the various nephron segments and by the tissue gradients of oxygenation. Glomeruli and collecting ducts are relatively resistant to a lack of oxygen. By contrast, both proximal and distal tubules (especially medullary thick limbs) are intrinsically susceptible to hypoxia [20]. Nevertheless, the distribution of tubular damage in vivo appears to be determined largely by intrarenal oxygen gradients. Some of the cellular events associated with cell death and the restoration of tubule integrity are shown in figure 3 [21]. Ultimately, the mainstay is the maintenance of systemic arterial pressure at a value compatible with renal perfusion pressure: other factors can be concomitant but don’t play such a primary role. From the above comes that the risk factors for ARF in ICU are all these conditions reducing an effective circulating volume and lead to a further decrease in mean arterial pressure and thus also renal perfusion pressure such as: hypotension, hypoxia, the presence of sepsis and/or SIRS, fluid restriction and depletion, nephrotoxicity, positive pressure ventilation, and raised intraabdominal pressure.

Piccinni/Carraro/Ricci

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Fig. 3. Tubular-cell injury and repair in ischemic acute renal failure. From Thadhani et al. [21], modified.

All this speculation confirms the idea that ARF is a ‘broad church’ with heterogeneity of causes and clinical presentation making extremely difficult the comparison of different study populations at different times ARF in ICU patients. These factors should be taken into account also when testing new approaches for the prevention and treatment of ARF and other organ dysfunctions in the critically ill [22] because the factors implicated in the development of ARF and its associated poor prognosis are not well defined in the literature and studies aimed at identifying risk factors could assist in our understanding of this disease process.

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Groeneveld AB, Tran DD, Van der Meulen J: Nauta JJ, Thijs LG: Acute renal failure in the medical intensive care unit: Predisposing, complicating factors and outcome. Nephron 1991;59:602–610. Vilkes B, Mailloux L: Acute renal failure: Pathogenesis and prevention. Am J Med 1986;80:1129. Pinsky MR, Matuschak GM: Multiple system organ failure: A unifying hypotesis. J Crit Care 1990;5:108–114. Brivet F, Kleinknecht D, Loirat P, Landais P: Acute renal failure in intensive care units – causes, outcome and prognostic factors: A prospective multicentre study. Crit Care Med 1996;24:192–198. Levy E, Viscioli C, Horowitz R: The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489–1494. Conlon PJ, Stafford-Smith M, White WD: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 1999;14:1158–1162. Ostermann ME, Taube D, Morgan CJ, Evans TW: Acute renal failure following cardiopulmonary bypass: A changing picture. Intens Care Med 2000;26:565–571. Vivino G, Antonelli M, Moro ML, Cottini F, Conti G, Bufi M, Cannata F, Gasparetto A: Risk factors for acute renal failure in trauma patients. Intens Care Med 1998;24:808–814. Endre ZH: Post cardiac surgery acute renal failure in the 1990s. Aust NZ J Med 1997;25:278–279. Brezis M, Rosen S: Hypoxia of the renal medulla: Its implications for disease. N Engl J Med 1995;332:647–655. American College of Chest Physisians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–874. Bone RC: Immunologic dissonance: A continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996;125:6780–6787. de Mendonça A, Vincent JL, Suter PM, Moreno R, Dearden NM, Antonelli M: Acute renal failure in the ICU: Risk factors and outcome evaluated by the SOFA score. Intens Care Med 2000;26:915–921. Abbis IA, Camerons JS: Epidemiology of acute renal failure in the intensive care unit; in Ronco C, Bellomo R (eds): Critical Care Nephrology. Amsterdam, Kluwer Academic Publishers, 1998, pp 133–141. Brady H, Singer G: Acute renal failure. Lancet 1995;346:1533–1540. Toda N, Takahashi T, et al: Tin chloride pretreatment prevents renal injury in rats with ischemic acute renal failure. Crit Care Med 2002;30:1512–1522. Tetta C, Mariano F, Buades J, Ronco C, Wratten ML, Camussi G: Relevance of platelet-activating factor in inflammation and sepsis: Mechanisms and kinetics of removal in extracorporeal treatments. Am J Kidney Dis 1997;5(suppl 4):S57–S65. Majno G, Joris I: Apoptosis, oncosis, and necrosis: An overview of cell death. Am J Pathol 1995; 146:3–15. Black SC, Huang JQ, Rezaiefar P, et al: Colocalization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. J Mol Cell Cardiol 1998;30:733–742. Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 1997;3:614. Thadhani R, Pascual M, Bonventre J: Acute renal failure. N Engl J Med 1996;334:1448–1460. Vincent JL: Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med 1997;371–374.

Pasquale Piccinni Department of Anesthesiology and ICU, St. Bortolo Hospital Via Rodolfi 37, IT–36100 Vicenza (Italy) Tel. ⫹39 444 993862 – 3400, Fax ⫹39 444 927567 E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 19–30

Pathophysiology of Ischemic Acute Renal Failure Inflammation, Lung-Kidney Cross-Talk, and Biomarkers

Joseph V. Bonventre Renal Division, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, and the Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Boston, Mass., USA

Ischemic acute renal failure (ARF) is a syndrome that results from a mismatch between oxygen and nutrient delivery to the nephrons and energy demand of the nephrons. At times there is a clearly defined transient drop in total or regional blood flow to the kidney which results from compromise of the systemic circulation; at other times, for example in the setting of sepsis, the reduction in perfusion may not be associated with systemic signs of hypotension or circulatory compromise. ARF is frequently associated with multiple organ failure and sepsis. Despite advances in preventative strategies and support measures, this syndrome continues to be associated with significant morbidity and mortality. In animal models, experimental renal ischemia results in rapid loss of cytoskeletal integrity and cell polarity. There is shedding of the proximal tubule brush border, mislocalization of adhesion molecules and other membrane proteins such as the Na
K
ATPase, as well as apoptosis and necrosis [37]. With severe injury, viable and non-viable cells are desquamated leaving regions where the basement membrane remains as the only barrier between the filtrate and the peritubular interstitium. This allows for backleak of the filtrate, especially under circumstances where the pressure in the tubule is increased due to intratubular obstruction resulting from cellular debris in the lumen interacting with proteins such as fibronectin which enter the lumen [41]. In contrast to the heart or brain, the kidney can completely recover from an ischemic or toxic insult that results in cell death. Surviving cells that remain adherent undergo repair with the potential to recover normal renal function. When the kidney recovers from acute injury it relies on a sequence of events

that include epithelial cell spreading and possibly migration to cover the exposed areas of the basement membrane, cell dedifferentiation and proliferation to restore cell number, followed by differentiation which results in restoration of the functional integrity of the nephron [2]. In this review I will focus briefly on three aspects of the pathogenesis of acute renal failure: (1) the role of inflammation; (2) pulmonary-renal cross-talk, and (3) biomarkers of injury.

Inflammation

The pathogenesis of ischemic acute renal failure has been attributed to abnormal regulation of local blood flow following the initial ischemic episode. Persistent generalized preglomerular vasoconstriction may be a contributing factor; however, we believe that a more important pathophysiological component of ischemic ARF is a reduction in local blood flow to the outer medulla. Despite the extensive literature suggesting that enhanced vasoconstriction, mediated by various endogenous vasoactive agents, contributes to the pathophysiology of acute renal failure, no vasodilator has proved useful in preventing or treating ARF associated with tubular necrosis in man. In animals protective effects of agents designed to block vasoconstrictors such as endothelin may be related to the effects of these agents on neutrophil adhesion or other aspects of leukocyteendothelial interactions [34]. Vasodilators, such as nitric oxide, also can have effects to decrease inflammation. NO inhibits TNF-induced adhesion of neutrophils to endothelial cells, stimulated by TNF-, which would also be protective [23]. It has been known for quite some time now that there is less flow to the medullary than the cortical region in the postischemic kidney [39]. In addition, as endothelial cells are injured with resulting cell swelling and increased expression of cell adhesion molecules, so also are leukocytes activated. Enhanced leukocyte-endothelial interactions can result in cell-cell adhesion, which can physically impede blood flow [5]. Furthermore, these interactions will additionally activate both leukocytes and endothelial cells and contribute to the generation of local factors that promote vasoconstriction especially in the presence of other vasoactive mediators, resulting in compromised local blood flow and impaired tubule cell metabolism [35]. These leukocyte-endothelial interactions likely impact the outer medulla to a greater extent than the cortex. The concept that endothelial cells are a target of post-ischemic renal injury was suggested as early as 1972 by Leaf and colleagues when they described endothelial swelling and narrowing of the blood vessel lumen as important features of post-ischemic injury [12]. There is marked congestion of the outer medulla after ischemia [28]. Recently, evidence for endothelial dysfunction in the cortex has also been presented in studies that demonstrated

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retrograde blood flow through peritubular capillaries upon reperfusion following ischemia [7]. With reperfusion, a partial transient compromise of the patency of the peritubular capillaries was also observed. When human umbilical vein endothelial cells or human embryonic kidney cells, stably expressing endothelial nitric oxide synthase, were administered either intravenously or into the renal artery following ischemia, these cells implanted into the kidney and resulted in partial functional protection against injury [7]. In addition, following prolonged ischemia (60 min) in the rat, peritubular capillaries suffer permanent damage [1]. The number of microvessels in the inner stripe of the outer medulla declines, with the reduction in number associated with increased tubulointerstitial fibrosis and altered concentrating ability. With ischemia-reperfusion, endothelial cells upregulate integrins, selectins, and members of the immunoglobulin superfamily, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM). Administration of anti-ICAM-1 antibodies prior to renal ischemia-reperfusion protects the kidney from injury [20]. Kidneys of ICAM-1 knockout mice also are protected [21]. There are many mechanisms by which leukocytes potentiate renal injury. Leukocytes are activated by inflammatory mediators, including cytokines, chemokines, eicosanoids, and reactive oxygen species (ROS), which upregulate adhesion molecules that engage counter-receptors on the activated epithelium. Leukocytes are recruited and activated by chemokines, which are upregulated by the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor- (TNF-). TNF-, IL-1, and IFN-, produce a number of injurious changes in proximal tubular epithelial cells. These cytokines also disrupt cell-matrix adhesion dependent on 1 integrin, inducing cell shedding into the lumen. Leukocyte subgroups are likely to contribute in different ways to ischemiareperfusion injury. Myeloperoxidase activity is elevated soon after ischemic insult and may originate from macrophages and/or neutrophils [28]. If neutrophil accumulation is prevented, however, tissue injury is ameliorated [21]. It is possible that neutrophil depletion models, however, may not adequately differentiate involvement of neutrophils from T lymphocytes and macrophages. Later phases of ARF are characterized by infiltration of macrophages and T lymphocytes which predominate over neutrophils. Knock-out mice lacking CD4
/CD8
, a cell adhesion receptor on T lymphocytes, are protected from ischemia-reperfusion injury [32], suggesting a causal role for T lymphocytes in mediating injury. In addition, blockade of T cell CD28-B7 costimulation protects against ischemic injury in rats and significantly inhibits T cell and macrophage infiltration and activation in situ [10]. The role of the T cell, however, has been recently questioned. Mice deficient in recombination-activating

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gene (RAG)-1 lack T and B cells and do not produce immunoglobulins or T cell receptor proteins. In the absence of these cells and their receptors, RAG-1 deficient mice are not protected from ARF induced by ischemia. Tubular necrosis and neutrophil infiltration are present to a degree comparable to that seen in wild type mice [30]. Complement may also potentiate leukocyte-endothelial interactions. In a number of different tissues exposed to ischemia-reperfusion, complementdependent upregulation of endothelial cell adhesion molecules, with resulting neutrophil accumulation in the vasculature, has been implicated as a mechanism for complement-mediated injury [15]. Some investigators, however, suggest that the primary effect of complement in kidney ischemia-reperfusion is on the epithelial cell due to a direct effect of the membrane attack complex of complement [40]. ROS that are generated during reperfusion and as a result of the inflammatory response play a major role in cell injury. ROS are generated by activated infiltrating leukocytes and by epithelial cells. ROS are directly toxic to tubular epithelial cells, with ROS generating systems mimicking the effects of ischemic injury [24]. In some cases, scavengers (superoxide dismutase, glutathione, vitamin E) and inhibitors of ROS (deferoxamine) have been found to protect against renal injury [26]. The presence of ROS can result in the peroxidation of lipids in cell membranes, protein denaturation and DNA strand breaks. Lipid peroxidation by ROS enhances membrane permeability and impairs function of membrane enzymes and ion pumps. ROS-induced strand breaks in DNA leads to activation of DNA repair mechanisms, including the nuclear enzyme poly(ADP-ribose) synthetase (PARS). PARS transfers ADP-ribose from nicotinamide adenine diphosphate (NAD) to nuclear proteins. Following ischemiareperfusion, PARS is activated, NAD is depleted and generation of cellular ATP is inhibited, worsening the injury. This amplification of injury, also called the PARS suicide, may be the major mechanism by which ROS is directly toxic to cells. Inhibiting PARS protects renal cells against ROS-induced injury, in particular, resulting from ischemia-reperfusion [8]. ROS also upregulate chemokine expression. Transgenic mice overexpressing the anti-oxidants, intracellular and extracellular glutathione peroxidases, are protected against ischemic injury [19]. These animals have less induction of the chemokines, interleukin8 (IL-8) and monocyte chemotactic protein-1 (MCP-1), less neutrophil infiltration and less functional injury compared to the wild type controls, suggesting that the effects of ROS are mediated by chemokines. Exposure of leukocytes to circulating cytokines reduces their deformability and enhances their tendency to be sequestered [36]. Sequestered leukocytes can then potentiate injury by further generating more ROS and eicosanoids, enhancing inflammation and vascular tone.

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Tubule Contribution to Inflammatory Injury

Both the S3 segment of the proximal tubule and the medullary thick ascending limb (MTAL) are located in the outer stripe of the outer medulla. This region of the kidney is marginally oxygenated under normal conditions and after an ischemic insult, oxygenation is further compromised because the return in blood flow is delayed. Both segments of the nephron contribute to the inflammatory response in ARF [4]. The tubule epithelial cells are known to generate proinflammatory and chemotactic cytokines such as TNF-, MCP-1, IL-8, interleukin-6 (IL-6), interleukin-1 (IL-1), and TGF-, MCP-1, IL-8, RANTES and ENA-78 [6]. Proximal tubular epithelial cells may respond to T lymphocyte activity through activation of receptors for T cell ligands [22]. When CD40 is ligated in response to interaction with CD154, there is MCP-1 and IL-8 production, TRAF6 recruitment, and MAPK activation in the proximal epithelial cell [22]. CD40 also induces RANTES production by human renal tubular epithelia, an effect which is amplified by production of IL-4 and IL-13 by Th2 cells, a subpopulation of T cells [11]. B7–1 and B7–2 can be induced on proximal tubule epithelial cells in vivo and in vitro. After B7–1 and B7–2 induction, proximal tubule epithelial cells costimulate CD28 on T lymphocytes resulting in cytokine production [25].

Protection against Injury by Ischemic Preconditioning

An area of increasing interest is the possibility of rendering an organ resistant to subsequent injury by a prior insult or preconditioning maneuver. Ischemic preconditioning of the kidney confers protection against a subsequent ischemic attack [3]. Identification of the mechanisms responsible for renal ischemic preconditioning will likely facilitate our understanding of the pathophysiology of ischemic injury and guide the development of novel therapeutics aimed at mimicking the protective mechanism(s). Several candidates that could potentially serve as mediators of preconditioning have been identified. These include activation of NOS [27] and phosphatidylinositol-3-kinase Akt/PKB pathways, reduction in the relative activation of JNK as compared to ERK1/2 [28, 29], and induction of heat shock proteins, heme oxygenase, and endoplasmic reticulum stress proteins [16]. A recent review discusses many of these candidate mediators of preconditioning in more detail [3]. Of these potential mediators, the NOS pathway is particularly important to mention. Recently, this laboratory demonstrated that iNOS is responsible for a component of the long-term protection afforded the kidney by ischemic preconditioning [27]. Thirty minutes of prior ischemia results in a prolonged increase

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in the expression of iNOS and eNOS as well as heat shock protein (HSP)-25. In addition, there is increased interstitial expression of alpha smooth muscle actin, an indicator of long-term renal interstitial changes. Gene deletion of iNOS, but not eNOS, increased kidney susceptibility to ischemia, as did treatment with pharmacological inhibitors of NO synthesis, including N-nitro-L-arginine (L-NNA) and L-N6-(1-iminoethyl)lysine (L-NIL), the latter a specific inhibitor of iNOS. When the initial period of ischemia was reduced (15 min), there was less protection of the kidney from subsequent ischemia on day 8. Under these conditions, there was no sustained increase in iNOS or eNOS expression, and protection was not abolished by L-NIL treatment, suggesting that the residual protection was not related to iNOS. In addition, renal function was not impaired and expression of interstitial alpha-smooth muscle actin did not change. The data indicate that iNOS plays an important role in kidney protection afforded by prolonged ischemic preconditioning and that persistent long-term changes in the renal interstitium may be critical in affording this protection by sustaining iNOS synthesis. In addition, this study is the first to demonstrate in any organ system that partial protection persists up to 12 weeks after an initial ischemic event. The iNOS-independent protection associated with preconditioning may be related, at least in part, to an upregulation of HSP-25. Mitogen-activated protein (MAP) kinases are also likely to be involved in affording protection following ischemic preconditioning [28]. MAP kinases are ubiquitously expressed serine/threonine kinases which, in mammalian cells, play central roles in determining if the response to multiple signaling inputs will be proliferation, differentiation or apoptosis. In mammalian cells, three MAP kinase cascades have been identified. The best studied of these include the extracellular signal-regulated kinase (ERK) cascade, involved in cell proliferation and differentiation in a variety of cell types. The ERK pathway is activated by growth factors and many other agonists, including vasoactive peptides. Jun N-terminal kinase (JNK), also known as stress-activated protein kinase (SAPK), and p38 are components of the two other MAP kinase cascades. JNK and p38 are activated by inflammatory cytokines (TNF and IL-1) and with cellular stress, including genotoxic stress and osmolar stress. They are only minimally activated by growth factors. JNK has been implicated in proximal tubular cell injury and is increased following ATP depletion in vitro and ischemia-reperfusion injury in vivo [31]. Interestingly, ERK is activated predominantly in distal cells (MTAL) [33], perhaps explaining in part the differential susceptibility to injury of the proximal and distal nephron segments. When the kidney is preconditioned to injury by ischemia, after the second ischemic exposure activation of JNK and p38 is markedly reduced, as is activation of their upstream MAPK kinases (MKK7, MKK4 and MKK3/6). By contrast, activation of ERK1/2 and its upstream MAPKK activator, MKK3/4, is unaltered by preconditioning. Thus, the relative ratio of

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60

L-NAME

*

50

*

40 30 †

20

†

10 0 VT 7

VT 20

VT 20NS

Albuminuria (mg/24h)

24-Hour total protein/creat (mg/g creat)

No treatment

70

16 14 12 10 8 6 4 2 0

*

VT 7

VT 20

VT 20NS

Fig. 1. Effects of mechanical ventilation and N-nitro-L-arginine methyl ester (LNAME) on urine protein excretion. Twenty-four-hour urine total protein normalized to total creatinine excretion (a) and albumin (b) are depicted. Ventilation was at 85 breaths/min for 2 h at 7 (VT 7) or 20 ml/kg without (VT 20) or with (VT 20 NS) normal saline (10 ml/kg) administration. Large tidal volume ventilation (VT 20), with or without normal saline administration, caused significant proteinuria compared with the VT 7 group (n  6 in each group). Proteinuria and albuminuria were mitigated by treating the animals with L-NAME *p  0.05 vs. VT 7; †p  0.05 vs. no treatment at VT 7. Modified with permission from Choi et al. [9].

ERK1/2 activation to JNK or p38 activation is enhanced in the preconditioned postischemic kidney.

Lung-Kidney Cross-Talk

Many of our patients with ARF have multiple organ failure and many are on positive pressure mechanical ventilation. We have recently found that ventilation of the lung has distal effects on the kidney even if the kidney has not been manipulated in the rat [9]. Rats were ventilated with room air at 85 breaths/min for 2 h with either VT 7 or 20 ml/kg. Positive pressure ventilation resulted in increased microvascular leak in the lung that is dependent on nitric oxide synthase (NOS) expression. Kidney microvascular leak, which was assessed by measuring 24-hour urine protein and tissue Evans blue dye, was found to be markedly increased. There was significant microvascular leak in both lung and kidney with large VT (20 ml/kg) ventilation. Injection of 0.9% NaCl corrected the hypotension and the decreased cardiac output related to large VT, but it did not attenuate microvascular leak in lung and kidney. There was an increase in total proteinuria and albuminuria resulting from the ventilation (fig. 1). Serum vascular endothelial growth factor was significantly elevated in large VT groups. Endothelial NOS but not inducible NOS expression significantly increased in the lung and kidney tissue with large VT ventilation. The NOS inhibitor, N-nitro-L-arginine methyl

Pathophysiology of Ischemic Acute Renal Failure

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ester (L-NAME), attenuated the microvascular leak in lung and kidney and the proteinuria seen with hyperventilation. Endothelial NOS may mediate the systemic microvascular leak in this model of ventilation-induced lung injury. These findings may have important implications for the pathophysiology of ischemic ARF since enhanced microvascular permeability in the renal parenchyma of the outer medulla could be expected to contribute to outer medullary congestion and impaired blood flow through the microcapillary bed supplying the tubule structures in that region of the kidney.

Biomarkers

A major shortcoming in our ability to conduct clinical studies to test putative therapeutic agents in ARF, and hence test pathophysiological concepts reflected by the therapeutic approach, is the lack of a biomarker that will herald the disease early enough so that intervention can be introduced at a time when there is a reasonable chance to alter the natural history of the disease. Therapeutic intervention is in general delayed in ARF. There is no equivalent of ‘troponin’ or creatinine phosphokinase (CPK) which can be used as early markers for ischemic injury in the heart. Biomarkers for ischemic injury could be monitored in the blood or urine. While several urinary proteins have been evaluated as potential non-invasive markers of renal injury [38] none of these markers have been used successfully to screen for early renal injury or to identify the site of injury within the kidney. The availability of sensitive and specific urine markers of ARF would lead to improvements in diagnosis, better enable monitoring of therapy, as well as establishment of prognosis and risk assessment. In addition, identification of urinary proteins expressed during ARF may lead to the identification of novel targets for therapy, or of markers that could be used to evaluate the effectiveness of therapeutic interventions. Hampel et al. [13] published urinary protein profiles in 25 patients following administration of radiocontrast material. Using surface-enhanced laser desorption/ionization (SELDI) protein chip array-time of flight mass spectrometry, they demonstrated perturbations in the patterns of urinary protein expression following cardiac catheterization. The temporal course of protein expression differed between patients with normal renal function and patients with impaired renal function at baseline. Since the patient population was small and the follow-up time was short, no correlation was found between changes in urinary protein expression patterns and the development of ARF. Furthermore, specific proteins were not identified. Nevertheless, it is quite likely that some of the proteins found could serve as markers of impending contrast-induced acute renal failure. While these results must be extended and confirmed by larger studies, they suggest that uroscopy

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with mass spectrometry may lead to the identification of markers of ARF with important diagnostic and/or predictive implications. Our laboratory has a long-standing interest in identifying clinically useful markers of acute renal failure. We cloned from rats, mice and humans a novel adhesion molecule, kidney injury molecule 1 (KIM-1 names the human form and Kim-1 names the rodent form), which may serve as a marker of ischemic tubular injury [17]. In addition to its upregulation in the postischemic kidney, Kidney injury molecule-1 is upregulated in various models of toxic renal injury in the rat [18]. In addition, it is expressed on the proximal tubule epithelial cells in human kidney biopsy sections from patients with acute tubular necrosis [14]. Importantly, there is no staining for KIM-1 in normal human kidney, suggesting that KIM-1 is a marker of injured renal tissue. We recently investigated the utility of KIM-1 as a marker of acute tubular damage in humans. We found that soluble KIM-1 was detected at higher levels in the urine of patients with acute tubular necrosis (ATN) compared to patients with other forms of acute renal failure or chronic renal disease [14]. These findings suggest that a soluble form of KIM-1 may be a clinically useful marker for proximal renal tubular injury. We also found that levels of KIM-1 increase and return to baseline following aortic cross-clamping in a patient with no overt clinical evidence of ARF. This suggests that KIM-1 may be useful as a marker of ATN early in the course of ARF, before other markers of ARF become evident. We are working to further characterize the function of KIM-1 and to characterize its utility as a biomarker for ATN.

Conclusions

Ischemic renal injury is a dynamic process that often exists in the context of multiple organ failure and involves hemodynamic alterations, inflammation and direct injury to the tubular epithelium followed by a repair process that restores epithelial differentiation and function. Inflammation is a significant component of this disease, playing a considerable role in its pathophysiology. Although significant progress has been made in defining the major components of this process, the complex cross-talk between endothelial cells, inflammatory cells and the injured epithelium, with each generating and often responding to cytokines and chemokines, is not well understood. In addition, we have not adequately integrated the contributions of other organs in this pathophysiology. A better understanding of the pathophysiology underlying this disease with better ways to limit the inflammatory component and/or promote the repair process, will depend upon the identification of biomarkers that can help us identify the disease early at a time when intervention can alter its

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natural history. Progress is being made on multiple fronts but we continue to be humbled by ARF whose mortality rate has not significantly changed over four decades.

Acknowledgments This work was supported by the National Institutes of Health (grants DK 39773, DK 38452, NS 10828, DK54741, DK 46267).

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Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M: Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 1998;273:4135–4142. Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV: Kidney injury molecule-1: A tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol 2004; 286:F552–F563. Ishibashi N, Weisbrot-Lefkowitz M, Reuhl K, Inouye M, Mirochnitchenko O: Modulation of chemokine expression during ischemia/reperfusion in transgenic mice overproducing human glutathione peroxidases. J Immunol 1999;163:5666–5677. Kelly KJ, Williams WW, Colvin RB, Bonventre JV: Antibody to intercellular adhesion molecule-1 protects the kidney against ischemic injury. Proc Natl Acad Sci USA 1994;91:812–816. Kelly KJ, Williams WW, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV: Intercellular adhesion molecule-1 deficient mice are protected against renal ischemia. J Clin Invest 1996;97:1056–1063. Li H, Nord EP: CD40 ligation stimulates MCP-1 and IL-8 production, TRAF6 recruitment, and MAPK activation in proximal tubule cells. Am J Physiol 2002;282:F1020–F1033. Linas S, Whittenburg D, Repine JE: Nitric oxide prevents neutrophil-mediated acute renal failure. Am J Physiol 1997;272:F48–F54. Malis CD, Weber PC, Leaf A, Bonventre JV: Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: Evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids. Proc Natl Acad Sci USA 1990;87:8845–8849. Niemann-Masanek U, Mueller A, Yard BA, Waldherr R, van der Woude FJ: B7–1 (CD80) and B7–2 (CD 86) expression in human tubular epithelial cells in vivo and in vitro. Nephron 2002;92:542–556. Paller MS: Renal work, glutathione and susceptibility to free radical-mediated postischemic injury. Kidney Int 1988;33:843–849. Park KM, Byun JY, Kramers C, Kim JI, Huang PL, Bonventre JV: Inducible nitric oxide synthase is an important contributor to prolonged protective effects of ischemic preconditioning in the mouse kidney. J Biol Chem 2003;278:27256–27266. Park KM, Chen A, Bonventre JV: Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment. J Biol Chem 2001;276:11870–11876. Park KM, Kramers C, Vayssier-Taussat M, Chen A, Bonventre JV: Prevention of kidney ischemia/reperfusion-induced functional injury, MAPK and MAPK kinase activation, and inflammation by remote transient ureteral obstruction. J Biol Chem 2002;277:2040–2049. Park P, Haas M, Cunningham PN, Bao L, Alexander JJ, Quigg RJ: Injury in renal ischemiareperfusion is independent from immunoglobulins and T lymphocytes. Am J Physiol 2002; 282:F352–F357. Pombo CM, Bonventre JV, Avruch J, Woodgett JR, Kyriakis JM, Force T: The stress activated protein kinases are major c-jun amino-terminal kinases activated by ischemia and reperfusion. J Biol Chem 1994;269:26545–26551. Rabb H, Daniels F, O’Donnell M, Haq M, Saba SR, Keane W, Tang WW: Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am J Physiol 2000;279: F525–F531. Safirstein RL, Bonventre JV: Molecular response to ischemic and nephrotoxic acute renal failure; in Schlündorff D, Bonventre JV (eds): Molecular Nephrology. New York, Marcel Dekker, 1995, pp 839–854. Sanz MJ, Johnston B, Issekutz A, Kubes P: Endothelin causes P-selectin-dependent leukocyte rolling and adhesion within rat mesenteric microvessels. Am J Physiol 1999;277:H1823–H1830. Sheridan AM, Bonventre JV: Cell biology and molecular mechanisms of injury in ischemic acute renal failure [In Process Citation]. Curr Opin Nephrol Hypertens 2000;9:427–434. Suwa T, Hogg JC, Klut ME, Hards J, van Eeden SF: Interleukin-6 changes deformability of neutrophils and induces their sequestration in the lung. Am J Respir Crit Care Med 2001;163: 970–976.

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Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996;334:1448–1460. Tolkoff-Rubin NE, Rubin RH, Bonventre JV: Noninvasive renal diagnostic studies. Clin Lab Med 1988;8:507–526. Vetterlein F, Pethö A, Schmidt G: Distribution of capillary blood flow in rat kidney during postischemic renal failure. Am J Physiol 1986;251:H510–H519. Zhou W, Farrar CA, Abe K, Pratt JR, Marsh JE, Wang Y, Stahl GL, Sacks SH: Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest 2000;105:1363–1371. Zuk A, Bonventre JV, Matlin KS: Expression of fibronectin splice variants in the postischemic rat kidney. Am J Physiol 2001;280:F1037–F1053.

Joseph V. Bonventre, MD, PhD Brigham and Women’s Hospital, Renal Division MRB-4, 75 Shattuck Street, Boston, MA 02115 (USA) Tel. +1 617 429 2146, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 31–43

Pathophysiology of Sepsis and Multiple Organ Failure: Pro- versus Anti-Inflammatory Aspects Michael R. Pinsky Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pa., USA

Many of the common severe illnesses, including sepsis and septic shock, severe trauma, burns or other overwhelming stresses, are characterized by the widespread activation of host innate immunity response. The hallmark of this activation is the release of potent inflammatory mediators into the circulation [1]. This response is often referred to as the systemic inflammatory response syndrome (SIRS) [2] to accentuate the non-specific inflammatory nature of the process as assessed by measures of circulating active small molecules capable of inducing a generalized inflammatory response on remote organ systems. Furthermore, if sustained, this system-wide inflammatory process may result in loss of the normal vasoregulatory adaptations to stress and metabolic demand. This peripheral vascular paralysis often precedes the development of multiple organ system dysfunction and death in critical illness. Historical perspectives, recent clinical trials of immunomodulating agents and cellular and molecular data have created an exciting and productive story that only recently lead to the first positive outcome trial of pharmacotherapy for severe sepsis.

Initial Cellular Events of Innate Immunity: Outside-In Signaling

Inflammatory processes require immune cell response, recruitment into the local area and further activation if the inflammatory response is to be sustained. This response involves initial cellular recognition of the stimulant via innate immune systems. This initial recognition process involves a complex interaction of host-derived co-factors, such as lipopolysaccharide-binding protein,

compliment activation and coating of foreign biological material (bacteria) and release of pro-coagulant materials. Many of these activation complexes nonspecifically bind to the host universal inflammation receptor CD14 whose transmembrane domain, the Toll-like receptor (TLR), activates an intracellular tyrosine kinase system that eventually activates the oxidant sensitive proinflammatory promoter, nuclear factor-
B (NF-
B). Presently, 10 specific TLR proteins have been identified; however, TLR-2 and TLR-4 appear to be primarily involved in the innate immunity aspects of circulating monocytes, polymorphonuclear leukocytes (PMN) and dendrocytes and TLR-4 appears to be trans-membrane moiety that it associates with in order to initiate outside-in cell signaling [31]. Simultaneously, expression of novel cell surface receptors and gene induction and new protein synthesis occur. Following this immune competent cells and responsive parenchymal cells make novel protein species needed to induce a localized inflammatory response. The release of immune active mediators stimulates primary target cell (immune cell) responses via similar mechanisms to those described by the primary activation sequence, except now more complex cell surface receptors, co-stimulating factors and parallel mediator systems interactions co-exist. These include activation of the contact system (compliment), fibrinolytic system (thrombin and activate protein C) and paired cytokine stimuli (TNF- and IL-1, or IL-8 and MIP-1). Secondary parenchymal cell response via these soluble mediators and formed cell interactions then occur via cell-cell, or paracrine activation. The low molecular weight protein mediators that initiate, sustain and modulated the inflammatory interactions are called cytokines. With the exception of pre-pro-IL-1, cytokines have to be synthesized de novo in response to a specific external stimulus. Thus, the inflammatory response is a determined process requiring energy and protein synthesis to occur, post-translational protein processing to mature the mediators, and secretion to get them into the microenvironment needed for cell-cell signaling. Based on our understanding of their actions, cytokines are presumably present to modulate cellular response and metabolism on a local or paracrine level. However, once these cytokines gain access to the blood stream in numbers capable of inducing a systemic immune cell response, then a generalized inflammatory response develops. It is still not clear to what extent this systemic response is adaptive or maladaptive to the host. On the one hand, fever and the induction of release of acute-phase proteins by the liver and heat shock proteins into the cells of the body improve survival in bacterial infections, and malaise may be a very adaptive symptom in limiting the host activity and excess consumption of limited energy resources. However, on several levels the generalized inflammatory response may not confer survival advantage for the host.

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Clearly, on a local level, a violent inflammatory response is highly effective at containing, killing and removing foreign biological material (alive or dead) and the lack of a vigorous local inflammatory response may impair survival. This was best exemplified by the recent documentation that patients with a mild TNF- response, as characterized by a specific genotype of a mild TNF- responder, had a greater likelihood of dying from meningococcal meningitis than patients who had the vigorous TNF- responds genotype. Still, persistent activation, rather than massive pulse activation appears to be detrimental for survival. Pinsky et al. [3] measured the circulating levels of TNF-, IL-1, and IL-2 and the immunomodulating cytokines IL-6 and interferon-. Although levels of IL-1, IL-2 and interferon- did not correlate with any aspect of the generalized inflammatory response, severity of illness nor mortality, sustained elevations of the pro-inflammatory cytokine TNF- and the immunomodulating cytokine IL-6 did. Thus, rather than the maximal serum levels of any specific cytokines, those patients who will subsequently develop multiple organ dysfunction and may eventually die display a persistent elevation of TNF- and IL-6 in their blood [3–5]. This observation of a sustained plasma elevation of TNF- and IL-6 in severe sepsis and its association with a poor outcome initially led to the erroneous assumption that SIRS reflected an isolated excess pro-inflammatory state. However, the increased expression of pro-inflammatory cytokines is only part of this evolving immunologic picture. First Goldie et al. and then others demonstrated that both pro-inflammatory cytokines (TNF-, IL-1, IL-6, and IL-8) and anti-inflammatory species (IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF- receptors I and II (sTNFr-I and sTNFr-II), respectively) co-exist in the circulation, and the anti-inflammatory specifics are markedly increased in patients with established SIRS [6, 7]. Thus, SIRS or sepsis may be more accurately described as a malignant form of intravascular inflammation, rather than merely the over expression of simply pro- or anti-inflammatory substances. This paradoxical expression in the blood of pro- and anti-inflammatory molecular species creates a cacophony of unregulated immunologic noise within the internal milieu that if sustained impairs host adaptability to stress. Since cytokines appear to be an important component of the SIRS we shall first consider cytokine actions.

Intracellular Inflammatory Events

The inflammatory response requires an inflammatory stimulus to initiate it. Initiating inflammatory mediators include bacterial and yeast cell walls, such as endotoxin (lipopolysaccharides or LPS), exotoxins and other products. Vascular

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Key intracellular events in innate immunity CD11b upregulation and activation

TNF-  p50 p65 I-
B 

 LPS TNF- TNF- IL-1 IF- C5a



Oxidative stress  

iNOS and COX2 mRNA



NF-
B

CD14

Serine TLR-4 kinase and MAP kinase

Hsp70



TNF- mRNA

I-
B

HSF Hsp70



Mitochondrial oxidative stress

Hsp70 mRNA



Cytochrome C

Fig. 1. A schematic representation of some of the intracellular processes of pro- and anti-intracellular processes operative in sepsis. External signaling, either from mediator binding to cell surface receptors of CD11b activation induces a series of redundant and parallel intracellular kinase reactions through Toll-like receptors (TLR). Part of this initial activation is the up-regulation the cell surface expression of CD11b/CD18. Inflammation primarily induces an intracellular oxidative stress that can be measured by changes in mitochondrial membrane potential. Oxidative stress activates nuclear factor
B (NF-
B) by phosphorylation cleavage of its inhibitory sub-unit I-
B as well as stressing the mitochondria. I
B is degraded by phosphorylation and ubiquinization and the free remaining active p50-p65 dimer translocates into the nucleus where it binds to promoter sites initiating and/or augmenting mRNA synthesis of specific genes that code for the synthesis of pro-inflammatory mediators (TNF-, IL-1, IL-8, iNOS, COX2, etc.). Intracellular oxidative stress also activates heat shock factor (HSF) that, like NF-kB, migrates into the nucleus and binds to its own promoter regions that augment the synthesis of mRNA coding for heat shock protein (Hsp). One such Hsp is I-kB and others of the 70s class (Hsp70). Hsp70 down-regulates NF-
B activation by both limiting subsequent mitochondrial oxidation and by limiting NF-
B phosphorylation. Also, Hsp70 by limiting mitochondrial oxidative stress minimizes cytochrome release thus decreasing apoptotic stress.

collagen, damaged endothelial surfaces, the denatured proteins caused by thermal injury and oxidative stress all stimulate the innate inflammatory response (fig. 1). These inflammatory mediators bind to cell surface receptors inducing a transmembrane signal transduction and intracellular response via activation of several specific gene promoter proteins. Numerous unrelated exogenous stimulants, such as endo- and exotoxins and endogenous stimulants, activated compliment (C5a), Hageman’s factor (XIIa), and products of generalized cell injury can

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induce immune competent cells (usually modeled as monocytes) to synthesize TNF- and IL-1. Presently, numerous cell surface receptors have been identified [reviewed in reference 31]. One cell-surface receptor with an amazing broad range of affinities to a variety of different types of pro-inflammatory substances is CD14. Many foreign substances, such as endotoxin require initial fusing with lipopolysaccharide binding protein before they can bind to CD14. Thus, hostderived factors (usually proteins) are probably necessary for the host recognition of foreign materials as foreign and initiate the inflammatory response. However, no such intermediate binding appears necessary for stimulation of the inflammatory response via the intrinsic mediators. CD14 then combines with TLR4 to induce a trans-membrane activation of a series of serine kinases that release potent pro-inflammatory promoter proteins which markedly enhance translation of numerous genes encoding proteins essential for the host inflammatory response. The major oxidative stress proinflammatory promoter protein is nuclear factor kappa B (NF-
B), so named because it was originally described as the kappa light chain promoter protein for B lymphocytes. NF-
B is an intracellular species that is resident in the cytosol as a p50p65 heterodimer attached to an inhibitory sub-unit called I
B. The I
B subunit binds to the p65 subunit masking is nuclear binding site. Activation of the heterodimer follows cleavage of I
B by serine kinase-induced I
B phosphorylation. Serine kinase, in turn requires an intracellular oxidative stress to trigger its activation via the TLR4 activation. Importantly, oxidative stress is an early event in inflammation. The phosphorylated I
B is rapidly digested. The active p50-p65 heterodimer migrates into the nucleus, binds to various promoter sites on the genome stimulating mRNA synthesis of genes coding for many if not most of the pro-inflammatory cytokines. A partial list of NF-
B inducible proteins is shown in table 1, and includes all the known potent proinflammatory mediators, such as TNF- and IL-1, as well as the pro-inflammatory enzymes inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). NF-
B is an excellent target for modulating the intracellular inflammatory response. In fact, several intracellular mechanisms exist that modulate NF-
B activity. Studies of endotoxin tolerance allow for examination of these processes. Exposure to small amounts of endotoxin induces an endotoxin-tolerant state in both cell culture and animal models about 8 hours later. In this state, subsequent exposure to a previously lethal dose of endotoxin often does not induce the fatal pro-inflammatory state. The endotoxin-tolerate state lasts in decreasing strength for about 24–36 h, depending on the species and the initial dose of endotoxin. Interestingly, following the induction of an endotoxin-tolerant state, the initial steps of pro-inflammatory signal transduction up to cleavage of I
B can occur. However, the liberated NF-
B appears to be dysfunctional. The reasons for this dysfunction are multiple and not fully defined.

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Table 1. Some of the known target genes regulated by NF-
B Cytokines

Adhesion molecular Immunoreceptors

Acute phase proteins Others

TNF- TNF- IL-2 IL-6 IL-8 interferon- G-CSF GM-CSF endothelial-leukocyte adhesion molecule-1 vascular cell adhesion molecule-1 immunoglobulin
-light chain T cell receptor A and B major histocompatibility class 1 and 2 tissue factor-1 complement factor B complement factor C4 COX-2 lipoxgenase 1

Under baseline conditions the body appears to have a distinctly antiinflammatory flavor. Thus, the initial pro-inflammatory processes operate on a system that at rest exists as a generalized anti-inflammatory one. For example, the endothelium is anti-thrombotic reducing platelet adhesion. Even the immune effector cells carry their preformed pro-inflammatory promoter proteins in a dysfunctional form. This resting anti-inflammatory state actually becomes more pronounced during generalized sepsis. Experimentally, it has been shown that inflammation induces its own counter-regulatory anti-inflammatory response that in the setting of sustain inflammatory stimuli causes a generalized anergic state, referred to as ‘inflammatory stimuli-induced anergy’ or ‘endotoxin tolerance’ [8]. Presumably, inflammatory stimuli-induced anergy minimizes the inflammatory response, preventing a chain-reaction, system-wide activation of the inflammatory processes. However, it also limits the host’s subsequent ability to mount an appropriate inflammatory defense to infection. Anti-inflammatory cytokines, such as IL-4, IL-10 and somewhat by IL-1 (but not TNF-), IL-6 or IL-8, and transforming growth factor- (TGF-) can induce this anergic response. NF-␬B Activation Biology

NF-
B activation requires cleavage of the I
B subunit off the p65 subuit. I
B kinase causes the phosphorylation and subsequent degradation of I
B

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allowing the translocation of NF-
B dimers into the nucleus. I
B binds to the responsive element of the p65 subunit and has a greater affinity for the p65 subunit that does the corresponding response element on the genome. Thus, I
B excess can pull active p50-p65 dimers off their promoter sites in the nucleus or prevent their release from the cytosol all together. NF-
B dimers exist in several forms. However, the two most common forms are the heterodimer p50-p65, which is comprised of the p65 subunit with its active DNA consensus domain binding site and a smaller subunit p50 subunit devoid the active binding site. Importantly, the p65 subunit with its DNA consensus domain-binding site allows gene activation once bound to such promoter regions on chromosomes. The p50 monomer has no such activity [9]. The other common NF-
B form is the p50-p50 homodimer, which does not bind I
B or the genome. Endotoxin-tolerance induced NF-
B dysfunction reflects excess synthesis of the inhibitor of NF-
B, I
B- [10] presumably due to the absence of induction of I
B kinase. When endotoxin tolerant cells are challenged with a second dose of LPS, cytosolic levels of I
B are not reduced, as they are with the initial challenge, and I
B remains in cytoplasm where it sequesters free NF-
B dimers [11]. Furthermore, the I
B- promoter can be up-regulated by NF-
B, thus providing a negative feedback loop for further NF-
B activation [12]. Another adaptive mechanism involves the balance of NF-
B p50-p65 to p50p50 species. The ratio of p65-p50 to p50-p50 determines transcription rates of genes coding for the NF-
B inflammatory proteins. Ratios of NF-
B p50-p65 heterodimer to p50-p50 homodimer of 1.8  0.6 or greater are associated with NF-
B activation inducing mRNA synthesis of these genes, while a ratio of 0.8  0.1 or less confers lack of mRNA transcription following cleavage of I
B [9]. Other post-translational controls on mRNA and protein trafficking also occur but at present have not been identified as being as important as these initial steps. Down-regulation of NF-
B-related intercellular processes is an important aspect of the overall intracellular inflammatory response. However, these mechanisms do not explain why both pro- and anti-inflammatory activation is often sustained in critical illness. Anti-inflammatory pathways are activated by the same stimuli that active pro-inflammatory pathways. The cell does have several anti-inflammatory processes. However, the heat shock protein system is the most prevalent, in terms of mass of protein and scope of its oversight.

Heat Shock Proteins and the Stress Response

The heat shock protein system is a complex, widespread and overarching basic cellular defense mechanism against numerous stresses, such as fever,

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37

trauma, and inflammation [13]. It is the oldest philogenetic cellar defense mechanism identified. The heat shock proteins constitute a significant proportion of the intracellular protein pool. At baseline in the un-stimulated cell they reflect 2% of the resting cellular protein component, whereas in the stressed cell they can comprise up to 20% of the cellular protein pool. Heat shock proteins have several important and varied functions. Their singular distinguishing characteristic is that their expression is up regulated in response to intracellular stress. Although originally described as a specific response to heat shock, it was subsequently demonstrated that many stresses, most notably oxidative stress (H2O2, peroxynitrate, ionized radiation) and even some pharmacologic agents could induce the up-regulation of the heat shock response. The exact mechanism by which heat induces the activation of the heat shock response is unknown. However, the initial intracellular signaling mechanisms are the release of heat shock factor (HSF) from its cytosolic pool complexed with three molecules of heat shock protein 70 (HSP-70). Presumably, oxidative stress induced protein unfolding (denaturation) stimulates HSP-70 to bind to these unfolded proteins and refold them, releasing its co-traveler HSF at the same time. HSF, which like NF-
B, is a protein resident in the cytosol that is activated by the intracellular oxidative stress to make a promoter protein to bind to specific genes to stimulate synthesis of heat shock proteins. Heat shock proteins are classified by the molecular size. This classification is not arbitrary because their functions tend to also follow class size. They are cellular chaperones that prevent nascent proteins from being degraded by cytosolic enzymes. They also aid in the subsequent quaternary folding of nascent proteins prior to export. As a repair process, they aid in the tertiary and quaternary refolding of intracellular protein structure after heat or ionizing radiationinduced unfolding (denaturation). Heat shock proteins confer a survival advantage to their host. Thermal pretreatment is associated with attenuated lung damage in a rat model of acute lung injury induced by intratracheal instillation of phospholipase A2 [14]. Thermal pretreatment reduces mortality rate and sepsis-induced acute lung injury produced by cecal ligation and perforation [15]. The subsequent increased expression of a broad variety of heat shock proteins confers a non-specific protection from not only subsequent oxidative stress but also minimizes the cellular response to proinflammatory stimuli. Survival, in cold blooded animals given an infectious inoculum, is linearly related to body temperature. Finally, if specific heat shock proteins are depleted, then multiple intracellular signaling processes can be affected. Both HSF and NF-
B are induced to become active by similar stimuli. It is not known if all the processes that stimulate HSF activation are the same as those that stimulate NF-
B activation, but during sepsis and other forms of intracellular oxidative stress HSF and NF-
B are activated in a parallel fashion.

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Mitochondria as Both a Marker and Target of Intracellular Inflammation

The production of reactive oxygen species and an associated oxidative stress on the mitochondria is an initial step in the intracellular activation of the inflammatory pathway. It links mediator binding to the cell surface, ischemiareperfusion and traumatic injury with inflammatory gene activation [16]. Mitochondria are the primary energy sources of the cell. They produce ATP by driving electrons down a chemi-osmotic gradient via a transmembrane charge induced by the Krebs’s cycle inside their inner membranes. Loss of internal membrane polarization is a cardinal sign of mitochondrial energy failure and results in leakage of cytochrome C from the mitochondria into the cytosol. Importantly, cytochrome C activates the intrinsic caspase system to initiate apoptosis or programmed cell death. Thus, preventing mitochondrial depolarization would be an important cytoprotective mechanism. The HSP-70 family of heat shock proteins prevents mitochondrial oxidative stress and blunts the inflammatory response. HSP-70 also minimizes nitric oxide, oxygen free radical and stretozotocin cytotoxicity [17]. For these and other reasons, HSP-70 is an inducible protective agent in myocardium against ischemia, reperfusion injury and nitric oxide toxicity [18]. Nitric oxide-induced HSP synthesis blunts the inflammatory response to endotoxin and TNF- in vitro. Evidence that HSP-70 may be active in human sepsis comes from the observation that higher HSP-70 expression is seen in peripheral mononuclear cells in septic patients. Although not conclusive, these data strongly suggest that heat shock proteins, and HSP-70 in particular, may be important in modulating the intracellular inflammatory signal acting at the level of NK-
B. Importantly, Wong et al. [19] identified a potential heat shock responsive element in the I-
B promoter that can be activated by HSF after heat shock. And the heat shock response can also modulate NF-
B inactivation by this increased I-
B expression. Thus, the primary inhibitor of NF-
B activation, I-
B is itself a heat shock protein. The interaction between the heat shock protein system and the pro-inflammatory pathway, however, has yet to be defined.

Is Sepsis Characterized by Excessive Pro- and Anti-Inflammatory Activity? Assessment by Inside-Out Signaling

Both pro- and anti-inflammatory processes are active during acute injury states. This is observable as intracellular activation of both NF-
B and HSF and extracellular expression of both pro- and anti-inflammatory mediators in the bloodstream. Thus, the immune effector cells and parenchyma receive mixed

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messages during acute injury. However, the phenotypic response of pro- or antiinflammatory posturing that they make is often difficult to predict. The normal cellular inflammatory response is essential to survival. It localizes and eliminates foreign material, including microorganisms. Similarly, some degree of systemic inflammatory response is adaptive. Fever reduces microorganism growth, malaise causes the host to rest, and induces both the intracellular heat shock response and the extracellular acute-phase protein release. Both of which minimize oxidative injury. However, inflammation is also destructive. Local abscess formation causes local necrosis, and generalized inflammation can induce both increased necrosis and apoptosis leading to multiple systems organ failure [30]. However, sepsis also carries a strong anti-inflammatory response, with expression of anergy and increased susceptibility to nosocomial infection. All acute severe processes result in the expression in the systemic circulation of cytokines. However, it is difficult to assess the degree of inflammatory stimulation by measuring serum cytokine levels. Serum cytokine levels can change within minutes and may be very different in adjacent tissue compartments [20]. Although an excellent marker of disease severity and a good positive predictor of the subsequent development of remote organ system dysfunction, measuring blood levels of cytokines, such as IL-6 [22], do not aid in defining the pro- to anti-inflammatory balance on in predicting response to therapy. We shifted our attention to the examination of the functional status of circulating immune effector cells. Since polymorphonuclear leukocyte (PMN) activation and localization represent the initial cellular host defense against infection, their tight control is essential to prevent widespread non-specific injury. Subsequently, monocytes localize at the site of inflammation. Their activity appears to become the predominant process in both host defense and repair, especially during the second and third day onward in the course of acute illness. Thus, inhibition of monocyte immune responsiveness is a powerful mechanism to downregulate the inflammatory response. Anergy is a cardinal characteristic of severe illness and reflects macrophage inhibition of antigen processing. Importantly, antigen processing reflects a primary aspect of this cellular response. In this regard, the cell surface receptor family, HLA-DR, is responsible for antigen presentation to antigen-processing cells. Immature monocytes cannot process antigen and have lower cell surface HLA-DR levels. Volk et al. [21] demonstrated that monocytes require HLA-DR levels 20% for normal cell meditated immunity. Lower levels of HLA-DR expression confirm immune suppression. Consistent with the overall theme of increased antiinflammatory responses in severe sepsis, these workers and others have found a profound decrease in HLA-DR expression on circulating monocytes from patients with sepsis.

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Rosenbloom et al. [22] examined the relation between circulating cytokine levels and the expression of the strong 2-integrin surface cell adhesion molecules on circulating immune effector cells. The activation state of circulating immunocytes can be indirectly assessed by measuring the intensity of display on their 2-integrin surface cell adhesion molecules. They showed that all circulating immune effector cells, including PMNs, lymphocytes and monocytes are activated in critical illness. Furthermore, the level of circulating immune effector cell activation is proportional to mean circulating IL-6 levels [22]. Importantly, the degree of organ dysfunction but not the level of shock severity correlated with CD11b expression. Since the level of activation of circulating PMN, as measured by total PMN count and its display of immature forms, is used clinically as an indicator of the host response to systemic inflammation, assessment of PMN responsiveness should also be a good measure of the proand anti-inflammatory balance in severe sepsis. Prior studies have shown that PMNs can be both overactive [23] and dysfunctional [24], and that their CD11b display can be either decreased [25] or increased [26] in critically ill patients. In essence, measuring immune responsiveness of circulating immune effector cells can be used as a functional bioassay. One can also expose native PMN to pro-inflammatory stimuli in vitro and assay their subsequent expression of CD11b. Many proinflammatory stimuli, such as TNF-, IL-8 and phorbol ester can be used to induce this response. The de novo display of CD11b on circulating PMNs and its subsequent change in expression of both total CD11b and its avid form, CBRM1/5 epitope, in response to in vitro stimulation to TNF- or IL-8 characterize the in vivo state of PMN activation and responsiveness. Circulating PMNs of septic humans have a similar phenotype characterized by high CD11b and low L-selectin expression [27]. This is the phenotype of acute activation of the inflammatory response. Thus, severe sepsis is associated with an increased de novo activation of circulating immune effector cells. Paradoxically, however, those same PMNs with a sustained inflammatory state are also impaired in their ability to upregulate CD11b further or to change surface CD11b to the avid state [28] in response to an ex vivo challenge by exposure to biologically significant levels of TNF-. Furthermore, circulating PMN from subjects with severe sepsis have impaired phagocytosis, reduced oxygen burst capacity and diminished in vitro adhesiveness [29]. This desensitization to exogenous TNF- or IL-8 was not due to a loss of TNF receptors because the cell surface TNF- receptor density is not reduced on the cells of septic patients. Importantly, the hyporesponsiveness is extended across all circulating PMN and monocytes in critically ill patients [27]. The NF-
B activity and in vitro responsiveness to LPS of peripheral blood monocytes from septic subjects displays a similar pattern to that seen with

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endotoxin tolerance [30]. The cause of the reduced nuclear translocation of NF-
B is apparently not due to a negative feedback interaction because cytosolic I
B are not increased in sepsis. Rather one sees an increase in the proportion of the inactive p50-p50 species relative to the active p65-p50 species, suggesting that alteration of NF-
B synthesis per se is the primary regulatory function seen in the immune suppression of sepsis. In one study [30], survivors had higher levels of NF-
B than non-survivors, again suggesting that although downregulation of inflammation is a normal aspect of sepsis, and excessive inhibition of the process is associated with a poor prognosis.

Acknowledgement This work was supported in part by the federal government (GM61992–03, NHLBI K-24 HL67181–01A2, and NRSA 2-T32 HL07820–06).

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7

8 9

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Schlag G, Redl H: Mediators of injury and inflammation. World J Surg 1996;20:406–410. Bone RC: Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: What we do and do not know about cytokine regulation. Crit Care Med 1996;24:163–172. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E: Serum cytokine levels in human septic shock: Relation to multiple-system organ failure and mortality. Chest 1993;103:565–575. Thijs LG, Hack CE: Time course of cytokine levels in sepsis. Intensive Care Med 1995;21 (suppl 2):S258–S263. Blackwell TS, Christman JW: Sepsis and cytokines: Current status. Br J Anaesth 1996;77:110–117. Goldie AS, Fearon KC, Ross JA, Barclay GR, Jackson RE, Grant IS, Ramsay G, Blyth AS, Howie JC: Natural cytokine antagonists and endogenous anti-endotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group. JAMA 1995;274:172–217. Vanderpoll T, Malefyt RD, Coyle SM, Lowry SF: Anti-inflammatory 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. Cavaillon JM: The nonspecific nature of endotoxin tolerance. Trends Microbiol 1995;3:320–324. Ziegler-Heitbrock HWL, Wedel A, Schraut W, Strobel M, Wendelgass P, Sterndorf T, Bauerle PA, Haas JG, Riethmuller G: Tolerance to lipopolysaccharide involves mobilization of nuclear factor
B with predominance of p50 homodimers. J Biol Chem 1994;269:17001–17004. Larue KEA, McCall CE: A liable transcriptional repressor modulates endotoxin tolerance. J Exp Med 1994;180:2269–2275. Kohler NG, Joly A: The involvement of an LPS inducible I
B kinase in endotoxin tolerance. Biochem Biophys Res Commun 1997;232:602–607. De Martin R, Vanhove B, Cheng Q, Hofer E, Csizmadia V, Winckler H, Bach FH: Cytokineinducible expression in endothelial cells of an I
B-like gene is regulated by NF
B. EMBO J 1993;12:2773–2779. Jäättelä M, Wising D: Heat shock proteins protect cells from monocyte cytotoxicity: Possible mechanism of self-protection. J Exp Med 1993;177:231–236. Villar J, Edelson JD, Post M, Mullen BM, Slutsky AS: Induction of the heat stress proteins is associated with decreased mortality in an animal model of acute lung injury. Am Rev Respir Dis 1993; 147:177–181.

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Villar J, Ribiero SP, Mullen BM, Kuliszewski M, Post M, Slutsky AS: Induction of the heat shock response reduces mortality rate and organ damage in a sepsis-induced acute lung injury model. Crit Care Med 1994;22:914–921. Polla BS, Jacquier-Sarlin MR, Kantengwa S, Mariethoz E, Hennet T, Russo-Marie F, Cossarizza A: TNF- alters mitochondrial membrane potential in L929 but not in TNF-resistance L929.12 cells: Relationship with the expression of stress proteins, annexin 1 and superoxide dismutase activity. Free Rad Res 1996;25:125–131. Bellmann K, Wenz A, Radons J, Burkart V, Kleemann R, Kolb H: Heat shock induces resistance in rat pancreatic islet cells against nitric oxide, oxygen radicals and streptozototocin toxicity in vitro. J Clin Invest 1995;95:2840–2845. Malyshev IY, Malugin AV, Golubeva LY, Zenina TA, Manukhina EB, Mikoyan VD, Vanin AF: Nitric oxide donor induces HSP70 accumulation in the heart and in cultured cells. FEBS Lett 1996;391:21–23. Wong HR, Ryan M, Wispé JR: Stress response decreases N-F
B nuclear translocation and increases I-
B expression in A549 cells. J Clin Invest 1997;99:2423–2428. Boutten A, Dehoux MS, Seta N, Ostinelli J, Venembre P, Crestani B, Dombret MC, Durand G, Aubier M: Compartmentalized IL-8 and elastase release within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 1996;153:336–342. Docke WD, Syrbe U, Meinecke A, Platzer C, Makki A, Asadullah K, Klug C, Zuckermann H, Reinke P, Brunner H, von Baehr R, Volk HD: Improvement of monocyte function: A new therapeutic approach; in Reinhart K, Eyrich K, Sprung C (eds): Sepsis: Current Perspectives in Pathophysiology and Therapy. Berlin, Springer, 1994, pp 473–500. Rosenbloom AJ, Pinsky MR, Bryant JL, Shin A, Tran T, Whiteside T: Leukocyte activation in the peripheral blood of patients with cirrhosis of the liver and SIRS: Correlation with serum interleukin-6 levels and organ dysfunction. JAMA 1995;274:58–65. Trautinger F, Hammerle AF, Poschl G, Micksche M: Respiratory burst capability of polymorphonuclear neutrophils and TNF-alpha serum levels in relationship to the development of septic syndrome in critically ill patients. J Leukocyte Biol 1991;49:449–454. McCall CE, Grosso-Wilmoth LM, LaRue K, Guzman RN, Cousart SL: Tolerance to endotoxininduced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome. J Clin Invest 1993;91:853–861. Nakae H, Endo S, Inada K, Takakuwa T, Kasai T: Changes in adhesion molecule levels in sepsis. Res Comm Mol Pathol Pharmacol 1996;91:329–338. Lin RY, Astiz ME, Saxon JC, Rackow EC: Altered leukocyte immunophenotypes in septic shock. Studies of HLA-DR, CD11b, CD14, and IL-2R expression. Chest 1993;104:847–853. Rosenbloom AJ, Pinsky, MR, Napolitano C, Nguyen T-S, Levann D, Pencosky N, Dorrance A, Ray BK, Whiteside T: Suppression of cytokine mediated 2-integrin activation on circulating neutrophils in critically ill patients. J Leukocyte Biol 1999;66:83–89. Diamond MS, Springer TA: A Subpopulation of Mac-1 (CD11b/CD18) Molecules Mediates Neutrophil Adhesion to ICAM-1 and Fibrinogen. J Cell Biol 1993;120:545–556. Terregino CA, Lubkin C, Thom SR: Impaired neutrophil adherence as an early marker of systemic inflammatory response syndrome and severe sepsis. Ann Emerg Med 1997;29:400–403. Adib-Conquy M, Adrie C, Moine P, Ashnoune K, Fitting C, Pinsky MR, Dhainaut J-F, Cavaillon J-M: NF-AB expression in mononuclear cells of septic patients resembles that observed in LPS-tolerance. Am J Respir Crit Care Med 2000;162:1877–1883. Lien E, Ingalls RR: Toll-like receptors. Crit Care Med 2002;30:S1–S11.

Michael R. Pinsky, MD 606 Scaife Hall, 3550 Terrace Street Pittsburgh, PA 15261 (USA) Tel. 1 412 647 5387, Fax 1 412 647 8060 E-Mail [email protected]

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Tropical Acute Renal Failure Rashad S. Barsoum Cairo Kidney Center, Cairo, Egypt

Acute renal failure (ARF) is one of the most challenging medical problems in the tropics. Typical weather conditions and compromised public health standards impose a highly polluted bio-ecological environment, which leads to a high prevalence of both primary and secondary infection. Late or misdiagnosis and inadequate management are often responsible for important complications, including ARF. Another key factor is the lack of professional primary medical care in remote areas in the tropics. Millions of people are treated by Witch Doctors, Sangomas and quacks, who often use traditional medications with obscure composition and side effects. These agents have been frequently blamed in the pathogenesis of toxic ARF, in addition to other organ damage. Secondary and tertiary care are also compromised by the lack of expertise, equipment and funds. All these factors make of ARF an issue of major importance and grave prognosis in tropical countries.

Epidemiology

There are no reliable statistics about the incidence of ARF in the tropics. Based on regional sporadic publications, it is possible to estimate the average annual incidence around 150 cases per million population [1]. This is certainly an underestimate, reflecting only those referred to large hospitals staffed with enthusiastic physicians who are keen to report. Nevertheless, these cases constitute the major source of our information on tropical ARF. As shown in table 1, medical causes of ARF are far more common in the tropics, as opposed to the predominance of surgical causes in the developed world.

Table 1. Principal causes of ARF in the Tropics compared to that in the developed world

Surgical and post-traumatic1 Obstetric2 Infections Exogenous toxins

South (%)

North (%)

10–15 15–25 45–50 15–20

65–70 1–3 5–10 10–30

1Mostly

urologic and abdominopelvic in the tropics, cardiopulmonary in the North [1, 2]. 2Septic abortion, pregnancy toxemia [2–4].

Medical Causes of Tropical ARF

Infection and chemical intoxication are the two major causes of medical ARF in the tropics. Their relative incidence varies in different countries, depending on the local bioecology and social behavior. Figure 1 shows some examples which illustrate this discrepancy.

Infection

Primary tropical infections can lead to acute renal injury in four ways: (a) Direct invasion of the renal parenchyma by microbial agents; (b) Induction of an immune response that leads to glomerular or tubulointerstitial inflammation; (c) Induction of hemodynamic disturbances that lead to tubular necrosis, and (d) Iatrogenic renal injury associated with treatment or prophylaxis against tropical infections. Direct Parenchymal Invasion Many bacterial agents may cause acute hematogenous ‘pyelonephritis’. The lesions are mostly interstitial. They may be diffuse or focal, the latter taking the form of micro-abscesses as with septicemic melioidosis, or typical solitary abscesses as with typhoid. Diffuse interstitial inflammation may be encountered in leptospirosis, diphtheria, scrub typhus, tuberculosis and leprosy [1]. It is unusual for these forms of renal invasion to cause ARF, although a transient oliguria and marginal retention of non-protein nitrogen is not uncommon. However, ARF may occur if the infection is associated with significant

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80 70

South Africa

Ghana

India

Thailand

Singapore

Egypt

USA

UK

Percent of cases

60 50 40 30 20 10 0 Medical

Obstetric

Surgical

Fig. 1. Main causes of ARF in selected tropical countries, compared to that in the USA and the UK.

hemodynamic effects as with septicemia, intravascular hemolysis, rhabdomyolysis or disseminated intravascular coagulation (DIC). Viral interstitial nephropathies are more likely to cause ARF by direct invasion. Typical examples include Dengue fever and Hantan viral disease, both of which can cause an acute hemorrhagic syndrome with reversible ARF. Direct glomerular invasion by viral particles has been suggested to explain the glomerular lesions with HIV [5], HCV [6] and other infections. Of the tropical parasitic infections Kala-azar may cause febrile ARF, particularly in immunocompromized patients [7]. Leishmanial amastigotes tend to reside inside the interstitial monocytes and evade their phagocytic function; yet the monocytes continue to release cytokines that mediate an acute interstitial nephritis. Immune-Mediated Renal Lesions Immune complex-mediated acute post-infectious glomerulonephritis, occasionally associated with transient mild to moderate renal insufficiency, has been described with streptococcal infections of the skin in African kids as opposed to the pharynx in the developed world. Other tropical infections that may cause acute nephritis include typhoid, paratyphoid and leptospirosis. Crescentic glomerulonephritis is more often associated with acute or rapidly progressive renal failure. This has been described with HIV, HAV, HCV, Mycoplasma pneumoniae lung infection, post-streptococcal glomerulonephritis, staphylococcal and other bacterial infections of the endocardium

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and visceral abscess. It may occur with secondary syphilis and lepromatous leprosy [8]. Many of these conditions may be associated with type II or III mixed cryoglobulinemia. Crescentic glomerulonephritis may also be pauci-immune. Patients with severe streptococcal or falciparum malarial infection have evidence of systemic or renal limited pANCA-positive vasculitis, in which case necrotizing glomerular lesions are characteristic [9]. Similar lesions are occasionally seen in hepatitis B viral infection [10], where ANCAs are not detected. A distinct type of immune-mediated ARF is the postdysenteric hemolytic uremic syndrome, which is notoriously common in children in North India and Bangladesh [11]. This syndrome is identical with the D⫹ HUS seen with certain Escherichia coli infections in the West. Hemodynamically Mediated ARF Pyrexial illness in the warm and humid tropical climate leads to excessive fluid loss with perspiration and sweating. Many infections are associated with vomiting and/or diarrhea, which add to the dehydration. Shrinkage of blood volume becomes particularly dangerous in kids. Although renal failure in these cases is usually pre-renal, the presence of infective toxemia (e.g. in cholera) and renal interstitial lesions often add up leading to more serious consequences. Hyperpyrexia may nonspecifically lead to rhabdomyolysis, which augments the renal injury even in the absence of significant circulatory impediment. Certain infections may cause an outrageous release of catecholamines (e.g. tetanus), thereby amplifying the consequences of renal ischemia [12]. The acute systemic effects of disseminated bacterial infection may lead to peripheral blood pooling and capillary leakage with subsequent reduction in blood volume, renal ischemia and acute tubular necrosis. Several mediators have been incriminated in this scenario including nitric oxide, TNF-␣, dilatory prostaglandins, kinins and free oxygen radicles. Tubular injury may be induced by intrinsic pigments as hemoglobin and bilirubin, as well as microbial toxins or medications. ARF is further propagated by tubular obstruction by detached viable tubular cells, necrotic cell debris and pigment casts. Sludging of red cells and platelets is often encountered in the renal microcirculation, due to the associated hemoconcentration. This factor is considerably augmented in falciparum malaria, owing to increased stickiness of the red cells and platelets. Increased mechanical fragility of the parasitized red cells leads to intravascular hemolysis, which adds up to the pathogenesis of ARF in malaria [9]. Many other infections may lead to intravascular hemolysis in patients with G6PD deficiency, as viral hepatitis, typhoid and typhus. The same and

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other infections may also lead to DIC, which further compromises the renal circulation [1]. Iatrogenic Renal Injury Renal injury in acute tropical infections may be attributed to treatment rather than to the primary disease. Typical examples are different antibiotics, notoriously amphotericin B, aminoglycosides, cephalosporines and vancomycin. Nephrotoxicity is considerably augmented when these agents are used in combination, and when diuretics or non-steroidal anti-inflammatory agents are added. Another interesting example of iatrogenic ARF is the vasculitic ARF occurring with interferon treatment for HCV infection [13]. This complication is often encountered with the first few injections, and is characterized by severe systemic effects including pyrexia, hypotension, leukopoenia and thrombocytopenia. The renal lesion is dominated by interstitial edema, cellular infiltration and variable degrees of tubular atrophy. Most patients respond to steroid treatment, which has lead to the inclusion of these agents in several interferon-based protocols in viral hepatitis. ARF may also occur as a result of vaccination. Anaphylactic and serumsickness types of immune response leading to ARF have been described with many vaccines. A recent alarming report from Brazil incriminates vaccination for transmitting yellow fever, resulting in fatal hemorrhagic ARF [14].

Intoxication

ARF may be attributed to exposure to a long list of occupational or environmental toxins, which are beyond the scope of this review. Of specific epidemiological and clinical interest in the tropics is the renal injury resulting from accidental exposure or therapeutic use of certain poisons of animal or plant origin as traditional medicines. Toxins of Animal Origin The prototype of these poisons is the bite of snakes, usually Viperidae or Elapidae occurring mainly in West Africa, the Indian subcontinent, South-East Asia, New Guinea and Latin America. ARF occurs in 5–80% of cases [15] being attributed to the induction of massive release of monokines, complement activation, hemolysis and intravascular coagulation. Snake venom may also lead to a widespread vasculitis which involves the glomerular capillaries. Specific antibody response may lead to immune complex formation and secondary glomerular injury.

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Less common are scorpion or jellyfish stings as well as spider or centipede bites, often encountered in southern America, North Africa and the Middle East. These may lead to ARF in 6–10% of cases by inducing hemodynamic sequelae similar to those of snakebites. Scorpion stings are associated with massive catecholamines release, which significantly contributes to renal ischemia. Insect stings may also lead to ARF particularly in sub-Saharan Africa. Oral ingestion of raw carp bile is a fairly common habit in South East Asia, Taiwan, China and Korea. The stuff is traditionally believed to improve visual acuity, stop cough, decrease body temperature and lower blood pressure. Ingestion of large quantities may lead to gastrointestinal toxicity that may be associated with ARF in up to 54%, hematuria in 77% and jaundice in 62% of patients [16]. The mechanism of ARF seems to be multifactorial, involving renal ischemia, tubular toxicity and bile pigment nephropathy. Toxins of Plant Origin Mushroom poisoning is the best known of this group. Accidental ingestion of certain wild mushrooms (Amanita or Galerina species) leads to gastrointestinal and hepatic toxicity. ARF occurs 10–14 h after exposure. The latter is usually severe, with up to 50% mortality. People in Indonesia, Malaysia and southern Thailand frequently use Djenkol beans as digestives. Toxicity follows ingestion of the raw bean in large amounts. ARF occurs in about 50% of patients [17]. Hair dyes have been incriminated in the pathogenesis of ARF in Turkey, Northern Africa and the Sudan. Accidental toxicity from Henna, a traditional cosmetic material used in the Middle East, has been described in the Turkey, being attributed to absorption through the skin. Suicidal ingestion of a similar cosmetic compound, paraphenylenediamine (PPD) was reported to induce a systemic inflammatory response, with respiratory distress and ARF in Morocco [18]. Combination of PPD and Henna seems to be even more toxic, with a reported mortality of 40% in the Sudan [19]. Other poisons of plant origin, frequently used as traditional medicines for the relief of cough, colics, impotence and many other common conditions may lead to ARF [20]. These include Callilepis laureola, Semecarpus anacardium, Securidaca longipedunculata, Euphorbia matabelensis and Crotalaria laburnifolia. The renal damage associated with these poisons is attributed to direct nephrotoxicity as well as to the non-specific effects of gastrointestinal and hepatic toxicity. Intoxication with Industrial Chemicals Accidental exposure to many industrial chemicals may induce ARF. Such accidents are particularly common in tropical countries owing to the poor control

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over the manufacture process, storage and waste disposal. Major accidents have been reported with copper sulphate in India and Bangladesh, naphthalene in Nigeria and many others.

Special Clinical Considerations in Tropical ARF

The clinical profile of ARF in the tropics is modified by a number of factors. Most significant is the overlap between the manifestations of ARF and those of severe systemic infection or intoxication. In many cases, there is severe toxemia, shock, dehydration, DIC, hepatocellular or pulmonary injury, central nervous system involvement, etc. These may impose difficulties in the selection of certain treatment modalities as hemodialysis in the presence of shock or a bleeding tendency. The complexity of pathogenetic factors involved such as hemolysis, rhabdomyolysis and DIC often leads to aggravation of the uremic syndrome. Most patients reaching the hospital are already severely anemic, thrombocytopenic, severely acidotic and critically hyperkalemic. Coma, convulsions, pericarditis, ascending paralysis, urea frost and similar clinical signs that are now seldom seen in the West, are an everyday experience in tropical ARF. Sky high serum creatinine concentrations and incredible serum potassium levels of 9 or 10 mEq/l associated with all the classical ECG signs may be seen when there is significant rhabdomyolysis. All that usually occurs in a patient with background chronic disease of variable severity. Many natives in the tropics would be living with multiple chronic parasitic infestations and significant protein-calorie malnutrition. The added catabolic effects of the new infection or intoxication, and subsequently that of the uremic state result in a considerable negative nitrogen balance that has a major impact on outcome. Finally, there is the effect of delayed referral. Lack of adequate information in the primary care units, patients’ reluctance to leave their own territories to be treated in central hospitals, inefficient and unsafe transfer vehicles may lead to a very high mortality from ARF that has been estimated in a consensus meeting to approach 80%. This is in sharp contrast to the reported mortality from referral hospitals that ranges between 20 and 30% [21].

Management of Tropical ARF

As with conventional ARF, the most effective intervention is prevention. Awareness of the potential renal complications of injury, surgery, obstetric

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complication, infections and medications is the most cost-effective single measure. Unfortunately, very little attention is paid by different medical specialities to this important issue. Timely intervention at the onset of ARF is usually rewarded by excellent results. Adequate attention to a primary infection, prompt control of hyperpyrexia, correction of shock, adequate hydration, avoidance of nephrotoxic drugs or drug combinations are simple but most effective. There is no evidence that induction of diuresis by osmotic or loop diuretics would change the outcome, nor does the use of dopamine, calcium channel blockers or ACE inhibitors. Adequate care of nutrition is of vital importance. Patients who are unable to eat or drink must be supported by enough fluids, electrolytes, calories and amino acids parenterally. This may be difficult with severe oliguria, when the total permissible fluid intake is restricted. An undoubted blessing, in this respect, is that patients treated in the tropical climate may lose a lot of fluid in sweat and insensible routes, which provides more room for intravenous fluid administration. Taking the multifactorial nature of ARF into consideration, dialysis is often needed as soon as the patient has reached the hospital. Fortunately, facilities for peritoneal dialysis, acute hemodialysis and even continuous renal replacement therapy are now available in most tropical countries, though critically restricted to teaching or army hospitals. In addition to logistic difficulties in transfer and acceptance of patients in these hospitals, there may be technical problems is implementing dialysis and other extracorporeal therapies due to vascular access problems, bleeding tendencies, circulatory instability etc. It is hoped that the use of peritoneal dialysis finds its way to smaller territorial hospitals where prompt renal replacement therapy can be implemented when needed. The challenge facing the medical profession will continue for many decades. Patients will continue to die of ARF until the value of proper education of the primary care physician is appreciated and implemented. Unfortunately, this simple fact is lost within the jungle of politics, inappropriate diversion of funds, and inequity of health care.

References 1 2 3 4

Barsoum R, Sitprija V: Tropical nephrology; in Schrier RW, Gottaschalk CW (eds): Diseases of the Kidney, ed 4. Boston, Little, Brown, 1996, pp 2221–2286. Kleinknecht D: Epidemiology of acute renal failure; in Cantarovich F, Rangoonwala B, Verho M (eds): Progress in Acute Renal Failure. New Jersey, Marion Roussel, 1998, pp 11–22. Firmat J, Zucchini A, Martin R, Aguirre C: A study of 500 cases of acute renal failure (1978–1991). Ren Fail 1994;16:91–99. Randeree IG, Czarnocki A, Moodley J, Seedat YK, Naiker IP: Acute renal failure in pregnancy in South Africa. Ren Fail 1995;17:147–153.

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5 6

7 8

9 10 11 12 13 14 15 16 17 18 19 20 21

Cohen AH: HIV-associated nephropathy: Current concepts. Nephrol Dial Transplant 1998;13: 540–542. Horikoshi S, Okada T, Shirato I, et al: Diffuse proliferative glomerulonephritis with hepatitis C virus-like particles in paramesangial dense deposits in a patient with chronic hepatitis C virus hepatitis. Nephron 1993;64:462–464. Caravaca F, Munoz A, et al: Acute renal failure in visceral leishmaniasis. Am J Nephrol 1991;11: 350–352. Barsoum R: The Kidney in tropical infections; in El-Nahas AM, Harris K, Anderson S (eds): Mechanisms and Clinical Management of Chronic Renal Failure, ed 2. Oxford, Oxford University Press, 2000, pp 371–400. Barsoum RS: Malarial acute renal failure. J Am Soc Nephrol 2000;11:2147–2154. Lai KN, Lai FM, Chan KW, et al: The clinicopathologic features of hepatitis B virus-associated glomerulonephritis. Q J Med 1987;63:323–333. Srivastava RN, Moudgil A, Bagga A, Vasudev AS: Hemolytic uremic syndrome in children in northern India. Pediatr Nephrol 1991;5:248–288. Daher EF, Abdulkader RC, Motti E, et al: Prospective study of tetanus-induced acute renal dysfunction: Role of adrenergic overactivity. Am J Trop Med Hyg 1997;57:610–614. Dimitrov Y, Heibel F, Marcellin L, et al: Acute renal failure and nephrotic syndrome with alpha interferon therapy. Nephrol Dial Transplant 1997;12:200–203. Vasconcelos PF, Luna EJ, Galler R, et al: Serious adverse events associated with yellow fever 17DD vaccine in Brazil: A report of two cases. Lancet 2001;358:91–97. Warrell DA: Venomous bites and stings in the tropical world. Med J Aust 1993;159:773–779. Park SK, Kim DG, Kang SK, et al: Toxic acute renal failure and hepatitis after ingestion of raw carp bile. Nephron 1990;56:188–193. Eiam-ong S, Sitprija V, Saetang P, et al: Djenkol bean nephrotoxicity in Southern Thailand. Proc First Asia Pacific Congress on Animal, Plant and Microbial Toxins, Singapore, 1989, p 628. Bourquia A, Jabrane AJ, Ramdani B, Zaid D: Systemic toxicity of paraphenylenediamine. 4 cases. Presse Med 1988;17:1798–1800. Devecioglu C, Katar S, Dogru O, Tas MA: Henna-induced hemolytic anemia and acute renal failure. Turk J Pediatr 2001;43:65–66. Kadiri S, Arije A, Salako BL: Traditional herbal preparations and acute renal failure in south west Nigeria. Trop Doct 1999;29:244–246. Barsoum RS: Dialysis in developing countries; in Jacobs C, Kjellstrand CM, Koch KM, Winchester JF (eds): Replacement of Renal Function by Dialysis, ed 4. Dordtrecht, Kluwer, 1996, pp 1433–1445.

Professor Rashad S. Barsoum The Cairo Kidney Center, 3, Hussein El-Memar Street, Antik-khana PO Box 91, Bab-El-Louk, 11513, Cairo (Egypt) Tel. ⫹20 2 5761673, Fax ⫹20 2 5769749, E-Mail [email protected]

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The Critically Ill Patients: Pathological Mechanisms Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 53–62

Mechanisms Underlying Combined Acute Renal Failure and Acute Lung Injury in the Intensive Care Unit Chu-Chun Chien, Landon S. King, Hamid Rabb Department of Medicine, Johns Hopkins University, Baltimore, Md., USA

Acute renal failure (ARF) is associated with high morbidity and mortality in intensive care unit patients [1]. It is increasingly recognized that ARF is an independent risk factor for death, and that ARF is a systemic disease. With the availability of dialysis, much of the mortality associated with ARF occurs due to extrarenal complications such as circulatory collapse, cardiopulmonary failure, and gastrointestinal bleeding [2, 3]. Lung dysfunction is particularly common, and astute clinicians have long observed that there is a predisposition to combined lung and kidney dysfunction in the critically ill patient. When ARF and acute lung injury (ALI) are combined, the mortality rate exceeds 80% [4]. We will briefly review the mechanisms underlying combined ARF and ALI (fig. 1). Classic renal-pulmonary syndromes such as Goodpasture’s disease, Wegeners and other autoimmune diseases, though important considerations in the differential diagnosis of a patient with combined ARF and ALI [5, 6], will not be discussed in this chapter. In addition, the pulmonary consequences of dialysis will not be discussed [7, 8].

Pulmonary Effects of Acute Renal Failure

ARF leads to fluid retention, which in turn contributes to venous congestion and impaired pulmonary gas exchange [9]. Acidosis stimulates compensatory hyperventilation and increases the work of breathing, potentially accelerating respiratory muscle fatigue [10]. However, the impact of renal failure on lung function extends beyond simply fluid overload and its sequelae.

Consequences Inflammation and increased vascular permeability Pulmonary edema Abnormalities in ENaC, AQP5, Na-K-ATPase

Mediators Macrophages Cytokines? Uremic toxins?

Acute lung injury Mediators Hemodynamics Cytokines? Leukocytes?

Acute renal failure

Consequences Increased vascular perm Proteinuria Abnormalities in ENaC, AQP2, Na-K-ATPase Inflammation Epithelial injury and apoptosis

Fig. 1. Interaction between injured kidney and lung. ARF leads to an increase in pulmonary vascular permeability and inflammation during ARF, which is in part, macrophagemediated. Lung epithelial sodium channel, aquaporin-5 and Na-K-ATPase are downregulated during ARF, which may be mediated by cytokines or uremic toxins. Conversely, mechanical ventilation leads to a decrease in renal epithelial sodium channel, aquaporin-2 and Na-KATPase. Potential mediators of these changes include hemodynamic factors, cytokines and leukocytes. Modified from Rabb H, Chamoun F, Hotchkiss J: Molecular mechanisms underlying combined kidney-lung dysfunction during acute renal failure; in Ronco C, Bellomo R, La Grecca G (eds): Blood Purification in Intensive Care. Basel, Karger, 2001.

The uremic milieu likely contributes to the development or exacerbation of lung injury and dysfunction [11], and this can be improved with renal transplantation [12, 13]. A marked decrease in lung diffusion capacity in uremic patients had been noted for decades [14–16], and this abnormality correlated well with the severity of renal impairment. However, many have argued that the ‘uremic lung’ was merely a consequence of volume overload, and that aggressive fluid removal with dialysis resolves the pulmonary changes. The important clinical association between combined ARF and ALI, as well as controversy in this area has led to studies to directly test causal links between ARF and ALI (table 1). Increased pulmonary vascular permeability is the hallmark of noncardiogenic pulmonary edema. It was hypothesized that ARF would directly lead to an increase in pulmonary vascular permeability, and hence predispose to adult respiratory distress syndrome (ARDS). Rats undergoing renal ischemia/reperfusion injury (IRI) demonstrated a significant increase in pulmonary vascular permeability to albumin compared to sham-operated animals at 24 h that peaked 48 h after reperfusion [17]. Lungs from rats subjected to renal IRI had a marked increase in red blood cells in the interstitium with accompanying edema, as well as alveolar hemorrhage and sludging of red blood cells in the microvasculature.

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Table 1. Effects of experimental ARF on lung Renal injury model

Animal species

Lung changes

Reference No.

30 min IRI or bilateral nephrectomy

rat

downregulated pulmonary ENaC, Na-K-ATPase, AQP5

11

30 min IRI

rat

increased pulmonary vascular permeability, interstitial edema and alveolar inflammation, partially macrophage-mediated

17

40 min IRI

mouse

increased wet to dry weight ratio and upregulation of signaling process ␣-MSH inhibited many effects

19

30 min IRI

mouse

increased expression of adhesion molecules and neutrophil infiltration

20

IRI ⫽ Ischemia-reperfusion injury; ENaC ⫽ epithelial sodium channel; AQP5 ⫽ aquaporin-5; ␣-MSH ⫽ ␣-melanocyte-stimulating hormone.

Although the literature suggested that neutrophils participate in the pathogenesis of ARDS, neutrophil depletion did not alter the effect of ARF on lung function. Macrophages were targeted with CNI-1493, an agent that inhibits macrophage function by blocking both cytokine-inducible arginine uptake and the p38 mitogen-activated protein (MAP) kinase signal transduction pathway. Rats in ARF receiving CNI-1493 displayed significant protection, with a reduction in the increase in pulmonary vascular permeability following IRI. The CN11493 treated animals demonstrated interstitial edema, but alveolar hemorrhage was absent. No effect on serum creatinine was observed. In another study, bilateral ischemic renal injury or bilateral nephrectomy, but not unilateral ischemia-reperfusion, led to down-regulation of Na-KATPase and aquaporin-5 (AQP5) levels in the lung [11]. Decreased pulmonary abundance of the epithelial sodium channel (ENaC) was also observed in this setting, and was associated with renal injury. The clinical relevance of decreased membrane transporters in the distal lung is supported by the observation of augmented pulmonary edema with amiloride or ouabain administration in a pulmonary IRI model [18]. Recent data indicate that lung injury occurs rapidly following renal ischemia. Mice with ischemic ARF had evidence of marked pulmonary edema and neutrophil accumulation at 4 and 8 h after ischemia, associated with an

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upregulation of proinflammatory signaling molecules in the lung. Treatment with ␣-melanocyte-stimulating hormone (␣-MSH) attenuated both the ARF and associated lung changes in this model [19]. The increase in pulmonary neutrophils during ARF is likely modulated in part by upregulation of leukocyte adhesion molecules [20]. The factors that link ARF and ALI are unknown. Circulating cytokines have been implicated in the pathogenesis of lung injury following distant organ IRI [21–23]. Macrophage-derived proinflammatory cytokines including tumor necrosis factor-␣ (TNF-␣) [24–26], interleukin-1 (IL-1) [27, 28], interleukin-6 (IL-6) [29] have been implicated. The type II alveolar epithelial cells might be the target of these macrophage-derived inflammatory mediators [30]. Remote effects of reperfusion injury have also been attributed to complement activation [31–33], and arachidonate derivatives such as thromboxane [34, 35] and leukotriene B4 [36, 37]. In view of recent data implicating T cells in ARF [38, 39], the T cell is an attractive circulating candidate to mediate the ARF-ALI association. In an effort to reduce the systemic inflammatory responses that can contribute to the high mortality associated with ARF, continuous renal replacement therapy is being explored as a therapeutic intervention beyond the conventional use for renal replacement [40, 41]. Innovative approaches with plasmapheresis are also promising for ARF [42].

Renal Effects of Mechanical Ventilation

Patients requiring mechanical ventilation often have renal dysfunction that may be a consequence of the underlying illness. However, it is increasingly recognized that mechanical ventilation itself can damage the kidney. Several clinical reports and experimental studies have shown that mechanical ventilation has significant influence on renal function. Positive-pressure ventilation alters venous return, cardiac preload, pulmonary vascular resistance, and cardiac afterload. A decrease in several parameters of renal function, including glomerular filtration rate (GFR), renal blood flow (RBF), and free-water clearance were noted using positive pressure ventilation [43]. The interaction between mechanical ventilation and renal function has been extensively examined in the setting of positive end expiratory pressure (PEEP). In an anesthetized canine model, institution of 10 cm of PEEP markedly decreased urine flow rate, urinary sodium excretion, and creatinine clearance [44]. Prompt deterioration in renal function following the initiation of PEEP [45], continuous positive airway pressure (CPAP) [46] and continuous positive-pressure ventilation (CPPV) [47] has been observed repeatedly in various animal models. Both animal and human studies indicate that positive

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intrathoracic pressure might negatively affect renal function by decreasing venous return and compromising cardiac output [48]. This effect may be worsened by concurrent volume depletion [49], consistent with the observation that intravascular volume expansion may decrease the injury; however, the effects of positive intrathoracic pressure on RBF have not been consistent. A comparison of intermittent mechanical ventilation (IMV) and continuous mechanical ventilation (CMV) in anesthetized canines with normal lung function indicated that IMV may have lesser negative influence on renal function [50], potentially a consequence of decreased mean intra-thoracic pressure that limits the retention of water and salt that occurs during prolonged mechanical ventilation [50, 51]. Positive pressure ventilation may change the expression of several mediators central to renal function. Mechanical ventilation reduces production of renal dopamine, potentially an independent factor mediating renal injury. Examination of the effects of IMV in awake humans with healthy lungs revealed a decrease in urine output and an increase in antidiuretic hormone (ADH) following institution of mechanical ventilation, without a change in free-water clearance [52]. PEEP has also been shown to increase antidiuretic hormone and aldosterone levels in some [53], but not all [54], animal studies, and may contribute to the decreasing urine output observed after institution of this modality. In some studies this effect can be ameliorated by adequate fluid resuscitation [55–57]. The rapid restoration of diuresis and natriuresis suggests the change of antidiuretic hormone in this setting may be a consequence of a decreased atrial transmural filling pressure caused by a positive intrathoracic pressure [58]. This topic has been comprehensively reviewed recently [59]. Ischemia remains the major cause of ARF in hospitalized patients, and recent studies suggest that renal injury is also regulated by circulating cytokines such as TNF-␣ [60–62] and growth factors such as hepatocyte growth factor (HGF) [63, 64] produced by extrarenal organs. Mechanical ventilation, especially with prior lung injury, produces similar changes in inflammatory molecules in kidney, such as TNF-␣, IL-6 [29, 65], and vascular endothelial growth factor (VEGF) [29, 65] (table 2). In a mouse model of 4 h of mechanical ventilation, marked decreases in renal ENaC, aquaporin-2 (AQP2) and Na-KATPase were found – similar to what occurs after direct ischemic injury to kidneys. Recent experiments have demonstrated that mechanical ventilation without change in blood pressure or central venous pressure caused flattening of epithelial cells in the canine kidney [66]. In a rabbit model of injurious mechanical ventilation, renal tubular apoptosis as well as biochemical markers of renal dysfunction were found, supporting a causal association between mechanical ventilation and the development of remote renal injury [67]. High tidal volume

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Table 2. Effects of experimental acute lung injury on kidney Lung injury model

Animal species

Renal changes

Reference No.

4 h ventilation ⫾ HCl

mouse

ventilation alone increases VEGF acid aspiration plus high VT ventilation increases IL-6, VEGFR-2

29

5 h ventilation

mouse

increased neutrophil infiltration increased Il-1, ICAM-1, and IL-6 decreased AQP2, ENaC increased AQP1 in high VT ventilation

65

6 h ventilation ⫾ LPS and HCl

dog

neutrophil margination in the peritubular capillaries tubular cell sloughing

66

4 and 8 h ventilation ⫾ HCl

rabbit

increased epithelial apoptosis index

67

1 h ventilation

rat

high VT group with more glomerular collapse and perivascular edema

68

2 h ventilation

rat

high VT group with renal vascular leak and proteinuria L-NAME attenuated this effect

69

HCl ⫽ Hydroxyl chloride; VEGF ⫽ vascular epithelial growth factor; IL-6 ⫽ interleukin-6; VEGFR-2 ⫽ vascular epithelial growth factor receptor 2; IL-1 ⫽ interleukin-1; ICAM-1 ⫽ intracellular adhesion molecule 1; AQP2 ⫽ aquaporin-2; ENaC ⫽ epithelial sodium channel; AQP1 ⫽ aquaporin-1; LPS ⫽ lipopolysaccharide; VT ⫽ tidal volume; L-NAME ⫽ N-nitroL-arginine methyl ester.

ventilation in rats produced a higher percentage of collapse of Bowman’s space [68] and proteinuria resulted from renal microvascular leak [69].

Conclusion

The persistent high mortality associated with ARF requires nephrologists to broaden mechanistic studies beyond the pathophysiology of isolated ARF and metabolites of dialysis approach, to the more complex arena of inter-organ failure. Advances in our understanding of inflammation and lung mechanics may provide a basis for investigation of these critically ill patients with ARF that will

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lead to new treatment strategies. It is likely that an important developmental link between lung and kidney also contributes to this problem. Integrative physiologic approaches on the bench and prospective cross-specialty clinical trials will be required to make the necessary inroads in this lethal syndrome.

Acknowledgements CC was supported by a training grant from Chang-Gung Memorial Hospital, Taipei, Taiwan. HR was supported by NIDDK R01 DK54770 and ROTRF 696313559. LK was supported by NHLBI R01 HL70217 and American Heart Association Grant Aid. Both HR and LK are supported by NHLBI SCCOR grant HL073944.

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Stegmayr BG, Banga R, Berggren L, Norda R, Rydvall A, Vikerfors T: Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003;31:1730–1736. Murdaugh HV Jr, Sieker HO, Manfredi F: Effect of altered intrathoracic pressure on renal hemodynamics, electrolyte excretion and water clearance. J Clin Invest 1959;38:834–842. Hall SV, Johnson EE, Hedley-Whyte J: Renal hemodynamics and function with continuous positive-pressure ventilation in dogs. Anesthesiology 1974;41:452–461. Steinhoff HH, Samodelov LF, Trampisch HJ, Falke KJ: Cardiac afferents and the renal response to positive pressure ventilation in the dog. Intens Care Med 1986;12:147–152. Marquez JM, Douglas ME, Downs JB, Wu WH, Mantini EL, Kuck EJ, Calderwood HW: Renal function and cardiovascular responses during positive airway pressure. Anesthesiology 1979;50: 393–398. Fewell JE, Bond GC: Renal denervation eliminates the renal response to continuous positivepressure ventilation. Proc Soc Exp Biol Med 1979;161:574–578. Mitaka C, Nagura T, Sakanishi N, Tsunoda Y, Amaha K: Two-dimensional echocardiographic evaluation of inferior vena cava, right ventricle, and left ventricle during positive-pressure ventilation with varying levels of positive end-expiratory pressure. Crit Care Med 1989;17:205–210. Shinozaki M, Muteki T, Kaku N, Tsuda H: Hemodynamic relationship between renal venous pressure and blood flow regulation during positive end-expiratory pressure. Crit Care Med 1988;16: 144–147. Steinhoff HH, Kohlhoff RJ, Falke KJ: Facilitation of renal function by intermittent mandatory ventilation. Intens Care Med 1984;10:59–65. Baratz RA, Ingraham RC: Renal hemodynamics and antidiuretic hormone release associated with volume regulation. Am J Physiol 1960;198:565–570. Khambatta HJ, Baratz RA: IPPB, plasma ADH, and urine flow in conscious man. J Appl Physiol 1972;33:362–364. Kaczmarczyk G, Jorres D, Rossaint R, Krebs M, Unger V, Falke K: Extracellular volume expansion inhibits antidiuretic hormone increase during positive end-expiratory pressure in conscious dogs. Clin Sci (Lond) 1993;85:643–649. Teba L, Dedhia HV, Schiebel FG, Blehschmidt NG, Lindner WJ: Positive-pressure ventilation with positive end-expiratory pressure and atrial natriuretic peptide release. Crit Care Med 1990; 18:831–835. Costa KN, Carvalho WB, Kopelman BI, DiDo R: Dosage of atrial natriuretic peptide in pediatric patients submitted to mechanical ventilation. Rev Assoc Med Bras 2000;46:320–324. Rossaint R, Jorres D, Nienhaus M, Oduah K, Falke K, Kaczmarczyk G: Positive end-expiratory pressure reduces renal excretion without hormonal activation after volume expansion in dogs. Anesthesiology 1992;77:700–708. Ramamoorthy C, Rooney MW, Dries DJ, Mathru M: Aggressive hydration during continuous positive-pressure ventilation restores atrial transmural pressure, plasma atrial natriuretic peptide concentrations, and renal function. Crit Care Med 1992;20:1014–1019. Andrivet P, Adnot S, Sanker S, Chabrier PE, Macquin-Mavier I, Braquet P, Brun-Buisson C: Hormonal interactions and renal function during mechanical ventilation and ANF infusion in humans. J Appl Physiol 1991;70:287–292. Pannu N, Mehta RL: Mechanical ventilation and renal function: An area for concern? Am J Kidney Dis 2002;39:616–624. Donnahoo KK, Meng X, Ao L, Ayala A, Shames BD, Cain MP, Harken AH, Meldrum DR: Differential cellular immunolocalization of renal tumour necrosis factor-alpha production during ischaemia versus endotoxaemia. Immunology 2001;102:53–58. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR: Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 1999;277:R922–R929. Meldrum KK, Meldrum DR, Meng X, Ao L, Harken AH: TNF-alpha-dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion. Am J Physiol 2002;282:H540–H546. Liu Y: Hepatocyte growth factor and the kidney. Curr Opin Nephrol Hypertens 2002;11:23–30. Matsumoto K, Mizuno S, Nakamura T: Hepatocyte growth factor in renal regeneration, renal disease and potential therapeutics. Curr Opin Nephrol Hypertens 2000;9:395–402.

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Tremblay LN, Miatto D, Hamid Q, Govindarajan A, Slutsky AS: Injurious ventilation induces widespread pulmonary epithelial expression of tumor necrosis factor-alpha and interleukin-6 messenger RNA. Crit Care Med 2002;30:1693–1700. Chien CC, Haas M, Jakobe A, McVerry B, Simon BA, Rabb H: Mechanical ventilation associated lung injury in canines causes renal histologic changes consistent with early acute tubular necrosis. J Am Soc Nephrol 2003;14:354A. King L, Doddo OJ, Becker P, Haas M, Chien CC, Burne-Taney MJ, Rabb H: Mechanical ventilation in mice leads to renal inflammation and dysregulation of transporters. J Am Soc Nephrol 2003;14:564A. Valenza F, Sibilla S, Porro GA, Brambilla A, Tredici S, Nicolini G, Miloso M, Tredici G, Gattinoni L: An improved in vivo rat model for the study of mechanical ventilatory support effects on organs distal to the lung. Crit Care Med 2000;28:3697–3704. Choi WI, Quinn DA, Park KM, Moufarrej RK, Jafari B, Syrkina O, Bonventre JV, Hales CA: Systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury. Am J Respir Crit Care Med 2003;167:1627–1632.

H. Rabb, MD Johns Hopkins University Hospital Ross 970, 720 Rutland Ave, Baltimore, MD 21205 (USA) Tel. ⫹1 410 502 1555, Fax ⫹1 410 614 5129, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 63–75

Cytokine Single Nucleotide Polymorphism Role in Acute Renal Failure

Orfeas Liangos, Vaidyanathapuram S. Balakrishnan, Brian J. G. Pereira, Bertrand L. Jaber Dialysis Research Laboratory, Division of Nephrology, Tufts-New England Medical Center, Boston, Mass., USA

Acute renal failure (ARF) is a serious complication and carries high mortality rate [1, 2], which has not improved despite advances in intensive care and dialytic support. The lack of improvement in patient outcomes calls for novel preventive and therapeutic approaches.

Mediators of the Systemic Inflammatory Response Syndrome in ARF

Sepsis or the broader syndrome, the systemic inflammatory response syndrome (SIRS), represents an overwhelming, host response to a variety of triggers such as gram-negative bacterial endotoxin [3]. During the initial phase of sepsis, pro-inflammatory cytokines are released, including tumor necrosis factor-
(TNF-
) and interleukin-1 (IL-1), which in turn stimulate the release of other biologically active molecules, resulting in vascular endothelial damage and organ dysfunction. This initial phase is followed by a compensatory anti-inflammatory response (CARS) in which anti-inflammatory cytokines are produced, which offset pro-inflammatory responses [4]. Interleukin-10 is the most potent anti-inflammatory cytokine, and its release inhibits production of TNF-
and IL-1 [5–7]. Acute renal failure often develops during sepsis, and pro-inflammatory cytokines released in response to endotoxin, organ ischemia-reperfusion, complement activation, and through other cytokines and immune modulators have been

Sepsis

Ischemia-reperfusion

Endotoxin release

Complement activation

 Genetic influence

TNF-


IL-10

Genetic influence

 Oxygen free radicals Nitric oxide

Arachidonic acid metabolites Cellular activation

Proteases Plateletactivating factor

Endothelins ↑ Urinary markers (NAG, KIM-1… )

Kidney injury

↑ Circulating markers (serum creatinine)

Fig. 1. Schematic representation of the inflammatory response to sepsis and resulting kidney injury. NAG  N-acetyl--D-glucosaminidase; KIM  kidney injury molecule 1. Modified from Jaber et al. [63], with permission.

shown to play a role in the development of endotoxin-mediated ARF [8, 9] (fig. 1). Leukocyte activation with expression of adhesion molecules, and the production of oxygen-free radicals, arachidonic acid metabolites, platelet-activating factor, nitric oxide, endothelins, and heat-shock proteins follows [10] whereby creating a pro-inflammatory cascade that contributes to injury of the glomerular and peritubular vasculature [11]. TNF-receptor-1 deficient mice are resistant to endotoxin-induced ARF, arguing for a critical role for TNF-
[9]. In addition, bacterial products can activate neutrophils in situ and IL-8-mediated chemotaxis further recruits neutrophils to sites of inflammation [12]. Morphological studies of acute tubular necrosis in humans have shown neutrophils in the vasa recta and the interstitium and support a role for inflammation in the pathogenesis of ARF [13]. Ischemic and Nephrotoxic Injury in ARF

Increasing evidence supports an important role for inflammatory mechanisms in both ischemic [11, 14] and nephrotoxic [15, 16] renal injury. Animal models of ischemic ARF have demonstrated an activation of renal myeloperoxidase (MPO) and increased gene expression of intercellular adhesion molecule-1

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(ICAM-1) and IL-6 [17]. A mouse model of cisplatin nephrotoxicity shows increased TNF-
and IL-1 mRNA expression and increased urinary TNF-
[16]. Inhibitors of TNF-
such as pentoxifylline and anti-TNF-
monoclonal antibodies have been shown to ameliorate the pro-inflammatory response. Similarly, TNF-
-deficient mice are resistant to cisplatin nephrotoxicity, arguing for a central role for TNF-
[16]. On the other hand, exogenous administration of IL-10 inhibits TNF-
and ICAM-1 mRNA expression in mouse kidneys following ischemic and nephrotoxic injury [15], and antibodies to ICAM-1 protect the kidney against ischemic injury [18].

Cytokines and ARF in Humans

Increased plasma and urinary cytokine levels have been shown to correlate with urinary levels of N-acetyl--D-glucosaminidase (NAG), a bio-marker of renal proximal tubular dysfunction following surgery with cardiopulmonary bypass (CPB) [19]. However, it is unclear as to whether urinary cytokines are filtered by the glomerulus or produced in situ. More studies, perhaps involving the recently described soluble form of human kidney injury molecule-1 (KIM-1), a highly specific bio-marker for renal proximal tubular injury [11] may shed light on a potential pathogenetic link between urinary cytokines and early tubular injury. In regards to plasma cytokine levels, IL-6 and IL-10 have been shown to differentiate surviving from non-surviving patients with ARF [20]. In addition, elevated serum levels of soluble TNF receptors among patients with septic shock were shown to predict ARF and mortality [21]. The above data support the role of cytokines as important mediators of kidney parenchymal injury, but the role of genetic factors affecting cytokine production in the inflammatory response cascade and their implications for ARF following ischemic or nephrotoxic injury have remained largely unexplored.

Human Gene Polymorphism and Biological Diversity

Among humans, there is a remarkable homogeneity of genetic information, with two unrelated individuals sharing greater than 99.9 percent of their DNA sequences [22]. Variations observed in the remaining 0.1% of the human genome have become the subject of intense investigation [23]. This variability, known as gene polymorphism, is the basis of biological diversity and some genotypic variations have been shown to correlate with specific phenotypes

Cytokine Gene Polymorphism in Acute Renal Failure

65

Start of transcription

Exons (coding sequences) • Silent • Alteration in gene expression • Alteration in gene function (structure, binding or trafficking of protein product

5'

3'

Initiator codon Termination Untranslated Promoter codon region region • Alteration in • Alteration in Introns (intervening sequences) mRNA half-life transcriptional activity • Defect in RNA processing • Alteration in • Defect in mRNA processing ribosomal mRNA Direction of transcription translation

Fig. 2. Sketch of the structure of a human gene with potential sites of polymorphism.

relevant to human disease [24]. It is not clear, however, whether many of these genetic variants are causal for the diseases in question or simply located in proximity to other, yet unknown pathogenic genetic factors, an occurrence known as linkage disequilibrium. Polymorphism of human genes occurs at one or more of the following sites (fig. 2): (1) the promoter or 5-flanking region affecting transcriptional activity [25]; (2) the exon(s) or the gene coding sequences affecting gene expression or function through changes in structure, binding or trafficking of the gene product; (3) the intron(s) or the gene intervening sequences where changes may lead to defects in RNA and mRNA processing, and (4) the 3-untranslated (3-UTR) region further downstream which may affect gene expression through altered RNA half-life or influencing ribosomal translation of mRNA. On a molecular level, gene polymorphism can be categorized into: (1) single nucleotide polymorphism (SNP); (2) variable number of tandem repeats (VNTR) or minisatellite polymorphism, and (3) microsatellite polymorphism [25], of which the single nucleotide polymorphism is the most common and consists of single nucleotide substitution. SNP in the promoter region may change transcriptional activity and thereby be of functional relevance.

Identification of Genes Relevant to Human Disease

There are two approaches to identifying genes relevant to human disease: Linkage analyses and association studies. Linkage analyses identify co-inheritance of a specific phenotype with a region of the genome in families. These analyses

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are successful in identifying novel genes for ‘monogenic’ diseases, and environmental factors play a minimal role in disease expression. One such example is polycystic kidney disease. Association studies identify susceptibility genes for common ‘polygenic’ diseases. This is known as the ‘candidate gene’ approach and relies on biological plausibility to identify highly likely candidate genes. In this analytical approach, environmental factors play a critical role in disease expression. Examples would include the study of genes encoding for cytokines in sepsis. Association Studies in Acute Infectious and Inflammatory Disorders

In recent years, the study of cytokine gene polymorphism has become the subject of intense interest, as these genetic markers may be potential determinants of susceptibility to disease incidence, severity of illness and clinical outcomes. For inflammatory conditions, polymorphisms of the TNF and IL-10 genes are of particular interest, particularly those associated with altered gene expression. Associations between these polymorphisms and acute inflammatory states are summarized (table 1). Tumor Necrosis Factor Locus

The TNF-
gene is located on the short arm of chromosome 6. Polymorphism within the promoter region of the TNF-
gene at positions 238 (G to A) and 308 (G to A) have been described. The 308 A-allele, also known as the TNF-
2 allele, has been associated with high promoter activity [26, 27] and enhanced TNF-
production [28]. The gene coding for TNF-, also known as lymphotoxin-
(LT-
), lies next to the TNF-
gene. Single nucleotide polymorphism at position 1069 (G to A) in the first intron of the TNF- gene has been characterized [29]. The ‘A’ variant is the TNF-2 allele whereas the less frequent ‘G’ variant is known as the TNF-1 allele. TNF-2 homozygous individuals produce significantly higher amounts of TNF-
and IL-1 [30, 31]. There is strong linkage disequilibrium between the TNF-
308 (G to A) and TNF- also called NcoI polymorphisms, whereby heterozygosity for both TNF polymorphisms is associated with higher TNF-
production [32]. This finding highlights the importance of linkage disequilibrium in studies examining the association between polymorphism of a single candidate gene and severity of disease. Polymorphism of the TNF-
gene has been studied extensively and has been associated with adverse clinical outcomes among patients with sepsis

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67

Table 1. Association between polymorphism of TNF, IL-10 genes and sepsis or acute renal failure (modified from Jaber et al. [63] with permission) Polymorphic allele TNF-a 308 A-allele (TNF-
2) 308 A-allele (TNF-
2) 308 A-allele (TNF-
2) 308 A-allele (TNF-
2) 238 A-allele TNF-b (LT-a) 250 AA genotype 1069 (NcO1) allele-2/2 1069 (NcO1) allele-2/2 1069 (NcO1) allele-2/2 IL-10 1082 GA genotype 1082 G-allele 592 A-allele

Acute illness

Reference

sepsis/septic shock meningococcal disease neonatal acute renal failure increased mortality in dialysis-requiring acute renal failure increased risk of death in community-acquired pneumonia

[33, 34, 36] [64] [39] [40]

increased risk of septic shock in community-acquired pneumonia septic shock following acute biliary pancreatitis increased mortality in severe sepsis susceptibility to severe post-traumatic sepsis meningococcal disease severity of illness in community-acquired pneumonia mortality in sepsis

[35]

[35, 37]

[65] [66] [36]

[42, 67] [43]

[44]

[33, 34] as well as patients with community-acquired pneumonia [35]. Other studies have linked TNF-2 homozygous status with higher mortality of and increased susceptibility to severe sepsis [36]. The TNF- 250 AA-genotype has been associated with a greater risk of septic shock in community-acquired pneumonia [37]. Both the TNF- 250 G and the TNF-
308 G-alleles have also been associated with prolonged mechanical ventilation following coronary artery bypass graft (CABG) surgery [38]. The 308 A-allele (TNF
2) has also been associated with an increased incidence of ARF among neonates [39] and with higher TNF-
production and a higher risk of death among adult patients with dialysis-requiring ARF (fig. 3) [40]. These data support the hypothesis that TNF-
gene polymorphisms linked to increased production of pro-inflammatory cytokines may have important

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1.0

0.8 Cumulative survival

Low TNF-
, high IL-10 Low TNF-
, low IL-10 0.6 High TNF-
, high IL-10 0.4

0.2

High TNF-
, low IL-10

0.0 0

20

10

30

Time (days)

Fig. 3. Cumulative survival in a cohort of patients with dialysis requiring ARF stratified by the combination of TNF-
and IL-10 gene-polymorphism and adjusted for APACHE II score. Modified from Jaber et al. with permission [40].

implications in the severity of ARF, and, consequently, the requirement for dialysis and hospital mortality.

The Interleukin-10 Gene

The IL-10 gene is located on the long arm of chromosome 1. The IL-10 promoter region is polymorphic with a single-base-pair substitution at position 1082 (G to A) [41]. In vitro studies have identified three phenotypic secretion levels based on allelic substitutions: GG, GA and AA genotype, for high, intermediate and low producer status, respectively [27, 41]. Additional polymorphisms at positions 819 (C to T) and 592 (C to A) have been described. Polymorphisms at these two sites are in linkage disequilibrium. Interleukin-10 1082 polymorphic alleles have been associated with susceptibility to meningococcal disease and adverse clinical outcomes [42], and severity of illness in community-acquired pneumonia [43]. In dialysis-requiring ARF, carriers of the IL-10 1082 G-allele had higher IL-10 production and lower risk of death after adjustment for severity of illness scores, especially when combined to the TNF-
low producer genotype (308 A-allele carrier) (fig. 3) [40]. The IL-10 592 A-allele has been associated with higher mortality in sepsis [44].

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Limitations of Gene Polymorphism-Association Studies

Polymorphism-association studies are typically designed in a case-control format. They frequently have a small sample size, and should be interpreted with caution. This is particularly true for diseases that are common and polygenic in nature and where a single candidate gene hypothesis lacks biological plausibility. Small, single center studies may also be limited in their external validity regarding ethnicity and geographical boundaries [45]. Survival bias is another concern in case control studies evaluating genetic markers as predictors of mortality. Proper matching for age and follow up time or using prospective cohort study designs can overcome these limitations [46].

The Future in ARF

Future developments in ARF will focus on development and establishment of early bio-markers of kidney injury such as NAG and KIM-1. There is also a need to develop non-invasive tools that help detect ARF-induced inflammation. The ultra-small super-paramagnetic iron oxide (USPIO) enhanced MRI is one such example. This technology can detect inflammation caused by experimental cerebral ischemia, arthritis, nephrotoxic nephritis, and renal transplant rejection [47]. The USPIO particles are internalized by leukocytes, and once internalized, MRI signal intensity decreases on T2-weighted images. This extremely promising tool awaits further studies in humans. Novel risk assessment and stratification tools to help allocate resources are also likely to be the focus of future research efforts, and cytokine genotype profiles are a good example for such use. Finally, targeted therapies, including the use of cytokine modulating strategies are another example of future interventions in ARF. Indeed, due to their importance in inflammatory diseases, the modification of cytokine responses through therapeutic intervention remains a focus of intense investigation. A summary of modulation of two particular cytokines, TNF-
and IL-10, is briefly reviewed.

Down-Regulation of TNF-␣

Glucocorticoids, pentoxifylline and thalidomide inhibit TNF-
synthesis at distinct points of its biosynthetic pathway. Glucocorticoids interfere with NF-B which in turn decreases expression of TNF-
activity [48], and reduces posttranscription protein translation [49]. The xanthine derivative pentoxifylline, reduces TNF-
mRNA expression in monocytes [50], which is partly mediated

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by generation of cyclic adenosine monophosphate (cAMP) which inhibits NF-B-mediated transcription [51]. Rolipram, a specific inhibitor of monocyte predominant phosphodiesterose inhibitor type-4, is a 500-fold more potent inhibitor of TNF-
synthesis in human monocytes, compared with pentoxifylline [52]. Thalidomide also selectively inhibits biosynthesis of TNF-
[53]. Interleukin-10 reduces expression of TNF-
[54], and its administration to healthy volunteers inhibits endotoxin-induced rise in body temperature and release of TNF-
[55]. Both monoclonal antibodies to TNF-
(Inflixmab, Adalilumab) as well as soluble TNF receptors (sTNFR) (Etanercept) can bind and neutralize this cytokine. Finally, somatostatin is also capable of down-regulating cell-surface TNF receptor expression in human macrophages, which become less responsive to TNF-
[56]. These therapeutic approaches of immune modulation in inflammatory diseases could play a role in ameliorating the inflammatory component in the pathophysiology of ARF.

Upregulation of IL-10

Cyclic AMP stimulates IL-10 gene transcription via activation of cAMP response element binding proteins [57]. The phosphodiesterase inhibitors theophylline and rolipram induce IL-10 expression [58, 59]. The xanthine derivatives pentoxifylline and caffeine, however, decrease IL-10 whereas dexamethasone increases its release [60]. Calcineurin inhibitors also increase IL-10 mRNA expression and synthesis [61]. Finally, glucocorticoids have been shown to modulate the inflammatory response syndrome in favor of IL-10, resulting in a decrease in TNF-
, interleukin-6 (IL-6) and interleukin-8 (IL-8) levels and an increase in IL-10 levels [62].

Summary and Conclusions

Although the pathogenesis of ARF is heterogeneous and results from a combination of different environmental influences and host responses, there is overwhelming data to suggest a common pathway that involves pro- and antiinflammatory molecules, which in turn, determines the extent of tissue injury. The number of recognized cytokine gene polymorphisms is growing daily. The development of cytokine gene mapping may help identify patients in whom an excessive systemic inflammatory response may follow a therapeutic intervention (e.g. CABG, contrast administration), and who may be at increased risk for developing acute organ dysfunction. Through these advances, tools may be developed to better understand, prevent and treat ARF.

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Low

High

e.g. TNF-
-308, IL-10 -1082 SNP…

Spectrum of genetic predisposition

Risk of acute renal failure

Spectrum of environmental predisposition

e.g. radiocontrast, sepsis, surgery… High

Low

Fig. 4. Acute renal failure risk stratification: A model for genetic and environmental interaction.

Genetic epidemiology studies may help characterize the importance of genetic markers in the development of ARF. This would require large prospective cohort studies aimed at examining associations between genetic markers, urinary (urine KIM-1 and NAG) and circulating (serum creatinine) markers of kidney injury. Once firmly established, the association of a particular genetic profile and outcome could be used to risk stratify patients for the development of ARF (fig. 4). Ultimately, cytokine-modulating therapies could be employed on the basis of genotypic risk stratification with the goal to prevent kidney injury or minimize its deleterious effects on patient outcome.

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 76–93

Mechanisms of Immunodysregulation in Sepsis Jean-Marc Cavaillon, Catherine Fitting, Minou Adib-Conquy UP Cytokines and Inflammation, Institut Pasteur, Paris, France

Tissue injury, blood loss, hypoxia, transfusion, bacterial translocation, microbial infection, and cell activation by microbial products occur in patients with systemic inflammatory response syndrome (SIRS) (e.g. trauma, hemorrhage, burns, surgery or sepsis). These events contribute to the inflammatory response and affect the quality of the immune status. In addition, drugs (e.g. anesthetics, opioids…) also influence immune responses (fig. 1). Depressed immune status including decreased blood cell counts, low expression of surface markers (e.g. MHC class II antigen), altered natural killer (NK) cell activity, diminished cellular cytotoxicity, reduced antigen presentation, poor proliferation in response to mitogens and depressed cytokine production, are seen in vitro, and illustrated in vivo by anergy to skin test antigens. These observations led Bone [1] to coin the concept of ‘compensatory anti-inflammatory response syndrome’ or CARS. Bone postulated that when the SIRS response predominates, the syndrome is associated with an organ dysfunction and cardiovascular compromisation leading to shock; in contrast, when CARS predominates, it is characterized by anti-inflammatory responses associated with a suppressive effect on the immune system, also known as ‘immunoparalysis’. However, this term is far too excessive and we will see that the alteration of the immune response is not a generalized phenomenon. It was initially accepted that the SIRS response occurred first and was followed in some patients by the CARS response. However, it is most probable that the two syndromes occur concomitantly [2]. Although alterations in immune responses are probably associated with an enhanced sensitivity to nosocomial infections, there is no clear demonstration that they are directly responsible for poor outcome in sepsis. Furthermore, the mechanisms behind the maintenance of the sustained suppression of the immune function remain incompletely understood.

Trauma—Hemorrhage—Burns—Surgery—Sepsis

Anesthetics Hypoxia

Blood loss Transfusion

Opioids Tissue injury Microbial agents

Bacterial translocation

Inflammatory response

Lymphocyte and monocyte populations changes

Immune status

Cell surface markers changes (e.g. HLA DR)

Anergy to skin test antigens

Immune dysregulation

Apoptosis Lymphocyte proliferation NK activity

Cytokine production

Fig. 1. Numerous events occurring during systemic inflammatory response syndrome contribute to modify the immune status as illustrated by various altered immune responsiveness that can be monitored either in vitro, ex vivo or in vivo.

Assessment of Immunodysregulation

Circulating Leukocytes and HLA-DR Expression The absolute number of circulating cells is modified during sepsis. Analysis of lymphocyte subsets reveal a decreased number of circulating NK cells, CD4⫹, and CD8⫹ lymphocytes, and an increase of B lymphocytes [3] and of regulatory T cells (CD4⫹/CD25⫹) [4]. Within monocytes, the subset of CD14low/CD16⫹ cells is increased [5]. In a mouse model of sepsis, an enhanced number of NK-T cells found in the spleen has been associated with immune suppression [6]. Abnormal antigen presentation has been observed in SIRS patients [7], and decreased HLA-DR expression on monocytes may contribute to this defect [8]. In a study by Hershman et al. [9], there was a significant decrease of

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HLA-DR expression on peripheral blood monocytes of trauma patients as compared to that of healthy volunteers. In those who developed sepsis, HLA-DR expression took 3 weeks to return to normal and in the patients who did not survive, this expression never returned to normal. HLA-DR antigen expression correlated directly with the clinical status and identified a group of patients at high risk of infection and death following trauma. Low HLA-DR expression is now widely recognized as a good marker of the intensity of the immune depression and of increased risk of bacterial infection [10]. In an elegant study, Fumeaux and Pugin [11] showed that the presence of circulating IL-10 in septic plasma was partially responsible of the reduced HLA-DR expression following intracellular sequestration of the molecule. Lymphocyte Proliferation Impaired lymphocyte proliferation in SIRS patients was reported more than three decades ago [12]. The impairment was proportional to the severity of the injury. In vitro, lymphocyte proliferative response to antigens, mitogens and mixed lymphocyte reaction are all significantly decreased. Longer depression of lymphocyte responses and lower responses were observed in patients who became infected and developed sepsis [13–15]. Increased level of apoptosis is not directly associated with lowered T-cell proliferative response [16]. However, a profound apoptosis of B and T lymphocytes has been found in humans [17, 18], and it has been established that prevention of lymphocyte apoptosis improves survival in a sepsis model in mice [19]. Natural Killer Cell Activity Significantly depressed NK cell activity has been described in burn and trauma patients. In the study by Maturana et al. [20], patients with septic shock had also a markedly lower NK activity than healthy controls. Pre-incubation of peripheral blood lymphocytes with either interferon-␣ (IFN␣) or interleukin-2 (IL-2) enhanced NK cell activity in healthy controls but not in patients with sepsis indicating the difficulty to reverse the depressed immune responsiveness [21]. Neutrophil Functions Apoptosis of circulating neutrophils (PMN) is delayed in patients with SIRS or sepsis [22], and mRNA expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, is upregulated in PMN of patients with sepsis [23]. In addition, some of the activities mediated by PMN appear to be altered. This is the case of phagocytosis, bactericidal activity [24] and migration [25]. The reduced responsiveness of PMN to chemoattractant agents may reflect the action of nitric oxide [25], the decreased expression of certain chemokine receptors [26], or a deactivation occurring in the blood stream after interacting

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with large amounts of circulating chemokines as assessed, for example, by the huge amounts of IL-8 found associated to PMN in septic patients [27]. Delayed Hypersensitivity The in vitro evidence of immune depression is also reflected in vivo by tests of delayed type hypersensitivity. Several years ago, Christou et al. [28] skin tested surgical patients with recall antigens prior to operation. Patients who had normal skin test responses were of similar age and had equal degrees of surgical procedures performed compared with those patients who were anergic (i.e. had depressed skin test responses). Post-operatively, sepsis, mortality and death due to sepsis were significantly higher in the anergic population, reconfirming the hypothesis that skin test anergy pre-operatively is a signal of increased risk for septic complications and death in such patients. These authors [29] reported that surgical patients who were anergic to a battery of five skin test antigens had a two-fold higher rate of postoperative infection than those who reacted to only two antigens and were more than fivefold likely to die in the post-operative period. The hallmark of anergy is a lack of recruited specific T cells at the site of injection in the skin [30]. Ex vivo Cytokine Production A reduced capacity of circulating leukocytes from septic patients to produce pro-inflammatory cytokines as compared to cells from healthy controls has been regularly reported in ex vivo experiments. The very first observation on the hyporeactivity of circulating cells in septic patients was demonstrated in peripheral blood lymphocytes: Wood et al. [31] reported a decreased IL-2 production upon phytohemagglutinin (PHA) stimulation. Interferon-␥ (IFN␥) production is affected in sepsis as well as in patients with severe injury [32]. It is often suggested that the depressed response mainly affects the production of Th1 cytokines (IL-2, IFN␥) whereas production of Th2 cytokines would be upregulated. However, we demonstrated in sepsis and in SIRS patients that the production of Th2 cytokines (IL-5, IL-10) could also be altered and that the nature of the triggering agent itself influences the observation [33]. Similarly, in patients resuscitated after cardiac arrest, identified as a sepsis-like syndrome, we showed that both concanavalin A-induced IL-10 (Th2) and IFN␥ (Th1) productions were significantly decreased in ex vivo assays [34]. Similarly, ex vivo cytokine production (IL-1␤, IL-1ra and IL-8) by LPSactivated neutrophils from septic patients is reduced as compared to PMN of healthy controls [35–37]. Most interestingly, van der Poll’s group [38] demonstrated that injection of endotoxin in healthy human volunteers led to hyporeactive blood derived-PMN in terms of production of the chemokines IL-8,

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GRO-␣ and ENA-78, when further challenged in vitro with either LPS, heatkilled Streptococcus pneumoniae or heat-killed Pseudomonas aeruginosa. The reactivity to LPS stimulation has been particularly studied in isolated monocytes and in whole-blood assays. Monocytes from septic patients have a diminished capacity to release TNF␣, IL-1␣, IL-1␤, IL-6, IL-10 and IL-12 [32, 39–42], whereas this is not the case for IL-1ra [40] and G-CSF [43]. In human volunteers, intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells (PBMC) when activated in vitro by LPS [44]. Most interestingly, it was shown that the reduced production of cytokines reflects a reduced number of cytokine-producing cells [45]. Many parameters of immmunoparalysis observed in SIRS patients are reminiscent of the endotoxin tolerance phenomenon, which characterizes the refractoriness of cells or whole animals to respond to a second endotoxin challenge, shortly after a first encounter. Cross-tolerance has been regularly reported in experimental models of endotoxin tolerance between LPS and other Toll-like receptors (TLR), ligands [46–48] or whole bacteria [49, 50]. Similarly, in sepsis patients and in LPS-injected human volunteers a reduced responsiveness to gram-positive bacteria and superantigens have been reported [44, 51–53]. However, this is not always the case and we showed that in SIRS patients, cells normally responded to certain stimuli [54]. Revisiting the crosstolerance with gram-positive bacteria in a mouse model of endotoxin tolerance, we showed that the phenomenon was only transient, especially in the blood compartment [55]. In addition to the nature of the stimuli, there are other observations that allow ascertaining that the cellular hyporeactivity is not a global phenomenon. For example, we showed that the release of ‘macrophage migration inhibitory factor’ (MIF) by circulating mononuclear cells was enhanced in sepsis [Maxime et al., submitted]. Furthermore, during sepsis and SIRS, cells derived from tissues are either fully responsive to ex vivo stimuli, or even primed, in contrast to cells derived from hematopoietic compartments (blood, spleen…), which are hyporeactive. This dichotomy illustrates the concept of compartmentalization, which occurs within the body during sepsis [56]. Thus, during systemic inflammation, SIRS and CARS seem to be present concomitantly [2]: SIRS predominating within the inflamed tissues, while in the blood the leukocytes show hyporeactivity.

Concept of Compartmentalization

The measurement of inflammatory mediators is in agreement with the concept of a compartmentalization of inflammation. For example, iNOS activity

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was found to be restricted to the nidus of infection in patients undergoing a septic shock after cellulitis [57]. TNF and IL-6 concentrations were higher in cerebrospinal fluids than in plasma of patients with meningitis [58]. After chest trauma, significantly higher levels of IL-1␤ and IL-8 were found in bronchoalveolar lavage fluids than in plasma, whereas anti-inflammatory mediators (sTNFRI and II, IL-1ra) were present both locally and systematically [59]. Measurement of pro-inflammatory cytokines and anti-inflammatory mediators in pleural fluids also suggested the occurrence of both systemic and compartmentalized response in septic as well as in non-septic patients [60]. Finally, the compartmentalized cytokine production was elegantly demonstrated by Dehoux et al. [61] who showed higher levels of inflammatory cytokines in broncho-alveolar lavage (BAL) fluids recovered from involved lung of patients with unilateral pneumonia as compared to the contralateral, non-involved lung. In this study, the authors showed that the productions of IL-1, IL-6, and TNF by alveolar macrophages activated with LPS were reduced as compared to the responses obtained with cells recovered from healthy controls. However, in contrast to this report, which deals with a local infectious process, and in contrast to the hyporeactivity of the circulating leukocytes, it has often been shown that cells derived from the inflamed tissues are activated and primed and fully responsive to ex vivo stimulation. In acute respiratory distress syndrome (ARDS) patients, alveolar macrophages displayed an enhanced capacity of producing IL-1 after ex vivo stimulation with LPS alone or together with IFN␥ [62]. Interestingly, in human volunteers, Smith et al. [63] reported that intravenous endotoxin primed alveolar macrophages for an enhanced in vitro LPSinduced production of IL-1, TNF and PGE2. We analyzed the reactivity of alveolar macrophages derived from baboons that had undergone unilateral lung irradiation. In the days following irradiation, not only the spontaneous production of IL-8 and TNF was enhanced, but those induced by LPS, Staphylococcus and Streptococcus were increased as compared to the response obtained with the alveolar macrophages recovered before irradiation [2]. The study of peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients revealed that LPS-activated cells released significantly more IL-1␤ during peritonitis as compared with the infection-free period [64]. In women with endometriosis, spontaneous and LPS-induced production of TNF␣, IL-6, IL-8, IL-10, IL-12 and nitric oxide (NO) by peritoneal macrophages was higher than in controls [65, 66]. In patients with inflammatory bowel disease, adherent lamina propria mononuclear cells activated with pokeweed mitogen or with a combination of LPS and IFN␥ displayed an upregulated production of TNF␣, IL-1␣, IL-1␤ and IL-6 [67]. The activation of intracellular signaling pathways has also been studied. Schwartz et al. [68] observed an increased activation of NF-␬B in alveolar

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macrophages from patients with ARDS. Moine et al. [69] subsequently showed decreased cytoplasmic levels of p50, p65 and c-Rel in alveolar macrophages from patients with ARDS, consistent with an enhanced migration of liberated NF-␬B dimers from the cytoplasm to the nucleus. In murine models of hemorrhage or of endotoxinemia, activation of NF-␬B, CREB, MEK-1/2 and Erk2 were found in alveolar neutrophils but not in blood neutrophils [70, 71]. It is worth noting that cells derived from inflammatory foci may be far less sensitive to anti-inflammatory mediators. This was elegantly demonstrated by Pang et al. [72] who showed, in chronic bronchial sepsis patients, that the production of IL-8 by PMN derived from sputum was not significantly reduced by the addition of increasing amounts of IL-10 in contrast to the inhibitory effect of IL-10 on circulating PMN. Similarly, we showed in cystic fibrosis patients that sputum-derived PMN that produce high levels of IL-8 were poorly downregulated by dexamethasone in contrast to circulating PMN [73].

Mechanisms of Hyporesponsiveness of Monocytes

Desensitizing Agents in Plasma The presence of deactivating or immunosuppressive agents within the blood stream may contribute to the hyporeactivity of circulating leukocytes. In the late 70’, it was reported that sera of burn patients were able to suppress the proliferative response of normal cells [74]. Prins et al. [75] showed that sera from septic patients had the capacity to downregulate the TNF production by activated monocytes from healthy donors. The fact that ‘septic plasma’ behave as an immunosuppressive milieu [76] is illustrated in human volunteers by the capacity of endotoxin to induce plasma inhibitors [77]. Most interestingly, in septic patients this suppressive effect was significantly reduced after passage of plasma through a resin and after incubation with anti-IL-10 antibodies [78]. IL-10 was identified as a major functional deactivator of monocytes in human septic shock plasma [79]. TGF␤ was also shown in animal models of hemorrhagic shock and of sepsis to be the causative agent of the depressed splenocyte responsiveness [80]. Monocytes from immunocompromised trauma patients seem to be a source of TGF␤ [81], and TGF␤ released by apoptotic T cells contributes to this immunosuppressive milieu [82]. In addition, there is accumulating evidence for a strong interaction between components of the nervous and the immune systems. Numerous neuromediators have been shown to behave as immunosuppressors. Catecholamines, found to be at higher concentrations in stressful situations [83], suppress the activity of immunocompetent cells, inhibit TNF production and favor IL-10 release. Alpha-melanocyte-stimulating hormone also contributes to immunosuppression by inducing IL-10 production

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by human monocytes [84]. In addition, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide directly inhibit endotoxin induced pro-inflammatory cytokine secretion [85]. SIRS is also associated with an activation of the hypothalamus-pituitary-adrenal axis which leads to the release of glucocorticoids, well known for their potent ability to limit cytokine production [86]. Prostaglandins are produced during sepsis and can also contribute to the down regulation of cytokine production [87]. Finally, the levels of circulating heat shock proteins (HSP) are elevated in SIRS and sepsis patients [88]. Since it has been shown that over-expression of HSP can inhibit LPS induced production of cytokines [89], one can postulate that HSP may play a role in desensitizing circulating cells. Endotoxin-Neutralizing Molecules in Plasma As mentioned previously, the reduced capacity of monocytes to produce inflammatory cytokines has been particularly established using LPS as a triggering agent. Since numerous recent studies analyzed the hyporeactivity phenomenon with whole blood samples, it is possible that endotoxin-neutralizing molecules interfered in these studies. Indeed, we showed that the hyporeactivity to LPS was both, an intrinsic property of circulating monocytes, as well as the reflection of a specific neutralizing activity within the plasma of SIRS patients [90]. It has been reported that plasma of septic patients content large amounts of LPS-binding protein (LBP) which can either inhibit the LPS molecules [91], or transfer LPS to lipoproteins [92] known for their inhibitory activity towards LPS [93]. Furthermore, sera from septic patients contain great amounts of soluble CD14 which also favors the shuttle of LPS towards lipoproteins [94]. More recently, enhanced levels of ubiquitin, an 8.6-kD protein involved in intracellular function, have been found in serum of sepsis and trauma patients and shown to specifically inhibit TNF induction by LPS [95]. Toll-Like Receptor Expression Toll-like receptors (TLR) are a family of receptors that recognize components of bacteria, virus, parasites and fungi and induce a pro-inflammatory response by several cell types. So far, 10 human TLRs differing in their specificity for microbial components have been cloned, which respond to various components, including LPS from Gram-negative bacteria, lipopeptides of Gram-positive cell walls, bacterial DNA, and flagella. TLR4 was identified as the receptor for LPS and requires the presence of an extracellular accessory protein called MD-2. CD14 physically associates with LPS complexed with LPS binding protein (LBP) and transfers the endotoxin to the TLR4 and MD-2 dimer. Each component of this complex is required for efficient LPS-induced signaling.

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Recent studies reported a downregulation of surface expression of TLR4 in endotoxin-tolerant macrophages [96, 97]. Therefore, it was of interest to investigate the expression of this molecule on the surface of monocytes from SIRS patients. A decreased expression of TLR4 but not TLR2, on CD14-positive cells was found in trauma patients compared with healthy subjects [54]. However, this lower expression of TLR4 was not sufficient to explain the decreased capacity of the cells to respond to some stimuli. Indeed, while LPS-induced TNF was decreased, this was not the case of LPS-induced IL-1ra and IL-10. This later observation suggests that the defect may occur at the level of the signaling pathways within the cell leading to TNF production, rather than at the initiation of the signaling cascade on the cell surface. In contrast to our observation, an enhanced expression of TLR4 was found on monocytes of SIRS patients [98], and at the present time we don’t have any explanations for these divergent findings. Nuclear Factor-kB Nuclear factor-␬B (NF-␬B) is critical for maximal expression of many cytokines involved in the pathogenesis of inflammation. Activation and regulation of NF-␬B are tightly controlled by a group of inhibitory proteins (I␬B), which maintain NF-␬B in the cytoplasm of effector cells. Blackwell et al. [99] investigated the role of NF-␬B in the mechanism of endotoxin tolerance in a rat alveolar macrophage cell line, which was made endotoxin-tolerant. This treatment induced a state of tolerance such that subsequent exposure to high-dose LPS resulted in decreased production of cytokines as compared to LPSsensitive cells. This decreased cytokine production was associated with an impaired activation of NF-␬B and a depletion of both p65 and p50 forms. This study suggested that endotoxin tolerance may be mediated by limiting the amount of NF-␬B available for activation and thus, inhibiting transcription of NF-␬B-dependent genes. On the other hand, Ziegler-Heitbrock et al. [100] demonstrated that endotoxin tolerance in monocyte cell line was associated with an increase of the inactive p50 homodimer of NF-␬B and a decrease of the p50p65 active heterodimer. Accordingly, we studied NF-␬B expression and dimer characteristics in mononuclear cells of patients with severe sepsis or major trauma and of healthy controls [101, 102]. The expression of p65p50 heterodimer was significantly reduced for all patients as compared to controls. The p50p50 homodimer was reduced in the survivors of sepsis. In addition, subsequent in vitro stimulation of PBMC with LPS did not induced further NF-␬B nuclear translocation: the survivors of sepsis showed low expression of both p65p50 and p50p50, while non-survivors of sepsis showed a predominance of the inactive homodimer and a low p65p50/p50p50 ratio when compared to controls. In the later group of patients there was a reverse correlation between plasma IL-10 levels and the p65p50/p50p50 ratio after in vitro LPS stimulation

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(r ⫽ ⫺0.8, p ⫽ 0.04). The reduced expression of nuclear NF-␬B was not due to its inhibition by I␬B␣, since very low expression of I␬B␣, and low levels of p65 and p50 were found in the cytoplasm of PBMC from sepsis patients when compared to controls. These results demonstrate that upon LPS activation, PBMC of SIRS patients show patterns of NF-␬B expression that resemble those reported during LPS tolerance: global downregulation of NF-␬B in survivors of sepsis, presence of large amounts of the inactive homodimer in the non-survivors of sepsis [101]. In trauma patients, we observed a long-term reduction of both p65/p50 heterodimers and p50/p50 homodimers and a reduced p65p50/p50p50 ratio after LPS stimulation in vitro [102]. Other mechanisms of NF-␬B regulation have been reported in a rat model of sepsis for which the reduced capacity of PMN to produce TNF was associated with an increased generation of I␬B␣ caused by the intrinsic generation of C5a [103]. Downregulation of TLR-Associated Signaling Pathways There are still very few studies, which have addressed in humans the link between immunodepression seen in circulating cells in SIRS patients and alteration of some signaling pathways. In the past few years, numerous intracellular molecules that negatively regulate LPS-activated signaling pathways have been discovered (table 1). This is the case of Toll-interacting protein (Tollip), an adaptor protein found to associate with the cytoplasmic TIR domain of IL-1R, TLR2 and TLR4 and to potently suppress the activity of IL-1 receptor associated kinase (IRAK) after TLR activation [104]. A splice variant of MyD88, termed MyD88s, induced upon LPS activation has been described. This molecule is defective in its ability to induce IRAK phosphorylation and behaves as dominant-negative inhibitor [105]. Single immunoglobulin IL-1R-related molecule (SIGIRR) and ST2, members of the TLR/IL-1R superfamily, are negative modulators of the signaling induced by IL-1 or TLR ligands in different types of cells [106a, 106b]. RanGTPase plays a major role in nuclear trafficking and reduces NF-␬B accumulation in the nucleus. As a consequence it acts as a dominant-negative regulator of LPS-induced TNF [107]. IRAK-M prevents the dissociation of IRAK and IRAK-4 from MyD88 and the formation of IRAK-TRAF6 complexes, and is a negative regulator of TLR signaling. Interestingly, endotoxin tolerance is significantly reduced in IRAK-M-deficient mice [108]. It has been recently reported that monocytes from septic patients when stimulated with LPS ex vivo, express IRAK-M mRNA more rapidly than cells from healthy donors [109]. Similarly to IRAK-M⫺/⫺ mice, endotoxin tolerance cannot be observed in mice deficient for suppressor of cytokine signaling-1 (SOCS-1) [110]. In contrast to IRAK-M and SOCS-1 that function during the second or continuous exposure to stimulation, phosphatidylinositol 3-kinase (pi3K) can behave as an early inhibitor of TLR signaling [111]. Learn et al. [112] reported in septic patients that the repressed

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Table 1. Negative regulators of LPS-induced TNF production Mediators

Mechanisms

Found in mouse models (M) or in human (H) SIRS

p50/p50 NF-␬B homodimer IRAK-M

prevents action of bioactive p65/p50 heterodimer prevents dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAKTRAF6 complexes early negative signal, favors IL-1Ra production dominant-negative inhibitor of MyD88 associates with the cytoplasmic TIR domain interacts with IL-1R, TLR4, 5 and 9 and TRAF6 sequestration of adaptators MyD88 and TIRAF/Mal reduces NF-␬B accumulation in the nucleus inactivation of STAT-1 and NF-␬B induced by IL-10 induced by IL-10 induced by IL-10 induced by IL-10

H, M

Pi3K MyD88s Tollip SIGIRR ST2 RanGTPase SOCS-1 SOCS-3 Bcl-3 Stat-3 HO-1

H, M H n.d. n.d. n.d. n.d. n.d. M M n.d. M H

HO-1 ⫽ Heme oxygenase-1; IRAK ⫽ IL-1 receptor-associated kinase; NF-␬B ⫽ nuclear factor-␬B; pi3K ⫽ phosphatidylinositol 3-kinase; SIGIRR ⫽ single immunoglobulin IL-1Rrelated molecule; SOCS ⫽ suppressor of cytokine signaling; STAT-1 ⫽ signal transducer and activator of transcription; Tollip ⫽ Toll-interacting protein; TRAF-6 ⫽ TNF receptorassociated factor-6. n.d. ⫽ Not determined (see text for references).

production of IL-1␤ and the selective elevation of secreted form of IL-1Ra in response to LPS was linked to a probably altered IRAK signaling pathway and a maintained efficient pi3K dependent signaling pathway. In addition to negative regulators directly induced upon activation by TLR ligands, other molecules induced by IL-10 can be involved such as heme oxygenase-1 [113], Bcl-3 [114], Stat-3 [115], or SOCS-3 [116]. Indeed, in an experimental model of sepsis, an upregulation of SOCS-3 was noticed in macrophages and neutrophils present in spleen, lung and peritoneal cavity [117].

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Reversal of Monocytes Hyporeactivity IFN␥ and GM-CSF can restore the responsiveness of monocytes from SIRS and sepsis patients [118–120]. These observations are reminiscent of the well-known capacity of these cytokines to reverse endotoxin tolerance [121, 122]. Whether an in vivo treatment by these cytokines could have beneficial effects remains to be fully established. Indeed, it is still unclear whether this immune alteration is responsible of poor outcome or only a reflect of a physiological adaptation. In this context, it is worth to mention the fact that extracorporeal immunotherapy with IL-2 lowered mortality of surgical infection [123]. Alteration or Physiological Adaptation?

Sepsis and non-infectious SIRS are paradoxically associated with an exacerbated production of cytokines, as assessed by their presence in biological fluids, and a diminished ability of circulating cells to produce cytokine upon in vitro activation. This may represent a protective response against an overwhelming dysregulation of the pro-inflammatory process, but on the other hand it may alter the immune status (‘endogenous immunosuppression’) leading to an increased risk of subsequent nosocomial infections [56]. However, cellular hyporeactivity is not a global phenomenon and some signaling pathways are unaltered and allow the cells to respond normally to certain stimuli. Furthermore, during sepsis and SIRS, cells derived from tissues or inflammatory foci are either fully responsive to ex vivo stimuli or even primed, in contrast to cells derived from hematopoietic compartments (blood) that are hyporeactive. The first analysis of intracellular signaling pathways within leukocytes of sepsis patients revealed that some alterations are associated with cellular hyporeactivity. Thus, the immunodysregulation reported in sepsis and SIRS patients, often illustrated by a diminished capacity of leukocytes to respond to LPS, is not a generalized phenomenon and SIRS is associated with a compartmentalized responsiveness, which involves either anergic or primed cells. References 1 2

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Wilhelm W, Grundmann U, Rensing H, et al: Monocyte deactivation in severe human sepsis or following cardiopulmonary bypass. Shock 2002;17:354–360. Adib-Conquy M, Moine P, Asehnoune K, et al: Toll-like receptor (TLR) 2-, TLR4- and TLR9mediated TNF and IL-10 production are not similarly affected during systemic inflammation. Am J Resp Crit Care Med 2003;168:158–164. Fitting C, Dhawan S, Cavaillon JM: Compartmentalisation of endotoxin tolerance. J Infect Dis 2004;189:1295–1303. Munford RS, Pugin J: Normal response to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 2001;163:316–321. Annane D, Sanquer S, Sébille V, et al: Compartmentalised inducible nitric-oxide synthase activity in septic shock. Lancet 2000;355:1143–1148. Waage A, Halstensen A, Espevik T, Brandzaeg P: Compartmentalization of TNF and IL-6 in meningitis and septic shock. Mediators Inflam 1993;2:23–25. Keel M, Ecknauer E, Stocker R, et al: Different pattern of local and systemic release of proinflammatory and anti-inflammatory mediators in severely injured patients with chest trauma. J Trauma 1996;40:907–914. Marie C, Losser MR, Fitting C, Kermarrec N, Payen D, Cavaillon J-M. Cytokines and soluble cytokines receptors in pleural effusions from septic and nonseptic patients. Am J Respir Crit Care Med 1997;156:1515–1522. Dehoux MS, Boutten A, Ostinelli J, et al: Compartmentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 1994;150:710–716. Jacobs RF, Tabor DR, Burks AW, Campbell GD: Elevated interleukin-1 release by human alveolar macrophages during adult respiratory distress syndrome. Am Rev Respir Dis 1989;140:1686–1692. Smith PD, Suffredini AF, Allen JB, Wahl LM, Parrillo JE, Wahl SM: Endotoxin administration to humans primes alveolar macrophages for increased production of inflammatory mediators. J Clin Immunol 1994;14:141–148. Fieren MWJA, Van Den Bemd GJ, Bonta IL: Endotoxin-stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin-1␤ in vitro during infectious peritonitis. Eur J Clin Invest 1990;20:453–457. Rana N, Braun DP, House R, Gebel H, Rotman C, Dmowski WP: Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil Steril 1996;65:925–930. Wu MY, Ho HN, Chen SU, Chao KH, Chen CD, Yang YS: Increase in the production of IL-6, IL-10 and IL-12 by LPS stimulated peritoneal macrophages from women with endometriosis. Am J Reprod Immunol 1999;41:106–111. Rugtveit J, Nilsen EM, Bakka A, Carlsen H, Brandtzaeg P, Scott H: Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. Gastroenterology 1997;112:1493–1505. Schwartz MD, Moore E, Moore FA, et al: Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med 1996;24:1285–1292. Moine P, McIntyre R, Schwartz MD, et al: NF-␬B regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome. Shock 2000;13:85–91. Shenkar R, Abraham E: Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: Roles of reactive oxygen intermediates, NF-␬B and cyclic AMP response element binding protein. J Immunol 1999;163:954–962. Abraham E, Arcaroli J, Shenkar R: Activation of extracellular signal-regulated kinases, NF-␬B, and cyclic adenosine 5⬘-monophosphate response element binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia. J Immunol 2001;166:522–530. Pang G, Ortega M, Zighang R, Reeves G, Clancy R: Autocrine modulation of IL-8 production by sputum neutrophils in chronic bronchial sepsis. Am J Respir Crit Care Med 1997;155:726–731. Corvol H, Fitting C, Chadelat K, et al: Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Am J Physiol 2003;284:L997–L1003. Constantian M: Association of sepsis with an immunosuppressive polypeptide in the serum of burn patients. Ann Surg 1978;188:209–215. Prins JM, Kuijper EJ, Mevissen ML, Speelman P, van Deventer SJ: Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: Influence

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of antibiotic class, antibiotic concentration, and presence of septic serum. Infect Immun 1995;63: 2236–2242. Cavaillon J-M: ‘Septic Plasma’: An immunosuppressive milieu. Am J Respir Crit Care Med 2002; 166:1417–1418. Spinas G, Bloesch D, Kaufmann M, Keller U, Dayer JM: Induction of plasma inhibitors of interleukin 1 and TNF-alpha activity by endotoxin administration to normal humans. Am J Physiol 1990;259:R993–R997. Ronco C, Brendolan A, Lonnemann G, et al: A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002;30:1250–1255. Brandtzaeg P, Osnes L, Øvstebø R, Joø GB, Westwik AB, Kierulf P: Net inflammatory capacity of human septic shock plasma evaluated by a monocyte-based target cell assay: Identification of interleukin-10 as a major functional deactivator of human monocytes. J Exp Med 1996;184: 51–60. Ayala A, Knotts JB, Ertel W, Perrin MM, Morrison MH, Chaudry IH: Role of interleukin-6 and transforming growth factor-beta in the induction of depressed splenocyte responses following sepsis. Arch Surg 1993;128:89–94. Miller-Graziano CL, Szabo G, Griffey K, Mehta B, Kodys K, Catalano D: Role of elevated monocyte transforming growth factor production in post-trauma immunosuppression. J Clin Immunol 1991;11:95–102. Chen W, Frank M, Jin W, Wahl S: TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 2001;14:715–725. Jones SB, Westfall MV, Sayeed MM: Plasma catecholamines during E. coli bacteremia in conscious rats. Am J Physiol 1988;254:R470–R477. Luger TA, Kalden DH, Scholzen TE, Brzoska T: ␣-melanocyte-stimulating hormone as a mediator of tolerance induction. Pathobiology 1999;67:318–321. Delgado M, Pozo D, Martinez C, et al: Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF␣ production by macrophages: In vitro and in vivo studies. J Immunol 1999;162:2358–2367. Annane D, Cavaillon JM: Corticosteroids in sepsis: From bench to bedside? Shock 2003;20: 197–207. Choudhry MA, Ahmad S, Ahmed Z, Sayeed MM: Prostaglandin E2 down-regulation of T cell IL-2 production is independent of IL-10 during Gram negative sepsis. Immunol Lett 1999;67:125–130. Njemini R, Lambert M, Demanet C, Mets T: Elevated serum heat-shock protein 70 levels in patients with acute infection: Use of an optimized enzyme-linked immunosorbent assay. Scand J Immunol 2003;58:664–669. Ding X, Fernandez-Prada C, Bhattacharjee A, Hoover D: Over-expression of hsp-70 inhibits bacterial lipopolysaccharide-induced production of cytokines in human monocyte-derived macrophages. Cytokine 2001;16:210–219. Cavaillon JM, Adrie C, Fitting C, Adib-Conquy M: Endotoxin tolerance: Is there a clinical relevance? J Endotoxin Res 2003;9:101–107. Zweigner J, Gramm HJ, Singer OC, Wegscheider K, Schumann RR: High concentration of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. Blood 2001;98:3800–3808. Vreugdenhil ACE, Snoeck AMP, van’t Veer C, Greve JWM, Buurman WA: LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction. J Clin Invest 2001;107:225–234. Cavaillon JM, Fitting C, Haeffner-Cavaillon N, Kirsch SJ, Warren HS: Cytokine response by monocytes and macrophages to free and lipoprotein-bound lipopolysaccharide. Infect Immun 1990;58:2375–2382. Kitchens RL, Thompson PA, Viriyakosol S, O’Keefe GE, Munford RS: Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. J Clin Invest 2001;108:485–493. Majetschak M, Krehmeier U, Bardenheuer M, et al: Extracellular ubiquitin inhibits the TNF-alpha response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness. Blood 2003;101:1882–1890.

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96 Nomura F, Akashi S, Sakao Y, et al: Endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface Toll-like receptor 4 expression. J Immunol 2000;164: 3476–3479. 97 Medvedev AE, Kopydlowski KM, Vogel SN: Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: Dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. J Immunol 2000;164:5564–5574. 98 Calvano J, Agnese D, Um J, et al: Modulation of the lipopolysaccharide receptor complex (CD14, TLR4, MD-2) and toll-like receptor 2 in systemic inflammatory response syndrome-positive patients with and without infection: Relationship to tolerance. Shock 2003;20:415–419. 99 Blackwell TS, Blackwell TR, Christman JW: Induction of endotoxin tolerance depletes nuclear factor-␬B and suppresses its activation in rat alveolar macrophages. J Leuk Biol 1997;62:885–891. 100 Ziegler-Heitbrock HWL, Wedel A, Schraut W, et al: Tolerance to lipopolysaccharide involves mobilization of nuclear factor-␬B with predominance of p50 homodimers. J Biol Chem 1994;269: 17001–17004. 101 Adib-Conquy M, Adrie C, Moine P, et al: NF-␬B expression in mononuclear cells of septic patients resembles that observed in LPS-tolerance. Am J Respir Crit Care Med 2000;162:1877–1883. 102 Adib-Conquy M, Asehnoune K, Moine P, Cavaillon J-M: Longterm impaired expression of nuclear factor-␬B and I␬B␣ in peripheral blood mononuclear cells of patients with major trauma. J Leuk Biol 2001;70:30–38. 103 Riedemann N, Guo R, Bernacki K, et al: Regulation by C5a of neutrophil activation during sepsis. Immunity 2003;19:193–120. 104 Zhang G, Ghosh S: Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem 2002;277:7059–7065. 105 Janssens S, Burns K, Tschopp J, Beyaert R. Regulation of interleukin-1- and lipopolysaccharideinduced NF-kappaB activation by alternative splicing of MyD88. Curr Biol 2002;12:467–471. 106a Wald D, Qin J, Zhao Z, et al: SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 2003;4:920–927. 106b Brint EK, Xu D, Liu H, et al: ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 2004;publ online. 107 Yuan Q, Zhao F, Chung S, et al: Dominant negative down-regulation of endotoxin-induced tumor necrosis factor alpha production by Lps(d)/Ran. Proc Natl Acad Sci USA 2000;97:2852–2857. 108 Kobayashi K, Hernandez LD, Galan JE, Janeway CAJ, Medzhitov R, Flavell RA: IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 2002;110:191–202. 109 Escoll P, del Fresno C, Garcia L, et al: Rapid up-regulation of IRAK-M expression following a second endotoxin challenge in human monocytes and in monocytes isolated from septic patients. Biochem Biophys Res Commun 2003;311:465–472. 110 Nakagawa R, Naka T, Tsutsui H, et al: SOCS-1 participates in negative regulation of LPS responses. Immunity 2002;17:677–687. 111 Fukao T, Koyasu S: PI3K and negative regulation of TLR signaling. Trends Immunol 2003;24: 358–363. 112 Learn CA, Boger MS, Li L, McCall CE: The phosphatidylinositol 3 kinase pathway selectively controls sIL-1ra not interleukin-1␤ production in the septic leukocytes. J Biol Chem 2001;276: 20234–20239. 113 Lee T, Chau L: Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 2002;8:240–246. 114 Kuwata H, Watanabe Y, Miyoshi H, et al: IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood 2003;102:4123–4129. 115 O’Farrell A-M, Liu Y, Moore KW, Mui ALF: IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: Evidence for Stat3-dependent and-independent pathways. EMBO J 1998;17:1006–1018. 116 Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F: Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharideinduced macrophage activation. J Immunol 2002;168:6404–6411. 117 Grutkoski P, Chen Y, Chung C, Ayala A: Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes. J Leukoc Biol 2003;74:916–922.

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118 Döcke WD, Randow F, Syrbe U, et al: Monocyte deactivation in septic patients: Restoration by IFN␥ treatment. Nat Med 1997;3:678–681. 119 Flohé S, Lendemans S, Selbach C, et al: Effect of granulocyte-macrophage colony-stimulating factor on the immune response of circulating monocytes after severe trauma. Crit Care Med 2003; 31:2462–2469. 120 Williams M, Withington S, Newland A, Kelsey S. Monocyte anergy in septic shock is associated with a predilection to apoptosis and is reversed by granulocyte-macrophage colony-stimulating factor ex vivo. J Infect Dis 1998;178:1421–1433. 121 Randow F, Döcke WD, Bundschuh DS, Hartung T, Wendel A, Volk HD: In vitro prevention and reversal of lipopolysaccharide desensitization by IFN␥, IL-12 and GM-CSF. J Immunol 1997;158: 2911–2918. 122 Adib-Conquy M, Cavaillon J-M: IFN␥ and GM-CSF prevent endotoxin tolerance in human monocytes by promoting IRAK expression and its association to MyD88, and not by modulating TLR4 expression. J Biol Chem 2002;277:27927–27934. 123 Pal’tsev A, Ovechkin A, Zakharova N, et al: Cytokines in the treatment of a generalized surgical infection. Anesteziol Reanimatol 2000;2:27–30.

Jean-Marc Cavaillon UP Cytokines and Inflammation Institut Pasteur, 28, rue Dr Roux, FR–75015 Paris (France) Tel. ⫹33 1 45 68 82 38, Fax ⫹33 1 40 61 35 92, E-Mail [email protected]

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Fluid, Electrolyte and Acid Base Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 94–104

Goals of Resuscitation from Circulatory Shock Michael R. Pinsky Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA

Cardiovascular insufficiency commonly occurs in critically ill patients and may be the reason for intensive care unit (ICU) admission or a complication of treatment or disease during ICU stay. If cardiovascular insufficiency is associated with inadequate O2 delivery to the tissues, then the patient is said to be in shock. The management of shock-like states depends on both the etiology of the condition and attaining certain cardiovascular targets of blood flow, O2 delivery and perfusion pressure. Thus, the physician caring for such individuals needs to have a rational approach to both the diagnosis of shock and its resuscitative therapy.

Shock States

Shock is a circulatory a state characterized by inadequate delivery of nutrients and O2 delivery to meet the metabolic requirements of the tissues. Shock etiologies have been traditionally divided into four broad categories based on pathophysiologic mechanisms [1]: hypovolemic, cardiogenic, distributive, and obstructive. Although resuscitation of patients in shock may restore adequate global O2 transport, it may not restore blood flow to damaged vascular beds due to the associated alterations in autoregulation and microvascular blood flow. Clearly, any given patient may demonstrate qualities that blur the separation of shock into these specific states. Still, the most common quality of a shock-like state is hypovolemia, as characterized by hypovolemic shock. In hypovolemic shock, the vascular volume is near or below the stressed volume, resulting in a profound decrease in venous return. Independent of any changes in vasomotor tone or cardiac pump function, a loss of 30–40% of the circulating volume will lead to marked hypotension and organ hypoperfusion [2]. Although not clearly

documented in humans, in animal models of hemorrhagic shock, a greater than a 40% loss of intravascular volume can result in irreversible shock and death if not treated effectively with fluid resuscitation in less than two hours [3]. The normal physiologic response to a hypovolemic stress is to increase sympathetic output that increases vascular tone and thus reduces unstressed volume. The resultant effect is to increase upstream pressure in the venous reservoirs increasing venous return. The associated increased sympathetic tone increases heart rate, contractility and cortisol secretion. Furthermore, the associated release of aldosterone from the adrenal cortex increases sodium and water reabsorption in the kidney. Although these endocrinological responses are effective in restoring intravascular volume in the long run, over the immediate resuscitative interval they only serve to prevent sodium excretion. Cardiogenic shock reflects any process wherein inadequate ventricular pump function induces hypoperfusion. Cardiac arrhythmia, ischemia, infarction, valvular dysfunction, or myocardial failure are all capable of inducing cardiogenic shock. Myocardial failure may also be secondary to systemic metabolic processes such as hypoxia, acidemia, hypothyroidism or hyperthyroidism. Only a small percentage of subjects with cardiogenic shock will demonstrate increased cardiac output in response to isolated inotropic during administration. Thus, patients demonstrating cardiogenic shock need to have their etiology quickly and accurately identified if appropriate etiology-specific therapy is to be given. Distributive shock represents a state in which the body looses its ability to autoregulate blood flow. Loss of vascular integrity often occurs in response to sepsis (malignant intravascular inflammation), adrenal cortical insufficiency, hypocalcemia and with the infusion of vasodilator drugs. Presently, physician’s interest in distributive shock focuses on systemic inflammatory states, such as severe sepsis, burns, pancreatitis and trauma. In these conditions, cytokine activation and release into the systemic circulation commonly occurs and induces a generalized inflammatory response characterized by up-regulation of vascular endothelial inducible nitric oxide synthase (iNOS), release of arachidonic acid metabolites and primary vascular smooth muscle dysfunction [4–6]. Moreover, localized production of nitric oxide, O2 radicals, prostaglandins, platelet aggregating factor, and up-regulation of CD11b/CD18 receptors on leukocytes lead to loss of capillary integrity, adherence of circulating leukocytes to the vascular endothelium, and localized disruption of the microcirculation [4, 6, 8–10]. Importantly, one needs not evoke infection to see this systemic response. Severe trauma also displays a similar sustained inflammatory mediator activation state. Non-cardiogenic obstructive shock includes all causes of diminished cardiac output secondary to compression on the vascular system or obstruction to blood flow other than from valvular disease, such as tension pneumothorax, pericardial tamponade, constrictive pericarditis, pulmonary embolism, and acute pulmonary

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hypertension with acute cor pulmonale. Pulmonary embolism and acute pulmonary hypertension deserve special mention, since both cause shock by inducing right heart failure and diminished left ventricular end diastolic volume. An acute rise in pulmonary artery pressure from massive pulmonary emboli or hypercarbic respiratory failure leads to dilation of the right ventricle. This in turn displaces the intraventricular septum toward the left ventricle, and by the process of ventricular interdependence, decreases left ventricular diastolic compliance. The resulting decrease in preload leads to diminished cardiac output. Thus, treating such patients with fluid resuscitation will induce only more right ventricular dilation and worsen the obstructive state.

Goals of Therapy

The individual who is in shock may exhibit a wide range of clinical signs (associated with increased sympathetic tone). There is no universal set of variables that may be assessed to determine the presence or absence of shock. The determination of shock is often made clinically from the history and physical examination. Patients often present with tachypnea and dyspnea as early signs of cardiovascular deterioration. They may appear pale, diaphoretic, with cold, clammy skin, or may appear warm, erythematous, and dry. The blood pressure may be normal, elevated, or low, and the heart rate may be tachycardic, bradycardic, and rarely normal. Urine output is often diminished, and mentation impaired. On laboratory evaluation, a metabolic acidosis may be present with elevation of serum lactate, excesses chloride loading or be unexplained [11, 12]. Except in acute hypovolemic shock the metabolic acidosis is in excess to that explained by anaerobic metabolism (lactic acidosis) alone. However, this is neither sensitive nor specific for the presence of shock [13]. The arterial blood gas analysis may reveal a respiratory alkalosis, metabolic acidosis or a combination of the two. Since the signs of circulatory shock can be non-specific, it follows that the end-points of therapy may also be difficult to define. Resuscitation of shock can be divided into primary and secondary periods. The primary period is the time from initial evaluation through the first round of resuscitation. The goals during this period are cardio-pulmonary-cerebral resuscitation [14]. Basic and advanced life support principles are utilized with the initial goal being attainment of an adequate coronary and cerebral perfusion pressure and perfusion of the tissues with oxygenated blood. This encompasses establishment of an adequate airway and, if necessary, mechanical ventilation, restoration of productive cardiac rhythm and forward blood flow, and attainment of a mean arterial blood pressure ⬎60 mm Hg [15]. Without reaching this immediate goal, all other resuscitative goals are of questionable value and thus

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should not be considered alone. Once mean arterial blood pressure is adequate to maintain cerebral and myocardial perfusion, then the secondary period of resuscitation begins. The goals of this period are: (1) establishment of an adequate organ perfusion pressure for all organs; (2) establishment of adequate organ blood flow, and (3) establishment of adequate O2 transport to the metabolically active tissues. The first two goals are reached by utilizing volume expansion and vasoactive agents, often using data acquired by invasive hemodynamic monitoring via a pulmonary artery (PA) catheter. Although the utility of the PA catheter in treating patients in shock has been questioned [16], data derived from the PA catheter is often critical in establishing the correct etiological diagnosis. Improving O2 content, cardiac output and vascular responsiveness accomplish the third goal in acute resuscitation. Delays in resuscitation of the previously healthy subject now in shock may render them not responsive to aggressive therapy later on, in an analogy to the irreversible shock model described by Wiggers in the 1920s. In support of this hypothesis is the recent large single center clinical trial of early goal-directed therapy for the management of severe sepsis. This study documented a marked improved outcome when subjects were aggressively treated for circulatory shock in the Emergency Department during the initial 6 h of hospitalization rather than waiting for them to be transferred to the ICU for better monitoring [17]. That study focused on rapidly achieving not only an adequate mean arterial pressure, central venous pressure and urine output, but also an adequate degree of tissue perfusion, as assessed by superior vena caval SO2 (SsvcO2). This study is in stark contract to the negative results of numerous large studies that aimed to improve survival for subjects once transferred into the ICU using similar resuscitation end-points [18–21]. These negative studies do not mean that resuscitation is ineffective to support life in the patient in shock. They merely demonstrate that there is no specific level of TO2 or mixed venous O2 saturation that one must attain to insure a good outcome [16, 22]. Clearly, what are needed are real time measures of tissue wellness and metabolic function, such as gastric tonometry [23], or functional measures of cardiovascular responsiveness [24]. Unfortunately, such non-invasive metabolic monitoring devices have yet to be validated as superior to non-specific measures presently available [25]. Potentially, the lack of documented benefit of these many noninvasive measures reflects inadequate study design.

Hemoglobin and the Optimal Hematocrit

Assuming that one has established an adequate mean arterial pressure, then one needs to insure that O2 transport (TO2) out of the heart to the body is adequate

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to meet the metabolic demands. Traditionally, resuscitation guidelines have mirrored the determinants of TO2. TO2 is equal to the product of cardiac output and arterial O2 content (CaO2). CaO2 in turn is equal to the amount of O2 adsorbed onto hemoglobin and dissolved in the plasma. Since 1,200 times more O2 is carried on hemoglobin than dissolved in the plasma one usually ignores the plasma component of TO2. The ideal hemoglobin concentration is unknown, but based on experience with Jehovah’s Witnesses, it seems the lowest limit tolerable below which even otherwise healthy people suffer cardiovascular collapse is 2–5 g/dl [26–29]. Many patients have done well during and after surgery despite very low hemoglobin and hematocrit levels as long as they can maintain adequate tissue perfusion and cardiac output. This infers that the body is able to augment cardiac output to sustain TO2. All else being equal, there seems to be little evidence to resuscitate a stable patient with a hematocrit ⱖ20% with red blood cells [30]. Rather, packed red blood cells (PRBCs) should be transfused to specifically correct evidence of tissue ischemia or hypoxia or to reverse a high outputinduced myocardial ischemia or failure state. Animal data suggest the maximum systemic extraction ratio for O2 is about 70%, with each organ having its own O2 requirements [31]. If O2 transport fails to meet this minimum, then O2 consumption will be dependent on organ blood flow [12, 31, 32]. Although we do not know the optimal hemoglobin concentration, aiming for adequate organ perfusion and O2 delivery with PRBC transfusions is reasonable up to a hemoglobin concentration of about 7 gm/dl [33, 34]. Above this, any additional benefit in O2 delivery is offset by increases in blood viscosity. Moreover, stored blood is depleted of 2,3-diphosphoglycerate, causing it to be very oxygen-avid, further limiting O2 utilization [35].

Fluid Resuscitation

Patients presenting with most forms of shock, excluding acute left ventricular failure with cardiogenic pulmonary edema, are initially responsive to intravascular volume replacement. Initial resuscitation, therefore should include intravascular volume replacement as part of a diagnostic and treatment strategy. For example, failure to show any significant increase in mean arterial pressure after rapid bolus infusion of crystalloid despite an increase in right atrial pressure usually signifies the need for vasoactive drug support. An adequate fluid challenge is defined as one in which either end-organ blood pressure or cardiac output increases (volume responsive); or in which either heart rate decreases or left ventricular filling pressure or central venous pressure increases without changes in systemic blood flow measurements (volume resistant).

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The choice of crystalloid or colloid solutions to treat a patient in shock is based more on religion than on science. Crystalloids are solutions that contain sodium as their major osmotically active particle [36]. Lactated Ringer’s and normal saline (0.9% NaCl) are examples of frequently used isotonic crystalloids. However, normal saline is still slightly hypertonic and carries a profoundly elevated chloride content relative to intravascular fluid. Hyperchloremic metabolic acidosis is a common occurrence in the ICU and is usually due to saline resuscitation. It is unclear, however, if the hyperchloremic metabolic acidosis induced by normal saline adversely affects outcome. Colloids are fluids with large molecular weight substances that do not readily pass across capillary walls [36]. Examples include albumin solutions, dextran, and hetastarch. Hetastarch gelatins are carried in a normal saline vehicle, thus they share the chloride load problems with normal saline. However, since one often gives less colloid than crystalloid, this concern is less important. Newer gelatins include put hetastarch in a lactated Ringer’s-like vehicle, thus minimizing the chloride loading. Recent interest in excess mortality in subjects given albumin has arisen. However, a large double blind multicenter trail of crystalloid versus albumin is presently underway in Australia to address this and other issues. Thus, conclusions about the risks and benefits of albumin infusions will need to wait until this trial is concluded. Infused albumin has a plasma half-life of approximately sixteen hours, but its effect lasts for approximately twenty-four hours. 25% albumin expands the vascular volume by translocation of interstitial fluid, such that for each 100 ml of 25% albumin given, the vascular volume will increase by 450 ml. Other albumin containing solutions have a near-physiologic colloid osmotic pressure, and therefore expand the vascular volume by 1 ml for each ml given. Dextran is a synthetic colloid that is rarely used because of its associated side effects [37, 38]. Hetastarch is also a synthetic colloid solution. It comes as a 6% solution in normal saline (Hesban) or lactated Ringers (Hextend) and functions similarly to 5% albumin solutions. It has a very long plasma half-life (17 days) and unlike dextran, is non-immunogenic [39]. Potential problems with hetastarch infusions arise when massive resuscitation is given (⬎1,500 ml) wherein one may see an elevation of serum amylase, osmotic diuresis, and increase bleeding tendency [39]. Colloids have several potential benefits, such as greater sustained intravascular volume presence and less edema formation, while being much more expensive. Despite all the potential benefits of using colloid as part of resuscitation, there is no proven benefit in outcome. A meta-analysis of eight studies in sepsis showed an overall 5.7% relative decrease in mortality in patients resuscitated with crystalloids alone, and a 12.3% difference in favor of crystalloid in trauma patients. A 7.8% difference was found in favor of colloid use in medical

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patients [40]. Due to the relatively few studies included in this analysis, it is difficult to make any conclusions regarding benefit in survival by use of colloid versus crystalloid.

Vasopressors

Since the goal of the primary resuscitation period is to obtain an adequate cerebral and coronary perfusion pressure, if this cannot be done with volume therapy alone, or if the blood pressure is profoundly depressed, then use of a vasoactive agent is required. These agents may also be necessary during the secondary resuscitation period to maintain adequate organ perfusion pressure and cardiac output in the setting of inflammatory mediator-induced pathological vasodilation. Selective use of agents may augment blood pressure and cardiac output to achieve the desired goals, but which agent is used often does not matter as long as the desired goals are achieved. Vasopressors induce their response by stimulating the ␣-adrenergic receptors on vascular smooth muscle cells. ␤-Adrenergic receptor stimulation augments contractility and induces vasodilation and tachycardia. Several vasopressor agents are available with varying degrees of ␣-, ␤- and vasopressin-2 receptor activity. Phenylephrine is a pure ␣-agonist and isoproterenol is a pure ␤-agonist [41, 42]. All other vasoactive agents have varying degrees of effect on both ␣ and ␤ types of receptors. The most potent vasoactive agent is epinephrine, since this will stimulate all adrenergic receptors. Dopamine is often used in states of shock to preserve renal function; however, no study has demonstrated a proven protective effect of dopamine on renal function [43, 44] and a recent large multicenter trail powered to show no effect documented or no effect of low dose dopamine on the development of renal failure in postoperative surgical ICU patients [45]. In septic shock, dopamine has not been shown superior to other agents such as dobutamine and norepinephrine in obtaining target values for O2 delivery and O2 consumption [46]. Furthermore, dopamine increased splanchnic O2 requirements over that of norepinephrine [47]. Finally, other agents such as dopexamine may produce similar hemodynamic profiles and renal preservation in patients with reduced cardiac index following coronary artery bypass surgery [48]. Furthermore, in a retrospective study of similarly matched subjects given norepinephrine versus all other vasopressor, Martin et al. [49] demonstrated that those subjects treated with norepinephrine had a markedly reduced mortality. Sepsis is associated with a reduction in vasopressin-2 receptor activity, making vascular smooth muscle cells less responsive to ␣-adrenergic stimulation. Infusions of low does vasopressin may reverse this desensitization. However,

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higher does of vasopressin induce profound splanchnic vasoconstriction. Thus, it is not clear that vasopressin infusions will improve outcome in distributive shock states. A large multicenter clinical trial of vasopressin is on going. We shall need to await the results of this trial before making any conclusions about the use of vasopressin in shock.

What Are the Targets for Cardiovascular Resuscitation?

Based on the clinical trials of early goal-directed therapy, vasopressorinduced ischemia and inflammation and unclear benefits from hemoglobinbased resuscitation the following approach seems reasonable. First, in the hypotensive patient restoration of a mean arterial pressure to ⬎60 mm Hg in a previously normotensive subject by the rapid infusion of volume and, if needed, vasopressor, is indicated to prevent and/or reverse cerebral and coronary ischemia. Second, rapid diagnosis of the etiology of shock should be undertaken. Except in the setting of obstructive or cardiogenic shock, volume resuscitation is the mainstay of initial therapy. The choice of fluid is optional, but lactated Ringer’s solution seems like a reasonable choice if blood products are not going to be infused simultaneously. The choice of vasopressor agent is still not defined, but norepinephrine is gaining increased usage because of its therapeutic profile. In the setting of cardiogenic or obstructive shock, although inotropic agents may transiently increase cardiac output, every effort needs to be done to make the diagnosis and treat the primary problem because few of the etiologies that induce either of these two types of shock respond to inotropic drug infusion alone. The infusion of packed red blood cells to treat patients with concomitant anemia and circulatory shock is problematic. In the setting of reduced cardiac reserve, red blood cells may be life saving, whereas in the otherwise healthy patient, there is little data to defend transfusing to a hematocrit above 25%. Clearly, the attempt in a resuscitated ICU patient to sustain TO2 at some defined elevated level is not justified.

Conclusion

Resuscitation from circulatory and respiratory failure represent mainstays of emergency and critical care management. Importantly, no amount of resuscitative effort will be successful in promoting patient survival if the primary reason for the shock state is not identified and treated, independent of resuscitation. Having said that, aggressive resuscitation to normal functional levels of blood flow and organ perfusion pressure during the first 6 h following the

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development of shock improves outcome both in patients with trauma or sepsis. However, clinical studies have demonstrated that restoration of total blood flow to supranormal levels in subjects with established shock that has been present for over 6 h does not improve survival. Still, some defined clinical targets are essential in these patients as well to prevent further organ injury due to ischemia and its associated inflammatory response. Thus, the rapid restoration of normal hemodynamics by conventional means, including fluid resuscitation and surgical repair, results in a better long-term outcome than inadequate or delayed resuscitative efforts. Clear initial targets for resuscitation are a mean arterial pressure ⬎65 mm Hg, and a cardiac output and O2 transport to the body adequate enough to prevent tissue hypoperfusion. The level of cardiac output needed to achieve this goal is probably different among subjects and within subjects over time. Indirect signposts of adequate perfusion, such as venous O2 saturation, mentation, urine output and local measures of tissue blood flow are useful in monitoring this response.

Acknowledgement This work was supported in part by the federal government (GM61992–03, NHLBI K-24 HL67181–01A2, and NRSA 2-T32 HL07820–06).

References 1 2

3 4 5 6 7

8 9 10 11

Hinshaw LB, Cox BG: The Fundamental Mechanisms of Shock, Plenum Press, New York, 1972. Calcagni DE, Bircher NG, Pretto E: Resuscitation: Blood, blood component, and fluid therapy; in Grande CM, et al (eds): Textbook of Trauma Anesthesia and Critical Care. St. Louis, Mosby-Year Book, 1993, p 400. Rush BF: Irreversibility in post-transfusion phase of hemorrhagic shock. Adv Exp Med Biol 1971; 23:215–221. Calandra T, Glauser MP: Cytokines and septic shock. Diagn Microbiol Infect Dis 1990;13: 377–381. Mason JW, et al: Plasma kallikrein and Hageman factor in gram-negative bacteremia. Ann Intern Med 1970;73:545–551. Pinsky MR, Vincent JL, et al: Serum cytokine levels in human septic shock: Relation to multiplesystem organ failure and mortality. Chest 1993;103:565–575. Rosenbloom AJ, Pinsky MR, et al: Leukocyte activation in the peripheral blood of patients with cirrhosis of the liver and SIRS: Correlation with serum interleukin-6 levels and organ dysfunction. JAMA 1995;274:58–65. Salin ML, McCord JM: Free radicals and inflammation: Protection of phagocytosing leukocytes by superoxide dismutase. J Clin Invest 1975;56:1319–1323. Bernard GR, et al: Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Am Rev Resp Dis 1991;144:1095–1101. Snyder SH, Bredt DS: Biologic roles of nitric oxide. Scient Am 1992;266:68–77. Cilley RE, et al: Low oxygen delivery produced by anemia, hypoxia, and low cardiac output. J Surg Res 1991;51:425–433.

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Cain SM: Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol 1977;42:228–234. Cohen RD, Woods F: Lactic acidosis revisited. Diabetes 1983;32:181–191. Safar P: Cerebral resuscitation after cardiac arrest: Research initiatives and future directions. Ann Emerg Med 1993;22:324–349. Fazekas JF, Kleh J, Parrish AE: The influence of shock on cerebral hemodynamics and metabolism. Am J Med Sci 1955;229:41–45. Sandham JD, Hull RD, Brant RF, Knox L, Pineo GF, Doig CJ, Laporta DP, Viner S, Passerini L, Devitt H, Kirby A, Jacka M, and Canadian Critical Care Clinical Trials Group: A Randomized, Controlled Trial of the Use of Pulmonary-Artery Catheters in High-Risk Surgical Patients. N Engl J Med 2003;348:5–14. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich E: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345: 1368–1377. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hindo CJ, Watson D: Evaluation of systemic oxygen delivery in the treatment of the critically ill. N Engl J Med 1994;330:1717–1722. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R: A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995;333:1025–1032. McKinley BA, Kozar RA, Cocanour CS, Valdiva A, Sailors RM, Ware DN, Moore FA: Normal versus supranormal oxygen delivery goals in shock resuscitation: The response is the same. J Trauma 2002;53:825–832. Velmahos GC, Demetriades D, Shoemaker WC, Chan LS, Tatevossian R, Wo CCJ, Vassiliu P, Cornwell III EE, Murray JA, Roth B, Belzberg H, Asensio JA, Berne TV: Endpoints of resuscitation of critically injured patients: Normal or supranormal? A prospective randomized trial. Ann Surg 2000;232:409–418. Miller MJ, Cook W, Mithoefer J: Limitations of the use of mixed venous pO2 as an indicator of tissue hypoxia. Clin Res 1979;27:401A. Gutierrez 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. Pinsky MR: Functional hemodynamic monitoring: Asking the right question. Intensive Care Med 2002;28:386–388. Pinsky MR: Beyond global oxygen supply-demand relations: In search of measures of dysoxia. Intens Care Med 1994;20:1–3. Olugbenga A, et al: Management of severe anemia without transfusion in a pediatric Jehovah’s Witness patient. Crit Care Med 1994;22:524–528. Parker RI: Aggressive non-blood product support of Jehovah’s Witnesses. Crit Care Med 1994; 22:381–382. Koenig HM, et al: Use of recombinant human erythropoietin in a Jehovah’s Witness. J Clin Anesth 1993;5:244–247. Viele MK, Weiskopf RB: What can we learn about the need for transfusion from patients who refuse blood? The experience with Jehovah’s Witnesses. Transfusion 1994;34:396–401. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetsir E: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409–417. Schlichtig R, et al: Tolerance of unusually low mixed venous oxygen saturation: Adaptations in the chronic low cardiac output syndrome. Am J Med 1986;80:813–818. Schwartz S, et al: Sequential hemodynamic and oxygen transport responses in hypovolemia, and hypoxia. Am J Physiol 1981;241:H864–H871. Welch HG, et al: Prudent strategies for elective red blood cell transfusion. Ann Intern Med 1992;116:393–402. Carson JL, et al: Severity of anemia and operative mortality and morbidity. Lancet 1988;i: 727–729. Weisel RD, et al: Adverse effects of transfusion therapy during abdominal aortic aneurysmectomy. Surgery 1978;83:682–690.

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Rainey TG, Read CA: Pharmacology of colloids and crystalloids; in Chernow B (ed): The Pharmacologic Approach to the Critically Ill Patient, ed 3. Baltimore, Williams & Wilkins, 1994, pp 272–290. Imm A, Carlson RW: Fluid resuscitation in circulatory shock. Crit Care Clins 1993;9:313–333. Thoren L: Dextran as a plasma volume substitute. Prog Clin Biol Res 1978;19:265–282. Waxman K, et al: Blood and plasma substitutes: Plasma expansion and oxygen transport properties. World J Med 1985;143:202–206. Velanovich V: Crystalloid versus colloid fluid resuscitation: A meta-analysis of mortality. Surgery 1989;105:65–71. Bisonni RS, et al: Colloids versus crystalloids in fluid resuscitation: An analysis of randomized control trials. J Fam Pract 1991;32:387–390. Almog Y, Breslow MJ: A rational approach to using vasopressors in the ICU. J Crit Ill 1995;10: 171–183. Duke GJ, Bersten AD: Dopamine and renal salvage in the critically ill patient. Anaesth Intens Care 1992;20:277–302. Duke GJ, Briedis JH, Weaver RA: Renal support in critically ill patients: Low-dose dopamine or low-dose dobutamine? Crit Care Med 1994;22:1919–1925. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J: Low-dose dopamine in patients with early renal dysfunction: A placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356:2139–2143. Hannemann L, et al: Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake in septic shock. Crit Care Med 1995;23:1962–1970. Marik PE, Mohedin M: The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994;272:1354–1357. Olsen NV, Lund J, et al: Dopamine, dobutamine, and dopexamine: A comparison of renal effects in unanesthetized human volunteers. Anesthesiology 1993;79:685–694. Martin C, Viviand X, Leone M, Thirion X: Effect of norepinephrine on the outcome of septic shock. Crit Care Med 2000;28:2758–2765.

Michael R. Pinsky, MD 606 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261 (USA) Tel. ⫹1 412 647 5387, Fax ⫹1 412 647 8060, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 105–118

Intravenous Fluids and Acid-Base Balance Rinaldo Bellomoa, Toshio Nakab, Ian Baldwinc a Department of Intensive Care and Department of Surgery, bAustin Hospital, University of Melbourne, and cRMIT University, Melbourne, Australia

The administration of intravenous fluids is one of the most common treatments given in the Intensive Care Unit. The rationale for such treatment is that critically ill patients have fluid losses that they cannot compensate for, that they have relative or absolute reductions in circulating blood volume, which in turn results in decreased organ flow, and that such organ ischemia is responsible for increased morbidity and mortality. According to this biologic rationale, ongoing fluid losses should be replaced to maintain fluid homeostasis and relative or absolute deficiencies in effective circulating blood volume should be prevented or rapidly corrected. There is also agreement that insensible fluid losses and isotonic fluid losses through urine or from other body cavities should be replaced with a judicious mixture of water and crystalloid solutions. All intravenous fluids, however, have a profound impact on acid-base physiology and acid-base balance that is not widely acknowledged. Furthermore, there is controversy on the biochemical, physiological and clinical meaning of their acidbase effects. Critical care physicians need to appreciate such controversy in order to understand the physiological consequences of their choices. Accordingly, this article focuses on the acid-base effects of intravenous fluids, the mechanisms responsible for such effects, the possible clinical consequences of intravenous fluids-induced changes in acid-base balance and the implications of the available evidence in this field of medicine for clinicians. Crystalloid Solutions and Acid-Base Balance

Crystalloid solutions contain water and electrolytes only. They have osmotic pressure but lack oncotic pressure. They are easily prepared and cheap.

Although they are typically seen as a uniform group of solutions with little to separate them from one another (unlike colloids), this view, particularly from the acid-base balance point of view, is simplistic. There are, in fact, profound physiological differences between the two major groups of near-isotonic crystalloid solutions: the chloride-rich solution and the so-called ‘balanced’ solutions (i.e. normal saline vs. Plasmalyte, Hartmann’s solution or Ringer’s lactate solution) especially in terms of their acid-base effect during massive resuscitation [1] and there are even more profound differences between isotonic and hypertonic crystalloid solutions [2]. In this manuscript we will focus on near-isotonic solutions. Therefore, when discussing crystalloids, even though normal saline is seen as the prototype, one should, firstly of all be aware of such differences. The major difference between these crystalloids lies in the different chloride content or, as we shall see later, their so-called ‘strong ion difference’. Saline solutions, of course, have an ‘unphysiologic’ or ‘supranormal’ concentration of chloride relative to sodium (i.e. the chloride concentration is equal to that of sodium) while the other ‘buffered’ solutions (lactate fluids such as Ringer’s in the USA and Hartmann’s in Europe or fluids with other buffers such as acetate or gluconate as in the case of plasmalyte) have a concentration of chloride relative to sodium, which more closely approximates that seen in plasma water (typically 38 mmol/l less than sodium). To use more recent acidbase physiology ideology [3–6], saline and saline-derived fluids have a strong ion difference of 0 mEq/l, while ‘buffered’ fluids more closely approximate the physiological strong ion difference of 42 mEq/l. In order to understand the physiological significance of the strong ion difference of a particular fluid, one needs to understand the theory behind the Stewart-Figge approach to acidbase analysis.

Acid-Base Analysis Using the Stewart-Figge Methodology

Recently, quantitative acid-base analysis using the Stewart-Figge’s approach [3, 4] has been introduced as a more useful way of approaching the effects of intravenous fluids on acid-base balance. This method first involves first calculating the apparent strong ion difference (SIDa) (all concentrations in mEq/l): SIDa ⫽ [Na⫹] ⫹ [K⫹] ⫹ [Mg2⫹] ⫹ [Ca2⫹] – [Cl⫺] – [lactate]

and then the taking into account the role of weak acids (CO2, albumin, and phosphate) in the balance of electrical charges in plasma water.

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The weal acid component is expressed through the calculation of the effective strong ion difference (SIDe; pCO2 in mm Hg, albumin in g/l and phosphate in mmol/l): SIDe ⫽ 1,000 ⫻ 2.46 ⫻ 10⫺11 ⫻ pCO2/(10⫺pH) ⫹ [Alb] ⫻ (0.12 ⫻ pH ⫺ 0.631) ⫹[Phos] ⫻ (0.309 ⫻ pH ⫺ 0.469).

Once weak acids are quantitatively taken into account, the SIDa to SIDe difference should equal zero unless there are unmeasured charges (anions). Such charges are then described by the strong ion gap (SIG): SIG ⫽ SIDa ⫺ SIDe. The component of albumin and phosphate is defined as the total concentration of non-volatile weak acid (Atot). [Atot], along with SID and pCO2, is an independent determinant of [H⫹] or pH. According to the Stewart-Figge approach, metabolic acidosis can then result from a reduction in the SID or from an increase in Atot, and respiratory acidosis can result from a gain in pCO2. The changes in each of these variables can be quantified to express how much each one is responsible (in mEq/l) for the findings on blood analysis. According to this paradigm, three forces are responsible for acid-base status: the SID, the CO2 tension and Atot. Bicarbonate concentration, hydrogen ion activity and, therefore, pH are dependent on the above three forces. The source of hydrogen ions is water, which becomes more dissociated as the SID falls, or the pCO2 rises or the Atot rises. According to this paradigm, the administration of fluids with a SID of 0 should change the SID in plasma downward, thereby inducing a iatrogenic low SID-induced, non-anion gap, non lactic acidosis due to increased dissociation of plasma water and release of hydrogen ions [6]. On the other hand, the administration of fluids with a near normal SID should have a minimal or no impact on the SID of plasma and, thereby, induce no acidosis [6]. As we shall discuss later, events are actually somewhat more complicated, especially when the system is tested to the extreme during continuous hemofiltration.

The Conventional Ideology

There is no argument with the fact that intravenous fluids induce a metabolic acidosis, as this observation has been made innumerable times [7–9]. However, there is much controversy on why this phenomenon occurs. As we have seen above, one possible explanation is that provided by the Stewart-Figge paradigm. Another is provided by the conventional understanding of acid-base physiology, which has dominated teaching for decades and still dominates worldwide. This conventional view of how fluids might affect acid-base status

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states that chloride-rich fluids induce acidosis simply by ‘diluting’ the buffers (esp. bicarbonate); conversely, the administration of ‘buffered’ solutions provides a metabolic source for bicarbonate generation such that the dilutional effect of fluids is compensated for by the transformation of lactate or acetate into bicarbonate and the restoration of a physiological concentration of bicarbonate. Although in the opinion of the authors, this approach does not satisfactorily explain a variety of clinical observations, no experiments have been devised so far to allow researchers to demonstrate that one explanation is ‘true’ or ‘false’.

The Biochemical Consequences

Irrespective of the mechanisms responsible for intravenous fluid induced acidosis, it is important for clinicians to understand the biochemical characteristics typically seen in this setting. Such understanding will avoid incorrect diagnoses and treatments, especially in the critically ill where these disorders are complex [10, 11] or in those patients with acute renal failure, where that complexity increases [12, 13]. When crystalloid solutions with a SID of 0 are given intravenously in sufficient quantities and rapidly enough, patients will develop the following biochemical changes: an increase in serum chloride concentration (this increase can be of up to 10 mmol/l if sufficient amounts are given), a mild increase in serum sodium (typically 1–2 mmol/l) and a decrease in serum albumin concentration (typically down to 20–25 g/l). As a consequence of these changes, a Base Deficit develops of about 4–5 mEq/l (Base Excess of ⫺4 or ⫺5 mEq/l). This metabolic acidosis is associated with a fall in serum bicarbonate of about 4–5 mmol/l and a normal anion gap and is mild to moderate in severity. The expected effect of a SID change of about 10 mEq/l (from 42 to 32–34 mEq/l) is attenuated by the alkalinizing effects of hypoalbuminemia (decreased Atot). This acid-base picture can be quantitatively predicted and neatly demonstrated when cardiac surgery patients become connected with the cardiopulmonary bypass pump and the pump has been primed with a solution containing a SID of 0. In this setting, as the pump prime enters the circulation and is distributed across the plasma volume, all of the above changes occur almost instantaneously [14–16] (fig. 1–4).

The Physiological Consequences of Iatrogenic Acidosis

Until recently, there was limited evidence to suggest a physiological effect for this mild to moderate iatrogenic hyperchloremic acidosis. However,

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1

Base excess

0.5 0 mEq/l

⫺0.5 ⫺1 ⫺1.5 ⫺2 ⫺2.5 ⫺3 Pre-CPB

Post-CPB

Fig. 1. Change in base excess from baseline (pre-CPB) to immediately after initiation of cardiopulmonary bypass (post-CPB) with a pump prime that has an SID of 0.

25

Bicarbonate

24

mmol/l

23 22 21 20 19 Pre-CPB

Post-CPB

Fig. 2. Change in bicarbonate from baseline (pre-CPB) to immediately after initiation of cardiopulmonary bypass (post-CPB) with a pump prime that has an SID of 0.

recent experimental work has sought to investigate whether different kinds of acidoses induce different physiological changes. Studies in rats by Kellum’s group have shown that hyperchloremic acidosis even of a moderate degree (5 mEq/l) decreases blood pressure and increases nitrate/nitrite levels. If severe (base deficit of 15 mEq/l), hyperchloremic acidosis induced hypotension but did not directly affect nitrate/nitrite levels [17]. The same group compared iatrogenic lactic acidosis to hyperchloremic acidosis and found that these two forms of

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39

SID

38

mEq/l

37 36 35 34 33 Pre-CPB

Post-CPB

Fig. 3. Change in SID from baseline (pre-CPB) to immediately after initiation of cardiopulmonary (post-CPB) bypass with a pump prime that has an SID of 0.

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Albumin

30 25

g/l

20 15 10 5 0 Pre-CPB

Post-CPB

Fig. 4. Change in serum albumin concentration from baseline (pre-CPB) to immediately after initiation of cardiopulmonary bypass (post-CPB) with a pump prime that has an SID of 0.

acidosis led to quite markedly different physiological immune responses: hyperchloremic is pro-inflammatory (increased NO release, increased Il-6:IL10 ratios and increased NFkB DNA binding) while lactic acidosis is anti-inflammatory (decreased NO release, increased IL-10 levels and decreased NFkB DNA binding) [18]. Thus, the choice of intravenous fluids appears to not only affect acid-base status but also the patients’ immune response.

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The Clinical Implications

As describe above, iatrogenic acidosis clearly has biochemical and physiological effects. What remains unclear is whether it has clinical consequences. Nonetheless, evidence exists to suggest that, when clinicians do not appreciate that the acidosis that is developing, for example, in a trauma patient receiving large amounts of saline is iatrogenic, they may be believe that the patient has internal bleeding or vital organ ischemia. They may then proceed to invasive interventions or to further unnecessary fluid administration or both, which can cause major injury to the patient. Whether the administration of a particular kind of fluid instead of another results in increased survival will have to wait for the official release of the results of the SAFE trial comparing fluid resuscitation with albumin to fluid resuscitation with saline in ICU patients [19]. The results of this trial should become available in 2004.

Colloids

Colloid solutions always contain water and electrolytes. They are typically isotonic. They also contain a class of agents, which because of their size confer oncotic pressure to the solution. Such agents can be natural (albumin) or synthetic (dextran, starches, gelatins). They can be iso-oncotic or hyperoncotic (20% albumin). These agents are diverse in terms of molecular size, molecular properties, pharmacokinetics, pharmacodynamics, hemodynamic effect, side effects and acid-base consequences. Their common property in respect to crystalloids is due to the oncotic pressure effect, which induces greater short-term (hours) intravascular permanence of the administered fluid. Accordingly, using the paradigms presented earlier in this article, similar acid-base effects could be expected to those seen with crystalloids containing different values of strong ion difference except for two additional considerations: the specific effect of the colloidal solutes on acid-base balance and the additional effect of greater initial intravascular permanence, which might translate into a more pronounced effect on acid-base physiology immediately after infusion [14].

The Controversy

Given all of these options (crystalloids with a SID of 0, crystalloids with a SID close to the physiological level, colloids with variable SID and variable contents of charged ions) there has been controversy from the start on which fluids to choose to resuscitate patients. Firstly, a crystalloid school (typically

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trauma-based and in North American centers) and a colloid school (typically among those dealing with older patients and in European centers) have been vehemently arguing about the merits of one or the other approach for more than 50 years [20, 21]. Secondly, more recently the debate has gained the additional dimension of chloride-rich vs. chloride-poor or unphysiologic SID vs. physiologic SID fluids. Most information available at this time comes from comparisons of two classes of fluids in terms of their physiological effects. Furthermore, only very small, grossly statistically under-powered studies have reported on mortality and major morbidity. In response to these deficiencies in the data available, meta-analyses have been conducted first comparing mortality with crystalloids to mortality with colloids [20] and then comparing albumin alone to crystalloids [21]. However, because these meta-analyses are based upon small, often poorly conducted trials with physiological outcome as the primary outcome, they have been heavily criticized and their conclusions only represent starting points for future investigations. In terms of acid-base physiology, no randomized studies exist comparing the clinically different effects of using fluids of different SIDs. Thus, clinicians are left with having to make thoughtful decisions in individual cases taking into account the limited information available. At this time and until further information emerges, it seem reasonable to avoid aggravating hyperchloremic acidosis, when already present, by administering more chloride rich fluids. It also seems reasonable to administer a mixture or a choice of fluids that would not markedly contribute to metabolic acidosis, if one already exists. In patients that already show hyperlactatemia, it seems undesirable to administer lactate-buffered fluids which might aggravate the acidosis or, in the very least, potentially create diagnostic confusion by increasing the blood lactate concentration. The choice of colloids or crystalloids remains a matter of debate, which may be partly resolved by the publication of the results of a recently completed randomized controlled trial comparing albumin to saline. This trial might also provide new and important data on the differential acid-base effects of these two solutions and the links between acid-base balance and clinical outcomes.

Effect of Replacement Fluids and Their Composition

The administration of intravenous fluids as fluid replacement during continuous hemofiltration represents a unique situation from the point of view of the effect of intravenous fluids on acid-base physiology because of several reasons: (1) up to 6 or even 8 liters may be administered per hour; (2) in most cases, more than 45 l of fluids are administered each day; (3) fluids of different

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compositions are available for such therapy especially from the point of view of their ‘buffer’ content [22], and (4) acute renal failure patients already have complex acid-base disorders even before the fluids are administered [23]. In this regard, lactate, acetate, and bicarbonate have all been used as ‘buffers’ (or SID generators according to Stewart) during RRT. Citrate has been used as ‘buffer’ and anticoagulation. These ‘buffers’ affect acid-base balance, thus we must understand their physiological characteristics. Bicarbonate has the major advantage of being the most physiologic anion equivalent. However, the production of a commercially available bicarbonatebased solution is not easy because of the formation of calcium and magnesium salts during long-term storage. Furthermore, the cost of this solution is approximately three times higher than that of other ‘buffer’ solutions. Accordingly, acetate and lactate have been used widely for fluid replacement therapy. Under normal conditions, acetate is rapidly converted on a 1:1 basis to CO2 and then bicarbonate by both liver and skeletal muscle. Lactate is also rapidly converted in the liver on a 1:1 basis [24, 25]. Studies of acetate-based solutions, however, appear to exert a negative influence on the mean arterial blood pressure and cardiac function in the critically ill [26–29]. Morgera et al. [29] compared acid-base balance between acetate- and lactate-buffered replacement fluids and reported that the acetatebuffered solution was associated with a significant lower pH and bicarbonate levels than the lactate-buffered solution. However, the acetate-buffered solution had 9.5 mmol/l less ‘buffer’ than the lactate-buffered solution. Thomas et al. [30] studied the effects of lactate- versus bicarbonatebuffered fluids. Hemofiltration fluids contained either 44.5 mmol/l of sodium lactate or 40.0 mmol/l of sodium bicarbonate with 3 mmol/l of lactate (43 mEq/l of buffer). Lactate rose from approximately 2 to 4 mmol/l when lactate-based fluids were given but not with bicarbonate. Both therapies resulted in a similar improvement in metabolic acidosis. Tan et al. [31] also studied the acid-base effect of CVVH with lactate or bicarbonate buffered solution. The lactate-buffered solution had an SID of 46 vs. 35 mEq/l for the bicarbonate fluid. From the Stewart-Figge point of view, the lactate-buffered solution should have led to a greater amount of alkalosis. However, this study showed a significant increase in plasma lactate levels in these critically ill patients (lactate intolerance) and a decrease in base excess with the lactate-buffered solution. According to the Stewart-Figge paradigm, lactate, if not metabolized and still present in blood, should act as a strong anion, which would have the same acidifying effect of chloride. Accordingly, iatrogenic hyperlactatemia can cause a metabolic acidosis. This effect can, of course, also be explained by the failure to convert exogenous lactate into bicarbonate.

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Citrate has been used for regional anticoagulation. During this procedure, citrate is administered to the circuit before the filter and chelates calcium, thus impeding coagulation. Once citrate enters the circulation, it is metabolized to CO2 and then bicarbonate on a 1:3 basis thus 1 mmol of citrate yields 3 mmol of CO2 and then bicarbonate. Under these circumstances, citrate acts as the ‘buffer’ as well as the anticoagulant. If the method described by Mehta et al. [32] is applied, approximately 48 mmol/h of ‘bicarbonate equivalent’ is given as citrate. This rate of alkali administration may result in metabolic alkalosis (up to 25% of cases). Attention must be paid in patients with liver disease who may not be able to metabolize citrate. In these patients, citrate may accumulate and result in severe ionized hypocalcemia and metabolic acidosis because the citrate anion (C6H5O73–) acts as an unmeasured anion and increases the SIG which has acidifying effects. When oxidizable anions are used in the replacement fluids, the anion (acetate, lactate and citrate) must be completely oxidized to CO2 and H2O in order to generate bicarbonate. If the metabolic conversion of non-bicarbonate anions proceeds without accumulation, their buffering capacity is equal to that of bicarbonate. Thus, the effect on acid-base status depends on the ‘buffer’ concentration rather than on the kind of ‘buffer’ used. When the metabolic conversion is impaired, the increased blood concentration of the anions leads to an increased strong anion in lactate or unmeasured anions for acetate and citrate: all lower the SIDa and acidify blood. The nature and extent of these acid-base changes is governed by the intensity of plasma water exchange/ dialysis, by the ‘buffer’ content of the replacement fluid and by the metabolic rate for these anions. High-Volume Hemofiltration Continuous hemofiltration has been shown to remove cytokines from the circulation of septic ARF patients [33]. However, studies of standard intensity CRRT have shown limited effects on physiological variables and outcomes in critically ill patients [34]. For these reasons, there has been a move to so-called high-volume hemofiltration with the goal of increasing the possible beneficial impact of CRRT. Recently, such high volume hemofiltration (HVHF) has been applied to the treatment of ARF with improved survival [35] and in septic shock patients with favorable hemodynamic results [36]. However, if commercial lactate-buffered replacement fluid is used during HVHF, patients might receive more than 270 mmol/h of exogenous lactate. This lactate load could easily overcome endogenous lactate metabolism even in healthy subjects [37] and result in progressive hyperlactatemia. Hyperlactatemia has been reported during lactate-buffered fluids in critically ill patients with ARF treated with intermittent hemofiltration and a lactate load of 190–210 mmol/h [38].

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6 5

Change in mEq/l

4 3

Lactate Bicarbonate Base excess

2 1 0 ⫺1

0

2

6

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⫺2 ⫺3 Hours of treatment

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Such hyperlactatemia might induce a metabolic acidosis. Cole et al. [36] studied the effect of HVHF on acid-base balance. HVHF with lactate-buffered replacement fluids (6 liters/h of lactate-buffered fluids) induced iatrogenic hyperlactatemia. Plasma lactate levels increased from a median 2.51 mmol/l to a median of 7.3 mmol/h at 2 h. This change was accompanied by a significant decrease in bicarbonate and base excess (fig. 5). However, such hyperlactatemia only had a mild and transient acidifying effect. A decrease in chloride and SIDe and the removal of unmeasured anions (decrease in SIG) all rapidly compensated for this effect. Thus, the final effect was that HVHF induced only a minor change in pH from 7.42 to 7.39 at 2 h. In the period from 2 to 8 h, the blood lactate concentration remained stable at around 7–8 mmol/l, while compensatory effects continued, which restored bicarbonate levels to 27.2 mmol/l and pH to 7.44 by 8 h of treatment. Although the chloride concentration in the replacement fluid was high compared to the serum chloride level, a progressive decrease in chloride was observed. This might be due to chloride losses in excess of gains. Uchino et al. [37] examined the sieving coefficient for chloride during HVHF and showed a sieving coefficient for chloride ⬎1. Another possible explanation for hypochloremia would be the intracellular movement of chloride in response to metabolic acidosis (chloride shift). A decrease in SIDe was explained by the aggregate minor changes in PaCO2, albumin and phosphate. The changes in SIG appeared most likely to be due to simple filtration of unmeasured anion. Consequently, HVHF with lactate-buffered fluids induced a marked hyperlactatemia but did not induce a progressive acidosis. However caution should be exerted in particular patients who have marked pretreatment hyperlactatemia

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(⬎5 mmol/l), liver dysfunction, or where the intensity of HVHF exceeds 6 liters/h of plasma water exchange. Bicarbonate use is warranted in such patients.

Conclusion

Intravenous fluids given in sufficient amounts or rapidly enough or both can markedly alter acid-base status. During hemofiltration and especially during high-volume hemofiltration, replacement fluid solutions containing ‘buffers’ such as lactate, acetate, bicarbonate and citrate are given rapidly and in large amounts and can have a variable effect on acid-base balance, depending on the dose and rate of metabolic disposition of the ‘buffer’. Evidence is accumulating that these iatrogenic acid-base alterations have physiological consequences and that the choice of fluids affects such physiological changes. Several observations also suggest that misdiagnosis of these disorders can lead to patient injury. Critical care physicians must understand the nature, origin and magnitude of the alterations in acid-base status caused by intravenous fluid therapy, if they wish to provide safe and effective care to their patients.

References 1

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Coran AG, Ballantine TV, Horwitz DL, Herman CM: The effect of crystalloid resuscitation in hemorrhagic shock on acid-base balance: A comparison between normal saline and ringer’s lactate solution. Surgery 1971;69:874–880. Prough DS, Whitley JM, Taylor CL, Deal DD, De Witt DS: Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline: Influence on subdural mass. Anesthesiology 1991;75:319–327. Stewart PA: Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983;61: 1444–1461. Figge J, Mydosh T, Fencl V: Serum proteins and acid-base equilibria: A follow-up. J Lab Clin Med 1992;120:713–719. Bellomo R, Ronco C: New paradigms in acid-base physiology. Curr Opin Crit Care 1999;5: 427–428. Story D, Bellomo R: The acid-base physiology of crystalloid solutions. Curr Opin Crit Care 1999; 5:436–439. Kellum JA, Bellomo R, Kramer DJ, Pinsky MR: Etiology of metabolic acidosis during saline resuscitation in endotoxemia. Shock 1998;9:1–5. Prough DS, Bidani A: Hyperchloremic metabolic acidosis is a predictable consequence of intraoperative infusion of 0.9% saline. Anesthesiology 1999;90:1247–1249. Skellett S, Mayer A, Durward A, Tibby SM, Murdoch IA: Chasing the base deficit: Hyperchloremic acidosis following 0.9% saline fluid resuscitation. Arch Dis Child 2000;83:514–516. Story D, Poustie S, Bellomo R: Quantitative physical chemistry analysis of acid-base disorders in critically ill patients. Anaesthesia 2001;56:530–533. Story DA, Morimatsu H, Bellomo R: Strong ions, weak acids and base excess: A simplified FenclStewart approach to clinical acid-base disorders. Br J Anaesth 2004;92:54–60.

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Rocktaeschel J, Morimatsu H, Uchino S, Goldsmith D, Pousie S, Story DA, Gutteridge G, Bellomo R: Acid-base status od critically ill patients with acute renal failure: Analysis based on Stewart-Figge methodology. Crit Care 2003;7:60–66. Rocktaschel J, Morimatsu H, Uchino S, Ronco C, Bellomo R: Impact of continuous veno-venous hemofiltration on acid-base balance. Int J Artif Organs 2003;26:19–25. Hayhoe M, Bellomo R, Liu G, Mc Nicol L, Buxton B: The etiology and pathogenesis of CPB-associated metabolic acidosis during polygeline prime. Intens Care Med 1999;25: 680–685. Liskaser F, Bellomo R, Hayhoe M, et al: Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis. Anesthesiology 2000;93:1170–1173. Hayhoe M, Bellomo R: The pathogenesis of acid-base changes during cardiopulmonary bypass. Curr Opin Crit Care 1999;5:464–467. Kellum JA, Song M, Venkataraman R: Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest 2004;125:243–248. Kellum JA, Song M, Li J: Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2003 [Epub ahead of print]. Finfer S, Bellomo R, Myburgh J, Norton R: Efficacy of albumin in critically ill patients. BMJ 2003;326:559–560. Choi PT-L, Yip GY, Quinonez LG, Cook DJ: Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999;27:200–210. Cochrane Injuries Group Albumin Reviewers: Human albumin administration in critically ill patients: Systematic review of randomised controlled trials. BMJ 1998;317:235–240. Rocktäschel J, Morimatsu H, Uchino S, Ronco C, Bellomo R: Impact of continuous veno-venous hemofiltration on acid-base balance. Int J Artif Organs 2003;26:19–25. Rocktaeschel J, Morimatsu H, Uchino S, Goldsmith D, Poustie S, Story D, Bellomo R: The complex nature of acid-base disorders in critically ill patients with acute renal failure. Crit Care 2003;7: R60–R66. Bellomo R, Ronco C: The pathogenesis of lactic acidosis in sepsis. Curr Opin Crit Care 1999;5: 452–457. Bellomo R: Bench-to-bedside review: Lactate and the kidney. Crit Care 2002;6:322–326. Heering P, Ivens K, Thumer O, Brause M, Grabensee B: Acid-base balance and substitution fluid during continuous hemofiltration. Kidney Int 1999;56:s37-s40. Davenport A, Will E, Davison AM: The effect of lactate-buffered solutions on the acid-base status of patients with renal failure. Nephrol Dial Transplant 1989;4:800–804. Mansell MA, Morgan SH, Moore L, Kong CH, Laker MF, Wing AJ: Cardiovascular and acid-base effects of acetate and bicarbonate haemodialysis. Nephrol Dial Transplant 1987;1:229–232. Morgera S, Heering P, Szentandrasi T, Manassa E, Heintzen M, Willers R, Passlick-Deetjen J, Grabensee B: Comparison of a lactate- versus acetate-based hemofiltration replacement fluid in patients with acute renal failure. Renal Fail 1997;19:155–164. Thomas AN, Guy JM, Kishen R, Geraghty IF, Bowles BJM, Vadgama P: Comparison of lactate and bicarbonate buffered haemofiltration fluids: Use in critically ill patients. Nephrol Dial Transplant 1997;12:1212–1217. Tan HK, Uchino S, Bellomo R: The acid-base effects of continuous hemofiltration with lactate or bicarbonate buffered replacement fluids. Int J Artif Organs 2003;26:477–483. Mehta RL, McDonald B, Aguilar M, Ward DM: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990;38:976–981. Bellomo R, Tipping P, Boyce N: Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med 1993;21:522–526. Cole L, Bellomo R, Hart G, Journois D, Davenport P, Tipping P, Ronco C: A phase II randomized controlled trial of continuous hemofiltration in sepsis. Crit Care Med 2002;30:100–106. Ronco C, Bellomo R, Homel P, et al: Effect of different doses in CVVH on outcomes of acute renal failure: A prospective randomized trial. Lancet 2000;356:26–30. Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P: High volume hemofiltration in human septic shock. Intensive Care Med 2001;27:978–986.

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Levraut J, Ciebera JP, Jambou P, Ichiai C, Labib Y, Grimaud D: Effect of continuous veno-venous hemofiltration with dialysis on lactate clearance in critically ill patients. Crit Care Med 1997;25: 58–62. Cole L, Bellomo R, Baldwin I, Hayhoe M, Ronco C: The impact of lactate-buffered high volume hemofiltration on acid-base balance. Intens Care Med 2003;29:1113–1120. Uchino S, Cole L, Morimatsu H, Goldsmith D, Ronco C, Bellomo R: Solute mass balance during isovolaemic high volume haemofiltration. Intens Care Med 2003;29:1541–1546.

Prof. Rinaldo Bellomo Department of Intensive Care, Austin and Repatriation Medical Centre Heidelberg, Vic. 3084 (Australia) Tel. ⫹61 3 9496 5992, Fax ⫹61 3 9496 3932, E-Mail [email protected]

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Glucose Control in the Critically Ill M. Schetz, G. Van den Berghe Department of Intensive Care Medicine, University Hospital Gasthuisberg, Leuven, Belgium

The subject of glucose and insulin metabolism after injury began 150 years ago with the observation by Reyboso of glucosuria after ether anesthesia and by Claude Bernard (1877) of hyperglycemia during hemorrhagic shock. Since then it has become clear that hyperglycemia, glucose intolerance and insulin resistance are features that are common to all types of severe acute illness and injury, even in patients without diabetes [1, 2]. This ‘stress diabetes’ used to be interpreted as an adaptive stress response and as such important for survival. Insulin was only administered if the glycemia exceeded 200 mg/dl. Insulin is the most important anabolic hormone known today. It promotes overall anabolic reactions for all three energy and structural components in the body: carbohydrates, proteins and fat. In addition, insulin has also been shown to have anti-inflammatory properties [3]. Recently, a large prospective randomized trial established the beneficial effect of treating even moderate hyperglycemia with insulin in critically ill patients [4]. In this review, the results of this trial and possible underlying mechanisms will be discussed.

Glucose Regulation in Critical Illness

The alterations in carbohydrate metabolism during stress, inflammation or infection include enhanced peripheral glucose uptake (largely non-insulin mediated and most prominent in tissues involved in the immune response and wound healing), hypermetabolism with augmented glycolysis and glucose oxidation (in order to satisfy the increased metabolic demands of the tissues involved in the repair processes) and increased gluconeogenesis and depressed glycogenesis (to maintain the availability of glucose for tissues that are obligate glucose consumers such as wound, brain, erythrocytes and immune cells).

In addition, the enhanced gluconeogenesis is resistant to inhibition by insulin and high glucose levels, permitting to reroute the glucose towards high metabolic priorities at the expense of insulin-dependent territories. The major site of insulin resistance appears to be the muscle (although it might also exist in adipose tissue and the heart), where it results in reduced insulin-stimulated glucose uptake. Insulin resistance in the liver reduces the suppressibility of gluconeogenesis by exogenous glucose (reviewed in [5, 6]). Stress hyperglycemia results from the integrated action of hormonal, cytokine and nervous ‘counter-regulatory’ signals on glucose metabolic pathways. The hormones involved include glucagons, adrenaline, noradrenaline and cortisol. The proinflammatory cytokines affect glucose homeostasis both indirectly by stimulating counter-regulatory hormone secretion and directly by incompletely understood post-receptor mechanisms inducing insulin resistance in liver and muscle [7, 8]. The development of modern intensive care medicine has enabled a dramatic increase in the short-term survival of previously lethal conditions such as multiple trauma, extensive burns, major surgery and severe sepsis. Many of these patients nowadays enter the chronic phase of critical illness, characterized by immune paralysis, a wasting syndrome and persistent organ dysfunction. The mechanisms regulating hyperglycemia during protracted critical illness remain relatively unclear. Growth hormone, cortisol, catecholamine and cytokine levels are usually decreased in this phase of protracted critical illness [9]. The putative adaptive nature of stress hyperglycemia lead Mizock [5] in 1995 to the following conclusion: ‘If one accepts the concept of hyperglycemia of injury or infection as beneficial by promoting cellular glucose uptake, then modest degrees of hyperglycemia should be tolerated without efforts to lower blood glucose to normal values of 90–120 mg/dl. The level of glycemia should be high enough to maximize cellular glucose uptake without causing hyperosmolarity. A glucose concentration of 160–200 mg/dl has been recommended to achieve this goal and is probably acceptable to most clinicians’. In addition, moderate hyperglycemia was often viewed as a buffer against the occurrence of hypoglycemia and brain damage, which was feared by many clinicians to develop under tighter glucose control. However, in 2001 the same author was forced to correct his opinion in view of the increasing evidence of adverse effects of even moderate hyperglycemia [6].

Adverse Effects of Hyperglycemia

It is generally accepted that hyperglycemia ⱖ200 mg/dl should be avoided because it induces osmotic diuresis and fluid shifts that may result in hypovolemia,

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electrolyte abnormalities and hyperosmolar non-ketotic coma. Increased glucose levels have been shown to enhance the risk of postoperative infection, as well in diabetics [10, 11] as in non-diabetics [2]. A decrease in the phagocytosis by polymorphonuclear neutrophils [12], a blunted oxidative burst of leukocytes following exposure to high concentrations of glucose [13, 14], decreased intracellular bactericidal activity and opsonic activity [12, 15] and nonenzymatic glycosylation of immunoglobulins [16] might be amongst the underlying mechanisms of this increased susceptibility to infections. In patients with type 1 diabetes the diabetes control and complications trial (DCCT) demonstrated that maintenance of blood glucose concentrations close to the normal range resulted in a highly significant decrease of the progression rates of diabetic retinopathy, nephropathy and peripheral and autonomic neuropathy [17]. A large clinical trial likewise provided evidence for the importance of tight glycemic control for the prevention of complications in patients with type 2 diabetes [18]. Mortality following acute myocardial infarction seems to be adversely affected by the presence of diabetes [19], or by hyperglycemia on admission in patients without previously diagnosed diabetes [20]. In the DIGAMI Study intensive insulin therapy in diabetic patients admitted to the hospital with an acute myocardial infarction resulted in a significantly improved 30-day and long-term survival [21, 22] and also the risk for re-infarction and new cardiac failure was remarkably reduced [23]. Admission hyperglycemia appears to be an independent predictor of mortality and poor neurological recovery after stroke [24] and traumatic brain injury [25, 26]. In patients with severe burns an association between hyperglycemia and mortality was also noted [27].

Intensive Insulin Therapy in the ICU

Recently, an extensive, prospective, randomized, controlled clinical trial studied the effects of strict glycemic control on mortality and morbidity of critically ill patients [4]. Previous studies by the same investigator had revealed high levels of insulin-like growth factor-binding protein-1 (IGFBP-1) in patients with protracted critical illness. In addition these increased IGFBP-1 levels appeared to be an independent predictor of mortality [28]. Since IGFBP-1 is transcriptionally repressed by insulin [29], its high levels were hypothesized to reflect lack of insulin effect in the liver, which together with the risks associated with hyperglycemia, generated the rationale for this intervention study targeting normoglycemia with exogenous insulin in critically ill patients. The results of this trial for the first time challenged the classical dogma that stress-induced hyperglycemia is beneficial to these patients. Over a

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one-year period, a total of 1,548 patients, admitted to the intensive care unit predominantly after extensive or complicated surgery or trauma and requiring mechanical ventilation, were enrolled in the study. The patients were randomly subdivided into two groups. One group received ‘intensive insulin therapy’ to keep blood glucose levels tightly between 80 and 110 mg/dl (4.5 and 6.1 mmol/l) by exogenous insulin infusion. In the ‘conventional treatment’ group insulin was only administered if blood glucose levels exceeded 220 mg/dl (12 mmol/l). When normoglycemia was strictly maintained by intensive insulin therapy a marked reduction in intensive care unit mortality was observed as compared with the conventional treatment. The effect was particularly present in the patients with ICU stay of more than 5 days, where mortality decreased from 20.2 to 10.6% (p ⫽ 0.005) (fig. 1). Even conventionally treated patients with only moderate hyperglycemia (110–150 mg/dl or 6.1–8.3 mmol/l) had a significantly higher mortality rate than the patients with strict glycemic control below 110 mg/dl (6.1 mmol/l) [30]. Although the study included a large number of cardiac surgery patients, the beneficial effect of tight glucose control was present in the different diagnostic subgroups [4].

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Fig. 2. Relative risk reduction of prolonged (⬎14 days) ICU stay, prolonged (⬎14 days) mechanical ventilation, critical illness polyneuropathy, requirement of renal replacement therapy, prolonged (⬎10 days) antibiotics and bacteremia in patients with strict glycemic control compared with conventional treatment.

Intensive insulin therapy also improved several morbidity-related factors. Thus, the need for prolonged ventilatory support, the duration of intensive care stay, the number of blood transfusions and the incidence of blood stream infections and excessive inflammation were all reduced. Even more striking was the highly significant decrease in the development of acute renal failure and critical illness polyneuropathy associated with intensive insulin therapy [4] (fig. 2).

Harmful Effect of Hyperglycemia or Beneficial Effect of Insulin?

Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality, critical illness neuropathy, bacteremia and inflammation. Whether the observed beneficial effect is due to normoglycemia per se or to another concurrent metabolic effect of insulin can not be inferred from this trial. For acute renal failure requiring renal replacement therapy, not the actual glucose level but the insulin dose was an independent negative predictor. This might be related to the reduced renal elimination of insulin and the extracorporeal elimination of glucose [30].

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It is conceivable that insulin played a direct role in the functional improvement of the insulin-sensitive organs. Since in normal individuals the heart and skeletal muscles are responsible for the majority of the insulin-stimulated glucose uptake and, in addition, hyperglycemic conditions aggravate muscle catabolism [31], amelioration of these processes could partially explain the beneficial effects of intensive insulin therapy on the duration of mechanical ventilation of the critically ill patients in the intensive insulin therapy trial. Subsequent analysis of muscle biopsies of non-survivors in the ‘insulin in critical illness study’ indeed suggests that, in comparison to the conventional treatment group, skeletal muscle steady-state mRNA levels of GLUT-4 (the glucose transporter that is only present in tissues where glucose uptake is mediated by insulin) and hexokinase II (HXK-II) (a rate-controlling step in intracellular insulin-stimulated glucose metabolism) are higher in patients following intensive insulin therapy. This suggests that peripheral glucose uptake is stimulated in the latter group of patients [32]. The liver is the major site for gluconeogenesis and is an important insulinsensitive organ that could be involved in the improved outcome of the patients intensively treated with insulin. However, the analysis of serum and hepatic gene expression levels of insulin-like growth factor binding protein-1 (IGFBP-1) (a marker of hepatic insulin sensitivity) and gene expression levels of phosphoenolpyruvate carboxykinase (PEPCK) (the rate-limiting enzyme in gluconeogenesis in the liver) revealed that neither of them is regulated by insulin in critically ill patients. This may indicate that controlling gluconeogenesis was not the major factor responsible for the normalization of blood glucose levels with exogenous insulin in the critically ill [33]. However, true glucose kinetics can only be estimated by glucose turnover studies. Such a study, using a well-designed canine model of critical illness, was recently performed. When a sublethal hypermetabolic infection was induced in dogs, hepatic glucose uptake was decreased and appeared to be unresponsive to insulin administration. In contrast, the peripheral uptake of glucose did respond to insulin infusion. Contrary to our findings, insulin therapy suppressed hepatic glucose production. This apparently occurred through inhibition of glycogenolysis rather than diminished hepatic uptake of gluconeogenic amino acids and gluconeogenesis [34]. Another major insulin-responsive organ is the adipose tissue. Similar to the diabetic patient [35], abnormal serum lipid profiles are observed in the critically ill patient [36–38]. Most characteristically, triglyceride levels are elevated whereas the levels of circulating high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol are low [39]. On the other hand, circulating small dense LDL particles, that presumably are more pro-atherogenic than the medium and large LDL particles [40], are increased [41]. Interestingly, this dyslipidemia could partially be restored by intensive insulin therapy, with almost

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complete obliteration of the hypertriglyceridemia and a substantial increase in, but not normalization of, the serum levels of HDL and LDL cholesterol [32]. The role of triglycerides in energy provision and the coordinating position of the lipoproteins in transportation of lipid components (cholesterol, triglycerides, phospholipids, lipid-soluble vitamins) are well established [42]. In addition, it has recently been shown that lipoproteins can scavenge endotoxins and by doing so are able to prevent death in animal models [43, 44]. Multivariate logistic regression analysis demonstrated that the improvement of the deranged lipidemia explained a significant part of the beneficial effect on mortality and organ failure and, surprisingly, surpassed the effect of glycemic control and insulin dose [32]. In the same way, the effect of intensive insulin therapy on inflammation, reflected by a lowering of the serum C-reactive protein (CRP) concentrations [45], was no longer independently related to the outcome benefit when the changes in lipid metabolism were taken into account [32]. This observation is suggestive of a link between the anti-inflammatory effect of intensive insulin therapy and its amelioration of the lipid profile. However, a mechanistic explanation for the dominant effect of serum lipid correction still needs to be delineated.

Role of Hyperglycemia in Critical Illness-Associated Renal Failure

Presumably, a different pathophysiology is involved in diabetic and critical illness-associated nephropathy. Whereas diabetic nephropathy mainly affects the glomerulus, in the critically ill acute tubular necrosis is the major pathophysiological mechanism of renal failure. The prevention of renal dysfunction and failure is of crucial importance in critically ill patients, since it has repeatedly been shown to be an independent predictor of mortality [46–48]. Strikingly, the number of critically ill patients that required renal replacement therapy was reduced by 42% when they were intensively treated with insulin, as compared to the conventionally treated patients. Hence, intensive insulin therapy emerged as an effective preventive measure for acute renal failure in critical illness. Whether this is directly related to a metabolic or anti-inflammatory effect of insulin or secondary to the reduced incidence of bacteremia and sepsis is not clear.

Role of Hyperglycemia in Critical Illness-Associated Neuropathy

The most frequent presentation of neuropathies in the diabetic patient is distal sensory neuropathy with the classic stocking distribution [49, 50]. Patients

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with protracted critical illness often suffer from a diffuse axonal polyneuropathy [50], which presents as a tetraparesis with muscle atrophy. Even though the course of critical illness polyneuropathy is self-limited in most cases and a good recovery should be expected once the underlying critical illness is overcome, it severely delays weaning from the ventilator and impairs early mobilization of the patient [51]. Sepsis, the use of high dose corticosteroids as well as the use of neuromuscular blocking agents are all factors that have been implicated in the etiology of critical illness polyneuropathy. Yet, the exact pathogenesis of this complication is still not understood [52]. Recently, strong indications became available that emphasize the importance of blood glucose levels in relation to the development of critical illness polyneuropathy. First, Bolton [53] described a strong link between the risk of critical illness polyneuropathy on one hand and increased blood glucose and decreased serum albumin levels, which are both metabolic manifestations of multiple organ failure and sepsis, on the other hand. Sepsis, and the accompanying release of cytokines, was considered to be the causal factor. In addition, the Leuven study on intensive insulin therapy in the ICU convincingly demonstrated that strict maintenance of glycemia within the normal range by infusion of insulin has an important preventive effect on the incidence of critical illness polyneuropathy, which is associated with a decrease in duration of mechanical ventilation of protracted critically ill patients [4].

Immune System Impairment and Risk of Infections caused by Hyperglycemia

The recent Leuven insulin in ICU study also provided a causal link between hyperglycemia and a higher risk of serious infections, regardless of a previous history of diabetes. Indeed, the occurrence of blood stream infections was reduced by almost 50% and sepsis-associated mortality was largely prevented when critically ill patients were intensively treated with exogenous insulin to keep glucose levels within the normal range. These observations suggest that insulin-titrated blood glucose control enhances the immune system [4]. Improved capacity to clear bacterial invaders was recently shown to mediate this benefit in a novel rabbit model of prolonged critical illness [54].

Effects of Critical Illness and Insulin on Inflammation and Coagulation

Critical illness also resembles diabetes mellitus in the activation of the inflammatory cascade. Intensive insulin therapy proved to be of high value in

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the prevention of excessive inflammation in critically ill patients [4, 45]. This finding was confirmed in an experimental rabbit model of prolonged critical illness [54]. The exact mechanisms explaining the anti-inflammatory effect of insulin have not yet been unravelled. Suppression of the secretion and antagonism of the harmful actions of tumor necrosis factor-␣, macrophage migration-inhibitory factor and superoxide anions have all been suggested (summarized in [3]). Furthermore, diabetes mellitus and critical illness both are hypercoagulable states [55, 56]. Putative causes in diabetes include vascular endothelium dysfunction [57], increased blood levels of several clotting factors [58, 59], elevated platelet activation [60, 61] and inhibition of the fibrinolytic system [62]. Levels of the anticoagulant protein C are also decreased [63]. Looking at the similarities between critical illness and diabetes [64, 65] and the powerful preventive effect of intensive insulin therapy on septicemia, multiple organ failure and mortality [4], it is very important to also investigate the influence of this simple and cheap metabolic intervention on the balance between coagulation and fibrinolysis in the critically ill. Also the effect of insulin on endothelial function deserves further investigation.

Possible Dangers of Intensive Insulin Therapy

This risk of hypoglycemia is a major concern of intensive insulin therapy during critical illness, the more so as clinical symptoms of the autonomic response (sweating, tachycardia, tremor) and central nervous symptoms like dizziness, blurred vision, altered mental acuity, confusion and eventually convulsions may be masked by concomitant diseases and by inherent intensive care treatments such as sedation, analgesia and mechanical ventilation. The brain can be irreversibly damaged in the situation of severe hypoglycemia, when glucose levels drop below 30 mg/dl (⬍1.67 mmol/l), or in case of persistent hypoglycemia. In the Leuven study, the risk of hypoglycemia increased form 0.8 to 5.2%. However, with the algorithm used, these episodes of hypoglycemia were always rapidly diagnosed and treated and thus did not detectably cause any serious adverse events or permanent damage. It is also important to note that hypoglycemia occurred in the stable phase, mostly after the first week and was often due to inadequate insulin dose reduction during interruption of enteral feeding [4]. Limiting the risk of hypoglycemia is of utmost importance, however, and this requires a number of precautions. These include, among others: (1) point of care measurement of blood glucose in order to shorten the delay between measurement and infusion adjustment; (2) using a method for blood glucose

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measurement that is accurate, particularly in the low range, and (3) adequate training of the nursing and medical staff.

Conclusion

Trauma, burns and critical illness are accompanied by the development of hyperglycemia, which results from the combined action of hormonal, cytokine and nervous ‘counter-regulatory’ signals on glucose metabolic pathways. Additionally, the major insulin-sensitive organs become resistant to insulin during critical illness, as manifested by increased serum insulin levels, impaired peripheral glucose uptake and elevated hepatic glucose production. Recently, Van den Berghe et al. [4] demonstrated the beneficial effects of strictly maintaining normoglycemia in ICU patients by administration of intensive insulin therapy. A remarkable reduction in mortality of ICU patients was observed, particularly of those with prolonged critical illness. Furthermore, the intensive insulin therapy to a large extent was able to protect against acute renal failure and the development of critical illness polyneuropathy, and partially counteracted the deranged serum lipid profile, excessive inflammation and impaired immunity seen in critically ill patients.

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Thorell A, Nygren J, Ljungqvist O: Insulin resistance: A marker of surgical stress. Curr Opin Clin Nutr Met Care 1999;21:69–78. McCowen KC, Malhotra A, Bistrian BR: Stress-induced hyperglycaemia. Crit Care Clin 2001;17: 107–124. Das UN: Is inslin an anti-inflammatory molecule? Nutrition 2001;17:409–413. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359–1367. Mizock BA: Alterations in carbohydrate metabolism during stress: A review of the literature. Am J Med 1995;98:75–84. Mizock BA: Alterations in fuel metabolism in critical illness: Hyperglycaemia. Best Pract Res Clin Endocrinol Metab 2001;15:533–551. Grimble RF: Inflammatory status and insulin resistance. Curr Opin Clin Nutr Met Care 2002;5: 551–559. Marette A: Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Met Care 2002;5:377–383. Van den Berghe G, de Zegher F, Bouillon R: Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827–1834. Pozzilli P, Leslie RD: Infections and diabetes: Mechanisms and prospects for prevention. Diabet Med 1994;11:935–941. Funari AP, Zerr KJ, Grunkemeier GL, Starr A: Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352–360.

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Mesotten D, Delhanty PJD, Vanderhoydonc F, Hardman KV, Weekers F, Baxter RC, Van den Berghe G: Regulation of insulin-like growth factor binding protein-1 during protracted critical illness. J Clin Endocrinol Metab 2002;87:5516–5523. Donmoyer CM, Chen SS, Lacy DB, Pearson DA, Poole A, Zhang Y, McGuinnes OP: Infection impairs insulin-dependent hepatic glucose uptake during total parenteral nutrition. Am J Physiol 2003;284:E574–E585. Taskinen MR: Pathogenesis of dyslipidemia in type 2 diabetes. Exp Clin Endocrinol Diab 2001; 109:S180-S188. Lanza-Jacoby S, Wong SH, Tabares A, Baer D, Schneider T: Disturbances in the composition of plasma lipoproteins during gram-negative sepsis in the rat. Biochim Biophys Acta 1992;1124: 233–240. Khovidhunkit W, Memon RA, Feingold KR, Grunfeld C: Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis 2000;181:S462–S472. Carpentier YA, Scruel O: Changes in the concentration and composition of plasma lipoproteins during the acute phase response. Curr Opin Clin Nutr Metab Care 2002;5:153–158. Gordon BR, Parker TS, Levine DM, Saal SD, Wang JC, Sloan BJ, Barie PS, Rubin AL: Low lipid concentrations in critical illness: Implications for preventing and treating endotoxemia. Crit Care Med 1996;24:584–589. Kwiterovich PO: Lipoprotein heterogeneity: Diagnostic and therapeutic implications. Am J Cardiol 2002;90:1i-10i. Feingold KR, Krauss RM, Pang M, Doerrler W, Jensen P, Grunfeld C: The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab 1993;76:1423–1427. Tulenko TN, Sumner AE: The physiology of lipoproteins. J Nucl Cardiol 2002;9:638–649. Harris HW, Grunfeld C, Feingold KR, Rapp JH: Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice. J Clin Invest 1990;86:696–702. Harris HW, Grunfeld C, Feingold KR, Read TE, Kane JP, Jones AL, Eichbaum EB, Bland GF, Rapp JH: Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death. J Clin Invest 1993;91:1028–1034. Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G: Intensive insulin therapy exerts anti-inflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 2003;88:1082–1088. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality: A cohort analysis. JAMA 1996;275:1489–1494. Metnitz PGH, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, LeGall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051–2058. de Mendonca A, Vincent JL, Suter PM, Moreno R, Dearden NM, Antonelli M, Takala J, Sprung C, Cantraine F: Acute renal failure in the ICU: Risk factors and outcome evaluated by the SOFA score. Intens Care Med 2000;26:915–921. Boulton AJ: Clinical presentation and management of diabetic neuropathy and foot ulceration. Diab Med 1991;8:S52–S57. Hund E: Neurological complications of sepsis: Critical illness polyneuropathy and myopathy. J Neurol 2001;248:929–934. Leijten FS, De Weerd AW, Poortvliet DC, De Ridder VA, Ulrich C, Harink-De Weerd JE: Critical illness polyneuropathy in multiple organ dysfunction syndrome and weaning from the ventilator. Intens Care Med 1996;22:856–861. Bolton CF, Young GB: Critical Illness Polyneuropathy. Curr Treat Options Neurol 2000;2: 489–498. Bolton CF: Sepsis and the systemic inflammatory response syndrome: Neuromuscular manifestations. Crit Care Med 1996;24:1408–1416. Weekers F, Giulietti A, Michalaki M, Coopmans W, Van Herck E, Mathieu C, Van den Berghe G: Metabolic, endocrine and immune effects of stress hyperglycaemia in a rabbit model of prolonged critical illness. Endocrinology 2003;in press. Carr ME : Diabetes mellitus: A hypercoagulable state. J Diabetes Complications 2001;15:44–54.

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Calles-Escandon J, Garcia-Rubi E, Mirza S, Mortensen A : Type 2 diabetes: One disease, multiple cardiovascular risk factors. Coron Artery Dis 1999;10:23–30. Williams E, Timperley WR, Ward JD, Duckworth T: Electron microscopical studies of vessels in diabetic peripheral neuropathy. J Clin Pathol 1980;33:462–470. Patrassi GM, Vettor R, Padovan D, Girolami A: Contact phase of blood coagulation in diabetes mellitus. Eur J Clin Invest 1982;12:307–311. Carmassi F, Morale M, Puccetti R, De Negri F, Monzani F, Navalesi R, Mariani G: Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res 1992; 67:643–654. Hughes A, McVerry BA, Wilkinson L, Goldstone AH, Lewis D, Bloom A: Diabetes, a hypercoagulable state? Hemostatic variables in newly diagnosed type 2 diabetic patients. Acta Haematol 1983;69:254–259. Garcia Frade LJ, de la Calle H, Alava I, Navarro JL, Creighton LJ, Gaffney PJ: Diabetes mellitus as a hypercoagulable state: Its relationship with fibrin fragments and vascular damage. Thromb Res 1987;47:533–540. Carmassi F, Morale M, Puccetti R, De Negri F, Monzani F, Navalesi R, Mariani G: Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res 1992;67: 643–654. Vukovich TC, Schernthaner G: Decreased protein C levels in patients with insulin-dependent type I diabetes mellitus. Diabetes 1986;35:617–619. Garcia Frade LJ, Landin L, Avello AG, Martin Yerro J, Navarro JL, Creighton LJ, Gaffney PJ: Changes in fibrinolysis in the intensive care patient. Thromb Res 1987;47:593–599. Mavrommatis AC, Theodoridis T, Economou M, Kotanidou A, El Ali M, Christopoulou-Kokkinou V, Zakynthinos SG: Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: Comparison with severe sepsis and septic shock. Intens Care Med 2001;27:1853–1859.

Miet Schetz, MD, PhD Department of Intensive Care Medicine University Hospital Gasthuisberg, Herestraat 49, BE–3000 Leuven (Belgium) Tel. ⫹32 16344021, Fax ⫹32 16344015, E-Mail [email protected]

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Dysnatremias in the Critical Care Setting Michael L. Moritza, J. Carlos Ayusb a

Division of Nephrology, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pa., and bDivision of Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Tex., USA

Under normal circumstances, the human body is able to maintain plasma sodium levels in the normal range (135–145 mEq/l). Many conditions can impair the body’s ability to maintain a normal plasma sodium by either interfering with free access to water or buy impairing renal concentration and dilution. When the serum sodium departs from the normal range, the cells of the body are subjected to an injurious osmotic stress which can lead to either an influx or efflux of water. The most serious complications of dysnatremias are related to central nervous system dysfunction, such as cerebral edema do to hyponatremia and cerebral dehydration from hypernatremia. Even when there is no apparent central nervous system manifestations, dysnatremias are a major comorbidity factor. In no setting is it more difficult to prevent and treat dysnatremias than in the critical care setting. Patients frequently have multiorgan system dysfunction where both access to fluids and renal water handling is impaired. Fluid management can be difficult as it must to be incorporated into the management of acute and chronic illnesses. The most severe dysnatremias with central nervous system manifestation will be managed in the intensive care unit where an immediate diagnosis and therapy is required. This review will focus on the common clinical reasons for encountering a dysnatremia in the critical care setting and on the prevention and treatment of dysnatremias.

Table 1. Disorders in impaired renal water excretion Effective circulating volume depletion Gastrointestinal losses: vomiting, diarrhea Skin losses: cystic fibrosis Renal losses: salt wasting nephropathy, diuretics, cerebral salt wasting, hypoaldosteronism Edemetous states: heart failure, cirrhosis, nephrosis, hypoalbuminemia Thiazide diuretics Renal failure Acute Chronic Non-hypovolemic states of ADH excess SIADH Cortisol deficiency Hypothyroidism

Hyponatremia

Pathogenesis of Hyponatremia Hyponatremia, defined as a serum ⬍135 mEq/l, is a common disorder that occurs in both the outpatient and inpatient setting. The body’s primary defense against developing hyponatremia is the kidney’s ability to generate a dilute urine and excrete free water. Rarely is excess ingestion of free water alone the cause of hyponatremia, as an adult with normal renal function can typically excrete over 15 liters of free water per day. It also rare to develop hyponatremia from excess urinary sodium losses in the absence of free water ingestion. In order for hyponatremia to develop, it typically requires a relative excess of free water in conjunction with an underlying condition that impairs the kidney’s ability to excrete free water (table 1). Renal water handling is primarily under the control of arginine vasopressin (AVP) which is produced in the hypothalamus and released from the posterior pituitary. AVP release impairs water diuresis by increasing the permeability to water in the collecting tubule. There are osmotic, hemodynamic and non-hemodynamic stimuli for AVP release. In most cases of hyponatremia there is a stimulus for vasopressin production which results in impaired free water excretion. The body will attempt to preserve the extracellular volume at the expense of the serum sodium, therefore a hemodynamic stimulus for AVP production will override and inhibitory effect of hyponatremia [1]. There are numerous stimuli for AVP production (table 1) that occur in hospitalized patients which make virtually any hospitalized patient at risk for hyponatremia.

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Diagnostic Approach

Before embarking on an aggressive therapeutic regimen, it is vital to confirm that hyponatremia is in fact associated with hypo-osmolality. Hyponatremia can be associated with either a normal or an elevated serum osmolality (fig. 1). The most common reasons for this are hyperglycemia, severe hyperproteinemia or hyperlipidemia. Hyperglycemia results in hyperosmolality with a translocation of fluid from the intracellular space to the extracellular space, resulting in a 1.6 mEq/l fall in the serum sodium for every 100 mg/dl elevation in the serum glucose concentration above normal. Severe hyperlipidemia, hypercholesterolemia and hyperproteinemia can cause a displacement of plasma water, which will result in a decreased sodium concentration (pseudohyponatremia) with a normal serum osmolality [2]. Serum sodiums are currently measured by either direct or indirect-reading ionselective electrode potentiometry. The direct method will not result in pseudohyponatremia, as it measures the activity of sodium in the aqueous phase of serum only. The indirect method on the other hand can result in pseudohyponatremia as the specimen is diluted with a reagent prior to measurement [3]. The indirect method is currently performed in approximately 60% of chemistry labs in the United States; therefore, pseudohyponatremia remains an entity that clinicians need to be aware of [4]. If hyponatremia is associated with hypo-osmolality (true hyponatremia), the next step is to measure the urinary osmolality to determine if there is an impaired ability to excrete free water (urineosm ⬎100mosm/kg). The information that is most useful in arriving at a correct diagnosis of hyponatremia is a detailed history of fluid balance, weight changes, medications (especially diuretics), and underlying medical illnesses. Hyponatremia is usually a multifactorial disorder and a detailed history will identify sources of salt and water losses, free water ingestion, and underlying illnesses that cause a nonosmotic stimulus for vasopressin production. An assessment of the volume status on physical examination and the urinary electrolytes can be extremely helpful, but both can be misleading [5]. In patients in whom hyponatremia is due to salt losses, such as diuretics, signs of volume depletion may be absent on physical examination, as the volume deficit may be nearly corrected due to oral intake of hypotonic fluids if the thirst mechanism is intact. In general a urinary sodium concentration less than 25 mEq/l is consistent with effective circulating volume depletion, while a urine sodium greater than 25 mEq/l is consistent with renal tubular dysfunction, use of diuretics or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [6]. Numerous factors can affect the urine sodium, making interpretation difficult, therefore the timing of the urinary measurements in relation to dosages of diuretics,

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Serum Na ⬍135 mEq/L

Plasma osmolality

⬎280mOsm/kg H2O • Hyperglycemia • Mannitol • Pseudohyponatremia
Hyperlipidemia
Hyperproteinemia

⬍ 280 mOsm/kg H2O

Urine osmolality

⬍ 100mOsm/kg H2O • Psychogenic polydypsia • Water intoxication in infants • Reset osmostat

⬎ 100 mOsm/kg H2O

Effective circulatory volume depletion

No

Renal insufficiency Hypothyroid Glucocorticoid deficiency Post-operative Spinal fusion Pain/stress/nausea Positive pressure ventilation

Yes

Urine Na ⬍25mEq/L • Extrarenal losses • Edemetous states Urine Na ⬎25mEq/L • Salt wasting nephropathy • Mineralocorticoid-deficiency • Cerebral salt wasting • Diuretics • Osmotic diuresis

No

Urine Na ⬎25mEq/L • SIADH • Reset osmostat Urine Na ⬍25mEq/L • Repeat algorithm

Fig. 1. Diagnostic approach to hyponatremia.

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intravenous fluid boluses, or fluid and sodium restriction are also important. If some cases assessment of volume status by the measurement of a central venous pressure may be helpful [7].

Hospital Acquired Hyponatremia and Its Prevention

Hyponatremia is a common electrolyte disorder occurring in about 3% of hospitalized patients [8]. The incidence of hyponatremia in the intensive care unit can be as high as 30% [9]. Hyponatremia is a major predictive factor of mortality in hospitalized patients with heart failure [10] and community acquired pneumonia [11]. The mortality in hospitalized patients with hyponatremia is over seven times higher than in those with out [12]. Over two thirds of all hyponatremia is hospital acquired due to a non-osmotic stimuli for AVP production [8, 13]. Hospitalized patients have numerous stimuli for AVP production, therefore all hospitalized patient should be considered at risk for developing hyponatremia and prophylactic measures must be taken. The most important factor resulting in hospital acquired hyponatremia is the administration of hypotonic fluids to a patient who has a compromised ability to maintain water balance [14–18]. In adults this will usually occur in the postoperative period. While a healthy male adult can excrete at least 15 liters of fluid a day and maintain sodium homeostasis, it has been shown that in a women as few as 3–4 liters of hypotonic fluid over 2 days can result in fatal hyponatremic encephalopathy in the postoperative setting [16, 19]. Hyponatremia can even develop if excessive near-isotonic saline, lactated Ringer’s solution, is administered in the postoperative period [20]. Thus, the most important measure which can be taken to prevent hyponatremia is to avoid using hypotonic fluids postoperatively and to administer isotonic saline, 0.9% sodium chloride, unless otherwise clinically indicated. The serum sodium should be measured daily in any patient receiving continuous parenteral fluid. Hospital acquired hyponatremia is commonly seen in the post-operative setting [21]. Postoperative patients develop hyponatremia due to a combination of nonosmotic stimuli for ADH release, such as subclinical volume depletion, pain, nausea, stress, edema-forming conditions, and administration of hypotonic fluids. ADH levels are universally elevated postoperatively when compared to preoperative values [22, 23]. Premenopausal females are most at risk for developing hyponatremic encephalopathy postoperatively [19]. Hospital acquired hyponatremia is of particular concern in children as the standard of care in pediatrics has been to administer hypotonic fluids containing 0.2–0.45% sodium chloride as maintenance fluids [24]. The safety of this approach has never been established. Hospitalized children have numerous

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Table 2. Anatomic and biochemical changes and clinical symptoms of hyponatremic encephalopathy Anatomic and biochemical changes

Clinical symptoms

Brain swelling

headache nausea vomiting seizures

Pressure on a rigid skull Excitatory amino acids Tentorial herniation

respiratory arrest

nonosmotic stimuli for vasopressin production which place them at risk for developing hyponatremia [25]. There are over fifty reported cases of neurologic morbidity and mortality in the past ten years resulting from hospital-acquired hyponatremia in children receiving hypotonic parenteral fluids [18]. Over half of these cases occurred in the postoperative setting in previously healthy children undergoing minor elective surgeries [26, 27]. Hyponatremia is especially dangerous in children with underlying CNS injury such as encephalitis, with mild hyponatremia (sodium ⬎130 mEq/l) resulting in cerebral herniation [28, 29]. We have recently argued that isotonic saline, 0.9% sodium chloride, should be the parenteral fluid of choice in pediatric patients unless there are ongoing free water losses or a free water deficit [18].

Hyponatremic Encephalopathy

Clinical Symptoms A major consequence of hyponatremia is the influx of water into the intracellular space resulting in cellular swelling, which can lead to cerebral edema and encephalopathy. The clinical manifestations of hyponatremia are primarily neurologic and related to cerebral edema caused by hypo-osmolality (table 2). The symptoms of hyponatremic encephalopathy are quite variable between individuals with the only consistent symptoms being headache, nausea, vomiting, emesis, and weakness. As the cerebral edema worsens, patients then develop behavioral changes, and impaired response to verbal and tactile stimuli. Advanced symptoms are signs of cerebral herniation, with seizures, respiratory arrest, dilated pupils and decorticate posturing. Hyponatremic encephalopathy is important to recognize early, as it accounts for one third of the seizures encountered in the ICU setting [30]. Not all patients have the usual progression in symptoms and advanced symptoms can present with sudden onset.

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Neurogenic Pulmonary Edema A common yet often unrecognized symptom of hyponatremic encephalopathy is neurogenic pulmonary edema [14, 31, 32]. Neurogenic pulmonary edema is a well described yet under diagnosed condition that occurs as a complication of severe CNS injury [33]. There is typically a rapid onset of pulmonary edema following the development of cerebral edema. No cardiac etiology is found and there is a complete and rapid resolution of respiratory systems following appropriate treatment of hyponatremic encephalopathy with hypertonic saline. If not recognized early the condition is almost universally fatal [14]. The pathophysiologic mechanism of neurogenic pulmonary edema is unclear, but appears to be due to (1) increased microvascular permeability to proteins [34], and (2) a sympathetic discharge resulting in pulmonary vasoconstriction with increased pulmonary hydrostatic pressure [35]. The incidence of neurogenic pulmonary edema complicating hyponatremic encephalopathy is uncertain, but 15% of patients with severe hyponatremia do have radiographic evidence of pulmonary edema [32]. Hyponatremic encephalopathy should be considered in any patient presenting with a non-cardiogenic pulmonary edema. Brains Cell Volume Regulation The brain’s adaptation to hyponatremia initially involves a loss of blood and cerebral spinal fluid. This is followed by volume regulatory decrease which occurs by the extrusion sodium, potassium and organic osmolytes in order to decrease the brain osmolality [36]. Various factors can interfere with successful brain adaptation and may a play a more important role than the absolute change in serum sodium in predicting whether a patient will suffer hyponatremic encephalopathy. Elevated AVP levels appear to be a contributing factor to the development of cerebral edema as AVP is know to increase water content in the absence of hyponatremia, and impair brain regulatory volume mechanisms [37, 38]. The major factors that interfere with brain adaptation are physical factors related to age, hormonal factors related to gender, and hypoxemia [39].

Risk Factors for Developing Hyponatremic Encephalopathy (table 3)

Age Children under 16 years of age are at increased risk for developing hyponatremic encephalopathy due to their relatively larger brain to intracranial volume ratio as compared to adults [27, 40]. A child’s brain reaches adult size by 6 years of age, whereas the skull does not reach adult size until 16 years of age [41, 42]. Consequently, children have less room available in their rigid

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Table 3. Risk factors for developing hyponatremic encephalopathy Risk factor

Pathophysiologic mechanism

Children Females

increase brain to intracranial volume ratio sex steroids (estrogens) inhibit brain adaptation increase vasopressin levels cerebral vasoconstriction hypoperfusion of brain tissue impaired brain adaptation

Hypoxemia

skulls for brain expansion and are likely to develop brain herniation from hyponatremia at higher serum sodium concentrations than adults. Children will have a high morbidity from symptomatic hyponatremia unless appropriate therapy is instituted early [18, 26–29]. After the third decade of life the brain begins to atrophy, with the steepest reduction in brain volume occurring after 50 years of age [43, 44]. The brain volume of an eighty year old is approximately that of a young child. Consequently, the elderly are at the lowest risk of developing central nervous system manifestation of hyponatremia. Gender Recent epidemiological data have clearly shown that menstruant women are at substantially higher risk for developing permanent neurological sequelae or death from hyponatremic encephalopathy than men or postmenopausal females [15, 16, 19, 45]. The relative risk of death or permanent neurologic damage from hyponatremic encephalopathy is approximately 30 times greater for women compared to men, and approximately 25 times greater for menstruant females than postmenopausal females [19]. Menstruant females can develop symptomatic hyponatremia at serum sodium values as high as 128 mEq/l [16]. Hyponatremic encephalopathy in menstruant females primarily occurs in healthy females following elective surgeries while receiving hypotonic fluids [16, 19]. Premenopausal women are at high risk for developing hyponatremic encephalopathy due to the inhibitory effects of sex hormones and the effects of vasopressin on the cerebral circulation, which in the female animal model as opposed to the male are characterized by cerebral vasoconstriction and hypoperfusion to brain tissue [40, 46]. Hypoxia Hypoxemia is a major risk factor for developing hyponatremic encephalopathy. The occurrence of a hypoxic event such as respiratory insufficiency

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is a major factor militating against survival without permanent brain damage in patients with hyponatremia [16]. The combination of systemic hypoxemia and hyponatremia is more deleterious than is either factor alone because hypoxemia impairs the ability of the brain to adapt to hyponatremia, leading to a vicious cycle of worsening hyponatremic encephalopathy [47]. Hyponatremia leads to a decrement of both cerebral blood flow and arterial oxygen content [14]. Patients with symptomatic hyponatremia can develop hypoxemia by at least two different mechanisms: neurogenic pulmonary edema or hypercapnic respiratory failure [14]. Respiratory failure can be of very sudden onset in patients with symptomatic hyponatremia [16, 31]. The majority of neurologic morbidity seen in patients with hyponatremia has occurred in patients who have had a respiratory arrest as a feature of hyponatremic encephalopathy [16, 19, 27, 45, 48]. Recent data has shown that hypoxia is the strongest predictor of mortality in patients with symptomatic hyponatremia [32].

Hyponatremic Encephalopathy in the Outpatient Setting

Symptomatic hyponatremia can be particularly difficult to recognize in the out-patient setting, as the most common symptoms, namely headache, nausea, vomiting and confusion, can be attributed to other causes. Also, neurogenic pulmonary edema which can be a presenting feature of hyponatremic encephalopathy can be erroneously attributed to cardio-pulmonary disease. Various conditions can result in hyponatremic encephalopathy in the outpatient setting. The most common causes would be psychogenic polydypsia, thiazide diuretics, and water intoxication in infants. There are some new and unusual presentations of hyponatremic encephalopathy that have been recently reported in the outpatient setting. Ayus et al. recently reported on hyponatremic encephalopathy occurring in marathon runners, with a presenting symptom of noncardiogenic pulmonary edema [31]. All patients had been taking NSAIDs. Patients treated with hypertonic saline had prompt resolution of symptoms without neurologic sequelae. Fatal hyponatremic encephalopathy has also been reported following colonoscopy [49, 50]. This appears to be due to a combination of large quantities of polyethylene glycol used for bowel preparation in conjunction with increased ADH levels from bowel manipulation. Hyponatremic encephalopathy has been reported to present with hip fractures in elderly women, resulting from an unexpected fall in the home [45]. Symptomatic hyponatremia has also been reported with the recreational drug 3,4-methylenedioxymetamphetamine (Ecstasy) [51]. This results from increased vasopressin secretion and excess water ingestion. Symptomatic

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hyponatremia can be particularly difficult to recognize in the outpatient setting as the most common symptoms, namely headache, nausea, vomiting and confusion, can be attributed to other causes.

Thiazide Diuretics

Thiazide diuretics are an important cause of symptomatic hyponatremia in the outpatient and hospitalized setting [52]. The main reason for this is that thiazide diuretics act at the distal convoluted tubule and therefore do not impair urinary dilation as loop diuretics do. Thiazide diuretics lead to hyponatremia by increasing renal sodium and potassium losses; this in turn leads to volume depletion, increased vasopressin production and impaired free water excretion [53]. Volume depletion may not be clinically apparent due to water retention. Thiazide-induced hyponatremia typically occurs within two weeks of the start of diuretic [52]. The elderly are most at risk for thiazide-induced hyponatremia, presumably due to an age-related decline in GFR [54]. Thiazide diuretics also exacerbate the hyponatremia seen in edema forming states. Treatment of thiazide-induced hyponatremia can be challenging as withdrawal of the diuretic can result an over correction of the serum sodium due to a free water diureses.

Syndrome of Inappropriate Vasopressin Production (SIADH)

SIADH is one of the most common causes of hyponatremia in the hospital setting and frequently leads to severe hyponatremia (plasma Na ⬍120 mEq/l) [8]. It is caused by elevated ADH secretion in the absence of an osmotic or hypovolemic stimulus [55]. SIADH can occur due to a variety of illnesses, but most often occurs due to central nervous system disorders, pulmonary disorders and medications (table 4) [56]. Among the latter, the chemotherapeutic drugs vincristine and cytoxan, and the antiepileptic drug carbamazapine are especially common. SIADH is essentially a diagnosis of exclusion as can be seen from figure 1. Before SIADH can be diagnosed, diseases causing decreased effective circulating volume, renal impairment, adrenal insufficiency, and hypothyroidism must be excluded. The hallmarks of SIADH are: mild volume expansion with low to normal plasma concentrations of creatinine, urea, uric acid, and potassium; impaired free water excretion with normal sodium excretion which reflects sodium intake [57]; and hyponatremia which is relatively unresponsive to sodium administration in the absence of fluid restriction.

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Table 4. Common causes of SIADH Central nervous system disorders Infection: meningitis, encephalitis Neoplasms Vascular abnormalities Psychosis Hydrocephalus Post-pituitary surgery Head trauma Pulmonary disorders Pneumonia Tuberculosis Asthma Positive pressure ventilation Pneumothorax

Carcinomas Bronchogenic carcinomas Oat cell of the lung Duodenum Pancreas Neuroblastoma Medications Vincristine Intravenous cytoxan Carbamazepine Oxcarbazepine Seritonin reuptake inhibitors

SIADH is usually of short duration and resolves with treatment of the underlying disorder and discontinuation of the offending medication. Fluid restriction is the cornerstone to therapy, but is a slow method of correction, and is frequently impractical in infants who receive most of their nutrition as liquids. All intravenous fluids should be of a tonicity of at least normal saline, and if this does not correct the plasma sodium, 3% sodium chloride may be given as needed. If a more rapid correction of hyponatremia is needed the addition of a loop diuretic in combination with hypertonic saline is useful [58, 59]. Agents which produce diabetes insipidus such as demeclocyline can be used if SIADH persists for greater than a month and is unresponsive to fluid restriction, increased sodium intake and loop diuretics [59]. Vasopressin 2 receptor antagonists are a promising therapy that are currently under investigation but are not approved for clinical use [60].

Cerebral Salt Wasting (CSW)

Hyponatremia is frequently encountered in the neurosurgical setting and in patients with CNS injury. This has usually been attributed to SIADH, a condition whose hallmark is euvolemia, with the corner stone of management being fluid restriction. More recently it has become apparent that an increasing number of neurosurgical patients with hyponatremia have a distinct clinical entity called cerebral salt wasting [61, 62], a condition whose hallmark is renal sodium loss leading to extracellular volume depletion, with the cornerstone of

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management being volume expansion and salt supplementation [63]. Because these two diseases have many clinical similarities, it can be difficult to confirm a diagnosis of CSW. It is essential to be able to distinguish between these two conditions as their management is completely different and fluid restriction would be harmful in CSW. The pathogenesis of CSW is not completely understood, but it appears to be due to the release of natriuretic peptides, such as atrial natriuretic peptide, brain natriuretic peptide and c-type natriuretic peptide [63]. These peptides appear to lead to a natriurersis via of complex mechanism of (1) hemodynamic effects leading to an increased GFR; (2) inhibition of the rennin-angiotensin system, and (3) inhibition of the secretion and action of AVP [64]. This complex mechanism can lead to biochemical features that are indistinguishable to SIADH with a low uric acid, plasma renin, aldosterone and vasopressin levels, despite volume depletion [65]. The only distinguishing feature between CSW and SIADH is extracellular volume depletion. This can be particularly difficult to assess in CSW and the biochemistries may not be helpful. Central venous pressure or pulmonary capillary wedge pressures may be useful. From a practical standpoint the administration of normal saline should be an adequate prophylaxis against developing clinically significant hyponatremia, ⬍130 mEq/l, in SIADH. If clinically significant hyponatremia develops in patient with a CNS disorder receiving only normal saline, than the diagnosis of CSW should be strongly considered. If there are no signs of extracellular volume depletion than a brief period of fluid restriction could be tried. If there are signs of volume depletion or a lack of response to fluid restriction than the patient should be managed as CSW. Patients with CSW should be volume expanded with normal saline, followed by sufficient quantities of normal saline and 3% NaCl to main fluid balance and a normal serum sodium. The administration of fluodrocortisone may be beneficial as aldosterone production is relatively decreased in CSW [66].

Treatment of Hyponatremic Encephalopathy

Despite the controversies surrounding the optimal treatment of hyponatremic encephalopathy there are two aspects generally accepted by experts in the field: (1) treatment should be directed based on the neurological involvement and not the absolute serum sodium, and (2) hypertonic saline is not indicated in the asymptomatic patient who is neurologically intact, regardless of the serum sodium [25, 48, 67–72]. In general, correction with hypertonic saline is unnecessary and potentially harmful if there are no neurologic manifestations of hyponatremia. Symptomatic hyponatremia, on the other hand, is a

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Table 5. Treatment of hyponatremia Most important step is prevention: avoidance of hypotonic fluid administration Measure plasma osmolality to confirm hypo-osmolality Symptomatic hyponatremia (headache, nausea, emesis, weakness) Start treatment with hypertonic saline infusion (513 mM): use an infusion pump in an intensive care unit setting Monitor serum sodium every 2 h until the patient is stable and symptom free Stop hypertonic saline when the patient is symptom free or serum sodium is increased by 20 mmol/l in the initial 48 h of therapy Avoid hyper- or normonatremia during the initial 5 days of therapy, particularly in alcoholic or liver disease patients Asymptomatic hyponatremia Fluid restriction Therapy of underlying disorder

medical emergency. Once signs of encephalopathy are identified prompt treatment is required in a monitored setting before imaging studies are performed. The airway should be secured and endotrachial intubation and mechanical ventilation may be necessary. Fluid restriction alone has no place in the treatment of symptomatic hyponatremia. If symptomatic hyponatremia is recognized and treated promptly, prior to developing a hypoxic event, the neurological outcome is good [45, 48, 70, 73]. Patients with symptomatic hyponatremia should be treated with hypertonic saline (3%, 513 mEq/l) using an infusion pump (table 5). The rate of infusion should raise the plasma sodium by about 1 mEq/l per hour until either (1) the patient is alert and seizure free; (2) the plasma sodium has increased by 20 mEq/l, or (3) a serum sodium of about 125–130 mEq/l has been achieved, whichever occurs first [15, 39, 48, 69, 70, 72–75]. If the patient is actively seizing or with impending respiratory arrest the serum sodium can be raised by as much as 4–8 mEq/l in the first hour or until seizure activity seizes [75]. Recent studies have demonstrated that the optimal rate of correction of symptomatic hyponatremia is approximately 15–20 mEq in 48 h, as patients with correction of hyponatremia in this range have a much lower mortality and an improved neurological outcome compare to those with a correction of less than 10 mEq in 48 h [32, 45, 48]. Assuming that total body water comprises 50% of total body weight, 1 ml/kg of 3% sodium chloride will raise the plasma sodium by about 1 mEq/l. In some cases furosemide can also be used to prevent pulmonary congestion and to increase the rate of serum sodium correction.

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Table 6. Risk factors for developing cerebral demyelination in hyponatremic patients

Development of hypernatremia Increase in serum sodium exceeding 25 mmol/l in 48 h Hypoxemia Severe liver disease Alcoholism Cancer Severe burns Malnutrition Hypokalemia

Risk Factors for Developing Cerebral Demyelination (table 6)

Cerebral demyelination is a rare complication which has been associated with symptomatic hyponatremia [76]. Animal data has demonstrated that correction of hyponatremia by ⬎25 mEq/l in 24 h can result in cerebral demyelination [77]. This has resulted in a mistaken belief that a rapid rate of correction is likely to result in cerebral demyelination [78]. Studies have shown that rate of correction has little to do with development of cerebral demyelinating lesions, and that lesions seen in hyponatremic patients are more closely associated with other comorbid factors or the magnitude of correction in serum sodium [32, 48, 79, 80]. In one prospective study it was observed that hyponatremic patients who develop demyelinating lesions had either (a) been made hypernatremic inadvertently; (b) had their plasma sodium levels corrected by greater then 25 mmol/l in 48 h; (c) suffered a hypoxic event, or (d) had severe liver disease [48]. Some data has suggested that azotemia may decrease the risk of developing cerebral demyelination [81]. It has also been demonstrated that if there is an overcorrection of hypernatremia that a therapeutic re-lowering can ameliorate the symptoms of cerebral demyelination [82]. Cerebral demyelination can be asymptomatic or can manifest in confusion, quadriplegia, pseudobulbar palsy, and a pseudocoma with a ‘locked-in stare’ [83]. When symptoms of cerebral demyelination occur following an overcorrection of hypernatremia it is typically a delayed phenomena that is best diagnosed on MRI approximately 14 days following correction [16, 84, 85]. The lesions of cerebral demyelination can be pontine or extrapontine. The lesions typically develop many days after the correction of hyponatremia, but can be seen in the absence of any sodium abnormalities [86]. In fact, the primary cause of brain damage in patients with hyponatremia is not cerebral demyelination, but cerebral edema and herniation [16, 19, 27, 45, 48]. Most brain damage occurs in untreated patients and is not a consequence of therapy.

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Serum Na ⬎145mEq/l Evaluate for contributing factors

Water losses

Renal

Insensible

Gastrointestinal

Central DI Nephrogenic DI Diuretics Tubulopathy Recovering acute renal failure Hyperglycemia High solute feeds Mannitol

Fever High ambient temperature Exercise Burns Respiratory illness

Gastroenteritis Osmotic diarrhea Lactulose Charcoal-sorbitol Colostomy/ileostomy Malabsorption Vomiting

Decreased fluid intake

Excess sodium administration

Neurologic impairment Hypothalamic disorder Restricted access to fluids Fluid restriction Ineffective breast feeding

Hypertonic NaCl NaHCO3 Normal saline, blood products High solute feeding Sodium ingestion Sodium polysterene Improper dialysis solution

Fig. 2. Diagnostic approach to hypernatremia.

Hypernatremia

Hypernatremia is defined as a serum sodium greater than 145 mEq/l. In both children and adults hypernatremia is primarily seen in the hospital setting occurring in individuals that have restricted access to water for a variety of reasons [87–89]. In most instances these patients are either debilitated by an acute or chronic illness or neurologic impairment, or are at the extremes of age. Hypernatremia is a particularly common problem in the intensive care unit as most patients are either intubated or moribund and have restricted access to fluids [90]. Additional contributing factors for hypernatremia in the intensive care setting are excess sodium administration, renal concentrating defects, gastrointestinal fluid losses and dialysis related complications (fig. 2). Unlike mild chronic hyponatremia, which may be physiologic in certain edematous diseases, a serum sodium greater than 145 mmol/l should always be considered abnormal and evaluated thoroughly in order to prevent the development of significant hypernatremia.

Pathogenesis

The body has two defenses to protect against developing hypernatremia: the ability to produce a concentrated urine and a powerful thirst mechanism. ADH release occurs when the plasma osmolality exceeds 275–280 mosm/kg and results in a maximally concentrated urine when the plasma osmolality

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exceeds 290–295 mosm/kg. Thirst is the body’s second line of defense, but provides the ultimate protection against hypernatremia. If the thirst mechanism is intact and there is unrestricted access to free water, it is rare for someone to develop sustained hypernatremia from either excess sodium ingestion or a renal concentrating defect.

Diagnosis

Hypernatremia is usually multifactorial and a systematic approach is required to determine the contributing factors (fig. 2). A serum sodium, glucose, and osmolality must be evaluated. An elevated serum sodium is always associated with hyperosmolality, and should be considered abnormal. In cases of significant hyperglycemia, the serum sodium will be depressed due to the associated translocation of fluids from the intracellular to extracellular space. Once the diagnosis of hypernatremia is established, a detailed history and review of fluid intake should be taken to determine if the patient has an intact thirst mechanism, has restricted access to fluids, or is not being provided adequate free water in intravenous fluids. Urine volume should be measured and compared to fluid intake, and the urine osmolality and electrolytes should be determined to assess if the renal concentrating ability is appropriate and to quantify the urinary free water losses. A less than maximally concentrated urine (less than 800 mosm/kg) in the face of hypernatremia is a sign of a renal concentrating defect, as hypernatremia is a maximal stimulus for ADH release. In patients with hypernatremia the following should be evaluated: gastrointestinal losses, dermal losses from fever or burns, diet history (including tube feedings), medication history (including diuretics) and sources of exogenous sodium.

Clinical Manifestations of Hypernatremia

Hypernatremia results in an efflux of fluid from the intracellular space to the extracellular space to maintain osmotic equilibrium. This leads to transient cerebral dehydration with cell shrinkage. Brain cell volume can decrease by as much as 10–15% acutely, but then quickly adapts [91]. Within one hour the brain significantly increases its intracellular content of sodium and potassium, amino acids and unmeasured organic substances called idiogenic osmoles. Within one week the brain regains approximately 98% of its water content. If severe hypernatremia develops acutely, the brain may not be able to increase its intracellular solute sufficiently to preserve its volume, and the resulting cellular shrinkage can cause structural changes. Cerebral dehydration from

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hypernatremia can result in a physical separation of the brain from the meninges leading to a rupture of the delicate bridging veins and intracranial or intracerebral hemorrhages [92, 93]. Venous sinus thrombosis leading to infarction can also develop [94]. Acute hypernatremia has also been shown to cause cerebral demyelinating lesions in both animals and humans [91, 95–97]. Patients with hepatic encephalopathy are at the highest risk for developing demyelinating lesions [98]. Children with hypernatremia are usually agitated and irritable but can progress to lethargy, listlessness and coma [99]. On neurologic examination they frequently have increased tone, nuchal rigidity and brisk reflexes. Myoclonus, asterixis and chorea can be present; tonic-clonic and absence seizures have been described. Hyperglycemia is a particularly common consequence of hypernatremia in children. Severe hypernatremia can also result in rhabdomyolysis [100]. While earlier reports showed that hypocalcemia was associated with hypernatremia, this has not been found in more recent literature [89]. In adults hypernatremia primarily manifests as central nervous system depression [88]. Adults with hypernatremia are rarely alert and most have confusion with abnormal speech and obtundation with stupor or coma. The degree of central nervous system depression appears to correlate with the severity of hypernatremia.

Mortality

The mortality associated with hypernatremia is high in both children and adults. Hypernatremia is associated with a mortality rate of 15% in children; this rate is estimated to be 15 times higher than the age-matched mortality in hospitalized children without hypernatremia [89]. The high mortality is unexplained. Most of the deaths are not directly related to central nervous system pathology and appear to be independent of the severity of hypernatremia. Recent studies have noted that patients who develop hypernatremia following hospitalization and patients with a delay in treatment have the highest mortality [89, 101, 102]. Approximately 40% of the deaths in children occurred while patients were still hypernatremic. The mortality in adults is between 40 and 70%, much higher than in age-matched hospitalized patients [87, 88, 102]. It is not clear how hypernatremia contributes to mortality in adults, but it does not appear to be affected by age or the severity of hypernatremia. The main predictive factors of death in adults with hypernatremia are the duration of hypernatremia and degree of neurologic impairment [88, 102]. A subset of patients that have a particularly high morbidity and mortality are those with end-stage liver disease [98, 103]. Patients with hepatic encephalopathy

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frequently have hypernatremia from an osmotic diarrhea from the oral administration of lactulose to treat hyperammonemia. The mortality in patients with hepatic encephalopathy due to lactulose induced hypernatremia is between 40 and 80% [103, 104]. Patients with liver disease who develop hypernatremia are also at high risk for developing cerebral demyelination [76, 95].

Treatment

The goal of therapy for hypernatremia is to both correct the serum sodium and simultaneously maintain a normal circulatory volume. The cornerstone in the management of hypernatremia is providing adequate free water to correct the serum sodium. The method of correction largely depends on the etiology of the hypernatremia and the renal concentrating ability. In cases of hypernatremic dehydration, the free water deficit can not be assessed by physical examination as the majority of the water losses are primarily intracellular. Signs of volume depletion are less pronounced in patients with hypernatremia due to better preservation of the extracellular volume [25]. A simple way of estimating the minimum amount of fluid necessary to correct the serum sodium is by the following equation: Free water deficit (ml) ⫽ 4 ml F lean body weight (kg) ⫻ [desired change in serum Na mEq/l].

Larger amounts of fluid will be required depending on the fluid composition. To correct a 3-liter free water deficit, approximately 4 liters of 0.2% sodium chloride in water or 6 liters of 0.45% sodium chloride in water would be required, as they contain approximately 75 and 50% free water, respectively. The calculated deficit does not account for insensible losses or ongoing urinary or gastrointestinal losses. Maintenance fluids, which include replacement of urine volume with hypotonic fluids, are given in addition to the deficit. Glucose-containing fluids should be limited as they can result in significant hyperglycemia [105, 106]. If there are signs of circulatory collapse, fluid resuscitation with normal saline or colloid should be instituted before correcting the free water deficit. Oral hydration should be instituted as soon as it can be safely tolerated. Plasma electrolytes should be checked every two hours until the patient is neurologically stable. The rate of correction of hypernatremia is largely dependent on the severity of the hypernatremia and the etiology. Due to the brain’s relative inability to extrude unmeasured organic substances called idiogenic osmoles, rapid correction of hypernatremia can lead to cerebral edema [91]. While there are no definitive studies that document the optimal rate of correction that can be undertaken

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without developing cerebral edema, empirical data have shown that unless symptoms of hypernatremic encephalopathy are present, a rate of correction not exceeding 1 mEq/h or 15 mEq/24 h is reasonable [107–109]. In severe hypernatremia (⬎170 mEq/l) serum sodium should not be corrected to below 150 mEq/l in the first 48–72 h [108]. Seizures occurring during the correction of hypernatremia are not uncommon in children, and may be a sign of cerebral edema [110–112]. They can usually be managed by slowing the rate of correction or by giving hypertonic saline to increase the serum sodium a few milliequivilents. The seizures are usually self-limited and not a sign of long-term neurologic sequelae [107, 108]. Patients with acute hypernatremia, corrected by the oral route, can tolerate a more rapid rate of correction with a much lower incidence of seizures [110, 113]. The type of therapy is largely dependent on the etiology of the hypernatremia and should be tailored to the pathophysiologic events involved in each patient. Certain forms of therapy for hypernatremia require special mention.

Central Diabetes insipidus

Central diabetes insipidus (CDI) is an important cause of hypernatremia in the intensive care setting which must be recognized early as it requires specific therapy [114]. CDI results from inadequate AVP secretion. CDI in the intensive care setting typically presents with abrupt polyuria with a free water diuresis. Severe hypernatremia can develop in an individual who has restricted access to fluids and is receiving sodium containing parenteral fluids. Common causes of CDI in the intensive care setting include brain tumors, pituitary surgery, central nervous system infections, deceleration injury, head trauma, and cerebral hemorrhages or infarcts. Because patient with CDI can conserve sodium appropriately, they typically do not manifest signs of volume depletion. A urine osmolality which is not maximally concentrated in the presence of hypernatremia suggests a renal concentrating defect. In CDI the urine osmolality is typically less than the plasma osmolalilty. The simplest way to distinguish CDI from nephrogenic DI is to administer desmopressin (dDAVP) a V2 receptor agonist. In CDI there will typically be a greater than 50% increase in urine osmolality in response to dDAVP. The administration of dDAVP either subcutaneously or intranasally is the preferred treatment for this condition.

Hypernatremia in the Edematous Patient

While hypernatremia is usually associated with volume depletion, an increasing number of patients in the intensive care setting have hypernatremia

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with edema [115]. This typically occurs in patients with either multisystem organ failure or edema forming conditions such as congestive heart failure, cirrhosis or acute renal insufficiency. These patients initially present with a normal serum sodium and become increasingly edematous following the administration of large amounts of volume in the form of saline, colloid, or blood products to restore circulatory volume. Hypernatremia then develops if the patient has either urinary or gastrointestinal free water losses in combination with fluid restriction and ongoing saline administration. The free water diuresis is usually due to loop diuretics, renal insufficiency, an osmotic diuresis or tubular dysfunction from medications. Gastrointestinal free water losses are usually from lactulose administration. This clinically scenario must be recognized early as the hypernatremia can be prevented if sodium is removed from all continuous infusions including parenteral nutrition and sufficient free in the form of 5% dextrose in water is administered to maintain a normal serum sodium. It may not be possible to correct hypernatremia in the edematous patient with free water alone if there is severe renal insufficiency or marked fluid overload leading to congestive heart failure or pulmonary congestion. In this situation, dialytic therapy may be required to correct both fluid overload and hypernatremia.

Dialytic Therapies in the Hypernatremic Patient

When hypernatremia can not be adequately managed with free water supplementation alone, dialysis may be required [116–118]. This would be the case in severe renal failure, fluid overload and possibly salt poisoning. Dialytic therapies provide an option to correct both fluid and electrolyte disorders simultaneously. Different dialytic therapies can be used and each has unique issues that must be considered. Peritoneal Dialysis Peritoneal dialysis is frequently employed in small children where hemodialysis access is difficult or when hemodialysis or hemofiltration therapies are unavailable or contraindicated. Peritoneal dialysis with standard dianeal solution, sodium concentration 132 mEq/l, will not result in a correction of hypernatremia unless free water is administered to the patient [119]. Peritoneal dialysated ultrafiltrate is hypotonic in relation to the patient’s serum sodium, and will result in worsening hypernatremia if the patient is fluid restricted or receiving isotonic fluids. In order to achieve sodium removal in excess of free water removal, a modified dialysate solution must be prepared by the pharmacy which (1) has a reduced sodium concentration in order to allow

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the diffusion of sodium across peritoneal membrane, and (2) has an increased dextrose concentration, compared to commercial dialysate solution, in order to maintain a hypertonic solution that will allow ultrafiltration [118]. Hemodialysis Hemodialysis has been successfully used in the management of hypernatremia in adults and is available in all modern hospital settings [116, 117]. Hemodialysis allows the correction of serum sodium in two ways (1) dialytic clearance of serum sodium, and (2) by allowing ultrafiltration during dialysis to replace with free water following dialysis. Before dialyzing a patient with hypernatremia, there must be an estimation of how rapid the serum sodium will fall during dialysis as rapid correction of hypernatremia can result in cerebral edema. The fall in serum sodium can be estimated for the KT/V for the dialysis treatment assuming the K is equal to the blood flow. For example, a dialysis treatment with a KT/V of 1.2 will result in a 66% reduction between the patient’s serum sodium and the sodium concentration of the dialysate bath. In severe hypernatremia both dialysis prescription and dialysate sodium concentration may have to be modified to prevent a rapid fall in serum sodium. Continuous Venovenous Hemofiltration Continuous venovenous hemofiltration is the preferred dialytic therapy for a patient with hypernatremia and fluid overload. It allows for both a slow correction of the hypernatremia and fluid removal can be adjusted as needed to best suite the patient. When correcting hypernatremia it is best to set the replacement fluid sodium concentration at 140 mEq/l and adjust the replacement fluid rate for an appropriate fall in serum sodium. If the serum sodium is failing to correct, free water can be administered to the patient without having to change the replacement fluid composition.

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Ayus JC, Arieff AI: Noncardiogenic pulmonary edema in marathon runners. Ann Intern Med 2000;133(12):1011. Nzerue C, Baffoe-Bonnie H, Dail C: Predictors of mortality with severe hyponatremia. J Am Soc Nephrol 2002;13:A0728. Fontes RB, Aguiar PH, Zanetti MV, Andrade F, Mandel M, Teixeira MJ: Acute neurogenic pulmonary edema: Case reports and literature review. J Neurosurg Anesthesiol 2003;15(2):144–150. McClellan MD, Dauber IM, Weil JV: Elevated intracranial pressure increases pulmonary vascular permeability to protein. J Appl Physiol 1989;67(3):1185–1191. Maron MB: Pulmonary vasoconstriction in a canine model of neurogenic pulmonary edema. J Appl Physiol 1990;68(3):912–918. McManus ML, Churchwell KB, Strange K: Regulation of cell volume in health and disease. N Engl J Med 1995;333(19):1260–1266. Vajda Z, Pedersen M, Doczi T, Sulyok E, Stodkilde-Jorgensen H, Frokiaer J, Nielsen S: Effects of centrally administered arginine vasopressin and atrial natriuretic peptide on the development of brain edema in hyponatremic rats. Neurosurgery 2001;49(3):697–704; discussion 704–695. Doczi T, Laszlo FA, Szerdahelyi P, Joo F: Involvement of vasopressin in brain edema formation: Further evidence obtained from the Brattleboro diabetes insipidus rat with experimental subarachnoid hemorrhage. Neurosurgery 1984;14(4):436–441. Ayus JC, Arieff AI: Pathogenesis and prevention of hyponatremic encephalopathy. Endocrinol Metab Clins N Am 1993;22(2):425–446. Arieff AI, Kozniewska E, Roberts TP, Vexler ZS, Ayus JC, Kucharczyk J: Age, gender, and vasopressin affect survival and brain adaptation in rats with metabolic encephalopathy. Am J Physiol 1995;268:R1143–R1152. Sgouros S, Goldin JH, Hockley AD, Wake MJ, Natarajan K: Intracranial volume change in childhood. J Neurosurg 1999;91(4):610–616. Xenos C, Sgouros S, Natarajan K: Ventricular volume change in childhood. J Neurosurg 2002; 97(3):584–590. Courchesne E, Chisum HJ, Townsend J, Cowles A, Covington J, Egaas B, Harwood M, Hinds S, Press GA: Normal brain development and aging: Quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology 2000;216(3):672–682. Takeda S, Matsuzawa T: Age-related brain atrophy: A study with computed tomography. J Gerontol 1985;40(2):159–163. Ayus JC, Arieff AI: Chronic hyponatremic encephalopathy in postmenopausal women: Association of therapies with morbidity and mortality. JAMA 1999;281(24):2299–2304. Fraser CL, Swanson RA: Female sex hormones inhibit volume regulation in rat brain astrocyte culture. Am J Physiol 1994;267:C909–C914. Vexler ZS, Ayus JC, Roberts TP, Fraser CL, Kucharczyk J, Arieff AI: Hypoxic and ischemic hypoxia exacerbate brain injury associated with metabolic encephalopathy in laboratory animals. J Clin Invest 1994;93(1):256–264. Ayus JC, Krothapalli RK, Arieff AI: Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med 1987;317(19):1190–1195. Ayus JC, Levine R, Arieff AI: Fatal dysnatraemia caused by elective colonoscopy. BMJ 2003; 326(7385):382–384. Cohen CD, Keuneke C, Schiemann U, Schroppel B, Siegert S, Rascher W, Gross M, Schlondorff D: Hyponatraemia as a complication of colonoscopy. Lancet 2001;357(9252):282–283. Holden R, Jackson MA: Near-fatal hyponatraemic coma due to vasopressin over-secretion after ‘ecstasy’ (3,4-MDMA). Lancet 1996;347(9007):1052. Sonnenblick M, Friedlander Y, Rosin AJ: Diuretic-induced severe hyponatremia: Review and analysis of 129 reported patients. Chest 1993;103(2):601–606. Abramow M, Cogan E: Clinical aspects and pathophysiology of diuretic-induced hyponatremia. Adv Nephrol Necker Hosp 1984;13:1–28. Clark BA, Shannon RP, Rosa RM, Epstein FH: Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol 1994;5(4):1106–1111. Bartter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967;42:790–806.

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72 73

74 75 76 77 78 79 80 81

Zerbe R, Stropes L, Robertson G: Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 1980;31:315–327. Cooke CR, Turin MD, Walker WG: The syndrome of inappropriate antidiuretic hormone secretion (SIADH): Pathophysiologic mechanisms in solute and volume regulation. Medicine (Baltimore) 1979;58(3):240–251. Hantman D, Rossier B, Zohlman R, Schrier R: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: An alternative treatment to hypertonic saline. Ann Intern Med 1973;78(6):870–875. Perks WH, Walters EH, Tams IP, Prowse K: Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone. Thorax 1979;34(3):324–327. Saito T, Ishikawa S, Abe K, Kamoi K, Yamada K, Shimizu K, Saruta T, Yoshida S: Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Clin Endocrinol Metab 1997;82(4):1054–1057. Wijdicks EF, Vermeulen M, ten Haaf JA, Hijdra A, Bakker WH, van Gijn J: Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm. Ann Neurol 1985;18(2):211–216. Sivakumar V, Rajshekhar V, Chandy MJ: Management of neurosurgical patients with hyponatremia and natriuresis. Neurosurgery 1994;34(2):269–274; discussion 274. Harrigan MR: Cerebral salt wasting syndrome. Crit Care Clin 2001;17(1):125–138. Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med 1998;339(5):321–328. Rabinstein AA, Wijdicks EF: Hyponatremia in critically ill neurological patients. Neurology 2003; 9(6):290–300. Ishikawa SE, Saito T, Kaneko K, Okada K, Kuzuya T: Hyponatremia responsive to fludrocortisone acetate in elderly patients after head injury. Ann Intern Med 1987;106(2):187–191. Gowrishankar M, Lin SH, Mallie JP, Oh MS, Halperin ML: Acute hyponatremia in the perioperative period: Insights into its pathophysiology and recommendations for management. Clin Nephrol 1998;50(6):352–360. Gross P: Treatment of severe hyponatremia. Kidney Int 2001;60(6):2417–2427. Lauriat SM, Berl T: The hyponatremic patient: Practical focus on therapy. J Am Soc Nephrol 1997;8(10):1599–1607. Sarnaik AP, Meert K, Hackbarth R, Fleischmann L: Management of hyponatremic seizures in children with hypertonic saline: A safe and effective strategy. Crit Care Med 1991;19(6):758–762. Soupart A, Decaux G: Therapeutic recommendations for management of severe hyponatremia: Current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 1996;46(3):149–169. Verbalis JG: Adaptation to acute and chronic hyponatremia: Implications for symptomatology, diagnosis, and therapy. Semin Nephrol 1998;18(1):3–19. Hantman D, Rossier B, Zohlman R, Schrier R: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: An alternative treatment to hypertonic saline. Ann Intern Med 1973;78(6):870–875. Fraser CL, Arieff AI: Epidemiology, pathophysiology, and management of hyponatremic encephalopathy. Am J Med 1997;102(1):67–77. Worthley LI, Thomas PD: Treatment of hyponatraemic seizures with intravenous 29.2% saline. Br Med J (Clin Res Ed) 1986;292(6514):168–170. Norenberg MD, Leslie KO, Robertson AS: Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol 1982;11(2):128–135. Kleinschmidt-DeMasters BK, Norenberg MD: Rapid correction of hyponatremia causes demyelination: Relation to central pontine myelinolysis. Science 1981;211(4486):1068–1070. Sterns RH: Treating hyponatremia: Why haste makes waste. South Med J 1994;87(12):1283–1287. Ayus JC, Krothapalli RK, Armstrong DL: Rapid correction of severe hyponatremia in the rat: Histopathological changes in the brain. Am J Physiol 1985;248(5 Pt 2):F711–F719. Ayus JC, Krothapalli RK, Armstrong DL, Norton HJ: Symptomatic hyponatremia in rats: Effect of treatment on mortality and brain lesions. Am J Physiol 1989;257(1 Pt 2):F18–F22. Soupart A, Penninckx R, Stenuit A, Decaux G: Azotemia (48 h) decreases the risk of brain damage in rats after correction of chronic hyponatremia. Brain Res 2000;852(1):167–172.

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82 Soupart A, Ngassa M, Decaux G: Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 1999;51(6):383–386. 83 Wright DG, Laureno R, Victor M: Pontine and extrapontine myelinolysis. Brain 1979;102(2): 361–385. 84 Brunner JE, Redmond JM, Haggar AM, Kruger DF, Elias SB: Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: A prospective magnetic resonance imaging study. Ann Neurol 1990;27(1):61–66. 85 Kumar SR, Mone AP, Gray LC, Troost BT: Central pontine myelinolysis: Delayed changes on neuroimaging. J Neuroimaging 2000;10(3):169–172. 86 Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin IM: Central and extrapontine myelinolysis in a patient in spite of a careful correction of hyponatremia. Clin Nephrol 2001;55(3):248–253. 87 Palevsky PM, Bhagrath R, Greenberg A: Hypernatremia in hospitalized patients. Ann Intern Med 1996;124(2):197–203. 88 Snyder NA, Feigal DW, Arieff AI: Hypernatremia in elderly patients. A heterogeneous, morbid, and iatrogenic entity. Ann Intern Med 1987;107(3):309–319. 89 Moritz ML, Ayus JC: The changing pattern of hypernatremia in hospitalized children. Pediatrics 1999;104(3 Pt 1):435–439. 90 Polderman KH, Schreuder WO, Strack van Schijndel RJ, Thijs LG: Hypernatremia in the intensive care unit: An indicator of quality of care? Crit Care Med 1999;27(6):1105–1108. 91 Ayus JC, Armstrong DL, Arieff AI: Effects of hypernatraemia in the central nervous system and its therapy in rats and rabbits. J Physiol 1996;492(Pt 1):243–255. 92 Finberg L, Luttrell C, Redd H: Pathogenesis of lesions in the nervous system in hypernatremic states. II. Experimental studies of gross anatomic changes and alterations of chemical composition of the tissues. Pediatrics 1959;23(1 Pt 1):46–53. 93 Luttrell CN, Finberg L: Hemorrhagic encephalopathy induced by hypernatremia. I. Clinical, laboratory, and pathological observations. AMA Arch Neurol Psychiatry 1959;81(4):424–432. 94 Grant PJ, Tate GM, Hughes JR, Davies JA, Prentice CR: Does hypernatraemia promote thrombosis? Thromb Res 1985;40(3):393–399. 95 Clark WR: Diffuse demyelinating lesions of the brain after the rapid development of hypernatremia. West J Med 1992;157(5):571–573. 96 Brown WD, Caruso JM: Extrapontine myelinolysis with involvement of the hippocampus in three children with severe hypernatremia. J Child Neurol 1999;14(7):428–433. 97 Soupart A, Penninckx R, Namias B, Stenuit A, Perier O, Decaux G: Brain myelinolysis following hypernatremia in rats. J Neuropathol Exp Neurol 1996;55(1):106–113. 98 Fraser CL, Arieff AI: Hepatic encephalopathy. N Engl J Med 1985;313(14):865–873. 99 FINBERG L: Pathogenesis of lesions in the nervous system in hypernatremic states. I. Clinical observations of infants. Pediatrics 1959;23(1 Pt 1):40–45. 100 Abramovici MI, Singhal PC, Trachtman H: Hypernatremia and rhabdomyolysis. J Med 1992; 23(1):17–28. 101 Moritz ML: Hypernatremia in hospitalized patients. Ann Intern Med 1996;125(10):860. 102 Mandal AK, Saklayen MG, Hillman NM, Markert RJ: Predictive factors for high mortality in hypernatremic patients. Am J Emerg Med 1997;15(2):130–132. 103 Warren SE, Mitas JA, 2nd., Swerdlin AH: Hypernatremia in hepatic failure. JAMA 1980;243(12): 1257–1260. 104 Nelson DC, McGrew WR Jr, Hoyumpa AM Jr: Hypernatremia and lactulose therapy. JAMA 1983; 249(10):1295–1298. 105 Mandell F, Fellers FX: Hyperglycemia in hypernatremic dehydration. Clin Pediatr (Philad) 1974;13(4):367–369. 106 Stevenson RE, Bowyer FP: Hyperglycemia with hyperosmolal dehydration in nondiabetic infants. J Pediatr 1970;77(5):818–823. 107 Banister A, Matin-Siddiqi SA, Hatcher GW: Treatment of hypernatraemic dehydration in infancy. Arch Dis Child 1975;50(3):179–186. 108 Rosenfeld W, deRomana GL, Kleinman R, Finberg L: Improving the clinical management of hypernatremic dehydration: Observations from a study of 67 infants with this disorder. Clin Pediatr (Philad) 1977;16(5):411–417.

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109 Pizarro D, Posada G, Levine MM: Hypernatremic diarrheal dehydration treated with "slow " (12-hour) oral rehydration therapy: A preliminary report. J Pediatr 1984;104(2):316–319. 110 Hogan GR, Pickering LK, Dodge PR, Shepard JB, Master S: Incidence of seizures that follow rehydration of hypernatremic rabbits with intravenous glucose or fructose solutions. Exp Neurol 1985;87(2):249–259. 111 Hogan GR, Dodge PR, Gill SR, Pickering LK, Master S: The incidence of seizures after rehydration of hypernatremic rabbits with intravenous or ad libitum oral fluids. Pediatr Res 1984;18(4): 340–345. 112 Hogan GR, Dodge PR, Gill SR, Master S, Sotos JF: Pathogenesis of seizures occurring during restoration of plasma tonicity to normal in animals previously chronically hypernatremic. Pediatrics 1969;43(1):54–64. 113 Pizarro D, Posada G, Villavicencio N, Mohs E, Levine MM: Oral rehydration in hypernatremic and hyponatremic diarrheal dehydration. Am J Dis Child 1983;137(8):730–734. 114 Verbalis JG: Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab 2003;17(4):471–503. 115 Kahn T: Hypernatremia with edema. Arch Intern Med 1999;159(1):93–98. 116 Pazmino PA, Pazmino BP: Treatment of acute hypernatremia with hemodialysis. Am J Nephrol 1993;13(4):260–265. 117 Chai J, Diao L, Sheng Z, Guo Z, Gao W, Jia X: Heparin-free hemodialysis in the treatment of hypernatremia in severely burned patients. Burns 2000;26(7):634–637. 118 Moritz ML, del Rio M, Crooke GA, Singer LP: Acute peritoneal dialysis as both cause and treatment of hypernatremia in an infant. Pediatr Nephrol 2001;16(9):697–700. 119 Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during hypertonic peritoneal dialysis: Physiologic mechanisms and clinical implications. Ann Intern Med 1969;70(5):931–941.

Juan C. Ayus, MD 1967 Haddon St., 3705 Fifth Ave, Houston, TX 77019–5762 (USA) Tel. ⫹1 713 942 8434, Fax ⫹1 713 942 9342, E-Mail [email protected]

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Pharmacological Issues in ARF and Sepsis Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 158–165

Rasburicase Therapy in Acute Hyperuricemic Renal Dysfunction Claudio Roncoa, Rinaldo Bellomob, Paola Inguaggiatoc, Monica Bonelloa, Valeria Bordonia, Gabriella Salvatoria, Vincenzo D’Intinia, Ranistha Ratanarata a

Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy; Department of Intensive Care Austin & Repatriation Medical Center, Heidelberg Victoria, Melbourne, Australia; cDepartment of Nephrology, S. Croce-Carle Hospital, Cuneo, Italy b

Among the different causes of acute renal failure (ARF) in the hospitalized patient, cancer may represent an important factor leading to kidney dysfunction. The underlying pathological condition generated by a neoplastic disorder, depends very much on the type of cancer: Solid tumors involving the kidney may cause Acute renal failure by obstruction, parenchymal disruption and vascular thrombosis; solid tumors (not of hematological origin) not primarily involving the kidney may cause ARF especially in the context of the tumor lysis syndrome (primary or secondary to therapy) [1]. Among these we may list solid tumors, small cell lung cancer, metastatic breast cancer, metastatic medulloblastoma, metastatic seminoma, ovarian cancer and hepatoblastoma [2]. Finally, hematological disorders such as high-grade non-H lymphoma, acute lymphoid leukemia, acute myeloid leukemia and chronic myeloid leukemia in the blastic phase, may cause ARF especially during hemolytic crisis, and tumor lysis syndrome (TLS) [3]. Paraproteinemia might represent another important disorder leading to renal dysfunction during multiple myeloma [4]. The mechanisms by which renal parenchyma can be damaged include hemodynamic changes and the presence of circulating toxins. The additional presence of obstruction or compression may further contribute to the syndrome. Whatever is the primary cause of the renal insult, a final common pathway leading to ARF includes intrarenal vasoconstriction and medullary ischemia, tubular obstruction, decreased glomerular filtration and back-leak of ultrafiltrate in the interstitial space. Several other mechanisms may take part in the process

of renal damage including loss of cellular polarity, loss of tight junction gate function, loss of cell substrate adhesion, exfoliation of viable cell from tubular basement membrane, aberrant cell-cell adhesion. Finally, the presence of altered gene expression and the process of cellular dedifferentiation lead to lethal cell injury with the two mechanisms of necrosis and apoptosis [5]. The mechanisms of cell necrosis in ARF are a severe depletion of ATP stores, a reduced activity of membrane transport, cell swelling, increase in intracellular free calcium, and activation of phospholipases and proteases. Apoptosis may also be enhanced in ARF due to the increased concentration of physiologic activators, the loss of renal growth factors, the impaired cell matrix adhesion and the loss of cell-cell adhesion. The presence of cytotoxic agents such as reactive oxygen species, intracellular free calcium, pharmacological agents and chemotherapy or the effect of physical factors such as hyperthermia or irradiation, may further contribute to enhance the cellular apoptotic patterns.

Uric Acid: A New Toxin?

The presence of a neoplastic disorder and associated acute illness may sometimes lead to the presence of immunodysfunction, septic complications and multiple organ dysfunction. In these settings the patient becomes critically ill and the clinical picture is sustained by a series of circulating biochemical mediators of inflammation and endothelial damage. Among these substances, in cancer patients there is a high chance of high circulating levels of uric acid [6]. Hyperuricemia is a potentially serious complication in patients with neoplasms characterized by rapid cell proliferation and destruction. Hyperuricemia is caused by the increased purine metabolism due to the enhanced catabolism of nucleic acid, result of the increased cellular turnover (primary TLS), or by the aggressive cancer chemotherapy regimens, that worsen cell lysis and release of purine metabolites (secondary TLS). Hyperuricemia may lead to acute renal failure through different mechanisms (fig. 1). Mechanical obstruction of the tubular lumen due to precipitation of urate crystals is one mechanism. A direct toxicity on renal tubular cells has also been postulated: this may be caused by a direct endothelial damage mediated by nitric oxide, an increased local oxidant stress on renal tissue and finally by abnormal platelet activation. Finally, the potential effect of high level of uric acid on local and systemic inflammation is another emerging pathway: Uric acid levels correlate with cytokine levels, they stimulate the synthesis of monocyte chemoattractant protein 1 (MCP1) and they stimulate the activation of monocytes with increased production of tumor necrosis factor and interleukin-1␤ (table 1).

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n

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Me Uric acid A new pathogenetic factor in ARF

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Fig. 1. Uric acid is involved in acute renal damage with three different mechanisms: mechanical obstruction of the tubular lumen, direct toxicity on renal cells, and induction of inflammation response. Table 1. Uric acid – A new pathogenetic factor in ARF

• •

•

Tubular obstruction (precipitation of urate crystals) Tissue damage – Endothelial dysfunction (NO mediated) – Oxidant stress and cell dysruption – Platelet activation Acute inflammation – Correlates with circulating cytokines – Stimulates synthesis of MCP1 (monocyte chemoattractant protein 1) – Stimulates monocyte production of IL-1␤ and TNF-␣

Moreover, uric acid is able to prevent the inactivation of superoxide dismutase by hydrogen peroxide that contributes to oxidant stress in vivo; high uric acid levels dramatically increase the vascular homeostasis of superoxide dismutase [7].

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Paradoxically, uric acid has also been reported to increase oxidative damage, to enhance platelet adhesiveness and to stimulate vascular smooth muscle cell growth [8]. In vitro, uric acid is effective in scavenging free radicals and can chelate transition metal ions. It has been also hypothesized that uric acid might be an evolutionary antioxidant substitute for the loss of the ability to synthesize ascorbate. Hence, the overall functional importance of urate in vivo remains unknown.

Rationale for Rasburicase Therapy

The leading cause of acute hyperuricemic states is the TLS. In this setting and in other hyperuricemic disorders, the precipitation of urate crystals in the tubular lumen may cause obstruction while the precipitation in the interstitial tissue may cause inflammation and edema. Often these disorders are accompanied by disorders of phosphate metabolism with formation of calcium phosphate and its precipitation in the renal tissue. All these events may contribute to an acute renal dysfunction. Even in the absence of a hyperuricemic state as a primary insult to the kidney, the development of such disorder, might represent a concomitant factor aggravating other previous or simultaneous insults. For this reason, all efforts should be made to protect the kidney for multiple insults and thus to prevent hyperuricemic states [9]. The strategy includes the identification of a patient at risk, the actuation of preventive measures and finally the implementation of a therapeutic plan in the early phases of the syndrome. Among the first, we count fluid resuscitation and maintenance of blood volume and pressure. This ensures the perfusion of the kidney even in the presence of a loss of autoregulation. In the second step, the maintenance of a urine flow is important to reduce the chance of obstruction and tubular damage. In spite of their satisfactory results in animal models, most renoprotective drugs do not appear to be efficacious in human clinical conditions. In the final group of preventive-therapeutic measures, we can hypothesize the utilization of drugs lowering uric acid concentration. In the therapy of hyperuricemic states and renal failure, allopurinol has been used but unfortunately it does not degrade the uric acid already present, it blocks production of new uric acid but it also causes the accumulation of xanthine and hypoxanthine, potentially toxic substances, it inhibits the degradation of the chemotherapeutic agents 6-mercaptopurine and azathioprine, increasing their chemotoxicity and finally it may worsen renal failure. Urate oxidase is the enzyme that oxidizes uric acid in allantoin, i.e. five to ten times more soluble than uric acid. Such enzyme is not present in humans

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Purine pathway Purine catabolism

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HN

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Fig. 2. Urate oxidase is the enzyme that oxidizes uric acid in allantoin, i.e. five to ten times more soluble than uric acid. Instead, allopurinol inhibits xanthine oxidase which catalyzes the conversion of xanthine in uric acid.

and other primates. It has been extracted from Aspergillus flavus in 1968, and commercialized in France since 1975 and in Italy since 1984 as Uricozyme®. This molecule reduces uric acid plasma concentration more effectively than allopurinol and it corrects renal dysfunction more rapidly than allopurinol; however, being non-recombinant it is associated with acute hypersensitivity reactions (urticaria, bronchospasm and/or hypoxemia occur in 5% of patients, even without any history of allergy) and has a production process with a low yield [10]. Rasburicase is the recombinant form of urate oxidase. The recombinant version has been obtained from a modified Saccharomyces cerevisiae and recently commercialized as Fasturtec®. It is well tolerated at a dose of 0.2 mg/kg/day i.v. (T1/2 of 21.2 ⫾ 12 h). Rasburicase has been shown to decrease uric acid from 9.7 to 1.0 mg/dl after one injection. It presents less allergic reactions than Uricozyme® but nevertheless, caution in patients with a history of severe allergies

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• Analysis of uric acid concentrations showed that the rate of decline in uric acid increases with increased dose of rasburicase (0.05mg/kg to 0.20mg/kg)

0

• At 2h after the start of infusion, linear regression of percentage change from baseline was statistically significant (p⫽ 0.0001)

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Fig. 3. Urate oxidase has a dose-dependent mechanism of action. At 2 h after the administration of 0.2 mg/kg of rasburicase, the reduction rate of uric acid was 80% from baseline.

Rasburicase

Allopurinol

1.5

Phosphorus 10 8

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Fig. 4. Urate oxidase is more efficient than allopurinol in reducing uric acid plasma levels. Moreover, urate oxidase does not induce hyperphosphoremia and is associated with ameliorated renal function in the first 5 days after the start of treatment.

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is suggested. There is no need of urine alkalinization. The molecule should be avoided in pregnancy and G6PDH deficiency syndromes [11]. In figure 2, the mechanism of action of urate oxidase and the structure of the molecule is depicted. Rasburicase has been shown to reduce the levels of uric acid much faster than allopurinol and it seems to have a uricolytic effect correlated with the dose (fig. 3). The drug tested in children with malignancies resulted 6 times more efficient than allopurinol [9, 12]. Allantoin excretion increases in parallel with the reduction of uric acid concentration. The amount of allantoin excreted in urine is a direct measure of the removal of both the plasma uric acid present before chemotherapy as well as the removal of any additional uric acid produced by chemotherapy-induced TLS. The drug appears to be beneficial as well in preventing an increase in concentration of uric acid. Furthermore, it has been shown to present an effect on creatinine levels as compared to allopurinol (fig. 4).

Conclusion

The presence of elevated concentrations of uric acid seems to represent an additional risk factor in acute renal failure or in the case of initial renal dysfunction. The early treatment of hyperuricemic states appears to be beneficial on renal function and we might hypothesize that such approach may represent an important protective measure for the kidney. Further studies should elucidate the mechanisms involved in this setting and should clarify the clinical rationale for this type of therapy.

References 1 2 3 4 5 6

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Rao GN, Corson MA, Berk BC: Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J Biol Chem 1991;266:8604–8608. Cairo MS: Prevention and treatment of hyperuricemia in hematological malignancies. Clin Lymphoma 2002;3(suppl 1):S26–S31. Mahmoud HH, Leverger G, Patte C, Harvey E, Lascombes F: Advances in the management of malignancy-associated hyperuricemia. Br J Cancer 1998;77(suppl 4):18–20. Pui CH, Relling MV, Lascombes F, Harrison PL, Struxiano A, Mondesir JM, Ribeiro RC, Sandlund JT, Rivera JK, Evans WE, Mahmoud HH: Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia 1997;11:1813–1816. Wolf G, Hegewisch-Becker S, Hossfeld DK, Stahl RA: Hyperuricemia and renal insufficiency associated with malignant disease: Urate oxidase as an efficient therapy? Am J Kidney Dis 1999; 34:E20.

Claudio Ronco, MD Department of Nephrology, St. Bortolo Hospital Viale Rodolfi, IT–36100 Vicenza (Italy) Tel. ⫹39 0444993869, Fax ⫹39 0444993949, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 166–181

Diuretics in Acute Renal Failure? Miet Schetz Department of Intensive Care Medicine, University Hospital Gasthuisberg, Leuven, Belgium

Oliguria is generally recognized as a bad prognostic sign in patients with acute renal failure (ARF) [1–4]. The temptation to increase urine output in patients with or at risk for ARF is therefore great. A survey by the European Workgroup of Cardiothoracic Intensivists reported that 11 of 38 centers employed furosemide continuously for ‘renoprotection’ and 34 used furosemide bolus injections when diuresis decreased [5]. In a recent observational study in the US, 59% of the patients with ARF received diuretics at the time of nephrology consultation [6] and in a large international epidemiological study 70% of the patients received diuretics before the start of renal replacement therapy [Bellomo et al., unpubl. data]. Despite this ubiquitous use, it is not clear whether loop diuretics beneficially affect renal function in ARF. This chapter provides evidence for the opposite being nearer to the truth.

Loop Diuretics in ARF: Experimental Evidence

Perfusion of an isolated rat kidney with furosemide in a hypoxic solution results in decreased damage to the medullary thick ascending limb of the loop of Henle (mTAL segment) and the S3 segment of the proximal tubule [7]. The effects of furosemide in experimental models of toxic tubular necrosis are somewhat controversial. In glycerol-induced [8], uranyl-nitrite-induced [9] as well as in myoglobin-induced ARF [10], no effect of furosemide on renal function could be established although some studies find an increase of urine output. Other investigators, however, found either a protective effect in HgCl2-induced ARF [11, 12], or a deleterious effect in glycerol-induced [10, 13, 14] or gentamicin-induced [15] ARF. Uffermann et al. [16] showed that the deleterious effect of furosemide in HgCl2-induced ARF could be prevented by the

replacement of urinary sodium losses. In experimental models of ischemic ARF no effect [17–19], renoprotection [15, 20–26] or even deleterious effects [11, 27] have been found. In contrast nephropathy a protective effect of pretreatment with furosemide has also been established [28]. On the other hand, furosemide appeared not to be able to prevent the endotoxin-induced decrease of renal blood flow (RBF) in dogs [29]. In these experimental models furosemide is mostly administered before or immediately after the toxic or ischemic insult.

Loop Diuretics in ARF: Clinical Evidence

In healthy volunteers most authors observed an increase of glomerular filtration rate (GFR) with furosemide, although this is not a consistent finding [30–32]. Several studies evaluated the effect of prophylactic administration of loop diuretics in patients at risk of ARF (table 1). In an uncontrolled observation in ICU patients, Lukas did not observe changes in GFR, RBF or RBF distribution. However 9% of the patients developed hypotension [33]. More recent trials with better design investigated the prophylactic use of loop diuretics in the setting of radiocontrast examination and in the perioperative setting. Weinstein prospectively randomized 18 patients with chronic renal insufficiency undergoing contrast examination: the control group received fluid administration alone and the study group a combination of furosemide and fluids. He found more deterioration of renal function in the furosemide group, which is not unexpected in view of a more pronounced negative fluid balance [34]. Another well-designed clinical trial randomized 78 patients with chronic renal insufficiency requiring cardiac angiography in three groups: the control group received 0.45% NaCl at a rate of l ml/kg/h starting 12 before and continued until 12 h after the contrast administration, whereas the two treatment groups received a similar fluid regimen combined with either 80 mg furosemide or 25 g mannitol, respectively, 30 and 60 min before the contrast administration. Despite comparable changes in body weight, the increase of serum creatinine and the incidence of ARF, defined as an increase of serum creatinine of at least 0.5 mg/dl, were significantly higher in the furosemide group. Mannitol also did not show a protective effect [35]. A prospective, randomized, controlled trial studied 100 patients with serum creatinine exceeding 1.8 mg/dl undergoing coronary angiography. The control group received placebo combined with fluid therapy at a rate of 150 ml/h. The other patients received a combination of fluids, furosemide 1 mg/kg and dopamine, with addition of mannitol if the left filling pressure appeared to be lower than 20 mm Hg. After the procedure the urinary losses of all patients were compensated with intravenous fluid administration. Despite a higher urine output, the administration of diuretics appeared to have no effect on the incidence

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Table 1. Clinical trials on the prophylactic use of loop diuretics in ARF Author

n

Setting

Design

Outcome parameter

Mortality

Lukas [33]

54

ICU patients

uncontrolled

no effect on GFR, RBF 9% hypotension

NR

Weinstein [34]

34

radiocontrast CRI

PRC Fluid Fluid ⫹ F

increase of Screat 2 ␮mol/l 37 ␮mol/l*

body weight ⫹1.3 ⫺0.7

NR

Solomon [35]

105

radiocontrast CRI

PRC saline saline ⫹ F saline ⫹ M

increase of Screat 0.1 mg/dl 0.5 mg/dl* 0.3 mg/dl

body weight ⫺0.49 ⫺0.78 ⫺0.23

no effect

Stevens [36]

66

radiocontrast CRI

PRPC saline ⫹ placebo saline ⫹ F ⫹ M⫹D

increase of Screat 0.51 mg/dl 0.56 mg/dl

fluid I/O 1.3 0.91

no effect

Lassnigg [5]

104

cardiac surgery nl RF

PRPC placebo F D

increase of Screat 0.14 mg/dl 0.40 mg/dl* 0.22 mg/dl

no effect

PRC ⫽ Prospective randomized controlled; PRPC ⫽ prospective randomized placebo-controlled; CRI ⫽ chronic renal insufficiency; RF ⫽ renal function; UO ⫽ urine output; F ⫽ furosemide; M ⫽ mannitol; D ⫽ dopamine; GFR ⫽ glomerular filtration rate; RBF ⫽ renal blood flow; Screat ⫽ serum creatinine; NR ⫽ not reported. *p ⬍ 0.05.

of renal insufficiency or the requirement for dialysis [36]. Lassnigg et al. [5] performed a placebo-controlled double-blind randomized trial on the effect of dopamine and furosemide in 126 patients with normal preoperative renal function undergoing cardiac surgery. Furosemide administration was started at a rate of 0.5 ␮g/kg/min at induction (or 2.5 mg/h for an 80-kg patient) and continued until 48 h postoperatively. Patients in the furosemide group had a significantly higher urine output but this appeared to be at the cost of a more pronounced postoperative increase of serum creatinine. A reduction of preload was not deemed responsible for this finding since the increased urine output was compensated with fluid administration and the groups did not differ with regard to blood pressure or filling pressures [5]. In summary, clinical trials on the prophylactic use of loop diuretics in patients at risk for ARF do not suggest a beneficial effect on renal function and even provide some evidence for a deleterious effect.

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Two older prospective randomized trials demonstrate a beneficial effect of furosemide on urinary output in patients with established oliguric ARF. However, a beneficial effect on renal function, the need for renal replacement therapy or mortality was not found [37, 38]. Such effects are only mentioned in retrospective or uncontrolled trials [39–41]. A more recent prospective, double-blind, placebo-controlled randomized trial investigated the effect of furosemide in 92 patients with established oliguric ARF, excluding patients with pre- and postrenal failure. The study group received furosemide at a dose of 3 mg/kg every 6 h (during 21 days or until recovery of renal function or death), combined with 100 ml mannitol 20% every 6 h and low-dose dopamine in continuous infusion. The diuretic regimen resulted in a significant increase of urine output, however without effect on the recovery of renal function, the need for dialysis or survival. 48% of the patients in the furosemide group increased their urine output versus 23% in the placebo group. These non-oliguric patients (that appeared to be less severely ill than the oliguric group) had a better survival, however without difference between the diuretic and placebo group [42]. In 121 patients undergoing major thoraco-abdominal or vascular surgery furosemide 1 mg/h appeared to have no effect on the postoperative decrease of creatinine clearance, nor on the mortality or the length of stay in the ICU. This low dose of furosemide even did not increase urine output, but was associated with significantly more hypokalemia [43]. Cotter et al. [44] randomized 20 patients with congestive heart failure in three groups: a combination of dopamine with furosemide 80 mg/day (group A) or 5 mg/kg/day (group B) or a high dose furosemide (10 mg/kg/day) alone (group C). Despite a similar urine output and decrease of body weight, creatinine clearance deteriorated significantly in group B and C, an effect that the authors attributed to a decreased blood pressure. The incidence of hypokalemia was also significantly higher in the groups receiving larger doses of furosemide. Sirivella et al. [45] compared the effect of a combined infusion of dopamine, furosemide and mannitol with intermittent administration of diuretics in 100 patients that ‘despite an adequate cardiac output’ developed oliguric renal failure after cardiac surgery. The combined infusion resulted in a significantly higher diuresis, an improved time course of serum creatinine and a significantly decreased need for dialysis. The beneficial effect appeared to be most pronounced when the infusion was started within 6 h after the start of oliguria. The doses of intermittent diuretics were rather high (1.5–3 mg/kg furosemide every 4–6 h) and no data are provided on the actually administered doses. A recent retrospective survey in 326 intensive care patients with ARF requiring nephrology consultation concluded that the use of diuretics at the time of consultation was associated with an increased risk of death and nonrecovery of renal function. The increased risk was borne largely by patients who were relatively unresponsive to diuretics [6]. However, analysis of a prospectively

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derived international database of patients requiring renal replacement therapy for ARF, could not confirm these findings [Bellomo, unpubl. data]. In conclusion, although most clinical studies report an increase of urine output, the evidence for a beneficial effect of loop diuretics on renal function is limited. Patients responding to loop diuretics with an increased urine output are probably characterized by a less severe form of renal failure, rather than representing a beneficial effect of the treatment. Some clinical studies even point to a deleterious effect of loop diuretics on renal function. On the other hand it should be acknowledged that none of the available studies has enough statistical power. This is also the conclusion of two recent meta-analyses [46, 47].

Pathophysiology of ARF

In order to understand the effect of loop diuretics on renal function, a short reminder of the pathophysiology of renal hypoperfusion is required. The normal blood supply to the kidney is very heterogeneous with approximately 90% entering the cortex and 10% the medulla. These regional differences are related to the flow-dependent functions of the cortex (glomerular filtration and tubular reabsorption), whereas the function of the medulla, that consists in concentrating the urine, requires a limited blood supply to prevent the washout of the interstitial osmotic gradient. In addition, the active tubular transport that is required to generate this gradient requires a high O2 consumption. The heterogeneous perfusion explains why, despite the large global blood supply, the kidney is very susceptible to hypoperfusion and why ischemic damage is mainly found in the tubular segments that are located in the outer medulla: the pars recta of the proximal tubulus (S3 segment) and the medullary thick ascending limb of the loop of Henle (mTAL) [48, 49]. The regulation of RBF is very complex and depends on the balance between vasoconstricting (the sympathoadrenal axis, the renin-angiotensin aldosteron system (RAAS) and arginine vasopressin) and vasodilator influences (vasodilating prostaglandins, mainly PGI2 and PGE2, atrial natriuretic peptide, kinins and nitric oxide (NO)) [50]. Both sympathetic stimulation and angiotensin II preferentially cause vasoconstriction in the cortex [51, 52] redistributing the blood flow to the deeper salt-retaining nephrons and the vulnerable medulla. A decreased RBF with corticomedullary redistribution has also been observed in sepsis [53]. A second mechanism controlling RBF and GFR is renal autoregulation, involving both myogenic autoregulation and the tubuloglomerular feedback (TGF) [50]. The TGF finetunes RBF and GFR by eliciting afferent vasoconstriction in response to an increased sodium chloride delivery at the macula

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densa in the distal tubule, whereas decreased NaCl delivery decreases the afferent tone. The apical membrane receptor(s) involved in this sensing mechanism have not been completely elucidated, but both the Na⫹-K⫹-2Cl– cotransporter (NK2CC) and the K-channel ROMK are unequivocally implicated. Experimental evidence suggests that adenosine is the mediator of the vasoconstrictive response via an adenosine-1 receptor (A1AR). The magnitude of the TGF response depends on the ambient level of angiotensin II. A second component of the juxtaglomerular apparatus is the macula densa control of renin secretion, with a decreased distal tubular solute delivery stimulating renin secretion. COX-2 mediated synthesis of prostaglandin E2 appears to be the underlying mechanism of this increased renin release [54, 55]. As well the extrinsic systems, causing corticomedullary redistribution of blood flow by cortical vasoconstriction with or without medullary vasodilation, as the TGF can be seen as protective mechanisms against excessive loss of salt and water or, by diminishing the filtered solute load, as a tool to prevent nephron oxygen deficiency [56, 57]. With mild renal hypoperfusion, GFR can be maintained by compensatory mechanisms, consisting of afferent vasodilation (mainly mediated by prostaglandins, NO and the myogenic and TGF component of autoregulation) and efferent vasoconstriction (mediated by angiotensin II) [58]. Prerenal failure, characterized by a decreased GFR with preserved tubular function, results when these compensatory mechanisms fail. Adaptive mechanisms to avoid medullary hypoxia and ischemic tubular damage in prerenal failure are paracrine vasodilatory mediators, such as adenosine (via adenosine-2 receptor), prostaglandins and NO, that dilate medullary vessels and decrease solute reabsorption and the associated O2 consumption [59]. The previously mentioned corticomedullary redistribution of RBF not only increases blood supply to the vulnerable medullary tubular segments but also decreases GFR. This reduces solute delivery, decreases medullary work and restores the balance between O2 delivery and consumption [48, 60]. Prerenal failure has therefore been called ‘acute renal success’ because the reduction of glomerular filtration prevents further damage to the vulnerable medullary tubular segments [56]. With ongoing renal hypoperfusion ischemic damage of tubular cells or acute tubular necrosis (ATN) ensues. Both vascular and tubular factors contribute to the further decrease of GFR in ATN [61, 62]. Vascular factors are a persisting renal vasoconstriction, a decrease of the permeability of the glomerular capillaries and medullary congestion. Tubular factors are tubular obstruction by cellular debris and backleak of glomerular filtrate. The TGF is thought to play an important role in the vascular pathogenesis of ATN: damage to more proximal tubular segments increases the NaCl load to the macula densa causing afferent vasoconstriction [62–64].

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Rationale for Administering Loop Diuretics in ARF

Theoretically, there are several reasons to expect a beneficial effect of loop diuretics on renal function in ARF: (1) The diuretic effect increases tubular flow with a flushing effect preventing tubular obstruction [26]. Since the swollen obstructed tubuli can hamper venous outflow from the medulla, prevention of tubular obstruction might also improve RBF [66]. (2) Loop diuretics may increase RBF by two mechanisms: induction of cyclooxygenases (COX) with increased production of vasodilating prostaglandins [22, 30, 66–69] and interruption of the TGF by inhibition of the NK2CC that initiates the signaling at the macula densa [70–73]. (3) The inhibition of NK2CC by loop diuretics reduces active sodium transport. The associated reduction of O2 consumption may prevent ischemic damage of the vulnerable medullary tubulus segments [7, 60, 74]. In an animal model of ARF characterized by severe medullary hypoxia, pretreatment with furosemide prevented renal ATP depletion [75]. (4) Apoptosis has been shown to play an important role in the pathophysiology of ARF [76]. Recent evidence suggests that COX-2 expression inhibits TNF-induced apoptosis in renal mesangial cells [77]. Since loop diuretics induce COX-2 expression, they might also prevent apoptosis.

How to Explain the Absence of a Beneficial Effect?

Several explanations can be put forward to explain the absence of a protective effect of diuretics on renal function in ARF. (1) Excessive preload reduction activating both the RAAS and the adrenergic system will result in renal vasoconstriction. Replacement of the urinary losses has been shown to prevent furosemide-induced decreases in GFR [78, 79]. In addition to the urinary losses, prostaglandin-mediated venodilation also contributes to a decreased preload [80, 81]. Maintenance of an adequate preload is therefore of utmost importance when administering loop diuretics in an attempt to prevent ARF. The optimal method to establish an ‘adequate preload’ remains, however, a matter of debate [82–87]. This makes it difficult to verify a comparable filling status in patient assigned to different treatment arms of randomized trials. (2) Loop diuretics do not improve RBF, or at least not under any circumstances. Although some (mostly older) animal studies find an increase of RBF after the administration of loop diuretics [20, 88–91], other experimental observations suggest the opposite [79, 92–97]. The use of different methods to

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measure RBF, differences in animal species, in the administered doses of loop diuretics and in the experimental conditions may have contributed to these contradictory results. Greven et al. [98] found and increase of RBF in control animals and a decrease in glycerol-treated rats. Burke et al. [99] found that furosemide only increases RBF when the renal perfusion pressure is above the lower limit of autoregulation and suggested that at lower perfusion pressures renal vascular resistance is already close to a minimum value. Furosemide also does not seem to affect the LPS-induced decline of RBF in anesthetized dogs [29]. In an animal model of ischemic ARF, the protective effect of furosemide was not influenced by a COX-inhibitor, questioning the role of vasodilatory prostaglandins in this setting [22]. A similar observation was made with regard to the bumetanide-induced increase of RBF in the isolated perfused rat kidney [91]. Most human studies measure RBF by PAH clearance, which is probably not a valid method in critical illness and ARF [100]. In healthy volunteers, furosemide increases RBF [30, 67, 101], an effect that can be suppressed by COX inhibitors [30]. However, no change is noted in critically ill patients [33, 102, 103] and a decrease is seen in patients with congestive heart failure [104]. This might be related to the inability of prostaglandins to counteract strong vasoconstrictive effects. Loop diuretics indeed may provoke vasoconstriction by stimulating renin release and angiotensin II formation [101, 105–107], an effect that is secondary to a decreased renal perfusion pressure and preload reduction resulting in adrenergic stimulation. Loop diuretics also have a direct effect at the macula densa where they diminish the NaCl transport-dependent renin-inhibitory signal to the granular cells, probably involving COX-2 dependent prostanoids [55, 108, 109]. It is interesting to note that in conscious animals a furosemide-induced renal vasoconstriction or decrease of renal perfusion was not noted after the administration of an angiotensin-converting enzyme inhibitor (ACEI) [79, 94, 96], pointing to a role for angiotensin II as a mediator of renal vasoconstriction during furosemide infusion. In addition, furosemide has been shown to stimulate the release of the thromboxane [68]. Loop diuretics inhibit the TGF, which might indeed be protective in patients who, as a result of ischemic damage to the proximal tubulus, have a high solute load at the macula densa. However, very high tubular concentrations of furosemide have been shown to be necessary for complete inhibition of the TGF [110]. On the other hand, in patients with prerenal failure, the same TGF might be protective against further ischemic damage of the vulnerable medullary segments. In conclusion, the final effect of loop diuretics on RBF is the resultant of several partially opposite effects. Added to the already disturbed balance between

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intrarenal vasodilator and vasoconstrictor substances, induced by the underlying pathology, it is not surprising that the net effect of loop diuretics on RBC is difficult to predict in patients. (3) The absence of a beneficial effect of loop diuretics on renal function could also be explained by an adverse effect on intrarenal blood flow distribution. This intrarenal distribution is even more difficult to measure than total RBF. Using laser Doppler flowmetry, which is probably the most reliable method, Dobrowolski et al. [112] confirmed the results of earlier investigations [74, 88, 90, 111], and demonstrated a more pronounced decrease of medullary compared with cortical blood flow after furosemide administration [112, 113]. The furosemide-induced decrease in medullary blood flow can be attenuated by saline loading, an ACEI [113] or an AT(1) receptor antagonist [104], again pointing to a role of the RAAS in the medullary vasoconstriction. Castrop et al. [114] showed that furosemide, though increasing COXs expression in the cortex, decreased medullary COXs mRNA. The differential effect of furosemide on cortical and medullary blood flow might endanger the medullary O2 balance and shift a prerenal failure to an acute tubular necrosis. (4) Furosemide adversely affects autoregulation. Already in 1977, it was shown that furosemide, by inhibiting the TGF, abolishes autoregulation of renal blood flow [115], a finding that has subsequently been confirmed [97, 116–118]. The increased lower limit of autoregulation might explain why the prophylactic use of furosemide can have a deleterious effect [5]. (5) It is possible that tubular obstruction is not prevented or remedied because the induced diuresis only relies on a decreased reabsorption in nonobstructed tubuli. An increased tubular aggregation of Tamm-Horsfall proteins has even been described with loop diuretics [119].

Toxicity of Loop Diuretics

Loop diuretics may be associated with toxicity, including ototoxicity [120, 121], interstitial nephritis, dermatological symptoms and arrhythmias due to furosemide-induced hypokalemia [42, 44]. An even more important disadvantage of the use of loop diuretics is, however, the loss of important diagnostic parameters due to furosemide-induced diuresis and natriuresis. Not only the urinary indices, that allow to distinguish between prerenal and renal failure, become unreliable but also the urine output as parameter of cardiac output and tissue perfusion is lost. The loop diuretic-induced increase of diuresis often induces a feeling of therapeutic success and further measures to improve renal perfusion and prevent renal dysfunction are omitted.

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Table 2. Clinical trials on the therapeutic use of loop diuretics in ARF Author

n

Setting

Design

Outcome parameter

Outcome parameter

Mortality

Kleinknecht [37]

66

established ARF

58

Shilliday [42]

92

posttrauma postsurgery ARF oliguric ARF

n dialysis 20 22 (NS) n dialysis 12 10 (NS) dialysis 40% 31% (p0.87)

Hager [43]

121

Cotter [44]

20

congestive heart failure

Sirivella [45]

100

cardiac surgery postoperative ARF

duration oliguria 17d 17d (p ⬎ 0.2) increased UO 6% 86% (p ⬍ 0.005) increased UO 23% 48% (p0.02) decrease of ClCr 19% 17% (NS) Change of Clcreat ⫹3 ml/min ⫺25 ml/min ⫺17 ml/min (p0.007) dialysis 90% 6.7% (p?)

NR

Brown [38]

PR F boluses controls PR F bolus F bolus ⫹ 3 g/24 h PRPC Fluid Fluid ⫹ F PRPC Placebo F PRC D ⫹ low dose F D ⫹ medium dose F High dose F PR intermittent F infusion of D⫹F⫹M

postoperative major surgery

57% 64% (NS) 50% 66% (NS) 5% 9% (NS)

PRC ⫽ Prospective randomized controlled; PRPC ⫽ prospective randomized placebo-controlled; CRI ⫽ chronic renal insufficiency; UO ⫽ urine output; F ⫽ furosemide; M ⫽ mannitol; D ⫽ dopamine; GFR ⫽ glomerular filtration rate; RBF ⫽ renal blood flow; ARF ⫽ acute renal failure; n dialysis ⫽ number of patients requiring dialysis; NR ⫽ not reported.

In recent years, it has become evident that continuous administration of loop diuretics results in an improved efficiency with decreased toxicity and should therefore be preferred above bolus administration [122–128]. Conclusion

An increase of urine output is the only irrefutably proven effect of loop diuretics in ARF. This, of course, may have beneficial effects on the cardiorespiratory system, facilitates fluid management of critically ill patients and creates space for adequate nutrition. In addition, the loop-diuretic-induced increase of urinary output yields prognostic information, since it points to a less severe renal insult [129].

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A beneficial effect of loop diuretics on renal function has, however, not been demonstrated, although it should be acknowledged that the available trials do not have adequate statistical power. In established ARF loop diuretics are probably administered too late to be of any help. However, their prophylactic administration in humans has also not been proven protective, presumably because they disturb renal autoregulation and the protective corticomedullary redistribution. It remains to be established whether a restricted temporary gap exists in which loop diuretics might be effective. However, since the majority of the available clinical trials does not show benefit and even suggest harm, a large prospective randomized trial can only be justified if clinically relevant animal models suggest a beneficial effect.

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93 Christensen S, Petersen JS: Effects of furosemide on renal haemodynamics and proximal tubular sodium reabsorption in conscious rats. Br J Pharmacol 1988;95:353–360. 94 Janssen BJ, Eerdmans PH, Smits JF: Mechanisms of renal vasoconstriction following furosemide in conscious rats. Naunyn Schmiedebergs Arch Pharmacol 1994;349:528–537. 95 Tenstad O, Williamson HE: Effect of furosemide on local and zonal glomerular filtration rate in the rat kidney. Acta Physiol Scand 1995;155:99–107. 96 de Wildt SN, Smith FG: Effects of the angiotensin converting enzyme (ACE) inhibitor, captopril, on the cardiovascular, endocrine, and renal responses to furosemide in conscious lambs. Can J Physiol Pharmacol 1997;75:263–270. 97 Pires SL, Julien C, Chapuis B, Sassard J, Barres C: Spontaneous renal blood flow autoregulation curves in conscious sinoaortic baroreceptor-denervated rats. Am J Physiol 2002;282:F51–F58. 98 Greven J, Klein H: Renal effects of furosemide in glycerol induced acute renal failure of the rat. Pflügers Arch 1976;365:81–87. 99 Burke TJ, Duchin KL: Glomerular filtration during furosemide diuresis in the dog. Kidney Int 1979;16:672–680. 100 Murray PT, Le Gall JR, Mranda DDR, Pinsky MR, Tetta C: Physiologic endpoints (efficacy) for acute renal failure studies. Curr Opin Crit Care 2002;8:519–525. 101 MacDonald TM, Craig K, Watson ML: Frusemide, ACE inhibition, renal dopamine and prostaglandins: Acute interactions in normal man. Br J Clin Pharmacol 1989;28:683–694. 102 Epstein M, Schneider NS, Befeler B: Effect of intrarenal furosemide on renal function and intrarenal hemodynamics in acute renal failure. Am J Med 1975;58:510–516. 103 Bradley VE, Shier MR, Lucas CE, Rosenberg IK: Renal hemodynamic response to furosemide in septic and injured patients. Surgery 1976;79:549–554. 104 Chen HH, Redfield MM, Nordstrom LJ, Cataliotti A, Burnett JC Jr: Angiotensin II AT1 receptor antagonism prevents detrimental renal actions of acute diuretic therapy in human heart failure. Am J Physiol 2003;284:F1115–F1159. 105 Meyer P, Menard J, Papnicolaou N, Alexandre J, Devaux C, Milliez P: Mechanism of renin release following furosemide diuresis in rabbit. Am J Physiol 1968;215:908–915. 106 Weber PC, Scherer B, Larsson C: Increase of free arachidonic acid by furosemide in man as the cause of prostaglandin and renin release. Eur J Pharmacol 1977;41:329–333. 107 Lorenz JN, Weihprecht H, Schnermann J, Skott O, Briggs JP: Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport. Am J Physiol 1991;260: 486–493. 108 Kammerl MC, Nüsing RM, Richthammer W, Krämer BK, Kurtz A: Inhibition of COX-2 counteracts the effects of diuretics in rats. Kid Intern 2001;60:1684–1691. 109 Mann B, Hartner A, Jensen BL, Kammerl M, Kramer BK, Kurtz A: Furosemide stimulates macula densa cyclooxygenase-2 expression in rats. Kidney Int 2001;59:62–68. 110 Mason J, Kain H, Welsch J, Schnermann J: The early phase of experimental acute renal failure. VI. The influence of furosemide. Pflügers Arch 1981;392:125–133. 111 Engelman RM, Gouge TH, Smith SJ, Stahl WM, Gombos EA, Boyd AD: The effect of diuretics on renal hemodynamics during cardiopulmonary bypass. J Surg Res 1974;16:268–276. 112 Dobrowolski L, B-dzynska B, Sadowski J: Differential effect of frusemide on renal medullary and cortical blood flow in the anaesthetised rat. Exp Physiol 2000;85:783–789. 113 Dobrowolski L, Badzynska B, Grzelec-Mojzesowicz M, Sadowski J: Renal vascular effects of frusemide in the rat: Influence of salt loading and the role of angiotensin II. Exp Physiol 2001;86: 611–616. 114 Castrop H, Vitzthum H, Schumacher K, Schweda F, Kurtz A: Low tonicity mediates a downregulation of cyclooxygenase-1 expression by furosemide in the rat renal papilla. J Am Soc Nephrol 2002;13:1136–1144. 115 Duchin KL, Peterson LN, Burke TJ: Effect of furosemide on renal autoregulation. Kid Int 1977; 12:379–386. 116 Wittmann U, Nafz B, Ehmke H, Kirchheim HR, Persson PB: Frequency domain of renal autoregulation in the conscious dog. Am J Physiol 1995;269:F317–F322. 117 Just A, Wittmann U, Ehmke H, Kirchheim HR: Autoregulation of renal blood flow in the conscious dog and the contribution of the tubuloglomerular feedback. J Physiol 1998;506:275–290.

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Miet Schetz, MD, PhD Department of Intensive Care Medicine University Hospital Gasthuisberg, Herestraat 49, BE–3000 Leuven (Belgium) Tel. ⫹32 16344021, Fax ⫹32 16344015, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 182–190

How to Manage Vasopressors in Acute Renal Failure and Septic Shock Maurizio Dana, Sandra Rossia, Luca Callegarina, Claudio Roncob Departments of aAnesthesia and Intensive Care, and bNephrology, Ospedale di Vicenza, Vicenza, Italy

Acute renal failure (ARF) occurs frequently in patients with septic shock and carries a marked increase in mortality [1]. Significant oliguria should prompt immediate attention to the adequacy of circulating blood volume and of mean arterial pressure (MAP) before the rising of serum creatinine concentration and the signs of established ARF [2, 3]. Shock is defined as a condition of inadequate supply or utilization of metabolic substrate and oxygen at tissues resulting in functional compromise (lactic acidosis) and eventually cellular damage (necrosis or apoptosis). Septic shock is characterized by peculiar features: hyperdynamic circulatory state with high cardiac output (CO), loss of vasomotor tone and low total peripheral resistance (TPR). The hyperdynamic stage develops after volume expansion, which is the first line therapy for arterial hypotension associated with shock. Without volume expansion septic shock would be characterized by low CO, elevated systemic vascular resistance (SVR), and decreased venous return (VR) due to a combination of increased venous capacitance, splanchnic blood pooling, and effective volume depletion (i.e. increased vascular permeability, fluid sequestration) [4]. To maintain or to increase CO the preload has to be restored and increased above normal values because of a concomitant septic myocardial depression [5, 6]. Despite the high global flow and globally decreased systemic vascular resistance occurring after volume resuscitation, there is a persistent cellular dysoxia. Therefore, it has been concluded that this flow is non-efficient for the metabolizing tissues of the periphery (distributive shock). Indeed focal vasoconstriction occurs in some peripheral vessels, particularly in the mesenteric, pulmonary and renal circulation and part of the blood

flow is shunted to the venous compartment past dysfunctioning and collapsed microcirculatory functional units [7, 8]. To confirm that the relation between global flow and effective regional flow to organ and tissues is not linear, it has been shown that strategies of increasing further CO and the delivery of O2 to the periphery do not improve survival [9]. Blood flow to the periphery is regulated by a complex interplay between autoregulatory control (proportional to local metabolic demand) and global autonomic control, which alter peripheral vasomotor tone to optimize inter-organs blood flow distribution. It is well known that arteriolar vessels of different organs have different sensitivity to sympathetic nerve stimulation and to catecholamines [10, 11]. Autonomic control is intended to preserve flow to tissues most susceptible to ischemia by sacrificing, if needed, tissues with better oxygen extraction capacities. Therefore, there is hierarchy into preserving flow: the brain and the heart are at the top and the kidneys right after. The general rule is that to maintain organ perfusion blood arterial pressure is important: below a ‘critical’ pressure (related to age, diseases and vasculature conditions) the regional autoregulation of flow is not preserved. Another important issue is that microcirculation is a heterogeneous and extremely complex network of vessels with different architecture, different autonomic/metabolic regulation of flow and different rheological and resistive properties related to the different structure and function of organs and tissues. This implies a heterogeneous responsiveness to the circulatory derangement of the shock state. Furthermore, blood flow to an organ is not equivalent to the effective capillary flow in all regions of that organ. Blood flow in the kidney is autoregulated over a wide range of arterial pressure but, out of this range, a steep relation exists between pressure and flow. This means that, out of the autoregulative range, flow drops in the kidney more than in other organs. Given its peculiar vascular architecture, the outer medullary region of the kidney is at higher risk of ischemia than the other parenchyma [12]. Since arterial pressure is the primary factor determining renal blood flow independently from CO, acute hypotension has to be treated without delay. The role of vasopressors to restore adequate mean arterial pressure (MAP) to achieve optimal renal resuscitation and the physiological sound underlying their use will be reviewed in this chapter.

Sepsis-Induced Circulatory Dysfunction

Sepsis induces a self-amplifying cascade of inflammatory cytokines and mediators with vasoactive properties such as nitric oxyde (NO), prostaglandins,

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endothelins, leukotrienes, platelet-activating factor (PAF) [13]. Inducible nitric oxide [iNO] appears to have a central role in the determination of septic vascular dysfunction and the inhibition of its synthesis improves blood pressure and increases the blunted responsiveness to vasopressors [14–16]. This mediator is pivotal to the disregulation of vasomotor tone resulting in distributive shock. After this considerations NO would appear to be the target of a modern resuscitation therapy for septic shock. Unfortunately inhibition of NO sinthasi [NOS] failed to demonstrate normalization of global oxygen extraction and in some studies revealed numerous adverse effects. NO it is not only a mediator induced by inflammation [iNO] but, first of all is a physiologic mediator with two constitutive isoforms [cNO]: the endothelial [eNO], regulating tissue perfusion, and neuronal [nNO], regulating nonadrenergic, non-cholinergic peripheral neurotransmission. It is worth to appreciate that the consequences of the distributive shock in the microcirculation are, as the word says, heterogeneously distributed owing to the following phenomena: adherence of activated polymorphonuclear leukocytes to vascular endothelium, O2 free radical-mediated injury to endothelial cells, thrombotic random obstruction of vessels and increased vascular permeability. Vascular critical closing pressure will be modified in the various organs and also in regions of the same organ. Given the wealth of data regarding the occurrence of endothelial dysfunction in sepsis that induces the concomitant presence of randomly distributed vasoconstriction together with general vasodilatation, the protective role of eNO needs to be taken into great consideration. NO synthesis prevents severe hypoperfusion of pancreas, small and large bowel, while its inhibition might lead to the appearance of patchy dysoxya [17].

An Hydraulic Point of View

The function of the left ventricle is to pump blood to the tissues so that they may be perfused with oxygen and nutrients according to their metabolic needs. Whereas blood flow through the tissues is continuous, or nearly so, the heart’s output is intermittent. Pulsation of pressure and flow are wasteful work and are the consequences of the design limitation of the heart: the left ventricle needs a phase of pause from contraction (diastole) in order to provide its own perfusion through the coronary circulation. The arterial system, that links the heart to the capillary circulation, subserves two functions: the first, as a low resistances circuit, and the second as a cushion to flow pulsation at its input (Windkessel model). Ventriculo-arterial interaction is optimized when the percentage of energy dissipated in pulsatile compared to total external work is 10–20%.

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MSP

PP

MSP MP MP MDP

a

MDP

b

Fig. 1. Diagrammatic representation of the arterial pressure wave contour in abdominal aorta: fluctuations around a mean during systole and diastole in two different conditions: (a) normal fluctuation or optimal cushioning (Windkessel), and (b) increased or non optimal systolic cushioning. PP ⫽ Pulse pressure; MSP ⫽ mean systolic pressure; MDP ⫽ mean diastolic pressure; MP ⫽ mean pressure.

If the pressure and flow in the arterial system are interdependent, the arterial pressure wave must include information regarding flow. From a mechanical point of view, one can usefully think in terms of its mean value and its fluctuation around this mean, rather than in terms of systolic and diastolic pressure. There is a mean pressure during the systolic phase and a mean pressure during diastolic phase and a mean arterial pressure (MAP) summarizing pressure fluctuations during the entire cardiac cycle. When the arterial system works efficiently, like in the normal young human there is small fluctuation around MAP (fig. 1). Surprisingly, MAP decreases very little (1–3 mm Hg) along the entire length of the arterial system from aorta to the most peripheral arterioles, but, at arterial termination, it falls abruptly over a very short distance. This phenomenon is due to the fact that the entire surface area of the post-arteriolar network is much increased compared to that of proximal arteries. The mean pressure at the input of the post-arteriolar network is the pressure necessary to drive blood flow through collapsible vessels. To reverse hypotension we have to restore a global vasomotor tone without inducing harmful vasoconstriction. Accordingly, how and to which extent we increase mean arterial pressure is the real key point rather than what vasopressor we use for this purpose. Our treatment should be targeted to reproduce optimal ventriculo-arterial coupling avoiding large systolic and diastolic fluctuation around the mean because only in this way we can rely on a fair relation between pressure and flow. A further important consideration in using vasopressors is that pressure and flow waveform are not superimposable. An important contribution to determine

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the pressure waveform and the pressure/flow coupling, is the timing and amplitude of wave reflection. This phenomenon must have an important physiologic role in the mammalian arterial system in transforming the intermittent flow of the heart. Wave reflection exists because the arterial system is not composed by long and uniform tubes with a remote end, but rather by vessels with different physical properties and branching at different angles. Architecture (length, branching, diameter), structure (wall, diameter), function (elastic properties, vascular tone) of the arterial system are optimized in normal young adult to increase diastolic pressure. An oscillatory phenomenon such as pressure and flow wave will be repetitively reflected to same extent wherever there is a discontinuity or an impedance mismatch. Looking from the proximal arterial system, from which departs all the vessels for major vital organs, there are many reflecting sites: branching points, areas of alteration of arterial distensibility, and high resistance arterioles. In the mathematical model, the extreme cases are when a tube with pulsatile liquid flow is completely blocked or opens into a large reservoir. In the first condition, we have total positive wave reflection (closed system) in the later we have total negative reflection (open system). In the real arterial system, we are obviously dealing with intermediates conditions. In aged patients with vascular diseases, increased wave reflection occurs in systole rather than in diastole, causing systolic hypertension and decreased ventricular ejection that results in a disproportioned pressure versus volume work (worse ventriculo-arterial coupling). This pathophysiologic process is well described [18]. What happens to the arterial system in the condition of profoundly reduced vasomotor tone (open system condition) is not described so far. Since we know that vasodilators used to treat hypertension modify wave reflection, we may infer that vasoactive mediators causing septic shock will do the same. The product of pressure by flow has dimension of power. While the product of instantaneous pressure by flow is the total hydraulic power transferred from the left ventricle to the systemic circulation, the product of mean pressure by mean flow is the part of this power converted into the steady flow. Steady continuous flow is the one really effective for organ perfusion [19]. The difference between total and steady power represents the pulsatile power, which is the wasteful part of power. As we know that MAP equals CO time TPR and also that CO is normal or increased during sepsis; the only way to restore adequate MAP is to manipulate TPR. The problem is that, looking at the pulsatile circulation, we want to modify the steady circulation. We assume that the MAP we calculate from the waveform analysis by integrating the area under the pulsation is the pressure driving effective flow to the periphery. We should at least take into account that that MAP is the mean between a mean pressure during systole and a mean pressure

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during diastole and that pressure fluctuations around MAP represents how much hydraulic power is wasted rather than converted in efficient flow to the periphery. Cholley et al. [20] suggest that, in the hemodynamic derangement of septic shock, an alteration of the mechanical properties of the large arteries induces a marked increase in percent pulsatile power. Pressure should be monitored more proximally than in the radial artery (this vessel has different reflection phenomenon than the aortic tract from which depart the splanchnic vasculature) and vasopressor therapy should be titrated to obtain the appropriate mean pressure with the smallest systolic and diastolic fluctuation. To match this result adequate preload (stroke volume) is necessary before increasing vasomotor tone with catecholamines.

Vasopressor Therapy for Septic Shock

Optimal hemodynamic treatment in septic shock means to support the cardiovascular function for providing adequate flow to metabolizing tissues. Early reversal of hypotension with the aid of vasopressors is a crucial point for maintaining flow particularly for the most vulnerable organs, brain, heart and kidneys. Vasopressin is an endogenous polypeptide hormone which produces vasoconstriction at a precapillary level. It has been recently proposed for the treatment of unresponsive shock, but, since its harmful effect in the splanchnic vasculature [12, 13], it is not to be considered standard therapy until prospective randomized study will demonstrate a survival advantage. Such a study is currently underway [21]. Although the complex pathophisiology of distributive shock, catecholamines are so far the mainstay treatment. Natural and synthetic catecholamines increase inotropism by beta receptors stimulation and modify vasomotor tone by ␣- and ␤-receptors; since the mechanism of adrenergic stimulation is the same, the difference between them resides exclusively in the degree to witch they stimulate the two kind of receptor. Norepinephrine is an endogenous cathecolamine with powerful vasoconstrictor effect secondary to ␣1-receptor agonism with absence of ␤2-receptor stimulation (␤-vasodilatation). It also has a ␤1-positive inotropic effect. Norepinephrine seems to have the good characteristics to treat the distributive shock. Its action, although qualitatively not different than that of epinephrine on the vasculature (␣1-agonism), is more selective because it is devoid of ␤2 stimulation. Epinephrine is an endogenous cathecolamine with powerful inotropic, chronotropic, vasoconstrictive effect because unselectively stimulates all adrenergic receptors.

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Catecholamines

Septic vasodilatation

Capillary network

Elastic arteries ⇒ muscular arteries ⇒ arterioles

No

Fig. 2. Diagrammatic representation of the sites of action of catecholamines and of the site of septic vasodilatation: the heart on the left, the systemic circulatory system from major elastic arteries to muscular arteries, arterioles and finally capillary network from the left to the right.

Dopamine is an endogenous indirect acting cathecolamine (norepinephrine precursor) which activates also a dopaminergic receptor in the renal and splanchnic vasculature producing selective vasodilatation of these arterial beds. This effect is dominant only at low doses (up to 3 ␮g/kg/min), at increasing doses ␤1 ␤2 (4–10 ␮g/kg/min) and ␣1 (⬎10 ␮g/kg/min) effects predominate. Dobutamine is a synthetic cathecolamine with ␤1 ␤2 agonism, then exerting only inotropic and vasodilator effect. Phenylephrine is a synthetic cathecolamine with selective ␣1 effect and virtually absent ␤-receptor stimulation.

Strategies for Treatment of Septic Shock

Volume expansion must be the first line treatment. Only when and adequate preload has been assured, the use of catecholamines should be considered to restore an appropriate arterial pressure [23]. Although randomized trials are missing, there is general agreement on the use of adrenergic agents. The same agreement is lacking on the choice of one catecholamine versus another. The reasons for this are quite obvious: these agents do not modify directly the pathophysiologic mechanism responsible for the loss of vasomotor tone (fig. 2). We relay on this indirect and simplistic strategy because other therapies directed to NO synthesis regulation, the core of the pathophysiologic process, have not shown to be effective. Catecholamines, although with different modulation, act on the same class of ␣- and/or ␤-receptors. Inappropriate stimulation of these receptors have potential detrimental effects. Major concern has always

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been addressed to the fact that intense ␣ stimulation, such that of norepinephrine, might induce visceral hypoperfusion/ischemia, leading to MODS, loss of gut mucosal integrity and finally worsening of microcirculatory dysfunction. However, recent animal studies showed an increase in renal blood flow when norepinephrine was used to restore blood pressure in a model of canine septic shock [24–26]. Moreover, retrospective studies showed that patients with septic shock had a better response if treated with norepinephrine rather than with other agents [27]. In this complex scenario of loss of vasomotor tone, possible down-regulation of ␣-adrenergic responsiveness and contemporary potential visceral ischemia induced by vasopressors, the key point is not which catecholamine to use but how to titrate its dose and modulate its receptors action. References 1

2 3 4 5 6

7 8 9 10 11 12 13 14 15 16

Brivet FG, Kleinknecht DJ, Loirat P: Acute renal failure in intensive care units: Causes, outcome, and prognostic factors of hospital mortality: A prospective multicenter study. Crit Care Med 1996;24:192–198. Brezis M, Rosen S: Hypoxia of the renal medulla: Its implications for disease. N Engl J Med 1995;332:647–655. Myers BD, Moran SM: Hemodynamically mediated acute renal failure. N Engl J Med 1986; 314:97–105. Parrillo JE: Septic shock in humans: Advances in understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990;113:227–242. Parker MM, Suffredini AF, Natanson C, et al: Response of left ventricular function in survivors and non survivors of septic shock. J Crit Care 1989;4:19–25. Parker MM, McCarthy KE, Ognibene FP, et al: Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterizes the cardiac depression of septic shock in humans. Chest 1990;97:126–132. Ince C, Sinaasappel M: Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 1999;27:1369–1377. Ince C: Microcirculatory weak units: An alternative explanation. Crit Care Med 2000;28: 3128–3129. 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. Daemen MJ, De May JG: Regional heterogeneity of arterial structure changes. Hypertension 1995;25:464–473. O’Rourke MF, Safar ME, Dzau VJ: Arterial Vasodilatation: Mechanism and Therapy. London, Edward Arnold, 1993. Heyman SN, Fuchs S, Brezis M: The role of medullary ischemia in acute renal failure. New Horizons 1995;3:597–607. Bone RC, Grodzin CJ, Balk RA: Sepsis: A new hypothesis for pathogenesis of the disease process. Chest 1997;112:235–243. Landry DW, Lewin HR, Gallant EM, et al: Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997;25:1279–1282. Landry DW, Lewin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122–1125. Murray PT, Wylam ME, Umans JG: Nitric oxide and septic vascular dysfunction. Anesth Analg 2000;90:89–101.

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17 18 19 20 21

22

23 24 25 26 27

Mulder MF, Van Lambalgen AA, Huisman E, et al: Protective role of NO in the regional hemodynamic change during acute endotoxemia in rats. Am J Physiol 1994;266:1558–1564. Nichols WW, O’Rourke MF: McDonald’s Blood Flow in Arteries, ed 4. London, Arnold, 1998, pp 284–293. Nichols WW, O’Rourke MF: McDonald’s Blood Flow in Arteries, ed 4. London, Arnold, 1998, pp 294–295. Cholley B, Lang R, Berger D, et al: Alterations in systemic arterial mechanical properties during septic shock: Role of fluid resuscitation. Am J Physiology 1995;269:H375–H384. Russell JA, Cooper DJ, Walley KR, et al: Vasopressin and septic shock trial (VASST): baseline characteristics and organ dysfunction in vasopressor dependent patients with septic shock. Am J Resp Crit Care Med 2003;167:A548. Bellomo R, Ronco C: The Use of Inotropic and Vasopressor Agents in Patients at Risk of Renal Dysfunction. Critical Care Nephrology. Amsterdam, Kluwer Academic Publishers, 1998, pp 1133–1137. Bellomo R, Kellum JA, Wisniewski SR, et al: Effects of norepinephrine on the renal vasculature in normal and endotoxemic dogs. Am J Resp Crit Care Med 1999;28:2758–2765. Di Giantomasso D, Morimatsu H, May CN, Bellomo R: Intrarenal blood flow distribution in hyperdynamic septic shock: Effect of norepinephrine. Crit Care Med 2003;31:2509–2513. Di Giantomasso D, May CN, Bellomo R: Vital organ blood flow durino hyperdynamic sepsis. Chest 2003;124:1053–1059. Martin C, Viviand X, Leone M, Thirion X: Effect of norepinephine on the outcome of septic shock. Crit Care Med 2000;28:2758–2765. Martin C, Papazian L, Perrin G, et al: Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993;103:1826–1831.

Dr. Maurizio Dan Department of Anesthesia and Intensive Care Medicine Ospedale di Vicenza, Viale Rodolfi 37, IT–36100 Vicenza (Italy) Tel. ⫹39 0444993895, E-Mail [email protected]

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Practical Aspects of CRRT Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 191–202

Management of Vascular Catheters for Acute Renal Replacement Therapy V. D’Intini, M. Bonello, G. Salvatori, C. Ronco Department of Nephrology, Dialysis and Transplantation San Bortolo Hospital, Vicenza, Italy

Central venous catheters (CVC or DLHDC – double lumen hemodialysis catheters) have facilitated the implementation of extracorporeal renal replacement therapy (RRT). The use of CVCs has grown exponentially and now is a fundamental and basic prerequisite in the management of a broad range of both renal and non-renal clinical scenarios. Such catheters have revolutionized clinical practice permitting the application of new therapeutic technologies aiding management of the patient with acute and chronic problems. For acute clinical situations, a CVC is fundamental for immediate vascular access in order to implement RRT. The clinician has at his disposal a wide range of catheters with different characteristics to optimize therapy. Such is their widespread utilization that up to 60% of new patients commencing chronic hemodialysis dialyze through a CVC initially and an overall prevalence of 30% of chronic patients are using a catheter for hemodialysis access [1]. The ideal temporary catheter must be easy and quick to insert, be simple and safe to use for nursing staff, avoid major risks both at the time of insertion and during continued use, avoid long-term damage to central vessels, be made of biocompatible material to prevent thrombosis, and be capable of providing adequate blood flows (100–400 ml/min) with low re-circulation at low hydrostatic pressures. Despite advances in design and material, catheters are associated with significant acute and long term morbidity. Life-threatening complications during catheter insertion such as hemorrhage and pneumothorax, thrombosis, local and systemic infection represent a potential risk for the patient and should be given special attention.

Most catheters used today are inserted by the Seldinger technique into jugular, subclavian and femoral veins. Ultrasound guided localization of the vein is recommended. Standard non-cuffed DLHDCs are generally indicated for temporary access. If a protracted treatment is foreseen, tunnelled cuffed DLHDCs should be utilized for their low infection risk profile.

Characteristics of Catheters

The ultimate DLHDC must be biocompatible, easy to insert and use, be functional and durable, carry a low risk of infection and thrombosis and must be inexpensive [2]. Structurally it should be designed to optimize size, flexibility, strength and compliance. A compromise of maximal luminal diameter for maximal blood flow, with compact dimensions to minimize complications is needed as well as a balance of flexibility and rigidity to maintain lumen patency. DLHDCs can be made from polyethylene, Teflon, silicone, polyurethane and polyurethane/polycarbonate copolymers. Each material has individual characteristics with advantages and disadvantages. Polyethylene is more rigid compared to silicone. Silicone is softer and thus a more flexible material, but more difficult to insert through ligamentous or fibrotic tissues and more prone to early mechanical failure because of lumen compression. However, a major advantage of flexible catheters is that the tip of the catheter may be left in the right atrium without danger of cardiac perforation. Polyurethane is intrinsically strong thus constructed with thin walls, preserving rigidity in the longitudinal axis while avoiding lumen collapse at high negative pressures. It also has thermoplastic properties, becoming softer at body temperature. Finally different materials are subject to chemical disruption by various products which can affect material performance. Alcohols including isopropyl alcohol and ointments containing polyethylene glycol (mupirocin or betadine ointment) can weaken polyurethane catheters considerably. Catheters created from copolymer materials are resistant to such chemicals and may be the principal material used for future DLHDCs.

Insertion Techniques

Insertion techniques have clearly improved contributing to reduced insertion-related complications and increasing catheter function duration. Insertion site (jugular, subclavian and femoral veins) is dictated by the clinical situation. Subclavian cannulation is associated with a high incidence of stenosis and is

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contraindicated if the risk of chronic dialysis is foreseen [3]. Real-time ultrasound guided cannulation is associated with less complications and has been strongly recommended by the DOQI committee on vascular access [4]. Such technology reduces the number of needle passes, failed placements, and insertion-related complications. Inexperienced operators increase their success rate to 95% with the use of ultrasound guidance [5]. Ultrasound imaging is a valuable tool in caring for dialysis patients because about 30% have significant vein abnormalities, such as total occlusion, non-occlusive thrombus, stenosis and anatomic variation [6]. Post-insertion chest X-ray after internal jugular or subclavian insertion confirms the position of the catheter tip in the superior vena cava and allows evaluation for possible pneumothorax and hemothorax. The length of time a catheter should be left in situ remains controversial. The rate of infection for internal jugular non-cuffed catheters suggests that they should be used for no more than 3 weeks [4]. Femoral catheters left in place for 7–14 days did not develop any complication whereas the number of complications rose significantly in patients whom femoral catheters was left in place for over 21 days [7]. Instruction on the technique of insertion of DLHDCs is beyond the scope of this review and can be found in various texts [8].

Catheter Positioning

Based on opinion and DOQI guidelines, fluoroscopy or chest X-ray control of correct catheter position and tip location should be done prior to use. Improper tip placement is a common cause of poor flow. The tip of a semi-rigid catheter should extend to the superior vena cava, 1–2 cm above the right atrium. Shorter catheters may be plagued by excessive re-circulation and longer catheters risk atrial perforation. The optimal length for a right internal jugular catheter is approximately 15 cm. Femoral catheters should be longer in order to reach the inferior vena cava to minimize re-circulation. The optimal orientation of the catheter tip is important for proper function and good flow. Silicone catheters allow higher blood flows when the distal tip is located in the right atrium. Fluoroscopy is required to optimize cuffed tunnelled catheter placement.

Catheter-Related Morbidity

The risk of insertion-related complications varies according to the skill of the operator, site of insertion, and use of imaging equipment such as ultrasound

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Table 1. Central complications

line

insertion

Vascular injuries Hemothorax Hydrothorax Carotid artery puncture Subclavian artery puncture Pneumothorax Air embolism Wire or catheter embolism Arrythmias

and fluoroscopy. Complications can be immediate or delayed. Early dysfunction is usually related to mechanical problems (e.g. inappropriate positioning, or kinking), while late dysfunction (⬎2 weeks) is often caused by thrombotic problems such as partial or total obstructive thrombosis of the catheter lumen, thrombosis or stenosis of the cannulated vein, external sheath formation on the catheter distal end and internal catheter clotting. In the latter case, the partial or complete occlusion of the lumen and distal and/or lateral perforations greatly increase the extracorporeal resistances and reduce the effective blood flow accordingly.

Immediate Complications

Severe immediate complications are almost entirely associated with use of the anatomic landmark technique (blind insertion technique). The success of the landmark guided placement of the catheter assumes normal vascular anatomy, the vein being patent and of normal caliber. The average complications reported in the literature are reported in table 1. These risks are greater in critical care patients because of coexistent coagulopathies, thrombocytopenia, liver disturbances and drug related bleeding problems. With insertion of a femoral catheter, bleeding is usually easily controlled unless severe deep damage to the arterial wall has occurred. Puncture of the femoral artery along its superficial path is rarely associated with more than a small hematoma, but heparin free dialysis is advised for a minimum of 24 h. Severe femoral artery damage or rupture, particularly if deep to the inguinal ligament, may cause uncontrollable hemorrhage into the retroperitoneal space, requiring urgent surgical intervention. Both subclavian and internal jugular vein line insertion have a low risk of uncontrolled arterial bleeding in case of accidental arterial puncture. Visualization of the anatomy, with a hand held ultrasound device, prior to the procedure has further decreased the incidence of arterial puncture, although

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a small risk is still recognized. Hemostasis can usually be obtained by pressure over the puncture site when the carotid artery has been punctured by the finder or introducer needle. If the large bore dialysis catheter has been introduced into the arterial system, the catheter should not be removed until the surgical team is present, as bleeding is less easily controlled once the catheter has been removed. Subclavian artery damage is more difficult to control and is commonly associated with a hemothorax. Urgent exploration by a vascular surgeon with repair of damaged vessel is required. Local bruising is rarely a problem unless the bleeding leads to the formation of a hematoma. This can become secondarily infected or, if the bleeding is arterial, form a false aneurysm. If during subclavian and internal jugular vein catheter insertion the patient complains of shortness of breath the procedure should be stopped and a chest X-ray obtained. Rarer complications include air embolism, damage to the superior vena cava, right common carotid artery fistula, right atrial thrombus, lymphorrhea, pericardial tamponade and arrhythmias occurring as a result of attempted catheterization (the latter is usually precipitated by the guidewire irritating the sino-atrial node or conducting tissues). The use of ultrasound-guided cannulation has resulted in a substantial decrease in procedural complications. Randolph et al., performed a meta-analysis of the literature and concluded that ultrasound guidance decreased central venous catheter placement failure (relative risk (RR) 0.32), decreased complications from catheter placement (RR 0.22), and decreased the necessity of multiple catheter placement attempts (RR 0.60) when compared to landmark cannulation techniques [5]. There exist meta-analyses comparing complications with the internal jugular or the subclavian central venous approach [9]. Six trials (2,010 catheters) found significantly more arterial punctures with jugular catheters compared with subclavian (3.0 vs. 0.5%, RR 4.70). In six trials (1,299 catheters), there were significantly fewer malpositions with the jugular access (5.3 vs. 9.3%, RR 0.66). In ten trials (3,420 catheters), the incidence of hemato- or pneumothorax was 1.3 vs. 1.5%. The authors concluded that there are more arterial punctures but less catheter malpositions with the internal jugular compared with the subclavian access, and that there is no difference in the incidence of hemo- or pneumothorax.

Long-Term Complications

These are more often caused by thrombotic problems such as partial or total obstructive thrombosis of the catheter lumen, thrombosis or stenosis of the cannulated vein, and catheter-related infections.

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Thrombotic Occurrences

The incidence of catheterized vein thrombosis varies from 20 to 70% according to the sites and diagnostic modalities used. Central vein stenosis and thrombosis are more common with a subclavian catheter. Recently, in prospective studies, stenosis/thrombosis was found to complicate up to 28% of subclavian dialysis catheters, and infection further increased the risk [10]. For this reason, subclavian catheters should be avoided if possible particularly if chronic hemodialysis is foreseen. Acute catheters in the jugular vein caused thrombosis/ stenosis in only 2% of cases surveyed with ultrasound in one study [11]. Femoral venous catheterization is associated with a greater risk of thrombotic complication than subclavian catheterization in ICU patients [12]. Several factors contribute to the thrombogenicity on the catheter. Schematically, they are represented by the catheter type (material and composition, flexibility, aspect and surface treatment), insertion mode, host vein (including diameter, local hemodynamics), duration of use, and clotting status of the patient (hyperfibrinogenemia, inflammatory disease, thrombocytosis, previous thrombosis). The prothrombotic risk of a patient may be reduced by administering anticoagulants (e.g. low-molecular-weight heparin) and/or antiplatelet drugs. Most cases of thrombosis can only be attributed to activation of the coagulation cascade by a relatively bioincompatible device. Most catheter flow problems are related to intrinsic thrombosis. Intraluminal thrombus, catheter tip thrombus, and fibrin sheath thrombus are the principal types of intrinsic thrombosis. Intraluminal thrombus usually occurs when an inadequate volume of heparin is instilled into the catheter after dialysis or when heparin escapes from the catheter lumen between dialysis sessions. Blood can enter into the catheter and form an intraluminal thrombus. When this occurs, the catheter may become completely occluded. Urokinase instillation characteristically resolves the thrombosis [4]. Many catheters have side holes at the tip of the arterial limb which does not retain heparin. A tip thrombus may be occlusive or it may act as a valve. Preventive measures that are commonly used to avoid intraluminal thrombosis are largely ineffective because of the presence of the side holes. Urokinase instillation usually resolves this problem. Fibrin sheath thrombus is the most common type of thrombus. The term ‘fibrin sheath’ refers to a sleeve of fibrin that surrounds the catheter starting at the point where it enters the vein. The fibrin sheath is only loosely attached to the catheter. As the sheath extends downward, it eventually closes over the tip of the catheter. It is probable that all central venous catheters become encased in a layer of fibrin within a few days of insertion. The incidence of catheter dysfunction secondary to fibrin sheath has been reported to be 13 to 57% [13].

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Chronic systemic anticoagulation (e.g. warfarin) may be beneficial in preventing this [14].

Prevention of Catheter Thrombosis

Proper flushing and heparinization of the catheter with concentrated heparin following dialysis will serve to decrease but not eliminate the risk of thrombosis. Each side of the hemodialysis catheter has a fill volume inscribed on the clear portion of the catheter just below the cap. This volume is different for both lumens. The venous volume is generally 0.1–0.2 cm3 greater than the arterial volume. However, a 0.1–0.2 cm3 overfill is recommended. Chronic anticoagulation with either warfarin or low-molecular-weight heparin has gained anecdotal support for preventing both lumen thrombus and fibrin sheath formation on hemodialysis catheters [14].

Treatment of Catheter Thrombosis

Thrombosed, non-cuffed catheters can be exchanged over a guide wire or treated with urokinase. Physical methods have been tried to recannulate blocked catheters, from forceful saline flush to brush or drill devices with variable success. Urokinase remains the most effective method successfully dissolving 70–90% of thrombus. Tissue plasminogen activator (tPA) may be superior to urokinase. If catheter exchange still demonstrates catheter dysfunction, a fibrin sheath may be present. This is diagnosed radiologically and can be stripped using a snare catheter. The snare is introduced through the femoral vein and advanced up to the level of the dialysis catheter. The report success of this procedure ranges from 92 to 98%. Fibrin sheath stripping generally results in asymptomatic embolization of the fibrin sheath. Advantages of this technique include a good success rate, safety and preservation of the catheter with a patency duration that is reasonable.

Catheter-Related Infections

Temporary catheters have higher rates of infection than tunnelled dialysis catheters (bacteremia 6.2 vs. 1.8 per 1,000 catheter days and exit site infection 3.6 vs. 1.4 per 1,000 catheter days in not cuffed or tunnelled catheter, respectively). In the intensive care unit, non-tunnelled catheters carry a bacteremia risk estimated between 3 and 10% and increases with duration exponentially at both the femoral and internal jugular site [15].

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The femoral site has a greater risk of infection than the internal jugular site. The instantaneous risk (hazard) of bacteremia at the femoral site increased after 1 week compared with 3 weeks at the internal jugular site. In addition, if an exit site infection occurred and the catheter was left in place, the risk of bacteremia rose from 2% at 24 h from onset of exit site infection to 13% at 48 h. These findings support the NKF-K/DOQI guidelines to limit acute dialysis catheter use in the femoral vein and internal jugular vein to 1 and 3 weeks, respectively, and to remove catheters immediately if an exit site infection occurs. Factors increasing infection risk include skin and nasal colonization with staphylococcus, catheter hub colonization, duration of catheterization, thrombosis, frequency of catheter manipulation, diabetes mellitus, iron overload, immunodeficiency, use of a transparent dressing (promotes skin colonization) and the conditions of catheter placement. Povidone and mupirocin ointments with dry gauze dressings have been shown to significantly reduce the risk of bacteremia from acute dialysis catheters in randomized controlled trials, however increase the risk of fungal infections in immunocompromised patients. Infections can develop at the exit site, within the tunnel with tunnelled catheters and cause catheter related bacteremia (CRB). The therapeutic approach to each of these is different. Exit site infection is defined as localized infection of the skin and soft tissue around the exit site. Erythema, purulent discharge and local tenderness are typically present. Fever and other signs of systemic infection are absent. With a temporary catheter, removal of the catheter is warranted with replacement at an alternate site. With tunnelled dialysis catheters, bacteremia has not been shown to be clearly associated with exit site infection. Most exit-site infections are caused by gram-positive organisms including Staphylococcus aureus and Staphylococcus epidermidis, although other bacteria can be involved. Exit-site infection can usually be treated effectively with oral or intravenous antibiotics. In more severe cases or those that fail to respond to antibiotics, revision of the catheter with creation of a new exit site remote from the infected area may resolve the exit-site infection. If these measures fail, the tunnelled catheter may ultimately need to be removed. Tunnel infections are invasive soft tissue infections that extend along the subcutaneous tunnel toward the vein. These typically involve the cuff and exit site, although in some cases they may appear only in the tunnel proximal to the cuff, with no drainage or communication to the exit site. Tenderness, swelling, and erythema along the catheter tract are typical, with purulent drainage from the exit site. Fever and other signs of systemic infection are often present, and bacteremia may occur. The catheter should be removed and antibiotics given parenterally. Catheter related bacteremia (CRB) from acute catheters should be treated with immediate catheter removal and appropriate antibiotics. The decision to

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remove a tunnelled catheter for suspected CRB must often be made clinically prior to blood culture results and individualized based on the severity of sepsis, co-morbid illnesses, status of permanent arteriovenous access, and alternatives for venous access. S. aureus is the most common organism representing 33–80% of positive cultures. The prevalence of nasal carriage of S. aureus among patients undergoing hemodialysis has ranged from 30 to 60%. Reduction of nasal carriage of S. aureus has resulted in a decrease in yearly bloodstream infections due to S. aureus. The prolonged empirical use of vancomycin should be avoided because of the risk of inducing vancomycin resistant enterococcus. Initial therapy with vancomycin and an aminoglycoside antibiotic (or a ␤-lactam with lactamase inhibitor or a quinolone) until culture results are available is prudent. Rapid conversion to appropriate antibiotics based on culture sensitivities is needed not only to prevent emergence of resistant organisms, but also to avoid ototoxicity. Antibiotic therapy should be continued for a minimum of 3 weeks. Blood cultures should be repeated a week following therapy to ensure that the infection has been eradicated. A major management dilemma is whether to attempt salvage of the tunnelled catheter if sepsis is controlled and alternative access is difficult. Recent reports show only 32–37% are salvageable. If significant symptoms persist beyond 48 hours despite effective antibiotics the tunnelled catheter should be removed [16]. A biofilm surrounding the catheter may predispose the CVC to infection and failure to eradicate it despite appropriate antibiotics. Instillation of concentrated antibiotic solutions into the lumen of silicone vascular catheters (antibiotic lock) in vitro eliminates the biofilm, suggesting a useful clinical application. Studies in tunnelled DLHDCs have suggested that the biofilm can be eradicated by an antibiotic lock solution instilled into the catheter lumen, permitting bacteriologic cure without replacing the catheter [17]. These studies have prompted a recent consensus panel to recommend use of antibiotic locks for clinical management of uncomplicated bacteremia related to tunnelled DLHDCs. However, there are no large, prospective studies assessing the efficacy of this approach in treating hemodialysis patients.

Catheter Performances and Recirculation

Blood flow through the catheter is directly proportional to the pressure generated by the blood pump across the catheter and inversely proportional to resistance in the catheter itself. Modern blood pumps have a limited capacity to generate pressure, and high pressures can be damaging to red cells, so a major goal of catheter design has been to reduce the resistance to flow as much as possible. The resistance to flow is directly related to length and inversely proportional

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to the fourth power of the catheter diameter, thus the manufacturer can modify length and diameter to reduce the pressures. All CVCs must be able to provide optimal dynamics at all blood flow requirements. Various design characteristics are essential to reduce the internal resistance, limit the risk of dysfunction through parietal suction and prevent its obstruction by the (internal or external) formation of a fibrin sleeve. The negative pressure recorded on the arterial side reflects resistance to blood suction. It depends on the blood flow applied, on the degree of venous collapse, blood pressure and on the patient’s intra-vascular fluid status. Negative pressure should not exceed ⫺300 mm Hg to prevent the risk of parietal vascular lesions and/or blood hemolysis. The positive pressure recorded on the venous side reflects resistance to venous return. It depends on the blood flow and the degree of obstruction of the venous catheter. With the catheters in use today, venous pressure approximates one half that of the blood flow displayed (such that for a blood flow rate of 300 ml/min, venous pressure is close 150–175 mm Hg). Thus, any change in arterial and/or venous blood pressures regimen must be indicative of catheter dysfunction that should be followed by suitable corrective actions. Oliver et al., in acute renal insufficiency patients demonstrated that early catheter mechanical dysfunction was more frequently associated with double-lumen catheters (non-tunnelled) in the subclavian vein than with those inserted in other sites [11]. Specific anatomic abnormalities (fibrous band, inter-osseous mobile zone) can create kinking or stricture along the subclavian pathway. Catheter re-circulation can reduce dialysis efficacy. It depends on the site of catheter insertion and blood flow prescribed. Re-circulation is much less important in continuous RRT modalities since lower flows are required. Femoral catheters, particularly short ones, exhibit a high re-circulation rate averaging 20% (5–38%). Internal jugular and subclavian catheters have a much lower re-circulation rate averaging 10% (5–15%). Catheter re-circulation is increased by reversing connecting lines (blood re-circulation rates reach 20–30%), but whether re-circulation in catheters relates to poor cardiac output, valvular insufficiency, use of vasopressor, or other clinical states is not known. An extra 20–30 min of dialysis time was recommended to compensate for the adverse effect of reversing the catheters on solute kinetics. Cardiopulmonary re-circulation is defined as flow of dialyzed blood back through the dialyzer via the central blood circuit (heart and lungs) without equilibration with blood in the rest of the body. Cardiopulmonary re-circulation accounts for much of the rebound in solute concentration following dialysis: approximately 30% of the total rebound of urea and less for other solutes. It might be speculated that in patients with isolated central venous catheters there is negligible cardiopulmonary re-circulation, so the efficiency of dialysis could be slightly higher than that achievable with arteriovenous fistulas. This concept however still remains

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to be proven but it could partially offset the lower clearance achievable through catheters due to their lower blood flow rates.

Care and Maintenance of the Catheters

Dialysis catheters, like all intravenous lines, should be kept clean and covered at all times. To avoid bacterial contamination, the line should not be used for administration of medications, parenteral nutrition or accessed for blood sampling, except during an emergency. The use of dry gauze dressing with povidone iodine and mupirocin ointment at the catheter exit site, rather than a transparent dressing, can reduce the incidence of exit site infections, especially in patients who have nasal carriage of S. aureus. Dressing should be changed at least twice weekly, or earlier if any discharge or moisture is noted at the exit site. In the patients with an allergy to povidone iodine, alternate agents such as polyantimicrobial gel can be substituted. The glycol constituents of ointment should not be used on polyurethane catheters. A surgical mask worn by the patient and nurse any time the catheter is accessed reduces the spread of infectious droplets and reduces contamination of the catheter site. When not in use the lumens should be filled with 1 ml heparin (5,000 units per ml) mixed with 2 ml normal saline and heparin should always be removed and discarded prior to using the line. Antibiotic use and an anticoagulant lock of the catheter appear to be efficient ways to prevent endoluminal bacterial contamination in high risk patients.

Conclusions

Double-lumen catheters are an essential and convenient way for implementing RRT. Semirigid polyurethane catheters are the first choice for shortterm use. Hemocompatibile, flexible silicone catheters which are less damaging to blood vessels seem better suited for medium and long term use. Acute catheters should be placed in the femoral or internal jugular veins if possible. The subclavian vein site should be avoided to reduce overall catheter-related complications, particularly subclavian stenosis. Ultrasound should be used to survey local anatomy prior to insertion and/or it should be used in real time to reduce complications and increase the success rate of insertion. Catheter management with dry gauze dressing with or without antibiotic ointments and eradication of nasal carriage of S. aureus can prevent infectious complications. Dysfunction through thrombosis remains the Achilles heel but chronic anticoagulation may decrease the incidence.

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References 1

2 3 4 5 6 7 8 9 10

11 12

13 14 15

16 17

Pisoni LR, Young EW, Dykstra DM, Greenwood RN, Hecking E, Gillespie B, Wolfe RA, Goodkin DA, Held PJ: Vascular access use in Europe and the United States: Results from DOPPS. Kidney Int 2002;61:305–316. Ash SR: The evolution and function of central venous catheters for dialysis. Sem Dial 2001;14: 416–424. Beenen L, van Leusen R, Deenik B, Bosch FH: The incidence of subclavian vein stenosis using silicone catheters for hemodialysis. Artif Organs 1994;18:289–292. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: UPDATE 2000. Am J Kidney Dis 2001;37:S137–S181. Randolph AG, Cook DJ, Gonzales CA, Pribble CG: Ultrasound guidance for placement of central venous catheters: A meta-analysis of the literature. Crit Care Med 1996;24:2053–2058. Forauer AR, Gloockner JF: Importance of US findings in access planning during jugular vein hemodialysis catheter placements. J Vasc Interv Radiol 2000;11:233–238. Weyde W, Wikiera I, Ginger M: Prolonged cannulation of the femoral vein is a safe method of temporary vascular access for hemodialysis. Nephron 1998;80:86. McGee DC, Gould MK: Preventing complications of central venous catheterization. N Engl J Med 2003;348:1123–1133. Ruesch S, Walzer B, Tramèr MR: Complications of central venous catheters: Internal jugular versus subclavian access. A systematic review. Crit Care Med 2002;30:454–460. Hernandez D, Diaz F, Rufino M, Lorenzo V, Perez T, Rodriguez A, De Bonis E, Losado M, Gonzales-Posada JM, Torres A: Subclavian vascular access stenosis in dialysis patients: Natural history and risk factors. J Am Soc Nephrol 1998;9:1507–1510. Oliver MJ: Acute dialysis catheters. Semin Dial 2001;14:432–435. Merrer J, De Joughe B, Golliot F, Lefrant JY, Raffy B, Barre E, Rigaud JP, Casciani D, Misset B, Bosquet C, Outin H, Brun-Buisson C, Nitenberg G: Complications of femoral and subclavian venous catheterisation in critically ill patients. JAMA 2001;286:700–707. Schwab SJ, Beathard G: The hemodialysis catheter conundrum: Hate living with them, but can’t live without them. Kidney Int 1999;56:1–17. Obialo CI, Conner AC, Lebon LF: Maintaining patency of tunnelled hemodialysis catheters. Scand J Urol Nephrol 2003;37:172–176. Oliver MJ, Callery SM, Thorpe KE, Schwab SJ, Churchill DN: Risk of bacteremia, from temporary hemodialysis catheters by site of insertion and duration of use: A prospective study. Kidney Int 2000;58:2543–2545. Mermel LA, Farr BM, Sherertz RJ, Raad II, O’Grady N, Harria JS, Crafen DE: Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 2001;32:1249. Krishnasami Z, Carlton D, Bimbo L, Taylor ME, Balkovetz DF, Barker J, Allon M: Management of hemodialysis catheter-related bacteremia with an adjunctive antibiotic lock solution. Kidney Int 2002;61:1136–1142.

Vincenzo D’Intini FRACP, San Bortolo Hospital, Viale Rodolfi, Vicenza (Italy) Tel. ⫹39 0444993869, Fax ⫹39 0444993949, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 203–213

Relationship between Blood Flow, Access Catheter and Circuit Failure during CRRT: A Practical Review Ian Baldwin, Rinaldo Bellomo Department of Intensive Care and Department of Medicine, Austin Hospital, Heidelberg, Vic., Australia

Continuous therapy for acute renal failure in the ICU setting places new demands on the extracorporeal circuit (EC) originally designed for shorter time frame intermittent therapy. In addition, both nurses and physicians often need to compromise on measures taken to maintain and promote the optimal function of the EC with the needs of the critically ill patient. For example, physicians may not be able to prescribe anticoagulant drugs at suggested doses in a post operative or trauma patient. Nurses may not be free to change a patient’s position in bed for comfort, pressure care, and physiotherapy of the chest, due to access catheter placement and the need to ensure patency. Both these issues can have a significant affect on optimal functional life of the EC, preventing it clotting. If the EC is failing frequently, treatment can be ineffective and costs increase with nursing and the need for new EC components [1]. This paper presents a discussion of blood flow mechanics during CRRT and how these factors may be important in the setting of clot formation and failure of the EC during CRRT.

Blood Pumping for Extracorporeal Circuits

Despite clot formation in the EC being the major impediment to successful operation of the CRRT system [2–7] investigations into the flow of blood through the EC of a CRRT system and into genesis of clot formation due to flow problems has been limited. This is not the case in the context of cardiopulmonary bypass (CPB) systems where a larger EC and membrane is used

during heart surgery [8–10]. The characteristics of this EC are different to the EC for CRRT and have been well investigated [11–13]. Current CPB systems are very efficient [8] and do not clot during use primarily due to the short time frame of approximately 45–90 min [9], the large access catheters used and the ability to administer higher doses of heparin [10]. In the CRRT setting, however, blood flow is much slower (⬃200 ml/min), the access catheter is not placed via a surgical approach direct into exposed vessels, the system is intended to be continuous (⬎24 h) in function and the critically ill patients are not able to tolerate high doses of heparin. In comparison, CPB is a well researched, standardized, controlled, efficient technique with the above stated system factors favoring success. In CRRT, however, the mechanical factors related to blood flow in the EC are different and have not been investigated. The EC and components are those designed for intermittent therapy used in a continuous setting. In preference, attention has mainly focused on the performance assessment of anti-clotting drugs with the result that blood flow mechanics, the consequences of flow reduction, small dual lumen access catheters and the different access catheter sites used in the critically ill patient have been overlooked. There are many resistance points in the EC which have the potential to impede blood flow and cause clot formation [4], e.g. the tubing, the shape and contour of the venous air trap chamber, the connection points of the EC to the access catheter, the access catheter itself and the blood flow-pump mechanism generating blood flow. The cessation of blood flow in the EC due to clotting is a complex process and there may be interrelationships between resistance points. Clotting occurring quickly and unexpectedly, such as when anticoagulation is used or there is an abnormal clotting profile such as in liver failure, may be related to three factors: • Inadequate performance of anticoagulant drugs in this patient. • Mechanical factors within the EC involving a dysfunction of blood flow. • Both of these. The significance of this insight may be in that if the focus is often on inadequate performance of anticoagulant drugs, high doses or unnecessary changes to anticoagulant methods may be prescribed inappropriately. This occurs clinically when circuit clotting (time to failure or filter life) is thought to be due to inadequate anticoagulant drug effect, although the cause may be mechanical. Bedside diagnosis of mechanical factors may be difficult and is sometimes made after alternative diagnoses are excluded. For example, a well-functioning EC is in use with anticoagulant drugs at therapeutic levels, and a patient with poorly clotting blood in whom there would be no valid hematological reason for circuit clotting, the EC suddenly clots. The relationship between pump performance, the EC tubing circuit, the access catheter and nursing activities during therapy may be as important as the effects of anticoagulant drugs. Roller pumps

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persist in current CRRT machine designs due to their perceived efficiency and simplicity. This is despite reports of inefficiency [14, 15], damaging affect on red blood cells and platelets, and the fact that there is no accepted measure of performance during operation [16, 17]. Therefore until a new blood pump design is tested and validated to be better, an understanding of the potential failings of current roller pump technology is useful for clinicians managing CRRT.

Roller Pumps and Segment Tubing

Blood roller pumps have been extensively studied in the context of cardiac bypass (CPB) surgery and their role in this form of extracorporeal circuit has played an important role in the development of cardiac surgery [12]. Cooley [12] reviewed development of the roller pump, indicating that the first form of this was patented in 1855 by Porter and Bradley. This was a two roller cam displacement pump suggested for many medical applications where pumping fluids is required and was further expanded upon to comprise three and four roller mechanisms in an extracorporeal context. Head et al. [13] described the addition of the extra rollers and how they decreased the stroke volume of the pump and were required to rotate faster to achieve the same flow and as a result of this increased the level of blood haemolysis or blood cell damage. Setting the diameter of the roller cams in the pump housing and therefore the occlusiveness of the blood pump tubing was thought to be a major cause of such hemolysis problems [13, 18, 19] and also affected the efficiency of the blood pump in generating flow. Total tubing occlusion has been reported to be causative of hemolysis [20] but necessary to generate effective blood flow whereas near occlusion or non-occlusive setting has been reported to provide reduced blood flow [13, 19, 21] related to resistance downstream of the roller; blood can slip back past the roller. In a review of roller pumps in CPB, Noon et al. [21] stated that: ‘the optimization of occlusion setting in the CPB context would require an in-line flow meter and a pump with occlusion setting adjustable during operation. Rotary speed and roller occlusion could then be reciprocally adjusted to provide the maximum degree of under occlusion consistent with the required flow rates’. In more simple terms, this would mean that the occlusion of the roller could be widened during operation until measured flow started to fall. This would set the correct occlusion for blood pumping, and at a level that would minimize haemolysis. Reed and Stafford [16] reinforced this concept. They cited the example of a nonocclusive setting of a pump and the resistance of vascular access cannulae affecting flow rate. In this situation, if an inline flowmeter was not used, a patient may have a blood flow at below acceptable

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rates with the pump operator being completely oblivious to the problem. This experience is very important to users of CRRT machines. Roller pump occlusion is a necessary part of machine maintenance. How many users of CRRT machines, particularly those that are independent of a dialysis service where technicians are more focussed to machine maintenance attend to this? However, if the pump occlusion is correct, vascular access resistance may cause blood flow to drop and the blood pump pressure alarms along with the operator not detect this. Anecdotal experience of the authors concluded this was occurring during our CRRT and may have contributed to premature filter clotting. This conclusion is derived from anecdotal observations such as: • Observing blood flow into venous air chambers to be poor despite the correct pump speed setting. This observation implies experience teaches the observant; ‘what looks right’; a steady stream, not a dribble. • Clotting of filter prematurely (2–3 h) despite anticoagulation drugs. • Observing air bubbles in the blood filled tubing moving forwards and then backwards implying there is reduced net flow forwards in the EC.

Blood Pumps and Flow Doppler Assessment of Blood Flow

Depner et al. [14] assessed the pressure effects on roller pump blood flow during dialysis. This report presented results from both in vitro and in vivo work. The in vitro study utilized either normal saline or haematocrit adjusted anticoagulated human blood at 37⬚C. The flow was measured with an ultrasonic probe clamped around the pump outlet line. Clamps were applied to the distal ends of both the inlet and outlet lines varying the pressures. The in vivo work involved the measurement of blood flow in 64 patients during routine dialysis. In this in vivo study, the ultrasonic probe was placed on the inlet side of the dialysis membrane. The investigators concluded that only inlet (pre-pump) pressure affected blood flow. This was due to low pressure of blood resulting in poor filling of the pump housing tubing, and the subsequent stroke of the pump being ‘dry’ or less in stroke volume. Such an effect was not according to a proportional relationship, but rather the flow dropped sharply when the pressure inside the tubing fell to sub atmospheric levels (less than 150 mm Hg) and the tubing collapses closing off the internal lumen and its ability to refill. In the clinical context of CRRT this would suggest that blood flow would abruptly stop without any warning signs, highlighting the need for reliable access catheter blood flow/pressure. High pump outlet (post-pump) pressures did not effect flow, but did create a water hammer effect in that the tubing pulsated or moved in response to revolutions of the roller pump and there was a corresponding reversal of flow as each roller completed its stroke and

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occlusion was lost. This meant that the blood leaked backwards past the cam compressing the tubing. There was no change in the resultant average flow. Many physicians and nurses experienced with CRRT have observed this, but may not be aware of the mechanism other than it appeared to be related to imminent filter clotting or high EC pressures. In vivo assessment of blood flow indicated that measured flow was accurate when the prescribed roller pump speed was slow. A slow rate of pump roller rotation means that the blood pump housing tubing has more time for refill before cam occlusion occurs again. The tubing recoil is complete following the previous compression stroke and the tubing has time to refill with incoming blood. A slow pump speed was less than 50 ml/min. At high blood pump speeds (⬎100 ml/min) the measured flow was consistently lower than that set or prescribed. This is presumed to be due to the reduction in ‘refill time’ created by the faster cam rotation. In their discussion, the authors outlined an important mechanism in relation to the roller pump tubing segment which would explain differences between prescribed and actual flows. The proposed mechanism for flow reduction is based on the collapse of the segment tubing into the roller pump due to a fall in inlet pressure. This fall in pressure can be caused by poor supply or availability of blood into the pump tubing. This creates impairment in the elastic recoil of the tubing in the pump housing after the compression stroke has occurred and the tubing segment feeding the pump effectively runs dry, therefore it does not re-expand to the correct size, and its volume drops. This loss of recoil or re-expansion of tubing causes a ‘decrease in pump output that is proportional to the reduction in cross-sectional area’. The collapsed tubing may then fill from the reverse direction after the roller completes its stroke and a subsequent drop in output occurs.

Access Catheters

In 1996, Uldall [22] published a review of vascular access for CRRT stating that the femoral, subclavian, and internal jugular veins were the sites of choice for CRRT. The author concluded that the femoral vein was the suggested choice in immobile and generally supine patients. Most of the material presented was in the context of ease of insertion, and safety, given the risks as a medical procedure. Wynckel et al. [23] concur with this review in many respects but suggest that ‘prolonged femoral site catheterization increases both risks of thrombosis and infection’. In both these reviews there were no comments with respect to the ongoing nursing care and management required and therefore no consideration of the site utilized and its suitability for the subsequent hours or days of treatment providing reliable blood flow.

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Bellomo and Ronco [24] comment on double lumen catheters making specific reference to the fact that they must be capable of high blood flows with all patient postures, physiotherapy, and when turning patients. They conclude that the safest and most expedient insertion site in the critically ill patient was the femoral site. This is of particular concern when there is a need to establish the access quickly. The femoral vein is closer to the skin surface and makes fast access possible. Again, this is based on anecdotal clinical experience by these physicians and no scientific assessment. Baldwin and Elderkin [2] related similar anecdotal experience with respect to the preferred access site, indicating that the femoral site was more difficult for the application of an adhesive dressing; was not easily observed when bed sheets were over the patient, and did limit the possibility of sitting the patient upright or out of bed. These activities in a patient with a catheter in the femoral site would be likely to kink off the catheter and stop blood flow. Sieffert and Sheppard [25] reviewed the nursing implications of vascular access sites, stating that any site should not be a cause of poor flow and must not impede the nursing management and progress of the patient in any way. They also made a comparison of the three sites indicating that the femoral site was susceptible to disturbed flow and was difficult to visualize under the bedclothes. Furthermore, these authors noted that catheterization from the left side of the chest can cause occlusion of the catheter as it tended to rest against the vessel wall and occlude the arterial lumen side holes. The authors stated that this was evidenced by the low arterial pressure alarm occurring each time the patient coughed during spontaneous breathing causing a change in thoracic pressure, and a reduction in access blood flow. These comments were, again, based on anecdotal experience of the authors and reinforce that in the literature there was no independent assessment of dual lumen access catheters and the effects of nursing care for a given access site. There is one study by Tapson et al. [26] which compares the performance of two brands of catheter placed in the subclavian position. Their results revealed that from 223 patient treatments in 29 patients with the two brands of catheter, 11 catheters were removed due to ‘catheter failure’ [p.197] or insufficient arterial flow, unresponsive to catheter repositioning. This study did not refer to the patient activities during the treatments and implied that these catheter failures could not be explained scientifically.

Access Site

Sands et al. [15] compared prescribed and delivered blood flow during 208 dialysis treatments using an ultrasonic sensor to measure flow. Twenty-three of

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the treatments were performed in patients with a dual lumen catheter for vascular access. The remaining 185 treatments were performed in patients whose vascular access was in the form of an arteriovenous fistula. All of the 23 treatments utilizing the vascular access catheter were associated with a blood flow which was less than that prescribed. There was a variety of pump speed settings tested (ranging from 200 to 500 ml/min) indicating the error was not speed dependent. Of the entire group being assessed, 22.8% had a delivered blood flow which was at least 10% less than prescribed. It was not clear in the method of this study how the data was collected in the context of the time period of the treatment. It appeared that the readings taken were at the start of the treatment and were a single data point analysis. In the discussion the investigators suggest that vascular access catheters were ‘particularly problematic’ and confirm ‘the well known difficulties with providing adequate dialysis on a long-term basis with indwelling catheters’. Despite any criticism of this study, the findings do reflect that there is a real difficulty drawing blood from, or returning blood via these access catheters. The authors suggest that this problem is particularly highlighted when they are in place for periods of weeks or months in patients being treated in the chronic dialysis setting. The experience described does reveal that access catheters used during CRRT often fail to provide adequate blood to the blood pump they serve. This may be clearly obvious and is attended to accordingly. However, there may also be prolonged periods where the failure is not obvious and the blood pump fails without any awareness but the reduced pump output becomes the cause of EC clotting and failure. This is where continuous and direct ultrasound blood flow measurement may have a place in future CRRT machines.

Blood Flow Monitoring

Blood flow monitoring cannot be performed with current CRRT technology. This ultrasonic direct measurement has the potential to be linked to the blood and fluids pumps via intelligence software automatically making adjustment and alarm alerts for operators, or as previously cited, make adjustment to the roller cam occlusion and or pump speed when flow reduces due to increases in downstream resistance. Furthermore, in addition, advisory alarms may sound and UF/dialysate/replacement fluids would decrease to maintain the blood flow UF ratio. An advisory for ‘pump calibration’ may also appear. We have developed the technique for continuous ultrasound blood flow monitoring [27] and are now further validating its usefulness. The following is a brief review of the method.

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Set up blood flow monitoring

Computer

* HT 109 transonic flow meter– Neomedix systems

Blood pump

Lap top PC.

* Flow monitor

Flow monitor Mini doppler

Fig. 1. Uncompressed view of the normal flow wave patterns seen during peristaltic pump action for the maintenance of blood flow during CRRT.

Blood Flow Probe

The ultrasound flow probe was manufactured to our tubing specifications by Neomedix systems (Neomedix, Ithaca, N.Y., USA) and is designed to interface with a Transonic HT 109 flow monitor (Neomedix). This probe is a four-crystal beam miniature device which clamps around the blood tubing illuminating the blood flow between the opposing walls of the tubing. A microchip processor receiving the Doppler signals calculates transit time for blood passing through the probe head and displays a measure of flow on a monitor (digital only) and computer screen (wave and digital) (fig. 1). The probe provides 200 samples per second to the software as millivoltage to generate a flow wave. This high frequency response ensures that instantaneous flow is accurate. The millivolt signal can then be cross-calibrated or zeroed against a known flow rate or no flow respectively for display in ml/min.

Doppler Flow Measurement Unit and Computer Interface

Data is acquired from this flow monitor by a lap top computer via an RS232 port. A Windows based data acquisition and playback software program (WinDaq Software, Transonic Systems Inc., Ithaca, N.Y., USA) converts this data to a waveform for recording and playback. This waveform indicates a peak and trough to the blood flow consistent with the pulsatile nature of the roller pump rotation. Flow reduction can then be detected from this wave as it occurs in association with the digital display for max., min., and mean [27]. This wave

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Flow reduction identified in compressed wave view Peak flow 198 mls/min

Trough flow 83 mls/min Flow reduction period

A

B

Flow reduction begins here

C

D Failure

Fig. 2. Compressed blood flow wave revealing onset of a flow reduction and subsequent associated filter clotting.

display has the same usefulness as current hemodynamic monitors for patient arterial blood pressure (fig. 1).

EC Failure

Figure 2 shows a long period of blood flow wave where the view is compressed using a software ‘option’ for ‘view’. Point A indicates normal flow set at 200 ml/min. Point B indicates a nursing patient positional change where access occlusion occurs and flow drops severely for a short time and then recovers. Point C indicates a period of deteriorating flow over approximately 45 min (with no operator awareness) until point D where the filter clots and blood flow stops completely with no recovery possible.

Conclusion

There is an important relationship between the access catheter, the blood pump and the hemofilter. This relationship may be even more important in

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respect of the functional time before the EC or filter clots. Many clinicians may be treating patients where they are unaware that blood flow is incorrect from their prescription and/or are making unnecessary changes to anticoagulation in response to EC failure. Blood flow may be as important as other measures to prevent clotting in the EC during routine CRRT. Blood flow monitoring can be considered a logical next step in the design of future CRRT machines.

References 1

2 3 4 5 6 7 8

9 10 11 12 13 14 15 16 17 18 19 20 21

Baldwin IC, Bridge NP, Elderkin TD: Nursing Issues, Practices, and Perspectives for the Management of Continuous Renal Replacement Therapy in the Intensive Care Unit. Critical Care Nephrology. Dordrecht, Kluwer, 1998, pp 1309–1327. Baldwin I, Elderkin T: Continuous hemofiltration: Nursing perspectives in critical care. New Horizons 1995;3:738–747. Webb AR, Mythen MG, Jacobsen D, Mackie IJ: Maintaining blood flow in the extracorporeal circuit: Heamostasis and anticoagulation. Intens Care Med 1995;21:84–93. Favre H, Martin PY, Stoermann C: Anticoagulation in continuous extracorporeal renal replacement therapy. Semin Dial 1996;9:112–118. Martin P-Y, Chevrolet JC, Suter P, Favre H: Anticoagulation in patients treated by continuous venovenous hemofiltration: A retrospective study. Am J Kid Dis 1994;24:806–812. Mehta R: Anticoagulation strategies for continuous renal replacement therapies: What works? Am J Kid Dis 1996;28(suppl 3):806–812. Mehta RL, Dobos GJ, Ward DM: Anticoagulation in continuous renal replacement procedures. Semin Dial 1992;5:61–68. Connolly MW, Guyton RA: Cardiopulmonary bypass and intra operative protection; in Schlant RC, Alexander RW (eds): Hurst’s The Heart, ed 8. New York, McGraw Hill, 1994, vol 141, chap 22, pp 2443–2450. Phillips SJ: Emergent cardiopulmonary bypass. Ann Thorac Cardiovasc Surg 1993;55:1281–1282. Bell PE, Diffee GT: Cardiopulmonary bypass. Principles, nursing implications. AORN J 1991;53: 1480–1496. Noon GP, Harrell JE, Feldman L, Petrson J, Kent PM, De Bakey ME: Development and evaluation of pulsatile roller pump and tubing for cardiac assistance. Artif Org 1983;7:49–54. Cooley D: Development of the roller pump for use in the cardiopulmonary bypass circuit. Tex Heart Inst J 1987;14:113–118. Head LR, Coenen JP, Angola E, Nogueira C, Mendelsohn D, Kay EB: Operation of the roller pump for extracorporeal circulation. J Thorac Cardiovasc Surg 1960;39:210–220. Depner TA, Rizwan S, Stasi TA: Pressure effects on roller pump blood flow during hemodialysis. ASAIO Trans 1990;36:m456–m459. Sands J, Glidden D, Jacavage W, Jones B: Difference between delivered and prescribed flow in hemodialysis. ASIO J 1996;42:M717–M719. Reed CC, Stafford TB: Cardiopulmonary Bypass, ed 2. Houston, Texas Medical Press, 1985, p 376. Ronco C, Brendolan A, Bellomo R: Current technology for continuous renal replacement therapies. Crit Care Nephrol 1998;1269–1308. Bernstein EF, Gleason LR: Factors influencing hemolysis with roller pumps. Surgery 1967;61: 432–442. Hodges PC, Cardozo R, Thevenet A, Lillehei CW: Comparison of relative merits of occlusive and nonocclusive pumps for open-heart surgery. J Thorac Surg 1958;36:470–478. Tamari Y, Lee-Sensiba K, Leonard EF, Tortolani A: A dynamic method for setting roller pumps non-occlusively reduces hemolysis and predicts retrograde flow. ASAIO J 1997;43:39–52. Noon GP, Kane LE, Feldman L, Peterson JA, DeBakey ME: Reduction of blood trauma in roller pumps for long term perfusion. World J Surg 1985;9:65–71.

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22 23

24 25

26 27

Uldall R: Vascular access for continuous renal replacement therapy. Semin Dial 1996;9:93–97. Wynckel A, Melin JP, Hanrotel C, Chanard J: Catheter and line requirements for continuous hemofiltration; in Journois D (ed): Continuous Hemofiltration in the Intensive Care Unit. Amsterdam, Harwood Academic Publishers, 1997, chap 18. Bellomo R, Ronco C: Circulation of the continuous artificial kidney: Blood flow, pressures, clearances and the search for the best. Blood Purif 1997;15:354–365. Sieffert E, Sheppard M: Continuous hemofiltration: The nursing perspective; in Journois D (ed): Continuous Hemofiltration in the Intensive Care Unit. Amsterdam, Harwood Academic Publishers, 1997, chap 12. Tapson JS, Hoenich NA, Wilkinson R, Ward MK: Dual lumen subclavian catheters for hemodialysis. Int J Artif Org 1985;8:195–200. Baldwin I, Bellomo R, Koch B: A technique for the monitoring of blood flow during continuous hemofiltration. Intens Care Med 2002;28:1361–1364.

Ian Baldwin Department of Intensive Care Austin Hospital, Studley Rd, Heidelberg, Victoria 3084 (Australia) Tel. ⫹1 61 3 9496 3340, Fax ⫹1 61 3 9496 3932, E-Mail [email protected]

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Renal Replacement Therapy in the ICU: Consensus and Recommendations from ADQI Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 214–221

CRRT: Selection of Patients and Starting Criteria Paul M. Palevsky Renal Section, VA Pittsburgh Healthcare System and Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA

Acute renal failure (ARF) is a common complication of critical illness with a mortality in excess of 50% [1]. Despite more than a half-century of experience in the use of hemodialysis and other forms of renal support in the management of ARF, consensus on the optimal management of renal replacement therapy in ARF does not exist. In particular, there are no standard guidelines for the use of continuous renal replacement therapies (CRRT), resulting in wide variations in practice patterns across regions and between individual centers within regions. The First Acute Dialysis Quality Initiative (ADQI) consensus conference was held in New York in August, 2000 with a goal of reviewing the available evidence regarding optimal management of CRRT in order to make evidencebased practice recommendations and to delineate key issues for future research [2]. Among the topics covered by the participants of this conference was the selection of patients for acute extracorporeal renal support in ARF with particular emphasis on the timing of initiation and selection of patients for CRRT [3]. Specific issues addressed included indications for renal replacement therapy in patients with ARF, timing of initiation of acute extracorporeal renal support, patient and institutional characteristics for selecting CRRT for the management of ARF, and non-renal indications for CRRT. In this review, the consensus findings on the selection of patients and criteria for initiation of CRRT are discussed in light of studies published in the past 3 years. Patient Selection for Acute Extracorporeal Renal Support

Therapy for intrinsic ARF is primarily supportive, with no effective pharmacologic therapy for renal failure due to acute tubular necrosis [4, 5]. Prior to the

development of dialysis as an effective renal replacement therapy, the most common causes of death in acute renal failure were directly related to uremia, electrolyte disturbances (primarily intractable metabolic acidosis and hyperkalemia), volume overload and hemorrhagic diatheses. Although mortality rates in ARF remain high despite the advent of dialysis, the causes of death have changed, with sepsis, gastrointestinal bleeding, cardiovascular and pulmonary dysfunction and withdrawal of life-support now being most common [4, 6, 7]. The timing for initiation of renal support in acute renal failure remains controversial. In its initial use, in the decade following World War II, hemodialysis was applied to patients with advanced symptoms of renal failure, including clinical uremia, severe hyperkalemia and pulmonary edema [8–10]. Although control of uremic symptoms and volume overload were achieved, a clear reduction in mortality could not be demonstrated [10]. Teschan et al. [10] introduced the concept of ‘prophylactic’ dialysis, initiated prior to the onset of overt symptoms, in the treatment of ARF in military causalities during the Korean conflict. Multiple studies in the intervening four decades have attempted to define the appropriate timing for initiation of renal support in ARF. In their landmark report, Teschan et al. [10] described a prospective, uncontrolled series of 15 patients with oliguric ARF in whom dialysis was initiated ‘prophylactically’, before the BUN reached 100 mg/dl (36 mmol/l). All cause mortality was 33% with mortality due to hemorrhage or sepsis of 20%. Although no control group was studied, the authors reported that the results contrasted dramatically with their own past experience in patients in whom dialysis was not initiated until ‘conventional’ indications were present. Similar conclusions were reached in a series of retrospective studies published in the 1960s and early 1970s. Easterling and Forland [11] reported on a series of 45 patients with ARF initiated on dialysis prior to the onset of symptoms and concluded that early initiation of therapy to prevent uremic symptoms was desirable. However, their study lacked a control group, and they were unable to draw any conclusions regarding improved survival with early dialysis. In a retrospective analysis of 33 patients with postoperative ARF treated with hemodialysis during two different periods, Parsons et al. demonstrated a survival of 75% in patients in whom dialysis was initiated when the BUN was between 120 and 150 mg/dl (43–54 mmol/l) as compared to 12% survival in patients in whom dialysis was not initiated until the BUN was greater than 200 mg/dl (71 mmol/l) [12]. Similarly, in a retrospective series of 162 patients, Fischer et al. [13] observed a mortality of 57% in patients with ARF in whom dialysis was initiated when the BUN reached 150 mg/dl (54 mmol/l) or when clinical deterioration was first observed, as compared to 74% mortality in patients in whom dialysis was not initiated until the BUN was greater than 200 mg/dl.

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In the largest of these retrospective studies, Kleinknecht et al. [14] reported on 500 patients with ARF treated between 1966 and 1970. Patients receiving ‘prophylactic’ dialysis, defined as early and frequent treatment to maintain pre-dialysis BUN less than 93 mg/dl (33 mmol/l), had a mortality of 29% as compared to 42% mortality in patients in whom dialysis was initiated only if the BUN was greater than 163 mg/dl (58 mmol/l) or if severe electrolyte disturbances were present. A marked reduction in mortality due to sepsis and gastrointestinal bleeding was observed in the more aggressively dialyzed group. The first prospective evaluation of ‘prophylactic’ dialysis in ARF was reported by Conger [15] in 1975. He described 18 patients with post-traumatic ARF sustained during the Vietnam War and treated on the Naval Hospital Ship USS Sanctuary between April and October 1970. Patients were alternately assigned to an intensive dialysis regimen to maintain the pre-dialysis BUN and creatinine at less than 70 mg/dl (25 mmol/l) and 5 mg/dl (440 ␮mol/l), respectively, or a non-intensive regimen in which dialysis was not initiated until the BUN approached 150 mg/dl (54 mmol/l) and the creatinine reached 10 mg/dl (885 ␮mol/l), or the patient developed clinical indications for dialysis (hyperkalemia, volume overload or uremic encephalopathy). Survival was 64% (5 of 8 patients) in the intensive treatment group as compared to 20% (2 of 10 patients) in the non-intensive dialysis group. In addition, complications of hemorrhage (36 vs. 60%) and gram negative sepsis (50 vs. 80%) were less frequent in the intensive treatment group. Expanding on this study, Gillum et al. [16] studied 34 patients with ARF who were randomized to receive either intensive hemodialysis, to keep the BUN ⬍60 mg/dl (21 mmol/l) and the serum creatinine ⬍5 mg/dl (440 ␮mol/l), or non-intensive dialysis, allowing the BUN to reach 100 mg/dl (36 mmol/l) and the serum creatinine to reach 9 mg/dl (795 ␮mol/l). Patients were stratified based on etiology of ARF (trauma-surgery or medical) and randomized in a paired fashion when the serum creatinine reached 8 mg/dl (705 ␮mol/l). Although not assessing only timing of initiation of therapy, mortality was higher in the intensively dialyzed group (58.8 vs. 47.1%), but given the small sample size, this was not statistically significant (p ⫽ 0.73). Hemorrhagic and septic complications were more common in the non-intensively dialyzed group; however, these differences also did not reach statistical significance. Gettings et al. [17] have reported the results of a retrospective analysis of early (BUN ⬍60 mg/dl; 21 mmol/l) versus late (BUN ⬎60 mg/dl; 21 mmol/l) initiation of continuous venovenous hemofiltration (CVVH) in 100 adult patients with post-traumatic acute renal failure. The 41 patients who were ‘early’ starters were younger (40.5 ⫾ 17.9 vs. 48.0 ⫾ 18.9 years) but otherwise comparable to the 58 ‘late’ starters. Patients had similar Injury Severity Scores (early: 33.0 ⫾ 13.5; late: 37.2 ⫾ 15.0) and Glasgow Coma Scores (early: 11.8 ⫾ 3.8;

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late: 12.5 ⫾ 3.7) on admission. No other indices of severity of illness were reported. CRRT was initiated on day 10.5 ⫾ 15.3, when the BUN was 42.6 ⫾ 12.9 mg/dl (15.2 ⫾ 4.6 mmol/l) in the ‘early’ group as compared to day 19.4 ⫾ 27.2, when the BUN was 94.5 ⫾ 28.3 mg/dl (33.8 ⫾ 10.2 mmol/l) in the ‘late’ group. Survival was 39.0% in the ‘early’ group as compared to 20.3% in the late group. Based on these data, the ADQI conference concluded that no specific recommendations on the timing of initiation of renal replacement therapy could be made beyond the conventional criteria of pulmonary edema not responsive to diuretics, hyperkalemia, metabolic acidosis and uremic complications [3]. However, because the consequences of these complications are likely to be more severe in critically ill patients with ARF, they recommended that renal replacement therapy should usually begin before these manifestations are present [3]. They further recommended that the issue of timing of initiation of renal replacement therapy should be the subject of further research. Since the consensus conference, one additional study has been published comparing early (within 12 h of fulfilling criteria for ARF based on presence of oliguria or a creatinine clearance of less than 20 ml/min; n ⫽ 35) or late (BUN greater than 112 mg/dl (40 mmol/l), potassium greater than 6.5 mmol/l or pulmonary edema; n ⫽ 36) initiation of continuous hemofiltration [18]. The mean BUN was 48 mg/dl (17.1 mmol/l) in the early treatment group and 104.4 mg/dl (37.4 mmol/l) in the late treatment group. No difference in survival was observed between the two groups, with 28-day survivals of 68.8% in the early initiation group and 75.0% in the late initiation group (p ⫽ 0.80). This study was, however, markedly underpowered. Thus, the data remain insufficient to make additional recommendations regarding the timing of initiation of renal replacement therapy in ARF.

Patient Selection for CRRT in ARF

It is generally accepted that hemodynamically unstable patients tolerate CRRT better than intermittent therapies. The initial development of these therapies was to permit renal support to hemodynamically unstable patients who were unable to tolerate conventional hemodialysis. The slower, more gradual removal of fluid and solute during CRRT results in less hemodynamic compromise than occurs with intermittent hemodialysis. This prescribing pattern is borne out in both retrospective and prospective observational comparisons of CRRT and intermittent hemodialysis [19, 20]. In a single-center retrospective comparison of CRRT and intermittent hemodialysis, Swartz et al. [19] observed that patients treated with CRRT had a higher acuity of illness, with lower mean

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systolic blood pressure, lower platelet count and greater percentage of patients requiring ventilatory support despite less advanced renal failure (lower BUN and creatinine) at the time of initiation of renal support. Similar findings were observed in a prospective, multicenter, observational study comparing continuous and intermittent renal replacement therapy that was published after the consensus conference [20]. The mean SAPS II score at time of initiation of renal support was 62 ⫾ 18 in 354 patients treated with CRRT as compared to 58 ⫾ 22 in 233 patients treated with intermittent therapy. Cardiovascular dysfunction was present in 85.9% of CRRT patients as compared to 53.6% of patients treated with intermittent therapy. Similarly, respiratory failure requiring ventilatory support was present in 92.7% of patients treated with CRRT as compared to 71.2% of patients initially treated with intermittent therapy. The mean number of failed organs was 3.6 ⫾ 1.1 in patients initially treated with CRRT as compared to 2.8 ⫾ 1.2 in patients initially treated with intermittent therapy. Thus, these two studies suggest that there is greater utilization of continuous renal support in patients with greater acuity of illness. The question of whether CRRT offers a survival advantage over intermittent hemodialysis in the management of ARF remains unresolved. Although unadjusted mortality was higher in patients treated with CRRT in the two observational studies discussed above, modality of renal replacement therapy had no prognostic value with regard to mortality risk after risk adjustment [19, 20]. Only one large randomized controlled trial comparing continuous to intermittent therapy has been published in a peer-reviewed journal [21]. In this study of 166 patients with ARF randomized to CRRT or intermittent hemodialysis, an intention-to-treat analysis found a 28-day all-cause mortality of 59.5% in patients randomized to CRRT as compared to 41.5% in patients randomized to intermittent therapy with in-hospital mortality rates of 65.5 and 47.6%, respectively. However, this study was flawed by unbalance randomization, which resulted in significantly higher APACHE III scores and a significantly greater percentage of patients with liver failure in the CRRT group. Using multivariable stepwise logistic-regression analysis, hepatic failure, APACHE III score and Organ System Failure (OSF) score were all independently related to ICU mortality. In this analysis, modality of therapy was not independently associated with mortality, with an odds of death associated with randomization to CRRT of 1.58 (95% CI: 0.7–3.3). Similarly, a time-to-event analysis using a Cox proportional hazards model yielded a similar conclusion (hazard ratio with CRRT: 1.35; 95% CI: 0.89 to 2.06). Despite the higher mortality in the CRRT group, surviving patients initially treated with CRRT had higher rates of recovery of renal function. Two meta-analyses have been published since the consensus conference comparing intermittent to continuous therapy in ARF [22, 23]. Kellum et al. [22]

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analyzed 13 studies encompassing a total of 1,400 patients with ARF. Only 3 of the 13 studies were prospective randomized trials. Overall, there was no difference in mortality in the pooled analysis. Adjusting for study quality and severity of illness, the authors calculated an adjusted relative risk of death in patients treated with CRRT of 0.72 (95% CI: 0.60–0.87). In a subanalysis of six studies in which patients treated with CRRT and intermittent therapy had similar baseline severity of illness, the unadjusted relative risk of death with CRRT was 0.48 (95% CI: 0.34–0.69). In the second meta-analysis, Tonelli et al. [23] found no difference in outcome associated with the modality of renal support in six randomized controlled trials encompassing 624 patients. The difference in conclusions between these two studies reflects the different criteria for study inclusion. Based on the data available at the time of the consensus conference, no firm recommendations for patient selection for CRRT could be made, except in patients who have, or are at risk, for cerebral edema [3]. In this subgroup of patients, data suggest that treatment with continuous hemofiltration is less likely to be associated with increased intracranial pressure and decreased cerebral perfusion pressure as compared to intermittent therapy [24–27]. The observational study [20] and two meta-analyses [22, 23] published since the consensus conference have not provided sufficient additional data to alter this conclusion. A large prospective randomized controlled trial comparing intermittent to continuous renal replacement therapy will be required to resolve this issue.

Non-Renal Indications for CRRT

There are multiple case-series of CRRT use in settings other than ARF, including acute intoxications [28], cardiac failure [29] and ARDS [30]. Significant interest has focused on the use of CRRT in the management of sepsis and systemic inflammation [31, 32]. For example, in trauma patients without renal failure, CVVH has been demonstrated to be associated with decreases in both TNF-␣ and IL-6 levels [33] and was associated with improved hemodynamic stability [34]. It is uncertain, however, whether the cytokine clearance is due to convective clearance or membrane adsorption [35]. The clinical relevance of the cytokine clearance that has been observed has also been questioned, as the clearances achievable with CRRT are markedly lower than their biological turnover [36]. Newer modalities using plasma filtration and adsorption may provide greater promise [37]. At present, however, the evidence remains insufficient to recommend the use of CRRT for non-renal indications outside of appropriately designed clinical trials [3].

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References 1

2 3 4 5 6 7 8 9 10 11 12

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Liano F, Junco E, Pascual J, Madero R, Verde E: The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group. Kidney Int 1998;66(suppl):S16–S24. Kellum JA, Mehta RL, Angus DC, Palevsky P, Ronco C: The first international consensus conference on continuous renal replacement therapy. Kidney Int 2002;62:1855–1863. Bellomo R, Angus DC, Star RA: The Acute Dialysis Quality Initiative. II. Patient selection for CRRT. Adv Ren Replace Ther 2002;9:255–259. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996;334:1448–1460. Star RA: Treatment of acute renal failure. Kidney Int 1998;54:1817–1831. Turney JH: Why is mortality persistently high in acute renal failure? Lancet 1990;335:971. Woodrow G, Turney JH: Cause of death in acute renal failure. Nephrol Dial Transplant 1992;7: 230–234. Kolf WJ: First clinical experience with the artificial kidney. Ann Intern Med 1965;62:608–619. Merrill JP, Smith S, Callahan EJ, Thorn GW: Use of artificial kidney. II. Clinical experience. J Clin Invest 1950;29:425–438. Teschan PE, Baxter CR, O’Brien TF, Freyhof JN, Hall WH: Prophylactic hemodialysis in the treatment of acute renal failure. Ann Intern Med 1960;53:992–1016. Easterling RE, Forland M: A five year experience with prophylactic dialysis for acute renal failure. Trans Am Soc Artif Intern Organs 1964;10:200–208. Parsons FM, Hobson SM, Blagg CR, McCracken BH: Optimum time for dialysis in acute reversible renal failure: Description and value of improved dialyzer with large surface area. Lancet 1961;i: 129–134. Fischer RP, Griffen WOJ, Reiser M, VClark DS: Early dialysis in the treatment of acute renal failure. Surg Gynecol Obstet 1966;123:1019–1023. Kleinknecht D, Jungers P, Chanard J, Barbanel C, Ganeval D: Uremic and non-uremic complications in acute renal failure: Evaluation of early and frequent dialysis on prognosis. Kidney Int 1972;1: 190–196. Conger JD: A controlled evaluation of prophylactic dialysis in post-traumatic acute renal failure. J Trauma 1975;15:1056–1063. Gillum DM, Dixon BS, Yanover MJ, et al: The role of intensive dialysis in acute renal failure. Clin Nephrol 1986;25:249–255. Gettings LG, Reynolds HN, Scalea T: Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intens Care Med 1999;25: 805–813. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J: Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med 2002;30:2205–2211. Swartz RD, Messana JM, Orzol S, Port FK: Comparing continuous hemofiltration with hemodialysis in patients with severe acute renal failure. Am J Kidney Dis 1999;34:424–432. Guerin C, Girard R, Selli JM, Ayzac L: Intermittent versus continuous renal replacement therapy for acute renal failure in intensive care units: Results from a multicenter prospective epidemiological survey. Intens Care Med 2002;28:1411–1418. Mehta RL, McDonald B, Gabbai FB, et al: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60:1154–1163. Kellum JA, Angus DC, Johnson JP, et al: Continuous versus intermittent renal replacement therapy: A meta-analysis. Intens Care Med 2002;28:29–37. Tonelli M, Manns B, Feller-Kopman D: Acute renal failure in the intensive care unit: A systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002; 40:875–885. Davenport A, Will EJ, Davison AM, et al: Changes in intracranial pressure during machine and continuous haemofiltration. Int J Artif Organs 1989;12:439–444.

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Davenport A, Finn R, Goldsmith HJ: Management of patients with renal failure complicated by cerebral oedema. Blood Purif 1989;7:203–209. Davenport A, Will EJ, Davison AM: Early changes in intracranial pressure during haemofiltration treatment in patients with grade 4 hepatic encephalopathy and acute oliguric renal failure. Nephrol Dial Transplant 1990;5:192–198. Davenport A, Will EJ, Davison AM: Continuous vs. intermittent forms of haemofiltration and/or dialysis in the management of acute renal failure in patients with defective cerebral autoregulation at risk of cerebral oedema. Contrib Nephrol. Basel, Karger, 1991, vol 93, pp 225–233. Bellomo R, Kearly Y, Parkin G, Love J, Boyce N: Treatment of life-threatening lithium toxicity with continuous arterio-venous hemodiafiltration. Crit Care Med 1991;19:836–837. Biasioli S, Barbaresi F, Barbiero M, et al: Intermittent venovenous hemofiltration as a chronic treatment for refractory and intractable heart failure. ASAIO J 1992;38:M658–M663. DiCarlo JV, Alexander SR, Agarwal R, Schiffman JD: Continuous veno-venous hemofiltration may improve survival from acute respiratory distress syndrome after bone marrow transplantation or chemotherapy. J Pediatr Hematol Oncol 2003;25:801–805. Ronco C, Tetta C, Mariano F, et al: Interpreting the mechanisms of continuous renal replacement therapy in sepsis: The peak concentration hypothesis. Artif Organs 2003;27:792–801. Tetta C, D’Intini V, Bellomo R, et al: Extracorporeal treatments in sepsis: Are there new perspectives? Clin Nephrol 2003;60:299–304. Sanchez-Izquierdo JA, Perez Vela JL, Lozano Quintana MJ, Alted Lopez E, Ortuno de Solo B, Ambros Checa A: Cytokines clearance during venovenous hemofiltration in the trauma patient. Am J Kidney Dis 1997;30:483–488. Sanchez-Izquierdo Riera JA, Alted E, Lozano MJ, Perez JL, Ambros A, Caballero R: Influence of continuous hemofiltration on the hemodynamics of trauma patients. Surgery 1997;122:902–908. Bouman CS, van Olden RW, Stoutenbeek CP: Cytokine filtration and adsorption during pre- and postdilution hemofiltration in four different membranes. Blood Purif 1998;16:261–268. Sieberth HG, Kierdorf HP: Is cytokine removal by continuous hemofiltration feasible? Kidney Int 1999;72(suppl):S79–S83. Bellomo R, Tetta C, Brendolan A, Ronco C: Coupled plasma filtration adsorption. Blood Purif 2002;20:289–292.

Paul M. Palevsky, MD Room 7E123 (111F-U), VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA 15240 (USA) Tel. ⫹1 412 688 6000 ext 5932, Fax ⫹1 412 688 6908, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 222–227

Fluid Composition for CRRT Martine Leblanc University of Montreal, Nephrology and Critical Care, Maisonneuve-Rosemont Hospital, Montreal, P.Q., Canada

Electrolyte and Acid-Base Disturbances in CRRT Patients

Critically ill patients with acute renal failure often present increased potassium and phosphate serum concentrations as well as metabolic acidemia. Serum sodium level may vary but can be found low in cases of massive fluid overload. To facilitate our understanding of electrolytes and acid-base imbalance in critical illness, the ‘strong ion approach’ is very useful [1]. A strong ion is considered almost completely dissociated in a solution; strong cations in blood plasma are sodium (Na⫹), potassium (K⫹), calcium (Ca2⫹) magnesium (Mg2⫹), whereas strong anions are chloride (Cl⫺), and lactate until metabolized. The strong ion difference corresponds to the net charge balance of all strong ions present in a solution; the apparent strong ion difference in blood plasma can be calculated as: [(Na⫹ ⫹ K⫹ ⫹ Ca2⫹ ⫹ Mg2⫹) ⫺ (Cl⫺ ⫹ lactate)]. Since the ‘normal’ apparent strong ion difference of human blood plasma is 40–42 mmol/l, it can be concluded that unmeasured anions are normally present [2]. However, in critical illness, the apparent strong ion difference is often found lower, in the 30–35 mmol/l range, as a consequence of an underlying metabolic acidosis with excessive unmeasured anions, and of a low serum albumin [1]. More than 15,000 mmol of CO2, as much as 4,500 mmol of lactic acid, and 100–200 mmol of other nonvolatile acids are produced daily by the human body from metabolism and nutrition [2]. During critical illness, volatile and nonvolatile acid load may increase as a result of enhanced catabolism. Although several pathways counteract the acid burden, nonvolatile acid elimination is reduced in renal failure and a normal strong ion difference can not be restored by the failing kidneys [3]. In renal failure, a mixed type of metabolic acidosis both hyperchloremic and high-anion gap is commonly found [4]; the apparent

Table 1. Composition of some of the commercially available fluids for CRRT (ion concentrations in mmol/l)

Na⫹ K⫹ Cl⫺ Ca2⫹ Mg2⫹ Phosphate HCO3⫺ Lactate⫺

Hemosol LG2 (Gambro)

Hemosol B0 (Gambro)

Premixed dialysate (Baxter)

Normocarb (Vaughan)

142 2 109.5 1.75 0.75 0 0 40

140 0 109.5 1.75 0.5 0 32 3

142 2 117 1.75 0.75 0 32 32

140 0 106.5 0 0.75 0 35 0

strong ion difference of renal failure patients is usually reduced. Chloride and unmeasured anions in blood plasma (phosphates, sulfates, various organic acids not completely oxidized, and other unknown molecules) just accumulate, being not eliminated by kidneys. A high anion gap metabolic acidosis in critically illness may indicate lactate accumulation, although hyperlactatemia does not necessarily translate into acidemia.

Fluids for CRRT

Besides azotemia control, a major aim of CRRT is the restoration of physiologic electrolyte concentrations and acid-base balance in blood plasma. The choice of fluids for CRRT will be determinant in the achievement of such a goal, and not only their composition but also the operational conditions of CRRT will have an impact. Fluids used for CRRT include dialysate and replacement/substitution solutions. Solutions generally used for CRRT contain electrolytes in concentrations similar to those unbound to proteins in blood plasma. The strong ion difference of those solutions has a significant impact on the acid-base balance, especially when high rates or massive amounts are delivered. Some of the commercially available solutions and their content are presented in table 1. It can be appreciated that strong ion differences of those solutions are relatively close to the strong ion difference of normal human blood plasma. For rare or very specific cases, customized fluids may be necessary, but this is certainly not a major concern. As the main alkalinazing anion, lactate and bicarbonate are most frequently used in CRRT solutions. Buffer anion in CRRT fluids is usually in a concentration

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above 25–30 mmol/l [5]. Controlled trials have demonstrated that lactate or bicarbonate buffered solutions for CRRT have a similar efficacy to correct metabolic acidosis [6–8]. However, serum lactate was found slightly higher with lactate solutions without clear evidence of detrimental impact on outcome. Nonetheless, this may complicate the clinical interpretation of blood lactate levels. Generally, the use of bicarbonate-buffered fluids has been associated with an improved control of metabolic acidosis [9]. Lactate solutions are usually well tolerated since the human body can rapidly metabolize large amounts of lactate (at a rate of 100 mmol/h for as much as 2,000 mmol/day). It is converted by the liver into bicarbonate in a 1:1 ratio and usually does not remain in circulation as a strong ion for a long time. Although lactate solutions are well tolerated during CRRT when infused at moderate flows of 2–3 liters/h, the infusion of large amounts of D,L-lactate could possibly increase catabolism and induce cerebral dysfunction [10]. In addition, in patients who are limited in lactate metabolism (liver failure, severe shock), lactate solutions should be avoided. In such circumstances, infused lactate remains in circulation as a strong anion and endogenous bicarbonate is lost through the effluent, both contributing to a metabolic acidosis. Bicarbonatebuffered fluids are preferred in such cases. However, since bicarbonate solutions for CRRT are not widely available, they may have to be prepared locally by the institution. Solutions used for CRRT may else contain citrate as the main alkalinizing anion [5, 11]. Citrate is converted to bicarbonate by the liver and by the muscle in a 1:3 ratio. Citrate is used for regional anticoagulation of the extracorporeal circuit during CRRT and is particularly appealing for patients at risk for bleeding. Most studies on citrate-CRRT show correction of the metabolic acidosis [12]. However, since one molecule of citrate provides 3 molecules of bicarbonate, metabolic alkalosis may be a consequence. Acetate has also been proposed as the alkalinizing anion, since it is metabolized into bicarbonate by the liver and muscle in a 1:1 ratio and will contribute to the restoration of the strong ion difference. However, acetate has not been frequently used in CRRT fluids, and potential uneventful effects of hyperacetatemia observed previously with intermittent hemodialysis, are unknown in CRRT. In 84 critically ill patients with acute renal failure treated with CVVH, lactate was associated with a significant increase in serum bicarbonate and pH after 48 h when compared to acetate [13]. Supraphysiologic sodium concentration in the dialysate is a well-known tool to improve hemodynamic stability during intermittent hemodialysis; it is unclear if enhancing sodium concentration in CRRT fluids could also be of benefit. Since most CRRT solutions have no or low potassium concentrations and do not contain phosphate, potassium and/or phosphate addition or

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Table 2. Our local protocol for the addition of potassium and phosphate to Hemosol LG2 and Hemosol B0 If serum phosphate is below 1.5 mmol/l Add 2 ml of potassium phosphate (racemic mixture of KH2PO4/K2HPO4) to a 5-liter bag of Hemosol LG2 or Hemosol B0; this is a fixed amount and maximum per bag and corresponds to a phosphate concentration of 1.2 mmol/l in the solution If potassium phosphate has been added and serum potassium is below 5 mmol/l Add 2 mmol of potassium chloride (KCl) per 5-liter bag of Hemosol LG2 or 12 mmol of KCl per 5-liter bag of Hemosol B0; this is a fixed amount and maximum per bag and corresponds to a potassium concentration of 4.2 mmol/l in the solution If potassium phosphate has not been added and serum potassium is below 5 mmol/l Add 10 mmol of potassium chloride (KCl) per 5-liter bag of Hemosol LG2 or 20 mmol of KCl per 5 -liter bag of Hemosol B0; this is a fixed amount and maximum per bag and corresponds to a potassium concentration of 4.0 mmol/l in the solution If potassium phosphate has not been added and serum potassium is above 5 mmol/l Do not add any potassium chloride (KCl) to Hemosol LG2; if potassium is below 7 mmol/l, add only 10 mmol of KCl per 5-liter bag of Hemosol B0 (corresponding to a potassium concentration of 2 mmol/l in the solution); if serum potassium is above 7 mmol/l, do not add any KCl to Hemosol B0

supplementation will frequently be required after the initial phase [10]. In our center, we usually add potassium chloride and potassium phosphate to reach a concentration of phosphate of 1 mmol/l and a concentration of potassium of 4 mmol/l in the solutions (dialysate and replacement). These additions are made only when serum phosphate is below 1.5 mmol/l and serum potassium below 5 mmol/l (table 2). We never encountered any problem with salt formation or crystallization even in bicarbonate solutions. We recently reported our results but they are unpublished at this time. The presence or absence of dextrose or glucose in CRRT fluids can be appraised from different perspectives. First, one may consider that loosing glucose and calories through the effluent is not desirable and that a physiologic glucose concentration (near 5 mmol/l) should be offered in the dialysate and replacement. On the other hand, it is certainly not desirable to use solutions with supraphysiologic glucose or dextrose content since this may induce hyperglycemia. Indeed, it has been recently shown that a tight glycemic control is associated with a better outcome in critical illness [14]. Also, dextrose-containing solutions may enhance lactate production and may be detrimental in presence of brain injury [15]. We may see in the near future more sophisticated CRRT solutions, for example containing nutrients or anti-oxidants. More research is definitely required in that area. Whatever solution is used, electrolytes and acid-base

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balance should be assessed frequently during CRRT, especially if high-volume exchanges are performed.

Influence of CRRT Prescription

Diffusion, the main exchange mechanism in CVVHD, is excellent to remove small molecules but is much more limited for middle-sized solutes. The cations and anions involved in the strong ion difference are available to be exchanged by diffusive fluxes. Convection is the exchange mechanism used during CVVH. Most ions considered in the strong ion difference equation pass easily through the membrane with convective fluxes and have sieving coefficients near one. Thus, diffusion and convection are efficient processes to restore electrolytes and acid-base balance, and can be considered equivalent from that perspective. However, during convection, large amounts of bicarbonate can be lost in the ultrafiltrate, inducing rapidly a metabolic acidosis if not replaced appropriately by the substitution fluid. For example, during CVVH at an ultrafiltration rate of 3 liters/h, as much as 50 mmol of HCO3⫺ can be lost hourly. The amount of bicarbonate lost in the effluent can be easily assessed since both the sieving coefficient and effluent rate are known. If the replacement consists in normal saline, a hyperchloremic acidosis would rapidly occur. Therefore, substitution fluids must be relatively similar to normal blood plasma, and must be alkalinizing. Nevertheless, since the composition of replacement fluids can be flexible, the alkalinizing performance of convective modalities may be superior and these approaches may be more versatile. This can be demonstrated by acetate-free biofiltration that corresponds to a hemodiafiltration in which bicarbonate is absent from the dialysate, bicarbonate being administered exclusively via replacement. This method offers the possibility to titrate more precisely the amount of given buffer and has been used to treat severe metabolic acidosis. Continuous renal replacement therapies provide a constant restoration of electrolytes and acid-base balance, avoiding large fluctuations. However, since flow rates during CRRT are lower than during intermittent modalities, acid-base balance restoration is progressive and usually occurs over 36–48 h in most cases. As well, at usual CRRT rates in average-size patients, a metabolic steady state is expected to occur after 3 or 4 days; this may apply to several electrolytes [16]. When applying higher flows, for example to reach an ultrafiltration rate of 35 ml/kg/h, as recommended by Ronco et al. [17], acid-base correction and metabolic steady state may both occur sooner. In high-volume CVVH, because of the potential massive influx of lactate anions, bicarbonate fluids are recommended. On the other hand, a metabolic alkalosis may be induced by high-volume

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CVVH if using replacement fluids containing too much bicarbonate, and its concentration may have to be reduced under certain circumstances.

References 1 2

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Kellum JA: Metabolic acidosis in the critically ill: Lessons from physical chemistry. Kidney Int 1998;53(suppl 66):S81–S86. Leblanc M, Kellum JA: Biochemical and biophysical principles of hydrogen ion regulation; in Ronco C, Bellomo R (eds): Critical Care Nephrology, ed 1. Dordrecht, Kluwer Academic Publishers, 1998, pp 261–277. Warnock DG: Uremic acidosis. Kidney Int 1988;34:278–287. Wallia R, Greenberg A, Piraino B, Mitro R, Puschett JB: Serum electrolytes in end-stage renal disease. Am J Kid Dis 1986;8:98–104. Macias WL, Clark WR: Acid-base balance in continuous renal replacement therapy. Semin Dialy 1996;9:145–151. Thomas AN, Guy JM, Kishen R, Geraghty IF, Bowles BJ, Vadgama P: Comparison of lactate and bicarbonate buffered haemofiltration fluids: Use in critically ill patients. Nephrol Dial Transplant 1997;12:1212–1217. Heering P, Ivens K, Thumer OM, Grabensee B: Acid-base balance and substitution fluid during continuous hemofiltration. Kidney Int 1999;56(suppl 72):S37–S40. Zimmerman D, Cotman P, Ting R, Karanicolas S, Tobe SW: Continuous veno-venous haemodialysis with a novel bicarbonate dialysis solution: Prospective cross-over comparison with a lactate buffered solution. Nephrol Dial Transplant 1999;14:2387–2391. Schetz M, Leblanc M, Murray P: The Acute Dialysis Quality Initiative. VII. Fluid composition and management in CRRT. Adv Renal Replacement Ther 2002;9:282–289. Veech RL: The untoward effects of the anions of dialysis fluid. Kidney Int 1988;34:587–597. Palevsky P: Continuous renal replacement therapy component selection: Replacement fluid and dialysate solutions. Semin Dial 1996;9:107–111. Palsson R, Niles JL: Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding. Kidney Int 1999;55:1991–1997. Morgera S, Heering P, Szentandrasi T, Manassa E, Heintzen M, Willers R, Passlick-Deetjen J, Grabensee B: Comparison of a lactate- versus acetate-based hemofiltration replacement fluid in patients with acute renal failure. Renal Failure 1997;19:155–164. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367. Sieber FE, Traystman RJ: Special issues: Glucose and the brain. Crit Care Med 1992;20:104–114. Clark WR, Mueller BA, Kraus MA, Macias WL: Extracorporeal therapy requirements for patients with acute renal failure. J Am Soc Nephrol 1997;8:804–812. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000;356:26–30.

Martine Leblanc MD Nephrology and Critical Care, Maisonneuve-Rosemont Hospital 5415 de l’Assomption, Montreal, PQ (Canada) Tel. ⫹1 514 252 3400, ext 3733, Fax ⫹1 514 255 3026 E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 228–238

Anticoagulation for Continuous Renal Replacement Therapy Andrew Davenport University College and Royal Free Hospital Medical School, and Center for Nephrology, The Royal Free Hospital, London, UK

Over the last three decades there have been great strides in the development of continuous forms of renal replacement therapy (CRRT), from a technique providing ultrafiltration aiding fluid balance, to an effective treatment for controlling solute, fluid, electrolyte and acid-base balance in the critically ill patient with multi-organ failure. More recently, it has been reported that the intensity of CRRT might improve the outcome of patients with acute renal failure in critical illness [1]. However, for CRRT to provide efficient effective treatment superior to that achieved with standard daily intermittent hemodialysis, the CRRT circuit has to operate continuously. Although there are many earlier publications reporting circuit lives in excess of 48 h, more recent studies have suggested an average circuit life of 16–18.6 h/day [2, 3]. In clinical practice premature circuit clotting leads to wasted time, as one circuit has to be dismantled, and a new one set up, primed and then connected to the patient. Thus the patient does not receive CRRT but discontinuous treatment, due to this so called circuit ‘down time’, which can vary from 3 to 8 h/day [2, 3]. In the intensive care unit, most patients with acute renal failure have associated sepsis with an inflammatory state resulting in activation of leukocytes, macrophages, platelets and coagulation protein pathways [4]. Passage through the extracorporeal circuit results in the formation of leukocyte-platelet aggregates and platelet micro-thrombi, resulting in premature thrombosis, which typically occurs on the dialyzer/hemofilter membrane, the venous air detector chamber and venous access catheter [5]. Ideally, treatments designed to reduce inflammatory cell activation and leukocyte-platelet interactions would help to maintain the integrity of the CRRT circuit. Some centers advocate the use of fresh frozen plasma, which may have a role in replacing complement inhibitors

and capsaises, and may have some analogous effect to the use of immunoglobulin in controlling acute vascular rejection in T and B cell positive cross-match allografting [6]. Whereas in current clinical practice anticoagulants targeted against thrombin generation are most commonly used.

Systemic Anticoagulants

Unfractionated Heparin Unfractionated heparin remains the most commonly used extracorporeal systemic anticoagulant for CRRT, with an action time of 3–5 min. Paradoxically, rather than reducing platelet activation, heparin activates platelets by complexing with platelet factor 4. In addition the effect of heparin is often decreased in the intensive care unit patient, as key co-factors such as antithrombin and heparin cofactor II levels are often reduced. Heparin is not removed by dialysis or hemofiltration, but is eliminated in a dose dependent manner, mainly by the liver, but also by the kidney. Thus, the half-life is increased in renal failure to 40–120 min. As heparin is a highly negatively charged molecule, it can be adsorbed to the plastic of the circuit tubing during priming, and priming doses vary from center to center, from 1,000 to 10,000 IU. Provided there is no risk of bleeding, a loading dose of heparin (10–20 U/kg) is given at the start of CRRT, followed by a maintenance infusion of 3–20 U/kg/h [4]. It is important that the effect of heparin is monitored, as individual patients differ in their response. The whole blood clotting time (WBCT) and the activated coagulation time (ACT), are the most common bedside tests of heparin anticoagulation. Fresh unanticoagulated whole blood samples should be rapidly placed into a glass tube at 37⬚C. The ACT is similar, but contains an activator of the intrinsic coagulation system. Both are prone to error, and require regular quality control [7]. In addition, the results are dependent upon the level of coagulation factors, platelets and hematocrit. Thus, the results of WBCT and ACT taken from the same patient will differ during hemofiltration with post-dilutional fluid replacement if taken before and after filter, simply due to ultrafiltration increasing the hematocrit and platelet concentration causing shorter post-filter times. The activated partial thromboplastin time (aPTT) is a laboratory test on plasma separated from citrated blood, and should be measured in conjunction with a prothrombin time, which although little affected by heparin, provides valuable information about the levels of coagulation factors. Centers differ not only in which monitoring tests are performed and their frequency, but also the site at which samples are taken [7, 8]. Sampling immediately prior to the arterial port of the hemofilter/hemodialyzer

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target whole blood activated clotting time (ACT) of around 140–180 s, or a laboratory aPTT of 100–140 s. Filter patency has not been proven to be determined either by the total heparin dose, or by aPTT or other clotting studies [7]. Although van der Wetering et al. [9] reported a reduced filter patency rate with systemic aPTT times less than 35 s. They also reported that with a systemic aPTT of 15–35 s the incidence of de novo patient hemorrhage was 2.9 per 1,000 h CRRT, which increased to 7.4 at an aPTT of 45–55 s [9]. Even using low-dose heparin (500 U/h) for CRRT in patients at risk of hemorrhage has not been proven to reduce the risk of bleeding complications [10]. The main complication of heparin is hemorrhage. Fortunately, the half-life is relatively short, and heparin activity can be quickly reversed with protamine, 1 mg given for every 1,000 U heparin. Rarely heparin administration can result in an acute allergic reaction, usually due to pork sensitivity. Occasionally patients can develop immunemediated heparin-induced thrombocytopenia (HIT) [11]. This is more likely following cardiac or vascular surgery, when the patient has been exposed to large doses of heparin, and often presents with repeated CRRT circuit clotting [11]. The standard laboratory method for detecting heparin dependent antibodies uses a platelet aggregation assay, utilising platelets from normal healthy donors, the patient’s plasma and the same heparin preparation, as administered to the patient. This screening test may be negative in up to 50% of cases, and if HIT is clinically suspected, then a more sensitive ELISA test using PF4 complexed with heparin should be performed. Low-Molecular-Weight Heparins Low-molecular-weight heparins (LMWHs) are glycosaminoglycans with a molecular weight of around 5 kD and cannot bind to both antithrombin and thrombin simultaneously, thus losing antithrombin activity compared to standard heparin. As inactivation of factor Xa does not require direct heparin binding, LMWH by activating antithrombin, retains anti-Xa activity. The currently available LMWHs, dalteparin, enoxaparin, nadroparin, reviparin, and tinzaparin differ in size, half-life and biological activity, but all have a half-life much greater than for unfractionated heparin, with enoxaparin having the longest at 27.7 h [4]. Compared to standard heparin, LMWHs have been reported to be more effective in reducing fibrin deposition on dialyzer membranes, and extracorporeal clotting, but also less hemorrhagic complications [4]. This appears to be due to both a quicker onset of action that standard heparin, and also less leukocyte and platelet activation [12]. When LMWHs were first used in CRRT most centers either used a loading dose followed by a continuous infusion, or gave further bolus doses

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6 hourly [13]. Although LMWHs are relatively small molecules, they are not significantly cleared during CRRT [7]. More recently, LMWHs have been shown to be effective when started as a continuous infusion without a loading dose (e.g. dalteparin 600 IU/h, tinzaparin 400–800 IU/h ) achieving a mean anti-factor Xa activity of 0.49 IU/ml (therapeutic range for systemic anticoagulation 0.3–0.8 IU/ml) within 1 h of starting CRRT [14]. However, most studies have shown that when low doses of LMWH are used for CRRT, although the risk of hemorrhage has been reduced, filter life and/or patency has similarly been reduced, whereas if higher doses are used the risk of hemorrhage is increased [7]. Thus, LMWH when used either as a fixed or variable dose regime for CRRT does not offer any benefit over standard unfractionated heparin [6, 15]. LMWH by activating antithrombin, retains anti-Xa activity, and special assays are required to determine the inhibition of factor Xa. Commercial kits for testing factor Xa activity must not contain exogenous antithrombin, so that the LMWH dose can be titrated and correlated against anticoagulant activity. The recommended anti-factor Xa activity range for CRRT is 0.2–0.4 U/ml, and this has been shown to allow successful treatment of critically ill patients at risk of hemorrhage [15]. If bleeding does occur, then this may be more severe than standard heparin, due to the prolonged half-life. Protamine may only have a moderate effect, and will depend upon the individual LMWH used, and in severe cases fresh frozen plasma and/or recombinant factor VII may be required. HIT may rarely develop with LMWHs [11], and if so then LMWHs must be discontinued. Danaparoid Danaparoid, is a mixture of glycosaminoglycans: 84% heparan sulphate, 12% dermatan sulphate and 4% chondroitin sulphate, derived from porcine intestinal mucosa. Danaparoid exerts its anticoagulant effect predominantly by activating antithrombin, primarily against FXa but also against thrombin. As danaparoid has a minimal effect on platelets, it has been successfully used in the management of patients with heparin-induced thrombocytopenia, although there is a potential cross reactivity of ⬍5% [11]. Prior to starting danaparoid in cases of HIT, laboratory testing should be undertaken to exclude crossreactivity, as very occasionally in vivo cross-reactivity has been reported [11]. An initial bolus dose is required for CRRT, 2,500 U (35 U/kg) of danaparoid, if there is no hemorrhagic risk, followed by an initial infusion of 400 U/h, which is then adjusted (usually between 200 and 400 U/h) to the desired anti-Xa (0.4–0.6) [11]. Although others have reported that lower doses of danaparoid, initial bolus of 750 U followed by a mean infusion of 138 U/h, have been effective maintaining an anti-Xa activity of 0.2–0.6 [16].

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The major problem with danaparoid is its prolonged half-life. If bleeding occurs, there is no simple antidote and patients may require supportive treatment with activated factor VII concentrate or fresh frozen plasma [4].

Direct Thrombin Inhibitors

Recombinant Hirudin Recombinant hirudin (lepirudin and desirudin) binds to both the active and exosite of thrombin, and is an irreversible thrombin antagonist licensed for treating patients with HIT. Hirudin is excreted renally and the plasma half-life is increased in renal failure from 1–2 to 36–75 h [17]. Thus, the dose has to be modified for CRRT with a bolus of 0.01 mg/kg followed by an infusion of 0.005 mg/kg/h for continuous hemofiltration [18]. Hirudin therapy is associated with an increased risk of hemorrhage, and there is no simple antidote. The dosing of hirudin is made more complex, particularly during CRRT, with greater clearances achieved with polysulphone and polyamide high flux membranes compared to polyacrylonitrile [19]. In addition, a varying number of patients treated continuously with hirudin develop anti-hirudin antibodies, which do not effect the activity of hirudin, but increase the plasma half-life by reducing elimination [11]. Thus there has to be careful monitoring of r-hirudin therapy. Unfortunately the relationship between plasma hirudin concentration and the activated partial thromboplastin time (aPTT) is not linear [11]. Thus maintaining a aPTT of 1.5–2.0 does not necessarily reduce the risk of hemorrhage. Other more specific assays of r-hirudin have been advocated, including a chromogenic assay to determine plasma concentrations, and directly measuring thrombin activity with a viper venom clotting test – the ecorin clotting time [11], but are not routinely available. In cases of hirudin overdosage and/or hemorrhage, high volume hemofiltration can be used to reduce the plasma hirudin levels. Argatroban Argatroban is derived from L-arginine, and reversibly binds to the active enzymatic site of thrombin. Unlike r-hirudin, argatroban is metabolised hepatically and excreted in the bile, with a half-life of 40–50 min. In addition, the aPTT has been shown to have a good correlation with argatroban plasma levels [20]. In the intensive care setting argatroban has become the anticoagulant of choice for the treatment of patients with HIT. As argatroban is a reversible inhibitor with a relatively short half-life, so has to be administered by constant infusion, starting at a dose of 2 ␮g/kg/min (reduced to 0.5 ␮g/kg/min for those with liver disease), and titrating the dose to

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achieve an aPTT ratio of 2–2.5. In clinical practice, an average dose of 0.9 ␮g/kg/min has been reported for CRRT [21].

Regional Anticoagulants

Citrate Although regional citrate anticoagulation has been used for more than 20 years, it is only in the last few years that there has been an increasing usage of citrate for CRRT. Anticoagulation with citrate induces a degree of complexity, as if trisodium citrate is used, then a specialised calcium free, low or zero magnesium, and reduced or bicarbonate free dialysate is required. Calcium then has to be infused centrally to restore the plasma ionised calcium concentration [4]. Citrate, by complexing calcium and reducing calcium concentration, not only prevents activation of the coagulation cascades but also platelets during passage through the dialyzer, but not complement or leukocyte activation. Thus, membrane fouling and deposition of fibrin and platelets is much reduced when citrate is used compared to LMWH and standard heparin. The half-life of the calcium-citrate complex is minutes, and thus citrate is a regional anticoagulant, allowing the successful dialysis of patients at risk of bleeding [22]. Bedside monitoring is possible by using WBACT (200–250 s), however most centers adjust the citrate infusion according the post dialyzer calcium concentration (target 0.25–0.35 mmol/l) [25]. As initially there were no commercially available calcium-free fluids for dialysate or replacement solutions, individual centers developed different protocols. The rate of the citrate infusion is dependent upon the blood flow, and the modality of CRRT, hemofiltration and/or dialysis. Thus during hemofiltration with a blood flow of 180 ml/min the citrate infusion was started at 13.6 mmol/h [23], whereas with continuous hemodialysis with a blood flow of 137 ml/min, the citrate infusion was 17.5 mmol/l [24], and for hemodiafiltration at 125 ml/min, citrate was started at 25 mmol/h [25]. Thereafter, the rate of citrate infusion is adjusted according to the calcium concentration, being reduced if the calcium is less than 0.25 mmol/l, and correspondingly increased when greater than 0.36 mmol/l [25]. More recently, citrate has been used as acid citrate dextrose and centers have successfully used commercial solutions containing both calcium and bicarbonate [26]. Citrate dialysis has been reported to result in citrate intoxication, either when citrate is not metabolised rapidly, if there is hepatic failure or muscle hypoperfusion, or during isolated ultrafiltration, when citrate is not being dialysed out. Failure to adequately metabolise citrate results in an increased total calcium to ionized calcium ratio (⬎2.5), due to the accumulation of the

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calcium-citrate complex. Not surprisingly this has been most commonly reported in patients with liver failure [27], and should be managed by decreasing the citrate infusion [25]. During CRRT hypernatremia can occur due to the sodium load if trisodium citrate is used, and thus many centers have developed specialised hyponatremic dialysates [22]. Similarly, as each citrate molecule is metabolised through to three bicarbonates, patients are at risk of developing a metabolic alkalosis. To compensate many centers use specialised dialysates and/or replacement solutions with a high chloride load [22]. Many patients treated by CRRT in one study developed metabolic alkalosis and hypomagesemia after 7 days when using commercial bicarbonate based fluids [26]. To overcome some of these problems, some centers have used citrate dextrose-A rather than 4% trisodium citrate, or reduced the citrate concentration, in combination with a reduced bicarbonate dialysate concentration to 25 mmol/l [26]. Another approach when using a twin bag bicarbonate system was not to add the bicarbonate compartment when patients developed alkalosis. Despite the apparent complexity of using citrate, and the potential array of metabolic disturbances, citrate use is growing in popularity for CRRT, as it is a highly effective anticoagulant, with much longer average circuit lives of 29–82 h compared to standard heparin [22–26]. Indeed as citrate is such an efficient regional anticoagulant, access problems are a more common cause of circuit clotting, especially if the calcium infusion is returned into the venous dialysis line. Prostanoids Prostacyclin (PGI2) is a natural anticoagulant produced by endothelial cells, by the breakdown of arachidonic acid. PGI2, and its analogue epoprostenol, are potent antiplatelet agents blocking cAMP, and have been shown to reduce platelet micro thrombi during hemodialysis and CRRT compared to standard heparin and LMWH [4]. Although both agents are potent arterial vasodilators, most patients do not develop symptomatic hypotension at the doses used (PGI2 5 ng/kg/min, range 2.5–10 ng/kg/min), as some 40% of the dose is lost during passage through the dialyzer [28]. As the half-life is in minutes, any hypotensive episode can readily be reversed by stopping the infusion. Other prostanoids, such as PGE1 (alprostadil), PGE2 and PGD also have antiplatelet effects and can be used as extracorporeal anticoagulants. As PGE1 is metabolised in the lung it has less systemic vasodilatory properties compared to prostacyclin, and does not cause hypotension. These prostanoids are not as potent as PGI2, and thus the dose of alprostadil required is 5–20 ng/kg/min. PGI2 does not have any direct effect on the plasma coagulation pathways, so its anticoagulant activity can not be readily assessed, even by thromboelastography [4]. Thrombin generation does occur during dialysis with PGI2,

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and some authors have advocated a combination of reduced doses of both heparin and PGI2 [29]. Some groups have found PGI2 and prostanoids to be equally effective as heparin in maintaining CRRT circuit life, with better filter patency [30]. When used as the sole extracorporeal anticoagulant, PGI2 has been shown to significantly reduce the incidence of haemorrhage in patients at risk of bleeding [30], as PGI2 and its analogues are essentially regional rather than systemic anticoagulants. However, PGI2 and epoprostenol are some 25⫻ more expensive than standard heparin. Nafamostat Maleate Nafamostat maleate is a serine protease inhibitor, which inhibits broad enzymatic systems including coagulation cascades, platelet and complement activation, kinin and fibrinolysis cascades. Nafamostat mesilate has a short half-life of 5–8 min, and some 40% is cleared during passage through the dialyzer [31]. By inhibiting thrombin, factor Xa and XIIa, nafamostat prolongs the WBCT, ACT and aPTT, thus allowing bedside monitoring. Most experience comes from Japan, where the circuit is primed with 20 mg of nafamostat in 1.0 l normal saline, and then nafamatostat initially infused at 40 mg/h during CRRT, to maintain a target aPTT ratio of 2.0 ⫻ normal [32]. As nafamostat is a small molecule which is partially cleared by the extracorporeal circuit, the dose required for CRRT using hemodiafiltration is greater than that for hemofiltration (0.3 vs. 0.1 mg/kg/h) [4]. Nafamostat contains a cationic portion which binds to negatively charged polyacrylonitrile membranes, and also to some extent to polymethylmethacrylate membranes, if these membranes are used then the nafamostat dose has to be increased.

Circuit Design for CRRT

The key with any extracorporeal circuit design is to minimise activation of leukocytes and platelets, as platelets preferentially move to the periphery of the flow, so contact the wall of the plastic tubing and dialyzer fibers. Clotting starts in the outer fibers of the dialyzer, where blood flow is slower. Membrane design, in terms of composition, surface and geometry has been shown to affect thrombus formation [33]. Similarly, a dialyzer with a large surface area will be more likely to result in thrombus deposition, than a more efficient, or porous membrane of smaller surface area. If ultrafiltration rates are high then this may additionally result in increased protein deposition or fouling of the hemofilter membrane and the combination with hemoconcentration increase the risk of filter clotting. Thus, administration of the hemofiltration

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substitution fluid pre-filter minimises hemoconcentration within the fiber bundles and prolongs circuit life [34]. Mechanical activation due to turbulent blood flow occurs both with the access catheter and the blood pump. Thus venous access catheter insertion site, catheter design, composition and coating all affect the risk of thrombosis [4], for example heparin coated venous access catheters have been reported to cause less circuit clotting [35]. Surprisingly, the change from spontaneous to pumped CRRT circuits was associated with a reduction in circuit lives [8], due to the introduction of faster blood flows, which generated wide pressure swings [4]. A redesign of the blood pump, to improve laminar flow may well help to reduce the propensity to clot the circuit.

Conclusions

When CRRT is truly continuous, it provides very effective solute control, with acid-base balance, electrolyte and water balance. However, the Achilles’ heel of CRRT is circuit clotting and down time. The advent of pumped CRRT with increasing ultrafiltration volumes to achieve greater treatment efficiency, has paradoxically led to shortened circuit lives with standard heparin regimes. Increased systemic heparinisation is associated with an increased risk of hemorrhage. This has led to an increased interest in regional anticoagulants such as citrate. When citrate was first introduced into CRRT, it was shown to be a highly effective regional anticoagulant with a prolonged circuit life, but required an on-site sterile pharmacy to produce specialised dialysate and replacement fluids. Today, units are now experimenting with dialysates and fluid replacement using commercially available bicarbonate twin bag systems.

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Ronco C, Bellomo R, Hamel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure. Lancet 2000; 356:26–30. Mehta RL, McDonald B, Gabbai FB, Aphl M, Pascual MTA, Karkas A, Kaplan RM: A randomised controlled trial of continuous versus intermittent dialysis for acute renal failure. Kid Int 2001;60:1154–1163. Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R: Continuous is not continuous: The incidence and impact of ‘circuit down time’ on uremic control during continuous veno-venous hemofiltration. Intens Care Med 2003;29:575–578. Davenport A: Anticoagulation in patients with acute renal failure treated with continuous renal replacement therapies. Home Hemodial Int 1998;2:41–60. Holt AW, Bierer P, Berstein AD, Bury LJ, Vedig AE: Continuous renal replacement therapy in critically ill patients: Monitoring circuit function. Anaesth Intens Care 1996;24:423–424.

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Shulman RI, Singer M, Rock J: Keeping the circuit open: Lessons from the lab. Blood Purif 2002; 20:275–281. Davenport A: Problems with anticoagulation; in Lameire N, Mehta R (eds): Complications of Dialysis: Recognition and Management. Boston, Marcel Dekker, 1999, pp 215–240. Favre H, Martin Y, Stoermann C: Anticoagulation in continuous extracorporeal renal replacement therapy. Semin Dial 1996;9:112–118. van der Wetering J, Westendorp RGJ, van der Hoeven JG, Stolk B, Feuth JDM, Chang PC: Heparin use in continuous renal replacement therapies: The struggle between filter coagulation and patient hemorrhage. J Am Soc Nephrol 1996;7:145–150. Bellomo R, Teede H, Boyce N: Anticoagulant regimens in acute continuous hemodiafiltration: A comparative study. Intens Care Med 1993;19:329–332. Davenport A: Heparin induced thrombocytopenia during renal replacement therapy. Hemodial Int 2004;in press. Leitienne P, Fouque D, Rigal D, Adeleine P, Trzeciak MC, Laville M: Heparins and blood polymorphonuclear stimulation in hemodialysis: An expansion of the biocompatibility concept. Nephrol Dial Transplant 2000;15:1631–1637. Wynckel A, Bernieh B, Toupance O, N’Guyen PH, Wong T, Lavaud S, Chanard J: Guidelines to the use of enoxparin in slow continuous dialysis. Contrib Nephrol. Basel, Karger, 1991, vol 93, pp 221–224. Schepens D, De Keulenaer B: Efficacy and safety of nadropine as anticoagulant therapy in continuous venovenous hemofiltration. Blood Purif 2002;20:314. Reeves JH, Cumming AR, Gallagher L, O’Brien JL, Santamaria JD: A controlled trial of low molecular weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration. Crit Care Med 1999;27:2224–2228. Lindhoff-Last E, Betz C, Bauersachs R: Use of a low-molecular-weight heparinoid (danaparoid sodium) for continuous renal replacement therapy in intensive care patients. Clin Appl Thromb Hemost 2001;7:300–304. Fischer KG: Hirudin in renal insufficiency. Semin Thromb Hemostat 2002;28:467–482. Schneider T, Heuer B, Deller A, Boesken WH: Continuous haemofiltration with r-hirudin (lepirudin) as anticoagulant in a patient with heparin induced thrombocytopenia (HIT II). Wien Klin Wochenschr 2000;112:552–555. Frank RD, Farber H, Lanzmich R, Floege J, Kierdorf HP: In vitro studies on hirudin elimination by haemofiltration: Comparison of three high flux membranes. Nephrol Dial Transplant 2002;17: 1957–1963. Hursting MJ, Alford KL, Becker JC, Brooks RL, Joffrion JL, Knappenberger GD, Kogan PW, Kogan TP, McKinney AA, Schwarz RP Jr: Novostatin (brand of argatroban): A small molecule, direct thrombin inhibitor. Semin Thromb Hemostat 1997;23:503–516. Reddy BV, Nahlik L, Trevino S, Murray PT: Argatroban anticoagulation during renal replacement therapy. Blood Purif 2002;20:313–314. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kid Int 1990;38:976–981. Palsson R, Niles JR: Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding. Kid Int 1999;55:1991–1997. Tolwani AJ, Campbell RC, Schenk MB, Allon M, Warnock DG: Simplified citrate anticoagulation for continuous renal replacement therapy. Kid Int 2001;60:370–374. Kutsogiannis DJ, Mayers I, Chi WD, Gibney RT: Regional citrate anticoagulation in continuous venovenous hemodiafiltration. Am J Kid Dis 2000;35:802–811. Bunchman T, Maxvold NJ, Barnett J, Hutchings A, Benfield MR: Pediatric hemofiltration: Normocarb dialysate solution with citrate anticoagulation. Pediatr Nephrol 2002;17:150–154. Meier-Kriesche H-U, Gitomer J, Finkel K, DuBose T: Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med 2001;29:748–752. Zobel G, Ring E, Kuttnig M, Grubbauer HM: Continuous arteriovenous hemofiltration versus continuous venovenous hemofiltration in critically ill pediatric patients. Contrib Nephrol. Basel, Karger, 1991, vol 93, pp 257–260.

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Langenecker SA, Felfernig M, Werba A, Mueller CM, Chiari A, Zimpfer M: Anticoagulation with prostacyclin and heparin during continuous venovenous hemofiltration. Crit Care Med 1994;22: 1774–1781. Davenport A, Will EJ, Davison AM: Comparison of the use of standard heparin and prostacyclin anticoagulation in spontaneous and pump driven extracorporeal circuits in patients with combined acute renal and hepatic failure. Nephron 1994;66:431–437. Akizawa T: Beneficial characteristics of protease inhibitor as an anticoagulant for extracorporeal circulation. Rinsho Ketsueki 1990;31:782–786. Matsuo T, Kario K, Nakao K, Yamada T, Matsuo M: Anticoagulation with nafamostat mesilate, a synthetic protease inhibitor, in hemodialysis patients with a bleeding risk. Haemostatasis 1993;23: 135–141. Sperschneider H, Deppisch R, Beck W, Wolf H, Stein G: Impact of membrane choice and blood flow pattern on coagulation and heparin requirement potential consequences on lipid concentrations. Nephrol Dial Transplant 1997;12:2638–2646. Davenport A: Pre vs. postdilution for continuous veno-venous hemofiltration? That is the question. Nephron Clin Pract. 2003;94:c83–c84. Davenport A: Central Venous Catheters for Hemodialysis: How to overcome the problems. Home Hemodial Int 2000;2:43–45.

Dr. A. Davenport Center for Nephrology, The Royal Free Hospital Pond Street, London NW4 2QG (UK) Tel. ⫹44 20 783 022 91, Fax ⫹44 20 783 021 25, E-Mail [email protected]

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Which Treatment for ARF in ICU? Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 239–254

Peritoneal Dialysis in Acute Renal Failure of Adults:The Under-Utilized Modality S.R. Ash Greater Lafayette Health Systems, Arnett Clinic, and HemoCleanse, Inc., Lafayette; Adjunct Associate Professor, Purdue University, West Lafayette, Ind., USA

Among various dialysis therapies for acute renal failure in the adult, today’s nephrologists think of CVVHD or intermittent hemodialysis long before considering peritoneal dialysis, making acute peritoneal dialysis a considerably underused therapy [1]. This is in spite of the numerous problems encountered with the extracorporeal therapies that are eliminated with use of the peritoneal membrane. In fact, the peritoneum can be considered the ‘perfect’ membrane for continuous arteriovenous hemofiltration and dialysis (CAVHD) providing: (a) natural membranes located within the body; (b) permeability to uremic toxins and limited passage of albumin and tightly-bound toxins; (c) limited passage of antibodies and that cause kidney failure in some patients; (d) infallible blood access with blood flow rate of about 200 ml/min; (e) controllable ultrafiltration rate; (f) biocompatibility of blood pathways, obviating need for anticoagulants; (g) impermeability to bacteria in dialysate, preventing septicemia after dialysate contamination; (h) permeability to white cells into dialysate if there is bacterial contamination, to limit proliferation and provide a visible sign of the contamination; (i) passage of effluent blood from the membranes directly to the liver, allowing metabolic conversion of lactate, glucose or various nutrients, and (j) ease of use, allowing continuous 24-hour dialysis by merely intermittently infusing and draining modest volumes of sterile dialysate through a permanent access. As with all dialysis procedures, peritoneal dialysis (PD) was first used in therapy of acute renal failure (ARF) [2]. Now CAPD or cycler therapy supports about 12% of patients with ESRD in the United States [3]. The success of CAPD in support of patients with ESRD has reminded physicians that PD can

Table 1. Comparison of mortality in ARF⫺PD vs. HD Group (first author)

Orofino [12] Firmat [13] Ash [2] Swartz [11] Struijk [14] Struijk [15] Phu [12]

Year

1976 1979 1983 1980 1980 1986–1999 2002

Patients

82 1,101 97 77 45 50 70

Mortality, % PD

HD

52 50 38 44 45 78 47

62 50 48 60 (same) (same) 15

also be used for treatment of ARF in adults. In some countries such as Japan, PD was a more common choice for treatment of ARF in adults than CAVH in 1987 [4]. In ARF, PD is appropriate for the same types of patients for which CAVH is chosen: those with heart failure and low cardiac index who cannot tolerate the rapid fluid removal rate of standard hemodialysis (HD) [4]. PD is still the mainstay for treatment of ARF in infants and children [5, 6] and has a risk of complications in the range or lower than CAVHD (as discussed below). In infants and children in one study, and using a surgically placed Tenckhoff catheter, incidence of all types of complications during the course of renal failure were only 9%, versus 49% for patients with a transcutaneously placed acute catheters [7]. With chronic peritoneal dialysis, complications are measured in number per year, rather than number per week. The first 6 studies in table 1 have shown that patients with ARF treated by PD have a mortality and incidence of renal recovery at least equal to similar patients treated by HD, and possibly better. In these studies the percentage of patients dying from ARF and complications was less than or equal for patients treated with PD treatments versus those treated with HD. The article by Firmat reviewed literature reports including over 1,100 patients, and in summation the mortality rate was identical for ARF patients receiving PD and HD. Most of these studies were performed in the 1970s and 1980s. However, Dr. Struijk continued analyzing patients treated by each modality at the Academic Free Hospital in Amsterdam from 1986 through 1999. Although the mortality was high for ARF patients treated by PD, the mortality was identical to that of patients treated with HD. In our own study of 100 patients with ARF in two community hospitals reported in 1983, over half were treated by PD [2]. There was a higher rate of recovery of renal function (and survival) following ARF for patients treated by PD vs. HD (fig. 1). Whether the course of ARF and dialysis

Ash

240

70 PD

p⫽0.3

HD

Percent recovery

60 50 p⫽ 0.3 40 p⫽0.17

30 20 10 0

45

00

⬍7 days

⬎7 days

13 1

24

⬍7 days

⬎7 days

*Statistics by chi-squared

Mode and length of treatment

Fig. 1. Comparison of patient recovery (survival) after acute renal failure, in patients treated by continuous peritoneal dialysis (left) versus those treated by intermittent hemodialysis (right) in two hospitals in Lafayette, Indiana between 1979 and 1982. For both types of dialysis, one bar indicates outcome for patients treated less than 7 days before recovery or death, and the other bar indicates outcome for patients treated for more than 7 days.

was short (less than 7 days) or long (more than 7 days) there was a higher rate of recovery for the PD patients versus HD patients (though results were not significant). We repeated this study 10 years later and in study of 145 patients we found the same result, a 10% higher patient survival for patients treated by PD versus HD. In a more recent study by Phu et al. [16], 70 adult patients with acute renal failure, 48 due to severe falciparum malaria and 22 due to sepsis, were randomized to treatment by peritoneal dialysis or by CVVH. The mortality was significantly higher in the group treated by peritoneal dialysis versus hemofiltration (47 vs. 15%) and there was a diminished rate of renal recovery. The peritoneal dialysis schedule was very aggressive (70 liters of fluid per day), and delivered a dialysis dose for urea probably equal to that of CVVH but a creatinine dose probably half of CVVH [49]. This study stands in opposition to prior studies of table 1 above, and what is most unusual is the exceedingly low mortality of the group treated with CVVH, rather than an unusually high mortality in the group treated with PD. Also the study dealt with a high proportion of renal failure following falciparum malaria. It is possible that the heparin anticoagulation of CVVH was of benefit to these patients. Also, hyperglycemia may have stimulated malarial growth in the liver or red cells, or high osmolality may have diminished white cell function [49]. Failure to correct acidosis may have been due to use of acetate rather than lactate or bicarbonate as buffer

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in the PD solution. Finally, the authors used rigid acute catheters for access and open drainage systems; there was a high incidence of cloudy fluid though a very low incidence of proven peritonitis [49]. Except for the study by Phu, none of these studies were randomized or prospectively controlled, and there was bias in patient selection in the studies. However, this bias was both for and against patients treated by PD. ARF patients with abdominal trauma, abdominal surgery and remaining drains, and severe ileus cannot be treated by PD, and these patients may have a higher mortality rate. However, in general, patients with ARF following surgery have a higher rate of recovery from ARF than do patients with other causes of ARF such as sepsis or shock. PD was often chosen in these studies for patients with hypotension or cardiovascular instability that would make HD dangerous, also selecting a group with a potentially worse outcome. The techniques used for PD in most of these studies were antiquated by today’s standards. In many of the studies, semi-rigid acute PD catheters were used. These catheters had irregular outflow characteristics, and had to be removed and re-inserted every three days. Each insertion carried an increased risk of bowel puncture and outflow failure. PD fluid was infused from bottles in many of the studies, and there were few Y-sets to allow drainage and infusion of PD fluid though a single catheter connection. In spite of all of these disadvantages, in these studies PD patients recovered renal function and survived at least as frequently as patients treated with HD, with the notable exception of the study by Phu. In many of the studies of PD versus HD for ARF, the reason for improved survival in the PD group was related to an increased rate of renal recovery. Very few patients with ARF recover general health and leave the hospital without recovering renal function, thus to be supported by dialysis as ESRD patients. In patients with ESRD, treatment by CAPD results in better preservation of intrinsic renal function than treatment by intermittent HD [17–20]. This preservation of renal function is important in ESRD because it maintains endocrine function of the kidneys, diminishes the clearance requirements for dialysis, minimizes required ultrafiltration during dialysis and therefore diminishes physiologic stress during dialysis [17]. Intermittent HD has several known nephrotoxic effects: (a) generation of inflammatory mediators by the extracorporeal circuit [17]; (b) concomitant and rapid decrease in osmolality and vascular volume, diminishing renal perfusion, and (c) hypotensive episodes resulting in fresh ischemic lesions in the kidneys [21]. By contrast, CAPD therapy has effects which help to maintain renal perfusion: (a) smaller daily variation in body weight; (b) more constant blood pressure; (c) continued mild overhydration, with higher mean pulmonary arterial pressure [17]; (d) persistent high blood osmolality, partly due to glucose [17], and (e) continued removal of proteins from the blood, including ␤2-microglobulin,

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albumin, plasminogen-activator inhibitor type 1 (PAI-1) and immunoglobulins [12, 22, 23]. Given the beneficial effects of PD, it is not surprising that some patients with ESRD and recent initiation of CAPD actually recover intrinsic renal function and no longer need dialysis (3.3%). Given the negative physiologic effects of HD, it is not surprising that very few ESRD patients treated by intermittent HD recover renal function (0.8%) [17]. Recovery of renal function is most frequent in patients whose renal failure was caused by: uncontrolled hypertension, cardiac failure, nephrotic syndrome, rapidly progressive renal failure, analgesic nephropathy, urinary obstruction, and cholesterol emboli [17]. Many of these underlying conditions are better corrected by CAPD than HD, due to its continuous chemical removal, better preservation of renal perfusion and glomerular filtration rate [10], and slow removal of immunoglobulins. These same physiologic and chemical benefits may account for the higher recovery of renal function in most studies, in patients with ARF treated by PD than with HD discussed above [8–14]. There is general consensus that continuous dialysis therapies such as CVVH or CVVHD are the most chemically effective therapies for ARF, with the fewest adverse physiologic effects. Approximately 1/4 of all ARF patients in the US are treated with CVVH and CVVHD. These ‘gentle’ forms of therapy remove fluid at a slow rate and therefore do not decrease cardiac output. They also do not adversely affect pulmonary function and do not activate the complement cascade [6]. CAVH was first described in 1967 [24]. Pump-assisted CVVH and CVVHD were developed to make blood flow rate through the hemofilter more consistent, improve clearances and make the therapy more nearly continuous. Continuous blood therapies require considerable attention by nurses to assure adequate blood flow, monitor anticoagulation status, adjust the ultrafiltration rate, and calculate the fluid balance of the patient. The patient is generally immobilized during the treatment. Continuous heparin administration increases risk of bleeding. Vascular access catheters often provide insufficient blood flow and have a risk of infection leading to sepsis [4–6]. In spite of the name and intent, the average duration of individual treatments with ‘continuous’ blood therapies is 20 h before clotting of the system or need for discontinuation to transport the patient for diagnostic or therapeutic procedures. By contrast, PD is a truly continuous dialysis therapy, with less risk and less nursing effort than CVVH or CVVHD, more mobility during therapy. Some centers previously performing CVVH or CVVHD for acute dialysis have begun using slow low efficiency hemodialysis (SLED) with extended duration (6–8 h per day) to avoid many of the problems of CVVH or CVVHD, limiting heparin use and immobility of the patient while keeping the advantages of vascular stability and improved clearances [25].

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Table 2. Comparison of time-averaged clearance of four modalities in treatment of ARF (average clearance per day, ml/min)

Urea Creatinine Phosphate Vitamin B12

CAVH

CVVHD

Daily HD

PD

15 15 10 5

35 30 12 6

25 25 10 6

12 8 6 5

The major criticism of PD, of course, is a low clearance of uremic toxins, and for low-molecular-weight toxins the clearance for small toxins is in fact lower than other therapies. For continuous therapies, the time-averaged clearance is the same as the immediate clearance. For intermittent therapies, the time-averaged clearance is diminished in proportion to the time between dialysis therapies. Table 2 compares the time averaged clearance of various modalities used in treatment of ARF, over 24-hour periods. The assumptions used in this analysis are: (a) CAVH is performed with ultrafiltrate rate of 1 liter/h (15 ml/min); (b) CVVHD is performed with ultrafiltrate rate of 15 ml/min and an additional 2 liters/h of dialysis flow; (c) HD is performed for 4 h, every other day, with blood flow of 250 ml/min and urea clearance of 150 ml/min, and (d) PD is performed with 2 liter exchanges every 2 h. From table 2, it is apparent that PD with a modest dialysate use of 1 liter/h is less efficient than other modalities for urea and creatinine, but is similarly efficient in removal of larger molecules such as vitamin B12. The real question is what are the real uremic toxins, and what are their molecular weights? Urea and creatinine are not toxic. The very success of peritoneal dialysis in ESRD and SLED in acute dialysis would indicate that it is likely that larger molecular weight toxins are the real causes of uremic illness. Peritoneal dialysis is quite effective in removing various anionic organic compounds that function as middle molecules (fig. 2). In ARF, clinical experience confirms that PD results in equal or greater rate of resolution of uremic symptoms and patient survival the same as the other therapies (described above). Besides removal of uremic toxins, of course, dialysis must also remove fluid and salt from the patients. With a properly functioning PD catheter, exchanges of 2 liters of dialysate with 2.5 or 4.25% glucose concentration provides daily fluid removal at the same or greater rate than other regimens, without causing hypotension in most patients. In patients with refractory congestive heart failure (CHF) fluid removal is the main goal, and with PD therapy and hypertonic dialysate, improvement in clinical symptomatology and left ventricular function

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100

Absorbance at 254nm UV (%)

Gradient: 0⫺100% in 20min Sensitivity: 0.01 A.U.F.S. Flow rate: 1ml/min Dwell: 2 h Dwell: 4 h Dwell: 8 h ␦

2h ␨

4h

8h

␤

␩ ␴␬ ␣ 0 100%

0%

100%

0% 0% Gradient

100%

Anion exchange chromatograms of 2L of peritoneal fluid removed from one patient after dwells of 2, 6, and 8 hours

Fig. 2. Increase in anionic organic compounds within peritoneal dialysis fluid, over periods of 2, 4 and 8 h in a patient with ESRD. Chromatograms generated by direct anionexchange chromatography without protein removal [22].

is routine. In one study of 20 patients with resistant CHF, all improved with only twelve in/out cycles [26]. Just as with CVVHD, the small molecular clearance of PD can be greatly increased by increasing the flow rate of dialysate to 1.5–2 liters/h or more. Tidal peritoneal dialysis (TPD) can easily deliver 2 liters/h into and out of the peritoneum, and using a cycler automated TPD is only a little more complicated than manual in/out exchanges. In a recent study of ARF patients, a peritoneal dialysate flow rate of 2 liters/h produced an average normalized creatinine clearance of 68.5 liters/week/1.73 m2 BSA and a urea Kt/V of 2.43, versus average values for ‘equilibrium’ PD of 58.9 and 1.80, respectively. Both TPD and manual exchange PD were adequate for treatment of ARF patients with mildto-moderate hypercatabolism [27]. The future of peritoneal dialysis for ARF may rest with an old but good idea, continuous flow PD (CFPD). CFPD utilizes two access points and CFPD, one for inflow of dialysate and the other for outflow. Since there is no interruption of inflow to allow outflow, flow rates are determined only by the rate at which the draining catheter can reproducibly drain the abdomen. With CFPD dialysate flow rates of up to 300 ml/min can be maintained through the peritoneum [28]. With use of an external dialyzer to ‘regenerate’ the dialysate, urea,

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creatinine, and urate clearances average 57, 35, and 39 ml/min, respectively, in adult patients [29]. At 170 ml/min of dialysate flow, urea and creatinine clearances have averaged 31 and 23 ml/min, respectively [30]. Recent studies with dialyzer-regenerated PD fluid and using dual Tenckhoff catheters have confirmed urea clearances of 50 ml/min or more in several ARF patients [31]. CFPD has also been used principally for fluid overload. In 6 pediatric patients with ARDS due to sepsis or SIRS, CFPD at 10–30 ml/kg/h with two Tenckhoff catheters resulted in a decrease of body weight by an average of 33% and an improvement in alveolar-arterial oxygen gradient [33]. With CFPD the timeaveraged clearance of PD can theoretically exceed that of daily 4-hour HD and come close to those of CVVH or CVVHD, and approach the KoA or maximal clearance theoretically obtainable from the peritoneum [32]. These high dialysate high flow rates seem unrealistic today only because we are accustomed to using expensive, pre-packaged dialysate and gravity flow. However, if PD machines reappear which proportion fluid on site, or if sorbent-based regenerative systems are commercialized [34–36], peritoneal dialysate will be available at just about any flow rate desired. Another requirement for CFPD to be successful is to have effective drainage of the peritoneum at relatively high flow rates. Theoretically this is not difficult because the standard Tenckhoff can drain the abdomen at 300 ml/min or more under gravity flow in CAPD during the early part of outflow. However, flow from Tenckhoff catheters is somewhat variable, and during in CAPD exchanges if there is a diminution in flow then this merely represents a slower outflow and some inconvenience. In CFPD at 300 ml/min, it is possible to build up an extra liter of fluid in the peritoneum in only a few minutes. The Advantage™ ‘t-fluted’ peritoneal catheter is a new chronic peritoneal catheter with grooves rather than holes on two limbs that lie against the parietal peritoneum. The catheter provides higher flow rate and more complete drainage of peritoneal fluid than the standard Tenckhoff catheter. The use of this catheter may make performance of PD in patients easier in patients with ARF, even if they have mild ileus [37, 38]. The catheter may also provide faster and more reliable drainage for CFPD, using a second site for infusion of fluid into the peritoneum or one limb of the T-shaped catheter for infusion and one for drainage [39]. The final challenge for CFPD to be successful is to develop methods for controlling the intraperitoneal volume. An animal study has demonstrated that there is an optimal peritoneal volume for highest efficiency of the peritoneum in CFPD, about 1.5 liters in the dog [40]. With in-and-out manual PD the abdomen is drained fairly well at the end of each outflow cycle. With CFPD, as with TPD, the amount of fluid going into and out of the abdomen may be known, but the intraperitoneal volume is unknown because of the variability of

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246

Gravity infusion at 1.5–3 liters/h

Drain bag placed flat at 6 cm above umbilicus: Advantage catheter

a

Viscera

b

Fig. 3 a, b. Simplified method for controlling intraperitoneal pressure and volume during CFPD by placing the drain bag above the umbilicus. a Proposed method in patient. b Method used in adult horse with ARF.

UF rate. In TPD the abdomen is drained in the middle of an 8 hour treatment, to restart the treatment with a near zero intraperitoneal volume. With CFPD a similar approach could be taken, but a simpler approach is to control the intraperitoneal pressure rather than the volume. Since the compliance of the peritoneum is relatively constant and symptoms relate to pressure rather than volume, controlling the pressure in the peritoneum provides a relatively constant volume and lack of symptoms [28]. To provide a constant peritoneal pressure using an Advantage catheter or other well-functioning catheter is fairly easy for a supine patient with ARF. Infusion of peritoneal fluid through a second site is performed at up to 1.5–3 liters/h, and the Advantage catheter is attached to a drain bag that lies flat upon a bedside stand, 6 cm above the umbilicus. This provides an intraperitoneal pressure of 12–15 cm, a comfortable level for the patient (fig. 3a). UF rate is determined by intermittently weighing the PD drain bag and subtracting the inflow bag weight. This method should be relatively simple to perform manually, but even simpler with automated regenerating PD equipment. Though pressure-control not yet been tested in CFPD in patients, it has been used in one horse with non-oliguric ARF and a creatinine

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level of 16 [41]. The draining catheter was a large chest tube in the lower abdomen, and for pressure control the drain bags were attached to the withers similar to saddle bags (fig. 3b). Fluid infusion rate was 72 liters per day and with CFPD chemical efficiency was approximately twice that of in/out exchanges (D/P near 1 for creatinine and urea). The horse recovered from renal failure and is doing well today. The fact that PD results in significant protein loss (5–20 g/day) is generally considered a nutritional problem. However, this loss of protein contributes to the chemical effectiveness of the procedure. In patients with hemolytic uremic syndrome, PD significantly reduces plasinogen-activator inhibitor type 1 (PAI-1) which inhibits fibrinolysis in hemolytic uremic syndrome [42]. Most of the organic anions removed by PD in uremic patients are in fact strongly bound to protein, so protein output or ‘loss’ increases their clearance [22]. These protein-bound organic anions act like middle molecules because the protein binding restricts their passage across dialysis membranes; they are still accumulating in peritoneal dialysate at 8 h dwell (fig. 2). The presence of protein within the dialysate facilitates the transfer of these compounds into the peritoneum. The peritoneal transfer of protein can be increased by application of hypertonicity and pharmacotherapy, the globulin removal by PD on a daily basis could equal or exceed daily therapeutic plasmapheresis [23]. Every therapy for ARF has some risks. In ARF the success and risks of various dialysis modalities relate in part to the access devices needed to provide them. If acute catheters are used in peritoneal dialysis, each catheter can be used for only three days without high risk of peritonitis or bowel perforation, and each successive catheter has a higher risk of these complications. For acute PD to be performed effectively and safely, a chronic tunneled peritoneal dialysis catheter must be the access device. Chronic PD catheters were used in the studies by Ash and Struijk but rigid acute catheters were used in the study by Phu [2, 14, 16]. Chronic PD catheters can be placed at the bedside in the ICU, procedure rooms, or surgery under local anesthesia. Using the peritoneoscopic technique and local anesthesia, it takes only 15–30 minutes to place a chronic 2-cuff Tenckhoff catheter for by peritoneoscopy with the Y-TEC procedure, just as is done for patients with ESRD [43]. Peritoneoscopically placed catheters are usually placed at the lateral border of the rectus and can be directed to lie against the parietal peritoneum in a direction avoiding adhesions and bowel loops. The parietal peritoneal surface provides a more consistent flow of fluid from the abdomen during outflow. Peritoneoscopically placed catheters have the highest rate of successful hydraulic function in the first few weeks of use and over years of use [44]. With a properly functioning chronic peritoneal access, the effectiveness of PD is increased and risks are considerably diminished, since one

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Table 3. Bacteriology of peritonitis in PD of ARF Organism Staphylococcus aureus Staphylococcus epidermidis Multiple gram-negative organisms Escherichia coli Other gram-negative organisms Multiple (gram-positive and -negative) Candida sp. Culture-negative Total

n

%

2 7 4 1 2 2 7 2

7 26 15 4 7 7 26 7

27

100

catheter is used for the duration of ARF therapy. Tenckhoff catheters allow peritoneal access for years rather than the days of safe use for acute PD catheters. Advantage catheters can also be placed peritoneoscopically by expanding the initial 2 mm puncture site to 9 mm diameter [45, 46]. During the same procedure a second small infusion catheter can also be placed with an entry to the peritoneum several inches or more from the Advantage catheter and directed towards the opposite quadrant if CFPD is planned. Among therapies for ARF, PD has the unique risk of causing peritonitis. However, in patients in whom infection is suspected as a cause of ARF, performing PD can be helpful in assuring that peritonitis is not present. In other patients, if peritonitis is detected, diagnostic tests can be implemented to determine the source and antibiotic therapy begun to treat the infection. When nurses are properly trained they soak the connectors with pvp-iodine, put on a mask and nonsterile gloves and use care in performing connections. The risk of contamination of PD fluid is minimal during each exchange. The incidence of peritonitis in PD therapy of ARF is much different than in CAPD therapy. If peritonitis is detected during therapy of ARF with PD it usually occurs within 2 or 3 days of starting therapy [11, 47]. This indicates that PD may detect contamination of the peritoneum that predates the implementation of PD. The organisms causing peritonitis in ARF patients are much different from the organisms causing peritonitis in CAPD patients. There is predominance of Staphylococcus epidermidis and Candida species not usually seen in peritonitis in CAPD patients (table 3) and mixed infection is frequent [48]. If peritonitis occurs during PD therapy, it causes cloudy dialysate and sometimes local symptoms, but does not usually result in septicemia in the ARF patient. This is a much different outcome than catheter infection during hemodialysis or CVVH, which always results in septicemia.

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Table 4. Complications of dialysis in ARF1 [9]

Number (dialyses, patients) Severe hypotension2 Severe hemorrhage3 Metabolic complications Hyperglycemia (250 mg/dl) Hypernatremia (150 mEq/l) Acidosis Neurologic complications Seizures Deterioration in state of consciousness Mechanical complications Mild bleeding Poor drainage, leaking Shunt clotting Infection Shunt infection Peritonitis Asymptomatic positive peritoneal cultures

HD

PD

240, 34 85/240 (35%) 15/34 (44%)

65, 43 8/65 (12%) 2/43 (5%) 37/65 (57%) 2/65 (3%)

9/34 (26%) 1/34 (3%)

3/43 (7%) 9/65 (14%) 17/65 (26%) 34/65 (52%)

11/34 (32%) 2/34 (6%) 4/34 (12%) 19/65 (29%)

1Expressed

as a fraction of total dialysis or total patients. pressure ⬍90 mm Hg systolic, requiring blood products or pressor administration. 3Requiring transfusion. 2Blood

The complications of PD and hemodialysis for ARF have been compared in one center providing both types of therapy [9]. In this study by Swartz, the patients treated by HD had a high incidence of severe hypotension and severe hemorrhage, acidosis and shunt clotting. PD patients had a high incidence of hyperglycemia, poor catheter drainage, and asymptomatic peritonitis (table 4). The major causes of death of ARF patients were also different for patients treated by HD and PD. Death from dialysis unrelated sepsis was higher for the HD group, while cardiac deaths were higher in the PD group due to the more frequent implementation of this therapy in patients with underlying heart disease (table 5). When comparing the overall risks of each type of therapy for ARF, there are marked differences between CVVH, CVVHD, HD and PD (table 6). The blood treatment therapies have a significant risk of septicemia, low flow from blood access, hypotension, membrane clotting, and bleeding. PD therapy

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Table 5. Cause of death from ARF1 [9] HD (n ⫽ 34)

PD (n ⫽ 43)

Dialysis-unrelated Sepsis Cardiac Hemorrhage Hepatorenal Other

16 (48%) 11 2 3 4 1

14 (33%) 2 72 3 2 0

Dialysis-related Sepsis3 Cardiac Hemorrhage

4 (12%) 3 3 2

5 (12%) 3 22 0

1Several

patients died from more than one cause. the 9 cardiac deaths in the PD group, 7 occurred in patients with underlying heart disease (p ⬍ 0.05). 3Shunt sepsis in HD; peritoneal sepsis in PD. 2Of

Table 6. Risks of various dialysis therapies for ARF CAVH CVVHD HD PD Septicemia Vascular occlusion Hypotension Membrane clotting Bleeding due to anticoagulant PD catheter outflow failure Hyperglycemia Asymptomatic peritonitis, often pre-existing

⫹ ⫹ ⫺ ⫹ ⫹

⫹ ⫹ ⫺ ⫹ ⫹

⫹ ⫹ ⫹ ⫹ ⫹

⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹

includes risks of PD catheter outflow failure, hyperglycemia, and asymptomatic peritonitis. Of these risks of PD, peritonitis is the only one with potential to adversely affect the patient. However, if the initiation of PD detects a pre-existing peritonitis, then antibiotic or surgical therapy may resolve the infection that caused ARF. In patients treated by PD during ARF, recognition and therapy of pre-existing peritonitis contributes to the improved outcome of these patients. There are no studies comparing the cost to perform of these four uremic therapies, or the cost of treatment of various complications (outside of the study

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by Phu et al. [16], where all therapies were relatively inexpensive). Nurses performing acute PD will confirm that performing this therapy is simple; every 2–4 h, a clamp is opened to drain the peritoneum, a new bag is attached to the inflow line and the inflow clamp is opened. The cost of the therapy is only the cost of 6–12 bags of peritoneal dialysate each day, plus the labor of an ICU nurse to open a clamp to drain the peritoneum then attach and infuse the volume of a new bag. Data collection is simple; the outflow volume is measured and recorded, and the fluid is inspected to determine whether it is clear or cloudy. Much more nursing time is required for procedures and measurements related to CVVH, CVVHD, and HD treatments. When a properly functioning chronic peritoneal access device is placed, PD is a safe, effective, and inexpensive modality for treatment of ARF. This modality is greatly underutilized for treatment of ARF in the United States and when improvements in chemical efficiency such as through CFPD are proven and implemented PD will become a much more widely used therapy.

References 1 2 3 4 5 6 7 8 9 10 11 12

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Rao P, Passadakis P, Oreopoulos DG: Peritoneal dialysis in acute renal failure. Perit Dial Int 2003; 23:320–322. Ash SR, Wimberly AL, Mertz SL: PD for acute and ESRD: An update. Hosp Pract 1983;2: 179–210. US Renal Data Systems: USRDS 2002 Annual Data Report. Bethesda, NIH, NIDDKD, 2002. Sugino N, Kubo K, Nakazatwo S, Nihei H: Therapeutic modalities and outcome in ARF; in Solez K, Racusen LC (eds): Acute Renal Failure. New York, Dekker, 1992, pp 443–454. Hansen HE: Dialysis treatment of ARF in children; in Solez K, Racusen LC (eds): Acute Renal Failure. New York, Dekker, 1992, pp 407–416. Fivush BA, Porter CC: Pediatric dialysis therapy; in Solez K, Racusen LC (eds): Acute Renal Failure. New York, Dekker, 1992, pp 417–431. Chadha V, Warady BA, Blowey DL, Simckes AM, Alon US: Tenckhoff catheters prove superior to Cook catheters in pediatric acute peritoneal dialysis. Am J Kidney Dis 2000;35:1111–1116. Stott RB, Cameron JS, Ogg CS, Bewick M: Why the persistently high mortality in ARF? Lancet 1972;ii:598. Posen GA, Lutsello J: Continuous equilibration PD in the treatment of ARF. Dial Bull 1980;1:6. Ng RCK, Suki WN: Treatment of ARF; in Brenner BN, Stein JH (eds): Acute Renal Failure. New York, Churchill-Livingstone, 1980, p 231. Swartz RD, Valk TW, Brain AJW, Hsu CH: Complications of HD in ARF. ASAIO J 1980;3:98. Orofino L, Lampreable I, Muniz R, De Sancho JL, Villar F, Gomez Ullate P, Montenegro J, Garcia Damborenea R: Survival of acute renal failure (ARF) on dialysis: Review of 82 patients. Rev Clin Esp 1976;141:155–160. Firmat J, Zucchini A: Peritoneal dialysis in acute renal failure. Contrib Nephrol. Basel, Karger, 1979, vol 17, pp 33–38. Struijk DG, Krediet RT, de Glas-Vos JW, Boeschoten EW, Arisz L: Experiences with acute peritoneal dialysis in adults. Ned Tijdschr Geneeskd 1984;128:751–755. Struijk DG: Pers. commun., 2000. Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP, Winearls C, Farrar J, White N, Day N: Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 2002;347:895–902.

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Rottembourg J: Residual renal function and recovery of renal function in patients treated by CAPD. Kidney Int 1993;43:S106–S110. Rottembourg J, Allouache M, Issad B, Baiab R, Benhmida M, Baumelous A, Jacobs C: Outcome and follow-up on CAPD. Contrib Nephrol. Basel, Karger, 1991, vol 89, pp 16–27. Slingeneyer A, Mion C: Five year follow-up of 155 patients treated by CAPD in European French speaking countries (abstract). Perit Dial Int 1989;9:176. Lysaght MJ, Vonesh EF, Gotch F, Ibels L, Keen M, Lindholm B, Nolph KD, Pollock CA, Prowant B, Farrel PC: The influence of dialysis treatment modality on the decline of remaining renal function. ASAIO Trans 1991;37:598–604. Conger JD: Does HD delay recovery from ARF? Semin Dial 1990;3:146–148. Ash SR, Bungu ATJ, Regnier FE: Dependence of middle molecular clearance on protein concentration of peritoneal fluid; in Maher JF, Winchester JF (eds): Frontiers in Peritoneal Dialysis. New York, Field, Rich & Associates, 1986, pp 56–63. Popovich R, He Z, Moncrief J: Peritoneal Membrane Plasmapheresis. Trans ASAIO 1992;38: M668–M672. Henderson L, Besarab A, Michaels A, Blumle LW: Blood purification by ultrafiltration and fluid replacement (diafiltration). Trans ASAIO 1967;13:216–222. Kumar VA, Craig M, Depner TA, Yeun JY: Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis 2000;36:294–300. Aggarwal HK, Sumit N, Sumit N, Sen J, Singh M: Evaluation of role of acute intermittent peritoneal dialysis in resistance congestive heart failure. J Assoc Phyns India 2002;50:1115–1119. Chitalia VC, Almeida AF, Rai H, Bapat M, Chitalia KV, Acharya VN, Khanna R: Is peritoneal dialysis adequate for hypercatabolic acute renal failure in developing countries. Kindey Int 2002;61: 747–757. Roberts M, Ash SR, Lee DBN: Innovative peritoneal dialysis: Flow-through and dialysate regeneration. ASAIO J 1999;45:372–378. Shinaberger JH, Shear L, Barry KG: Increasing efficiency of peritoneal dialysis: Experience with peritoneal-extracorporeal recirculation dialysis. Trans ASAIO 1965;11:76–82. Stephen RL, Atkin-Thor E, Kolff WJ: Recirculating PD with subcutaneous catheter. Trans ASAIO 1976;22:575–585. Amerling R, Glezerman I, Savransky E, Dubrow A, Ronco C: Continuous flow peritoneal dialysis: Principles and applications. Semin Dial 2003;16:335–340. Cruz C, Melendez A, Gotch F, Folen T, Levin NW: Continuous flow peritoneal dialysis (CFPD): Preliminary clinical experience. Perit Dial Int 2000;20(suppl 1):S6. Sagy M, Silver P: Continuous flow peritoneal dialysis as a method to treat severe anasarca in children with acute respiratory distress syndrome. Crit Care Med 1999;27:2532–2536. Ash SR, Carr DJ, Blake DE, Thornhill JA: The sorbent suspension reciprocating dialyzer for use in peritoneal dialysis; in Maher JF, Winchester JF (eds): Frontiers in Peritoneal Dialysis. New York, Field, Rich & Associates, 1986, pp 148–156. Gordon A, Lewin AJ, Maxwell MH, Morales ND: Augmentation of efficiency by continuous flow sorbent regeneration peritoneal dialysis. Trans ASAIO 1976;22:599–604. Ash SR: The Allient™ Dialysis System. Semin Dial 2004;17:164–165. Ash SR, Janle EM: T-fluted peritoneal dialysis catheter. Adv Perit Dial 1993;9:223–226. Ash SR, Sutton JM, Mankus RA, Rossman J, de Ridder V, Nassvi MS, Ross J: Clinical trials of the T-fluted (ash advantage) peritoneal dialysis catheter. Adv Renal Replacement Ther 2002;9:133–143. Diaz-Buxo JA: What is the role of automated peritoneal dialysis and continuous flow peritoneal dialysis? Contrib Nephrol. Basel, Karger, 2003, vol 140, pp 264–271. Ash SR, Janle EM: Continuous flow-through peritoneal dialysis (CFPD): Comparison of efficiency to IPD, TPD, and CAPD in an animal model. Periton Dialysis Int 1997;17:365–372. Gallatin L, Couetil L, Ash SR: Continuous flow peritoneal dialysis for the treatment of acute renal failure in an adult horse. 2004;in press. Bergstein JM, Riley M, Bank NU: Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome. N Engl J Med 1992;327:755–759. Ash SR: Peritoneal access devices and placement techniques; in Nissenson AR, Fine RN (eds): Dialysis Therapy. Philadelphia, Hanley & Belfus, 1992, pp 23–30.

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Ash SR, Daugirdas JT: Peritoneal access devices; in Daugirdas JT, Ing TS (eds): Handbook of Dialysis. Boston, Little, Brown, 1985, pp 195–218. Ash SR: Chronic peritoneal dialysis catheters: Procedures for placement, maintenance, and removal. Semin Nephrol 2002;22:221–236. Ash SR: Chronic peritoneal dialysis catheters: Overview of design, placement, and removal procedures. Semin Dial 2003;16:323–334. Dandecha P, Sangthawan P: Peritonitis in acute peritoneal dialysis in a university hospital. J Med Assoc Thai 2002;85:477–481. Sharma RK, Kuma J, Gupta A, Gulati S: Peritoneal infection in acute intermittent peritoneal dialysis. Ren Fail 2003;25:975–980. Daugirdas JT: Peritoneal dialysis in acute renal failure – why the bad outcome? N Engl J Med 2003;347:933–935.

Stephen R. Ash, MD, FACP HemoCleanse, Inc., 3601 Sagamore Parkway N., Lafayette, IN 47904 (USA) Tel. ⫹1 765 742 4813, Fax ⫹1 765 742 4823, E-Mail [email protected]

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Intermittent Hemodialysis for Acute Renal Failure Patients – An Update Norbert Lameire, Wim Van Biesen, Raymond Vanholder, Eric Hoste Department of Medicine, University Hospital, De Pintelaan, Gent, Belgium

Acute renal failure (ARF) is a frequent complication in the intensive care unit (ICU), and is associated with increased morbidity, mortality and health care costs [1]. According to Maher et al. [2], ARF requiring dialysis reduced survival by 50% and Morgera et al. [3] found an in-hospital mortality of 69%. Of the patients discharged from the hospital, however, 77 and 70% still survived after 6 and 12 months, respectively, but 10% remained dialysis-dependent. Although considerable advances have been made in the treatment of ICU-related ARF, several important issues still remain a matter of debate. It has repeatedly been suggested that continuous renal replacement therapies (CRRT) as compared to intermittent dialysis (IHD) were linked to improved outcomes, but convincing evidence is lacking. Even for secondary endpoints like hemodynamic stability or removal of water and solutes, data on the superiority of CRRT are missing or at least contradictory. Studies on these questions are jeopardized by biases, leading to unsatisfactory randomization and stratification of risk factors between the observed populations, and to the inclusion of insufficient numbers of patients [4]. Hard data remain absent or conflictive regarding the timing to start dialysis, the adequacy levels necessary to optimize survival as well as to the impact of biocompatible membranes [5]. CRRT vs. IHD Two major types of renal replacement therapy (RRT) are currently available for the treatment of ARF: IHD and CRRT. A survey by the Acute Dialysis

Quality Initiative (ADQI) group revealed that the choice between CRRT and IHD was based on local circumstances rather than on scientific evidence [6]. Although the most obvious difference between the two treatments is the time span over which they are applied, some other technical differences may in fact be more relevant. IHD is performed as a highly efficient technique, relying on diffusion, and thus necessitating high dialysate flows to maintain high concentration gradients. CRRT is mostly performed as a low efficiency technique, mainly relies on convection, and implies the need for sterile substitution fluids. As consequence, a water treatment system and a dialysis monitor are mandatory for IHD, whereas CRRT can principally be performed with more simple hardware, but necessitates the use of industrially prepared substitution fluids. These technical peculiarities imply also that an IHD machine can be programmed to perform continuous therapy, but that a CRRT machine cannot be used to perform intermittent treatment, as the low-efficient nature of the set-up necessitates prolonged treatment duration to achieve adequacy goals. To enhance efficiency, CRRT has evolved from continuous arteriovenous hemofiltration (CAVH), without blood pump, to high volume continuous venovenous hemo(dia)filtration (CVVH(D)), applying sophisticated blood pumps and fluid balance systems equilibrating hemofiltered and substituted fluids. In this way, the technical simplicity as a major advantage of CRRT is completely lost. Hence, the evolution to hybrid therapies, whereby IHD machines are used to perform extended treatments, is a logical next step. Only a limited number of randomized controlled studies compared outcomes on CRRT vs. IHD in ARF [7–11]. A meta-analysis by Tonelli et al. [12] including over 600 patients, found no significant difference in mortality of critically ill patients with ARF treated with IHD compared to CRRT. This result remained present even after addition of non-randomized trials, and after controlling for potential remaining differences in baseline severity of illness. Another meta-analysis by Kellum et al. [4] allows no definite conclusion, as it included mainly non-randomized trials, and omitted some available randomized trials. In addition, the weighing of the impact of the different studies and the methodology to correct for differences in severity of disease were not appropriate. In a recent Canadian study, mortality in the CRRT group was higher than in the IHD group (71.9 vs. 42.2%, p ⫽ 0.001, respectively) [11]. The wellperformed randomized controlled trial by Mehta et al. [7] demonstrated the near impossibility to stratify for all underlying risk factors. In view of the emergence of hybrid therapies, it can even be questioned whether there is a real need for another large randomized trial in this area, since overall, both techniques have a similar outcome. In specific conditions, however, one of both is an absolute preference, like, for example, CRRT in patients with cerebral edema or liver failure, or IHD in patients with increased bleeding risk. Another recent

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comparative multicenter study has been performed in France by Guérin et al. [13]. Among the 587 patients who were included in this study, 354 received CRRT and 233 intermittent renal replacement therapy as first choice. CRRT patients had a higher number of organ dysfunctions on admission and at the time of ARF and higher SAPS II at time of ARF. Mortality was 79% in the CRRT group and 59% in the IRRT group. Logistic regression analysis showed decreased patient survival to be associated with SAPS II on admission, oliguria, admission from hospital or emergency room, number of days between admission and ARF, cardiac dysfunction at time of ARF, and ischemic ARF. No underlying disease or nonfatal disease, and absence of hepatic dysfunction were associated with an increase in patient survival. The type of renal replacement therapy was not significantly associated with outcome. The most logical conclusion, as we pointed out before [14], is that all centers taking care of critically ill patients with ARF should have the possibility to perform both techniques in a qualitatively acceptable way. The emergence of SLEDD (slow low efficient daily dialysis) might have a positive influence in this regard, as this allows performing both strategies with one single machine. An important aspect might be the cost. CRRT is more expensive due to higher labor costs, more expensive all-inclusive disposables, and the need for specific ‘additional’ machines that can only be used for treatment of ARF in the ICU. A cost-analysis in 32 Canadian hospitals [11] revealed that the mean cost of CRRT per week ranged from USD 3,486 to 5,117, compared to only USD 1,342 for IHD. In contrast, the length of dialysis treatment in survivors was longer in the IHD group, but not statistically significant (14.8 vs. 19.1 days, p ⫽ 0.9 ⫽ NS). Dialysis Dose In chronic renal failure (CRF), Kt/Vurea (urea clearance per minute, multiplied by dialysis time, normalized for distribution volume of urea) is currently used as a marker of small solute clearance. This is based on the assumption that Kt/Vurea not only reflects the removal of toxic waste products, but offers also an indication of dietary protein intake and catabolism. In ARF patients, blood urea levels are often used as a marker to start RRT and to monitor dialysis adequacy. Blood urea levels in highly catabolic ICU patients can however be the reflection of many factors besides dialysis adequacy. A recent Canadian survey [15] found that in more than 75% of the centers, no formal method of the monitoring of the dialysis prescription was applied. The use of conventional urea kinetic modeling might lead to erroneous conclusions, since the assumptions at the basis of these calculations are violated in most ICU patients. The distribution volume, e.g., is frequently expanded, and the urea generation rate is not in a steady state. Clark et al. [16] have developed

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different kinetic models to capture the differences in kinetic behavior between chronic and acute renal failure patients. If Kt/V is used as an index of adequacy in ARF, the thresholds should undoubtedly exceed those aimed at in CRF. An accurate estimate of volume of distribution of urea (Vurea) is critically important to guide the prescription of therapy and the quantification of delivered dialysis dose in patients with chronic and acute renal failure (ARF). While Vurea has been shown to be substantially the same as total body water (TBW) in other patient populations, this relationship is not automatically true in ARF patients. A study by Himmelfarb et al. [17] showed that determination of TBW by anthropometric measurements yielded significantly lower measures compared to TBW determined by physiological formulae and by bioelectrical impedance analysis and that all measures of Vurea by blood-based kinetics exceeded TBW measurements by any method (7–50% difference). It was thus concluded that estimates of TBW cannot be used as a surrogate for Vurea in determining dialysis adequacy in ARF patients. It has been registered before that most nephrologists prescribe a dialysis dose below those recommended for CRF patients, and that actually delivered doses are often still below those prescribed [18] due to clotting, insufficient vascular access, hemodynamic instability, or practical pitfalls. Prospective, formal, blood-side, urea kinetic modeling (UKM) has yet to be applied in intermittent hemodialysis for acute renal failure (ARF). Methods for prescribing a target, equilibrated Kt/V (eKt/V) are described for this setting by Kanagasundaram et al. [19]. eKt/V was derived using delayed posthemodialysis urea samples and formal, double-pool UKM (eKt/Vref), and by applying the Daugirdas-Schneditz venous rate equation to pre- and posthemodialysis samples (eKt/Vrate). Individual components of prescribed and delivered dose were compared. Prescribed eKt/V values were determined using in vivo dialyzer clearance estimates and anthropometric (Watson and adjusted Chertow) and modeled urea volumes. eKt/Vref was well-approximated by eKt/Vrate. Modeled V exceeded Watson V by 25 ⫾ 29% and Adjusted Chertow V by 18 ⫾ 28%, although the degree of overestimation diminished over time. This difference was influenced by access recirculation (AR) and use of saline flushes. The median % difference between Vdprate and Watson V was reduced to 1% after adjusting for AR for the 22 sessions with ⬍ or ⫽ 1 saline flush. The median coefficients of variation for serial determinations of Adjusted Chertow V, modeled V, urea generation rate, and eKt/Vref were 2.7, 12.2, 30.1 and 16.4%, respectively. Because of comparatively higher modeled urea Vs, delivered eKt/Vref was lower than prescribed eKt/V, based on Watson V or Adjusted Chertow V, by 0.13 and 0.08 Kt/V units. The median absolute errors of prescribed eKt/V vs. delivered therapy (eKt/Vref) were, however, not large and were similar in prescriptions based on the Adjusted Chertow V (0.127) vs. those

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based on various double-pool modeled urea volumes (approximately 0.127). Equilibrated Kt/V can be thus be derived using formal, double-pool UKM in intensive care unit ARF patients, with the venous rate equation providing a practical alternative. A target eKt/V can be prescribed to within a median absolute error of less than 0.14 Kt/V units using practical prescription algorithms. A recent study by Liao et al. [20] compared the effective dose delivery by three acute dialysis therapies: continuous venovenous hemofiltration (CVVH), daily HD, and sustained low-efficiency dialysis (SLED). A modified equivalent renal clearance (EKR) approach to account for the initial unsteady-state stage during dialysis was employed. Effective small solute clearance in CVVH was found to be 8 and 60% higher than in SLED and daily HD, respectively. Differences are more pronounced for middle and large solute categories, and EKR in CVVH is approximately 2- and 4-fold greater than the corresponding values in daily HD and SLED, respectively. The superior middle and large solute removal for CVVH is due to the powerful combination of convection and continuous operation. In CVVH, a decrease in the initial BUN from 150 to 50 mg/dl is predicted to decrease TAC and, therefore, increase EKR by approximately 35%. After clinical validation, the quantification method presented in this article could be a useful tool to assist in the dialytic management of critically ill ARF patients. Only a few studies have tried to relate dialysis dose to outcome in ARF patients. Ronco et al. [21] randomized 425 patients with ARF treated with CRRT to different doses of hemofiltration with substitution: 20, 35 or 45 ml/min/kg. Survival in the 20-ml/kg/min group was inferior to that observed in the 35- and 45-ml/kg/min groups. No survival advantage was observed between the two highest doses, implying that 35 ml/kg/min is probably the most optimal dose. In contrast, a randomized controlled study by Bouman et al. [22] found that neither the 28th day of survival nor the recovery of renal function were improved by high ultrafiltrate volumes (up to a median of 48.2 ml/kg/min). In the field of IHD, the Cleveland group pointed out that dose of dialysis was inversely related to mortality, at least in the subgroup of patients with a ‘moderate risk’ profile [23]. In patients with a low or high risk, dialysis dose did not independently predict mortality, probably because other, non-RRTrelated factors play a more important role in these patients. For patients with ‘moderate’ risk, a urea reduction rate higher than 58% was associated with a significant reduction in mortality. Schiffl et al. [24] compared daily versus alternate day IHD treatment in 160 ARF patients. An intention-to-treat analysis revealed a mortality of 28% in the daily dialysis group, vs. 46% in the alternate day group. In a multiple regression analysis, alternate day dialysis was an independent risk factor for

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mortality. The delivered cumulative weekly Kt/V, as measured by the Daugirdas formula, was twice as high in the daily treatment group compared to the alternate day group. The time averaged blood urea concentration was 60 vs. 104 mg/dl (p ⫽ 0.001) in the daily vs. alternate day group. Both delivered dose and resulting ‘clearance’ of toxic waste products were thus superior in the more intensively treated group. In addition, hypotension was less prevalent in the daily treated (5 vs. 25%, p ⫽ 0.001) group, which was most likely related to the lower ultrafiltration volume per session, whereas also time to recover renal function was shorter (9.2 vs. 16 days, p ⫽ 0.001). Biocompatibility of the Dialysis Membranes Considerable controversy exists whether in patients with ARF the use of biocompatible dialysis membranes can positively influence patient survival and recovery of renal function as compared to bio-incompatible membranes. The problem ‘biocompatibility’ in this discussion is limited to the property of some dialyzer membranes, e.g. cuprophane, to activate leukocytes and complement. Different trials yielded contradictory results. The discussion is hampered by the divergence of definitions of ‘biocompatibility’. Some authors compared cellulosic with synthetic membranes, whereby ‘cellulosic’ is considered bioincompatible. However, modified cuprophane membranes (e.g. hemophan) have a lower complement activating capacity than cuprophane, and should hence be considered ‘biocompatible’. It has also been argued that differences in flux are responsible for the observed differences, whereby it has to be understood that the non-modified cellulosic membranes are always low-flux, whereas biocompatible (either synthetic or modified cellulose) membranes may be both low or high flux. Increasing flux improves the removal of middle- and high-molecularweight uremic retention products, which might be important in catabolic ICU patients [25]. Whether the removal of cytokines by RRT is possible and/or beneficial remains controversial [26–29]. In a recent meta-analysis, including a total of 867 patients, Subramanian et al. [30] observed a relative risk of mortality for cellulosic membranes of 1.37 (CI: 1.02–1.83). A separate subanalysis of studies with only unmodified cellulose as control group vs. studies where both unmodified as modified cellulose membranes served as control, revealed that the observed survival benefit for synthetic membranes was largely due to the difference with unmodified cellulose. When only correctly randomized trials were included in the meta-analysis, the statistical significance of the survival advantage of biocompatible membranes was lost. Jaber et al. [31] performed another meta-analysis comparing unmodified cellulose (bioincompatible) vs. synthetic and modified cellulose membranes (biocompatible), including a total of 722 patients. The survival advantage for the biocompatible membranes did not reach statistical significance.

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In none of these two meta-analyses was an attempt made to dissect the impact of biocompatibility from that of flux. Meta-analyses of the published literature are increasingly being used, allowing similar clinical trials to be combined quantitatively, thereby increasing the precision of the estimation of treatment effect. However, several metaanalyses on the topic of membrane biocompatibility in ARF were discordant and in analysis of these meta-analyses, Teehan et al. [32] observed that this divergence was due in part to the differences among meta-analyses in inclusion and exclusion criteria, the paucity of randomized controlled trials, variation in individual study quality, and heterogeneity in the study populations and settings. Understanding these issues is important to properly interpret results from these meta-analyses. The use of low complement-activating membranes implies a potential survival advantage, but this effect might in clinical practice be lower than expected. However, none of the published studies has ever demonstrated a negative impact of low complement-activating membranes. Hence, the only reason not to prefer these membranes is their cost. In conclusion, both CRRT and IHD have advantages and disadvantages, and any attempt to improve either of them makes them more and more similar. A RRT modality for ICU should be easy to use, convenient, and offer the possibility to deliver a broad range of therapeutic modalities while reducing the workload. The emergence of ‘hybrid techniques’ such as slow low efficient extended daily dialysis (SLEDD) is therefore a logical consequence [33, 34]. In these hybrid techniques, a classical dialysis monitor allowing online preparation of dialysate, and, if necessary, substitution fluid is used to perform extended dialysis treatments, whereby the intensity and the duration of the treatment can be adapted to the needs of the patient. Regardless of whether the treatment is diffusive, convective, or a combination of both, the technical set-up of the machine is always the same for the ICU nurse. The advantages and results of SLEDD will be discussed elsewhere in this volume.

References 1 2

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Lameire N, Van Biesen W, Vanholder R, Colardijn F: The place of intermittent hemodialysis in the treatment of acute renal failure in the ICU patient. Kidney Int Suppl 1998;66:S110–S119. Maher ER, Robinson KN, Scoble JE, Farrimond JG, Browne DR, Sweny P, Moorhead JF: Prognosis of critically-ill patients with acute renal failure: APACHE II score and other predictive factors. Q J Med 1989;72:857–866. Morgera S, Kraft AK, Siebert G, Luft FC, Neumayer HH: Long-term outcomes in acute renal failure patients treated with continuous renal replacement therapies. Am J Kidney Dis 2002;40: 275–279.

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Kellum JA, Angus DC, Johnson JP, Leblanc M, Griffin M, Ramakrishnan N, Linde-Zwirble WT: Continuous versus intermittent renal replacement therapy: A meta-analysis. Intensive Care Med 2002;28:29–37. Abdeen O, Mehta RL: Dialysis modalities in the intensive care unit. Crit Care Clin 2002;18:223–247. Ronco C, Brendolan A, Bellomo R: Continuous renal replacement techniques. Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 236–251. Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, Kaplan RM: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60: 1154–1163. John S, Griesbach D, Baumgartel M, Weihprecht H, Schmieder RE, Geiger H: Effects of continuous haemofiltration vs. intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: A prospective, randomized clinical trial. Nephrol Dial Transplant 2001;16:320–327. Uehlinger DE, Jacob S, Eichelberger M: A randomized, controlled single center study for the comparison of continuous renal replacement therapy with intermittent hemodialysis in critically ill patients with acute renal failure (abstract). J Am Soc Nephrol 2001;12:278A. Sandy D, Moreno L, Paganini EP: A randomized stratified dose equivalent comparison of continuous veno-venous hemodialysis vs. intermittent hemodialysis support in ICU acute renal failure patients (abstract). J Am Soc Nephrol 1998;9:225A. Manns B, Doig CJ, Lee H, Dean S, Tonelli M, Johnson D, Donaldson C: Cost of acute renal failure requiring dialysis in the intensive care unit: Clinical and resource implications of renal recovery. Crit Care Med 2003;31:449–455. Tonelli M, Manns B, Feller-Kopman D: Acute renal failure in the intensive care unit: A systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002;40:875–885. Guerin C, Girard R, Selli JM, Ayzac L: Intermittent versus continuous renal replacement therapy for acute renal failure in intensive care units: Results from a multicenter prospective epidemiological survey. Intens Care Med 2002;28:1411–1418. Dhondt A, Van Biesen W, Vanholder R, Lameire N: Selected practical aspects of intermittent hemodialysis in acute renal failure patients. Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 222–235. Hyman A, Mendelssohn DC: Current Canadian approaches to dialysis for acute renal failure in the ICU. Am J Nephrol 2002;22:29–34. Clark WR, Ronco C: Renal replacement therapy in acute renal failure: Solute removal mechanisms and dose quantification. Kidney Int Suppl 1998;66:S133–S137. Himmelfarb J, Evanson J, Hakim RM, Freedman S, Shyr Y, Ikizler TA: Urea volume of distribution exceeds total body water in patients with acute renal failure. Kidney Int 2002;61:317–323. Evanson JA, Himmelfarb J, Wingard R, Knights S, Shyr Y, Schulman G, Ikizler TA, Hakim RM: Prescribed versus delivered dialysis in acute renal failure patients. Am J Kidney Dis 1998;32: 731–738. Kanagasundaram NS, Greene T, Larive AB, Daugirdas JT, Depner TA, Garcia M, Paganini EP: Prescribing an equilibrated intermittent hemodialysis dose in intensive care unit acute renal failure. Kidney Int 2003;64:2298–2310. Liao Z, Zhang W, Hardy PA, Poh CK, Huang Z, Kraus MA, Clark WR, Gao D: Kinetic comparison of different acute dialysis therapies. Artif Organs 2003;27:802–807. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000;356:26–30. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J: Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med 2002;30:2205–2211. Paganini EP, Tapolyai M, Goormastic M, Halstenberg WK, Kozlowski L, Leblanc M, Lee J, Moreno L, Sakai K: Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kid Dis 1996;28(suppl 3):S81–S89.

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Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305–310. Vanholder R, De Vriese A, Lameire N: The role of dialyzer biocompatibility in acute renal failure. Blood Purif 2000;18:1–12. De Vriese AS, Colardijn F, Phillippé JJ, Vanholder R, De Sutter JH, Lameire NH: Cytokine removal during continuous hemofiltration in septic patients. J Am Soc Nephrol 1999;10:846–853. Tetta C, D’Intini V, Bellomo R, Bonello M, Bordoni V, Ricci Z, Ronco C: Extracorporeal treatments in sepsis: Are there new perspectives? Clin Nephrol 2003;60:299–304. Venkataraman R, Subramanian S, Kellum JA: Clinical review: Extracorporeal blood purification in severe sepsis. Crit Care 2003;7:139–145. Ronco C, Inguaggiato P, D’Intini V, Cole L, Bellomo R, Poulin S, Bordoni V, Crepaldi C, Gastaldon F, Brendolan A, Trairak P, Khajohn T: The role of extracoporeal therapies in sepsis. J Nephrol 2003;16(suppl 7):S34–S47. Subramanian S, Venkataraman R, Kellum JA: Influence of dialysis membranes on outcomes in acute renal failure: A meta-analysis. Kidney Int 2002;62:1819–1823. Jaber BL, Lau J, Schmid CH, Karsou SA, Levey AS, Pereira BJ: Effect of biocompatibility of hemodialysis membranes on mortality in acute renal failure: A meta-analysis. Clin Nephrol 2002; 57:274–282. Teehan GS, Liangos O, Lau J, Levey AS, Pereira BJ, Jaber BL: Dialysis membrane and modality in acute renal failure: Understanding discordant meta-analyses. Semin Dial 2003;16:356–360. Van Den Noortgate N, Verbeke F, Dhondt A, Colardijn F, Van Biesen W, Vanholder R, Lameire N: The dialytic management of acute renal failure in the elderly. Semin Dial 2002;15:127–132. Van Biesen W, Vanholder R, Lameire N: Dialysis strategies in critically ill acute renal failure patients. Curr Opin Crit Care 2003;9:491–495.

Norbert Lameire, MD Renal Division, Department of Medicine, University Hospital 185, De Pintelaan, BE–9000 Gent (Belgium) Tel. ⫹32 9 2404524, Fax ⫹32 9 2404599, E-Mail [email protected]

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Continuous Renal Replacement Techniques William R. Clarka,b, Claudio Roncoc a

NxStage Medical, Inc., Lawrence, Mass., and bIndiana University School of Medicine, Indianapolis, Ind., USA; cDepartment of Nephrology, Ospedale San Bortolo, Vicenza, Italy`

Acute renal failure (ARF) occurring in patients admitted to the intensive care unit is often different from the syndrome observed in renal wards. Patients are critically ill and several organ systems are involved in the syndrome. Frequently, sepsis and a multiple organ dysfunction syndrome complicate the clinical picture. Under such circumstances, an adequate renal replacement therapy must be instituted providing effective blood purification and correction of the various homeostatic disorders [1]. Standard hemodialysis and peritoneal dialysis have displayed significant limitations in these patients while continuous renal replacement therapies are rapidly gaining consensus and displaying interesting clinical advantages. The critically ill patient presents a severe hemodynamic instability, sepsis and septic shock, he or she may require mechanical ventilation, cardiac mechanical support and other types of vital supports. In these conditions, intermittent hemodialysis appears to produce further hemodynamic instability and only partial correction of the uremic syndrome [2]. Peritoneal dialysis on the other hand may present mechanical and infectious complications and it is limited by the low clearances and ultrafiltration rates. Under all these circumstances the logical approach is the one of providing a therapy with the following characteristics: (a) Excellent clinical tolerance. (b) Excellent capacity of blood purification for different molecules. (c) Optimal correction of electrolyte disorders. (d) Optimal correction of acid-base disorders. (e) Excellent biocompatibility with minimal or no proinflammatory effects. (f) Minimal or absent side effects including a negative impact on recovery of the native organ function.

(g) Possibly improved outcomes. (h) Easy institution and easy monitoring of treatment. Most of these targets have been achieved with the use of continuous renal replacement therapy (CRRT). This is especially true considering the most recent techniques in which the treatment dose and the applied technology have been optimized. In this paper, the major modalities comprising CRRT are discussed. Prior to doing this, we feel however that it is important to review the basic concepts underlying each single technique to better interpret the possible advantages and to better target the prescription of the selected therapy. Finally, we will also present emerging applications of CRRT for disorders beyond ARF.

Mechanisms of Solute and Water Transport

The most important mechanisms of solute and water transport across semipermeable membranes can be considered: diffusion, convection and ultrafiltration [3]. Diffusion Diffusion is a process of transport in which the molecules that are present in a solvent and can freely cross the membrane tend to move from the region at higher concentration into the region at lower concentration (fig. 1). In reality, molecules present a random movement. However, since they tend to reach the same concentration in the available space occupied by the solvent, the number of particles crossing the membrane towards the region at lower concentration will be statistically higher. This is therefore a transport mechanism that occurs in the presence of a concentration gradient for solutes that are not restricted in diffusion by the porosity of the membrane. Besides the concentration gradient (dc), the diffusion flux is influenced by the characteristics of the membrane including surface area (A) and thickness (dx), the temperature of the solution (T), and the diffusion coefficient of the solute (D). The diffusion flux of a given solute (Jx) will therefore result from equation (1): Jx ⫽ D T A (dc/dx)

(1)

Based on the above-mentioned concepts, one could predict with reasonable accuracy the clearance value in the presence of given solute, solvent, membrane and operational conditions. However, several factors influencing the final clearance values may lead to a certain discrepancy between the theoretically expected value and the empirically obtained value. As an example, protein binding or electrical charges in the solute may negatively affect the final clearance value.

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P

N

C

Diffusion

Convection

Fig. 1. Mechanisms of solute removal in different blood purification techniques.

Pressure

Membrane

Uf

Uf

Fig. 2. The mechanism of ultrafiltration in response to a transmembrane pressure gradient.

On the other hand, an increased amount of convection may contribute to a greater transport of solutes especially in the higher-molecular-weight range. Convection Convection is a form of transport that requires a movement of fluid across the membrane as a consequence of a transmembrane pressure gradient (TMP). In conjunction with this fluid transport, the crystalloids present in the solution (but not the cells or the colloids that are retained by the membrane) are transported to the other side of the membrane with a mechanism defined solvent drag. The fluid transport is defined ultrafiltration (fig. 2) and it can be described by equation (2): Jf ⫽ Kf ⭈ TMP

(2)

where Kf is the coefficient of hydraulic permeability of the membrane and TMP ⫽ (Pb ⫺ Puf) ⫺ ␲. In the TMP expression, Pb is the hydrostatic pressure of blood, Puf the hydrostatic pressure of ultrafiltrate or dialysate, and ␲ the oncotic pressure generated by plasma proteins in the blood.

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Low-flux membrane Kf ⫽ 6ml/h/mmHg ⫻ m2

Sieving coefficient

Ultrafiltration (ml/min)

1.00 High-flux membrane Kf ⫽ 40 ml/h/mmHg ⫻m2

0.80 High flux 0.60 0.40 0.20

Low flux

0.00 10 Transmembrane pressure (mmHg)

102

103

104

105

Molecular weight (daltons)

Fig. 3. Characteristics of dialysis membranes.

The convective flux of a given solute x will, therefore, depend on the amount of ultrafiltration (Jf), on the concentration of the solute in plasma water (Cb) and by the sieving characteristics of the membrane for the solute (S): Jx ⫽ Jf Cb (1 ⫺ ␴) ⫽ Jf CbS

(3)

The sieving coefficient (S) is, under theoretical conditions, regulated by the reflection coefficient of the membrane (Staverman reflection coefficient: ␴) according to equation (4) [4]: S ⫽ 1 ⫺ ␴.

(4)

In clinical practice, however, because plasma proteins and other factors modify the original reflection coefficient of the membrane, the final observed sieving coefficient is smaller than that expected from a simple theoretical calculation [5–7]. Dialysis membranes are classified according to their ultrafiltration coefficient [8] and solute sieving profile [9] as high flux and low flux (fig. 3). In clinical practice, membranes are incorporated into specific devices designed to optimize the performance of the membrane itself. These devices may either be designed as dialyzers, working prevalently in diffusion with a countercurrent flux of blood and dialysate, or as hemofilters, working prevalently in convection. Improvements in membrane design have allowed diffusive and convective mass transport to be combined, leading to therapies (high flux dialysis and hemodiafiltration) in which the advantages of both mechanisms are significantly enhanced. CRRT Techniques

Several techniques are today available in the spectrum of CRRT. Techniques may differ in terms of vascular access and extracorporeal circuit

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design, frequency and intensity of treatment, predominant mechanism of transport utilized and type of membrane [10]. The following description is based primarily on the operational parameters normally employed and the target efficiency with respect to solute and fluid control. Slow Continuous Ultrafiltration (SCUF) In the intensive care unit, SCUF is typically employed for 24 h/day, but may also be applied during some portion of the day. The treatment is carried out with high flux membranes and the objective is to achieve volume control in patients with severe, diuretic-resistant volume overload [11, 12]. Relative to hemofiltration, low filtration rates (approximately 2–5 ml/min) are required. As such, filters of relatively small surface area and low blood flow rates can be employed. Machines used for this therapy require an ultrafiltration control system to prevent excessive ultrafiltration. Although very effective for volume reduction, the low filtration rates used and lack of substitution fluids (see below) render this therapy ineffective as a blood purification modality. Extracorporeal ultrafiltration is now being carefully assessed as an adjunctive therapy for patients with refractory congestive heart failure (see below). Continuous Venovenous Hemofiltration (CVVH) Continuous hemofiltration is normally applied for an extended period of time up to several weeks [13]. The technique utilizes high flux membranes and the prevalent mechanism of solute transport is convection. Ultrafiltration rates in excess of the amount required for volume control are prescribed, requiring partial or total replacement of ultrafiltrate losses with fresh substitution fluid. Blood flow is regulated by a pump and systems for ultrafiltration and reinfusion control are generally utilized. Different machines use either volumetric control systems or volumetric pumps regulated by one or multiple scales. Heparin is infused in the arterial line to prevent clotting of the circuit. The replacement solution can either be infused before the filter (pre-dilution) or after the filter (post-dilution) [14]. In the first case, ultrafiltration must be relatively increased to maintain the same efficiency observed in post-dilution mode [15, 16]. Since the ultrafiltrate is replaced by toxin-free substitution fluid, the treatment is appropriate for both blood purification and volume control. As noted above, the primary solute removal mechanism in HF is convection. In post-dilution HF, the relationship between solute clearance and ultrafiltration rate is relatively straightforward. In this situation, solute clearance is determined primarily by and related directly to the solute’s sieving coefficient and the ultrafiltration rate. Consequently, as discussed below, the concept that ultrafiltrate volume can be assumed to be a surrogate for treatment dose is reasonable, particularly in the context of small solute clearance [17]. However,

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post-dilution HF is limited inherently by the attainable blood flow rate and the patient’s hematocrit (Hct). More specifically, the ratio of the ultrafiltration rate to the plasma flow rate delivered to the filter, termed the filtration fraction (FF), is the limiting factor: FF ⫽

Quf Qb (1 ⫺ Hct)

(5)

Previous studies suggest FF values ⬎35% in post-dilution may be undesirable due to hemoconcentration-related effects on filter performance [18, 19]. Pre-dilution HF avoids the post-dilution hemoconcentration-related effects on hemofilter performance and is being increasingly used for CVVH therapy. However, the above mass transfer benefits must be weighed against the predictable dilution-induced reduction in plasma solute concentrations, one of the driving forces for convective solute removal. The extent to which this reduction occurs is determined mainly by the ratio of the replacement fluid rate to the blood flow rate [20]. However, the ultrafiltration rate afforded by such a high replacement fluid rate allows the dilution-related loss of efficiency to be overcome. For reasons described above, the relationship between clearance and ultrafiltration rate may not be as predictable in pre-dilution, relative to the case of post-dilution. Until recently, a standard ultrafiltration rate employed in CVVH has been 1–2 liters/h. However, based on recent clinical outcome data indicating survival is improved by the use of higher ultrafiltration rates, ‘high-volume’ hemofiltration is increasing being applied in many intensive care units (see below). Continuous Venovenous Hemodialysis (CVVHD) Continuous hemodialysis is a treatment carried out over an extended period of time with a pump-driven circuit. Because of the nature of the membrane and the gradient provided by the dialysate, the prevalent mechanism of solute transport in this technique is diffusion. As such, either a low-flux or highflux filter can be used [21, 22], although the latter is typically prescribed. Because of the nature of the membrane and the gradient provided by the dialysate, the prevalent mechanism of solute transport in this technique is diffusion. Ultrafiltration is obtained exactly in the range of values adequate to maintain patient’s fluid control without requirement of fluid reinfusion. For this reason, dialyzers with higher surface area and modified cellulosic membranes such as triacetate could be effectively used [23]. Even when CVVHD is performed with a relatively small surface area filter (⬍0.5 m2), the use of relatively low dialysate flow rates (⬍25 ml/min) results in saturation of the effluent dialysate with respect to small solutes [24]. This saturation phenomenon can be preserved at even higher dialysate flow rates (⬎35 ml/min) by use of higher

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surface area filters [25]. As dialysate flow rate is increased, although saturation of the effluent dialysate is not complete, an increase in small-molecular-weight solute clearances is nevertheless achieved [26]. In most cases, designated machines must be used to control inlet and outlet dialysate flows and to achieve the desired volume of ultrafiltration. For a given set of operating parameters (including filter effluent rate), the clearance of large-molecular-weight solutes in CVVHD is less than that achieved with CVVH [27, 28]. The primarily diffusive nature of CVVHD explains this finding. However, for typical blood and dialysate flow rates in CVVHD, a pressure profile that promotes enhanced removal of large toxins is created when a high flux filter is used [29]. Due to the high water permeability of such a filter, the spontaneous filtration would be much greater than the patient’s desired net volume removal. However, the ultrafiltration control mechanism present in most contemporary CRRT devices prevents such ‘runaway’ filtration by applying positive pressure in the dialysate compartment [30]. In a certain segment of the filter at the venous end, the dialysate compartment pressure is actually greater than blood compartment pressure. Thus, an ‘internal filtration’ circuit, characterized by a high rate of blood-to-dialysate filtration in the arterial end of the device and a nearly equal rate of dialysate-to-blood filtration in the venous end, routinely occurs during CVVHD. This phenomenon, which has also been recognized in high flux dialysis in the ESRD setting [31], promotes convective solute removal. Thus, despite its diffusive foundation, convective forces also are operative in CVVHD. Continuous Venovenous Hemodiafiltration (CVVHDF) Continuous hemodiafiltration requires a high flux hemodiafilter and operates combining the principles of hemodialysis and hemofiltration [32]. As such, this therapy may allow for an optimal combination of diffusion and convection to provide clearances over a very broad range of solutes. Dialysate is circulated in countercurrent mode to blood and at the same time ultrafiltration is obtained in excess of the desired fluid loss from the patient. This is totally or partially replaced with substitution fluid either in pre-dilution or in post-dilution mode. Recent machines allow a combination of pre- and post-dilution aiming at combining the advantages of both modalities. Information from the chronic hemodiafiltration literature suggests that a combination of pre- and post-dilution may be optimal [33]. This may also be the case for CVVHDF although this has not been assessed carefully. The optimal balance is most likely dictated by the specific set of CVVHDF operating conditions, namely blood flow rate, dialysate flow rate, ultrafiltration rate, and filter type. The specific manner in which diffusion and convection interact in continuous hemodiafiltration differs significantly from the situation when this

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treatment is applied in the ESRD setting. In the latter situation, diffusion and convection interact in such a manner that total solute removal is significantly less than what is expected if the individual components are simply added together. This phenomenon is explained in the following way. Diffusive removal results in a decrease in solute concentration in the blood compartment along the axial length (i.e. from blood inlet to blood outlet) of the hemodialyzer/hemofilter. As convective solute removal is directly proportional to the blood compartment concentration, convective solute removal decreases as a function of this axial concentration gradient. On the other hand, hemoconcentration resulting from ultrafiltration of plasma water causes a progressive increase in plasma protein concentration and hematocrit along the axial length of the filter. This hemoconcentration and resultant hyperviscosity causes an increase in diffusive mass transfer resistance and a decrease in solute transport by this mechanism. Due to the markedly lower flow rates used and clearances obtained in CVVHDF, the effect of simultaneous diffusion and convection on overall solute removal is quite different. Therefore, the small solute concentration gradient along the axial length of the filter (i.e. extraction) is minimal compared to that which is seen in chronic hemodiafiltration, in which extraction ratios of 50% or more are the norm. Thus, the minimal diffusion-related change in small solute concentrations along the filter allows any additional clearance related to convection to be simply additive to the diffusive component. This has been demonstrated clearly both in continuous hemodialysis [22] and hemodiafiltration [25].

Technical Aspects of CRRT

The evolution of CRRT has been accompanied by a parallel evolution in the related technology. A series of double lumen catheters has been developed in order to achieve higher blood flows with lower flow resistance and reduced risk of recirculation [34]. Double lumen catheters are in some cases substituted by twin separate catheters in order to maximize blood flow and prevent unwanted recirculation. Several machines have incorporated the heparin pump or other systems for regional heparinization and citrate anticoagulation. The most common anticoagulant remains heparin, although high blood flows and pre-dilution techniques allow for a smooth conduction of CRRT without any anticoagulant in patients at risk. Regional heparinization and the use of citrate is mostly reserved for special cases as it is for low-molecular-weight heparin and prostacyclin. In recent years, catheters, blood lines and filters with heparin bound on the inner surface have been developed. Their use, however, is still

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experimental and requires further evaluation. Dialyzers with different membranes have been created making possible to choose among a variety of membrane materials. Membranes with different porosity and ultrafiltration coefficients are available. There is a tendency to increase the filter surface area since the pumped circulation can operate at higher blood flows compared to arteriovenous circuits. A series of on-line monitoring techniques are today under evaluation including blood volume monitoring and blood temperature monitoring [35–36]. Finally, a great deal of development has taken place in the operator interface of the CRRT machines [37]. Most of these machines are equipped with large color screens and step-by-step guidelines to prime the circuit and run the treatment smoothly and effectively.

Clinical Indications for CRRT

The different techniques described in this chapter have been used in different settings and different clinical conditions. In those departments in which dialysis machines or CRRT equipment are not available, arteriovenous treatments still represent an important resource. In most cases however one or more machines or simply different types or adaptive technologies are available and venovenous pump-driven therapies can be carried out. In these cases, the indication for one or another technique is based on the knowledge of the capabilities of each technique and the clinical objectives that the clinician seeks to achieve. If small molecule clearance is the main target, there is no point in using expensive high-flux membranes. On the other hand, if a wider spectrum of molecules is to be removed, convective therapies or combined diffusive-convective therapies should be implemented. Combination therapies are today more and more utilized especially in the setting of multiple organ failure and acute renal failure complicated by sepsis. When blood purification is the main target, the efficiency of continuous renal replacement therapies seems to be unparalleled. While intermittent hemodialysis in fact presents the typical limitations imposed by the double pool kinetics of most molecules [38], CRRT, in spite of a lower clearance, presents an improved removal due to the continuous action and the steady concentration of the solutes in blood [39]. Recent studies have demonstrated that CRRT can improve survival in acute renal failure patients if the dose of treatment is increased up to 35 ml/h/mm Hg [17]. This observation has been elaborated by Gotch [40] who described this level of efficiency as the only one approaching the function of the native kidney. Comparing the efficiency of different therapies is complicated and it required special parameters of calculation such as the standard Kt/V [40]. When comparing hemodialysis and

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peritoneal dialysis, weekly standard Kt/V as high as 2–2.5 can be obtained. In CRRT, standard Kt/V can be four or five times higher displaying the enormous superiority of continuous therapies. The same concept can be described for the correction of acid-base and electrolyte derangement. By performing a continuous correction, the electrolyte pools can be normalized and so can be done with the serum concentrations, leading to a stable maintenance of an optimal homeostatic equilibrium [2]. The effect of slow and continuous water removal is the other important advantage of these therapies since a continuous refilling from the interstitial space can be obtained. Under such circumstances, overhydrated patients or patients with congestive heart failure can be treated achieving the normalization or the improvement of cardiac filling pressures, preload and afterload, in the absence of dangerous reductions of circulating blood volume [35].

New Horizons

In the clinical scenario of acute renal failure and the application of CRRT, it is worth underscoring not only the continuous evolution of the techniques but also the continuous evolution of the possible clinical indications. As an example, there is increasing evidence that a beneficial effect from the hemodynamic point of view can be obtained by CRRT in patients with multiple organ failure and septic shock. Since the explanation for some of the possible benefits seems to lie on the capacity of these therapies to remove chemical mediators from the patient’s circulation, new studies and research have been directed towards the mechanism of humoral response to sepsis, and the possibility to attenuate the immunological disequilibrium that seems to characterize the septic patients [41]. Since some effects induced by CRRT could be related to the removal of proinflammatory mediators, this hypothesis has spurred new interest in the application of therapies with increased amount of convection such as high volume hemofiltration, or with membranes characterized by increased sieving coefficients [42]. High volume hemofiltration is a purely convective therapy which can be performed with two basic schedules: (a) continuous hemofiltration with a fluid exchange rate ⬎3 liters/h, and (b) hemofiltration performed for some hours [3–6] during the day exchanging 6–8 liters/h while the patient continues a standard CVVH for the rest of the day. In the first case, if the therapy is performed for 24 h, clearances in the range of 80 liters/day can be obtained. Technical requirements for this technique consist especially on the increased blood flow rates and the availability of large volumes of substitution fluid. These therapies have been shown to produce a beneficial effect on patient’s hemodynamics,

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with a significant reduction of vasopressor drugs requirement [42]. The technology involved is in most cases borrowed from the chronic hemodialysis setting. The large volumes of fluid exchanged may render the treatment somehow impractical. The new methods for on-line production of substitution fluid may however contribute in the coming future to reduce the costs and the problems of fluid supply. Congestive heart failure (CHF) represents another disease state which may be benefit from the application of extracorporeal therapy. Current pharmacotherapy of CHF involves agents which generally have very narrow therapeutic ranges and are associated with a wide range of adverse effects. Extracorporeal ultrafiltration is increasingly being studied as a CHF adjunctive therapy which may decrease the morbidity and possibly mortality associated with CHF and its medical management. Numerous studies [43–50] have characterized UF’s specific clinical benefits, which include decreases in cardiac filling pressures and improvements in diuretic responsiveness, hyponatremia, edema, renal function, and dyspnea. A common element of many of these studies has been the ability of UF to ‘reset’ the neurohormonal axis, as evidenced by decreases in plasma norepinephrine, aldosterone, and renin activity. A relatively common prescription in these studies was an ultrafiltration rate of 300–600 ml/h, administered over a several-hour treatment period for consecutive days. The clinical benefits reported for UF in CHF patients may relate to the difference in the composition of the volume removed by UF vs. diuretics. In UF, the fluid removed is an ultrafiltrate of plasma and, as such, has electrolyte concentrations that are isotonic with respect to plasma water. On the other hand, urine inherently is hypotonic with respect to plasma water. Therefore, sodium removal is significantly greater in ultrafiltrate relative to the same volume of urine. Moreover, due to the isotonicity of the ultrafiltrate, UF induces no acute changes in electrolyte concentrations.

Conclusions

Different techniques are today available for the therapy of acute renal failure in the critically ill patient. Continuous therapies seem to display important advantages in terms of clinical tolerance and blood purification capacity [51]. The field is in continuous evolution and prospective randomized controlled trials will soon prove if there is any significant rationale for the application of CRRT and derived techniques in patients with sepsis and multiple organ dysfunction syndromes, beyond the simple indication of acute renal failure.

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9 10 11 12 13

14 15 16 17

18 19

20

21 22 23 24

Bellomo R, Ronco C: Acute renal failure in the ICU: Adequacy of dialysis and the case for continuous therapies. Nephrol Dial Transplant 1996;11:424–428. Bellomo R, Ronco C: Continuous versus intermittent renal replacement therapy in the intensive care unit. Kidney Int 1998;53(suppl 66):S125–S128. Ronco C, Ghezzi P, Bellomo R: New perspective in the treatment of acute renal failure. Blood Purif 1999;17:166–172. Henderson LW: Biophysics of ultrafiltration and hemofiltration; in Jacobs C (ed): Replacement of Renal Function by Dialysis, ed 4. Dortdrecht, Kluwer Academic Publishers, 1996, pp 114–118. Rockel A, Hertel J, Fiegel P, Abdelhamid S, Panitz N, Walb D: Permeability and secondary membrane formation of a high flux polysufone hemofilter. Kidney Int 1986;30:429–432. Langsdorf LJ, Zydney AL: Effect of blood contact on the transport properties of hemodialysis membranes: A two-layer model. Blood Purif 1994;12:292–307. Morti SM, Zydney AL: Protein-membrane interactions during hemodialysis: Effects on solute transport. ASAIO J 1998;44:319–326. Ronco C: Continuous renal replacement therapies in the treatment of acute renal failure in intensive care patients. 1. Theoretical aspects and techniques. Nephrol Dial, Transplant 1994;9(suppl 4): 191–200. Clark WR, Ronco C: Determinants of hemodialyzer performance and the effect on clinical outcome. Nephrol Dial Transplant 2001;16(suppl 3):56–60. Clark WR, Ronco C: Renal replacement therapy in acute renal failure: Solute removal mechanism and dose quantification. Kidney Int 1998;53(suppl 66):S133–S137. Silverstein ME, Ford CA, Lysaght MJ, Henderson LW: Treatment of severe fluid overload by ultrafiltration. N Engl J Med 1974;291:747–751. Paganini EP, Nakamoto S: Continuous slow ultrafiltration in oliguric acute renal failure. Trans Am Soc Artif Intern Organs 1980;26:201–204. Macias WL, Mueller BA, Scarim SK, Robinson M, Rudy D: Continuous venovenous hemofiltration: An alternative to continuous arteriovenous hemofiltration and hemodiafiltration in acute renal failure. Am J Kidney Dis 1991;18:451–458. Henderson LW: Pre- vs. post-dilution hemofiltration. Clin Nephrol 1979;11:120–124. Clark WR, Turk JE, Kraus MA, Gao D: Dose determinants in continuous renal replacement therapy. Artif Organs 2003;27:815–820. Liao Z, Zhang W, Poh CK, Huang Z, Hardy PA, Kraus MA, Clark WR, Gao D: Kinetic comparison of different acute dialysis therapies. Artif Organs 2003;27:802–807. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000;356:26–30. Grootendorst F, Van Bommel E, Van De Hoven B: Light-volume hemofiltration improves hemodynamics of endotoxin-induced shock in the pig. Int Care Med 1992;18:235–240. Grootendorst F, Van Bommel E, Van Leenooed L, Van De Hoven B: Infusion of ultrafiltrate from endotoxemic pigs depresses myocardial performance in normal pigs. J Crit Care 1993;8: 161–169. Ahuja A, Rodby R, Huang Z, Gao D, Zhang W, Clark WR: Effect of pre-dilution replacement fluid administration on solute clearance in high-volume hemofiltration (abstract). J Am Soc Nephrol 2003;14:734A. Sigler MH, Teehan BP: Solute transport in continous hemodialysis: A new treatment for acute renal failure. Kidney Int 1987;32:562–571. Relton S, Greenberg A, Palevsky P: Dialysate and blood flow dependence of diffusive solute clearance during CVVHD. ASAIO J 1992;38:691–696. Ronco C, Ghezzi PM, Hoenich N, Delfino PG: Membranes and filters for hemodialysis. Contr Nephrol. Basel, Karger, 2000. Bonnardeaux A, Pichette V, Ouimet D, Geadah D, Habel F, Cardinal J: Solute clearances with high dialysate flow rates and glucose absorption from the dialysate in continuous arteriovenous hemodialysis. Am J Kidney Dis 1992;19:31–38.

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Brunet S, Leblanc M, Geadah D, Parent D, Corteau S, Cardinal J: Diffusive and convective solute clearance during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis 1999;34:486–492. Schlaeper C, Amerling R, Manns M, Levin NW: High clearance continuous renal replacement therapy with a modified dialysis machine. Kidney Int Suppl 1999;72:S20–S23. Clark WR, Ronco C: CRRT efficiency and efficacy in relation to solute size. Kidney Int 1999; 56(suppl 72):S3–S7. Troyanov S, Cardinal J, Geadah D, Parent D, Courteau S, Caron S, Leblanc M: Solute clearances during continuous venvenous haemofiltration at various ultrafiltration flow rates using Multiflow100 and HF1000 filters. Nephrol Dial Transplant 2003;18:961–966. Ronco C: Continuous renal replacement therapies for the treatment of acute renal failure in intensive care patients. Clin Nephrol 1993;4:187–198. Ronco C, Ghezzi PM, Hoenich N, Delfino PG: Membranes and filters for hemodialysis. Contr Nephrol. Basel, Karger, 2000. Clark WR, Gao D: Low-molecular weight proteins in end-stage renal disease: Potential toxicity and dialytic removal mechanisms. J Am Soc Nephrol 2002;13:S41–S47. Mehta RL: Therapeutic alternatives to renal replacement for critically ill patients in acute renal failure. Semin Nephrol 1994;14:64–82. Pedrini LA, de Christofaro V, Pagliari B, Sama F: Mixed predilution and post-dilution online hemodiafiltration compared with traditional infusion modes. Kidney Int 2000;58:2155–2165. Ronco C, Bellomo R: Critical Care Nephrology. Dortrecht, Kluwer Academic Publishers, 1998. Ronco C, Brendolan A, Bellomo R: On-Line monitoring in continuous renal replacement therapies. Kidney Int 1999;56(suppl 72):S8–S14. Rahmati S, Ronco F, Spittle M, Morris AT, Schlaeper C, Rosales L, Kaufman A, Amerling R, Ronco C, Levin NW: Validation of the blood temperature monitor for extracorporeal thermal energy balance during in vitro continuous hemodialysis. Blood Purif 2001;19:245–250. Ronco C, Brendolan A, Bellomo R: Current technology for continuous renal replacement therapies; in Ronco C, Bellomo R (eds): Critical Care Nephrology. Dortrecht, Kluwer Academic Publishers, 1998, pp 1269–1308. Clark WR, Leypoldt JK, Henderson LW, Mueller BA, Scott MK, Vonesh EF: Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model. J Am Soc Nephrol 1999;10:601–610. Clark WR, Mueller BA, Kraus MA, Macias WL: Extracorporeal therapy requirements for patients with acute renal failure. J Am Soc Nephrol 1997;8:804–812. Gotch F: The current place of urea kinetic modeling with respect to different dialysis schedules. Nephrol Dial Transplant 1998;13(suppl 6):10–14. Tetta C, Mariano F, Ronco C, Bellomo R: Removal and generation of inflammatory mediators during continuous renal replacement therapies; in Ronco C, Bellomo R (eds): Critical Care Nephrology. Dortrecht, Kluwer Academic Publishers, 1998, pp 1239–1248. Bellomo R, Baldwin I, Cole L, Ronco C: Preliminary experience with high volume hemofiltration in human septic shock. Kidney Int 1998;53(suppl 66):S182–S185. Marenzi G, Grazi S, Giraldi F, et al: Interrelation of humoral factors, hemodynamics, and fluid and salt metabolism in congestive heart failure: Effect of extracorporeal ultrafiltration. Am J Med 1993;94:49–56. Agostoni P, Marenzi G, Pepi M, et al: Isolated ultrafiltration in moderate congestive heart failure. J Am Coll Cardiol 1993;21:424–431. Agostoni P, Marenzi G, Lauri G, et al: Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: Failure of furosemide to provide the same result. Am J Med 1994;96:191–199. Blake P, Paganini EP: Refractory congestive heart failure: Overview and application of extracorporeal ultrafiltration. Adv Ren Replace Ther 1996;3:166–173. Canaud B, Leblanc M, Leray-Moragues H, Delmas S, Klouche K, Beraud JJ: Slow continuous and daily ultrafiltration for refractory congestive heart failure. Nephrol Dial Transplant 1998; 13(suppl 4):51–55.

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Ronco C, Ricci Z, Bellomo R, Bedogni F: Extracorporeal ultrafiltration for the treatment of overhydration and congestive heart failure. Cardiology 2001;96:155–168. Marenzi G, Lauri G, Grazi M, Assanelli E, Campodonico J, Agostoni P: Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure. J Am Coll Cardiol 2001;38:963–968. Ronco C, Bellomo R, Ricci Z: Hemodynamic response to fluid withdrawal in overhydrated patients treated with intermittent ultrafiltration and slow continuous ultrafiltration: Role of blood volume monitoring. Cardiology 2001;96:196–201. Ronco C, Bellomo R: Continuous versus intermittent renal replacement therapy in the treatment of acute renal failure. Nephrol Dial Transplant 1998;13:79–85.

William R. Clark, MD Wishard Hospital/Myers D711 1001 West 10th St., Indianapolis, IN 46202 (USA) Tel. ⫹1 317 613 2315 (ext 327), Fax ⫹1 317 613 2317, E-Mail [email protected]

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Hybrid Renal Replacement Therapies for Critically Ill Patients Thomas A. Golper Vanderbilt University Medical Center, Nashville, Tenn., USA

Despite the fact that in prospective randomized controlled trials continuous renal replacement therapy (CRRT) was not shown to deliver superior outcomes to intermittent hemodialysis (IHD) [1, 2], many clinicians, including me, continue to prefer CRRTs over IHD for critically ill patients with hemodynamic instability. The reason for the preference is that our collective clinical experience shows that fluid removal under continuous operating conditions is less complicated than during intermittent therapy. Most patients needing renal replacement therapy have already undergone fluid resuscitation and are often fluid overloaded, compromising ventilation, despite being hypotensive. Outcomes have been shown to be superior when IHD is applied daily vs. thrice weekly [3] and when the ultrafiltration rate (UFR) is ⱖ35 ml/kg/h [4]. As currently practiced, many CRRTs require specially prepared sterile solutions to serve as either filtration substitution fluid (hemofiltration) or dialysate (hemodialysis). Specialized equipment has been developed by several manufacturers, but in each case the CRRT machine is more expensive to purchase than are machines used predominantly for IHD (table 1). Thus, in the absence of clear outcome superiority for CRRT over IHD, and because there is an enormous cost difference, hybrid therapies have emerged [5–7]. This recent work is based on the work of clinicians who attempted this approach with traditional hemodialysis equipment [8, 9]. One such name for this hybrid of continuous and intermittent therapy is called slow low efficiency dialysis (SLED). Cost Analysis

At Vanderbilt University, we utilize Gambro’s PRISMA™ machine to perform hemodiafiltration with a routine delivered clearance of approximately

Table 1. Cost comparison of SLED with Fresenius K™ machine and CRRT with Gambro PRISMA™ in USD Fresenius K

20,000.00

PRISMA

25,000.00

Portable R.O.

5,000.00

F50 dialyzer (each)

17.00

Prisma circuit includes dialyzer

170.00

Medisystem™ bloodlines

2.90

Liquid bicarbonate (4 gal)

12.32

Baxter pre-mixed dialysate (USD 27.00 per 5 liters) @ 2 liters/h use over 24 h, or

324.00

Citrasate™ 4 gal or 8 gallons

27.00

Gambro Prismasate™ with bicarbonate (USD 35.00 per 5 liters) @ 2 liters/h use over 24 h

420.00

NS prime (2 liters)

1.26

Saline prime (4 liters) Heparin (per day)

2.52 15.00

Diasafe™ ultrafilter for Fresenius K USD 50.00/filter replacement every 7 weeks ⫻ 4 machines USD 1,485.72 per year ⫹ Biomed labor for installation

USD 4/day over whole year

Monthly AAMI standard culture and endotoxin for each Fresenius K (4) and each portable R.O. (4) plus bi-annual AAMI standard chemical analysis per R.O. USD 2,144.00 per year ⫹ follow-up samples as needed

USD 6/day over whole year

Supply cost 1 SLED setup and projected run 14 h (8 gallons of Citrasate™)

97.48

Supply cost 1 CRRT setup bicarbonate pre-mixed dialysate and average 24-hour run per circuit

511.52 or 607.52

54.00

Labor description Dialysis RN setup and monitor over first hour then check minimally three times/day; provide 24/7 coverage for troubleshooting and new setups when needed

Hybrid Renal Replacement Therapies

Dialysis RN setup and monitor over first hour then check minimally three times/day; provide 24/7 coverage for troubleshooting and new setups due to clotting

279

Table 1 continued ICU RN monitor and calculate UF each hour; basic troubleshooting alarms and terminate if needed; notify dialysis staff.

ICU RN monitors and calculates UF each hour; change dialysate bags every 2.5 h and empty effluent bag every 2.5 h; basic troubleshooting alarms and terminates if needed; notify dialysis staff.

2 liters/h (half by dialysis diffusion, half by hemofiltration convective). Alternatively, SLED is employed using the Fresenius K™ hemodialysis machine, with dialysis operating for 6–12 h on a daily basis. Nursing intensity varies by therapy with the greatest consumption of Intensive Care Unit (ICU) nurses’ time being changing the substitution fluid bags, dialysate bags and effluent bags on the PRISMA™. For SLED the ICU nurses simply adjust the UFR on an hourly basis, which takes 15–30 s. A more detailed cost analysis is shown in table 1.

Clearances and Dose Versatility

Ronco’s landmark study demonstrating the survival advantage of clearance ⭓35 ml/kg/h of convective clearance has set the standard certainly for purely convective therapies [4]. This is approximately a urea clearance of 40 ml/min. The lowest operating conditions of SLED with a dialysate flow rate (Qd) of 100 ml/min generate a urea clearance of ⬎60 ml/min [10]. CRRTs run approximately 22 of 24 h and the hybrid therapies such as SLED are generally applied for ⬎6 h [11]. Depending on the dose needed, SLED and hybrid therapies can run longer and even continuously. Since many critically ill patients require procedures, often outside of the ICU, the starting and stopping of renal replacement therapy is common. The hybrids lend themselves better to this disruption because the disposable components are considerably cheaper. If SLED is performed intermittently, then daily application can be considered more efficacious, extrapolating from the IHD experience [3]. At a Qd of 100 ml/min, a jug of dialysate concentrate lasts ⬎16 h. Obviously as Qd is increased the concentrate is depleted more rapidly. We utilize high flux polysulfone modest surface area hemodialyzer (e.g. Fresenius F-50™) for SLED treatments. The K™ machine has an internal filter which filters the

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dialysate water prior to its reaching the hemodialyzer blood-dialysate interface. Prior to that stage a portable reverse-osmosis device is utilized to process the hospital water. So the dialysate is essentially ultrapure for SLED treatments, a recommendation with European origins [12]. By adjusting blood flow rate, dialysate flow rate and treatment length, a large operational diversity and potential for dose delivery are created. The dialysate can vary in concentration of 2⫹ need adjustelectrolytes which is particularly relevant as K⫹, HCO⫺ 3 and Ca ment. As citrate is utilized more often, alkalosis can be easily rectified by reducing the dialysate HCO3⫺ and, depending on the need for Ca2⫹ infusion, dialysate can contain low levels or be absent of Ca2⫹.

Nursing Time

Vanderbilt’s ICU nurses spend at least an hourly average of 15 min when performing PRISMA™ CRRT. This time is spent handling fluid bags. For SLED the time commitment is to perform any calculations of intakes and outputs (which are done regardless of the renal replacement therapy) and then to set the hourly UFR on the K machine. Dialysis nurses set up both SLED and PRISMA™ machines and disposables. Dialysis nurses trouble-shoot both therapies during their hours of operation. There is limited use of SLED during hours that dialysis nurses are out of the hospital, but upon completion of additional in-service training, this will change, such that ICU nurses can discontinue an inoperable SLED treatment in the absence of a dialysis nurse.

Future Issues in Hybrid Therapies

Hybrid therapies as currently used are predominantly diffusion based. As we develop cleaner water systems, there is no reason that on-line hemodiafiltration substitution fluid and dialysate are not utilized to improve the convective component [13]. The use of the high flux dialyzers already greatly enhances the convective contribution to total clearance. If a greater delivered dialysis dose does improve survival [3, 4, 14], hybrids will be the preferred delivery system. Regional anticoagulation regimens are constantly improving. The blood pump of dialysis machines can generate much higher flow rates can CRRT machines. This may lead to less aggressive anticoagulation, especially because the filtration fraction is minimal (e.g. ⬍4%) in the hybrid therapies. Furthermore, the greater blood flow may allow for Ca2⫹ reinfusion via stop cock

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specifically at the blood access return site, obviating the need for a central Ca2⫹ infusion line. As mentioned above, regional citrate regimens are evolving that utilize the enormous small solute clearance capacity of SLED to correct potential side effects of citrate anticoagulation, such as hypernatremia, hyperglycemia (if Anticoagulant Citrate Dextrose-A™ is used), alkalosis, or hypocalcemia.

Conclusion

Not only are the hybrid therapies here to stay, but their advantages and versatility will lead them to be the mainstay renal replacement therapy for the critically ill before the end of this decade.

References 1

2

3 4

5 6

7 8 9

10 11 12

13

Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MTA, Farkas A, Kaplan RMl: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001; 60:1154–1163. Misset B, Timsit J-F, Chevret S, Renaud B, Tamion F, Carlet J: A randomized cross-over comparison of the hemodynamic response to intermittent hemodialysis and continuous hemofiltration in ICU patients with acute renal failure. Intens Care Med 1996;22:742–746. Schiffl H, Lang S, Fischer R: Daily hemodialysis and the outcomes of acute renal failure. N Engl J Med 2002;346:305–310. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca GI: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000;356:26–30. Schlaeper C, Amerling R, Manns M, Levin NW: High clearance continuous renal replacement therapy with a modified dialysis machine. Kidney Int 1999;56(suppl 72):S20–S23. Kumar V, Craig M, Depner T, Yeun J: Extended daily dialysis: A new approach to renal replacement therapy for acute renal failure in the intensive care unit. Am J Kidney Dis 2000;36: 294–300. Marshall M, Golper TA, Shaver MJ, Chatoth DK: Sustained low efficiency dialysis for critically ill patients requiring renal replacement therapy: Clinical experience. Kidney Int 2001;60:777–785. Hombrouckx R, Bogaert AM, Leroy F, De Vos JY, Larno L: Go-slow dialysis instead of continuous arteriovenous hemofiltration. Contrib Nephrol. Basel, Karger, 1991, vol 93, pp 149–151. Kihara M, Ikeda Y, Shibata K, Masumori S, Fujita H, Ebira H, Toya Y, Takagi N, Shionoiri H, Umemura S, Ishii M: Slow hemodialysis performed during the day in managing renal failure in critically ill patients. Nephron 1994;67:36–41. Marshall MR, Golper TA, Shaver MJ, Chatoth DK: Urea kinetics during sustained low-efficiency dialysis. Am J Kidney Dis 2002;39:556–570. Frankenfield DC, Reynolds HN, Wiles CE 3rd, Badellino MM, Siegel JH: Urea removal during continuous hemodiafiltration. Crit Care Med 1994;22:407–412. Lonnemann G, Floege J, Kliem V, Brunkhorst R, Koch K: Extended daily veno-venous high flux haemodialysis in patients with acute renal failure and multiple organ dysfunction syndrome using a single path batch dialysis system. Nephrol Dial Transplant 2000;15:1189–1193. Marshall MR, Ma T, Galler D, Rankin APN, Williams AB: Sustained low-efficiency daily diafiltration (SLEDD-f) for critically ill patients requiring renal replacement therapy: Towards an adequate therapy. Nephrol Dial Transplant 2004;in press.

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Paganini EP, Tapolyai M, Goormastic M, Halstenberg W, Kozlowski L, Leblanc M, Lee JC, Moreno L, Sakal K: Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis 1996;28(suppl 3):S81–S89.

Thomas A. Golper, MD S3301 MCN, Vanderbilt University Medical Center 21st Avenue South, Nashville, TN, 37232 (USA) Tel. ⫹1 615 343 2220, Fax ⫹1 615 322 8653, E-Mail [email protected]

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Pediatric Acute Renal Failure: Demographics and Treatment Stuart L. Goldstein Baylor College of Medicine, Medical Director, Renal Dialysis Unit, Texas Children’s Hospital, Houston, Tex., USA

Provision of appropriate renal replacement therapy for pediatric patients with acute renal failure (ARF) requires special considerations not commonly encountered in the care of adult patients. Pediatric patients with acute renal failure may range in weight from a 1.5-kg neonate to a 200-kg young adult. In addition, disease states that may require acute renal replacement therapy in the absence of significant renal dysfunction, such as inborn errors of metabolism or post-operative care of an infant with congenital cardiac defects, are more prevalent in the pediatric setting. Optimal care for the pediatric patient requiring renal replacement therapy demands an understanding of the causes and patterns of pediatric ARF and multi-organ dysfunction syndrome (MODS) and recognition of the local expertise with respect to the personnel and equipment resources. The aim of this paper is to review the pediatric specific causes necessitating renal replacement therapy provision with an emphasis on emerging practice patterns with respect to modality and the timing of treatment. Pediatric ARF Epidemiology

Advancements and improvements in care for critically ill neonates, infants with congenital cardiac disease, and children with bone marrow and solid organ transplantation has lead to a dramatic broadening of pediatric ARF epidemiology. While multicenter epidemiological pediatric ARF data do not exist, single center data from the 1980s report hemolytic uremic syndrome, other primary renal causes, sepsis and burns [1, 2] as the most prevalent causes leading to pediatric ARF. More recent single center data detail the underlying causes of pediatric ARF in large cohorts of children and demonstrate an epidemiological

shift where ARF is more often a co-morbidity of another underlying disease or systemic process. Bunchman et al. [3] reported data from 226 children with ARF treated with renal replacement therapy with the most common causes being congenital heart disease, ATN and sepsis. Transition from the use of adaptive continuous renal replacement therapy (CRRT) equipment [4, 5] to production of hemofiltration machines with volumetric control allowing for accurate ultrafiltration flows has likewise lead to a change in pediatric renal replacement therapy modality prevalence patterns. Accurate ultrafiltration (UF) and blood flow rates are crucial for pediatric CRRT since the extracorporeal circuit volume can comprise more than 15% of a small pediatric patients’ total blood volume and small UF inaccuracies may represent a large percentage of a small pediatric patient’s total body water. Polls of US pediatric nephrologists demonstrate increased CRRT use over peritoneal dialysis as the preferred modality for treating pediatric ARF [6, 7]. In 1995, 45% of pediatric centers ranked PD and 18% ranked CRRT as the most common modality used for initial ARF treatment. In 1999, 31% of centers chose PD versus 36% of centers reported CRRT as their primary initial modality for ARF treatment [7]. Until very recently, most pediatric ARF treatment studies were limited to review articles [8–10]. Such dearth of pediatric data may result, in part, from the only recent changes noted above in the clinical spectrum of pediatric ARF and the increased use of CRRT to treat more critically ill children with ARF. The remainder of this article will focus upon the application of the different renal replacement therapy modalities and assessment of the outcome of children with ARF who receive renal replacement therapy.

Specific Pediatric Patient Populations

The Critically Ill Pediatric Patient Survival rates for critically children with ARF receiving renal replacement therapy have been fairly consistent from 1978 through 2001. Overall reported patient survival ranges from 52 to 58% [2, 3, 11, 12]. In the last decade, survival rates stratified by renal replacement therapy modality have also been stable; survival rates for patients receiving hemodialysis (73–89%) are higher than those receiving PD (49–64%) or CRRT (34–42%) [3, 12, 13]. Understanding the pattern of pediatric multi-organ dysfunction syndrome (MODS) lends insight into some of the shortcomings and strengths of pediatric ARF outcome data presented later in the article. As opposed to adult patients, Proulx et al. [14] demonstrated that children develop severe and lifethreatening MODS very early in their ICU course; 87% of children developed the maximum number of organ failures occurs within 72 h of ICU admission

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and that children die with MODS very early in ICU course as 88.4% of deaths occur within 7 days of MODS diagnosis. Thus, methods to quickly identify children at risk of developing MODS would lead to early and aggressive initiation of supportive measures, including renal replacement therapy to treat or prevent ARF sequelae, which could conceivably improve pediatric patient outcome. Unfortunately, many issues plague the pediatric ARF outcome literature, which include a relative lack of prospective study, the mixture RRT modality with a lack of modality stratification in subject populations studied and the inconsistent use of methods to control for patient illness severity in outcome analysis. A few studies have considered the effect of a clinical variable on outcome. Smoyer et al. [15] reviewed the outcome of 98 infants and children with ARF who received either arteriovenous or venovenous CRRT modalities and found that higher mortality in patients on pressors. Subsequent work by Bunchman et al. [3] upheld this finding by showing patient survival was only 35% for those requiring pressors versus 89% for those without a pressor requirement in the course of their ARF treatment. As a result, pressor use has been construed as a surrogate for worse patient illness severity in the pediatric population requiring CRRT. Few pediatric outcome studies use a standardized scoring system control for patient illness severity, which may result from the fact that published data provide contradictory conclusions with respect to the utility of various illness severity scoring systems in predicting death in pediatric patients with ARF. Faragson et al. [16] demonstrated significant overlap in Pediatric Risk of Mortality (PRISM) scores [17] between surviving and non-surviving children who received intermittent hemodialysis and therefore concluded that PRISM scores should not be used to differentiate patients who would likely or not benefit from dialysis initiation. Zobel et al. [18] demonstrated that children who received CRRT with worse illness severity by PRISM score had increased mortality, but this study included patients who received both arterio-venous and venovenous CRRT therapies, and did not stratify by modality. A more recent study performed at our center [12] examined the outcome of 22 critically ill children who received only venovenous CRRT modalities and used the PRISM 2 score to control for illness severity at ICU admission and CRRT initiation. Neither mean PRISM scores at the time of PICU admission nor time of CRRT initiation differed between survivors and non-survivors. Of the clinical variables studied (GFR, pressor number, mean airway pressure, patient size or % fluid overload), only the degree of % fluid overload at the time of CRRT initiation differed between survivors (16.4 ⫾ 13.8%) and nonsurvivors (34.0 ⫾ 21.0%, p ⫽ 0.03), even when controlled for severity of illness by PRISM score using a multiple regression model. In addition, we found that 75% of non-survivors died within 21 days of ICU admission. We hypothesize

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that initiation of CRRT a lesser patient % fluid overload may allow for more optimal nutrition and blood product provision without the further accumulation of additional fluid or catabolic waste products. Our data coupled with the predilection for early multi-organ system failure and death in critically ill children with acute renal failure argues for early and aggressive initiation of CRRT. Although mean PRISM scores were no different between survivors and non-survivors, controlling for patient illness severity using PRISM scores was essential to mitigating concerns that the patients who received more fluid prior to CRRT initiation were more ill, and therefore had a higher risk of mortality. Further study of a much larger cohort, using PRISM or other illness severity scoring systems, is clearly warranted to substantiate the findings of our relatively small study. Infants Infants and neonates with ARF present unique problems for renal replacement therapy provision. As noted earlier, delivery of hemodialysis or CRRT to these small patients entails a significant portion of their blood volume to be pumped through the extracorporeal circuit. Therefore, extracorporeal circuit volumes that comprise more than 10–15% of patient blood volume should be primed with whole blood to prevent hypotension and anemia. Since the prime volume is not discarded, it is important to not re-infuse the blood into the patient at the end of the treatment in order to prevent volume overload and hypertension. Acute peritoneal dialysis requires much less technical expertise, expense and equipment compared to intermittent hemodialysis and CRRT. PD catheters can be placed quickly and easily. Initial dwell volumes should be limited to 10 cm3/kg of patient body weight in order to minimize intra-abdominal pressure and potential for fluid leakage along the catheter tunnel. Although PD may deliver less efficient solute removal than hemodialysis or CRRT, its relative simplicity and minimal associated side effects allow for renal replacement therapy provision in settings lacking pediatric dialysis specific support and personnel. CRRT has been prescribed since the mid-1980s for treatment of ARF in critically ill infants [19, 20]. The first CRRT modalities were arteriovenous in configuration, since the extracorporeal volumes were small in these circuits and ultrafiltration was driven by patient perfusion pressure, thereby reducing the risk of hypotension from too much ultrafiltration. As mentioned before, introduction of more accurate machines with volumetric control has increased venovenous modality CRRT in pediatric patients, including neonates and infants. Zobel et al. [20] noted that technical problems occurred only with CVVH in an early neonatal outcome 1991 study reporting patients who received either CAVH or CVVH. Symons et al. [21] reported data from a more recent retrospective multi-center

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study evaluating the CVVH course for 90 infants less than 10 kg from 1993 through 2001, which demonstrate very few technical complications using newer CVVH machinery. Infant for survival for patients receiving CRRT has also been consistent over the past decade at 35–38%, which is similar to survival rates noted above for older pediatric patients [20, 21], although patients less than 3 kg exhibited a trend toward worse survival (24%) when compared to infants larger than 3 kg (41%) [21]. Congenital Heart Disease Infants with acute renal failure after corrective congenital heart surgery comprise a well-studied cohort [22–28]. These patients represent a nearly unique group of pediatric patients in that the timing of the event leading to acute renal failure, namely cardiopulmonary bypass (CPB), is precisely known. In this sense, children undergoing cardiopulmonary bypass are akin to adults receiving nephrotoxic radiologic contrast or emergent surgery for aortic aneurysms; they all provide an opportunity to follow the time course of ARF from beginning to end in patients without significant underlying renal disease. The incidence of infant ARF after CPB ranges from 2.7 to 5.3% with survival rates ranging from 21 to 70% [22, 23, 26]. Risk factors for mortality include increasing underlying complexity of the congenital heart disease and poor cardiac function [22, 26]. A recent trend toward providing PD therapy earlier in the post-CPB course has been reported, with one study of 20 patients demonstrating 80% patient survival [27]. While improved survival with early PD initiation may result from prevention of fluid overload, some posit [28] improved survival with early PD initiation results from increased clearance of CPB-induced pro-inflammatory cytokines, although further study is required to support this hypothesis. In our center, patients with underlying an underlying diagnosis of hypoplastic left heart syndrome, transposition of the great arteries or anomalous pulmonary venous return receive PD immediately postoperatively in order to prevent fluid accumulation.

Future Studies

The recent epidemiological pediatric ARF data presented in this paper has demonstrated the need and laid the groundwork for future pediatric prospective study. Since pediatric ARF is relatively rare, multicenter study will be required to enroll a sufficient patient number for appropriate statistical analysis. Currently, a group of 10 US pediatric centers, the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group (ppCRRT Registry) is prospectively gathering data with respect to critically ill children who receive CRRT.

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The ppCRRT Registry aims to provide insight into the potential clinical factors that affect pediatric patient outcome, compare the efficacy of different anticoagulation protocols, assess specialized patient populations including patients with metabolic disorders and bone marrow transplantation, and evaluate the efficacy and effects of CRRT cytokine removal. At the current time, ppCRRT Registry data comprise information from 180 patients representing over 20,000 h of CRRT time. Future endeavors will include assessment of CRRT pharmacokinetics, broadening the scope to include all pediatric patients with ARF and performing prospective randomized trials to evaluate the effect of CRRT dose and modality upon patient outcome. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Lattouf OM, Ricketts RR: Peritoneal dialysis in infants and children. Am Surg 1986;52:66–69. Williams DM, Sreedhar SS, Mickell JJ, Chan JC: Acute kidney failure: A pediatric experience over 20 years. Arch Pediatr Adolesc Med 2002;156:893–900. Bunchman TE, McBryde KD, Mottes TE, Gardner JJ, Maxvold NJ, Brophy PD: Pediatric acute renal failure: Outcome by modality and disease. Pediatr Nephrol 2001;16:1067–1071. Bunchman TE, Donckerwolcke RA: Continuous arterial-venous diahemofiltration and continuous veno-venous diahemofiltration in infants and children. Pediatr Nephrol 1994;8:96–102. Bunchman TE, Maxvold NJ, Kershaw DB, Sedman AB, Custer JR: Continuous venovenous hemodiafiltration in infants and children. Am J Kidney Dis 1995;25:17–21. Belsha CW, Kohaut EC, Warady BA: Dialytic management of childhood acute renal failure: A survey of North American pediatric nephrologists. Pediatr Nephrol 1995;9:361–363. Warady BA, Bunchman T: Dialysis therapy for children with acute renal failure: Survey results. Pediatr Nephrol 2000;15:11–13. Andreoli SP: Acute renal failure. Curr Opin Pediatr 2002;14:183–188. Flynn JT: Choice of dialysis modality for management of pediatric acute renal failure. Pediatr Nephrol 2002;17:61–69. Parekh RS, Bunchman TE: Dialysis support in the pediatric intensive care unit. Adv Ren Replace Ther 1996;3:326–336. Gallego N, Gallego A, Pascual J, Liano F, Estepa R, Ortuno J: Prognosis of children with acute renal failure: A study of 138 cases. Nephron 1993;64:399–404. Goldstein SL, Currier H, Graf C, Cosio CC, Brewer ED, Sachdeva R: Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001;107:1309–1312. Maxvold NJ, Smoyer WE, Gardner JJ, Bunchman TE: Management of acute renal failure in the pediatric patient: Hemofiltration versus hemodialysis. Am J Kidney Dis 1997;30:S84–S88. Proulx F, Gauthier M, Nadeau D, Lacroix J, Farrell CA: Timing and predictors of death in pediatric patients with multiple organ system failure. Crit Care Med 1994;22:1025–1031. Smoyer WE, McAdams C, Kaplan BS, Sherbotie JR: Determinants of survival in pediatric continuous hemofiltration. J Am Soc Nephrol 1995;6:1401–1409. Fargason CA, Langman CB: Limitations of the pediatric risk of mortality score in assessing children with acute renal failure. Pediatr Nephrol 1993;7:703–707. Pollack MM, Ruttimann UE, Getson PR: Pediatric risk of mortality (PRISM) score. Crit Care Med 1988;16:1110–1116. Zobel G, Kuttnig M, Ring E, Grubbauer HM: Clinical scoring systems in children with continuous extracorporeal renal support. Child Nephrol Urol 1990;10:14–17. Ronco C, Brendolan A, Bragantini L, Chiaramonte S, Feriani M, Fabris A, Dell’Aquila R, La Greca G: Treatment of acute renal failure in newborns by continuous arterio-venous hemofiltration. Kidney Int 1986;29:908–915.

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20 21 22 23 24

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Zobel G, Ring E, Kuttnig M, Grubbauer HM: Five years experience with continuous extracorporeal renal support in paediatric intensive care. Intensive Care Med 1991;17:315–319. Symons JM, Brophy PD, Gregory MJ, McAfee N, Somers MJ, Bunchman TE, Goldstein SL: Continuous renal replacement therapy in children up to 10 kg. Am J Kidney Dis 2003;41:984–989. Book K, Ohqvist G, Bjork VO, Lundberg S, Settergren G: Peritoneal dialysis in infants and children after open heart surgery. Scand J Thorac Cardiovasc Surg 1982;16:229–233. Rigden SP, Barratt TM, Dillon MJ, De Leval M, Stark J: Acute renal failure complicating cardiopulmonary bypass surgery. Arch Dis Child 1982;57:425–430. Giuffre RM, Tam KH, Williams WW, Freedom RM: Acute renal failure complicating pediatric cardiac surgery: A comparison of survivors and nonsurvivors following acute peritoneal dialysis. Pediatr Cardiol 1992;13:208–213. Fleming F, Bohn D, Edwards H, Cox P, Geary D, McCrindle BW, Williams WG: Renal replacement therapy after repair of congenital heart disease in children: A comparison of hemofiltration and peritoneal dialysis. J Thorac Cardiovasc Surg 1995;109:322–331. Picca S, Principato F, Mazzera E, Corona R, Ferrigno L, Marcelletti C, Rizzoni G: Risks of acute renal failure after cardiopulmonary bypass surgery in children: A retrospective 10-year casecontrol study. Nephrol Dial Transplant 1995;10:630–636. Sorof JM, Stromberg D, Brewer ED, Feltes TF, Fraser CD Jr: Early initiation of peritoneal dialysis after surgical repair of congenital heart disease. Pediatr Nephrol 1999;13:641–645. Bokesch PM, Kapural MB, Mossad EB, Cavaglia M, Appachi E, Drummond-Webb JJ, Mee RB: Do peritoneal catheters remove pro-inflammatory cytokines after cardiopulmonary bypass in neonates? Ann Thorac Surg 2000;70:639–643.

Stuart L. Goldstein Assistant Professor of Pediatrics Texas Children’s Hospital, 6621 Fannin Street Mail Code 3–2482, Houston, TX 77030 (USA) Tel. ⫹1 832 824 3800, Fax ⫹1 832 825 3889, E-Mail [email protected]

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Technical Aspects of CRRT Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 291–307

Vascular Access for Extracorporeal Renal Replacement Therapy in the Intensive Care Unit Bernard Canaud a,c, Cédric Formet a, Nathalie Raynala, Laurent Amiguesb, Kada Kloucheb, Hélène Leray-Moraguesa, Jean-Jacques Béraud b aIntensive

Care Unit, Nephrology, bMetabolic Intensive Care, and cRenal Research and Training Institute Lapeyronie, University Hospital Montpellier, Montpellier, France

Vascular access (VA) management in intensive care unit (ICU) is faced to a twofold problem: first, the installation of an angioaccess that must be adequate for extracorporeal renal replacement therapy (RRT) in the acute setting; second, the prevention of angioaccess-related morbidity [1]. VA is a basic and common tool required to perform all modalities of extracorporeal RRT [2]. Central venous dialysis catheters have become the preferred form of vascular access in acute renal failure (ARF) patients where peripheral arteriovenous shunts (e.g. Scribner, Busselmeier) have virtually disappeared. Catheters provide a rapid and easy way for blood access permitting to launch dialysis without delay in critically ill situation. Central venous catheters are used temporarily during the phase of acute renal failure and removed at the time of renal recovery (usually 4–6 weeks later). Despite significant technical advances, temporary dialysis catheters remain a major cause of morbidity and mortality in intensive care units (ICU) and catheter care must be reinforced. Renal replacement therapy in the ICU relies on two main therapeutic options defined by blood flow regimen, periodicity and length of sessions, namely continuous low-flow methods versus intermittent high-flow methods. Indication for continuous or intermittent modality relies on clinical judgment accounting for local technical expertise and patient clinical conditions. Venous catheter design does not differ fundamentally either for intermittent or continuous RRT modalities.

In this chapter, we will address the following issues: (1) implantation and management of venous catheters in the ICU setting, and (2) prevention of venous angioaccess-related morbidity.

Insertion and Management of Venous Catheters in the ICU Setting

Venous catheters are clearly the preferred option of blood access in acute patient. Catheters are easily inserted at the bedside; they are immediately usable; they provide adequate blood flow for all forms of dialysis modality. Catheters and Material Several types of hemodialysis catheters are available on the market. Catheters are usually made of polymers (e.g. polyvinyl chloride, polytetrafluoroethylene, polyethylene, polyurethane, silicone elastomer, tecoflex) that translate into specific catheter characteristics (resistance, softness, hemocompatibility) [3]. Catheter design and engineering are important factors contributing to their performances (low or high-flow catheter) and complications [4]. Due to their hemocompatibility properties, polyurethane and silicone material are now the most widely used. Catheter stiffness is a physical characteristic that dictates the procedure for percutaneous vein insertion. Catheter rigidity depends mainly on the polymer nature, the plasticizer content and the extrusion mode. Rigid and semirigid catheters, usually referred to acute catheters, are easily introduced percutaneously using the Seldinger method over a metallic guidewire. However, this stiffness leads to a greater risk of vascular perforation and vascular wall lesion. In this respect, semirigid polyurethane catheters are likely to cause more stenosis and thrombosis to host vein than that softer ones. Now, it must be noted that certain type of catheters made of polyurethane which are semirigid at ambient temperature soften up at the body temperature, thereby losing their mechanical aggressiveness. Soft silicone catheters, usually referred to chronic or permanent catheters, are more difficult to insert percutaneously but nevertheless have a major advantage associated to their tunneling capacity. Several modalities of percutaneous insertion, derived from the Seldinger’s method using introducer with sheath dilator (pealable or not) have been substituted to the surgical approach [5]. Most of these silicone rubber catheters are manufactured with a subcutaneous anchoring system (dacron cuff, purse ring suture). The subcutaneous anchoring system is advantageous: it stabilizes the catheter, it enlarges the distance from catheter skin emergence to vein insertion site, it promotes tissue scaring around the catheter,

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Outflow Outflow Inflow

Fig. 1. Acute catheter: Double-lumen polyurethane catheter.

Inflow Double-lumen, PermCath Outflow

Double-catheter, DualCath

Double split catheter, SplitCath

Fig. 2. Chronic or permanent catheters.

and finally it provides a physical barrier against bacterial intrusion along catheter pathway. Single- and double-lumen dialysis catheters are available on the market. Single lumen catheters have a single port used alternatively for both inflow and outflow. Although, two single-lumen catheters (inflow and outflow) inserted in the same central vein are used in some units, catheters featuring a double-lumen design (one arterial port and one venous port) are most popularly used (fig. 1). Layout of the lumen and distal ends of catheters may vary considerably from one type to another. According to venous and arterial port locations, two main types of catheter may be designed: one with port sites attached in a doublebarreled gun fashion (coaxial, double-D, double-O); the other with independent or separated port sites (Dual catheter, Split catheter) (fig. 2). From a flow perspective, it has been shown that independent catheter lines offered higher and more consistently adequate blood flow than attached ones. To summarize, one may consider that semirigid double-lumen polyurethane catheters (acute catheters) are a fairly reasonable choice for a short time use up to 2 weeks while soft silicone double catheters or double-lumen catheters (chronic or permanent catheters) are a best indication for prolonged RRT up to 4–6 weeks.

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Technical Aspects of Catheter Insertion Over the last decade, the methods of percutaneous catheter implantation have gained in easiness and safety, contributing to reduce traumatic complications and to increase catheter life expectancy. Major advances in securing catheter insertion have been provided by ultrasound based methods. These methods have several benefits over the conventional anatomical landmark method, including a reduction in catheter failure rate, a reduction in time spent to insert catheter, an increase in patient’s comfort and a significant reduction of major traumatic complications (pneumothorax and/or hemothorax) [6]. It has also been observed that routine use of ultrasound exploration identifies anatomical variations of the jugular vein position (right or left) in about 15–20% of cases. Ultrasound method may also be used either to locate vein prior any attempt of venipuncture offering a precise skin external landmark or to guide directly the vein cannulation at the time of catheter insertion. Basic rules for catheter insertion are known [7]. Catheter insertion must be performed in a clean room following strict aseptic rules including a meticulous skin preparation and disinfection of the patient, the use of sterile drape, gown, gloves, mask and hat being worn by the operator. Sites of Insertion The placement of the hemodialysis catheter is restricted to anatomical vein locations offering access to a central high-flow system (superior and inferior vena cava system). Selection of the anatomical venous site depends on the clinical context, the patient’s state and the physician’s expertise. Femoral approach should preferred as first option with critically ill respiratory condition (pulmonary edema, respiratory failure), or when thoracic access appears risky or because patient’s condition dictates prolonged stay in bed (coma, ventilatory assistance, and multiple injuries). Internal jugular access is preferable in the absence of thoracic life-threatening conditions. Subclavian access should be reserved for short-term treatment or when no other central vein access option exists. In all cases the percutaneous vein cannulation should be performed after skin preparation, under local anesthesia in very strict aseptic condition. The detailed procedures of catheter insertion will not be described here, and the interested reader is referred to textbook and technical reports in the field.

Femoral Vein

Femoral vein represents the first and original route for percutaneous vein catheterization described by Shaldon in the early 1960s. Nowadays, the femoral

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Femoral double-lumen silicone catheter (tunnel) Femoral double-lumen polyurethane catheter

Fig. 3. Venous accesses via the inferior cava system.

vein remains an indication of choice in case of emergency when hemodialysis has to be launched without delay in a patient with critical cardiopulmonary condition. Femoral catheterization is also useful in bedridden patients with severe neurologic disorders, ventilatory assistance (tracheotomy) or multiple organ failure (fig. 3). Double-lumen polyurethane catheters represent the best option in this case to start the dialysis within few minutes. The right or left femoral vein offers the same facility of insertion. The length of femoral catheters that provide optimal flow performances is between 25 and 35 cm. The insertion site is located approximately 1–2 cm below the crural arcade and 1 cm medially apart from the femoral artery. Although such type of femoral catheters may be extended to several weeks, it is commonly accepted for safety reason to restrict their use up to 2 weeks. Two single-lumen polyurethane catheters inserted in the same ipsi-femoral vein may represent another useful option to increase flow performances. Tunnelized soft silicone catheters used in chronic patients [8] have been also successfully used in acute condition. These types of catheters represent a new and quite interesting option in the acute setting providing high flow performances with reduced complication rates that deserve further studies.

Subclavian Vein

Subclavian catheter cannulation for hemodialysis was popularized by Uldall in the early 1980s. Subclavian catheters entailing a major risk of stenosis and/or thrombosis of the subclavian vein or one of its affluent vein superior vena cava, innominate vein, brachiocephalic troncus, have reduced dramatically

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Fig. 4. Acute catheters, Double-lumen polyurethane.

the indications for subclavian cannulation [9]. It is however important to acknowledge that these complications were mainly observed with use of semirigid and poorly hemocompatible catheters. From these historical reports, no prospective study has been carried out to really assess the incidence of catheter-related complications with soft and hemocompatible material. Indeed, subclavian cannulation should be considered a second line venous angioaccess intent for very short-term use or in absence of other alternative (fig. 4). Several methods have been described for the percutaneous insertion of subclavian catheters. Insofar as subclavian cannulation is indicated, soft catheters made preferably of silicone rubber should be considered for insertion. The right subclavian approach is preferable to reduce the distance from insertion site to right atrium. The left subclavian vein is more difficult to cannulate and exposed to a higher risk of left brachiocephalic thrombosis. In case of polyurethane catheters short cannula (20–25 cm) are indicated to prevent cardiac trauma (atrium and ventricule perforation). This fatal risk is clearly minimized with the use of soft silicone rubber catheters.

Internal Jugular Vein

Over the last 15 years, internal jugular access has gained popularity in acute conditions. Irrespective of the catheter used, jugular vein catheterization

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Fig. 5. Chronic tunnelized dual-catheter silicone inserted in the internal jugular vein (DualCath).

(particularly the right vein) entails a reduced incidence of venous thromboses relative to the subclavian access [10, 11]. The jugular route is prone to infectious complications. Straight catheters exiting close to the ear and/or in patients with tracheotomy bear a higher risk of infection (fig. 4). Kinked double-lumen polyurethane catheters have recently proposed to reduce this risk. Such type of acute catheter does not provide a safe and comfortable venous access site either for patient of nurses. Interestingly, soft polyurethane and silicone rubber catheters (double-lumen, double-catheter, split-catheter) (PermCath, Quinton Instrument Co, Seattle, Wash., USA; DualCath, Hemotec, Ramonville, France & Medcomp, Harleysville, Pa., USA) implanted percutaneously into the internal jugular with a tunnel have been employed as a first intent in acute patients with excellent results (fig. 5). The percutaneous insertion of the catheter into the internal jugular vein is preferably performed in the low position of the Sedillot’s triangle. The right internal jugular vein represents the best anatomical option offering a straight and short distance to reach the right atrium. The left internal jugular vein may be indicated as second intent since it is technically more difficult to cannulate and it bears higher risk of vein thrombosis. Soft silicone rubber catheters offers the possibility of creating a 10- to 12-cm subcutaneous tunnel on the chest wall below the clavicle. According to the type of catheters (single part, double parts) the tunnelization will be performed either upwards or downwards.

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Subcutaneous anchoring system (dacron cuff, purse ring suture) will secure and protect catheter from infection. From this section, it must be acknowledged that each vein location and each type of catheters has specific advantages but bears the risks of foreign material inserted into a vein. To ensure continuity of renal replacement therapy in acute patient it is often necessary to change the venous site (catheter dysfunction, catheter infection). The femoral vein is the first site of insertion in critical conditions for commodity. The right internal jugular and subclavian approaches are in most cases the preferred sites of insertion for mid-term use. They facilitate the mobilization of patients (care, physiotherapy, imaging) and should be preferred in conscious or mobile patients. Catheter Positioning Correct positioning of the catheter’s tip is essential to prevent mechanical complications and catheter dysfunction. Thoracic catheters inserted in the superior vena cava system should have their tips located between the superior vena cava and the right atrium to optimize flow rate. However, such position is associated with specific risks of cardiac trauma or atrial thrombosis. Fluoroscopic or chest X-ray checking correct catheter position and tip location must performed prior catheter use. To ensure safety, semirigid catheters should have their tips located in the superior vena cava system (1 or 2 cm above the right atrium) and not in the heart. Although reduced, this risk still persists with soft catheter and a high level of vigilance must be maintained. Twenty centimeters is the optimal length for a thoracic catheter inserted on the right site in an adult. Three to four additional centimeters are required when catheters are inserted on the left side. Femoral catheters accessing the inferior vena cava system should have their tips positioned in the central lumen of the inferior vena cava. This position supports a regular and correct functioning of the catheter and reduces the risk of vein perforation. Twenty-five to thirty centimeters length is needed for a femoral catheter to reach the desired location in an adult.

Catheter Care and Catheter Maintenance

In a recent meta-analysis study, it has been shown that appropriate and strict hygienic rules and good medical practices are the best warranty of successful catheter handling [12]. In order to achieve highest quality hemodialysis catheter should be used exclusively for renal replacement therapy avoiding their use for blood samples, parenteral feeding and intravenous injections. These acts increase the risk of catheter contamination. Nurse training is essential in the

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prevention of infection. Strict aseptic conditions in catheter handling must be adopted at any time [13, 14]. Interestingly, the use of a betadine ointment and/or antiseptic protective box on catheter hubs significantly reduces the incidence of bacteremias in hemodialyzed patients [15, 16]. Catheter dressing is highly desirable to protect the emergence of catheters. Indeed, tight occlusive polyurethane occlusive dressings promoting moisture and proliferation of cutaneous bacteria are not suitable since they have been associated with an increase risk of catheter infection [17, 18]. Preliminary studies comparing bioactive material (silver or antibiotic impregnated material) to regular catheter have led to encouraging results in reducing infection incidence. Catheter locking solutions based on antithrombotic/antiseptic or antibiotic mixture have also proved to be efficient in preventing endoluminal bacteria contamination. Real benefice of these approaches deserve further studies before being proposed as preemptive therapeutic option.

Catheter Performances

The nature of the material used and the inner diameter of the catheter directly condition its performances. Thus, compliance and elastance of the material, catheter’s length and diameter and the presence of distal holes, condition the resistance to the blood circulation. An internal port lumen diameter of 2.0–2.2 mm, such as found in silicone rubber catheters, is able to provide an optimal flow/resistance regimen [19]. Intermittent RRT modalities requiring high blood flows (250–400 ml/min) are mostly dependent upon catheter’s physical characteristics. Continuous RRT modalities requiring fairly low blood flows (150–200 ml/min) are much less blood flow dependent. Patency of the internal lumen and its stability in the venous bulk flow are key factors for proper operation of a catheter. Two independent catheter ports (or split catheter) bearing circular distal holes are essential to reduce probability of catheter dysfunction (parietal suction, partial lumen obstruction, fibrin sleeve formation). Extracorporeal blood pressure (arterial and venous side) recorded by the dialysis monitoring module provide indirect evidence of catheter’s patency. The negative pressure recorded on the inflow side and/or the positive pressure recorded on the outflow side, reflect blood resistance in the extracorporeal circuit. These values may be used as indirect bed-side index of partial catheter obstruction [20]. For example, it is convenient to observe that the venous pressure is half the blood flow (e.g. for a blood flow rate of 300 ml/min, venous pressure is close to 150 mm Hg) in the silicone rubber DualCath device. Early catheter mechanical dysfunction is more frequent with double-lumen catheters inserted via the subclavian way than with those inserted in other sites.

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In these cases, causes of catheter kinking and striction (subclavian pathway or suture) must be ruled out. Catheter recirculation, a factor reducing dialysis efficacy, depends both on site of catheter insertion and flow prescribed [21]. The deleterious role of recirculation is much less important in continuous modalities than in intermittent ones. Femoral catheters, particularly short ones, exhibit a high recirculation rate averaging 20% (5–38%). Internal jugular and subclavian catheters have much lower recirculation rate averaging 10% (5–15%). It is also interesting to note that the inversion of the connecting lines (by using the arterial line for venous return and the venous line for blood aspiration) on double-lumen catheters, that is sometimes performed to increase flow when a pressure problem occur, significantly increases blood recirculation rates. In this context recirculation up to 20 or 30% have been observed [22, 23].

Catheter Complications

The causes of hemodialysis catheter dysfunction are usually related to the delay after insertion [24]. Immediate or early dysfunction usually result from mechanical problems, among which are a malpositioning of the catheter tip (sucking the wall of the vein), a kinking of the catheter and a striction caused by ligatures or aponevrosis [25]. Late dysfunctioning (more than 2 weeks) is more often caused by thrombotic problems: partial or total obstructive thrombosis of the catheter lumen, thrombosis or stenosis of the cannulated vein, external sheath formation on the catheter distal end (external fibrin sleeve), internal coating of the catheter (endoluminal fibrin sleeve) [26]. In the latter case, the partial or total occlusion of the lumen and distal and/or lateral perforations greatly increase the extracorporeal resistances and reduce accordingly the effective blood flow delivered. Thrombotic complications can occur in several ways. Endoluminal thrombosis of the catheter is the most common. This is revealed by intermittent or permanent catheter dysfunction. The catheter may be reopened in these cases by mechanical (brush) or chemical methods (fibrinolytic). External thrombosis of the catheters caused by a fibrin sheath covering the tip of the catheters requires either fibrinolysis, catheter stripping through a percutaneous femoral route, or removing and replacement of catheters. Thrombosis of the host cannulated veins is a severe situation (potential source of pulmonary embolism). The incidence may vary from 20 to 70% of reports according to the sites and diagnostic modalities used [27]. Thrombosis of the right atrium is the most serious and potentially lethal complication. Symptoms of thrombotic complications are dysfunction of the catheter, rarely

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onset of edema of the ipsilateral limb or unexplained febricula are the appealing symptom. Several factors contribute to the thrombogenicity of the catheter including the catheter (material and composition of the catheter, softness, aspect and surface treatment), the mode of insertion, the type of vein (diameter, local hemodynamics), the duration of cannulation, the clotting and inflammatory state of the patient (hyperfibrinemia, inflammatory syndrome, hyperthrombocytemia, previous venous thrombosis), and the contamination of the catheter. Infections represent a major burden for hemodialysis catheters [28–30]. Nontunneled polyurethane catheters used as a short-term therapy entail a bacteremia risk estimated to a median value of 5.9 episodes per 1,000 patientdays in intensive care units [31]. The incidence of bacteremias varies greatly according units and catheter practice [32]. Non-tunneled internal jugular access bears a higher risk of infections, notably in patients with a tracheotomy [33, 34]. Early infection may be related to catheter placement problems or skin and catheter track infection. Placement of a percutaneous catheter disrupts the continuous protecting solution of the skin. Bacterial colonization of the skin is most often incriminated in these catheter infections. The skin acts as a bacterial reservoir and contributes to the subcutaneous penetration of germs along the catheter pathway. Hence, the need to carefully disinfect the skin prior to any catheter insertion but equally to prevent the onset of cutaneous lesions and ensure a particular care in the patients with catheters is always suitable. Late infections are most often associated with endoluminal catheter contamination and may be the expression of microbial biofilm seeding the catheter lumen. The prolonged use of a dialysis catheter in acute patient entails an infectious risk increasing with time. This risk is known but unfortunately unavoidable. It must be alleviated through suitable nursing care and handling. Two types of infections are observed with catheters: local infection (skin exit, track infection) and systemic infection (bacteremia, septicemia, infected thrombosis). Skin exit and bacteremia are the most frequent forms of infection that may be treated by local and systemic antibiotic therapy while keeping the catheter in situ. Catheter track infection, septicemia and infected venous thrombosis are most severe form of infections requiring both catheters withdrawal and systemic antibiotic therapy. Endoluminal catheter contamination from hubs may be the source of microbial biofilm. In this case, bacteria entering into the lumen, adhere onto the catheter surface, growth, produce glycocalyx (slyme) and become resistant to antibiotic. Occasionally, bacteria may be released from this biofilm (e.g. higher stress conditions due to blood pump speed) being the source of bacteremia and fever episode.

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In the event of an unexplained septic condition, it is reasonable to refer first to the role of the catheter as the infection carrier. Several authors have proposed a catheter replacement over a guidewire through the same subcutaneous track [35]. This unsafe microbiological approach appears undesirable in our opinion and should be abandoned. In another approach, the catheters are systematically changed every 4 days and inserted in different venous sites. However, whether this change is pertinent remains highly debatable. In all cases it is essential to cultivate the withdrawn catheter. The insertion of soft tunnelized catheters (with or without anchoring system) for long-term use appears more suitable to prevent catheter hazards. Strict aseptic rules (gloves, mask, drapes, antiseptic) shall be followed at any time to handle catheters and particularly at the time of blood lines connection to prevent contamination of catheter hubs. Stenosis of the host vein is a common risk of catheter in the long term. It is more common with semirigid than with soft catheters. This troublesome complication may compromise the creation of arteriovenous fistula in a chronic renal failure patient.

Technical Catheter Advances

Biomaterial research and technical development have suggested new solutions to render safer the use of catheter. New polymer or surface treatment of the catheter may reduce the hemoreactivity and the prothrombotic activity of the catheter lines substantially [36, 37]. Introduction of bioactive material with ion bombardment, silver impregnation and anticoagulant or antibiotic/antiseptic are intended to prevent platelet adhesion and subsequent clotting and to prevent bacterial adhesion [38]. Recent studies comparing the incidence of infection using antibiotic impregnated catheters to regular ones have confirmed the efficacy in reducing streamline infection over short period of time [39, 40]. However, the true protective effect of this bioactive material is effective on longer period of time (⬎6 months) remains to be proved [41]. Catheter locking solution during the interdialytic period, based on antithrombotic/antiseptic mixture, appears more appealing in this context. Locking solutions (Neutrolin, Citralock) are already available on the market [42, 43]. They have been proved highly effective both in reducing significantly catheter-related infection and in preventing bacterial biofilm formation in chronic patients [44]. It remains to be proved that these solutions are applicable to acute setting without risks and this concern deserve further studies [45].

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Prevention of Venous Catheter-Related Morbidity

Reducing venous catheter-related complications implies for an ICU managing team to establish and follow very stringent rules of use. These rules may be summarized in a ‘good medical practice act’ that we call humorously ‘The Ten Commandments for Catheter Users in the ICU’. Thou shalt select the best venous access site according to the clinical condition of your patient. It is important to choose the venous access site taking into account the clinical condition and particularly the critical illness of the patient. Femoral approach should preferred as first option with critically ill respiratory condition or because patient’s condition dictates prolonged stay in bed. Internal jugular access is preferable in the absence of thoracic life-threatening conditions. Subclavian access should be reserved for short-term treatment or when no other central vein access option exists. Thou shalt discuss the type of catheter according to the modality of renal replacement therapy that you indicate. The type of catheter to be inserted will be defined according to the expected duration of use and to the critical condition of the patient. Acute catheters (e.g. polyurethane double lumen) are indicated as emergency and salvaging angioaccess method to launch immediate hemodialysis in very critically ill patient. Chronic tunnelized catheters (e.g. dual catheters, split catheters) are indicated for prolonged treatment period when life-threatening conditions are controlled. Thou shalt select an experienced and trained operator. The insertion of venous catheter should be reserved to experienced operator. This technical act should not be trivialized and performed by the youngest inexperienced fellow. Ultrasound-based methods provide a major advance for safety and easiness of catheter insertion particularly for trainees. They should be used as much as possible. These methods may be used either to locate vein prior any attempt of venipuncture offering a precise skin external landmark or to guide directly the vein cannulation at the time of catheter insertion. Thou shalt establish a precise protocol in your unit for the catheter use. A precise procedure for catheter use and handling must be established in each ICU. This is quite important to respect the working constraints of each unit. All details must be mentioned and periodic checking should be performed to verify that the procedure is applied and fit ICU needs. Very strict aseptic conditions (catheter and local disinfection, use of sterile gown, mask and gloves) applied any time when catheter is manipulated are the first protective line [46]. Thou shalt educate your nursing staff and collaborators to carefully respect the defined handling procedures.

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Training of the nursing personnel is essential to prevent catheter dysfunction and infection. This aspect should be part of a continuous training program in the ICU. It is recommended to have a referent experienced nurse for this aspect that will coordinate actions and report results of the ICU. Thou shalt evaluate the particular risk of your patient according to the clinical situation. ICU treated patients have multiple risk factors for developing venous catheter complications. Among them, one can identify some very risky factors such as sepsis, ventilation, stomized (colostomy, ureterostomy…), severe inflammation, malnutrition, and postoperative patients with multiple drainage. All these factors should be considered for venous access choice and for catheter care in order to enhance catheter protection barriers. Thou shalt watch carefully and regularly catheter to detect earlier any complication. Catheter performances should be checked regularly in order to achieve dialysis delivery dose. That could be performed by evaluating dialysis efficacy and blood flow and flow resistance. Catheter aspect and skin exit must be assessed regularly to detect a local inflammation or infection. This is an important part of the nursing task that should be reported and recorded in the patient flowchart. Thou shalt restrict exclusively the use of catheter for renal replacement therapy. Venous catheter should be used exclusively for dialysis. Parenteral nutrition, intravenous fluid infusion, blood samplings and drug administration should be prohibited via dialysis catheters except when dialysis is running. Such manipulations increase significantly the risk of catheter dysfunction (partial thrombosis or precipitation) and bacterial contamination. Thou shalt correct individual patient risk factors in order to prevent complications. When specific patient’s risks are identified, they should be corrected. Chronic bearers of bacteria (e.g. Staphylococcus aureus) should be treated by topical antiseptics or antibiotics to eradicate the source. Skin cleaning and disinfection of the surrounding area should be performed with an appropriate disinfectant. Dressing covering the catheter must be proof and adequately adhesive to skin surface. Stomies should be adequately isolated. The use of catheter locking solution with dual action, antithrombotic and antiseptic, are strongly recommended within the interdialytic period to prevent catheter clotting and bacterial contamination. Thou shalt institute with your nursing staff a continuous quality improvement assurance program. All these measures are virtually ineffective if they are not part of a continuous quality improvement program. In other words, a specific quality

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assurance program for catheter care must be implemented in each unit under the expertise of a dedicated staff member. Catheter care protocols will be adjusted to the results of the ICU and nursing staff will be associated to this thought [47].

Conclusion

Venous catheters are the preferred form of angioaccess in the acute setting. Catheter insertion is facilitated by the use of ultrasound devices. Catheter care and handling require complying with strict protocols in order to prevent catheter-related complications. Catheter performances should be evaluated in the acute setting in order to deliver adequate dialysis dose in ARF patients. Best clinical results with venous catheters will be guaranteed when applying ‘The Ten Commandments for Catheter Users in the ICU’ every day.

References 1

2

3 4

5 6 7 8

9 10 11

12

Canaud B, Martin K, Nguessan C, Klouche K, Leray-Moragues H, Beraud JJ: Vascular access for extracorporeal renal replacement therapies in the intensive care unit in clinical practice. Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 266–282. Uldall R: Hemodialysis access. Part A: Temporary; in Jacobs C, Kjellstrand CM, Koch KM, Winchester JFW (eds): Replacement of Renal Function by Dialysis. Dordrecht, Kluwer Academic Publishers, 1996, pp 277–292. Maclean-Ross AH, Griffith CDM, Anderson JR, Grieve DC: Elastomer subclavian catheters. J Parenter Enteral Nutr 1982;6:61–63. Curelalu I, Gustavsson B, Hansson AH: Material thrombogenicity in central venous catheterization. II. A comparison between plain silicone elastomer and plain polyethylene, long, antebrachial catheters. Acta Anaesthesiol Scand 1983;27:158–164. Canaud B, Leray-Moragues H, Garred LJ, Turc-Baron C, Mion C: Permanent central vein access. Semin Dial 1996;9:397–400. Defalque RJ, Campbell C: Cardiac tamponade from central venous catheter. Anesthesiology 1979;50:249–252. Food and Drug Administration: Precautions Necessary with Central Venous Catheters. Washington, US Government Printing Office, 1989, p 15. Montagnac R, Bernard CI, Guillaumie J, Hanhart P, Clavel P, Yazji J, Martinez LM, Schillinger F: Indwelling silicone femoral catheters: Experience of three haemodialysis centres. Nephrol Dial Transplant 1997;12:772–775. De Moor B, Vanholder R, Ringoir S: Subclavian vein hemodialysis catheters: Advantages and disadvantages. Artif Organs 1994;18:293–297. Cimochowski GE, Worley E, Rutherford WE, Sartain J, Blondin J, Harter H: Superiority of the internal jugular over the subclavian access for temporary dialysis. Nephron 1990;54:154–161. Schillinger F, Schillinger D, Montagnac R, Milcent T: Post-catheterisation vein stenosis in hemodialysis: Comparative angiographic study of 50 subclavian and 50 internal jugular access. Nephrol Dial Transplant 1991;6:722–724. Mcgee WT, Ackerman BL, Rouben LR, Prasad VP, Bandi V, Mallory DL: Accurate placement of central venous catheters: A prospective, randomized, multicenter trial. Crit Care Med 1993;21: 1118–1123.

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13

14

15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30

31 32 33 34 35 36

Vanherweghem JL, Dhaene M, Goldman M, Stolear JC, Sabot JP, Waterlot Y, Serruys E, Thayse C: Infections associated with subclavian dialysis catheters: The key role of nurse training. Nephron 1986;42:116–119. Alonso-Echanove J, Edwards JR, Richards MJ, Brennan P, Venezia RA, Keen J, Ashline V, Kirkland K, Chou E, Hupert M, Veeder AV, Speas J, Kaye J, Sharma K, Martin A, Moroz VD, Gaynes RP: Effect of nurse staffing and antimicrobial-impregnated central venous catheters on the risk for bloodstream infections in intensive care units. Infect Control Hosp Epidemiol 2003;24:916–925. Levin A, Mason AJ, Jindal KK, Fong IW, Goldstein MB: Prevention of hemodialysis subclavian vein catheter infections by topical providone-iodine. Kidney Int 1991;40:934–938. Maki DG, Alvarado CJ, Ringer M: A prospective, randomized trial of providone-iodine, alcohol and chlorhexidine for prevention of infection with central venous and arterial catheters. Lancet 1991;338:339–344. Conly JM, Grieves K, Peters B: A prospective, randomized study comparing transparent and dry gauze dressings for central venous catheters. J Infect Dis 1989;159:310–315. Hoffman KK, Weber DJ, Samsa GP, Rutala WA: Transparent polyurethane film as an intravenous catheter dressing: A meta-analysis of infection rates. JAMA 1992;267:2072–2076. Athirakul K, Conlon P, Schwab S: Cuffed central venous hemodialysis catheters and adequacy of dialysis. J Am Soc Nephrol 1996;7:1402–1403. Stroud CC, Meyer SL, Bawkon MC, Smith HG, Klein MD: Vascular access for extracorporeal circulation: Resistance in double lumen cannulas. ASAIO J 1991;37:M418–M419. Sherman RA, Matera JJ, Novik L, Cody RP: Recirculation reassessed: The impact of blood flow rate and the low-flow method reevaluated. Am J Kidney Dis 1994;23:846–848. Leblanc M, Fedak S, Mokris G, Paganini EP: Blood recirculation in temporary central catheters for acute hemodialysis. Clin Nephrol 1996;45:315–319. Level C, Lasseur C, Chauveau P, Bonarek H, Perrault L, Combe C: Performance of twin central venous catheters: Influence of the inversion of inlet and outlet on recirculation. Blood Purif 2002;20:182–188. Leblanc M, Bosc JY, Paganini EP, Canaud B: Central venous dialysis catheter dysfunction. Adv Renal Replacement Ther 1997;4:377–389. Kelber J, Delmez JA, Windus DW: Factors affecting delivery of high-efficiency dialysis using temporary vascular access. Am J Kidney Dis 1993;22:24–29. Hoshal VL, Ause RG, Hoskins PA: Fibrin sleeve formation on indwelling subclavian central venous catheters. Arch Surg 1971;102:353–358. Trottier SJ, Veremakis C, Oíbrien J, Auer AI: Femoral deep vein thrombosis associated with central venous catheterization: Results from a prospective, randomized trial. Crit Care Med 1995;23:52–59. Gil RT, Kruse JA, Thill-Baharozian MC, Carlson RW: Triple- vs single-lumen central venous catheters: A prospective study in a critically ill population. Arch Intern Med 1989;149:1139–1145. Collignon P, Soni N, Pearson I: Sepsis associated with central vein catheters in critically ill patients. Intens Care Med 1988;14:227–232. Richet H, Hubert B, Nitemberg G: Prospective multicenter study of vascular-catheter-related complications and risk factors for positive central-catheter cultures in intensive care unit patients. J Clin Microbiol 1990;28:2520–2526. Maki DG: Nosocomial infection in the intensive care unit; in Parillo JE, Bone RC (eds): Critical Care Medicine Principles of Diagnosis and Management. St-Louis, Mosby, 1995, pp 893–954. Eyer S, Brummitt C, Crossley K: Catheter-related sepsis: Prospective, randomized study of three methods of long-term catheter maintenance. Crit Care Med 1990;18:1073–1078. Pezzarossi HE, Ponce De Léon S, Calva JJ: High incidence of subclavian dialysis catheter-related bacteremias. Infect Control 1986;7:596–602. Cheesbrough JS, Finch RG, Burden RP: A prospective study of the mechanisms of infection associated with hemodialysis catheters. J Infect Dis 1986;154:579–586. Cobb DK, High KP, Sawyer RG: A controlled trial of scheduled replacement of central venous and pulmonary-artery catheters. N Engl J Med 1992;327:1062–1068. Baumann M, Witzke O, Dietrich R, Haug U, Deppisch R, Lutz J, Philipp T, Heemann U: Prolonged catheter survival in intermittent hemodialysis using a less thrombogenic micropatterned polymer modification. ASAIO J 2003;49:708–712.

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37 38 39

40

41

42 43 44

45 46 47

Eberhart RC, Clagett CP: Catheter coatings, blood flow, and biocompatibility. Semin Hematol 1991;28:42–48. Tobin EJ, Bambauer R: Silver coating of dialysis catheters to reduce bacterial colonization and infection. Ther Apher 2003;7:504–509. Darouiche RO, Raad II, Heard SO, Thornby JI, Wenker OC, Gabrielli A, Berg J, Khardori N, Hanna H, Hachem R, Harris RL, Mayhall G: A comparison of two antimicrobial-impregnated central venous catheters. Catheter Study Group. N Engl J Med 1999;340:1–8. Chatzinikolaou I, Finkel K, Hanna H, Boktour M, Foringer J, Ho T, Raad I: Antibiotic-coated hemodialysis catheters for the prevention of vascular catheter-related infections: A prospective, randomized study. Am J Med 2003;115:352–357. Bambauer R, Mestres P, Schiel R, Bambauer S, Sioshansi P, Latza R: Long-term catheters for apheresis and dialysis with surface treatment with infection resistance and low thrombogenicity. Ther Apher Dial 2003;7:225–231. Sodemann K, Polaschegg HD, Feldmer B: Two years’ experience with Dialock and CLS (a new antimicrobial lock solution). Blood Purif 2001;19:251–254. Quarello F, Forneris G: Prevention of hemodialysis catheter-related bloodstream infection using an antimicrobial lock. Blood Purif 2002;20:87–92. Weijmer MC, Debets-Ossenkopp YJ, Van De Vondervoort FJ, ter Wee PM: Superior antimicrobial activity of trisodium citrate over heparin for catheter locking. Nephrol Dial Transplant 2002;17:2189–2195. Polaschegg HD, Sodemann K: Risks related to catheter locking solutions containing concentrated citrate. Nephrol Dial Transplant 2003;18:2688–2690. Raad II, Gilbreath J: Prevention of central venous catheter-related infections by using maximal sterile barrier precautions during insertion. Infect Control Hosp Epidemiol 1994;15:231–236. Coopersmith CM, Zack JE, Ward MR, Sona CS, Schallom ME, Everett SJ, Huey WY, Garrison TM, McDonald J, Buchman TG, Boyle WA, Fraser VJ, Polish LB: The impact of bedside behavior on catheter-related bacteremia in the intensive care unit. Arch Surg 2004;139:131–136.

Professor Bernard Canaud Department of Nephrology, Lapeyronie University Hospital CHU Montpellier, FR–34295 Montpellier (France) Tel. ⫹33 4 67 33 84 95, Fax ⫹33 4 67 60 37 83, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 308–316

Anticoagulation in Continuous Renal Replacement Therapy O. Vargas Hein, W.J. Kox, C. Spies Department of Anesthesiology and Intensive Care, University Hospital Charité, Campus Mitte, Berlin, Germany

The incidence of acute renal failure (ARF) varies in critically ill patients but it can be as high as 25% [1]. If ARF is part of the multiple organ dysfunction syndrome the mortality increases to over 50% [2]. Continuous renal replacement therapy (CRRT), occurring in up to 20% of the ICU patients with ARF has become the treatment of choice for ARF in the intensive care unit (ICU) [3]. During CRRT the blood-foreign membrane interactions lead to an activation of different cascades involving the plasmatic and cellular coagulation system, the complement system and the inflammatory cascade. In the last years, a close relationship of interactions between the inflammatory and the coagulation system have been investigated [4, 5]. The result is clotting of the hemofiltration system, mainly the filter [4, 6]. To counteract these interactions anticoagulation is necessary [4, 7]. However, the critically ill patients under CRRT are mostly highly compromised in their hemostatic system. Coagulopathies and underlying diseases with a high risk for bleeding are present as well as hypercoagulable states [8, 9]. The equilibrium between avoiding bleeding complications and keeping the system open considering patients’ multiple diseases is difficult to achieve with the anticoagulation regimes used at present.

High-Molecular-Weight (HMW) Heparin

HMW heparin is used as the standard for anticoagulation in CRRT. Heparin, a mucopolysaccharide composed of equal amounts of D-glucosamine and uronic acid, has a molecular weight of 3,000–30,000 daltons and a short halflife of 1–1.5 h. The mechanism of action of HMW heparin is antithrombin III

(AT III) dependent, potentiating the inhibitory action of AT III mainly on factors IIa, IXa, Xa, XIa and XIIa [10]. The main metabolism and elimination is renal function independent so that no accumulation has to be expected. However, as HMW heparin metabolism is dependent on the interaction of various proteins and endothelial cells the effective time of action can be very variable [7, 10]. Antagonizing heparin effectively can be achieved by protamine. Nevertheless, bleeding complications are as high as 20–30% [1, 6, 11]. Especially in critically ill patients with high risk of bleeding the preexisting coagulation state has to be taken into consideration in order to choose the right dose. The hemofiltration system is rinsed with saline containing 5,000–20,000 IU of HMW heparin. At initiation of CRRT a bolus of 500–1,000 IU of HMW heparin is given followed by a continuous infusion of 300–1,000 IU/h or 5–10 IU/kg/h [6, 12]. Monitoring accurately the dosing regime is essential to avoid bleeding complications. The partial thromboplastin time (aPTT) has shown a good correlation with filter survival, heparin dose has not. An aPTT of 35–45 s seems to keep the best balance between bleeding complications and keeping the system free of clotting [6, 12]. Besides bleeding events heparin induced thrombocytopenia type II (HIT II) is a further complication with an incidence of up to 10% in critically ill patients. After its diagnosis further anticoagulation with heparin is strictly contraindicated [1]. Because of pathological thrombocyte adhesion and agglutination in HIT II life-treathening thromboembolisms as well as augmented filter clotting can occur. Alternative anticoagulation is mandatory.

Low-Molecular-Weight (LMW) Heparin

LMW heparins are depolymerized HMW heparin and have a molecular weight of 4,500–9,000 daltons. As HMW heparin LMW heparin binds to AT III but has a major action on factor Xa [6]. The half-life is 3–4 h and the elimination is to 50% renal. LMW heparin is not reliably filtered and antagonized by protamine. The dose correlation with aPTT is insufficient. Dosage monitoring has to be performed measuring the anti-Xa-activity, which is not a routine parameter. In renal failure LMW heparin can accumulate, reinforced by the problematic dosage monitoring [6]. The studies performed with LMW heparin for anticoagulation in CRRT have described either comparable results or less bleeding complications than with HMW heparin with comparable filter effectivity [13, 14]. The optimum dose lies in the range of 15–20 IU/kg bolus followed by 5–10 IU/kg/h with a target anti-Xa-activity between 0.3–0.6 IU/ml [12, 14, 15]. Even though LMW heparin has a weaker action on thrombocytes than HMW heparin, 90% cross-reactivity with HIT II antibodies have been described. Therefore, LMW heparin is contraindicated in patients with HIT II [6, 12].

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Danaparoid-Sodium

Danaparoid is a low-molecular glucosaminoglykan (heparinoid) with a molecular weight of 5,500 daltons. The mechanism of action is AT III dependent inhibiting factor Xa. The half-life is 24 h. Renal elimination is 50%. Therefore, in renal failure half-life is prolonged to 31 h with the risk of drug accumulation. Danaparoid cannot be filtered or antagonized [6]. The monitoring of anticoagulation is performed with the anti-Xa-activity. Danaparoid has been described to be effective and safe in intermittent hemodialysis [6, 16]. A study performed in CRRT with danaparoid as anticoagulant with a dose of 70–225 IU/h with an approximate level of 0.3–0.8 IU/ml showed a satisfactory filter patency. However, in all patients with coagulopathies bleeding complications occurred [16]. In patients with HIT II 10% in vitro cross-reactivity has been observed for danaparoid sodium. The clinical relevance (in vivo crossreactivity) is described to be negligible and danaparoid has been used successfully in patients having HIT II [16–18]. However, case reports have described life-threatening thromboembolic complications in patients who have been switched from HMW heparin to danaparoid because of HIT II [18]. Therefore, under close monitoring of thrombocytes count and when no other alternative anticoagulation is feasible danaparoid can be seen as an alternative to heparin in HIT II patients.

Hirudin

Hirudin, a polypeptide made by recombinant technology with a molecular weight of 7,000 daltons, acts independently of cofactors and directly inhibits bound and unbound thrombin. Its elimination half-life is 1–3 h and the elimination pathway is ⬎90% unmetabolized through the kidneys. In the presence of renal failure the half-life of hirudin is considerably prolonged up to 100 times the normal half-life [1]. Hirudin is removed through hemofiltration membranes at a rate dependent on the sieving coefficient of the used membrane [19]. In case of ARF, hirudin could persist at low levels even when it is not given any more because of redistribution. In interaction with coagulation disorders due to other underlying diseases it could possibly lead to bleeding complications [20]. aPTT has been considered an unreliable monitoring parameter during hirudin anticoagulation, because it does not correlate with high hirudin levels [1]. Ecarin clotting time (ECT), a bedside whole blood plasma clotting time assay based on thrombin activation through the snake venom ecarin, has shown adequate dose-response curves [20]. However, ECT is no routine parameter. In this case aPTT can be used with a target of 50–60 s. Hirudin has been applied

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continuously (12–500 ␮g/kg/day) and as bolus (4–128 ␮g/kg/day) application in CRRT showing adequate filter patency in comparison to HMW heparin [1, 20, 21, 22]. However, continuous application led to bleeding complications in patients with plasmatic or cellular coagulopathies even though hirudin was under or in the therapeutic range [1, 20, 21]. Beside the coagulation status of the patient, an important issue is also the difference in risk of bleeding between surgical and medical patients. Comparable doses of continuous hirudin led to bleeding complications in surgical patients as medical patients did not bleed [1, 20–22]. Regarding HIT II patients, hirudin does not show cross-reactivity with HIT II antibodies and is the first-line choice in HIT II patients.

Prostaglandins

Prostaglandins are products of the arachidonic acid metabolism and are produced in the vascular endothelial tissue. The mechanism of action is an inhibition of thrombocyte aggregation without influence on the plasmatic coagulation pathway [6]. The half-life is ⬍5 min. The synthetic prostaglandins prostacyclin (PGI2) and alprostadil (PGE1) have been successfully used as anticoagulants in CRRT. Because of their potent vasodilatory action with possible hemodynamic compromise and because of higher rates of bleeding episodes using higher doses of prostaglandins, they have been used in combination with HMW heparin in lower doses of both anticoagulants [23, 24]. Systemic vasodilatory action can also be reduced in applying prostaglandins prefilter [5, 7]. The studies performed with prostaglandins in a dose range of 1–20 ng/kg/min showed a better or comparable filter patency in comparison to heparin with lower incidence of bleeding complications [23–25]. The idea is to reduce the incidence of bleeding complications through reduced dose while blocking effectively not only the thrombin production but also the thrombocyte activation and consecutively the inhibition of HMW heparin through platelet factor 4 [7]. One study using low-dose prostacyclin alone in CRRT showed comparable filter patency to HMW heparin without higher incidence of bleeding complications. However, 15% of the patients had to be treated because of hypotension [26].

Sodium-Citrate

Systemic effective anticoagulation for CRRT is crucial if the patient is at risk of bleeding. Sodium-citrate anticoagulation is a regional anticoagulation regime [11, 27–29]. Citrate binds ionized calcium which is required as co-factor

Anticoagulation in CRRT

311

Vargas Hein/Kox/Spies

312

2–5 ␮g/kg/h

5–10 ␮g/kg

Hirudin [1, 6, 20]

none

Na-citrate is dosed according to ionized calcium post-filter; CaCl2 is dosed according to ionized calcium in the blood

2–10 ng/kg/min

0.4 aXa IU/ml

0.25 mmol/l 1.0–1.3 mmol/l

none

aPTT 50–60 s ECT 80–100 s hirudin 300–600 ng/ml concentration

aXa

AT III dependency, contraindicated in HIT II patients

Limitations

hypernatremia, metabolic alkalosis and acidosis, hypocalcemia, in HIT II patients alternative anticoagulation is mandatory

hemodynamic instability in higher dose, together with HMW heparin contraindicated in HIT II patients

sole renal elimination with accumulation risk, therefore primarily bolus dosage

no routine monitoring, long half-life, renal elimination, no routine monitoring, not filtered, AT III dependency, in vitro cross-reactivity with HIT II antibodies

0.3–0.6 aXa IU/ml no routine monitoring, renal elimination, not filtered, AT III dependency, contraindicated in HIT II patients

35–60 s

Target values

20

1,500

25

209

62

2

Anticoagulation costs/24 h (€)

Cont. ⫽ Continuous; HMW ⫽ high molecular weight; aPTT ⫽ activated partial thromboplastin time; AT III ⫽ antithrombin III; LMW ⫽ low molecular weight; aXa ⫽ anti-factor Xa-activity; HIT II ⫽ heparin-induced thrombocytopenia; ECT ⫽ ecarin clotting time.

Na-citrate [6, 11, 27]

Iloprost (prostaglandin) [6, 23, 24]

50–150 IU/h

750 IU

Danaparoid [6, 16]

aXa

15–20 IU/kg

Dalteparin (LMW heparin) [6, 12, 14, 15]

5–10 IU/kg/h

500–1,000 IU/kg 300–1,000 IU/kg/h aPTT

Monitoring

HMW heparin [6, 11, 12]

Dose (cont.)

Dose (bolus)

Anticoagulant

Table 1. Anticoagulation in CRRT – summary

in multiple steps of the coagulation cascade. 4% tri-sodium-citrate solution is applied pre-filter in a rate adapted to the measured ionized calcium post-filter which should be 0.25 mmol/l ideally. Calcium free, low-sodium and bicarbonate low or free dialysate and replacement solution are used. Calcium replacement is done through a separate venous line directly into the patient according to the measured ionized calcium in the patients’ blood which should be hold at normal levels. In this way, just the dialysis circuit is anticoagulated. Approximately 60% of the sodium-citrate applied is extracted through the filter. Citrate is metabolized to bicarbonate in the liver [11, 27–29]. The filter run time achieved in the performed studies were extensively longer than with other anticoagulation regimes without causing bleeding complications in high risk patients. However, in performing citrate anticoagulation some problems can arise regarding to metabolic disorders which must be accounted for [12]. Possible sodium overload is taken into account by using hypotonic dialysate and replacement solution. Metabolic alkalosis, caused by the metabolism of citrate to bicarbonate in the liver, can be avoided in most cases by using bicarbonate low or free dialysate and replacement solution. If the patient develops liver insufficiency citrate is not metabolized to bicarbonate which can lead to metabolic acidosis and elevated total calcium content due to an accumulation of calcium-citrate complexes [30]. Therefore, accurate monitoring of the pH and electrolytes of the patient is mandatory when performing sodium-citrate anticoagulation [7, 12]. In the last years, many different protocols have been studied in order to reduce the metabolic derangement and ease the procedure without remarkable better results [11, 31, 32]. In terms of HIT II it is important to mention that citrate anticoagulation is no alternative for heparin anticoagulation. The patient must be systemically anticoagulated to counteract HIT II pathophysiology. In conclusion, considering the characteristics of an ideal anticoagulant (rapid onset, short time of action, rapid elimination independent of renal and liver function, effective antagonization, routine monitoring, minimal side effects) HMW heparin remains as first-line anticoagulant. Also, taking the important point of cost-effectiveness into account HMW heparin remains the cheapest anticoagulation regime for CRRT. In terms of costs citrate anticoagulation seems to be cheaper than HMW heparin anticoagulation if overall costs, including the hemofiltration systems needed, are compared [unpubl. data]. The other alternatives are clearly more expensive but must be taken into consideration in patients with HIT II, with the exclusion of LMW heparin. Kozek-Langenecker et al. [24] could show, that the overall costs of CRRT with prostaglandins were more intensive than with HMW heparin. Prostaglandins seem to offer some advantages just in combination with HMW heparin, excluding their use for patients with HIT II. Danaparoid is used effectively in HIT II patients, although a risk for cross-reactivity remains. Hirudin is

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313

effective but extreme caution must be taken because of accumulation especially in patients with risk of bleeding. A promising alternative could be the direct thrombin inhibitor argatroban. This anticoagulant is eliminated through the liver with a half-life of 21–61 min and no cross-reactivity with HIT II antibodies could be found [33, 34]. A few case reports have shown preliminary satisfactory results regarding effectiveness and safety [33, 34]. Experience with heparin-coated or other regional anticoagulation systems involving immobilized heparinase or protamine remain experimental at this time point [35, 36]. Also experimental, but potentially promising, are nitric oxide (NO)releasing silicon rubbers. The potent inhibition of platelet activation caused by NO did show an improved thromboresistivity in an extracorporeal circuit animal study [37].

References 1

2

3

4

5 6 7 8 9 10 11 12 13

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Vargas Hein O, von Heymann C, Lipps M, Ziemer S, Ronco C, Neumayer HH, Morgera S, Welte M, Kox WJ, Spies C: Hirudin versus heparin for anticoagulation in continuous renal replacement therapy. Intens Care Med 2001;27:673–679. Vargas Hein O, Spies C, Kox WJ: Renal dysfunction in the Perioperative Periode; in Gullo A (ed): Anaesthesia, Pain, Intensive Care and Emergency Medicine (A.P.I.C.E.). Milano, Springer, 2001, pp 309–315. Kellum JA, Angus DC, Johnson JP, Leblanc M, Griffin M, Ramakrishnan N, Linde-Zwirble WT: Continuous versus intermittent renal replacement therapy: A meta-analysis. Intens Care Med 2002;1:29–37. Van de Wetering J, Westendorp RGJ, van der Hoeven JG, Stolk B, Feuth JD, Chang PC: Heparin use in continuous renal replacement procedures: The struggle between filter coagulation and patient hemorrhage. J Am Soc Nephrol 1996;1:145–150. Suhlman RI, Singer M, Rock J: Keeping the Circuit Open: Lessons from the Lab. Blood Purif 2002;20:275–281. Vargas-Hein O-R: Antikoagulation für die CVVHF. J Anästh Intensivbehandl 2001;3:136–138. Schetz M: Anticoagulation in continuous renal replacement therapy. Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 283–303. Davenport A: The coagulation system in the critically ill patient with acute renal failure and the effect of an extracorporeal circuit. Am J Kidney Dis 1997;5(suppl 4):20–27. Metha RL: Anticoagulation strategies for continuous renal replacement therapies: What works? Am J Kidney Dis 1996;5(suppl 3):8–14. Hirsh J, Anand SS, Halperin JL, Fuster V: Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol 2001;7:1094–1096. Palsson R, Niles JL: Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding. Kidney Int 1999;5:1991–1997. Abramson S, Niles JL: Anticoagulation in continuous renal replacement therapy. Curr Opin Nephrol Hypertens 1999;6:701–707. Jeffrey RF, Khan AA, Douglas JT, Will EJ, Davison AM: Anticoagulation with low molecular weight heparin (Fragmin) during continuous hemodialysis in the intensive care unit. Artif Organs 1993;8:717–720. Reeves JH, Cumming AR, Gallagher L, O’Brien JL, Santamaria JD: A controlled trial of lowmolecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration. Crit Care Med 1999;10:2224–2228.

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de Pont AC, Oudemans-van Straaten HM, Roozendaal KJ, Zandstra DF: Nadroparin versus dalteparin anticoagulation in high-volume, continuous venovenous hemofiltration: A double-blind, randomized, crossover study. Crit Care Med 2000;2:421–425. Lindhoff-Last E, Betz C, Bauersachs R: Use of a low-molecular-weight heparinoid (danaparoid sodium) for continuous renal replacement therapy in intensive care patients. Clin Appl Thromb Hemost 2001;4:300–304. Schenk JF, Pindur G, Stephan B, Morsdorf S, Mertzlufft F, Kroll H, Wenzel E, Seyfert UT: On the prophylactic and therapeutic use of danaparoid sodium (Orgaran) in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2003;1:25–32. Plassat R, Cognet F, Ternisien C, Menoret N, Dubus-Bausiere V, Brunel P, Bontoux L, Bernat C, Richard I: Heparin induced thrombocytopenia: Case report with acute thrombotic complications and literature review. Ann Readapt Med Phys 2002;5:216–223. Frank RD, Farber H, Stefanidis I, Lanzmich R, Kierdorf HP: Hirudin elimination by hemofiltration: A comparative in vitro study of different membranes. Kidney Int 1999;56(suppl 72):41–45. Vargas Hein O, von Heymann C, Diehl T, Ziemer S, Ronco C, Morgera S, Siebert G, Kox WJ, Neumayer HH, Spies C: Intermittent hirudin versus continuous heparin for anticoagulation in continuous renal replacement therapy; in press. Kern H, Ziemer S, Kox WJ: Bleeding after intermittent or continuous r-hirudin during CVVH. Intens Care Med 1999;25:1311–1314. Fischer KG, Van de Loo A, Böhler J: Recombinant hirudin (lepirudin) as anticoagulant in intensive care patients treated with continuous hemodialysis. Kidney Int 1999;56(suppl 72): 46–50. Kozek-Langenecker SA, Spiss CK, Gamsjager T, Domenig C, Zimpfer M: Anticoagulation with prostaglandins and unfractionated heparin during continuous venovenous haemofiltration: A randomized controlled trial. Wien Klin Wochenschr 2002;3:96–101. Kozek-Langenecker SA, Kettner SC, Oismueller C, Gonano C, Speiser W, Zimpfer M: Anticoagulation with prostaglandin E1 and unfractionated heparin during continuous venovenous hemofiltration. Crit Care Med 1998;7:1208–1212. Greuel MS, Birnbaum J, Klotz E, Saalmann R, Spies C, Lehmann C, Kox WJ: Der Einfluss von Iloprost auf die Filterlaufzeit, die Thrombozytenzahl und die Retentionsparameter im Rahmen einer CVVH-Behandlung. J Anästh Intensivmed 2003;2:17. Fiaccadori E, Maggiore U, Rotelli C, Minari M, Melfa L, Cappe G, Cabassi A: Continuous haemofiltration in acute renal failure with prostacyclin as the sole anti-haemostatic agent. Intens Care Med 2002;5:586–593. Mehta R, McDonald B, Aguilar M, Ward D: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990;38:976–981. Gabutti L, Marone C, Colucci G, Duchini F, Schönholzer C: Citrate anticoagulation in continuous venovenous hemodiafiltration: A metabolic challenge. Intens Care Med 2002;28:1419–1425. Pinnick E, Wiegmanson TE, Diederich DA: Regional citrate anticoagulation for hemodialysis in a patient at high risk for bleeding. N Engl J Med 1983;308:258–261. Meier-Kriesche HU, Gitomer J, Finkel K, DuBose T: Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med. 2001;4:748–752. Tobe SW, Aujla P, Walele AA, Oliver MJ, Naimark DM, Perkins NJ, Beardsall M: A novel regional citrate anticoagulation protocol for CRRT using only commercially available solutions. J Crit Care 2003;2:121–129. Mitchell A, Daul AE, Beiderlinden M, Schafers RF, Heemann U, Kribben A, Peters J, Philipp T, Wenzel RR: A new system for regional citrate anticoagulation in continuous venovenous hemodialysis (CVVHD). Clin Nephrol. 2003;2:106–114. Dager WE, White RH: Argatroban for heparin-induced thrombocytopenia in hepato-renal failure and CVVHD. Ann Pharmacother 2003;9:1232–1236. Ohteki H, Furukawa K, Ohnishi H, Narita Y, Sakai M, Doi K: Clinical experience of Argatroban for anticoagulation in cardiovascular surgery. Jpn J Thorac Cardiovasc Surg 2000;1:39–46. Zhang Y, Singh VK, Yang VC: Novel approach for optimizing the capacity and efficacy of a protamine filter for clinical extracorporeal heparin removal. ASAIO 1998;5:M368–M373.

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Dr. med. Ortrud Vargas Hein Department of Anesthesiology and Intensive Care, University Hospital Charité Campus Mitte, Schumannstrasse 20/21, DE–10117 Berlin (Germany) Tel. ⫹49 30 450 631043, Fax ⫹49 30 450 531911, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 317–328

Replacement and Dialysate Fluids for Patients with Acute Renal Failure Treated by Continuous Veno-Venous Haemofiltration and/or Haemodiafiltration Andrew Davenport Centre for Nephrology, Royal Free Hospital Campus, Royal Free and University College Hospital Medical School, London, UK

When Peter Kramer first described continuous arteriovenous haemofiltration, it was a technique designed to provide ultrafiltration and was not a substitute for intermittent haemodialysis, so fluid replacement was not required [1]. With the advances in CRRT over the last three decades, CRRT has become an efficient treatment for acute renal failure in the ICU. The ideal replacement or dialysate solution would bear resemblance to normal plasma and extracellular fluid (table 1). Originally peritoneal dialysates were used, as these were a ready source of sterile fluid, and became the basis for substitution and dialysates. Recent studies have shown that survival can potentially be improved with larger exchanges of fluid and/or dialysate flows [2], and is supported by in vivo animal experimental data [3]. This trend for high volume CRRT, coupled with the resurgence in citrate based anticoagulation, has necessitated the development of specialised dialysate and substitution fluids.

Sterility

During haemofiltration, substitution fluids are directly infused, and similarly during continuous dialysis, due to back filtration, again there is direct infusion of dialysate. Thus sterile fluids are required. Commercially available fluids are heat sterilised. Heat sterilisation of glucose containing solutions leads

Table 1. Differences in the electrolyte composition of peritoneal dialysate (Baxter Health Care, Deerfield, USA), plasma, extracellular fluid (ECF) and intracellular fluid (ICF): all units expressed in mmol/l Fluid

Dianeal®

Plasma

ECF

ICF

Sodium Potassium Calcium Magnesium Chloride Bicarbonate Lactate Glucose

132 0 1.75 0.75 102 0 45 72

143 4.0 2.5 1.0 100 27 1.0 4.0

144 4.0 1.25 0.75 114 30 1.5 4.0

10 155 2.0 15 2.0 10 variable 4.0

to the formation of glucose degradation products (GDPs). In vitro these lead to increased carbonyl stress, and have been reported to have cytotoxic effects and impair macrophage and other inflammatory cell function [4]. There is no data on the effect of exposure to GDPs in the critically ill patient with acute renal failure (ARF). Although peritoneal dialysates contain hypertonic glucose, and are therefore hyperosmolar, the relative blood flow through the haemofilter/ dialyzer to replacement solution/dialysate flow, means that there is only ⱕ1 mosm/kg increase in plasma osmolality. The newer dialysates, and substitution fluids are isotonic and glucose free, so do not contain GDPs. Standard CRRT is more expensive than daily intermittent haemodialysis, primarily due to the cost of the commercially available sterile dialysates/substitution fluids. These costs increase with high volume CRRT. To reduce costs, some centres prepare their own fluids to the same standards as ultra-pure dialysates, used in haemodiafiltration [5]. Quality control of these on-site fluids is paramount, not only in terms of bacterial and endotoxin contamination, but also chemical contamination, so that trace elements, nitrates and organic compounds, such as chloramines have been removed. Although the AAMMI and European Dialysis and Transplant Association have issued guidelines for the quality of dialysate [5], there is no consensus on the purity of ultrapure dialysate, in terms of how to quantify bacterial and endotoxin contamination [6]. Although contamination of dialysate and/or substitution fluids with environmental microorganisms and small amounts of endotoxin has in vivo effects [7], it is unknown whether this has significant clinical impact. However, in the absence of specific legislation [6], it is recommended that in Europe, the European Community Directive 93/42/EEC on medical devices is followed for on-line fluid production.

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Table 2. Standard lactate based fluids for haemofiltration and/or haemodiafiltration mmol/l Fluid

Baxter®

Filtrasol®

Lactasol®

Baxter UK

Sodium Potassium Calcium Magnesium Chloride Bicarbonate Lactate Glucose

140 1 1.60 0.80 100 0 46 10.8

140 0 1.60 0.75 100 0 45 0

140 0 1.45 0.75 105 0 40 0

140 0 1.5 0.75 110 0 35 0

Baxter® ⫽ Baxter Health Care, Sydney, Australia; Filtrasol® ⫽ Pharmacia AB, Uppsala, Sweden; Lactasol® ⫽ Hospal, Gottenberg, Sweden.

Table 3. Differences in electrolyte composition of bicarbonate based fluids used for CRRT (mmol/l) Solution

Normocarb®

Bicarbonate

Bicarbonate

Bicarbonate

Lactate free*

Sodium Calcium Magnesium Chloride Bicarbonate Lactate Reference

140 0 0.75 106.5 35 0 22

155 1.8 0.77 120 40 3.0 20

140 1.5 0.5 109 35 0 21

140 1.75 0.5 110 34.5 3.0 24

110 1.75 0.75 110 0 0 23

*Lactate-free solution – sodium bicarbonate added separately to achieve zero base excess.

Electrolyte Composition

The first dialysates and substitution fluids were based on peritoneal dialysate (table 1), which is hyponatraemic. As critically ill patients with ARF are often enterally or parenterally fed with hyponatraemic feeds, receive multiple drug infusions, often in dextrose, then patients could become hyponatraemic. Thus the newer specialised fluids usually have a sodium concentration within the normal plasma range (tables 2, 3). Diffusive sodium transport depends upon the concentration gradient between the plasma and the dialysate. However, the plasma sodium activity – the

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Table 4. Differences in sieving coefficients of pre- and post-dilutional continuous venovenous haemofiltration (2 litre exchanges using Baxter UK substitution fluid and 1.2 m2 polysulfone hemofilter, blood pump speed 200 ml/min) Sieving coefficient

Pre-filter

Post-filter

Urea Creatinine Sodium Potassium Calcium Phosphate Chloride Protein

0.74 0.72 0.97 0.918 0.709 0.71 1.01 0.001

1.06 1.04 1.00 0.923 0.706 1.04 1.06 0.003

amount of sodium available for potential diffusion, is not the same as the plasma sodium concentration. In healthy patients plasma sodium activity is similar to plasma concentration. This is the result of two opposing effects, firstly plasma water sodium is about 7% greater than that of plasma sodium concentration, due to the volume occupied by plasma proteins, but then plasma sodium activity is reduced by plasma sodium binding to proteins, and proteins deposited on the dialyzer membrane. As proteins are generally negatively charged, sodium is held back to maintain electrical neutrality, in accordance with the Gibbs-Donnan effect. In the septic ICU patient, the plasma sodium is usually low or at the lower end of the normal range, due to increased capillary permeability, coupled with hypoalbuminaemia. If the patient is also on a low sodium diet, and in receipt of no other sodium containing fluids, then CRRT performed as dialysis alone, could provide a modest daily positive sodium balance. Most ICUs offer haemofiltration and/or haemodiafiltration. The convective losses of haemofiltration result in sodium losses due to solvent drag. However, again due to the Gibbs-Donnan effect, the sieving coefficient of sodium will be ⬍1.0. Thus if the replacement fluids have a sodium concentration greater than plasma, patients will have a positive sodium balance [8]. The sieving coefficient for sodium is greater for pre- than post-dilutional fluid replacement (table 4), due to the effect of diluting proteins, so reducing the Gibbs-Donnan effect. This is exemplified by comparing high volume haemofiltration (6 litres/h), when the sodium sieving coefficient fell from 0.96 with predilution to 0.94 with post-dilution. Although these changes in sieving coefficient appear small, when one considers the volumes exchanged, patients would be in a daily positive sodium balance of almost 250 mmol/day. Thus, if

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patients are going to be treated by high volume CRRT for prolonged periods, then lower sodium solutions will be required. All currently commercially available fluids contain calcium and magnesium, designed to maintain the plasma levels within the normal range, although the concentrations vary from manufacturer to manufacturer (calcium 1.65–2.0 and magnesium 0.75–0.77). Whereas the magnesium concentrations are set towards the lower limit of the normal range, the calcium concentrations are higher than normal plasma ionised calcium, and studies from chronic dialysis have suggested a zero calcium balance with a dialysate calcium concentration of 1.25 mmol/l. Although more recent studies with daily extended hours haemodialysis have reported that higher calcium of 1.5 mmol/l was required to maintain a zero calcium balance [10]. In ARF, calcium binding can be affected by albumin concentration and acidosis. During dialysis the fraction of diffusible calcium decreases, due to both ultrafiltration leading to increased plasma albumin concentration, and the rise in plasma bicarbonate, which increases plasma protein binding. Thus during CRRT using dialysis, calcium balance will differ according to whether lactate or bicarbonate dialysates are used. However, using these high calcium dialysates (tables 2, 3) will lead to a net positive calcium influx into the patient. Similarly during convective forms of haemofiltration, the calcium sieving coefficient (table 4), would suggest that patients develop a positive daily calcium balance. During high volume haemofiltration, the calcium sieving coefficient fell from 0.78 to 0.6 when the site of fluid replacement was switched from the pre- to post-dilution mode [9]. As there is no apparent increase in plasma calcium concentration, this would suggest a net increase in intracellular calcium. Magnesium concentrations in the dialysates/replacement fluids are similar to free diffusible plasma magnesium (normal plasma 0.8–1.2 mmol/l of which 60–65% is free). During dialysis mode CRRT, as with calcium the concentration of diffusible magnesium will decrease during passage through the dialyzer, and this may allow a positive magnesium balance. As with calcium during haemofiltration, the sieving coefficient of magnesium was greater for predilution compared to post-dilution (table 4). Similarly, during high volume haemofiltration, the magnesium sieving coefficient changed from around 0.84 with pre-dilution, to 0.70 with post-dilution. Although this may suggest a positive magnesium balance with high volume post-dilution mode, there were no changes in plasma magnesium. However, magnesium is primarily an intracellular cation, so that changes in magnesium flux may occur without discernable changes in plasma concentration. Typically, the commercial dialysates/replacement solutions are potassium and phosphate free, as patients with ARF require potassium and phosphate removal.

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Some patients may then require potassium and/or phosphate supplementation, in addition to that in administered in parenteral/enteral nutrition [11, 12].

Acid-Base Balance

One of the main purposes of CRRT is to correct the metabolic acidosis, which develops in patients with ARF. Although bicarbonate is the natural buffer, bicarbonate based solutions have not been available until recent times, as bicarbonate is not stable in the presence of calcium and magnesium ions, and there is an increased risk of bacterial contamination. Initially peritoneal dialysate fluids were used for CRRT, as these were sterile fluids with a prolonged shelf storage life, containing acetate or a racemic mixture of lactate, as the anionic base. Acetate and l-lactate are metabolised, indirectly in liver and muscle, to bicarbonate on an equimolar basis. D-Lactate, is not the naturally occurring isomer of lactate, and has a different and slower metabolic pathway than l-lactate, mainly by skeletal muscle. In ARF D-lactate metabolism is reduced and D-lactate can accumulate [13]. Specialised solutions were then developed for CRRT based on l-lactate and acetate. However, studies in patients undergoing intermittent haemodialysis using acetate based dialysate, noted that acetate accumulated during dialysis, resulting in hyperacetataemia, and cardiovascular instability, typically in patients with left ventricular dysfunction [14]. Replacement of acetate by bicarbonate was reported to improve both patient intra-dialytic symptoms and cardiovascular tolerance. Endogenous lactate metabolism has been estimated at 1,500 mmol/day in healthy subjects. During high volume CRRT using lactate based solutions, the rate of lactate administration may well exceeded hepatic metabolism (normal ⱕ100 mmol/h in healthy subjects and ⬇0.6 mmol/kg/h in patients with ARF) [15] resulted in hyperlactataemia. In cases of severe liver failure, the obligatory losses of bicarbonate and lactate during intermittent high volume haemofiltration can exceed the rate of bicarbonate generation, so resulting in an increase in arterial hydrogen ion concentration, and worsening acid-base status [16]. During CRRT the rate of administration of these substitution fluids/ dialysates is substantially less than that during intermittent haemodialysis and/or filtration, and thus the accumulation of acetate or lactate with a worsening acidbase status has rarely been reported [17]. Even so, the currently available commercial lactate based solutions can lead to acid-base disturbances. Currently lactate concentrations vary from 45 mmol/l (chloride 100 mmol/l) down to 35 mmol/l (chloride 110 mmol/l) (table 2). These differences in solution composition can lead to clinical consequences, with the development of a hypochloraemic metabolic alkalosis on one hand after several days of CRRT using a high

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lactate low chloride solution, and a hyperchloraemic metabolic acidosis on the other, when a low lactate high chloride fluid is used [19]. In short term studies of high volume haemofiltration, although patients became hyperlactataemic, with a fall in pH and base excess, this was limited by hypochloraemia by using a replacement solution with a lower chloride concentration, and increased loss of strong acids [19]. Chloride, being negatively charged has a sieving coefficient ⬎1.0, and studies have shown that pre-dilution mode has a higher sieving coefficient than post dilution (table 4) [9]. Thus pre-dilution mode for high volume exchanges will have least effect on acid-base balance, by increasing losses of chloride, CO2, and other acids. Whereas bicarbonate based dialysate is universally used for treating patients with ARF by intermittent haemodialysis, the use of commercially available bicarbonate based fluids for CRRT has been delayed due to problems in manufacture and storage of fluids containing both bicarbonate and the divalent cations, calcium and magnesium. Such fluids are at greater risk of bacterial contamination, due to the higher pH, and precipitation of calcium and magnesium carbonate. Commercially available bicarbonate based fluids are now available; as either solutions containing bicarbonate and calcium, which have a limited shelf life [20]; or as twin bag systems, one containing the bicarbonate, the other the electrolytes and the two compartments being mixed immediately prior to use [21, 22]; or as ‘buffer free’ or ‘lactate free’ solutions, with bicarbonate being added distally [23]. The question arises as to whether these more expensive bicarbonate solutions provide any advantages over standard acetate and lactate based fluids. Heering et al. [21] reported that both bicarbonate and lactate based solutions resulted in better control of acid-base balance, and improved cardiovascular tolerance compared to acetate. Similarly, others have reported superior control of acidosis and cardiovascular stability with bicarbonate when compared to lactate [23, 24]. These latter studies were biased by their patient recruitment; ARF post cardiac surgery and liver failure, but both showed better correction of acidosis with less total anionic base administered, compared to lactate. Not all studies have reported such a positive effect for bicarbonate based solutions [20, 21], and this may be due to the differences in the amount of bicarbonate and the other components of the solutions (table 3), as the best results were obtained when a variable amount of bicarbonate was titrated to meet individual patient requirements [23]. During CRRT bicarbonate is given as a net iso-osmolar solution, at a rate of 60–80 mmol/h, which markedly differs from that during acute bolus administration (60 mmol/min). Although in vitro experiments suggested that the acute rapid bicarbonate administration could result in increased intracellular acidosis, due to the generation and passage of CO2 into cells. More recent studies,

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Table 5. Differences in electrolyte composition of replacement and dialysate fluids used for citrate based CRRT (units mmol/l, or in case of dextrose %) Solution

Replacement

Dialysate

Replacement

Dialysate

Replacement

Sodium Calcium Magnesium Chloride Bicarbonate Dextrose Reference

150 0 0.70 121 33.3 0 27

117 0 0.75 121.5 0 0 27

140 0 0 140 0 0 26

117 0 0.75 117 0 2.5 26

140 0 0.75 101.5 0 0.2 28

designed specifically to emulate the clinical situation, have reported an increase in intracellular pH [25]. Similarly, although the rapid administration of bicarbonate causes an increase in end-tidal CO2 and PaCO2, bicarbonate based CRRT, has not been reported to result in a significant increase in PaCO2, such that changes in ventilatory settings were required [21, 22]. The advantage of using a buffer free replacement solution, and then titrating the dose of bicarbonate to a target base excess, means that acid-base control can be achieved in ventilated patients treated with permissive hypercapnia, whereas this could be more problematical in patients given a fixed bicarbonate concentrate.

CRRT Using Citrate Anticoagulation

Citrate is increasingly being used as a regional anticoagulant for CRRT, and as each citrate molecule is indirectly metabolised through to three bicarbonates, then the need for additional anionic base varies from circuit design to design. When citrate anticoagulation is used, then the predilutional fluid traditionally has been calcium and bicarbonate free [26]. A special hyponatraemic dialysate (117 mmol/l) is required containing no calcium or alkali, with a relatively high chloride content of 122.5 mmol/l [26]. The hyponatraemic dialysate is required because of the high sodium load pre-filter due to the combination of trisodium citrate and the pre-dilution infusion of normal saline. Dextrose was then added to the dialysate to maintain osmolality. Others have used citrate anticoagulation for continuous haemodiafiltration, and whilst using a similar dialysate, found that they had to add bicarbonate to the postfilter replacement fluid (table 5) [27]. When citrate is used to anticoagulate haemofiltration circuits, then customised post-dilutional fluids are required [28] (table 5). As calcium is complexed with citrate and lost into the dialysate,

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or ultra-filtrate, calcium must be infused as calcium chloride centrally, to maintain a normal ionised calcium returning to the patient [26]. With the increasing interest in citrate anticoagulation, centers without the facility to produce their own specialised dialysates and replacement fluids, have used commercially available bicarbonate based calcium containing solutions as dialysates and replacement fluids [28]. As each citrate molecule is eventually metabolised, to three bicarbonate molecules, up to 26% of patients will develop a mild metabolic alkalosis, more common in those given additional bicarbonate, patients with hepatic dysfunction, and those given blood products (containing acid citrate dextrose anticoagulant). Patients given commercially available bicarbonate based fluids have the highest incidence of alkalosis, but this can often be simply managed by not opening the bicarbonate compartment of the twin bag systems, and reducing the citrate load by using acid-citrate dextrose [29]. Alkalosis also occurs more often with haemofiltration circuits, as the clearance of citrate is less than that during dialysis [28].Modest alkalosis can be managed by either reducing the citrate infusion rate, or increasing bicarbonate losses and chloride gain. This can be done most effectively by increasing the dialysate flow, or less effectively by increasing the pre-dilution infusion. In extreme cases, 0.2 M HCl can be infused through a major vein [26]. Other metabolic complications include hypercitrataemia, which has been reported in 10–15% of patients, usually those with some degree of hepatic dysfunction. This can usually readily be corrected by slowing the citrate infusion to 1.5–2.5% of the blood flow. Typically, hypercitrataemia occurs in the setting of alkalosis. Hypernatraemia occurs in less than 10% of patients [30], more commonly with trisodium citrate and haemofiltration, as the prefilter sodium load can not be removed as effectively as with dialysis, or when an insufficiently hyponatraemic dialysate/substitution fluid has been used. Occasionally, patients may develop hypercitrataemia, hypercalcaemia and metabolic acidosis [30]. This is usually in the setting of ARF with rhabdomyolysis and initial hypocalcaemia. Despite a normal ionised plasma calcium, total plasma calciums in excess of 4.0 mmol/l have been observed, in association with hypercitrataemia (plasma citrate ⬎20 mmol/l, normal range 0.07–0.14 mmol/l) [31]. Such hypercitrataemia suggests hepatic dysfunction, and if the citrate can not be metabolised through to bicarbonate, then the patient will become acidotic, due to the loss of plasma bicarbonate through the dialyzer.

Temperature

Centres differ in their approach to heating replacement solutions and/or dialysates [32]. During CRRT significant thermal energy is lost, which may

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have advantages in improving cardiovascular stability, but could also potentially adversely effect nutritional balance, immune function, and increase the risk of clotting of the CRRT circuit. In addition cooling could theoretically reduce solute clearances both during diffusive techniques, as diffusion coefficients are temperature dependent, and also convective therapies by increasing membrane protein deposition. Even warming both the dialysate and replacement solutions to 37⬚C still leads to thermal energy losses, which are increased with larger exchange/ dialysate volumes.

Conclusions

The advance of CRRT from simple arteriovenous ultrafiltration to a treatment using 50 plus litres a day has spurred on the creation of specialised dialysate/replacement solutions. As the volumes used are large, quality control is vitally important not only in terms of electrolyte composition, but also preventing bacterial and endotoxin contamination. There are small differences in solute flux between dialysis and both pre- and post-dilution haemofiltration. If high volume haemofiltration is to be used for any extended period, then predilution mode will cause less electrolyte imbalance than post-dilution. Lactate remains the standard anionic base, as this increases fluid storage time and reduces the risk of bacterial contamination. The composition varying between manufacturers, such that those patients given high lactate, low chloride fluid, will be prone to hypochloraemic alkalosis, whereas those give a lower lactate but higher chloride can develop hyperchloraemic acidosis. There is an increasing usage of citrate anticoagulation, and the citrate load provides a supply of anionic base. Varying protocols have been developed to cope with the sodium and citrate loads, but now several centers are using citrate based CRRT with commercial fluids. Hypotensive patients with severe tissue acidosis and/or liver failure, and those receiving high volume CRRT may be unable to convert the lactate, or citrate load effectively, resulting in hyperlactataemia or hypercitrataemia with acidosis. In these circumstances bicarbonate based fluids are advantageous, but are currently somewhat more expensive that standard lactate fluids. The use of bicarbonate based dialysate/replacement fluid during CRRT does not mask lactate overproduction, and lactate remains a reliable marker of tissue oxygenation in patients treated by CRRT. Bicarbonate CRRT alone does not treat the underlying cause of metabolic acidosis, but allows better control of acidosis, so allowing time for the institution of other therapies designed to reverse the underlying cause.

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Kramer P, Wigger W, Rieger J, Mathaei D, Scheler F: Arteriovenous hemofiltration: A new and simple method for the treatment of over hydrated patients resistant to diuretics. Klin Wochenschr 1977;5:1121–1122. Ronco C, Bellomo R, Hamel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure. Lancet 2000; 356:26–30. Grootendorst AF, van Saase JLCM: Blood purification by hemofiltration in septic shock and multiple organ dysfunction syndrome patients; in Bellomo R, Ronco C (eds): Update in Intensive Care and Emergency Medicine. Heidelberg, Springer-Verlag, 1995, vol 20, pp 311–325. Davenport A: Peritoneal host defence in patients with end-stage renal failure treated by peritoneal dialysis; in Sweny P, Rubin R, Tolkoff-Rubin N (eds): The Infectious Complications of Renal Disease. Oxford, Oxford University Press, 2003, pp 41–68. The EBPG Expert Group on Haemodialysis: European Best Practice Guidelines for haemodialysis. Part 1; section IV. Dialysis fluid purity. Nephrol Dial Transplant 2002;17(suppl 7):45–62. Ministère de l’Emploi et de la Solidarieté: Circulaire relative aux specifications techniques de la securitié de pratique de l’hémofiltration et de l’hémodiafiltration en ligne dans établissements de santé. Republique Française, Circulaire DGS/DH/AFSSAPS no 311, June 7, 2000. Schindler R: Passage of LPS and non-LPS like cytokine inducing substances across synthetic dialyzer membranes. Blood Purif 2003;21:343–344. Morimatsu H, Uchino S, Bellomo R, Ronco C: Continuous renal replacement therapy: Does technique influence electrolyte and bicarbonate control? Int J Artif Organs 2003;26:289–296. Uchino S, Cole L, Morimatsu H, Goldsmith D, Ronco C, Bellomo R: Solute mass balance during isovolemic high volume hemofiltration. Intens Care Med 2003;9:1541–1546. Lindsay RM, Leitch R, Heidenheim AP, Kortas C: Daily short hours and long slow nocturnal hemodialysis: The London, Ontario study. Blood Purif 2003;21:335–340. Davenport A: Hemofiltration in patients with fulminant hepatic failure. Lancet 1991;338:1604. Davenport A, Kirby SA: Hemofiltration/dialysis treatment in patients with acute renal failure. Care Crit Ill 1996;12:54–58. Veech RL: The untoward effects on anions of dialysis fluids. Kid Int 1991;34:587–589. Katzarski KS: Fluid state and blood pressure control in patients on maintenance hemodialysis, MD thesis, Stockholm, 1999. Wright DA, Forni LG, Carr LG, Treacher DF, Hilton PJ: Use of continuous hemofiltration assess the rate of lactate metabolism in acute renal failure. Clin Sci 1996;90:507–510. Davenport A, Will EJ, Davison AM: Hyperlactatemia and metabolic acidosis during hemofiltration using lactate buffered fluids. Nephron 1991;59:461–465. Nimmo GR, Grant IS, Mackenzie SJ: Lactate and acid base changes in the critically ill. Post-Grad Med J 1991;67(suppl 1):S56–S61. Davenport A, Worth DP, Will EJ: Hypochloremic alkalosis after high flux continuous hemofiltration and continuous arterio-venous hemofiltration with dialysis. Lancet 1988;i:658. Cole L, Bellomo R, Baldwin I, Hayhoe M, Ronco C: The impact of lactate buffered high-volume hemofiltration on acid-base balance. Intens Care Med 2003;7:1113–1120. Thomas AN, Guy JM, Kishen R, Bowles BMJ, Vadgama P: Comparison of lactate and bicarbonate buffered hemofiltration fluids: Use in critically ill patients. Nephrol Dial Transplant 1997; 12:1212–1217. Heering P, Ivens K, Thümer O, Moergera S, Heintzen M, Passlick-Deetjen J, Willers R, Strauber BE, Grabenensee B: The use of different buffers during continuous hemofiltration in critically ill patients with acute renal failure. Intens Care Med 1999;25:1244–1251. Zimmerman D, Cotman P, Ting R, Karanicolas S, Tobe SW: Continuous veno-venous haemodialysis with a novel bicarbonate dialysis solution: Prospective cross-over comparison with a lactate buffered solution. Nephrol Dial Transplant 1999;14:2387–2391. MacLean AG, Davenport A, Cox D, Sweny P: Effects of continuous haemodiafiltration against lactate buffered and lactate-free dialysate in patients with, and without liver dysfunction. Kid Int 2000;58:1765–1772.

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Kierdorf HP, Leue C, Arns S: Lactate or bicarbonate buffered solutions in continuous extracorporeal renal replacement therapies. Kid Int 1999;56(suppl 72):S32–S36. Goldsmith DJA, Forni LG, Hilton PJ: Bicarbonate therapy and intracellular acidosis. Clin Sci 1997;93:593–598. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate anticoagulation for continuous arterio-venous hemodialysis in critically ill patients. Kid Int 1990;38:976–981. Kutsogiannis DJ, Mayers I, Chi WD, Gibney RT: Regional citrate anticoagulation in continuous venovenous hemodiafiltration. Am J Kid Dis 2000;35:802–811. Palson R, Niles JL: Regional citrate anticoagulation in continuous veno-venous hemofiltration in critically ill patients with a high risk of bleeding. Kid Int 1999;55:1991–1997. Bunchman T, Maxvold NJ, Barnett J, Hutchings A, Benfield MR: Pediatric hemofiltration: Normocarb dialysate solution with citrate anticoagulation. Pediatr Nephrol 2002;17:150–154. Davenport A: Dialysate and substitution fluids for patients treated by continuous forms of renal replacement therapy (CCRT). Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 313–322. Nowak MA, Campbell TE: Profound hypercalcaemia in continuous veno-venous hemofiltration dialysis with trisodium citrate anticoagulation and hepatic failure. Clin Chem 1997;43:412–413. Yagi N, LeBlanc M, Sakai K, Wright EJ, Paganini EP: Cooling effect of continuous renal replacement therapies in critically ill patients. Am J Kid Dis 1999;32:1023–1030.

Dr. A. Davenport Centre for Nephrology, Royal Free Hospital Pond Street, London NW3 2QG (UK) Tel. ⫹44 20 783 022 91, Fax ⫹44 20 783 021 25, E-Mail [email protected]

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CRRT Information Technology Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 329–349

A Practical Tool for Determining the Adequacy of Renal Replacement Therapy in Acute Renal Failure Patients Trairak Pisitkuna, Khajohn Tiranathanagula, Sonya Poulinb, Monika Bonellob, Gabriella Salvatorib, Vincenzo D’Intinib, Zaccoria Riccib, Rinaldo Bellomoc, Claudio Roncob a

Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; bDivision of Nephrology, St. Bortolo Hospital, Vicenza, Italy; cDepartment of Intensive Care, Austin and Repatriation Hospital, Melbourne, Australia

Acute renal failure (ARF) is one of the components of multiple organ failure, a devastating syndrome in intensive care unit (ICU) patients. Although several aspects of medical care in ARF have been improved, including renal replacement therapy (RRT), morbidity and mortality of the patients is still high [1–3]. Nevertheless, a great deal of development in RRT is ongoing concerning both quality and quantity of therapy in the attempt to ameliorate the outcome in ARF patients. Improvement in quality involves new techniques, membranes, and integrated equipment. The quantity aspect is also important, but still many questions remain unanswered. This article will focus on the main controversial issues on the quantity of RRT: – How would you define an adequate renal replacement therapy? – Does treatment dose correlate with outcome? – How can you measure treatment dose in different treatments?

How Would You Define an Adequate Renal Replacement Therapy?

There is still no consensus about the definition of adequacy for RRT in acute renal failure patients [4]. Indeed, the true meaning of adequacy itself could already express the authentic definition. In Latin, adequacy, ‘ad aequatum’

means ‘equal to…’. Thus, adequacy should be the state of treatment that closely mimics the features of the native kidney [5]. Therefore, adequacy should cover three aspects of kidney function, including blood purification, homeostasis regulation, and biosynthesis. As far as blood purification is concerned, RRT should eliminate the wide range, small-to-larger sizes, of metabolic end products and other molecules normally handled by the human kidney. To regulate homeostasis, RRT should restore and maintain the ‘milieu enterieur’ regarding acid-base, electrolytes, and water balance in a continuous fashion as performed by the human kidney. For the biosynthesis aspect, RRT should provide an adequate stimulus to erythropoiesis and participate in the control of mineral balance and bone physiology. Unfortunately, no such RRT currently exists. Thus, the more realistic definition of adequacy for RRT should be the treatment that could sufficiently dominate the uremic syndrome and improve the survival rate. ‘How much treatment is sufficient?’ is a question that all of us should define. Beyond this question, a second question will rise: ‘How much treatment is optimal?’ The optimal dose should in fact be the one that provides best possible outcomes given a certain degree of risk. In this condition, in fact, no further benefits can be observed from an increased dose and outcome becomes dependent on other variables.

Does Treatment Dose Correlate with Outcome?

While the treatment dose of RRT has been shown to affect outcome in chronic hemodialysis patients, it is still a matter of debate in acute renal failure patients. Gillum et al. [6] found that there is no advantage to intensive dialysis in the management of acute renal failure. However, this study should be interpreted with caution because there was no effective control of prescription and delivery; no random allocation; no control of urea generation rate, protein catabolic rate, and hydration status; and the results were only based on blood levels of urea nitrogen and creatinine. Bouman et al. [7] showed that survival at 28 days was not improved by using high ultrafiltration volume when compared with low ultrafiltration volume in critically ill patients with oliguric acute renal failure. Nevertheless, all patients enrolled in this study were postsurgical and survival rate was relatively high compared with previous reports. On the other hand, recent evidence supported the concept of dose-outcome linkage in acute renal failure patients. Storck et al. [8] reported that in acute renal failure after surgery, the survival rate was significantly higher with pump-driven hemofiltration (PDHF) than with spontaneous continuous arteriovenous hemofiltration (CAVH). The main difference between these two groups was daily ultrafiltration volume that was significantly higher with PDHF than with CAVH, 15.7 vs. 7.0 liters/day, respectively. Paganini et al. [9] showed the

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survival benefit of a higher delivered dose in patients with intermediate severity, making their assessment with the Cleveland Clinical Foundation ARF score. However, the significance was not seen in the two tales of the severity curve including mild and severe patients. The explanation was that the outcome in such patients might be predominated by the underlying comorbidity of patients rather than the effects of treatment. Schiffl et al. [10] reported the superiority of survival in daily intermittent hemodialysis as compared with alternate-day intermittent hemodialysis among patients with acute renal failure. The authors stated that this partially resulted from the higher dose in the daily treatment group. Ronco et al. [11] demonstrated that the higher ultrafiltration rate, 35 vs. 20 ml/h/kg, of continuous venovenous hemofiltration (CVVH) improved survival significantly. A further increase in ultrafiltration rate did not result in additional benefit in terms of survival although in septic patients an improvement was observed. The authors recommended that ultrafiltration should be prescribed according to patient’s bodyweight and should reach at least 35 ml/h/kg. At this point, it seems that a dose and outcome relationship of RRT in acute renal failure patients exists, especially in specific groups of patients such as those with moderate levels of severity and patients with sepsis. Furthermore, it seems that such a correlation is only linear within specific ranges of severity and doses. Beyond a given dose, the correlation becomes less significant and survival tends to steady. However, it is still not clear how much an adequate or optimal dose is and therefore we are going to scrutinize where the curve reaches the plateau and which other factors affect the level of the plateau. To define the dose effect on outcome, we need large-scale multicenter studies using a quantitative measuring tool that is effective, practical, and equivalent among the study groups. Furthermore, we need to select some marker molecules to be used to measure dose. Finally, we need to establish the effect of different modalities (convection, diffusion, and adsorption) at the same dose for a particular marker molecule such as urea.

How Can You Measure Treatment Dose in Different Treatments?

Renal replacement therapy consists of various modalities which differ in many features including continuity of treatment (intermittent vs. continuous), vascular access (arteriovenous vs. venovenous), and mechanism of solute removal (diffusion vs. convection) [12, 13]. Accordingly, it is difficult to find an ideal marker employed for comparing the doses of these different treatments. As such, it needs the comprehensive view to search out the best solution for this matter. Using urea as a marker molecule, as is done in chronic hemodialysis, the treatment dose of RRT can be defined by various aspects such as efficiency, intensity, frequency, and clinical efficacy. In spite of its moderate toxicity, urea is often used

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80 30 SLED

CVVHD

Daily clearance (ml/day)

Clearance (ml/min)

200

IHD

CVVHD 24h

Weekly clearance (ml/week)

a

38,400

36,000

SLED 8h

IHD 3h

b

302,400 268,800

252,000

134,400 108,000 CVVHD 24 h continuous

c

43,200

SLED 8h alt. days

SLED 8h
7 days

IHD 3h
3 days

IHD 3h
7 days

Fig. 1. Comparisons of doses between different RRT modalities: (a) comparison by clearance (K); (b) comparison by daily clearance (Kt), and (c) comparison by weekly clearance (Kt
treatment days/week). CVVHD  Continuous venovenous hemodialysis; IHD  intermittent hemodialysis; SLED  sustained low efficiency dialysis.

as a marker. Urea in fact has the advantage of being easily measurable, and representing the end of protein metabolism, its accumulation defines the requirement for dialysis while its elimination defines the ability of treatment to remove toxins. Of course, urea just represents a surrogate of the low-molecular-weight toxin.

Efficiency

The efficiency of RRT can be represented by clearance (K). Technically, K depends on blood flow rate (Qb), dialysate flow rate (Qd), ultrafiltration rate (Qf), reference molecules, and hemodialyzer type and size. K can be normally used to compare the treatment dose within each modality. Between different modalities, however, K is typically higher in intermittent hemodialysis (IHD) than in continuous renal replacement therapy (CRRT) and sustained low efficiency dialysis (SLED) (fig. 1a) even though IHD does not really remove the solutes better than the others. This is not surprising since K represents only the amount of treatment per unit of time. Therefore, K cannot be employed to compare various modalities which differ in treatment duration. Furthermore,

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K represents an instantaneous measurement and it correlates with the amount of solute removal at the time point of the measurement. Although K might remain stable over time, if blood levels of the reference molecule change, the removal rate will also change. In its original conception, in fact, K was signed to confer renal function among disparate individuals where, however, function was operating 24 h per day and blood levels were at a steady state.

Intensity

The intensity of RRT can be described by the product clearance
time (Kt). Because the time is accounted, Kt is more effective than K in the comparison of various RRT modalities. As depicted in figure 1b, Kt in daily clearance is higher in CVVHD than in SLED and IHD even though CVVHD has the lowest K compared with the other treatments (fig. 1b).

Frequency

Frequency is an essential factor to further describe treatment dose in different modalities. Thus, weekly clearance, intensity
frequency (Kt
treatment days/week), is superior to Kt since it offers the comparison of different modalities in the more extensive view (fig. 1c).

Efficacy

Efficacy of RRT represents the effective clinical outcome resulting from the implication of a given treatment. It can be described by a fractional clearance (Kt/V), where V is the volume of distribution of the marker molecule. Kt/V is an established marker of adequacy correlating with survival in chronic hemodialysis patients [14]. Kt/V, however, has not been proved as a marker of adequacy in acute renal failure patients [15]. Of interest, all of the above methods have one common problem impairing their ability to compare between different RRT modalities. This problem results from the limitation of using K as a representation of solute removal capacity. Because solute removal is a product of K and serum levels of solute (C) (solute removal  K
C). The same K in different modalities does not mean the same solute removal. In CRRT, for example, serum levels of solutes are nearly constant during the treatment while these decline during a dialysis session in IHD [13]. As a consequence, solute removal in CRRT is stable while it decreases

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120 SLED Kt/V 1.32 Rebound 6% Eq Kt/V 1.24

BUN (mg/dl)

100 80

CVVHD Kt/V  0.9 No rebound Eq Kt/V 0.9

60 40

D short HD Kt/V 1.34 Rebound 22% Eq Kt/V 1.12

20 0 0

60

120

180 240 300 360 Minutes of treatment

420

480

540

Fig. 2. Postdialytic rebound in different modalities. CVVHD provided a gradual removal of BUN without rebound as compared to daily short hemodialysis which speedy removed BUN with significant rebound.

Table 1. Comparison of treatment dose between different modalities

K, ml/min Predialysis BUN, mg/dl Postdialysis BUN, mg/dl Treatment time, min Kt/V Eq Kt/V Daily clearance, liters Daily urea nitrogen removal, g Rebound

Daily short HD

SLED

CVVHD

200 110 30 180 1.34 1.12 36 18 22%

80 110 30 480 1.32 1.24 38.4 27 6%

30 70 65 1440 0.9 0.9 43.2 33.6 0%

Eq Kt/V  Equilibrated Kt/V.

along the dialysis time in IHD. Furthermore, the rapid removal of solutes in IHD results in unfinished equilibration of serum levels of solutes between the body pools as evidenced by the rebound of solutes after dialysis (fig. 2) [16, 17]. Thus, CRRT would remove more solutes from the total body pool and accomplish much greater blood purification than IHD even though K and Kt/V of CRRT are lower than IHD (both daily short HD and SLED) (table 1) [18]. After a correction of the equilibration problem by measuring the equilibrated Kt/V (Eq Kt/V) [19], this contention is still the same since Eq Kt/V of CRRT remains lower than IHD (table 1). There is an attempt to make the different RRT

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modalities comparable by transforming the intermittent clearance to continuous clearance. Equivalent renal clearance (EKR) [20] and standard Kt/V (stdKt/V) [21] are established as the tools for this purpose in chronic hemodialysis patients. However, these methods cannot apply to calculations in the setting of acute renal failure because the key assumption, urea generation rate is equal to urea removal rate, is not true in this hypercatabolic state. The solute removal index (SRI) is another representative of efficacy and it has been proposed as the best method for comparing the dose between different RRT modalities [15, 22]. SRI reflexes fraction urea removal during RRT by using the dialysate-side measuring method. Therefore, SRI is not influenced by blood-side kinetics, including intercompartmental distribution of the solutes, of various RRT [22]. When the frequency of RRT is included in the consideration, weekly SRI (SRI
treatment days/week) might become the gold standard for comparing between disparate RRT modalities in acute renal failure patients. Essentially, it needs the scientific proof for the merit of these various methodologies formerly described. In practice, it is difficult to manually calculate the dose of RRT by all of these various methods. To simplify the complicated calculations, computer software is introduced to circumvent this obstacle. Computer software can assist in further studies to clarify the best dose measuring method and it can also be utilized in current RRT practice. Accordingly, we have developed a program on Microsoft Excel entitled ‘Adequacy Calculator for ARF’ which is easily used and can calculate most of the described methods in a real time basis. In the program, it consists of calculators for the various RRT modalities including continuous mode (SCUF, CVVH, CVVHD, and CVVHDF) and intermittent mode (IHD and SLED) as shown in the main menu (fig. 3).

Continuous Mode

SCUF SCUF is a technique where blood is driven through a highly permeable filter via an extracorporeal circuit in the veno-venous mode. The ultrafiltrate produced during membrane transit is not replaced and it corresponds exactly to the patient’s weight loss. It is used only for fluid control in overhydration [12]. Therefore, it is not necessary to measure the treatment dose in terms of solute removal and the program calculates only fluid balance per day (fig. 4). The required input data are SCUF prescription, including treatment time per day and ultrafiltration rate, and non-CRRT fluid input-output per day. The output will be shown in both descriptive (‘Removal’, ‘Zero’, or ‘Repletion’) and numerical data (ml/day).

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Fig. 3. Main menu of Adequacy Calculator for ARF program.

Fig. 4. Slow continuous ultrafiltration (SCUF) calculator sheet.

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CVVH CVVH is a technique whereby blood is driven through a highly permeable filter via an extracorporeal circuit in the venovenous mode. The ultrafiltrate produced during membrane transit is replaced in part or completely to achieve blood purification and volume control. Ultrafiltration is in excess of patient weight loss and replacement is needed. Because it is purely a convective therapy, the clearance for most solutes equals ultrafiltration rate [12]. At the start of the CVVH program, the methods of fluid replacement comprising predilution, postdilution, or pre-  postdilution are requested (fig. 5). The input data consist of body weight, height, hematocrit, blood flow rate, treatment time per day, fluid replacement rate, and ultrafiltration rate. The estimated urea clearance will be derived directly from ultrafiltration rate in the postdilution setting as seen by the following equations: Equation 1: Clearance 

Cuf
Quf Cbi

,

where, Cuf  ultrafiltrate urea nitrogen level; Quf  ultrafiltration rate, and Cbi  prefilter BUN level. Since the ultrafiltrate urea nitrogen level will be equivalent to the prefilter BUN level in a usual CVVH setting then: Equation 2: Clearance  Quf.

In the predilution and pre-  postdilution setting, however, the BUN level entering the filter will lower after fluid replacement, thus the ultrafiltration rate will overestimate the exact clearance. Thus, the program will correct this error by using the following equation: Equation 3: Clearance 

Quf 1 (Qr Qb)

,

where Qr  predilution fluid replacement rate, and Qb  blood flow rate. In addition, if one needs to declare the actual in vivo urea clearance, the instantaneous urea clearance can be measured by two options. Firstly, bloodside urea clearance is determined by collecting the simultaneous blood samples of pre- and postfilter urea levels and calculating it with the following equation: Equation 4: Clearance 

Cbi
Qbi  Cbo
Qbo Cbi

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Fig. 5. Continuous venovenous hemofiltration (CVVH) calculator sheet.

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where Cbi  prefilter BUN level, Cbo  postfilter BUN level, Qbi  prefilter blood flow rate, and Qbo  postfilter blood flow rate. Secondly, ultrafiltrate-side urea clearance is determined by collecting the simultaneous blood and ultrafiltration samples of prefilter and ultrafiltration urea levels, respectively, and calculating as for equation 1. After the value of urea clearance (K) is obtained, the other values including clearance per body surface area (K/BSA), daily urea clearance (Kt), and daily Kt/V are calculated simply. The BSA is derived from the Du Bois formula [23]. The volume distribution of urea (V) is attained by estimating at 60% of the body weight since there is still no established method for V determination in acute renal failure patients. For the estimation of daily urea nitrogen removal, steady state prefilter BUN level (Cbi) is required for calculation by the following equation: Equation 5: Daily urea nitrogen removal  K
t
steady state Cbi.

However, if Cbi is not constant, daily average Cbi should be used instead of steady state Cbi. After daily urea nitrogen removal is obtained, the daily solute removal index (SRI) of urea is simply estimated by dividing the daily urea nitrogen removal with total body urea nitrogen level at the start of the same treatment day as seen in the following equation [22]: Equation 6: Daily SRI 

daily urea nitrogen removal V start of the day Cbi
V

.

Eventually, when the superior comparison between disparate RRT modalities is concerned, weekly urea clearance, weekly urea nitrogen removal, and weekly SRI are easily estimated by multiplying the daily urea clearance, the daily urea nitrogen removal, and the daily SRI, respectively, with the number of treatment day in a week. Other than measuring the dose of RRT, the program can also calculate urea generation rate (G), normalized protein equivalent of total nitrogen appearance (nPNA), and residual renal urea clearance (Kr). The urea generation rate was calculated by the following equation: Equation 7: G

body UNA + ultrafiltrate UNA + urine UNA t

where UNA  urea nitrogen appearance; body UNA  (Cbit
Vt  Cbi0
V0); ultrafiltrate UNA  (Quf
(Cuf0  Cuft/2)
t); urine

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UNA  urine volume
average urine urea nitrogen; Cbi0  prefilter BUN level at time 0; Cbit  prefilter BUN level at time t; Cuf0  ultrafiltrate urea nitrogen level at time 0; Cuft  ultrafiltrate urea nitrogen level at time t; V0  volume distribution of urea at time 0, V0  BW0
0.6; Vt  volume distribution of urea at time t, Vt  BWt
0.6; t  time between two points of sample collections. These calculations required information on the change of BUN and the amount of urea nitrogen removal in ultrafiltrate and urine between two time points, preferably 24 h apart, which can be obtained by 3 methods. The best method requires two time points of urea nitrogen levels in both blood and ultrafiltrate samples (option 1 in the part of urea generation rate calculation of the program). In option 2, it is only necessary to know the urea nitrogen levels in blood because the urea nitrogen levels in ultrafiltrate can be estimated from those in blood based on the assumption that, in the usual setting of CVVH, a small molecule solute such as urea will be equivalent between blood and ultrafiltrate sides. On the other hand, option 3 requires only the urea nitrogen levels in ultrafiltrate because the urea nitrogen levels in blood can be estimated based on the same assumption. In the predilution setting, these estimations cannot be performed directly since they require the involvement of the predilution fluid replacement rate in the calculation. Nevertheless, the program will take this point into account and accomplish this complicated calculation. After the urea generation rate is obtained, nPNA is approximated by the following equation: Equation 8: nPNA 

G
6.25 average BW

.

Residual renal urea clearance is simply calculated by dividing the urine UNA with time between two points of sample collections. Moreover, the program will determine the fluid balance per day as described above in the SCUF mode. Continuous Venovenous Hemodialysis CVVHD is a technique whereby blood is driven through a low permeable dialyzer and a countercurrent flow of dialysis solution is delivered to the dialysate compartment. The ultrafiltrate produced during membrane transit corresponds to patient weight loss. Solute clearance is mainly achieved by diffusion. A replacement solution is not needed. Because it is mainly a diffusive therapy, its efficiency is limited to small molecules [12]. At the start of the CVVHD program, the input data consist of body weight, height, hematocrit, blood flow rate, treatment time per day, dialysate inflow rate, and dialysate outflow rate are requested (fig. 6).

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Fig. 6. Continuous venovenous hemodialysis (CVVHD) calculator sheet.

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The estimated urea clearance will be derived directly from dialysate outflow rate as the following equation: Equation 9: Clearance 

Cdo
Qdo Cbi

,

where Cdo  dialysate outflow urea nitrogen level, Qdo  dialysate outflow rate, and Cbi  prefilter BUN level. Since the dialysate outflow urea nitrogen level will be equivalent to prefilter BUN level in a usual CVVHD setting, then: Equation 10: Clearance  Qdo.

This assumption is not true when blood flow rate is too low and dialysate flow rate is too high because in this condition the dialysate outflow will not be saturated with urea nitrogen from the blood side [24]. However, this will not be the problem for calculation if the instantaneous urea clearance is measured. As in the CVVH mode, the instantaneous urea clearance can be determined by two options. Firstly, blood-side urea clearance is determined by collecting the simultaneous blood samples of prefilter and postfilter urea levels and calculating as in equation 4. Secondly, dialysate-side urea clearance is determined by collecting the simultaneous blood and dialysate samples of prefilter and dialysate outflow urea levels, respectively, and calculating as in equation 9. After the value of urea clearance (K) is obtained, the other values as in the CVVH mode including clearance per body surface area (K/BSA), daily urea clearance (Kt), daily Kt/V, daily urea nitrogen removal, daily solute removal index (SRI), weekly urea clearance, weekly urea nitrogen removal, and weekly SRI are determined by the program. For the urea generation rate (G) determination, it can be done by using the dialysate outflow urea nitrogen level instead of ultrafiltrate urea nitrogen level for the calculation in equation 7. The normalized protein equivalent of total nitrogen appearance (nPNA), residual renal urea clearance (Kr), and the fluid balance per day are also determined by the program. CVVHDF Continuous venovenous hemodiafiltration is a technique whereby blood is driven through a highly permeable dialyzer and a countercurrent flow of dialysis solution is delivered on the dialysate compartment. The ultrafiltrate produced during membrane transit is in excess to the patient weight loss. Solute clearance is obtained both by diffusion and convection. Replacement solution is needed to

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obtain fluid balance. Since it is a convective plus diffusive therapy, its efficiency is extended from small to larger molecules [12]. At the start of the CVVHDF program, the methods of fluid replacement comprising pre- and postdilution are requested (fig. 7). The input data consist of body weight, height, hematocrit, blood flow rate, treatment time per day, fluid replacement rate, dialysate inflow rate, and dialysate outflow rate. Based on the assumption that the dialysate outflow urea nitrogen level will be equivalent to the prefilter BUN level in a usual CVVHDF setting, the estimated urea clearance will be derived directly from dialysate outflow rate in the postdilution setting as in equations 9 and 10. In the predilution setting, however, dialysate outflow rate will overestimate the exact clearance. Thus, the program will correct this error by using the following equation: Equation 11: Clearance 

Qdo 1 (Qr/Qb)

.

This estimation cannot be used when the blood flow rate is too low and the dialysate flow rate is too high because in this condition the dialysate outflow will not be saturated with urea nitrogen from the blood side [25]. However, the instantaneous urea clearance, determined as in the CVVHD mode, can be employed to circumvent this limitation. After the value of urea clearance (K) is obtained, the other values as in the CVVH and CVVHD mode including clearance per body surface area (K/BSA), daily urea clearance (Kt), daily Kt/V, daily urea nitrogen removal, daily solute removal index (SRI), weekly urea clearance, weekly urea nitrogen removal, and weekly SRI are determined by the program. For the urea generation rate (G) determination, it can be performed as in the CVVHD mode; in addition, the program will also take account of the methods of fluid replacement in the calculation. The normalized protein equivalent of total nitrogen appearance (nPNA), residual renal urea clearance (Kr), and the fluid balance per day are also determined by the program.

Intermittent Mode

This mode consists of standard intermittent hemodialysis (IHD) and sustained low efficiency dialysis (SLED). These therapies are mainly the diffusive therapy performed in intermittent fashion. The differences between these two modalities are in the aspects of efficiency and treatment time. SLED is designed to operate at a lower efficiency (clearance) but longer treatment time

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Fig. 7. Continuous venovenous hemodiafiltration (CVVHDF) calculator sheet.

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than IHD [26]. In the SLED mode, blood flow rate and dialysate flow rate are usually set at the range of 150–200 and 100 ml/min, respectively, while the treatment time is extended to at least 8 h. In both IHD and SLED, however, the doses of the treatments can be measured by using the same principle of calculation. The program can determine dialyzer urea clearance of these therapies by two methods. Firstly, the estimated urea clearance can be obtained by multiple step calculation, as described by Daugirdas [27], which requires input data including in vitro urea clearance (K) at the specific in vitro blood flow rate (Qb) and in vitro dialysate flow rate (Qd), actual blood and dialysate flow rate, ultrafiltration rate, and hematocrit. In vitro data of K, Qb, and Qd can be obtained automatically from the program database by selecting the brand and the model of dialyzer (as shown in the list boxes in fig. 8) or these data can be acquired from the dialyzer manufacturer and entered manually into the program. The ultrafiltration rate is calculated from total body weight loss during dialysis divided by treatment time. Secondly, the actual in vivo urea clearance can be measured by adding the pre- and postfilter levels of simultaneous BUN samples into the program which will perform the calculation by the equation 4. After the value of dialyzer urea clearance (K) is obtained, the clearance per body surface area (K/BSA), daily urea clearance (Kt), and Kt/V derived from the formal urea kinetic modeling (UKM) method are calculated. In the UKM method, the volume distribution of urea (V) is attained by a complicated mathematical iteration of two formulae described by Gotch as the following [28]: Equation 12: 1 ⎡⎡ ⎤ Quf ⎤ ⎢ ⎢ ⎡ GCt(K Kr Quf) ⎤ KKr Quf ⎥ ⎥ V  Quf
t ⎢ ⎢1⎢ 1⎥ ⎥ ⎥ ⎢ ⎢ ⎣ GC0(K Kr Quf) ⎦ ⎥ ⎥⎦ ⎢⎣ ⎣ ⎥⎦

Equation 13: Kr ⎡ ⎤  ⎡ V ⎤  ⎥ (Kr ) ⎢C0Ct ⎢ ⎥ ⎢ ⎥ ⎣ V ⎦ ⎢ ⎥⎦ ⎣ G Kr  ⎤ ⎡  ⎢1 ⎡ V ⎤  ⎥ ⎢ ⎢⎣ V ⎥⎦ ⎥ ⎢⎣ ⎥⎦

where V  the volume distribution of urea, Quf  ultrafiltration rate, t  treatment time, G  the urea generation rate, K  the dialyzer urea clearance, Kr  the residual renal urea clearance, C0  the BUN level at the beginning of

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Fig. 8. Intermittent hemodialysis (IHD) calculator sheet. Remark: Sustained low efficiency dialysis (SLED) calculator sheet is similar to IHD calculator sheet (figure not shown).

a dialysis treatment, Ct  the BUN level at the end of a dialysis treatment,   the rate of interdialytic volume expansion,   the length of the interdialytic interval. These formulas share common terms and solve for V and G. The program will repeat these formulas until unique values for V and G are found that satisfy both equations. The requisite input for these calculations include body weights at before dialysis (BW pre1), after dialysis (BW post), and before the next dialysis (BW pre2); treatment time; BUN level immediately before dialysis (BUN pre1), immediately after dialysis (BUN post, using slow flow/stop

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pump technique), 30 min after dialysis (BUN post 30), and immediately before the next dialysis (BUN pre2); duration between the beginning of a dialysis (pre1) and the next dialysis (pre2); and, for calculating the Kr, urine volume and average urine urea nitrogen level between the end of a dialysis (post) and the next dialysis (pre2). For single-pool Kt/V (spKt/V) and equilibrate Kt/V (eqKt/V) determinations, the values of V are obtained by using ‘BUN post’ and ‘BUN post 30’, respectively, as the Ct in the above UKM formulas. In addition, the program also determines the spKt/V and eqKt/V by using a natural logarithm formula [29] and rate equation [19], respectively. The type of vascular access between arteriovenous (AV) and venovenous (VV) is required to perform the rate equation. For the estimation of daily urea nitrogen removal per and daily solute removal index (SRI), the dialysate samples for urea nitrogen levels (Cd) are requested. Even though the dialysate samplings are tedious tasks, these dialysate-side dose-measuring methods might provide the best solution for comparing between disparate RRT modalities in acute renal failure patients. For more practicality, spot sampling rather than total dialysate collection is preferred. The program has designed a time table for dialysate sampling by using the mid point of time in the particular hours as references. After the urea nitrogen levels from all dialysate samples are obtained, the daily urea nitrogen removal is calculated using the following equation: Equation 14: Daily urea nitrogen removal  (Qd  Quf)
(Cd1
t1  Cd2
t2  Cd3
t3  …)

where Qd  dialysate flow rate, Quf  ultrafiltration rate, Cd1,2,3,…  dialysate urea nitrogen level at mid point of hours 1, 2, 3,…, and t1,2,3,…  duration of treatment (minute) at hours 1, 2, 3,… As a consequence, SRI is simply estimated by dividing the daily urea nitrogen removal with total body urea nitrogen level at predialysis as in the following equation [22]: Equation 15: SRI 

daily urea nitrogen removal predialysis BUN
V

.

As in continuous mode, the weekly urea clearance, weekly urea nitrogen removal, and weekly SRI are easily estimated by multiplying the daily urea clearance, the daily urea nitrogen removal and the daily SRI, respectively, with the number of treatment days in a week. Because G is already obtained from the UKM calculation described above, the normalized protein equivalent of total nitrogen appearance (nPNA) is simply determined from G by the Borah formula [30].

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Conclusion

Even though the adequacy of RRT does not clearly influence the survival rate of the critical acute renal failure patient at this moment, this issue is still drawing much concern from the intensive patient care team. To decipher the unresolved issues about the survival benefit and the sufficient quantity of the dose of RRT in acute renal failure, long-term, large-scaled multicenter studies using the same tool for measuring and comparing the dose of various treatment modalities are needed. Of interest, the Adequacy Calculator for ARF program is innovated to provide the practicality in this matter since this program is designed on the worldwide used software Microsoft Excel and it can perform the extensive calculations covering all dimensions of adequacy including efficiency, intensity, frequency and efficacy of RRT. Other than a tool for the study, this program can also be readily employed in clinical practice. Thus, this program is aspired to be a valuable tool for exploring the unforeseeable arena of adequacy of RRT in acute renal failure patients. References 1

2

3 4 5 6

7

8 9

10 11

Parker RA, Himmelfarb J, Tolkoff-Rubin N, Chandran P, Wingard RL, Hakim RM: Prognosis of patients with acute renal failure requiring dialysis: Results of a multicenter study. Am J Kidney Dis 1998;32:432–443. Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051–2088. McCarthy JT: Prognosis of patients with acute renal failure in the intensive-care unit: A tale of two eras. Mayo Clin Proc 1996;71:117–126. Ronco C, Kellum JA, Mehta R: Acute dialysis quality initiative (ADQI). Nephrol Dial Transplant 2001;16:1555–1558. Bellomo R, Ronco C: Adequacy of dialysis in the acute renal failure of the critically ill: The case for continuous therapies. Int J Artif Organs 1996;19:129–142. Gillum DM, Dixon BS, Yanover MJ, Kelleher SP, Shapiro MD, Benedetti RG, Dillingham MA, Paller MS, Goldberg JP, Tomford RC, et al: The role of intensive dialysis in acute renal failure. Clin Nephrol 1986;25:249–255. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J: Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med 2002;30:2205–2211. Storck M, Hartl WH, Zimmerer E, Inthorn D: Comparison of pump-driven and spontaneous continuous haemofiltration in postoperative acute renal failure. Lancet 1991;337:452–455. Paganini EP, Tapolyai M, Goormastic M, Halstenberg W, Kozlowski L, Leblanc M, Lee JC, Moreno L, Sakai K: Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis 1996;28(suppl 3):S81–S89. Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305–310. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000;356:26–30.

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12 13 14 15 16

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Ronco C, Bellomo R: Continuous renal replacement therapy: Evolution in technology and current nomenclature. Kidney Int 1998;66(suppl):S160–S164. Clark WR, Ronco C: Renal replacement therapy in acute renal failure: Solute removal mechanisms and dose quantification. Kidney Int 1998;66(suppl):S133–S137. Gotch F, Sargent J: A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int 1985;28:526–534. Evanson JA, Ikizler TA, Wingard R, Knights S, Shyr Y, Schulman G, Himmelfarb J, Hakim RM: Measurement of the delivery of dialysis in acute renal failure. Kidney Int 1999;55:1501–1508. Depner TA, Rizwan S, Cheer AY, Wagner JM, Eder LA: High venous urea concentrations in the opposite arm: A consequence of hemodialysis-induced compartment disequilibrium. ASAIO Trans 1991;37:M141–M143. Schneditz D, Kaufman AM, Polaschegg HD, Levin NW, Daugirdas JT: Cardiopulmonary recirculation during hemodialysis. Kidney Int 1992;42:1450–1456. Clark WR, Mueller BA, Alaka KJ, Macias WL: A comparison of metabolic control by continuous and intermittent therapies in acute renal failure. J Am Soc Nephrol 1994;4:1413–1420. Daugirdas JT, Schneditz D: Overestimation of hemodialysis dose depends on dialysis efficiency by regional blood flow but not by conventional two pool urea kinetic analysis. ASAIO J 1995;41: M719–M724. Casino FG, Lopez T: The equivalent renal urea clearance: A new parameter to assess dialysis dose. Nephrol Dial Transplant 1996;11:1574–1581. Gotch FA: Evolution of the single-pool urea kinetic model. Semin Dial 2001;14:252–256. Keshaviah P, Star RA: A new approach to dialysis quantification: An adequacy index based on solute removal. Semin Dial 1994;7:85–90. Du Bois D, Du Bois EF: A formula to estimate the approximate surface area if height and weight be known. Nutrition 1989;5:303–311. Sigler MH, Teehan BP: Solute transport in continuous hemodialysis: A new treatment for acute renal failure. Kidney Int 1987;32:562–571. Brunet S, Leblanc M, Geadah D, Parent D, Courteau S, Cardinal J: Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis 1999;34:486–492. Marshall MR, Golper TA, Shaver MJ, Alam MG, Chatoth DK: Sustained low-efficiency dialysis for critically ill patients requiring renal replacement therapy. Kidney Int 2001;60:777–785. Daugirdas JT: Appendix A: Estimating dialyzer blood water clearance from KoA, QB, and QD (Table A-1); in Daugirdas JT, Blake PG, Ing TS (eds): Handbook of Dialysis, ed 3. Philadelphia, Lippincott, Williams & Wilkins, 2001, p 674. Gotch FA: Kinetic modeling in hemodialysis; in Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis, ed 3. Englewood Cliffs, Prentice Hall, 1995, pp 156–189. Daugirdas JT: Second generation logarithmic estimates of single-pool variable volume Kt/V: An analysis of error. J Am Soc Nephrol 1993;4:1205–1213. Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, Wolfsen M, Humphreys MH: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 1978;14:491–500.

Claudio Ronco, MD Department of Nephrology, St. Bortolo Hospital Viale Rodolfi, IT–36100, Vicenza (Italy) Tel. 39 0444 993 869, Fax 39 0444 993 949, E-Mail [email protected]

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New Frontiers in the Management of ARF, MOF and Sepsis Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 350–361

How to Approach Sepsis Today? Jean-Louis Vincent Department of Intensive Care, Erasme Hospital, Free University of Brussels, Brussels, Belgium

Over the last decade or so, vast amounts of time, energy, and money have gone into investigating the multiple facets of the pathophysiology and effects of sepsis. These efforts have not been in vain, and while sepsis continues to be a leading cause of morbidity and mortality in intensive care units (ICUs) worldwide, the development and licensing of the first immunomodulatory therapy for patients with severe sepsis, along with encouraging results from other clinical trials, has provided the intensivist with some strategies to curb the often tragic outcomes of this disease process. Diagnosis of Sepsis

Advances in understanding of the sepsis response have led to a need for an update of the widely used 1992 SCCM/ACCP definitions referring to the systemic inflammatory response syndrome (SIRS). At a Sepsis Definitions Conference involving 29 physicians from Europe and North America held in 2001, the participants agreed that sepsis should still be defined as infection plus signs of systemic inflammation, but that the SIRS criteria should be abandoned [6]. Unfortunately, as yet, no individual sign is specific for sepsis and clinical diagnosis relies on the combined presence of several signs and symptoms (the majority of which are listed in table 1). Severe sepsis is defined as sepsis plus organ dysfunction, and septic shock as severe sepsis with hypotension despite adequate fluid resuscitation, and evidence of perfusion abnormalities. This conference also introduced the idea of staging sepsis, as cancer is staged, to facilitate assessment of likely patient prognosis and potential to respond to therapy. The PIRO system (table 2) stratifies patients according to their Predisposing conditions, the nature of the Infection, the extent of the host Response, and the degree of concomitant Organ dysfunction.

Table 1. Signs of sepsis

• General signs and symptoms

• •

•

Rigor-fever (sometimes hypothermia) Tachypnea/respiratory alkalosis Positive fluid balance – edema General hematologic/inflammatory reaction Increased (sometimes decreased) WBC – increased immature forms Increased CRP, IL-6 and procalcitonin concentrations Hemodynamic alterations Arterial hypotension Tachycardia Increased cardiac output/wide pulse pressure/low SVR/high SvO2 Altered skin perfusion (cold, mottled extremities, petechiae, …) Decreased urine output Hyperlactatemia – increased base deficit Signs of organ dysfunction Hypoxemia (ALI) Altered mental status Alteration in renal function Thrombocytopenia, DIC Alteration in liver tests (hyperbilirubinemia) Intolerance to feeding (altered GI motility) Hyperglycemia

Predisposing Conditions. This includes individual patient characteristics that make them more or less likely to develop sepsis and to succumb when they do, e.g. age, gender, chronic disease processes such as cancer, history of alcohol abuse, genetic polymorphisms, etc. Infection. This includes characteristics of infection that may influence a patient’s response to that infection and/or response to treatment, e.g. the site of infection, the specific organism, the size of the inoculum, and the susceptibility of the organism to antimicrobial agents. Response. The degree of immune response to the infection can be characterized by the presence or absence, or the degree of elevation of various signs and symptoms, e.g. white cell count, C-reactive protein, procalcitonin, etc. (table 1). The response will vary between individual patients and in the same patient at different times. Organ Dysfunction. This can be measured and monitored using organ dysfunction scores such as the sequential organ failure assessment (SOFA), which use simple, routinely available parameters to assess organ function in various, usually six, organ systems.

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Table 2. The PIRO system P

Predisposing factors

I

Infection

R

Response

O

Organ dysfunction

Age Sex Past history Genetic factors Alcoholism, tobacco abuse, … Source (lungs, abdomen, urine, cerebrospinal fluid, …) Degree of extension (e.g. for pneumonia, one lobe vs. one lung vs. bilateral) Type of microorganism (gram-positive, gram-negative, fungus, virus) Fever, tachycardia, tachypnea, … WBC, CRP, PCT, cytokines, … PaO2/FiO2 Platelet count e.g. SOFA score Bilirubin Creatinine Need for vasopressors GCS

The PIRO system is in its infancy and requires further development and refinement, but it is an important advance and, in addition to characterizing individual patients, will help compare patient populations for clinical trial purposes, and help direct clinical research. Basic Management of Sepsis

The essentials of the management of patients with severe sepsis remain unchanged and can be broadly divided into infection control and hemodynamic stabilization. For the purposes of this chapter, each aspect will be considered separately, although in practice many are started simultaneously, as ‘time is tissue’ and early, effective therapy saves lives. Infection Control Infection control involves an in depth search for the source of the sepsis, with rapid institution of appropriate antibiotic therapy, after relevant cultures have been taken, and surgical removal of any focus. Delayed or initially ineffective antibiotic therapy has been shown to be associated with worse prognosis, and it is important that all likely microbial culprits are covered by the empiric antibiotic(s), which can then be altered as culture results become available.

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Hemodynamic Stabilization Resuscitation of the patients with severe sepsis or septic shock can be considered using the VIP mnemonic proposed by Weil and Shubin back in 1969: V – ventilate; I – infuse; P – pump.

Ventilate

Adequate oxygenation is essential and, when needed, mechanical ventilation should be instituted early rather than late as, in addition to providing adequate oxygenation, mechanical ventilation can reduce the work of breathing and hence reduce oxygen demand. Specific indications for instituting mechanical ventilation include severe tachypnea, muscular respiratory failure (use of accessory muscles), altered mental status, and severe hypoxemia despite supplemental oxygen. However, if uncertain as to whether or not to intubate, then intubate! While mechanical ventilation carries attendant risks, delaying ventilation is equally harmful in that tissue oxygenation is further threatened. The choice of ventilatory mode is large and studies continue to try and determine which method if any is superior to the next. In essence, mechanical ventilation should be aimed at providing hemoglobin oxygen saturations of at least 90% (arterial oxygen pressure [PaO2] greater than 60 mm Hg). The use of positive end-expiratory pressure (PEEP) can increase mean airway pressure and reduce the concentrations of oxygen needed. Higher PEEP levels are not indicated, however, and the short-term use of higher inspired oxygen concentrations when necessary is preferred over the risks of barotrauma or hemodynamic impairment seen with higher PEEPs. Prone positioning can improve oxygenation in patients with acute respiratory distress syndrome (ARDS), a common complication of sepsis. However, a large randomized trial of this strategy failed to demonstrate any overall improvement in survival in patients positioned prone, although mortality was reduced in patients who responded to prone positioning by reducing their PaCO2. Considerable interest has focused on the optimal tidal volume since the National Institutes of Health-sponsored ARDS Network study [13] showing improved outcomes in patients ventilated with tidal volumes of 6 ml/kg versus those ventilated with tidal volumes of 12 ml/kg predicted body weight. However, this study has been criticized in its choice of 12 ml/kg as the ‘traditional’ tidal volume, and it is generally felt that rather than showing 6 ml/kg to be the ideal tidal volume, the study rather demonstrated that tidal volumes of 12 ml/kg are too high. The optimum tidal volume is probably somewhere in between, round 8–9 ml/kg [9].

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Other ventilatory techniques have also been explored for their potential beneficial effects in ARDS. These include: inhaled nitric oxide (NO), which has been shown to improve oxygenation but not survival; aerosolized surfactant, which had no effect on oxygenation or survival; and partial liquid ventilation, which may improve oxygenation and have anti-inflammatory effects. The optimum approach to ventilation of the patient with severe sepsis, and in particular, sepsis-related ARDS is an active field of current research.

Infuse

Fluid administration is an essential aspect of resuscitation from septic shock, the aims being to preserve intravascular fluid volume, restore effective tissue perfusion, and re-establish a balance between tissue oxygen demand and supply. However, while in most forms of circulatory shock, hypotension and reduced tissue perfusion are due to a fall in cardiac output, and endpoints of fluid resuscitation are thus relatively easy to identify, in sepsis the situation is much more complex with cardiac output often normal or raised, and tissue perfusion being hindered by microcirculatory alterations. The endpoints of fluid therapy in sepsis are thus much more difficult to define, largely because of problems in monitoring the regional microcirculation and oxygenation, and changes may persist at a local level while systemic hemodynamic and oxygenation parameters appear to have stabilized. Several markers of perfusion and oxygenation have been proposed, including blood lactate levels, mixed venous oxygen saturation (SvO2), and the gastric tonometry-derived variables gastric intramucosal pH (pHi) or PCO2 gap, but none alone are reliable indicators of adequate resuscitation. The combination of clinical parameters (mean arterial pressure, urine flow, skin perfusion, level of consciousness) with blood lactate levels is most useful. Hyperlactatemia (blood lactate ⬎2 mEq/l) is typically present in patients with septic shock, and may be secondary to anaerobic metabolism due to hypoperfusion, although in septic patients, elevated lactate levels may also result from cellular metabolic failure in sepsis and from decreased clearance by the liver. Raised blood lactate levels nevertheless are associated with worse outcomes in septic shock patients, particularly if the high levels persist, and blood lactate levels have been shown to have greater prognostic value than oxygenderived variables. The normal SvO2 is 70–75% in critically ill patients, but can be elevated in septic patients due to maldistribution of blood flow. Admittedly, a normal or high SvO2 does not necessarily indicate adequate tissue oxygenation, but there is no definitive evidence that further increasing oxygen supply to the tissues in these circumstances will improve outcome. On the other hand, a low SvO2

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should prompt rapid intervention to increase oxygen delivery to the tissues. This concept is supported by a recent study by Rivers et al. [10], who evaluated the effects of early goal-directed therapy in patients with severe sepsis and septic shock versus standard therapy, using restoration of a central venous oxygen saturation (ScvO2) greater than 70% as one of its goals. This target was achieved by 95% of the early goal-directed group, compared to just 60% of the standard treatment group (p ⬍ 0.001), and the strategy was associated with improved hospital mortality rates (30.5% in the goal-directed group versus 46.5% in the standard therapy group, p ⫽ 0.009). Gastric tonometry-derived parameters have been studied as possible tools to detect regional hypoxia, but the use of traditional gastric tonometry is limited due to potential methodological pitfalls, substantial measurement errors, and doubts regarding the validity of intramucosal pH (pHi) calculations. Automated air tonometry also has sources of error including buffering of gastric acid by bicarbonate secreted by the stomach. Several studies have shown the prognostic value of pHi or PCO2 gap, but although some studies have suggested that the pHi may be a useful guide in surgical patients, treatment titrated against pHi was not shown to be beneficial in a heterogeneous population of critically ill patients. Newer techniques of monitoring the microcirculation are being developed including orthogonal polarization spectral (OPS) imaging, in which the microcirculation of mucosal surfaces, e.g. the sublingual area, is directly visualized. The microcirculatory changes seen in sepsis are related to prognosis and this technique may provide useful information regarding adequacy of resuscitation, although it remains experimental at present. Fluids The debate as to which fluid provides greatest benefit in sepsis continues and we will not discuss it in great detail here. In fact, it is the quantity of fluid rather than the type of fluid per se that is of greatest importance. Certainly, more crystalloid is needed to achieve the same effect as colloid, thus potentially increasing the risk of edema, but colloids are more expensive and carry their own risks. The most commonly used crystalloid solutions for resuscitation purposes are normal/isotonic (0.9%) saline and Ringer’s lactate (also called Hartmann’s solution). Hypertonic saline rapidly improves hemodynamic status and with its possible immunomodulatory and beneficial microcirculatory effects, may be a valuable initial resuscitation fluid in patients with septic shock [8]. However, there are few clinical data available at present to confirm or refute the benefits of hypertonic saline in sepsis. Colloid solutions include human albumin and artificial colloids such as dextrans, gelatins, and hydroxyethyl starch (HES) solutions. Albumin use has

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come under heavy fire in recent years since a meta-analysis suggested that human albumin administration was associated with an increased mortality rate, even though a subsequent meta-analysis failed to demonstrate any adverse effect of albumin on mortality. Albumin may have a particular place in critically ill patients with hypoalbuminemia. Of the artificial colloids, HES solutions are the most frequently used. Experimental studies have suggested that HES solutions may have beneficial effects on the microcirculation in sepsis, but these have not been confirmed in clinical trials, and others have suggested that HES solutions increase blood viscosity and may thus further compromise microcirculatory flow. HES solutions can prolong prothrombin time and the total amount infused thus needs to be limited, although its use has not been related to increased bleeding in septic shock patients. The molecular weight (MW) of these solutions may be important. In patients with severe sepsis, infusion of a medium MW HES solution (hexastarch) was associated with an increased risk of developing acute renal failure. Newer generation HES solutions with smaller MW may have beneficial effects, including on the microcirculation and endothelial cells, while limiting side effects [5]. Whatever fluid is decided on, assessment of adequacy of fluid infusion can be facilitated by repeated fluid challenges, in which a predefined amount of fluid (e.g. 250 or 500 ml) is infused over a set time. Preselected endpoints, e.g. mean arterial pressure 75 mm Hg, and pressure safety limits, e.g. central venous pressure (CVP) or pulmonary artery wedge pressure (PAWP), are then monitored, and fluids continued or stopped accordingly. Transfusion With several studies in recent years suggesting worse outcomes in critically ill patients who received blood transfusions [16], this field has undergone something of an upheaval with transfusion procedures and triggers being widely re-assessed. However, a more recent observational study, the SOAP study, showed no increased mortality in transfused patients, results that may be related to the widespread introduction of leukodepletion in the preparation of blood for transfusion. The rationale behind transfusion of red blood cells is that they will improve the blood’s oxygen carrying ability and hence improve tissue oxygenation; however, the resultant increase in hematocrit may increase viscosity, impairing blood flow, and limiting tissue oxygen delivery. This may be even more true if red blood cells are stored for any length of time. Thus, transfusion policies need to be flexible, and while some patients will undoubtedly benefit from blood transfusion, each patient needs to be assessed individually. Hemoglobin solutions, with their beneficial effects on oxygen carriage and potential immunomodulatory effects, may find a place in the treatment of septic shock, but further clinical trials are needed before these can be recommended [13].

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Pump

Fluid administration alone is often not sufficient to restore hemodynamic stability, and vasoactive agents are required. As with all aspects of the management of sepsis, there has been keen debate in recent years as to which vasoactive agent(s) is superior to the others [4]. Vasopressor Agents Dopamine has often been used as the first-line vasopressor to raise blood pressure. Dopamine combines ␣- and ␤-adrenergic properties, and at low doses, can also stimulate dopaminergic receptors, resulting in a selective increase in splanchnic and renal blood flow. However, the routine use of low (renal) dose dopamine to prevent renal failure is not recommended, a major argument being that a large randomized controlled trial failed to demonstrate any protective effect on renal function. Norepinephrine is also widely used in patients with septic shock. Norepinephrine has predominantly ␣-adrenergic properties, and hence is a stronger vasoconstrictor, but carries the risk that peripheral blood flow will be reduced by an excessive increase in vascular tone. Dobutamine is therefore often added when norepinephrine is given. Some studies have suggested that norepinephrine may be a better first choice in patients with septic shock [7], but the jury is still out, and current guidelines recommend both drugs as appropriate first line agents [12, 15]. Epinephrine decreases the splanchnic blood supply and is not recommended as a first line vasopressor in septic shock. Patients with septic shock often have inappropriately low levels of serum vasopressin and low dose vasopressin (0.01–0.04 U/min) as replacement therapy has been demonstrated to produce a significant rise in mean arterial pressure in septic shock, and can reduce requirements for traditional vasopressors. Although this strategy has been shown to improve survival in animal models, no randomized, prospective clinical trials have assessed outcomes. Inotropic Agents While cardiac index is often normal or even high in the volume resuscitated septic shock patient, cardiac function is often impaired. The mechanism of the myocardial dysfunction is complex, likely involving alterations in intracellular calcium homeostasis and in ␤-adrenergic signal transduction, and mediated by various inflammatory mediators including cytokines and NO. Dobutamine, an adrenergic agonist that stimulates ␤1-, ␤2- and ␣1-adrenergic receptors, is generally used as the first-line inotrope in septic shock. Dopexamine is an alternative inotrope, a dopamine analog, that initially seemed

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to have beneficial effects on splanchnic circulation, but these were not confirmed. Studies have suggested that the phosphodiesterase inhibitor, enoximone, may have beneficial anti-tumor necrosis factor (TNF) effects, and improve the splanchnic circulation when compared to dobutamine, with similar effects on cardiac index and oxygen delivery, but these drugs are not widely used in septic shock patients.

Other Management Strategies in Sepsis

Immunomodulatory Therapies After many years of apparently fruitless research into immunomodulatory therapies for patients with sepsis, there was a breakthrough in 2001 with the licensing of drotrecogin alpha (activated) for the treatment of adult patients with severe sepsis or septic shock. This drug, a recombinant version of a natural anticoagulant protein, was shown in a multicenter randomized controlled trial involving 1,690 patients to improve survival from 30.8% in the placebo group to 24.7% in the drotrecogin alpha (activated) group, giving a 19.4% relative reduction in mortality rate; i.e. only 16 patients need to be treated to save one life [2]. Drotrecogin alpha (activated) (licensed under the name Xigris) also improves organ function, and its effects on outcome are sustained beyond the traditional 28-day endpoint. Obviously there are increased risks of bleeding with drotrecogin alpha, but these are limited. In a study evaluating all reported use of this drug so far, serious bleeding events occurring during the infusion period in 2.8% of patients and during the 28-day study period in 5.3% of patients. Of the bleeding events during the infusion period, 43% were procedurerelated. Patients at high risk of bleeding should not be given drotrecogin alpha (activated) and it is contraindicated in patients with active internal bleeding, recent hemorrhagic stroke, intracranial or intraspinal surgery, severe head trauma, presence of an epidural catheter, intracranial neoplasm or evidence of cerebral herniation. In addition, infusion should be interrupted for surgery or invasive interventions. Importantly, early treatment with drotrecogin alpha (activated) seems to convey a survival advantage, and its use needs to be considered early rather than as a last-resort option. Although expensive, its costeffectiveness profile seems to be in keeping with other commonly used interventions in intensive care. As our understanding of the sepsis response broadens, other immunomodulatory strategies are continually being suggested, developed, and tested. Agents currently attracting interest include anti-oxidants, apoptosis manipulating drugs, and anti-Toll-like receptor 4 (TLR-4) therapies. Hemofiltration strategies with large-pore hemofilters or coupled plasma filtration absorption [11]

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have also been used in the hope that removal of inflammatory mediators may limit the sepsis response. Further study is needed to evaluate the best filter and optimum filtration rates, but this is a promising approach. Corticosteroids Corticosteroid therapy in septic patients has come in from the cold with Annane et al. [1] demonstrating improved survival in patients with septic shock and relative adrenal insufficiency treated with a 50-mg intravenous bolus of hydrocortisone every 6 h and fludrocortisone (50-␮g tablet once daily). So far, this strategy has only been tested in patients with septic shock and whether it also applies to patients with less severe forms of sepsis remains to be seen. In addition, definitions of relative adrenal insufficiency are not clear and if corticosteroid administration is to be guided by ACTH stimulation tests, which test should be used, and when? Glucose Control In a milestone study, Van den Berghe et al. [14] randomized more than 1,500 ICU patients to intensive management aimed at keeping blood sugar levels within tight limits of 80–110 mg/dl vs. conventional management of hyperglycemia; mortality rates were reduced from 8.0 to 4.6% (p ⬍ 0.04) in the intensive treatment group. In addition, intensive treatment was associated with shorter ICU stays, less requirement for renal replacement therapy, less hyperbilirubinemia, fewer bloodstream infections, fewer ICU neuropathies, and a reduced need for transfusion. Further study has suggested that these results were due to the control of glucose levels rather than to the insulin administered. While this strategy seems an attractively cheap and simple means of improving outcomes in our septic patients, additional blood sampling and nursing time can make it more complex and costly than would seem to be the case at first glance. Nevertheless, glucose levels clearly need to be more carefully monitored and adjusted than has perhaps previously been the case.

Conclusion

The last few years have seen exciting developments in the treatment of severe sepsis and septic shock. The standard, and still vitally important, management of severe sepsis relies on adequate resuscitation with fluids and vasoactive agents, eradication of the causative infection using antibiotics and surgical removal where necessary, and individual organ support including renal dialysis and mechanical ventilation. Now, immunomodulatory strategies have

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been shown to be effective at reducing mortality and can now be added to our management protocols. These results are encouraging for all involved in the treatment of sepsis, but do not provide all the answers. For example, as other immunomodulating drugs are developed that also reduce mortality, the challenge will be to decide which agent should be given to which patient? Or will combinations of drugs be needed, and if so which? Genetic typing and improved markers of sepsis may help answer some of these questions. The recently suggested PIRO (predisposition, infection, immune response, organ dysfunction) system of ‘staging’ sepsis is still in the early stages of development but will help to characterize patients, to target treatments, and to monitor response to therapy. Following the positive results from recent trials, the future is certainly looking brighter for the patient with severe sepsis.

References 1

2

3 4

5 6

7 8 9 10

11

12

13

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaut P, Bellissant E: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288: 862–871. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709. Creteur J, Vincent JL: Hemoglobin solutions: Not just red blood cell substitutes. Crit Care Med 2000;28:894–896. De Backer D, Creteur J, Silva E, Vincent JL: Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Crit Care Med 2003;31: 1659–1667. Dieterich HJ: Recent developments in European colloid solutions. J Trauma 2003;54:S26–S30. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250–1256. Martin C, Viviand X, Leone M, Thirion X: Effect of norepinephrine on the outcome of septic shock. Crit Care Med 2000;28:2758–2765. Oliveira RP, Velasco I, Soriano F, Friedman G: Clinical review: Hypertonic saline resuscitation in sepsis. Crit Care 2002;6:418–423. Ricard JD, Dreyfuss D: ARDS controversies: Where do we stand now? in Vincent JL (ed): Yearbook of Intensive Care and Emergency Medicine. Heidelberg, Springer, 2004, pp 419–428. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–1377. Ronco C, Brendolan A, Lonnemann G, Bellomo R, Piccinni P, Digito A, Dan M, Irone M, La Greca G, Inguaggiato P, Maggiore U, De Nitti C, Wratten ML, Ricci Z, Tetta C: A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002;30:1250–1255. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine: Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 1999;27:639–660. The ARDS Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308.

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15 16

Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patient. N Engl J Med 2001;345:1359–1367. Vincent JL: Hemodynamic support in septic shock: Guidelines for the management of severe sepsis and septic shock. International Sepsis Forum. Intens Care Med 2001;27(suppl 1):S80–S92. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D: Anemia and blood transfusion in critically ill patients. JAMA 2002;288:1499–1507.

Prof. Jean-Louis Vincent Department of Intensive Care, Erasme University Hospital Route de Lennik 808, BE–1070 Brussels (Belgium) Tel. ⫹32 2 555 3380, Fax ⫹32 2 555 4555, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 362–375

High Volume Hemofiltration in Critically Ill Patients: Why,When and How? Ciro Tettaa, Rinaldo Bellomob, John Kellumc, Zaccaria Riccid, Robert Pohlmeiera, Jutta Passlick-Deetjena, Claudio Roncod a

Research Extracorporeal Therapies, Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany; bIntensive Care Research and Division of Surgery, Austin Hospital and Melbourne University, Heidelberg, Australia; cUniversity of Pittsburgh School of Medicine, Department of Critical Care Medicine, and MANTRA Laboratories, Pittsburgh, Pa., USA; dDepartment of Nephrology, Dialysis and Transplantation, St Bortolo Hospital, Vicenza, Italy

The systemic inflammatory response syndrome (SIRS) is characterized by widespread endothelial damage caused by persistent inflammation from both infectious and non-infectious stimuli. The host uses hormonal and immunologic mechanisms to counteract SIRS. Hypoperfusion and shock result when homeostatic mechanisms are no longer able to keep the system in balance, leading to organ dysfunction. Septic shock can be defined as sepsis with hypotension, despite adequate fluid resuscitation, along with evidence of multiple organ dysfunction syndrome (MODS). Sepsis is the leading cause of acute renal failure (ARF). The mortality rate of patients requiring dialysis for ARF in the ICU (50–60%) is nearly twice as high as comparable patients without ARF [1, 2]. For example, one large study (17,000 patients admitted to Austrian ICUs) found that ARF was associated with a greater than fourfold increase in mortality [3]. Even after controlling for underlying severity of illness, mortality was still significantly higher in people with ARF (62.8 vs. 38.5%), suggesting that ARF is independently responsible for increased mortality, even if renal replacement therapy is used. The pathogenesis of sepsis is complex. Endotoxins or lipopolysaccharides produce both cellular and humoral effects. Increased levels of plasma cytokines such as tumor necrosis factor-␣ (TNF␣), interleukins (IL-1, IL-6, IL-8 and IL-10), IL-1 receptor antagonist, soluble TNF receptors types I and II

and lipid mediators such as platelet-activating factor (PAF) are produced and are considered to be of pathogenetic relevance [4–6]. Initially, several experimental and clinical approaches attempted to remove (or neutralize) bacterial components or cytokines produced early in the inflammatory response. The major therapeutic approaches (reviewed in [4, 5, 7]) include: • Blocking of microbial products (from gram-negative or gram-positive bacteria; anti-LPS antibodies, antibacterial proteins, circulating proteins). • Blocking of cellular stimulation (soluble CD14, anti-CD14 antibodies, anti-lipopolysaccharide-binding protein). • Blocking of cytokine activity (monoclonal antibodies, soluble receptors). • Removal or neutralization of endotoxin by several strategies aimed specifically at endotoxin removal or neutralization included: blood passage through polymyxin immobilized cellulose filters, antibodies directed against the anti-O side chain antibody, anti-core or anti-lipid A antibodies, or by the use of binding peptides that neutralize or enhance endotoxin clearance. Although many in vitro and animal models provided encouraging results, large-scale clinical trials provided little or no confirmation of clinical benefit derived from the removal of bacterial components. Therefore, there is widespread doubt on the efficacy of LPS removing strategies. In animal models of endotoxic shock, intravenously injected endotoxin disappears rapidly from the plasma (usually in less than 2 h) [8]. It is common, even in these well-defined models, to observe a high degree of individual variability to endotoxin tolerance, cytokine levels, mortality related to dose as well as genetic susceptibility and cytokine polymorphism (fig. 1). The concept of sepsis as a simply proinflammatory event has been subsequently challenged [9–11]. Terms such as ‘monocyte hyporesponsiveness’ or ‘monocyte deactivation’ have been introduced in order to indicate what is manifested as a ‘Compensatory Anti-inflammatory Response Syndrome’ (CARS). As the network acts like a cascade, early intervention would seem most beneficial. On the other hand, sepsis does not fit a one-hit-model but shows complex and multiple increases and decreases in mediator levels over time. Neither single-mediator-directed nor one-time interventions therefore seem appropriate. One of the major criticisms attributed to continuous renal replacement therapy (CRRT) in sepsis – its lack of specificity – could turn out to be a major strength. Non-specific removal of soluble mediators – be they pro- or antiinflammatory – without completely eliminating their effect may be the most logical and adequate approach to a complex and long-running process like sepsis. The concept of cutting peaks of soluble mediators, e.g. through continuous hemofiltration is a paradigm called ‘the peak concentration hypothesis’ [12]. However, removal rates and clearances of pro-inflammatory cytokines by conventional hemodialysis are hindered by limited diffusive or convective rates.

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LBP BPI

Endotoxin Exotoxin Genetic susceptibility

Macrophage monocytes Cytokine polymorphism TNF-␣, IL-1, IL-6, IL-8 Mono/granulocytes

Histamine

Prostaglandins

Endothelial dysfunction

PAF

Elastase

Activation of coagulation

O2-Metabolites

Cell and organ damage

sCD14

C1,C3 activation

Complement activation

SIRS

MODS

Fig. 1. Sepsis represents a complex series of cascade events involving the activation of the innate response, synthesis and release of pro- and anti-inflammatory mediators and the initial functional derangement of vascular endothelium, and activation of the coagulation. These events together with the biological expression of complement activated products (via the C1 classical or C3 alternate pathway) converge to inducing cell and organ functional and anatomical damage thus ensuing in the systemic inflammatory response syndrome (SIRS) and in the multiple organ dysfunction syndrome (MODS). Individual sensitivity to gramnegative endotoxin and gram-positive exotoxin is played by different mechanisms: at the cell-membrane receptor recognition pathway (Toll-like receptors), by the enhancing effect of lipopolysaccharide-binding protein (LBP) in complex with endotoxin and/or the competing clearance role of bactericidal/permeability-inducing protein. Furthermore, cytokine polymorphism (for TNF and IL-10) is associated with increased susceptibility [for review, see refs 52 and 53].

High Volume Hemofiltration (HVHF):Why?

For several years now, the real capability of hemofiltration in removing inflammatory mediators has remained controversial. Numerous ex vivo as well as animal and human studies have shown that hemofilters can extract nearly every substance involved in sepsis to a certain degree [as reviewed in ref. 7]. Prominent examples are complement factors [13, 14] TNF, IL-1, IL-6 [15, 16], IL-8, and PAF [17, 18]. Regarding plasma cytokine levels, their decrease appeared nevertheless of minor degree. Other studies could not show any

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influence on cytokine plasma levels by CRRT [19–22]. Furthermore, even the relevance of plasma cytokines has been questioned (reviewed in [23]). More important is the proof that significant hemodynamic improvement has been achieved even without measurable decreases in cytokine plasma levels [24]. The removal of substances different to the measured cytokines might have been responsible for the achieved effect. Alternatively, bioactive substances including some of the measured cytokines might be removed causing the observed beneficial effect. Nowadays, the removal from plasma of substances exerting measurable biologic effects rather than of a single or a single class of mediators seems more important. Several explanations have been discussed in the recent literature: the removal of the priming effect on polymorphonuclear neutrophils [18], of the myocardial depressant factor(s) [25, 26] and of the endotoxin-mediated pro-apoptogenic activity on myocytes [27]. When the response to sepsis is viewed in a network perspective, absolute values would be less relevant than relative ones within an array of interdependent mediators as even small decreases could induce major balance changes. This makes measurement of cytokine plasma levels debatable while more local or tissue levels should be preferably measured whenever possible. These issues are still extremely controversial. However, these data emphasize that convection and possibly also diffusion may achieve a certain degree of ‘blood purification’. Consequently, it would be logical to try to improve the efficiency of the extracorporeal treatments by increasing the amount of plasma water exchange, i.e. increasing ultrafiltration rates. Animal studies provide great support to this concept. Starting in the early nineties, several studies using different septic animal models examined the effect of high ultrafiltration rates (up to 300 ml/kg/h) on physiological parameters and outcome. In a landmark study, a porcine model of septic shock induced by endotoxin infusion was investigated [28]. The animals developed profound arterial hypotension, a decrease in cardiac output, stroke volume, and right ventricular stroke work index. With HVHF (at 6 liters/h), right ventricular function, blood pressure and cardiac output showed a remarkable improvement compared to control and sham-filtered animals [28, 29]. The same group extended their findings in the same model by i.v. administration of ultrafiltrate from LPS-infused animals into healthy animals. The animals receiving ultrafiltrate from endotoxemic animals rapidly developed hemodynamic features of septic shock while animals infused with ultrafiltrate from healthy animals showed a moderate blood pressure rise [28]. In a further study by the same group, a bowel ischemia-reperfusion model in pigs was investigated. HVHF started before clamping of the superior mesenteric artery significantly diminished bowel damage and prevented hemodynamic deterioration [30].

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These studies established that a convection-based treatment can remove substances with hemodynamic effects resembling septic shock, when sufficiently high ultrafiltration rates are applied [31, 32]. Several animal studies confirmed and refined these results. In three of them [33–35], the correlation of survival with ultrafiltration rate was demonstrated. Significant improvements in cardiac function, systemic and pulmonary vascular resistance, and hepatic perfusion were found. Another study in lambs showed significant improvements in lung function [36]. A study in pigs made septic by induced pancreatitis compared low-volume hemofiltration with HVHF at 100 ml/kg/h of ultrafiltrate. In this study, the influence of frequent filter changes on survival, changes in TNF levels as well as monocyte and polymorphonuclear neutrophil function were analyzed [35]. Early filter change was used to delineate the effect of cytokine removal by adsorption on the filter since membrane capacity was saturated after a few hours. By changing filters, adsorption continued to a certain extent. In this model, a hyperdynamic septic state was induced through an intervention which approximates the underlying conditions encountered in human sepsis. Additionally, the intervention started late to simulate real clinical conditions. Hemofiltration was commenced when the animals had already developed the clinical picture of hyperdynamic septic shock. HVHF was superior for all measured endpoints. Of relevance, increasing ultrafiltration had more effect than frequency of filter change [35]. Closer to human sepsis has been the finding that the ultrafiltration dose is correlated to outcome in critically ill patients with ARF. In a large randomized, controlled study including 425 patients, an ultrafiltration dose of 35 ml/kg/h increased survival rate from 41 to 57% compared to a dose of 20 ml/kg/h [37]. Eleven to 14% (per randomization group) of the patients had sepsis. In these subgroups there was a trend of a direct correlation between treatment dose and survival even above 35 ml/kg/h in contrast to the whole group where a survival plateau was reached. This lends support to the concept of a ‘sepsis dose’ of hemofiltration in septic patients contrasting to a ‘renal dose’ in critically ill patients without systemic inflammation, the former being probably distinctly higher (without proven upper limit). Of note, there was no increase in adverse effects even with the highest ultrafiltration dose [38]. Over the last few years several human studies have examined the clinical effects of HVHF. In 20 children undergoing cardiac surgery, zero-balanced HVHF was administered with UF rates equivalent to 7–9 liters/h for a 70-kg adult [39]. Cytokine plasma levels and clinical endpoints associated with the cardiopulmonary bypass were examined. There was a significant reduction in postoperative blood loss, time to extubation and improvement in the alveolar to arterial oxygen gradient as well as reduction of cytokine plasma levels at different time points.

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In a prospective cohort study, observed and predicted mortality was compared in prospectively stratified prognostic groups (306 critically ill patients with varying underlying diseases) treated with a mean ultrafiltration rate of 3.8 liters/h [40]. Observed survival rates were significantly higher in the treated population compared to predicted survival by three well-validated scores. In another trial in 11 septic patients with shock and MODS, a randomized cross-over design of 8 vs. 1 liter/h ultrafiltration was applied [41]. The HVHF group displayed significantly greater reduction in vasopressor requirements. Both treatment groups showed a decrease in C3a and C5a plasma levels which was significantly greater in the HVHF group. Impressive clinical results were obtained in an evaluation of short-term HVHF in 20 patients in catecholamine-refractory septic shock comprising a patient cohort with very poor expected survival [42]. A control group was not defined. Only one 4-hour session of HVHF removing 35 liters of ultrafiltrate replaced by bicarbonate-containing fluid was applied as soon as mean blood pressure could not be stabilized above 70 mm Hg with dopamine, norepinephrine and epinephrine after appropriate volume resuscitation. HVHF was followed by conventional continuous venovenous hemofiltration (CVVH). Endpoints included an increase in cardiac index, mixed venous oxygen saturation and arterial pH and decrease in norepinephrine requirements. Eleven patients reached all predefined endpoints and showed impressively good survival (9 of 11) at 28 days. Nine patients did not reach all endpoints and had a 100% mortality rate. Apart from responding to HVHF, only time from admission to start of HVHF and body weight were survival-associated factors in the analysis. Patients with higher body weight did worse possibly because they received a smaller ultrafiltration dose per body weight as discussed by the authors [42]. Furthermore, time to start treatment also appeared to be correlated with higher mortality [42]. These trials should be interpreted with caution with respect to their limited design but they certainly deliver sound evidence of feasibility and efficacy to set the stage for a large-scale trial on HVHF in sepsis. Studies comparing HVHF and standard CVVH often lack the statistical power. In their studies, Bouman et al. [43] showed no difference in 28-day mortality and recovery of renal function between early (within 12 h from ARF appearance) HVHF, early standard CVVH and late standard CVVH. In this population, survival was very high compared to other reports, and recovery of renal function was 100% in all hospital survivors. Due to the high clearance, HVHF was at least not less effective in the study endpoints with the noteworthy advantage that in case of need (for logistic reason, medical needs etc), it could be interrupted. However, this study lacks the statistical power and was performed in a restricted number of closed format ICUs.

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Despite the positive results of the Ronco trial [37], the practice of higher intensity CRRT has not been widely adopted in the common practice of ICUs. In Australia and New Zealand, almost 100% of treatments are continuous therapies (CVVH or continuous venovenous hemodiafiltration, CVVHDF). A survey of several units active in the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group (CTG) found that very few (⬍3) units had adopted the intensive CRRT regimen proposed by Ronco’s study [37; Bellomo, unpubl. data, 2002]. Data from such Australian units shows instead that the vast majority (⬎90%) prescribes a ‘fixed’ standard therapy dose of 2 liters/h which is not adjusted for body weight. Thus, a 100-kg man would receive 20 ml/kg/h, the dose shown to have the worst outcome in Ronco’s study [37]. In another recent study that involved several Australian units [‘BEST kidney study’ – Bellomo et al., in press], the median body weight for Australian patients was 81 kg, thus indicating that the vast majority receive a CRRT intensity of approximately 25 ml/kg/h of effluent. Finally, while in Ronco’s study [37], the technique of CRRT was uniform as CVVH with post-filter fluid replacement, current practice in Australia includes a variety of techniques with CVVH in the pre-dilution mode representing perhaps 80% of techniques in use and CVVHDF representing most of the remainder. There is some awareness of Ronco’s study [37] in the Intensive Care community but specialists reported having doubts over the applicability of the results to the wider Intensive Care population. Major concerns relate to the somewhat unusual patient population studied (very low incidence of sepsis which, on the other hand, dominates as the major cause of ARF in Australia), the fact that the study was conducted over 5 years, the fact that the typical dose of CRRT in Australia is already on average 20% greater than the lowest dose prescribed in the study, the additional cost of intensifying therapy, and great concern about extrapolating the results of an unblinded, single-center study to the wider Australian Intensive Care population. Thus, the findings of this study have not induced a change in practice despite the potential survival benefits of more intensive continuous therapies. In essence, HVHF has been found to produce unexpected physiological benefits in terms of ‘blood purification’ on different surrogate outcome measures in both animal and human studies. However, the real benefit (i.e. on survival) still needs to be proven.

HVHF:When?

The initial hemodynamic improvement with HVHF seems to be maintained over the next 96 hours, with a significant decrease in norepinephrine

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ml/h

9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0

85ml/h/kg

35ml/h/kg

50

70 Weight (kg)

Fig. 2. The relevance of relating effluent volumes to body weight is shown here. In a 70-kg patient, 6 liters/h.

requirement (more than 70%) [42]. The reason for the reduction of norepinephrine requirement has not been clarified as this seems to be independent of the fluid balance and the decrease in body temperature. Removal of sedative drugs with vasodilatory effect such as midazolam and sufentanil has not extensively been studied. However, for morphine, only 1–3% of the infused dose is removed by high efficiency, high flux hemodialysers [44]. The removal of mediators is likely to play a role. Filtration volume is an important factor influencing the efficacy of the technique. A sequence of adsorption and filtration was shown with platelet-activating factor using high permeability polysulfone membranes [17]. The question of when to start the treatment is obviously related to the major indication for initiating HVHF, i.e. restoring hemodynamic stability. Thus, HVHF could become the elective treatment in hemodynamically unstable patients. Treatment should be started as early as this is possible as this was clearly shown to affect survival rates [45]. We have proposed the concept of HVHF in the framework of a ‘pulse therapy’ (fig. 2). This concept meets also with practical and technical considerations. A daily schedule of HVHF (85 ml/kg/h) associated with CVVH (at 35 ml/kg/h) leading to a cumulative dose of approximately 48 ml/kg/h (in a 70 kg patient) would be practical and less costly. This schedule is now under clinical investigation. HVHF: How?

To reach ultrafiltration rates such as 50–60 ml/kg/h, two major determinants of ultrafiltration need to be considered. A high blood flow rate (as compared to conventional CRRT) requires a vascular access (e.g. 14 F catheters) to attain a constant flow of 300 ml/min. A filtration fraction of 25% can then be

The Rationale of High Volume Hemofiltration

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370

Edwards

Baxter

Braun

Medica

Bellco

Infomed

Kimal*

Rand

Hospal

FMC

BM25

BM25

Diapact

Equa-smart

Multimat

HF 400*

Hygeia plus

Performer

Prisma

Multifiltrate*

4

4

4

4

4

2 or 3

3

3

3

3

4

4

Pumps

10–500

0–180

5–500

0–500

0–450

0–400

5–400

10–500

30–500

30–500

0–450

0–450

Blood flow

Blood warm yes

yes

yes

yes

no

yes

yes

no

no

yes

yes

Heater

yes

yes

yes

yes

yes

yes

yes

no

no

no

yes

yes

Heparin pump

Pre-Post-Pre/ Post Pre-Post-Pre/ Post

Pre-Post-Pre/ Post Pre-Post-Pre/ Post Pre-Post

Pre-Post

Pre-Post

Pre-Post

Pre-Post

Pre-Post-Pre/ Post Pre-Post-Pre/ Post Pre-Post

Reinfection site

4

3

1

volumetric

2

1

3

1

2

2

2

2

Scales

SCUF/CVVH/HVHF/CVVHD/ CVVHDF/MPS(PEX)/HP - ped SCUF/CVVH/HVHF/CVVHD/ CVVHDF/MPS(PEX)/HP - ped SCUF/CVVH/CVVHD/ PEX - ped SCUF/CVVH/CVVHD/ PEX - ped IHD/IHFD/IHF/Pex/SCUF/ CVVH/CVVHD/CVVHDF SCUF/CVVH/HVHF/CVVHD/ CVVHDF/MPS(PEX)/HP - ped SCUF/CVVH/HVHF/CVVHD/ CVVHDF/CPFA SCUF/CVVH/CVVHD/CVVHDF/ HVHF/MPS(PEX)/HP - ped SCUF/CVVH/CVVHD/ CVVHDF/MPS(PEX)/HP - ped SCUF/CVVH/CVVHD/CVVHDF/ MPS(PEX)/HP - ped SCUF/CVVH/CVVHD/ CVVHDF/MPS(PEX)/HP - ped SCUF/CVVH/HVHF/CVVHD/ CVVHDF/MPS(PEX)/HP - ped

Available treatments

SCUF ⫽ Slow continuous ultrafiltration; CVVH ⫽ continuous venovenous hemofiltration; HVHF ⫽ high volume continous venovenous hemofiltration; CVVHD ⫽ continuous venovenous hemodialysis; CVVHDF ⫽ continuous venovenous hemodiafiltration; MPS ⫽ membrane plasma separation for plasmapheresis (PEX) or hemoperfusion; CPFA ⫽ coupled plasma filtration adsorption; ped ⫽ indicates whenever pediatric treatments can be performed. The asterisk indicates the monitors that may perform HVHF. Information derived from Company brochures and from ref 48.

Baxter

Edwards

Aquarius*

Accura*

Company

Monitors

Table 1. Technical features of commercially available CRRT monitors

b

a c Fig. 3. New technology for HVHF. The example of MultiFiltrate (Fresenius Medical Care) is shown. a Two integrated heating systems (35/39⬚C) with fast, effective temperature control. b 4 high precision scales with on-line continuous testing with a capacity up to 24 liters HF solution; C ⫽ cassette for easy, quick line system set-up.

set. Bicarbonate buffered hemofiltration fluid (35 mmol/l) should be administered 1/3 in predilution and 2/3 in post-dilution [46]. A highly biocompatible, synthetic membrane and a dialyzer surface of 1.8–2 m2 (in 70-kg patients) should be considered. Pre-dialyzer pressures can be informative in the early stages of dialyzer clotting [47]. In this context, the membrane biocompatibility and the dialyzer geometry are important. High pre-dialyzer pressures especially in HVHF will inevitably impact negatively on dialyzer life, making the technique cumbersome, increasing patient’s risk and the staff workload. For several years, the major hindrance to the widespread use of HVHF has been the lack of reliable monitors capable of insuring safety, precision and continuation of this therapy. On the other hand, the controversy on the real advantages and the increased costs of the therapy did not immediately persuade industry on such a therapy [48]. Nowadays, different monitors from different manufacturers exist and are available. Table 1 lists the different features of commercially available monitors. Figure 3 provides an example of how continuous therapy monitors have developed in order to make HVHF practical. Some important hardware and software aspects must be considered such as high precision scales (equipped with software for on-line continuous testing and a high capacity) and powerful heating systems for maintaining constant sufficiently high temperature of the high volumes of infusion solution. The practice of HVHF needs adequate tailoring of the therapy. Uchino et al. [49] studied the effect of changing the amount of pre-dilution replacement fluid on the sieving coefficient (SC) and mass transfer of small solutes during isovolemic HVHF. These authors interestingly concluded with the warning that

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during isovolemic HVHF, small solute sieving coefficients and mass transfer (sodium, potassium, chloride, total calcium, total magnesium, phosphate, total CO2, urea, creatinine and glucose) are significantly affected by the proportion of replacement fluid administered pre-filter. Isovolemic HVHF is neither isonatremic nor isochloremic and requires close monitoring of sodium, glucose, and acid-base balance. Conclusion

A vast array of mostly water-soluble mediators play a strategic role in the septic syndrome. At variance with targeting single mediators, therapeutic intervention aiming at the non-selective removal of pro- and anti-inflammatory mediators seems a rational concept. Therefore, sequentially appearing peaks of systemic mediator overflow could be curbed as well as persistently high plasma levels reduced. Antagonizing pro- and anti-inflammatory processes by reducing the relative excess of active substances could be summarized under the term of ‘peak concentration hypothesis’. Recent animal and human trials have delivered much support to this concept. It has been conclusively shown that treatment dose in continuous therapies is a major factor influencing survival in the critically ill patient with ARF. Accumulating evidence suggest that HVHF compared to conventional CVVH improves laboratory severity markers and clinical outcome, i.e. survival. Monitors to perform HVHF safely are now available. Yet the evidence still is not strong enough to recommend HVHF outside clinical studies taking into account possible adverse effects of the technique. A large-scale clinical trial is urgently needed to resolve the issue. Other blood purification techniques using large pore membranes or plasma filtration with adsorbent perfusion are in the early stages of clinical testing [50, 51]. They are conceptually promising and possibly constitute an important refinement. Acknowledgment The authors would like to thank Dr. S. Civardi and M. Brambilla for providing useful information.

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Pathan N, Sandiford C, Harding SE, Levin M: Characterization of a myocardial depressant factor in meningococcal septicemia. Crit Care Med 2002;30:2191–2198. Pathan N, Hemingway CA, Alizadeh AA, et al: Role of interleukin 6 in myocardial dysfunction in meningococcal septic shock. Lancet 2004;363:203–209. Carlson DL, Lightford E, Bryant DD, et al: Burn plasma mediates cardiac myocyte apoptosis via endotoxin. Am J Physiol 2002;282:H1907–H1914. Grootendorst AF, van Bommel EFH, van der Hoven B, van Leengoed LAM, van Osta ALM: High volume hemofiltration improves right ventricular function of endotoxin-induced shock in the pig. Intens Care Med 1992;18:235–240. Grootendorst AF, van Bommel EFH, van der Hoven B, et al: High volume hemofiltration improves hemodynamics of endotoxin-induced shock in the pig. J Crit Care 1992;7:67–75. Grootendorst AF, van Bommel EFH, van Leengoed LAM, et al: High volume hemofiltration improves hemodynamics and survival of pigs exposed to gut ischemia and reperfusion. Shock 1994;2:72–78. Grootendorst AF, van Bommel EF, van Leengoed LA, et al: Infusion of ultrafiltrate from endotoxemic pigs depresses myocardial performance in normal pigs. J Crit Care 1993;8:161–169. Nagashima M, Shin⬘oka T, Nollert G, et al: High-volume continuous hemofiltration during cardiopulmonary bypass attenuates pulmonary dysfunction in neonatal lambs after deep hypothermic circulatory arrest. Circulation 1998;98(suppl 19):II378–II384. Lee PA, Matson JR, Pryor RW, Hinshaw LB: Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine. Crit Care Med 1993;21:914–924. Rogiers P, Zhang H, Smail N, et al: Continuous venovenous hemofiltration improves cardiac performance by mechanisms other than tumor necrosis factor-alpha attenuation during endotoxic shock. Crit Care Med 1999;27:1848–1855. Yekebas EF, Eisenberger CF, Ohnesorge H, et al: Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis. Crit Care Med 2001;29:1423–1430. Nagashima M, Shin⬘oka T, Nollert G, et al: High volume continuous hemofiltration during cardiopulmonary bypass attenuates pulmonary dysfunction in neonatal lambs after deep hypothermic circulatory arrest. Circulation 1998;98(suppl 19):II378–II384. Ronco C, Bellomo R, Homel P, et al: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000; 356:26–30. Chertow GM, Lazarus JM, Paganini EP, et al: Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Failure Study Group. J Am Soc Nephrol 1998;9:692–698. Journois D, Israel Biet D, Pouard P, et al: High-volume, zero-balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85: 965–976. Oudemans-van Straaten HM, Bosman RJ, et al: Outcome of critically ill patients treated with intermittent high-volume hemofiltration: A prospective cohort analysis. Intens Care Med 1999;25: 814–821. Cole L, Bellomo R, Journois D, et al: High-volume hemofiltration in human septic shock. Intens Care Med 2001;27:978–986. Honore PM, Jamez J, Wauthier M, et al: Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 2000;28:3581–3587. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J: Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med 2002;30:2205–2211. Jamal JA, Hoh J, Bastani B: Removal of morphine with the high-efficiency and high-flux membranes uring hemofiltration and heamodiafiltration. Nephrol Dial Transpl 1998;13:1535–1537. Rivers L, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;145:1368–1377.

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Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R: Pre-dilution vs. post-dilution during continuous veno-venous hemofiltration: Impact on filter life and azotemic control. Nephron Clin Pract. 2003;94:c83–c84. Pacitti A, Cantaluppi V, Fenoglio R, et al: Continuous hemofiltration with polyethersulfone membranes evaluated by tele-monitoring. Contrib Nephrol. Basel, Karger, 2003, vol 138, pp 126–143. Bellomo R, Balwin I, Ronco C, Golper T: Atlas of Hemofiltration. London, Saunders, 2002. Uchino S, Cole L, Morimatsu H, et al: Solute mass balance during isovolaemic high volume haemofiltration. Intens Care Med 2003;29:1541–1546. Epub 2003 Jul 10. Morgera S, Haase M, Rocktaschel J, et al: High permeability hemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial Transplant 2003;18:2570–2576. Tetta C, D’Intini V, Bellomo R, et al: Extracorporeal treatments in sepsis: Are there new perspectives? Clin Nephrol 2003;60:299–304. Stuber F, Petersen M, Bokelmann F, Shade U: A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996;24:381–384. Stuber F: Another definite candidate gene for genetic predisposition of sepsis: Interleukin-10. Crit Care Med 2003;31:314–315.

Ciro Tetta, MD Research Extracorporeal Therapies, Fresenius Medical Care Deutschland GmbH Else Kroener Strasse 1, DE–61352 Bad Homburg (Germany) Tel. ⫹49 6172 609 2417, Fax ⫹49 6172 609 2314, E-Mail [email protected]

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Coupled Plasma Filtration Adsorption: Rationale, Technical Development and Early Clinical Experience Alessandra Brendolana, Claudio Roncoa, Zaccaria Riccia, Valeria Bordonia, Monica Bonelloa, Vincenzo D’Intinia, Mary Lou Wrattenb, Rinaldo Bellomoc a

Department of Nephrology, St. Bortolo Hospital, Vicenza, and Scientific Research Department, Bellco SpA, Mirandola (MO), Italy; Department of Intensive Care, Austin and Repatriation Medical Centre, Melbourne, Australia b

Treatment Rationale: Learning from Past Lessons ‘only by rethinking the assumptions underlying the failed treatments for sepsis can we hope to make strides in saving patients from sepsis induced death’ R. Bone 1996 [1]

We still lack a good definition of sepsis. There have been many attempts to better define clinical symptoms, categories and scoring systems, however as time passes the definitions always seem to grow more complex in spectrum. Early attempts at treatment met with failure due to over-simplistic approaches to treatment. It was thought that, if an infectious agent was responsible for sepsis, early intervention by neutralizing the infectious agent or a component of the early phases of the inflammatory cascade would result in prevention of the secondary symptoms. Often, in animal models that utilized targets towards specific mediators or endotoxin, such approaches had some success, due to the controlled nature of the experiment. These ‘magic bullets’ often stirred excitement within the medical community, only to be met with great disappointment after their failure during human clinical trials. Other attempts to define sepsis looked at more systemic approach to the pathology. Pinsky [2] suggested that sepsis was a ‘malignant form of intravascular

Blood in Plasmafiltration unit Plasma Resin target

Excess mediators Normal physiological range

Unit for

Hemofiltration Hemodialysis Hemodiafiltration

Blood out

Fig. 1. Schematic diagram of CPFA. The plasmafilter separates the plasma. This passes through the resin cartridge and is returned to the patient after depurification. The resin adsorbs various inflammatory mediators by non-specific adsorption. The target molecules for adsorption are all of the excess pro- and anti-inflammatory mediators.

inflammation’. Others have suggested that it may be more of ‘a type of disseminated local inflammation in which the actual process occurs at the tissue level’ [3]. In this case, the increase in plasma cytokines is thought to originate from ‘spillage’ from the local sites into the circulation with consequent disseminated inflammation. What seems to be the accepted operating paradigm at this time is that sepsis is an exaggerated immune response to infection that includes the production and release of a wide array of both pro- and anti-inflammatory molecules. Coupled plasma filtration adsorption (CPFA) is an extracorporeal therapy that utilizes a plasma filter to separate plasma from the blood and then allows passage of the separated plasma through a sorbent cartridge for the nonspecific removal of various mediators [4–8]. After purification, the plasma is returned to the blood. The blood can then pass through a hemodialyzer/hemofilter for additional blood purification by conventional hemodialysis, hemofiltration or hemodiafiltration in patients who have acute renal failure (fig. 1). The treatment goal of CPFA is to target the excess in circulating mediators (both proand anti-inflammatory molecules) in order to restore normal immune function.

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Infectious or initiating agent

Tissue/organ injury

Activation of inflammation

Microcirculatory injury

Activation of signal pathways

Endothelial injury

Proinflammatory cytokines

Antiinflammatory cytokines

Margination of neutrophils

Chemoattractants

Immunosuppression

Systemic activation of monocytes

Inappropriate monocyte hypo-responsiveness

Fig. 2. Different steps in the evolution of sepsis.

Figure 2 shows a diagrammatic scheme of inflammatory cell activation and hyporesponsiveness and how these may relate to the amplified response seen in septic patients. The development of CPFA was a complex process that underwent numerous evolutionary changes to find a suitable resin with good adsorption for a wide variety of mediators and at the same time suitable for extracorporeal therapy. Historically, the use of resins or sorbents appeared an attractive concept to achieve blood purification. Hemoperfusion was used in animals as early as 1948 to test the removal of urea with an Amberlite ion exchange resin [9]. This was followed by the use of a lactated anion exchange resin by Schreiner in 1958 for a patient with pentobarbital poisoning and various other attempts in the mid1960s [10–13]. These early trials were associated with severe side effects which included hemolysis, electrolyte disturbances, pyrogenic reactions and thrombocytopenia. Attempts to increase the biocompatibility of such resins by external coating of the matrix often led to compromises in adsorption efficacy. Today there is a renewed interest in the use of sorbent techniques to complement other types of extracorporeal blood purification therapies. There are a wide range of commercial adsorption therapies ranging from specific adsorption

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therapies such as a polymyxin B endotoxin adsorbing resin to more generalized or combination systems for artificial liver support devices [14–18].

How Do Sorbents Work?

The resin used in the CPFA sorbent cartridge was chosen based on its adsorption capacity for inflammatory mediators, low levels of extractable toxins/metals and good pressure flow performance. This section will describe in greater detail some of the basic characteristics of the sorbent cartridge and the mechanisms responsible for the inflammatory mediator removal. The resin used in CPFA sorbent cartridge is a synthetic cross-linked styrenic divinylbenzene resin. This type of resin is used in diverse processes ranging from laboratory chromatography to industrial purification of foods, beverages and pharmaceuticals. The resin is well suited for extracorporeal applications because of its high homogeneity, good pressure-flow performance, and excellent mechanical and chemical stability. In addition to its mechanical properties, the choice of this particular resin was based on several different factors related to its capacity to adsorb a wide variety of inflammatory mediators and its adsorption characteristics during different flow rates. In this regard, it may be useful to compare the processes that occur during the adsorption of mediators with CPFA to similar processes that occur in traditional chromatography (table 1). Chromatography is commonly used to separate molecules from a complex mixture. There are many factors that can influence this process and many of the important factors are summarized in table 2. Traditional column chromatography has two important phases: the mobile phase (the fluid or solvent that moves through the column) and the stationary phase (the ‘resin’ or matrix). The active sites of the stationary phase interact with the functional groups of the compound to be separated by noncovalent bonds, nonpolar interactions, Van der Waals forces and hydrophobic interactions. The less tightly bound compounds are eluted out by the mobile phase at an earlier time allowing different classes of compounds or molecules to be separated. The mobile phase can be easily changed by using a combination of different solvents. In the case of CPFA, the patient’s plasma is a complex milieu that contains a wide variety of excess mediators – as well as lipids, proteins and other physiologically important molecules. The patient’s plasma can be considered the mobile phase and the treatment goal is to maximize the interaction of the mediators with the resin so that they will prefer the resin and be retained the cartridge. This is not an easy task as the excess inflammatory mediators have a wide range of sizes and different physicochemical properties.

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Table 1. Comparison between chromatography and CPFA resin adsorption Chromatography

CPFA (resin adsorption)

• Separate molecules from a complex

• Separate and retain pro- and anti-

• •

mixture Molecules of interest leave the column at different times depending on the affinity for either the resin or the mobile phase Eventually all molecules are usually eluted from the column/resin

• Works with well-defined mobile phase that can be modified by the user (polarity, mixed solvents, pH, salt concentration)

•

inflammatory molecules that are produced in excess of normal physiological levels The primary treatment goal is to retain excess molecules within the resin. A secondary goal is the eventual restitution of physiological molecules and the avoidance of large amounts of exogenous reinfusion fluid

• In this case – the mobile phase is actually the patient’s plasma

• This creates a unique milieu that varies from individual to individual and that can change over the treatment period

There are several factors that are important in determining the resin’s adsorption efficacy. These include: the type of resin, the size of the resin bead and the internal pores of the resin bead. Resins vary greatly in their chemical properties. The resin used for CPFA is a reverse phase type resin that interacts with hydrophobic sites on the molecule. The pore size can be important as pore dimensions limit the size of the molecules that can cross them. An important concept related to the molecule’s size is the Stokes’ radius (fig. 3). In aqueous solutions, molecules rotate around their center of gravity – describing a sphere that corresponds to their effective size. The radius of this ‘sphere’ governs the molecules’ access to the matrix pores. The capacity of the resin refers to the quantity of a given molecule that is adsorbed by a specific quantity of resin.

In vitro Experiments

The resin for CPFA was initially tested under static conditions to determine the binding capacity for pro- and anti-inflammatory mediators. Individual mediators were first tested by adding a known quantity of the mediator to saline and observing the adsorption to a small quantity of resin in a test tube. The adsorption could then be easily measured by monitoring the concentration in the supernatant. This method allowed a general assessment of adsorption for a wide variety of inflammatory mediators and different sorbents. Some of the

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Table 2. Factors affecting adsorption What influences adsorption/elution? The Molecule of Interest size charge hydrophobicity charge

The Resin particle size pore size resin type charge

The Mobile Phase salt pH polarity

Column resin quantity geometry linear velocity resin capacity packing

300

Adsorption

250 200 150 100 50 0 50

100

150

200

Linear velocity

Fig. 3. Linear velocity is related to the speed at which fluid – and thus sample components – moves along a flow path. The figure shows the binding of an inflammatory mediator to three different resins at various linear velocities. Some resins have good binding over a wide range of linear velocities, where others have a sharp decrease in binding at high linear velocities.

various sorbents that were tested included activated carbon, ion exchange resins and several reverse phase resins with varying bead and pore dimensions. The next step involved adding the inflammatory mediators to healthy control plasma, incubating this with a small amount of resin and then monitoring the supernatant. Not surprisingly, the adsorption can change dramatically when incubated with saline versus plasma. An example of this difference was found for the high binding of ␣2-macroglobulin from plasma. This protein has a high affinity for several cytokines. In some cases, cytokines that had only moderate binding to the resin in saline showed dramatically improved binding after they were added to plasma. It appeared that this was a consequence of the fact that ␣2-macroglobulin was able to bind to the resin and subsequently the cytokine became bound to the ␣2-macroglobulin. Thus, the resin became an effective remover of cytokines in plasma not through direct cytokine binding but through an intermediary step. A final step for the completion of static measurements

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Linear structure

Globular structure

Fig. 4. Stokes’ radius of proteins with similar molecular weights but different stokes’ radii.

included incubating whole blood with endotoxin to produce a wide array of inflammatory mediators, isolating the plasma and then incubating the plasma with the resin in the test tube. All of these different static tests helped choose resins that have a good capacity for the molecules of interest. After several resins were chosen for their adsorptive capacity, they were then evaluated for safety (leachable toxins or metals), ability to be sterilized and mechanical stability. The optimization of flow and column geometry is a parameter that also greatly influences adsorption efficacy. The linear velocity is a term that describes the relationship between fluid speed (and thus the sample components) and a flow path. It is typically reported as cm/hr. Since the linear velocity is related to the square of the column radius- it is directly influenced by sample flux through the column and the column radius. Linear velocity ⫽

flux cm 3 /h area cm 2

Some resins have good adsorption of a particular molecule over a wide range of linear velocities, while others may have a dramatic decrease in adsorption as the linear velocity increases (fig. 4). This translates into an important point related to plasma adsorption: there is a balance between the volume of plasma being treated and the plasma contact time with the resin. Decreased adsorption efficacy is often observed if plasma flow rate becomes too fast. Figure 2 shows the influence of linear velocity on sample adsorption for three different resins for an inflammatory mediator. In some cases the adsorption is quite high at low linear velocities, but the adsorption is greatly diminished at higher linear velocities. It is also possible to see the relationship of column diameter by comparing the diameters of a ‘thin’ column of 4 cm to a ‘wide’ column of 8 cm. If there is a flux of 50 ml/min, this will give a linear velocity of 238 cm/h for the ‘thin’ column and 60 cm/h for the ‘wide’ column. A small change in column diameter can greatly influence the linear velocity and adsorption, even if the flow rates are similar. The next series of experiments evaluated resin adsorption under flow conditions in vitro. For these experiments small cartridges were constructed to

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enable testing of various resins under the same linear velocity as those expected during plasma filtration (about 20 ml/min). The parameters that were important with these experiments were overall adsorption of mediators in both plasma and saline, good flow performance without any increases in pressure and the absence of fines or small particles that could clog the external safety filter. After careful consideration of the static and dynamic in vitro results, the resin that gave the best overall performance was a 100-␮m reverse-phase resin with an average pore diameter of 30 nm.

Animal Studies

A rabbit model for endotoxic shock was used to determine whether the use of coupled plasma filtration and adsorption could reduce 72-hour mortality [19]. Rabbits were subdivided into groups to receive endotoxin plus CPFA, endotoxin with plasma filtration (no resin), CPFA only (no endotoxin) or CPFA plus endotoxin. The rabbits were anesthetized, cannulated and underwent 3 hours of treatment. Plasma concentrations of endotoxin, bioactive tumor necrosis factor, resin-adsorbed platelet-activating factor, mean arterial pressure, base excess, and white cell count were assessed and a global severity score was established. At 72 h, cumulative survival was significantly (p ⫽ 0.0041) improved in septic rabbits treated with coupled plasma filtration-adsorption, and cumulative survival of the resin with LPS group was not significantly different (p ⬎ 0.05) from that of the control groups (plasma filtration or CPFA without any endotoxin). One of the more surprising results of the study was that survival was not directly correlated with any single parameter (endotoxin, cytokine, MAP, etc.). Only the global severity score based on severity of several different parameters was inversely correlated with survival. This supports the current trend to a more global treatment of sepsis rather than restricting treatment to specific removal strategies.

Human Clinical Studies

There have been two recent studies using CPFA for septic patients. The first study by Ronco et al. [20] was a pilot cross-over study that compared CPFA to hemodiafiltration by measuring hemodynamics and immune responsiveness in acute renal failure patients with septic shock. In this study, patients were randomly assigned to10 h of treatment using CPFA followed by 10 h of hemodiafiltration (or vice versa). These authors observed a significant improvement in hemodynamics with the use of CPFA compared to

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hemodiafiltration. They also observed a significant increase in leukocyte responsiveness after CPFA treatment. For these experiments they monitored spontaneous and endotoxin stimulated leukocyte TNF␣ production after 10 h of treatment. At the beginning of the treatment there was a marked leukocyte hyporesponsiveness to endotoxin stimulation (immunosuppression). As the treatment progressed the responsiveness increased. Further support for the role of CPFA in the restoration of immune responsiveness was observed by incubating pre- and post-resin plasma with monocytes obtained from healthy donors. The pre-resin plasma at the beginning of treatment had a strong immunosuppressive effect – unless the plasma was first incubated with monoclonal antibodies to IL10. In contrast, the post-resin plasma (at the beginning of treatment) produced higher quantities of TNF␣ after endotoxin challenge, and nearly normal quantities after the 10-hour treatment. One of the interesting observations of this study was that there were no significant changes in circulating plasma levels of IL10 or TNF␣, even though there was almost complete adsorption of these cytokines by the resin cartridge. This suggests that there may still be other factors that are adsorbed by the cartridge that play a role in immunosuppression. For this reason, the results presented in this study may be particularly relevant as the end point of the study was restoration of immune responsiveness, rather than a net increase or decrease in specific inflammatory mediators. A second clinical study using CPFA was conducted by Formica et al. [21]. This study examined the effect of repeated applications of CPFA on the hemodynamic response in septic shock patients. One of the unique aspects of this study was that both ARF and non-ARF patients were eligible if they met the enrollment criteria. All patients had a high APACHE II score (24.8 ⫾ 5.6) and multi-organ failure. Six of the 10 patients had normal renal function. The authors performed 10 consecutive sessions and observed a net decrease in vasopressor requirement, increased mean arterial pressure and decreased C reactive protein. The patients treated with CPFA had a 70% survival. Although the sample size was small for both clinical studies, they both showed improved hemodynamics and good treatment tolerance. Further studies are needed to better identify patient groups that may benefit from early intervention in the complex interactions between various immunosuppressive and inflammatory mediators.

Conclusion

Sepsis is a leading cause of ARF in ICUs, however the use of extracorporeal blood purification techniques in non-ARF septic patients remains

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controversial [3, 22, 23]. Current guidelines, for example, state that ‘hemofiltration should not be used in patients with sepsis without renal indications unless ongoing studies provide positive results’ [24]. The role of plasma exchange remains equally controversial [25, 26]. In contrast, the initial findings with CPFA are consistent and provide provocative observations, which will no doubt encourage clinical investigators to further pursue the path of blood purification. It may be that CPFA will be the first non-renal blood purification technique to be tested in a phase IIb multicentre randomized controlled trial for the treatment of severe sepsis and multiorgan failure.

References 1 2

3 4 5 6

7

8 9 10 11

12 13 14 15 16

17 18

Bone R: Why sepsis trials fail. JAMA 1996;276:565–566. Pinsky M: Multiple systems organ failure: Malignant intravascular inflammation; in Pinsky M, Matuschak G, (eds): Critical Care Clinics, Multiple Systems Organ Fialure, vol 5, 1989, pp 195–198. Kellum J, Bellomo R: Hemofiltration in sepsis: Where do we go from here? Crit Care 2000;4:69–71. Bellomo R, Tetta C, Ronco C: Coupled plasma filtration adsorption. Intensive Care Med 2003;26:26. Bellomo R, Tetta C, Brendolan A, Ronco C: Coupled plasma filtration adsorption. Blood Purif 2002;20:289–292. Brendolan A, Bellomo R, Tetta C, Piccinni P, Digito A, Wratten ML, Dan M, Irone M, La Greca G, Inguaggiato P, Ronco C: Coupled plasma filtration adsorption in the treatment of septic shock; in Ronco C, Bellomo R, La Greca G, (eds). Blood Purification in Intensive Care. Contrib Nephrol. Basel, Karger, 2001, vol 132, pp 383–390. Tetta C, Cavaillon JM, Schulze M, Ronco C, Ghezzi PM, Camussi G, Serra AM, Curti F, Lonnemann G: Removal of cytokines and activated complement components in an experimental model of continuous plasma filtration coupled with sorbent adsorption. Nephrol Dial Transplantation 1998;13:1458–1464. Tetta C, Cavaillon JM, Camussi G, Lonnemann FG, Brendolan A, Ronco C: Continuous plasma filtration coupled with sorbents. Kidney Int suppl 1998;66:S186–S189. Muirhead E, Reid A: Resin artificial kidney. J Lab Clin Med 1948;33:841–844. Kissack A, Gliedman L, Karlson K: Studies with ion exchange resins. Trans Am Soc Artif Intern Organs 1962;8:219. Yatzidis H: A convenient haemoperfusion micro-apparatus over charcoal for the treatment of endogenous and exogenous intoxidations. Its use as an artificial kidney. Proc Eur Dial Transplant Assoc 1964;1:83. Chang T: Semipermeable aqueous micocapsules (artificial cells): With emphasis on experiments in an extracorporeal shunt. Trans Am Soc Artif Organs 1966;12:13. Gordon A, Greenbaum M, Marantz L, McArthur M, Maxwell M: A sorbent based low volume recirculating dialysate system. Trans Am Soc Artif Intern Organs 1969;15:347–352. Greil J, Wyss PA, Ludwig K, Bonakdar S, Scharf J, Beck JD, Ruder H: Continuous plasma resin perfusion for detoxification of methotrexate. Eur J Pediatr 1997;156:533–536. Takenaka Y: Bilirubin adsorbent column for plasma perfusion. Ther Apher 1998;2:129–133. Ryan CJ, Anilkumar T, Ben-Hamida AJ, Khorsandi SE, Aslam M, Pusey CD, Gaylor JD, Courtney JM: Multisorbent plasma perfusion in fulminant hepatic failure: Effects of duration and frequency of treatment in rats with grade III hepatic coma. Artif Organs 2001;25:109–118. Sechser A, Osorio J, Freise C, Osorio RW: Artificial liver support devices for fulminant liver failure. Clin Liver Dis 2001;5:415–430. Winchester J, Kellum J, Ronco C, Brady J, Quartaro P, Salsberg J, Levin N: Sorbents in acute renal failure and the systemic inflammatory response syndrome. Blood Purif 2003;21:79–84.

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Tetta C, Gianotti L, Cavaillon J, Wratten M, Fini M, Braga M, Bisagni P, Giavaresi G, Bolzani R, Giardino R: Continuous plasma filtration coupled with sorbent adsorption in a rabbit model of endotoxic shock. Crit Care Med 2000;28:1526–1533. Ronco C, Brendolan A, Lonnemann G, Bellomo R, Piccinni P, Digito A, Dan M, Irone M, La Greca G, Inguaggiato P, Maggiore U, De Nitti C, Wratten ML, Ricci Z, Tetta C: A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002;30:1250–1255. Formica M, Olivieri C, Livigni S, Cesano G, Vallero A, Maio M, Tetta C: Hemodynamic response to coupled plasmafiltration adsoprtion in human septic shock. Intensive Care Med 2003;29:703–708. Kellum J, Bellomo R, Mehta R, Ronco C: Blood purification in non-renal critical illness. Blood Purif 2003;21:6–13. Cuhaci B: Plasma exchange in multi organ failure: Changing gears in sepsis and organ failure. Crit Care Med 2003;31:1875–1877. Carlet J: Immunological therpay in sepsis: Guidelines for the managment of severe sepsis and septic shock. Intensive Care Med 2001;27:S93–S103. Reeves JH, Butt W, Shann F, Layton JE, Stewart A, Waring P, Presneill JJ: Continuous plasmafiltration in sepsis syndrome. Crit Care Med 1999;27:2096–2104. Busund R, Koukline V, Utrobin U, Nedashkovsky E: Plasmapheresis in severe sepsis and septic shock: A prospective randomized controlled trial. Intensive Care Med 2002;28:1434–1439.

Claudio Ronco, MD Director, Department of Nephrology St. Bortolo Hospital, Viale Rodolfi, IT–36100 Vicenza (Italy) Tel. ⫹39 0444993869, Fax ⫹39 0444993949, E-Mail [email protected]

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Ronco C, Bellomo R, Brendolan A (eds): Sepsis, Kidney and Multiple Organ Dysfunction. Contrib Nephrol. Basel, Karger, 2004, vol 144, pp 387–394

Plasmapheresis in Sepsis Giorgio Berlota, Gabriella Di Capuab, Paola Nosellaa, Sara Rocconia, Corrado Thomanna a

Department of Anaesthesia, Intensive Care and Pain Therapy, University of Trieste, Trieste, and bDepartment of Anaesthesia and Intensive Care, University of Naples ‘Federico II’, Naples, Italy

The successful treatment of sepsis is based on the surgical drainage of septic foci, on the administration of appropriate antibiotics and on the correction of the sepsis-induced cardiovascular, metabolic and respiratory derangements [1]. Thus, it is clear that all these approaches are implemented only once the network of sepsis mediators with either pro- or anti-inflammatory actions have been activated [2]. In the recent past, two strategies have been developed to neutralize the actions of the inflammatory mediators in septic patients. The first one takes advantage of the impressive advances in genetic engineering techniques, which allowed the production of antagonists of the sepsis mediators, including antibodies directed against them and inhibitors of the mediator-cell interaction. However, despite the sound biological basis and the promising experimental results, many multicenter, randomized, placebo-controlled trials (RCT) repeatedly failed to demonstrate any substantial positive effect on the survival [3, 4]. Only recently, the administration of the human recombinant activated protein C (rAPC) which is a natural occurring anticoagulant with also a strong anti-inflammatory action has been demonstrated to exert a clear, albeit limited, positive action on the survival of septic patients [5]. The second approach is based on the removal of the sepsis mediators from the bloodstream by means of extracorporeal techniques, including those commonly used in the treatment of the acute renal failure (ARF) occurring in critically ill patients and especially in those developing multiple organ dysfunction syndrome (MODS) [6, 7]. Collectively, these techniques are grouped under the term continuous renal replacement therapy (CRRT) as they are basically used to provide renal support on a 24-hour basis in patients who cannot tolerate hemodialysis (HD) [7].

The rationale for their use with this indication is based on two assumptions. The first is that either the size and molecular weight (MW) of the mediators remain within the cut-off value of the membrane used or, alternatively, that their chemicophysical properties allow their adsorption on the surface of the filter [8], and the second is that they are present in the bloodstream in relevant concentration when the procedure is running, since both too early or too late treatments can be ineffective [4, 9]. Unfortunately, both conditions are hard to assess in the clinical settings, since the blood concentration of the sepsis mediators are subjected to wide fluctuations [10]; furthermore, they can be considered as the tip of the iceberg poorly reflecting what is going on at the tissue level [11]. Several studies have been performed aimed to evaluate either the efficacy of these techniques in the removal of septic mediators and the possible impact on the outcome. However, results from clinical investigations were largely inferior to what was expectable from laboratory experiences, as the blood concentration of sepsis mediators decreased in some studies but remained stable or even increased in others [12]. Several factors can account for this inconsistency, including the heterogeneity of the patients, the timeframe of the treatment, its duration, the different properties of the membrane used and the volume of fluid exchanged [12, 13]. Then, it appears that the extracorporeal removal of the sepsis mediators can be accomplished via two different approaches. The first takes advantage of the characteristics of the membrane used in the CRRT, whose depurative efficacy can be enhanced either by increasing the volume of the ultrafiltrate or by maximizing their absorptive capabilities [8, 14]. The second strategy is based on the use membranes with larger cut-off values commonly used during plasmapheresis (PP) or plasma exchange (PE), which allow the removal of substances whose MW exceeds the cut-off of the membranes commonly used in CRRT [15, 16].

Applications of Plasma-Separation Techniques in Sepsis

Description of the Technique and Terminology The process of separation of the blood into its main components is based on two different approaches [15, 16], namely plasma-exchange (PE) and plasmapheresis (PP). Albeit these two terms are often used as synonymous, the differences between them are profound. The PE is basically a one-step procedure, consisting in the separation of the blood in its components, namely the cells and the plasma; the former are returned to the patient, and the latter is discarded and substituted with other fluids, including plasma expanders, albumin or freshfrozen plasma (FFP) in order to maintain an adequate volemia and/or to supply the substances lost. Conversely, the PP is a double-step procedure, aimed at the

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selective removal of determined component(s) via single or double cascade process, during which the plasma obtained by means of filtration or centrifugation run flows through columns containing different types of beads or other materials able to adsorb more or less selectively the target substance(s); the processed plasma is subsequently reinfused. Both techniques have been used in a wide number of diseases characterized by the presence in the bloodstream of substances supposed to be responsible for the disorders [15]. However, clinical results have often been inconclusive due to different reasons [16], including (a) the role played by the target substance(s) (causative agents vs. simple marker of the disease); (b) the low rate of occurrence of many disorders treated with PE or PP which prevents to collect a sufficient experience to draw definite conclusions about their efficacy, and (c) the bizarre clinical course of several disease treated with these techniques, which can undergo spontaneous relapses and remissions. For these reasons, the number of diseases in which PE and/or PP are currently used is far lower than a few years ago [17]; among them, the treatment of sepsis could represent a promising field of application. Laboratory Experiences As stated above, the main theoretical indication for the use of PP or PE in sepsis consists in the removal of mediators exerting a detrimental action. However, in different timeframes, one class of substances can prevail on the other, leading to a systemic inflammatory response syndrome (SIRS), associated or not with an infection, or, conversely, to a status characterized by the progressive blunting, till the exhaustion, of this response [10]. This latter circumstance has been defined as a compensatory anti-inflammatory response syndrome (CARS). Although probably an oversimplification, this is a reasonable model to understand the bizarre clinical course of many septic patients in whom a hypo- or anergic condition often follows, and sometimes concludes, a critical illness initiated with a typical inflammatory process (e.g. pneumonia or peritonitis) [18]. Recently, it has become clear that genetic factors are relevant in up- and downregulating these reactions [19]. Hence, as far as the extracorporeal removal of sepsis mediators is concerned, the theoretical risk of removing anti-inflammatory substances during the florid phase of sepsis and SIRS should be taken into account, thus determining the potential harmful imbalance between the two classes of substances. Results from experimental studies carried conflicting results. Busund et al. [20] studied three groups of dogs in septic shock: the first and the second groups were treated with PE or the infusion of plasma (PI) whereas the third served as control. In the groups treated with PE and PI, the blood concentrations of endotoxin, TNF and interleukin 1 (IL-1) decreased significantly as compared with the controls, and this decrease was more marked in the PE group. Either the cardiovascular function or the

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overall survival was better in both the treatment arms. However, these encouraging results are in sharp contrast with those deriving from another similar study, in which a marked worsening of the hemodynamic variables and a reduced survival was observed in the PE group as compared with the control and the sham PE groups, respectively [21]. A possible explanation could derive from another study, in which dogs were given i.v. endotoxin and subsequently treated with repeated PIs: in many cases an irreversible cardiovascular collapse occurred, which was ascribed to a sudden decrease of the plasma ionized Ca2⫹; remarkably, this decrease was not observed in non-endotoxemic animals [22]. Clinical Studies Despite the conflicting experimental results and the lack of conclusive clinical trials clearly demonstrating a beneficial effect associated with their use, PE and PP, alone or in association with other blood depurative techniques, have been used in sepsis patients. The available studies suffer from some of the limitations encountered in those concerning the effects of PE and PI in diseases other than sepsis, namely the heterogeneity of patients and related clinical conditions. Then, it appears more useful to consider separately the efficacy of PE and PP in terms of: (a) removal of mediators; (b) improvement of some variables commonly deranged during sepsis and septic shock, and (c) effect on the outcome. As will appear, there is not a clear relationship among these variables. As far as the first point is concerned, PE has been demonstrated to effectively reduce the plasma concentration of both endotoxin and sepsis mediators both in septic patients [23] and in patients with acute liver failure [24]. Reeves et al. [25] treated septic patients with continuous PE, titrated to remove approximately 5 vol of plasma during 30–36 h; the replacement regimen included FFP, colloids and crystalloids. Some mediators, including C-reactive protein, haptoglobin, C3 fragment and ␣1-antitripsin, were removed with a sieving coefficient approaching 1.0, but other substances, e.g. IL-6, TBX2 and granulocyte-stimulating factors, were not substantially affected. Although there was no significant decrease in mortality, a trend toward less-severe organ involvement was observed. A different pattern of removal of the sepsis mediators has also been demonstrated in other studies: as an example, in septic patients treated with PE a decrease of the TNF-␣ concentration but not of other cytokines has been observed [26]. Possible mechanisms responsible for the failed decrease of the blood levels of sepsis mediators include a volume of distribution largely exceeding the intravascular space [11], a pulse production (as an example, following the administration of certain antibiotics with elevated endotoxin-releasing properties) [27] or a positive feedback loop promoting an elevated production to cope with the increased elimination [2, 3]. Independent of the substances removed, it appears that PE/PP is associated with an improvement of several physiological variables. In a group of septic

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patients undergoing PE aimed at the removal of a full volume of plasma which was replaced with crystalloids and FFP, Berlot et al. [28] observed a significant improvement of several hemodynamic variables in the absence of any change of the preload or afterload; interestingly, these changes were more marked in those patients who, before the procedure, exhibited the lowest hemodynamic values. Despite these beneficial effects, the mortality rate exceeded 60%. An overall improvement of the cardiovascular variables in association with PE/PP has also been demonstrated in other studies, involving both adult and pediatric septic patients [29–30]. Although it is relatively easy to measure circulating septic mediators or to assess the variations of some cardiovascular variable, to draw definite conclusions on the effect on the outcome exerted by PE and/or PP is much less straightforward. As an example, a survival of 74% has been reported in a review of the available outcome data [31]; however, the analysis included a limited number of patients (total 76, ranging from 2 to 19 in 10 different studies) who had been treated with 4 different plasma-processing techniques. More recently, the same authors [32] reported a survival of 82% in a group of septic patients treated with PE as last option during MODS. These results are clearly encouraging, but, likewise, other studies involving PE, PP and CRRT are biased by the lack of an objective indicator for its application [33].

Plasma-Processing Techniques

Description of the Technique and Terminology The availability of new molecules able to stick on their surface one or more septic mediators lead to the development of newer extracorporeal techniques, based on the principle of coupled plasma removal and absorption (CPFA). Basically, this procedure consists of a PP in which the removed plasma is returned to the bloodstream after flowing through a resin cartridge with elevated absorptive capabilities. If needed, the CPFA can be coupled with CRRT; in this case, the filter is located distally to the cartridge in order to avoid an excessive hemoconcentration [34]. Laboratory Experiences Basically, the experimental investigations parallel what has been already described with PE and PP. In a rabbit model of sepsis, Tetta et al. [35] were able to demonstrate that a 3-hour CPFA significantly increased the survival at 72 h of the treated animals as compared with the control group, without any concomitant decrease of blood endotoxin and TNF-␣ levels; however, endotoxin

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concentrations were significantly lower in animals still surviving at 72 h. During the treatment time, significant amounts of PAF stuck onto the cartridge. The authors ascribed the failed decrease of the endotoxin either to different kinetics of this molecule and/or to individual variability to its effects. Clinical Studies Ronco et al. [36] used intermittent CPFA (each session lasting 10 h) in two groups of patients with septic shock and ARF who also received HD or CRRT in a random order. Arterial pressure increased in both groups but more markedly in those treated with CRRT, in whom there was also a decrease in the request for vasopressor support. Surprisingly enough, macrophages of patients in the CPFA-CRRT group presented a time-dependent increased production of TNF-␣ when challenged with endotoxin, and the authors ascribed this effect to a restoration of the leukocyte responsiveness induced by the removal of some sepsis mediators. Similar results have also been recently reported by Formica et al. [37] who observed a marked hemodynamic improvement associated with an improved survival in patients with septic shock treated with CPFA.

Conclusions

The neutralization of sepsis mediators is a therapeutic option which underwent a profound evolutionary process. At the beginning of the 1990s, it was thought that the cascade of mediators could be interrupted by some agent(s) directed against them and/or their cellular receptors. Several RCTs demonstrated that this approach was not as effective as expected from the preliminary experimental studies. Then, it was supposed that these substances could be removed by means of CRRT, and some but not all studies demonstrated that the increase in their depurative efficiency was associated with an improved survival of sepsisinduced MODS patients. The next step consisted of the use of PE and/or PP, but a firm conclusion on the efficacy of both techniques in this setting is difficult to draw because different procedures, different replacement regimens and different strategies (single vs. continuous treatments) have been used. The last innovation is CPFA, whose initial results appear extremely promising, and which can be used in association with the currently used CRTT devices.

References 1

Hotchkiss RS, Karl IE: Medical progress: The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138–150.

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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

Adrie C, Pinsky MR: The inflammatory balance in human sepsis. Intens Care Med 2000;26: 364–375. Cain BS, Meldrum DR, Harken AH, McIntyre RC: The physiologic basis for anticytokine clinical trials in the treatment of sepsis. J Am Coll Surg 1998;186:337–350. Abraham E: Why immunomodulatory therapies have not worked in sepsis. Intens Care Med 1999; 25:556–566. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709. van Bommel EFH: Should continuous renal replacement therapy be used for ‘non-renal’ indications in critically ill patients with shock? Resuscitation 1997;33:257–270. Bellomo R, Ronco C: Continuous renal replacement therapy in the intensive care unit. Intens Care Med 1999;25:781–789. De Vriese AS, Colardyn FA, Philippè JJ, Vanholder RC, de Sutter JH, Lameire NH: Cytokine removal during hemofiltration in septic patients. J Am Soc Nephrol 1999;10:846–853. De Vriese AS, Vanholder RC, Pascual M, Lameire NH, Colardyn FA: Can inflammatory cytokine be removed efficiently by continuous renal replacement therapies? Intens Care Med 1999;25: 903–910. van der Poll, van Deventer SJH: Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clins N Am 1999;13:413–426. Cavaillon JM, Munoz C, Fitting C, Misset B, Carlet J: Circulating cytokines: The tip of the iceberg? Circ Shock 1992;38:145–152. Gotloib L: Hemofiltration in multiorgan failure syndrome secondary to sepsis: A critical analysis of heterogeneity. Nephron 1996;73:125–130. Schetz M, Ferdinande P, Van Den Berghe Verwaest C, Lauvers P: Removal of proinflammatory cytokines with renal replacement therapy: Sense or non-sense? Intens Care Med 1995;21: 169–176. Ronco C, Bellomo R, Hormel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous hemofiltration on outcomes of acute renal failure: A prospective, randomised trial. Lancet 2000;355:26–30. Madore F, Lazarus JM, Brady HR: Therapeutic plasma exchange in renal diseases. J Am Soc Nephr 1996;7:367–386. Patten E: Therapeutic plasmapheresis and plasma exchange. Crit Rev Cin Lab Sci 1986;23: 147–175. Berlot G, Tomasini A, Silvestri L, Gullo A: Plasmapheresis in the critically ill. Kidney Int 1998; 53(suppl 66):178–181. Bone RC: Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 1996;24:1125–1136. Villar J, Siminovitch KA: Molecular intensive care medicine. Intens Care Med 1999;25:652–661. Busund R, Lindsetmo RO, Rasmussen LT, Rikke O, Revkig OP, Revhaug A: Tumour necrosis factor and interleukin–1 appearance in experimental gram-negative septic shock: The effect of plasma exchange with albumin and plasma infusion. Arch Surg 1991;126:591–597. Natanson C, Hoffman WD, Koev LA, et al: Plasma exchange does not improve survival in a canine model of human septic shock. Transfusion 1993;33:243–248. Busund R, Lindsetmo RO, Balteskard L, Revkig OP, Revhaug A: Repeated plasma therapy induces fatal shock in experimental septicemia. Circ Shock 1993;40:268–275. Stegmayr B: Apheresis of plasma compounds as a therapeutic principle in severe sepsis and multiorgan dysfunction syndrome. Clin Chem Lab Med 1999;37:327–332. Iwai H, Nagaki M, Naito T, Ishiki Y, Murakami N, Sugihara J, Muto Y, Moriwaki H: Removal of endotoxin and cytokines by plasma exchange in patients with acute hepatic failure. Crit Care Med 1998;26:873–876. Reeves JH, Butt WW, Shann F, Layton JE, Stewart A, Waring PM, Presneill JJ, Plasmafiltration in Sepsis Study Group: Continuous plasmafiltration in sepsis syndrome. Crit Care Med 1999;27: 2096–2104. Gardlund B, Syolin J, Nillson A, Roll M, Wickerts CJ, Wretlind B: Plasma levels of cytokines in primary septic shock in humans: Correlation with disease severity. J Infect Dis 1995;172: 296–301.

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27 28 29 30 31 32

33 34 35 36 37

Mock CN, Jurkovich GJ, Dries DJ, Maier RV: Clinical significance of antibiotic endotoxin-releasing properties in trauma patients. Arch Surg 1995;130:1234–1241. Berlot G, Gullo A, Fasiolo S, Serra S, Silvestri S: Hemodynamic effects of plasma exchange in septic patients: Preliminary report. Blood Purif 1997;15:45–53. Reeves JH, Butt WW: Blood filtration in children with severe sepsis: Safe adjunctive therapy. Intens Care Med 1995;21:500–504. Mok Q, Butt WW: The outcome of children admitted to intensive care with meningococcal septicaemia. Intens Care Med 1996;22:259–263. Stegmayr BG: Plasmapheresis in severe sepsis or septic shock. Blood Purification 1996;14: 94–101. Stegmayr BG, Banga R, Berggren L, Norda R, Rydvall A, Vikerfors T: Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003;31: 1730–1736. Rogiers P: Hemofiltration treatment for sepsis. Is it time for controlled trials? Kidney Int 1999; 56(suppl 72):S99–S103. Bellomo R, Tetta C, Ronco C: Couplet plasma filtration adsorption. Intens Care Med 2003;29: 1222–1228. Tetta C, Gianotti L, Cavaillon JM, et al: Coupled plasma filtration-absorption in a rabbit model of endotoxic shock. Crit Care Med 2003;28:1526–1533. Ronco C, Brendolan A, Lonnemann G, et al: A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002;31:1250–1255. Formica M, Olivieri C, Livigni S, et al: Hemodynamic response to coupled plasmafiltrationadsorption in human septic shock. Intens Care Med 2003;29:703–708.

Prof. Giorgio Berlot Department of Anaesthesia and Intensive Care Cattinara Hospital, Strada di Fiume 449, IT–34100 Trieste (Italy) E-Mail [email protected]

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Author Index

Adib-Conquy, M. 76 Amigues, L. 291 Ash, S.R. 239 Ayus, J.C. 132 Balakrishnan, V.S. 63 Baldwin, I. 105, 203 Barsoum, R.S. 44 Bellomo, R. IX, 105, 158, 203, 329, 362, 376 Béraud, J.-J. 291 Berlot, G. 387 Bonello, M. 158, 191, 329 Bonventre, J.V. 19 Bordoni, V. 158 Brendolan, A. IX, 376 Callegarin, L. 182 Canaud, B. 291 Carraro, R. 12 Cavaillon, J.-M. 76 Chien, C.-C. 53 Clark, W.R. 264 Dan, M. 182 Davenport, A. 228, 317 Di Capua, G. 387 D’Intini, V. 158, 191, 329, 376

Fitting, C. 76 Formet, C. 291 Goldstein, S.L. 284 Golper, T.A. 278 Hoste, E.A. 1, 255 Inguaggiato, P. 158 Jaber, B.L. 63 Kellum, J.A. 1, 362 King, L.S. 53 Klouche, K. 291 Kox, W.J. 308 Lameire, N. 255 Leblanc, M. 222 Leray-Moragues, H. 291 Liangos, O. 63 Moritz, M.L. 132 Naka, T. 105 Nosella, P. 387 Palevsky, P.M. 214 Passlick-Deetjen, J. 362 Pereira, B.J.G. 63 Piccinni, P. 12

Pinsky, M.R. 31, 94 Pisitkun, T. 329 Pohlmeier, R. 362 Poulin, S. 329 Rabb, H. 53 Ratanarat, R. 158 Raynal, N. 291 Ricci, Z. 12, 329, 362, 376 Rocconi, S. 387 Ronco, C. IX, 158, 182, 191, 264, 329, 362, 376 Rossi, S. 182 Rotonorot, R. 158 Salvatori, G. 158, 191, 329 Schetz, M. 119, 166 Spies, C. 308 Tetta, C. 362 Thomann, C. 387 Tiranathanagul, K. 329 Van Biesen, W. 255 Van den Berghe, G. 119 Vanholder, R. 255 Vargas Hein, O. 308 Vincent, J.-L. 350 Wratten, M.L. 376

395

Subject Index

N-acetyl-␤-D-glucosaminidase (NAG), acute renal failure marker 65, 72 Acid-base balance, see Fluids Acidosis, acute renal failure patients, prognosis 3, 4 Acute lung injury, see Lung Adequacy, renal replacement therapy continuous venovenous hemodiafiltration 342–344 continuous venovenous hemodialysis 340–342 continuous venovenous hemofiltration 337–340 definition 329, 330 dose correlation with outcome 330, 331 dose measurement, different treatments 331, 332 efficacy 333–335 efficiency 332, 333 frequency 333 intensity 333 intermittent hemodialysis 343, 345–347 slow continuous ultrafiltration 335–337 sustained low-efficiency dialysis 343, 345–347 Anemia, acute renal failure patients, prognosis 5 Antibiotics, dosing, acute renal failure 6 Anticoagulation, see Continuous renal replacement therapy

Apoptosis acute renal failure mechanisms 159 pathways 15 Argatroban, anticoagulation, extracorporeal circuits 232, 233 Association studies candidate gene identification 66, 67 cytokine polymorphisms, acute renal failure 67, 68 limitations 70 B cells, sepsis response 78 Benzodiazepines, dosing, acute renal failure 6, 7 Blood transfusion, sepsis management 356 Cancer acute renal failure association 158 hyperuricemia, see Hyperuricemia Cardiac surgery, acute renal failure risks 13 Cardiogenic shock, see Shock Catheters care and maintenance 201, 298, 299 complications delayed complications 193, 195 immediate complications 193–195 infections 197–199, 301, 302 prevention guidelines, intensive care units 303–305 stenosis, host vein 302

396

thrombosis fibrin sheath thrombus 196, 197, 300 incidence 196 prevention 197 risk factors 196, 301 treatment 197 double-lumen hemodialysis catheter materials 192 incidence, catheterization 191 performance factors 299, 300 performances and recirculation 199–201 peritoneal dialysis 248, 249 positioning 193, 298 stiffness 292 surface treatments 302 temporary catheter ideal characteristics 191 types 292, 293 vascular access, see Vascular access CD11b expression, sepsis 41 CD14, inflammation signaling 35 Central diabetes insipidus (CDI), features 150 Central venous catheters, see Catheters Cerebral demyelination features 145 risk factors, hyponatremic patients 145 Cerebral salt wasting (CSW) diagnosis 142, 143 management 143 pathogenesis 143 Citrate, anticoagulation, extracorporeal circuits 233, 234, 311, 313, 314, 324, 325 Compensatory anti-inflammatory response syndrome (CARS) monocyte hyporesponsiveness mechanisms desensitizing agents, plasma 82, 83 endotoxin-neutralizing molecules, plasma 83 nuclear factor-␬B expression 84, 85 toll-like receptor expression and signaling pathway downregulation 83–87

Subject Index

overview 79, 80, 363 reversal 87 overview 76 Complement, ischemic acute renal failure pathophysiology 22 Continuous renal replacement therapy (CRRT) adequacy calculation continuous venovenous hemodiafiltration 342–344 continuous venovenous hemodialysis 340–342 continuous venovenous hemofiltration 337–340 anticoagulation argatroban 232, 233 citrate 233, 234, 311, 313, 314, 324, 325 comparison of agents 312 danaparoid 231, 232, 310 hirudin 232, 310, 311 low-molecular-weight heparin 230, 231, 309 nafamostat mesilate 235 prostanoids 234, 235, 311 unfractionated heparin 229, 230, 308, 309 blood flow monitoring circuit failure detection 211 Doppler flow 206, 207, 210, 211 ultrasound flow probe 210 catheters, see Catheters; Vascular access congestive heart failure patients 274 cost analysis 278–280 extracorporeal circuits, see Extracorporeal circuits fluids buffers 223, 224, 322–324 composition 223 electrolytes 224, 225, 319–322 glucose 225 prescription mode influences 226, 227 sterility 317, 318 warming 325, 326 high-volume hemofiltration 273, 274 hybrid renal replacement therapy, see Slow low-efficiency dialysis

397

Continuous renal replacement therapy (CRRT) (continued) ideal characteristics 264, 265 patient selection acute renal failure 217–219, 272, 273 non-renal indications 219 rationale 387, 388 principles 243 technical aspects 271, 272 techniques continuous venovenous hemodiafiltration 270, 271 continuous venovenous hemodialysis 269, 270 continuous venovenous hemofiltration 268, 269 high-volume hemofiltration, see High-volume hemofiltration slow continuous ultrafiltration 268 transport mechanisms, solutes and water convection 266, 267 diffusion 265, 266 Corticosteroids, sepsis management 359 Coupled plasma filtration adsorption (CPFA) animal studies 383, 391, 392 chromatography comparison 379, 380 clinical trials, sepsis 383, 384, 392 development 378 principles 377, 378, 391 prospects 384, 385, 392 sorbents mechanisms 379, 380 testing 380–383 Danaparoid, anticoagulation, extracorporeal circuits 231, 232, 310 Delayed-type hypersensitivity, sepsis response 79 Distributive shock, see Shock Diuretic therapy hyponatremia induction, thiazide diuretics 141 loop diuretics, acute renal failure absence of protective effects 172–174, 176 animal model studies 166, 167 clinical trials 167–170

Subject Index

pathophysiology 170, 171 rationale 172 toxicity 174, 175 Dobutamine, sepsis management 357, 358 Dopamine, dosing, acute renal failure 6 Dopexamine, sepsis management 357, 358 Double-lumen hemodialysis catheters, see Catheters Drotrecogin alpha, sepsis management 358 Drug dosing, acute renal failure patients 5–7 Endothelial cells, ischemic acute renal failure pathophysiology 20, 21 Enoximone, sepsis management 358 Epinephrine, dosing, acute renal failure 6 Extracorporeal circuits blood flow assessment 206, 207, 209–211 blood pumping 203–205 design, continuous renal replacement therapy 235, 236 pumps 206, 207 roller pumps, segment tubing 205, 206 Femoral vein, catheterization 294, 295 Fluids acid-base balance effects acidosis consequences 108–110, 222, 223 clinical consequences 111 colloid versus crystalloid solutions 111, 112 conventional view 107, 108 ‘strong ion difference’ calculation 106, 107, 222 buffers acetate 113 bicarbonate 113 citrate 113, 114 high-volume hemofiltration 114–116 lactate 113 colloid solutions 111 continuous renal replacement therapy buffers 223, 224, 322–324 composition of fluids 223 electrolytes 224, 225, 319–322

398

glucose 225 prescription mode influences 226, 227 sterility 317, 318 warming 325, 326 crystalloid solutions 106 sepsis management 354–356 shock resuscitation 98–100 Gene polymorphisms cytokines, acute renal failure 67–71 sites 66 types 66 Glomerular filtration rate (GFR), acute renal failure pathophysiology 170, 171 Glucose control, see Hyperglycemia Heat shock proteins (HSPs) abundance, cells 38 activation mechanism 38 immunosuppression, sepsis 83 mitochondrial oxidative stress protection 39 nuclear factor-␬B interactions 39 thermal preconditioning and survival 38 Heparin, see Low-molecular-weight heparin; Unfractionated heparin High-volume hemofiltration (HVHF) fluid composition 114–116 inflammatory cytokine removal 364, 365 sepsis management animal studies 365, 366 clinical trials 366–368 monitors 370, 371 prospects 372 rationale 364, 365 technique 369, 371, 372 timing 368, 369 Hirudin, anticoagulation, extracorporeal circuits 232, 310, 311 HLA-DR expression, sepsis 40, 77, 78 Hybrid renal replacement therapy, see Slow low-efficiency dialysis Hyperglycemia adverse effects 120, 121 hypercoagulability 126, 127 immune system impairment, infection risk 126

Subject Index

induction, critical illness 119, 120 insulin therapy beneficial mechanisms 123–125 dosing, intensive care units 121–123 precautions 127, 128 neuropathy, association, critical illness 125, 126 renal failure, association, critical illness 125 sepsis management 359 Hyperkalemia, acute renal failure patients, prognosis 5 Hypernatremia central diabetes insipidus 150 clinical manifestations 147, 148 definition 146 diagnosis 146, 147 dialysis therapy continuous venovenous hemofiltration 152 hemodialysis 152 peritoneal dialysis 151, 152 edema, association 150, 151 mortality 148, 149 pathogenesis 146, 147 treatment 149, 150 Hyperuricemia acute renal failure mechanisms 159–161 allopurinol therapy 161, 162 pathogenesis, cancer 159 rasburicase therapy 161, 162, 164 Hyponatremia acute renal failure patients, prognosis 4, 5 cerebral demyelination 145 cerebral salt wasting 142, 143 definition 133 diagnosis 134–136 disorders, impaired renal water excretion 133 encephalopathy brain cell volume regulation 138 neurogenic pulmonary edema 138 risk factors age 138, 139 hypoxia 139, 140 sex 139 symptoms 137

399

Hyponatremia (continued) incidence, hospital patients 136 outpatients 140, 141 pathogenesis 133 prevention 136, 137 syndrome of inappropriate antidiuretic hormone 141, 142 thiazide diuretic induction 141 treatment 143, 144 Hypovolemic shock, see Shock Incidence, acute renal failure, critically ill patients 1, 12 Infants, acute renal failure 287, 288 Infection acute renal failure patients, prognosis 4, 13 tropical acute renal failure injury mechanisms direct parenchymal invasion 45, 46 hemodynamic disturbances 47, 48 iatrogenic injury 48 immune system mediated lesions 46, 47 Inflammation compartmentalization concept 80–82 critical illness 126, 127 intracellular events 34–36 ischemic acute renal failure pathophysiology 20–22, 27 mechanical ventilation response 57 mitochondria, role 39 sepsis, pro- and anti-inflammatory activities 39–41 tubule contribution to inflammatory injury 23 Insulin therapy, see Hyperglycemia Integrins, expression, sepsis 41 Interferon gamma (IFN-␥) ischemic acute renal failure pathophysiology 21 sepsis response 79 Interleukin-1 (IL-1) ischemic acute renal failure pathophysiology 21 sepsis response 79, 80

Subject Index

Interleukin-6 (IL-6) expression, sepsis 40, 41 infection response 34 prognostic marker, acute renal failure 65 Interleukin-10 (IL-10) gene locus 69 polymorphisms, acute renal failure 69 inducers, acute renal failure management 71 prognostic marker, acute renal failure 65 sepsis response 79 Intermittent hemodialysis adequacy calculation 343, 345–347 biocompatibility of membranes 260, 261 continuous renal replacement therapy, comparison studies, acute renal failure 255–257, 261 cost analysis 278–280 dosing, acute renal failure 257–260 patient selection, acute extracorporeal renal support 214–217 Internal jugular vein, catheterization 296–298 Ischemia pathophysiology, acute renal failure 16, 17, 19–28 preconditioning protection against renal injury 23–25 Kidney injury molecule 1 (KIM-1), acute tubular damage marker 27, 65, 72 Linkage analysis, candidate gene identification 66, 67 Lipopolysaccharide (LPS), binding protein levels, sepsis 83 Low-molecular-weight heparin (LMWH), anticoagulation, extracorporeal circuits 230, 231, 309 Lung acute lung injury animal model studies acute lung injury effects on kidney 57, 58 acute renal failure effects on lung 54, 55 mortality, acute renal failure 53

400

acute renal failure effects cytokines 56 edema 53, 54 ion channel expression 55 macrophage activation 55 neutrophil activity 55, 56 vascular permeability 53–55 kidney cross talk, ischemic acute renal failure pathophysiology 25 mechanical ventilation effects on kidney 56–58 Mechanical ventilation effects on kidney 56–58 sepsis management 353, 354 Mitochondria cytotoxic mechanisms 39 inflammation interactions 39 Mitogen-activated protein kinases (MAPKs), ischemic preconditioning response 23–25 Monocyte hyporesponsiveness, see Compensatory anti-inflammatory response syndrome Mortality acute renal failure, critically ill patients 1, 12, 13, 53, 214 dialysis effects on acute renal failure outcome statistics 255, 362 hypernatremia 148, 149 Multiple organ failure, see Sepsis Nafamostat maleate, anticoagulation, extracorporeal circuits 235 Natural killer cell, sepsis activity 78 Necrosis, acute renal failure mechanisms 159 Neutrophil, sepsis function 78, 79 Nitric oxide (NO) ischemic acute renal failure pathophysiology 20, 25, 26 synthase responses, ischemic preonditioning 23, 24 Non-cardiogenic obstructive shock, see Shock Norepinephrine, dosing, acute renal failure 6

Subject Index

Nuclear factor-␬B (NF-␬B) activation 36, 37 endotoxin tolerance induced dysfunction 37 heat shock protein interactions 39 inflammation, role 35 inhibitory subunit 35–37 sepsis response 41, 42, 84, 85 target genes 35, 36 Opioids, dosing, acute renal failure 6, 7 Oxidative stress, see Reactive oxygen species Pediatric acute renal failure congenital heart disease patients 288 critically ill patients 285–287 epidemiology 284, 285 infants 287, 288 prospects for study 288, 289 Peritoneal dialysis (PD) acute renal failure management acute therapy 248 catheters 248, 249 complications compared with hemodialysis 250–252 continuous-flow peritoneal dialysis 245–248 mortality versus hemodialysis 240–242 peritonitis incidence 249 popularity 239, 240 renal function recovery 243 tidal peritoneal dialysis 245, 247 clearance versus other dialysis modes 244, 245 peritoneum advantages, dialysis membrane 239 protein loss 248 renal perfusion maintenance 242, 243 Plasma exchange animal studies 389, 390 clinical trials, sepsis 390, 391 principles 388, 389 Plasmapheresis, see also Coupled plasma filtration adsorption animal studies 389, 390

401

Plasmapheresis (continued) clinical trials, sepsis 390, 391 principles 388, 389 Poly(ADP ribose) synthetase, ischemic acute renal failure pathophysiology 22 Prostaglandins, anticoagulation, extracorporeal circuits 234, 235, 311 Protein C, sepsis management 387 Rasburicase, hyperuricemia management 161, 162, 164 Reactive oxygen species (ROS) ischemic acute renal failure pathophysiology 22 mitochondria generation 39 Renal blood flow (RBF) acute renal failure pathophysiology 170, 171 regulation 183 Risk factors, acute renal failure, intensive care units 12–15 Sepsis circulatory dysfunction 183–187 compartmentalization, inflammation 80–82 cytokine and chemokine responses 34, 39–42, 79, 80, 362 definition 376, 377 delayed-type hypersensitivity response 79 diagnosis using PIRO system 350–352 HLA-DR expression 40, 77, 78 lymphocytes proliferation 76 subsets 77 management blood transfusion 356 corticosteroids 359 coupled plasma filtration adsorption, see Coupled plasma filtration adsorption fluids 354–356 glucose control 359 hemodynamic stabilization 353 high-volume hemofiltration animal studies 365, 366

Subject Index

clinical trials 366–368 monitors 370, 371 prospects 372 rationale 364, 365 technique 369, 371, 372 timing 368, 369 immunomodulation 358, 359 infection control 352 inotropic agents 357, 358 plasma exchange, see Plasma exchange plasmapheresis, see Plasmapheresis vasopressors 187–189, 357 ventilation 353, 354 monocyte hyporesponsiveness mechanisms desensitizing agents, plasma 82, 83 endotoxin-neutralizing molecules, plasma 83 nuclear factor-␬B expression 84, 85 toll-like receptor expression and signaling pathway downregulation 83–87 overview 79, 80, 363 reversal 87 natural killer cell activity 78 neutrophil function 78, 79 pro- and anti-inflammatory activities 39–41 septic shock definition 362 therapeutic targets 363 Shock cardiogenic shock 95 definition 182 distributive shock 95 hypovolemic shock 94, 95 non-cardiogenic obstructive shock 95, 96 resuscitation cardiovascular resuscitation targets 101 fluid resuscitation 98–100 goals 96, 97 hematocrit, goals 97, 98 periods 96 vasopressors 100, 101 septic shock, see Sepsis vasopressor therapy, septic shock 187–189

402

Slow continuous ultrafiltration (SCUF) adequacy calculation 335–337 technique 268 Slow low-efficiency dialysis (SLED) adequacy calculation 343, 345–347 clearance rates 280, 281 cost analysis 278–280 dose versatility 280, 281 nursing time 281 prospects 281, 282 Sodium balance, see Hypernatremia; Hyponatremia Stress hyperglycemia, see Hyperglycemia Subclavian vein, catheterization 295, 296 Syndrome of inappropriate antidiuretic hormone (SIADH) causes 141, 142 management 142 Systemic inflammatory response syndrome (SIRS), see also Sepsis cytokine response, acute renal failure 34, 63, 64 definition 31 modifiers of immune response 76, 77 T cells acute renal failure-acute lung injury association 56 ischemic acute renal failure pathophysiology 21, 22 Toll-like receptors (TLRs) inflammation signaling 32 sepsis, expression and signaling pathway downregulation 83–87 types 32, 83 Transforming growth factor beta (TGF-␤), immunosuppression, sepsis 82 Tropical acute renal failure clinical considerations 50 epidemiology 44 infection and injury mechanisms direct parenchymal invasion 45, 46 hemodynamic disturbances 47, 48 iatrogenic injury 48 immune system mediated lesions 46, 47

Subject Index

management 50, 51 toxin sources, etiology animal toxins 48, 49 industrial chemical toxins 49, 50 plant toxins 49 Tubules inflammatory injury contribution, ischemic acute renal failure pathophysiology 23 lesions, ischemic acute renal failure 16 Tumor necrosis factor alpha (TNF-␣) gene locus 67 polymorphisms, acute renal failure 67, 68 infection response 33, 34 inhibitors, acute renal failure management 70, 71 ischemic acute renal failure pathophysiology 20, 21, 65 systemic inflammatory response syndrome, role 63, 64 Tumor necrosis factor beta (TNF-␤) gene locus 67 polymorphisms, acute renal failure 67, 68 Unfractionated heparin, anticoagulation, extracorporeal circuits 229, 230, 308, 309 Urate oxidase, see Rasburicase Uric acid, see Hyperuricemia Vascular access (VA), see also Catheters continuous renal replacement therapy access sites femoral vein 294, 295 internal jugular vein 296–298 overview 207–209, 294 subclavian vein 295, 296 insertion techniques 192, 193, 294 positioning, catheters 193, 298 Vasopressors septic shock management 187–189, 357 shock resuscitation 100, 101 Volume overload, acute renal failure patients, prognosis 2, 3

403