Continuous Renal Replacement Therapy (Pittsburgh Critical Care Medicine)

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Continuous Renal Replacement Therapy

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Continuous Renal Replacement Therapy Edited by

John A. Kellum Professor and Vice Chair Department of Critical Care Medicine University of Pittsburgh Pittsburgh, Pennsylvania

Rinaldo Bellomo Professor of Medicine Director of Intensive Care Research Melbourne University Melbourne, Australia

Claudio Ronco Professor of Clinical Nephrology and Medicine Director, Department of Nephrology St. Bortolo Hospital Vicenza, Italy

1

2010

1

Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With ofﬁces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Copyright © 2010 by Oxford University Press, Inc. Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Continuous renal replacement therapy/edited by John A. Kellum, Rinaldo Bellomo, Claudio Ronco. p. ; cm. Includes bibliographical references and index. ISBN 978–0-19–539278-4 (pbk. : alk. paper) 1. Acute renal failure—Treatment. 2. Continuous arteriovenous hemoﬁltration. I. Kellum, John A. II. Bellomo, R. (Rinaldo), 1956- III. Ronco, C. (Claudio), 1951[DNLM: 1. Kidney Failure, Acute—therapy. 2. Hemodialysis Solutions. 3. Kidney— injuries. 4. Renal Dialysis. 5. Renal Replacement Therapy—methods. WJ 342 C7625 2009] RC918.R4C658 2009 616.6’14—dc22 2009011944 Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work.

10 9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper

We dedicate this volume to the nursing professionals that deliver CRRT—for without their hard work and dedication this therapy would not exist—and to the patients and their families in the hope that we can make some difference in their lives.

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Preface

John A. Kellum Rinaldo Bellomo Claudio Ronco 2009

vii

Signiﬁcant advances have occurred in the care of patients with acute kidney injury. Continuous renal replacement therapy (CRRT) has become the standard of care for many critically ill patients with severe acute kidney injury, and most major medical centers have developed the capability of providing CRRT. However, many hospitals lack the capacity, and many that have it underutilize it. Our goal with the CRRT handbook is to provide a concise but authoritative guide to the use of CRRT. In a single, slim volume, we have covered the basics to management of acute kidney injury both with and in addition to CRRT. The intent of this book is to provide a quick reference for both novice and experienced CRRT providers, to enrich existing expertise, and to achieve a better understanding of this powerful treatment. Our ultimate goal is to improve outcomes for patients with acute kidney injury through teamwork and education.

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Contents Abbreviations xiii Contributors xvii

Part 1 Theory 1 The critically ill patient with acute kidney injury Aditya Uppalapati and John A. Kellum 2 History and rationale for continuous renal replacement therapy Ilona Bobek and Claudio Ronco 3 Terminology and nomenclature Ian Baldwin and Rinaldo Bellomo 4 Basic principles of solute transport Zhongping Huang, Jeffrey J. Letteri, Claudio Ronco, and William R. Clark 5 Principles of ﬂuid management Rinaldo Bellomo and Sean M. Bagshaw 6 Indications, timing, and patient selection John A. Kellum 7 Extended indications for continuous renal replacement therapy Rinaldo Bellomo and Ian Baldwin 8 Dose adequacy and assessment Zaccaria Ricci and Claudio Ronco 9 Acid-base and electrolyte disorders John A. Kellum

3

11 19

25 33 39

47 53 61

Part 2 Practice 10 Choosing a renal replacement therapy in acute kidney injury Jorge Cerdá and Claudio Ronco 11 Vascular access for continuous renal replacement therapy Alexander Zarbock and Kai Singbartl 12 The circuit and the prescription Rinaldo Bellomo and Ian Baldwin

79 93 99

CONTENTS

x

13 The membrane: size and material Zhongping Huang, Jeffrey J. Letteri, Claudio Ronco, and William R. Clark 14 Fluids for continuous renal replacement therapy Paul M. Palevsky and John A. Kellum 15 Alarms and troubleshooting Zaccaria Ricci, Ian Baldwin, and Claudio Ronco 16 Nonanticoagulation strategies to optimize circuit function in renal replacement therapy Ian Baldwin 17 Anticoagulation Rinaldo Bellomo and Ian Baldwin 18 Regional citrate anticoagulation Nigel Fealy 19 Drug dosing in continuous renal replacement therapy Kimberly A. Maslonek, Kelly A. Killius, and John A. Kellum

107 115 121

129 135 141 147

Part 3 Special Situations 20 Renal replacement therapy in children Michael L. Moritz 21 Therapeutic plasma exchange in critical care medicine Joseph E. Kiss 22 MARS: molecular adsorbent recirculating system Nigel Fealy and Rinaldo Bellomo 23 Sorbents Dehua Gong and Claudio Ronco 24 Hybrid therapies Dinna N. Cruz and Claudio Ronco

159 167 175 181 189

Part 4 Organizational issues 25 The ICU environment Younghoon Kwon 26 Patient care quality and teamwork Kimberly Whiteman and Frederick J. Tasota 27 Organizational aspects: developing policies and procedures for continuous renal replacement therapies Jorge Cerdá

199 205

213

223

CONTENTS

28 Documentation, billing, and reimbursement for continuous renal replacement therapy Kevin W. Finkel 29 Machines for continuous renal replacement therapy Claudio Ronco 30 Quality assurance for continuous renal replacement therapies Ian Baldwin and Rinaldo Bellomo 31 Educational resources Ian Baldwin and Kimberly Whiteman

229

247 253

xi

Index 263

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AC ACD ACE ACT ADQI AKI AKIN AoCLF APACHE aPTT ARDS ARF ASFA AV VH BUN CAVH CAVHD CAVHDF CDI CPFA CRBSI CRRT CVC CV VH CV VHD CV VHDF DP EC ECLS ECU ECV EDD ESRF

Activated Charcoal Acid Citrate Dextrose Angiotensin-Converting Enzyme Activated Clotting Time Acute Dialysis Quality Initiative Acute Kidney Injury Acute Kidney Injury Network Acute on Chronic Liver Failure Acute Physiology and Chronic Health Evaluation Activated Partial Thromboplastin Time Acute Respiratory Distress Syndrome Acute Renal Failure American Society for Apheresis Accelerated Venovenous Hemoﬁltration Blood Urea Nitrogen Continuous Arterio-Venous Hemoﬁltration Continuous Arterio-Venous Hemodialysis Continuous Arterio-Venous Hemodiaﬁltration Central Diabetes Insipidus Coupled Plasma Filtration and Adsorption Catheter-Related Bloodstream Infections Continuous Renal Replacement Therapy Central Venous Catheter Continuous Veno-Venous Hemoﬁltration Continuous Veno-Venous Hemodialysis Continuous Veno-Venous Hemodiaﬁltration Drop Pressure Extracorporeal Circuit Extracorporeal Lung Support System Emergency Case Units Extracorporeal Volume Extended Daily Dialysis End-Stage Renal Failure

xiii

Abbreviations

ABBREVIATIONS

xiv

GFR GPCI HF HFR HITTS HP HPHD HVHF ICU IHD IJV INR LMW MODS MOST MPM NSAID PD PIRRT PT PTH RBRVS RCA RHTE RIFLE RRT RVU SAg SAPS SBE SC SCrt SCUF SID SIRS SLED SLEDD

Glomerular Filtration Rate Geographic Practice Cost Indexes Hemoﬁltration Double Chamber Hemodiaﬁltration Heparin Induced Thrombocytopenia Thrombosis Syndrome Hemoperfusion Hemoperfusion Coupled with Hemodialysis High-Volume Hemoﬁltration Intensive Care Unit Intermittent Hemodialysis Internal Jugular Vein International Normalization Ratio Low Molecular Weight Multiple Organ Dysfunction Syndrome Multi-Organ Support Therapy Mortality Prediction Model Nonsteroidal Antiinﬂammatory Drug Peritoneal Dialysis Prolonged Intermittent Renal Replacement Therapy Prothrombin Time Parathyroid Hormone Resource-Based Relative Value Scale Regional Citrate Anticoagulation Right Heart Thromboembolism Risk, Injury, Failure, Loss, and End-Stage Kidney Disease Renal Replacement Therapy Relative Value Unit Superantigen Simpliﬁed Acute Physiologic Score Standard Base Access Sieving Coefﬁcient Serum Creatinine Slow Continuous Ultraﬁltration Strong Ion Difference Systemic Inﬂammatory Response Syndrome Slow Low Efﬁciency Dialysis Sustained Low Efﬁciency Daily Dialysis

ABBREVIATIONS

Sustained Low Efﬁciency (Daily) Diaﬁltration Sepsis-Related Organ Failure Assessment Temporary Dialysis Catheter Toll-Like Receptor Transmembrane Pressure Tumor Necrosis Factor Therapeutic Plasma Exchange Ultraﬁltration

xv

SLEDD-f SOFA TDC TLR TMP TNF TPE UF

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Contributors Sean M. Bagshaw, MD

William R. Clark, MD

Assistant Professor Division of Critical Care Medicine University of Alberta Hospital University of Alberta Edmonton, Canada

Vice President, Medical Strategy and Therapy Development Gambro Renal Products Lakewood, Colorado

Clinical Educator Department of Intensive Care Austin Hospital Department of Nursing and Health Sciences RMIT University Melbourne, Australia

Rinaldo Bellomo, MD Professor of Medicine Director of Intensive Care Research Department of Intensive Care Melbourne University Melbourne, Australia

Ilona Bobek, MD Nephrologist Department of Nephrology, Dialysis and Transplantation San Bartolo Hospital Vicenza, Italy

Jorge Cerdá, MD, FACP, FASN Clinical Associate Professor of Medicine Albany Medical College and Capital District Renal Physicians Albany, New York

Assistant Clinical Professor of Medicine Nephrology Division Indiana University School of Medicine Indianapolis, Indiana

Dinna N. Cruz, MD, MPH Nephrologist Department of Nephrology, Dialysis and Transplantation San Bortolo Hospital International Renal Research Institute Vicenza Vicenza, Italy

Nigel Fealy, RN Clinical Nurse Educator Department of Intensive Care Austin Hospital Heidelberg, Australia

Kevin W. Finkel, MD, FACP, FASN Professor and Director Division of Renal Diseases and Hypertension University of Texas Medical School at Houston Houston, Texas

xvii

Ian Baldwin, RN

CONTRIBUTORS

Dehua Gong, MD Associate Professor Research Institute of Nephrology Jinling Hospital Nanjing University School of Medicine Nanjing, P.R.China

Zhongping Huang, PhD Assistant Professor Department of Mechanical Engineering Widener University Chester, Pennsylvania

xviii

John A. Kellum, MD Professor of Critical Care Medicine, Medicine, Bioengineering, and Clinical and Translational Sciences Vice Chair of Research Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Kimberly A. Maslonek, PharmD Clinical Pharmacist Cardiothoracic and Surgical ICU University of Pittsburgh Medical Center Presbyterian Pittsburgh, Pennsylvania

Michael L. Moritz, MD Associate Professor of Pediatrics Division of Nephrology Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Paul M. Palevsky, MD Professor of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Zaccaria Ricci, MD

Clinical Pharmacy Specialist, Emergency Medicine Boston Medical Center Boston, Massachusetts

Consultant Intensive Care Unit Department of Pediatric Cardiac Surgery Bambino Gesù Children’s Hospital Rome, Italy

Joseph E. Kiss, MD

Claudio Ronco, MD

Associate Professor of Medicine Department of Medicine Division of Hematology/Oncology Pittsburgh, Pennsylvania

Director Department of Nephrology, Dialysis and Transplantation San Bortolo Hospital Vicenza, Italy

Kelly A. Killius, PharmD, BCPS

Younghoon Kwon, MD Staff Intensivist Health East Care System Saint Paul, Minnesota

Jeffrey J. Letteri, BS, CHT Director Development Gambro, Inc. Lakewood, Colorado

Kai Singbartl, MD, EDIC Assistant Professor of Critical Care Medicine and Anesthesiology Department of Critical Care Medicine University of Pittsburgh Pittsburgh, Pennsylvania

Critical Care Advanced Practice Nurse University of Pittsburgh Medical Center Presbyterian Pittsburgh, Pennsylvania

Advanced Practice Nurse Educator University of Pittsburgh Medical Center Presbyterian Pittsburgh, Pennsylvania

Aditya Uppalapati, MD

Alexander Zarbock, MD

Resident Internal Medicine University of Pittsburgh Medical Center McKeesport, Pennsylvania

Resident Department of Anesthesiology and Critical Care Medicine University of Muenster Muenster, Germany

CONTRIBUTORS

Kimberly Whiteman, RN, MSN, CCRN

xix

Frederick J. Tasota, RN, MSN, CCRN

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Part 1

Theory

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Chapter 1

The critically ill patient with acute kidney injury The terms acute kidney injury (AKI) and acute renal failure (ARF) are not synonymous. While the term renal failure is best reserved for patients who have lost renal function to the point that life can no longer be sustained without intervention, AKI is used to describe the milder as well as severe forms of acute renal dysfunction in patients. Although the analogy is imperfect, the AKI–ARF relationship can be thought of as being similar to the relationship between acute coronary syndrome and ischemic heart failure. AKI is intended to describe the entire spectrum of disease from being relatively mild to severe. In contrast, renal failure is deﬁned as renal function inadequate to clear the waste products of metabolism despite the absence of or correction of hemodynamic or mechanical causes. Clinical manifestations of renal failure (either acute or chronic) include the following: • Uremic symptoms (drowsiness, nausea, hiccough, twitching) • Hyperkalemia • Hyponatremia • Metabolic acidosis

Oliguria Persistent oliguria may be a feature of ARF but nonoliguric renal failure is not uncommon. Patients may continue to make urine despite an inadequate glomerular ﬁltration. Although prognosis is often better if urine output is maintained, use of diuretics to promote urine output does not seem to improve outcome (and some studies even suggest harm).

Classiﬁcation International consensus criteria for AKI have been purposed. The acronym RIFLE is used to describe three levels of renal impairment (Risk, Injury, Failure) and two clinical outcomes (Loss and End-stage kidney disease), as shown in Figure 1.1.

3

Aditya Uppalapati and John A. Kellum

Urine output criteria

Increased creatinine x 1.5*

UO < 0.5mL/kg/h x6h

Increased creatinine x2

UO < 0.5mL/kg/h x 12 h

Injury

Failure

Loss

ESRD

Increased creatinine x3 UO < 0.3mL/kg/h or creatinine ≥4mg/dL x 24 h or (Acute rise of Anuria x12 h ≥0.5 mg/dL)

High sensitivity

Oligu ria

The critically ill patient with AKI CHAPTER 1

4

Risk

Creatinine criteria

High specificity

Persistent ARF = complete loss of renal function > 4 weeks End stage renal disease

Figure 1.1 The RIFLE Criteria for diagnosis and staging of AKI—used to describe three levels of renal impairment (Risk, Injury, Failure) and two clinical outcomes (Loss and End-stage kidney disease). Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure— deﬁnition, outcome measures, animal models, ﬂuid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204-R212. Used with permission. *An alternative proposal is to deﬁne “Risk” to include any increase in serum creatinine of at least 0.3 mg/dL, over 48 hours or less even if less than 50% increase.

Incidence and etiology of acute kidney injury The classiﬁcation system includes separate criteria for serum creatinine and urine output. The criteria, which lead to the worst classiﬁcation, deﬁne the stage of AKI. Note that RIFLE-F is present even if the increase in serum creatinine (SCrt) is less than threefold, so long as the new SCrt is <4.0 mg/dL in the setting of an acute increase of at least 0.5 mg/dL. The ﬁgure shows that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less speciﬁcity). In contrast, at the bottom, the criteria are strict and therefore speciﬁc, but some patients will be missed.

Incidence and progression Acute kidney injury occurs in 35%–65% of ICU admissions and 5%–20% of general hospital admissions. Mortality rates increase signiﬁcantly with AKI, and most studies show a—threefold to ﬁvefold increase in the risk of death among patients with AKI compared to patients without AKI. Furthermore, increases in severity of AKI are associated with a stepwise increase in risk of death such that patients reaching RIFLE-F are far more likely to die before hospital discharge

Etiology of AKI Clinical features may suggest the cause of AKI and dictate further investigation. AKI is common in the critically ill, especially in patients with sepsis and other forms of systemic inﬂammation (e.g., major surgery, trauma, burns), but other causes must be considered. In sepsis, the kidney often has a normal histological appearance. Volume-responsive AKI It is estimated that as many as 50% of cases of AKI are “ﬂuid responsive,” and the ﬁrst step in managing any case of AKI is to ensure appropriate ﬂuid resuscitation. However, volume overload is a key factor contributing to the mortality attributable to AKI, so ongoing ﬂuid administration to nonﬂuid responsive patients should be discouraged. In general, ﬂuid resuscitation should be guided by hemodynamic monitoring. Sepsis-induced AKI Sepsis is a primary cause or contributing factor in more than 50% of cases of AKI, which includes cases severe enough to require renal replacement therapy (RRT). Patients with sepsis, including those outside the ICU, develop AKI at rates as high as 40%. Septic shock appears to be an important factor in the development of sepsis-induced AKI; however, patients without overt shock do not appear to be any less likely to develop AKI.

The critically ill patient with AKI

Risk factors for developing AKI as deﬁned by RIFLE criteria are as follows: • Sepsis • Increasing age, especially age > 62 years • Race—Black patients for developing RIFLE-F • Greater severity of illness as per Acute Physiology and Chronic Health Evaluation (APACHE) III or Sepsis-related Organ Failure Assessment (SOFA) scores • Preexisting chronic kidney disease • Presiding admission to a non-ICU ward in the hospital • Surgical admissions more likely than medical admissions • Cardiovascular disease • Emergent surgeries • Being on mechanical ventilation

CHAPTER 1

Risk factors for AKI

5

compared to patients who do not progress from RIFLE-R or RIFLE-I. Hospital mortality rates for ICU patients with AKI are approximately as follows: R—9%, I—11%, F—26% compared to 6% for ICU patients without AKI. Unfortunately, more than 50% of patients with RIFLE-R progress to class I (in approximately 1–2 days) or F (in approximately 3–4 days), and almost 30% of RIFLE-I progress to F.

The critically ill patient with AKI CHAPTER 1

Hypotension Hypotension is an important risk factor for AKI, and many patients with AKI have sustained at least one episode of hypotension. Treating ﬂuid-responsive AKI with ﬂuid resuscitation is clearly an important step, but many patients will also require vasoactive therapy (e.g., dopamine, norepinephrine) to maintain arterial blood pressure. Despite a common belief among many practitioners, norepinephrine does not increase the risk of AKI compared to dopamine and renal blood ﬂow actually increases with norepinephrine in animals with sepsis. Postoperative AKI Risk factors include hypovolemia, hypotension, major abdominal surgery, and sepsis. Surgical procedures (particularly gynecological) may be complicated by damage to the lower urinary tract with an obstructive nephropathy. Abdominal aortic aneurysm surgery may be associated with renal arterial disruption. Cardiac surgery may be associated with atheroembolism and sustained periods of reduced arterial pressure as well as systemic inﬂammation.

Other causes

6

• Nephrotoxins—may cause renal failure via direct tubular injury, interstitial

• •

• •

•

•

nephritis, or renal tubular obstruction. In patients with AKI, all potential nephrotoxins should be withdrawn. Rhabdomyolysis—suggested by myoglobinuria and raised creatine kinase in patients who have suffered a crush injury, coma, or seizures. Glomerular disease—red cell casts, hematuria, proteinuria, and systemic features (e.g., hypertension, purpura, arthralgia, vasculitis) are all suggestive of glomerular disease. Renal biopsy or speciﬁc blood tests (e.g., Goodpasture’s syndrome, vasculitis) are required to conﬁrm diagnosis and guide appropriate treatment. Hemolytic uremic syndrome—suggested by hemolysis, uremia, thrombocytopenia, and neurological abnormalities. Crystal nephropathy—suggested by the presence of crystals in the urinary sediment. Microscopic examination of the crystals conﬁrms the diagnosis (e.g., urate, oxalate). Release of purines and urate are responsible for acute renal failure in the tumor lysis syndrome. Renovascular disorders—loss of vascular supply may be diagnosed by renography. Complete loss of arterial supply may occur in abdominal trauma or aortic disease (particularly dissection). More commonly, the arterial supply is partially compromised (e.g., renal artery stenosis) and blood ﬂow is further reduced by hemodynamic instability or locally via drug therapy [e.g., nonsteroidal antiinﬂammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors]. Renal vein obstruction may be due to thrombosis or external compression (e.g., raised intra-abdominal pressure). Abdominal compartment syndrome—suggested by oliguria, a ﬁrm abdomen on physical examination, and increased airway pressures (secondary to upward pressure on the diaphragms). Diagnosis is likely when sustained increased

Table 1.1 lists some common nephrotoxins.

Key references Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure—deﬁnition, outcome measures, animal models, ﬂuid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204-R212. Kellum JA. Acute Kidney Injury. Crit Care Med. 2008;36:S141-S145. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813-818.

The critically ill patient with AKI

Nephrotoxins

CHAPTER 1

intra-abdominal pressures (bladder pressure measured at end-expiration in the supine position) exceed 25 mmHg. However, abdominal compartment syndrome may occur with intra-abdominal pressures as low as 10 mmHg.

Identiﬁcation and correction of reversible causes of AKI is critical. All cases require careful attention to ﬂuid management and nutritional support.

Urinary tract obstruction Lower tract obstruction requires the insertion of a catheter (suprapubic if there is urethral disruption) to allow decompression. Ureteric obstruction requires urinary tract decompression by nephrostomy or stent. A massive diuresis is common after decompression, so it is important to ensure adequate circulating volume to prevent secondary AKI.

Hemodynamic management Fluid-responsive AKI may be reversible in its early stage. Careful ﬂuid management to ensure adequate circulating volume and any necessary inotrope or vasopressor support to ensure renal perfusion will help improve chances for renal recovery. Admission to intensive care and use of hemodynamic monitoring should be considered for all patients with AKI and is mandatory for patients not responding to conservative therapy. Table 1.1 Common nephrotoxins Allopurinol

Organic solvents

Aminoglycosides Amphotericin Furosemide

Paraquat Pentamidine Radiographic contrast

Herbal medicines Heavy metals NSAIDs

Sulfonamides Thiazides

7

Management of AKI

The critically ill patient with AKI CHAPTER 1

8

Glomerular disease Speciﬁc therapy in the form of immunosuppressive drugs may be useful after diagnosis has been conﬁrmed.

Interstitial nephritis Acute interstitial nephritis most often results from drug therapy. However, other causes include autoimmune disease, and infection (e.g., Legionella, leptospirosis, Streptococcus, cytomegalovirus). Numerous drugs have been implicated, but the most common ones are as follows: • Antibiotics (penicillins, cephalosporins, sulfa, rifampin, quinolones) • Diuretics (furosemide, bumetanide, thiazides) • NSAIDs (including selective COX-2 inhibitors) • Allopurinol • Cimetidine (rarely other H-2 blockers) • Proton pump inhibitors (omeprazole, lansoprazole) • Indinavir • 5-Aminosalicylates Urine sediment usually reveals white cells, red cells, and white cell casts. Eosinophiluria is present in about two-thirds of cases and speciﬁcity for interstitial nephritis is only about 80%. Other causes of AKI in which eosinophiluria is relatively common are rapidly progressive glomerulonephritis and renal atheroemboli. Discontinuation of the potential causative agent is a mainstay of therapy.

Abdominal compartment syndrome Abdominal compartment syndrome is a clinical diagnosis in the setting of increased intra-abdominal pressure—pressures below 10 mmHg generally rule it out, while pressures above 25 mmHg make it likely. Baseline blood pressure and abdominal wall compliance inﬂuence the amount of intra-abdominal pressure that can be tolerated. Surgical decompression is the only deﬁnitive therapy and should be undertaken before irreversible end-organ damage occurs.

Renal replacement therapy CRRT forms the mainstay of replacement therapy in critically ill patients who often cannot tolerate standard hemodialysis due to hemodynamic instability. Hybrid techniques (discussed in Chapter 24) may be reasonable alternatives in settings where CRRT cannot be accomplished but outcome data are limited. Peritoneal dialysis is not usually sufﬁcient. Mortality in the setting of acute renal failure in the critically ill is high (50%–60%). Renal recovery in survivors may be as high as 90% but recent studies suggest that sustained renal failure or incomplete renal recovery is more common than previously thought (as many as 50% of survivors do not return to baseline renal function following an episode of acute renal failure).

System Electrolyte disturbances

Mechanisms 1. Hyponatremia 2. Hyperkalemia 1. Downregulation of Beta receptors, increased iNOS 2. Hyperchloremia 3. Impairing the insulin resistance 4. Innate immunity

Acid-base (decreased chloride excretion, accumulation of organic anions like PO4, decreased albumin l decreased buffering) Cardiovascular 1. Volume overload Pulmonary

Gastrointestinal

Immune

Hematological

Nervous system

Pharmacokinetics and dynamics

1. Volume overload, decreased oncotic pressure 2. Inﬁltration and activation of lung neutrophils by cytokines 3. Uremia 1. Volume overload 2. Gut ischemia and reperfusion injury

1. Decreased clearance of oxidant stress 2. Tissue edema 3. White cell dysfunction 1. Decreased synthesis of RBC increased destruction of RBC, blood loss 2. Decreased production of erythropoietin, von willebrand’s factor 1. Secondary hepatic failure, malnutrition, altered drug metabolism 2. Hyponatremia, acidosis 3. Uremia 1. Increased volume of distribution 2. Decreased availability, albumin binding, elimination

Complications 1. CNS (see below) 2. Malignant arrhythmias 1. Decreased cardiac output, blood pressure 2. Lung, Intestinal injury, decreases gut barrier function 3. Hyperglycemia, increased protein break down 4. See below 1. Congestive heart failure 2. Secondary hypertension 1. Pulmonary edema, pleural effusions 2. Acute lung injury 3. Pulmonary hemorrhage 1. Abdominal compartment syndrome 2. Acute gastric and duodenal ulcerlbleeding; impaired nutrient absorption 1. Increased risk of infection 2. Delayed wound healing

1. Anemia 2. Bleeding

1. Altered mental status 2. Seizures, impaired consciousness, coma 3. Myopathy, neuropathyl prolonged length on mechanical ventilation 1. Drug toxicity or under dosing

The critically ill patient with AKI

Table 1.2 Clinical consequences of AKI

CHAPTER 1

Until recently it was assumed that patients with AKI died not because of AKI itself but because of their underlying disease. Several studies, however, have documented a substantial mortality attributable to AKI after controlling for other variables, including chronic illness and severity of underlying acute illness. Table 1.2 lists some of the more important clinical consequences of AKI.

9

Clinical consequences of AKI

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Chapter 2

History and rationale for continuous renal replacement therapy Ilona Bobek and Claudio Ronco

11

New therapeutic advances have coped with an increasing clinical demand for adequate and effective renal replacement therapies in the critically ill patient. The history of continuous renal replacement therapy (CRRT) is one of the best examples of multidisciplinary progress and collaboration between medical knowledge and industrial technology toward therapy improvement.

Medical demand/necessity for CRRT Change in the clinical picture of acute renal failure in the 1980s Severe sepsis was considered to be the underlying disease leading to ARF, and earlier ARF occurred frequently after abortions; however, ARFs epidemiological pattern and the involvement of other organs became more and more clear after the 1990s: • The cases of isolated (purely nephrological) ARF decreased due to early diagnosis and better prophylaxis. • More patients received increasingly extensive operations and survived serious accidents. • Number of intensive care unit (ICU) patients signiﬁcantly increased. • There was evidence of longer stay with possibility of better outcomes in ICU.

Change in the pathogenesis of ARF Main factors that are currently considered to be responsible for ARF are as follows: • Shock • Perfusion disturbances • Hypoxia

History and rationale for CRRT CHAPTER 2

12

Chronology/cornerstones of CRRT 1960s The idea of CRRT was born, but resources and technology were not available. Most ARF cases were treated with peritoneal dialysis (PD) because hemodialysis (HD) was difﬁcult to perform and it was not tolerated by intensive care patients.

1970s Henderson played an important role in developing the technical groundwork for hemoﬁltration (HF). Isolated ultraﬁltration (UF) and the use of convection for solute removal was experimentally established.

1977 First description of an arterio-venous hemoﬁltration technique was given by Kramer et al. in Göttingen, Germany. A vascular catheter that was accidentally placed into the femoral artery gave rise to the idea of using the systemic arterio-venous pressure difference in an extracorporeal circuit to generate the ultraﬁltrate, providing an effective method for elimination of both ﬂuid and solutes. Heparin could be added before and fluid could be reinfused after the ﬁltration. Continuous arterio-venous hemoﬁltration (CAVH) was soon accepted worldwide in ICUs (Figure 2.1). Advantages of CAVH: • Hemodynamic stability over conventional HD at that time • Simplicity • No necessity of blood pump • Continuous physiological ﬂuid removal Limitations of CAVH: Low efﬁciency compared to HD Reduced clearance capacity in the presence of high catabolic states Necessity of additional, intermittent HD or HF Complications associated with arterial access (indwelling catheters, thrombosis) • Reliance on arterial pressure to pump blood through the circuit • Danger of balancing errors • Necessity of continuous supervision by the staff • • • •

1979 Continuous veno-venous hemoﬁltration (CVVH) was ﬁrst employed in ARF after a cardiac surgery in Cologne, Germany. Any desired ﬁltrate volume could be arranged and uraemia could be controlled. A pump and control and balancing system became necessary (see Figure 2.2).

Ultrafilter

A

B

Venous return line

Pr Po

(2)

Substitutions lösung

Pi

(1) Ultrafiltrate clamp Graduated cylinder

(3)

Blood pump

Bubble trap Venous return clamp

Figure 2.1 The concept from Peter Kramer and Lee Henderson of continuous ﬁltration and the ﬁrst patient treated with continuous arterio-venous hemoﬁltration in Vicenza, 1978.

Minifilters

Figure 2.2 A typical system for continuous veno-venous hemoﬁltration (Hospal BM32).

13

CHAPTER 2

Heparin

History and rationale for CRRT

Po

(2) To dialyzer

History and rationale for CRRT CHAPTER 2

14

1980s Numerous technical and methodical improvements in CRRT have contributed to the following: Changes in arterio-venous technique: • Different types of catheters to obtain adequate blood ﬂow • Shorter blood line with no gadgets to reduce resistance • Positioning the collecting bag to apply a negative pressure • Optimization of treatment parameters and the concept of ﬁltration fraction • Changes in ﬁlter geometry and in the structure of ﬁber; an entire family of diaﬁlters was created to fulﬁl the hemodynamic requirements • Implementation of CAVHD; to increase the efﬁcacy, dialyses ﬂuid was ﬁltered through the external port of the ﬁlter • Combination of hemofiltration and hemodialysis, that is, CAVHDF was performed Replacement of the arterio-venous techniques by the pump-driven venovenous techniques: • Introduction of CVVH, employing blood pump to further increase efﬁciency • Use of double lumen catheters through jugular vein • Development of highly permeable polysulfone, polyacrylonitrile, and polyamid membranes with a cut off between 15,000 and 50,000 dalton • Availability of bicarbonate-buffer solutions • Establishment of new anticoagulation methods, even for patients at high risk of bleeding

1982 The use of CAVH in intensive care patients was approved by the Food and Drug Administration (FDA) in the United States.

1984 For the ﬁrst time in the world history a neonate was treated with CAVH in Vicenza, Italy (Figure 2.3).

1990–2000 Establishment of new technologies, modalities, and adequate dose of CRRT. • Adoptive technology • Machines speciﬁcally created for CRRT (Figure 2.4) • Different modalities chosen for the need of the patient • The progression of dose delivery and prescription • CRRT is achievable in most of the ICUs worldwide

2000 to present Multiorgan support therapy Patients do not die of ARF, but of multiorgan failure. The probability of death is directly correlated to the number of failing organs other than the kidney and

Reinfusion pump

Blood pump

Figure 2.3 The ﬁrst neonate treated in the world with continuous arterio-venous hemoﬁltration (CAVH) and a special miniﬁlter (Vicenza, 1984).

Evolution

CRRT evolution

RT

f CR

so gres

Pro

1977

1985

1989

2004

?

Years Figure 2.4 Evolution of continuous renal replacement therapy (CRRT) technology over the years. The case of a single company.

the severity of physiological disorders. The proper goal of extracorporeal blood puriﬁcation in ICU should be multiorgan support therapy (MOST). Treatment should not be directed at various organs as separate entities (Figure 2.5). It should be integrated and directed at patients. Therefore a wide range of supportive therapy in sepsis and liver failure were established, such as high-volume

History and rationale for CRRT

Heparin

CHAPTER 2

Bubble trap

15

Pressure monitoring

History and rationale for CRRT CHAPTER 2

CRRT

ECLS

M.O.S.T SCUF

LiverSupport - HVHF CPFA - CAST

16

Figure 2.5 The concept of MOST: Multiorgan supportive therapy. Blood can be circulated by a platform through different ﬁltration/adsorption systems, leading to removal of speciﬁc compounds and support to different failing organs.

hemoﬁltration (HVHF), coupled plasma ﬁltration and adsorption (CPFA), bioartiﬁcial liver, and endotoxin removal strategies. Acute dialysis quality initiative Acute dialysis quality initiative (ADQI) is an ongoing process that seeks to produce evidence-based recommendations for the prevention and management of acute kidney injury (AKI) and on different issues concerning acute dialysis. The following goals have been achieved: • Definition and classification of ARF [RIFLE criteria, acute kidney injury network (AKIN)] • Practice guidelines adopted in clinical practice (cardiac surgery-associated AKI)

Recent interests focus on timing of treatment initiation on patient survival and the effect of dialysis modality on recovery of renal function in ARF. Future processes involve the online preparation of reinfusion ﬂuids during high-volume hemoﬁltration, intracorporeal microﬂuidics and technology for plasma separation, intracorporeal ultraﬁltration plasma water extraction, bioartiﬁcial tubulus, new sorbent techniques, nanotechnology, and wearable/transportable devices. Renal replacement therapy (RRT) has evolved from the concept that we need to treat the dysfunction of a single organ, the kidney. However, CRRT has opened the door also to the concept of MOST. The future should require a single multifunctional machine with a very user-friendly interface and ﬂexibility in parameters and prescription such that it can be used to respond to

History and rationale for CRRT

Henderson LW, Besarab A, Michaels A, Bluemle LW. Blood puriﬁcation by ultraﬁltration and ﬂuid replacement (Diaﬁltration). Trans ASAIO. 1967;13:216-222. Henderson LW. Peritoneal ultraﬁltration dialysis: enhanced urea transfer using hypertonic peritoneal ﬂuid. JCI 1966;45:950-961. Kellum JA, Mehta R, Angus DC, Palevsky P, Ronco C; ADQI Workgroup. The ﬁrst international consensus conference on continuous renal replacement therapy. Kidney Int. 2002;62:1855-1863. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. Arterio-venous hemoﬁltration: a new simple method for treatment of overhydrated patients resistant to diuretic. Klin Wschr. 1977;55:1121-1122. Ronco C, Bellomo R, Brendolan A, et al. Effect of different doses in continuous venovenous haemoﬁltration on outcomes of acute renal failure: a prospective randomized trial. The Lancet. 2000;355:26-30. Ronco C, Bellomo R. Acute renal failure and multiple organ dysfunction in the ICU: from renal replacement therapy (RRT) to multiple organ support therapy (MOST). Int J Artif Organs. 2002;25:733-747. Sieberth HG, History and development of continuous renal replacement (CRRT). Critical Care Nephology. 1161-1167, Dordrecht: Kluwer Academic Publishers, 1998.

CHAPTER 2

Key references

17

different medical needs using different disposable layouts. The new generation of machines should be usable by different operators in different hospitals and settings.

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Chapter 3

Terminology and nomenclature Ian Baldwin and Rinaldo Bellomo

As with any specialized ﬁeld of therapy, speciﬁc terms and languages are used to describe the use of renal replacement therapy (RRT). Key acronyms are also used to describe different extracorporeal circuits (EC) for the various techniques used for RRT. These terms generally differentiate solute and solvent removal methods, treatment schedule or timing, and the intensity or “dose” of treatment. In addition, there are also speciﬁc terms used for the circuit itself and “system” components for the clinical device or machine used for RRT and for the prescription of a treatment. For clinical care, clarity of prescription orders, research, audits, reporting, and publications it is necessary and useful to have a common language.

Deﬁnitions and relevant key terms Continuous renal replacement therapy (CRRT) Continuous renal replacement therapy is a general term referring to any extracorporeal blood puriﬁcation therapy intended to substitute for impaired renal function over an extended period of time and applied for or aimed at being applied for 24 hours per day.

Continuous veno-venous hemoﬁltration (CV VH) Continuous veno-venous hemoﬁltration is a technique of CRRT whereby blood is driven through a highly permeable membrane by a peristaltic pump and via an EC originating in a central vein and also terminating in a central vein (Figure 3.1). The pressure generated by the pumped blood induces the passage of plasma water (the solvent) across the membrane. This process is called ultraﬁltration. The ultraﬁltrate produced during the transit of blood through the membrane contains all molecules to which the membrane is permeable. As solvent moves across the membrane it takes with it (solvent drag) many toxins that require removal. This process of blood puriﬁcation is called convection. The ﬂuid loss is

19

Introduction

Terminology and nomenclature CHAPTER 3

CVVH

Replacement fluid

Membrane Blood pump

Pump

Waste collection

Pump

Heater Patient

20

Figure 3.1 Continuous veno-venous hemoﬁltration (CVVH) circuit. In this circuit, the replacement ﬂuid is being delivered before the ﬁlter in predilution mode.

replaced in part or completely with appropriate replacement solutions to achieve blood puriﬁcation while maintaining volume and electrolyte homeostasis.

Continuous veno-venous hemodialysis (CV VHD) Continuous veno-venous hemodialysis is a technique of CRRT whereby blood is driven through a highly permeable membrane by a peristaltic pump and via an EC originating in a central vein and also terminating in a central vein but where solute removal is achieved by diffusion (exchange of solutes dependent on a concentration gradient) of molecules across a membrane. Such diffusion is achieved by pumping a toxin-free ﬂuid, which contains appropriate plasma electrolytes, into the nonblood side of the membrane and in a direction countercurrent to that of blood (Figure 3.2). As this ﬂuid (dialysate) passes through the blood, molecules to which the membrane is permeable move from plasma water to dialysate. The dialysate is then discarded.

Continuous veno-venous hemodiaﬁltration (CV VHDF) Continuous veno-venous hemodiaﬁltration is a technique of CRRT that combines CV VH and CV VHD. During CV VHDF, solute removal is achieved by a combination of convection and diffusion (Figure 3.3). Blood is pumped into the EC from a central vein and returned into a central vein.

Continuous arterio-venous techniques Continuous arterio-venous techniques include all techniques of CRRT (hemoﬁltration, hemodialysis, and hemodiaﬁltration) whereby the patient’s blood pressure (instead of pump) drives blood through a ﬁlter, which contains the highly permeable membrane. This process is achieved via an EC originating in an artery and terminating in a vein. The method of blood puriﬁcation is otherwise

CVVHD Heater

Blood pump

Spent dialysate

CHAPTER 3

Pump

Terminology and nomenclature

Dialysate

Patient

Figure 3.2 Continuous veno-venous hemodialysis (CVVHD) circuit.

CVVHDF

21

Dialysate

Replacement fluid Heater

Blood pump

Pump

Pump Heater

Diafiltrate/waste

Patient

Figure 3.3 Continuous veno-venous hemodiaﬁltration (CVVHDF) circuit in predilution mode.

identical to veno-venous techniques. They can be abbreviated in the same way as veno-venous techniques except for the use of AV instead of VV. Thus, for example, continuous arterio-venous hemoﬁltration would be abbreviated as CAVH. These techniques have all been abandoned in developed countries in favor of veno-venous techniques. For all techniques, ﬂuid balance is maintained by the difference between ﬂuid input (dialysate and/or replacement ﬂuid or both) and output (spent dialysate and/or ultraﬁltrate or both). Both input and output can be regulated by pumps.

Terminology and nomenclature CHAPTER 3

22

If output is greater than input, there is a negative ﬂuid balance, which can be regulated in intensity as deemed necessary.

Predilution Predilution is the administration of replacement ﬂuid into the patient’s blood before its entry into the hemoﬁlter (preﬁlter delivery).

Postdilution Postdilution is the administration of replacement ﬂuid into the patient’s blood after its exit from the hemoﬁlter (postﬁlter delivery).

Intermittent hemodialysis (IHD) Intermittent hemodialysis is a term that describes a diffusive blood puriﬁcation treatment during which blood and dialysate are circulated on the opposite sides of a semipermeable membrane in a countercurrent direction in order to achieve diffusive solute removal. IHD is performed using a machine, which is purpose-built for this technique and which can generate dialysate ﬂow rates that are much higher than those used during CRRT. IHD machines can generate dialysate from tap water through a process of bacteria and endotoxin removal and reverse osmosis with subsequent electrolyte and buffer additives to provide a dialysate ﬂuid for high ﬂow use (Figure 3.4). Prescription is commonly for 3–4 hours per session with the frequency and intensity of such sessions regulated in response to perceived clinical need. Ultraﬁltration can also be achieved to remove ﬂuid by applying a negative pressure on the dialysate side of the membrane. This allows the removal of excess ﬂuid as clinically estimated.

Tap water Electrolytes R.O.

IHD

K+ HCO3Heater

Waste

Blood pump

Patient

Figure 3.4 Intermittent hemodialysis circuit. Tap water is further puriﬁed by reverse osmosis and mixed with concentrates containing potassium, sodium, chloride, and bicarbonate to achieve physiological concentrations of each. The dialysate is then run countercurrent to blood and discarded as waste.

Extracorporeal circuit (EC) Extracorporeal circuit is the path for blood ﬂow outside the body. The EC includes the plastic tubing carrying the blood to the ﬁlter (or hemoﬁlter or dialyzer) from the vascular access catheter and from the ﬁlter back to the body via the access catheter again.

Terminology and nomenclature

Slow low efﬁciency dialysis is a dialysis treatment equivalent in nature to IHD but where dialysate and blood ﬂow rates are reduced to provide a less efﬁcient clearance rate but with an extended time of treatment (e.g., 8–12 hours instead of 3–4 hours). The acronym SLEDD is used when this technique is applied daily (D = daily). SLEDf is used when the technique includes some convective clearance in addition to diffusion (Figure 3.5). Extended daily dialysis (EDD) and extended daily dialysis with ﬁltration (EDDf) are also used to describe these respective techniques.

CHAPTER 3

Slow low efﬁciency dialysis (SLED)

Vascular access catheter is a device inserted into a central vein to allow blood to be pumped in and out of a ﬁlter. This device is typically in the form of a large central vein catheter (French gauge from 11.5 to 14.0) and has two lumens, one for outﬂow of blood from the body (typically referred to as “arterial” lumen) and one for the return of blood to the body (typically referred to as the “venous” lumen). Blood ﬂows between 150 and 300 mL/min can be typically achieved through such catheters.

Tap water Electrolytes R.O.

SLED(f)

K+ HCO3Fluid pump

Heater

Waste

Blood pump Patient

Figure 3.5 The circuit used to provide diffusive and convective clearance for SLED(f) usually for a daily treatment of 6–12 hours. The dialysate and blood ﬂow rates are lower than that for intermittent hemodialysis.

23

Vascular access catheter

Terminology and nomenclature CHAPTER 3

Diffusion Diffusion is a term that describes a type of solute transport across a semipermeable membrane. During diffusion a solute has a statistical tendency to reach the same concentration in the available distribution space on both sides of a semipermeable membrane. Thus, molecules move from the compartment with higher concentration to the compartment with lower concentration.

Convection Convection is a term that describes a type of solute transfer across a semipermeable membrane in which solute is transported together with a solvent by means of a process (ﬁltration) that occurs in response to a transmembrane pressure gradient.

Filter or dialyzer Filter or dialyzer is a tubular-shaped device that is made up of the plastic casing and the capillary ﬁbers of the semipermeable membrane within it.

24

Summary There are many techniques of CRRT, and it is useful to understand their nomenclature for ease of communication and understanding. Comparison of such circuits with those of intermittent therapies such as IHD and SLED can further help one understand the mechanisms and principles involved in achieving blood puriﬁcation during CRRT. Familiarity with the various abbreviations used in the clinical setting can help with rapid communication with other medical and nursing personnel.

Key references Bellomo R, Baldwin I, Ronco C. High-volume hemofiltration. Curr Opin Crit Care. 2000;6:442-445. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; ADQI workgroup. Acute renal failure-deﬁnition, outcome measures, animal models, ﬂuid therapy an dinformation technology needs: the second international consensus conference of the ADQI Group. Crit Care. 2004;8:R204-R212. Bellomo R, Ronco C. Nomenclature for CRRT. In: Bellomo R, Baldwin I, Ronco C, Golper T, eds. Atlas of Hemoﬁltration. London: WB Saunders; 2001:11-14. Bellomo R. Choosing a therapeutic modality: hemoﬁltration vs. hemodialysis vs. hemodiaﬁltration. Semin Dial. 1996;9:88-92. Ronco C, Bellomo R. A nomenclature of continuous renal replacement therapies. Contrib Nephrol. 1995;116:28-33.

Chapter 4

Basic principles of solute transport Zhongping Huang, Jeffrey J. Letteri, Claudio Ronco, and William R. Clark

Renal replacement therapy (RRT) is required in a signiﬁcant percentage of patients developing acute kidney injury (AKI) in an intensive care unit (ICU) setting. One of the foremost objectives of continuous renal replacement therapy (CRRT) is the removal of blood solutes retained as a consequence of decreased or absent glomerular ﬁltration. Because prescription of CRRT requires goals to be set with regard both to the rate and extent of solute removal, a thorough understanding of the mechanisms by which solute removal occurs during CRRT is necessary. This chapter provides an overview of solute transfer during CRRT.

Characterization of ﬁlter performance in CRRT Clearance Quantiﬁcation of dialytic solute removal is complicated by the confusion relating to the relationship between clearance and mass removal for different therapies. By deﬁnition, solute clearance (K) is the ratio of mass removal rate (N) to blood solute concentration (CB): K = N/CB

[1]

From a kinetic perspective, Figure 4.1 depicts the relevant ﬂows for determining CRRT clearances while Figure 4.2 provides the solute clearance expressions, which differ from those used in conventional hemodialysis. In the latter therapy, the mass removal rate (i.e., the rate at which the dialyzer extracts solute from blood into the dialysate) is estimated by measuring the difference in solute concentration between the arterial and venous lines. In other words, a “blood-side” clearance approach is used. On the other hand, in CRRT, the mass removal rate

25

Introduction

Basic principles of solute transport CHAPTER 4

QACA

QECE i

QR d

QD d QCCV

Filter

Clearance =

Mass removal rate Blood concentration QECE

=

CA

Figure 4.1 Relevant ﬂow considerations for the determination of solute clearance in CRRT. The modality represented is CV VHDF.

CVVHD/CVVHDF

(

K = E·QD

Concentration in effluent dialysate/diafiltrate Concentration in blood

)

26

E=

Postdilution CWH Concentration in filtrate ( S = Concentration ) in blood

K = S·QUF

Predilution CWH

( Q Q+ Q ) BW

K = S·QUF ·

BW

R

Figure 4.2 Solute clearance in CRRT.

is estimated by measuring the actual amount of solute appearing in the efﬂuent. The mass removal rate is the product of the efﬂuent ﬂow rate (QE) and the efﬂuent concentration of the solute (CE). In continuous veno-venous hemodialysis (CV VHD) and continuous venovenous hemodiaﬁltration (CV VHDF), the efﬂuent is dialysate and diaﬁltrate, respectively. For these therapies, the extent of solute extraction from the blood is estimated by the equilibration ratio (E), also known as the degree of efﬂuent saturation. The benchmark for efﬁciency in these therapies is the volume of ﬂuid (dialysate and/or replacement ﬂuid) required to achieve a certain solute clearance target (see below). Clearance in postdilution CV VH is the product of the SC (see below) and the ultraﬁltration rate (QUF). For small solutes like urea and creatinine, the SC is

When a dialyzer is operated as an ultraﬁlter (i.e., ultraﬁltration with no dialysate ﬂow, e.g., CV VH), solute mass transfer occurs almost exclusively by convection. Convective solute removal is primarily determined by membrane pore size and treatment ultraﬁltration rate. Mean pore size is the major determinant of a dialyzer’s ability to prevent or allow the transport of a speciﬁc solute. The sieving coefﬁcient (SC) represents the degree to which a particular membrane permits the passage of a speciﬁc solute: SC = C UF/CP

[2]

In this equation, CUF and CP are the solute concentrations in the ultraﬁltrate and the plasma (water), respectively. Irrespective of membrane type, all ﬁlters in the “virgin” state have small solute SC values of 1, and these values are typically not reported by dialyzer manufacturers. SC values for solutes of larger molecular weight are more applicable and manufacturers frequently provide data for one or more middle molecule surrogates, such as vitamin B12, inulin, cytochrome C, and myoglobin. As is the case for solute clearance, the relationship between SC and solute molecular weight is highly dependent on membrane mean pore size. Sieving coefﬁcient (SC) data provided by manufacturers are usually derived from in vitro experimental systems in which (nonprotein containing) aqueous solutions are used as the blood compartment ﬂuid. In actual clinical practice, nonspeciﬁc adsorption of plasma proteins to a dialyzer membrane effectively reduces the permeability of the membrane. Consequently, in vivo SC values are typically less than those derived from aqueous experiments, sometimes by a considerable amount.

Transmembrane solute removal mechanisms Diffusion Diffusion is the process of transport in which molecules that are present in a solvent and can freely move across a semipermeable membrane tend to move

Basic principles of solute transport CHAPTER 4

Sieving coefﬁcient

27

essentially 1 (under normal ﬁlter operation). Therefore, small solute clearance in postdilution CV VH essentially is equal to the QUF. On the other hand, estimation of clearance in predilution CV VH has to account for the fact that the blood solute concentrations are reduced by dilution of the blood before it enters the ﬁlter. Thus, the clearance has a “dilution factor” that is represented by the third term on the right hand side of the second equation above. This term essentially is the ratio of the blood ﬂow rate (QB) to the sum of QB and the replacement ﬂuid rate (QRF). (The actual blood ﬂow parameter, QBW, is blood water ﬂow rate.) In essence, the dilution factor can be viewed as a measure of the extent to which predilution differs from postdilution for a speciﬁc combination of QB and QUF.

Basic principles of solute transport CHAPTER 4

28

from the region of higher concentration into the region of lower concentration (Figure 4.3). 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 toward the region of lower concentration is statistically higher. Therefore, this transport mechanism occurs in the presence of a concentration gradient for solutes that are not restricted in diffusion by the porosity of the membrane. In addition to transmembrane concentration gradient, Fick’s Law states that diffusive solute is inﬂuenced by the following: • Membrane characteristics: surface area, thickness, porosity • Solute diffusion coefﬁcient (primarily a function of molecular weight) • Solution temperature Based on the previous discussion, the clearance of a given solute can be predicted with reasonable certainty under a given set of operating conditions. However, several factors may lead to a divergence between theoretical and empirically derived values. As an example, protein binding or electrical charges in the solute may negatively impact the ﬁnal clearance value. Conversely, convection may result in a measured clearance value that is signiﬁcantly greater than the value based on a “pure” diffusion assumption. Diffusion is an efﬁcient transport mechanism for the removal of relatively small solutes, but as solute molecular weight increases, diffusion becomes limited and the relative importance of convection increases.

Convection Convection is the mass transfer mechanism associated with ultraﬁltration of plasma water. If a solute is small enough to pass through the pore structure of the membrane, it is driven (“dragged”) across the membrane in association Diffusion is solute transport across a semipermeable membrane—molecules move from an area of higher to an area of lower concentration

Best for small molecule clearance

Convection is a process where solutes pass a cross the semipermeable membrane along with the solvent (‘‘solvent drag’’) in response to a positive transmembrane pressure

Effectiveness less dependent on molecular size

Figure 4.3 Mechanisms of diffusion and convection.

In this equation, KF is the membrane-speciﬁc hydraulic permeability (units: mL/h/ mmHg/m2) and TMP is a function of both the hydrostatic and oncotic pressure gradients. Convective ﬂux of a given solute is a function mainly of the following parameters: • Ultraﬁltration rate • Blood solute concentration • Membrane sieving properties In clinical practice, however, because plasma proteins and other factors modify the “native” properties of the membrane, the ﬁnal observed SC is smaller than that expected from a simple theoretical calculation. As noted above, nonspeciﬁc adsorption of plasma proteins (i.e., secondary membrane formation) occurs instantaneously to an extracorporeal membrane after exposure to blood. This changes the effective permeability of the membrane and can be explained by the action of proteins to essentially “plug” or block a certain percentage of membrane pores. Postdilution ﬂuid replacement tends to accentuate secondary membrane effects because protein concentrations are increased within the membrane ﬁbers (due to hemoconcentration). On the other hand, higher blood ﬂow rates work to attenuate this process because the shear effect created by the blood disrupts the binding of proteins to the membrane surface.

Kinetic considerations for different CRRT techniques In CV VH, high-ﬂux membranes are utilized 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 reinfusion (replacement) ﬂuid. As described in greater detail elsewhere, replacement ﬂuid can either be infused before the ﬁlter (predilution) or after the ﬁlter (postdilution). Postdilution hemoﬁltration is inherently limited by the attainable blood ﬂow rate and the associated ﬁltration fraction constraint. On the other hand, from a mass transfer perspective, the use of predilution has several potential advantages over postdilution. First, both hematocrit and total blood protein concentration are reduced signiﬁcantly before the blood enters into the hemoﬁlter. This effective reduction in the red cell and protein content of the blood attenuates the secondary membrane and concentration

Basic principles of solute transport

[3]

CHAPTER 4

JF = KFTMP

29

with the ultraﬁltrated plasma water. This movement of plasma water is a consequence of a transmembrane pressure (TMP) gradient. Quantitatively, the ultraﬁltration ﬂux (JF), deﬁned as the ultraﬁltration rate normalized to membrane surface area, can be described by

Basic principles of solute transport CHAPTER 4

30

polarization phenomena described above, resulting in improved mass transfer. Predilution also favorably impacts mass transfer due to the augmented ﬂow in the blood compartment because preﬁlter mixing of blood and replacement ﬂuid occurs. This achieves a relatively high membrane shear rate, which also reduces solute-membrane interactions. Finally, predilution may also enhance mass transfer for some compounds by creating concentration gradients that induce solute movement out of red blood cells. However, the major drawback of predilution hemoﬁltration is its relatively low efﬁciency, resulting in relatively high replacement ﬂuid requirements to achieve a given solute clearance. In a group of patients treated with a “traditional” blood ﬂow rate for CRRT, the efﬁciency loss associated with predilution has recently been quantiﬁed. Troyanov et al. demonstrated the signiﬁcant negative effect on efﬁciency when a relatively low QB (less than 150 mL/min) is used with a relatively high QUF and QRF in predilution CV VH. This speciﬁc combination of QB = 125–150 mL/min and QUF = 4.5 L/h (75 mL/min) is associated with a loss of efﬁciency of 30%–40% relative to postdilution for several different solutes. In other words, to achieve the same solute clearance, 30%–40% more replacement ﬂuid is required in predilution under these conditions, relative to postdilution under the same conditions. However, it should be noted that the likelihood of achieving such an ultraﬁltration rate in postdilution is very remote at such a low blood ﬂow rate, as this would require a ﬁltration fraction in excess of 50%. This condition is likely to lead to very short-term ﬁlter patency. In CV VHDF, a high-ﬂux hemodiaﬁlter is used, and the operating principles of hemodialysis and hemoﬁltration are combined. 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. The ultraﬁltrate is partially or totally replaced with reinfusion ﬂuid, either in predilution or postdilution mode. Latergeneration CRRT machines allow a combination of predilution and postdilution with the aim of combining the advantages of both reinfusion techniques. Information from the chronic hemodiaﬁltration literature suggests that a combination of predilution and postdilution may be optimal in terms of clearance and operational parameters. This may also be the case for CV VHDF in AKI, although this possibility has not been assessed carefully. The optimal balance is most likely dictated by the speciﬁc set of CV VHDF operating conditions, namely blood ﬂow rate, dialysate ﬂow rate, ultraﬁltration rate, and ﬁlter type. Due to the markedly lower ﬂow rates used and clearances obtained in CV VHDF, the effect of simultaneous diffusion and convection on overall solute removal is quite different from the situation in chronic hemodiaﬁltration (HDF). In the latter application, 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. On the other hand, in CV VHDF

M-100 70

Urea, CVVH Urea, CVVHDF B2-Microglobulin, CVVH B2-Microglobulin, CVVHDF

Clearance (mL/min)

60 50 40 30 20 10 0 0

0.5

1.0

1.5

2.0 2.5 3.0 Effluent (mL/h)

3.5

4.0

4.5

Figure 4.4 Comparison of solute clearance in predilution CVVH and CVVHDF. From Troyanov S, Cardinal J, Geadah D, et al. Solute clearances during continuous venvenous haemoﬁltration at various ultraﬁltration ﬂow rates using Multiﬂow-100 and HF1000 ﬁlters. Nephrol Dial Transplant. 2003;18:961-966. Reprinted by permission of Oxford University Press.

Basic principles of solute transport CHAPTER 4

31

the small solute concentration gradient along the axial length of the ﬁlter (i.e., extraction) is minimal compared to the one that is seen in chronic HDF, in which extraction ratios of 50% or more are the norm. Thus, the minimal diffusionrelated change in small solute concentrations along the ﬁlter length allows any additional clearance related to convection to be simply additive to the diffusive component Troyanov et al. have performed a direct clinical comparison of CV VHDF and predilution CV VH with respect to urea and E2-microglobulin (B2M) clearance at a “traditional” blood ﬂow rate of 125 mL/min. The study compared clearances at the same efﬂuent rate over an efﬂuent range of up to 4.5 L/h. As Figure 4.4 indicates, urea clearance was higher in CV VHDF than in predilution CV VH and, in fact, the difference between the two therapies increased as efﬂuent rate increased. These results are consistent with the “penalizing” effect of predilution, which is especially pronounced at low blood ﬂow rates. For B2M, the results are contrary to the “conventional wisdom,” which would suggest that a purely convective therapy like CV VH should inherently be superior to a partly convective therapy like CV VHDF for clearance of a molecule of this size. However, once again, the penalty of predilution in CV VH is apparent, as the B2M clearances for the two modalities are equivalent except at very high efﬂuent rates (greater than 3.5 L/h). Until the impact of higher blood ﬂow rates on solute clearances in CRRT can be assessed, these and other data suggest that CV VHDF is a logical modality choice to achieve the broadest spectrum of solute molecular weight range in the most efﬁcient way.

Basic principles of solute transport CHAPTER 4

32

Summary Rational prescription of CRRT to critically ill patients with AKI is predicated upon an understanding of the basic principles of solute and water removal. In this chapter, the major ways in which ﬁlter function is characterized have been reviewed clinically. In addition, the fundamental mechanisms for solute and ﬂuid transport have been discussed. Finally, these principles have been applied in a therapeutic context to the various CRRT modalities used by clinicians managing AKI patients.

Suggested readings 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. Clark WR, Turk JE, Kraus MA, Gao D. Dose determinants in continuous renal replacement therapy. Artif Organs. 2003;27:815-820. Henderson LW. Biophysics of ultrafiltration and hemofiltration. In: Jacobs C, ed. Replacement of Renal Function by Dialysis. 4th ed. Dordrecht: Kluwer Academic Publishers; 1996:114-118. Huang Z, Letteri JJ, Clark WR, Ronco C. Operational characteristics of continuous renal replacement therapy modalities used for critically ill patients with acute kidney injury. Int J Artif Organs. 2008;31:525-534. Huang Z, Letteri JJ, Clark WR, Zhang W, Gao D, Ronco C. Ultraﬁltration rate as dose surrogate in pre-dilution hemoﬁltration. Int J Artif Organs. 2007;30:124-132. Troyanov S, Cardinal J, Geadah D, et al. Solute clearances during continuous venvenous haemoﬁltration at various ultraﬁltration ﬂow rates using Multiﬂow-100 and HF1000 ﬁlters. Nephrol Dial Transplant. 2003;18:961-966.

Chapter 5

Principles of ﬂuid management Rinaldo Bellomo and Sean M. Bagshaw

The control and optimization of ﬂuid balance is a clinically important component of continuous renal replacement therapy (CRRT). Inadequate ﬂuid removal is associated with peripheral edema and vital organ edema (i.e., pulmonary edema). Such edema can retard weaning from mechanical ventilation or comprise wound healing. Fluid overload has been identiﬁed as an independent predictor of increased mortality in critically ill patients and is clearly undesirable. Similarly, excessive ﬂuid removal may contribute to hypovolemia with increased doses of vasopressor drug therapy, exposing the patients to the risks of unnecessary beta and alpha receptor stimulation. Hypovolemia may induce hypotension and, thereby, possibly aggravate organ injury and, speciﬁcally, retard or block renal recovery. Accordingly, careful clinical assessment of the patient’s ﬂuid status and careful prescription of CRRT to optimize ﬂuid balance, together with frequent review of such assessment and prescription, represent a key aspect of best practice in the ﬁeld of CRRT. Patient ﬂuid balance: This term refers to the total balance over a 24-hour period of ﬂuids administered (intermittent drugs, continuous infusion of drugs, blood, blood products, nutrient solutions, additional ﬂuids) and measurable ﬂuids removed (drainage from chest or abdomen, urine —if present, blood loss, and excess ﬂuid removed by the CRRT machine). Machine (CRRT) ﬂuid balance: This term refers to the total balance over a 24-hour period of ﬂuids administered by the CRRT machine (dialysate or replacement ﬂuid or both depending on the technique and any additional anticoagulant infusion) and ﬂuids removed by the CRRT machine (spent dialysate or ultraﬁltrate or both depending on the technique). Efﬂuent: It is the total amount of ﬂuid discarded by the machine. In continuous veno-venous hemoﬁltration (CV VH), this is the same as ultraﬁltrate. In continuous veno-venous hemodialysis (CV VHD), this is equal to the spent dialysate + any additional ultraﬁltrate generated by the machine. In continuous veno-venous

33

Introduction

Principles of ﬂuid management CHAPTER 5

34

hemodiaﬁltration (CV VHDF), this is the same as the sum of spent dialysate and ultraﬁltrate discarded by the machine (also called spent ultradiaﬁltrate). Dry weight: This is the patient’s normal/optimal weight before the onset of illness. This weight is often available in detail in elective operative patients where it is typically measured before the operation. In other cases, it might need to be estimated. Edema: This term refers to the accumulation of excess ﬂuid in the extracellular compartment. In the subcutaneous tissue, it can be detected by the phenomenon of pitting of the skin under pressure. In the lungs, if signiﬁcant, it can be detected by radiography. Assessment of ﬂuid status: This term refers to the clinical process of estimating the patient’s intravascular and extravascular ﬂuid status. Such assessment is complex and imperfect. It requires consideration of vital signs, invasive and noninvasive hemodynamic measurements, information of ﬂuid balance and body weight, and radiological information. Such assessment is necessary to guide ﬂuid balance prescription during CRRT.

Approach to ﬂuid balance during CRRT The prescription of CRRT-related ﬂuid management and its integration into overall patient ﬂuid management can be assisted by a speciﬁc order chart (Table 5.1) for the machine ﬂuid balance. The above order chart will tell the nurse how to set the machine and how to achieve the planned hourly ﬂuid balance. However, in the intensive care unit (ICU), the ﬂuid needs of the patients are not static and require frequent review. For example, should the same patient require the administration of 600 mL of fresh frozen plasma over 2 hours prior to an invasive procedure, necessary adjustments to the order should be made with speciﬁcation for the duration of change and the reasons (Table 5.2). The ﬂuid balance prescription related to the machine can be usefully related to the patient and a ﬂuid balance prescription describing the overall patient ﬂuid balance goal for a 12-hour time period is useful for informing the nurse what the broad goals of ﬂuid therapy are in a given patient. This may be expressed in an additional prescription attached to the previous machine ﬂuid balance chart (Table 5.3).

Table 5.1 Example Order Chart Technique

Dialysate ﬂow rate

CV VHDF

1000 mL/h

Replacement ﬂuid ﬂow rate 1000 mL/h

Efﬂuent ﬂow rate 2300 mL/h

Anticoagulant infusion ﬂow rate 100 mL/h

Machine ﬂuid balance –200 mL/h

Dialysate ﬂow rate

CV VHDF

1000 mL/h

Replacement Efﬂuent Anticoagulant Machine ﬂuid balance ﬂuid ﬂow rate ﬂow rate infusion ﬂow rate 1000 mL/h 2600 mL/h 100 mL/h –500 mL/h (for 2 hours only during FFP treatment)

Note: FFP = Fresh frozen plasma

Table 5.3 Example Order Chart 3 Patient

Medical record number

Name

00123

Overall ﬂuid balance from midnight to 12:00 (noon) –1000 mL

Overall ﬂuid balance from 12:00 (noon) to midnight –1000 mL/h

Right atrial pressure notiﬁcation range

Principles of ﬂuid management

Technique

CHAPTER 5

Table 5.2 Example Order Chart 2

<6 or >15 mmHg

The above goals can be achieved by means of physician and nursing education and by ensuring that no CRRT session can be started unless such orders are clearly and legibly written, signed, and accompanied by the physician’s printed name and contact number. They also require the regular recording of ﬂuid balance on an hourly basis and its correct ﬁnal addition of ﬂuid losses and gains. This can be done in a computerized system or added by the nurse at the bedside using a pocket calculator and then charted. This process allows the creation of a running hourly balance, which is useful in ensuring that progress is being made at the appropriate speed, in the appropriate direction, and to the prescribed amount.

Expected outcomes, potential problems, cautions, and beneﬁts The expected outcome of a systematic process for the prescription, delivery, and monitoring of ﬂuids during CRRT is the ability to ensure that the patient will receive prescribed therapy in a safe and effective manner. This approach will minimize errors and their consequences (persistent ﬂuid overload or dangerous intravascular volume depletion). Despite this careful approach, problems can still arise. A relatively common problem is related to off-time (time during which CRRT is not operative due to ﬁlter clotting or an out-of-ICU procedure or investigation). Under such circumstances, the ﬂuid removal cannot proceed as planned. If the patient has 5 hours of off-time, then the consequence may be that close to 1 L of planned

35

Practical considerations

Principles of ﬂuid management CHAPTER 5

36

ﬂuid removal fails to occur (assuming ﬂuid balance of 200mL/h). Moreover, during this off-time, patients may be administered additional ﬂuid that will counter earlier ﬂuid balance goals. If this happens, the physician and the nurse need to be alert to the consequences and respond appropriately. This my require an adjustment in ﬂuid removal during the ensuing 12 or 24 hours, which safely compensates for the off-time by increasing the hourly ﬂuid removal by, for example, an extra 100 mL/h. Due consideration needs to be paid to speciﬁc patients where such ﬂuid removal may be problematic. However, typically, machine ﬂuid removal rates of 300–400 mL/h are well tolerated in ﬂuid-overloaded patients. Nonetheless, caution should be exerted and the patient’s condition should be reviewed frequently. Another relatively common problem is the frequent interruptions of therapy due to machine alarms. In some patients who are agitated or who have frequent leg ﬂexion in the presence of a femoral access catheter or who sit up and move in the bed in the presence of a subclavian access device, the machine pressure alarms may be frequently triggered. In addition, other alarms related to substitution ﬂuids bag or waste bag changes interrupt treatment. This may lead to periods of 5–10 minutes over an hour and over a day create “lost treatment time” and failure to achieve ﬂuid balance goals. It is often prudent to prescribe a greater ﬂuid loss than desired to compensate for these factors. Most machines allow the operator to check what the actual ﬂuid removal achieved was over a given time period. Such checks should be done to ensure that the correct ﬂuid removal is entered into the ﬂuid balance calculations; many nursing protocols mandate ﬂuid balance check each hour particularly for inexperienced nurses. The beneﬁts of such continuous monitoring of ﬂuid delivery and removal are many. They include frequent patient assessment, vigilance with regard to other simultaneous therapies, attention to detail, avoidance of dangerous swings in ﬂuid status, and competent and detailed machine operation.

Conclusion Attention to ﬂuid balance during CRRT is of great clinical importance. Inadequate ﬂuid removal leads to clinical complications, especially in relation to weaning from mechanical ventilation. Excessive ﬂuid removal can cause hypovolemia and hypotension, and retard renal recovery. Best practice in this ﬁeld can only be achieved by a systematic combination of frequent and thoughtful assessment, attention to detail, rigorous and vigilant monitoring of ﬂuid input and output, and clear and explicit description and prescription of the goals of therapy with regard to both machine settings and patient management.

Principles of ﬂuid management CHAPTER 5

Bagshaw SM, Baldwin I, Fealy N, Bellomo R. Fluid balance error in continuous renal replacement therapy: a technical note. Int J Artif Organs. 2007;30:435-440. Bagshaw SM, Bellomo R. Fluid resuscitation and the septic kidney. Curr Opin Crit Care. 2006;12:527-530. Bagshaw SM, Bellomo R. The inﬂuence of volume management on outcome. Curr Opin Crit Care. 2007;13:541-548. Bagshaw SM, Brophy PD, Cruz D, Ronco C. Fluid balance as a biomarker: impact of ﬂuid overload on outcome in critically ill patients with acute kidney injury. Crit Care. 2008;12:169.

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Key references

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Chapter 6

Indications, timing, and patient selection John A. Kellum

Indications for renal replacement therapy

39

Indications for renal replacement therapy (RRT) fall into two broad categories, so-called “renal” (i.e., to speciﬁcally address the consequences of renal failure) and “nonrenal” (without necessitating renal failure). Although the distinction is not always precise, it is a reasonably easy way to categorize indications for RRT.

Renal indications The manifestations of acute kidney disease (as discussed in Chapter 1 and summarized in Table 6.1) include oliguria, (leading to volume overload), azotemia (leading to a host of clinical complications), hyperkalemia, and metabolic acidosis. While there is no consensus regarding the precise level of dysfunction in any of these areas that should prompt initiation of RRT, general agreement exists on the following general indications for RRT: • Volume overload (e.g., pulmonary edema) • Azotemia with uremic symptoms • Hyperkalemia (>6.0 mmol/L) • Metabolic acidosis (pH < 7.2) due to renal failure Volume overload Volume overload usually occurs in the setting of oliguria, but it may occur simply because urine output is insufﬁcient to maintain ﬂuid balance in the face of large

Table 6.1 Diuretic dosing Metolazone Chlorothiazide Furosemide Torsemide Bumetanide

Oral 10–20 mg qd 20–40 mg 6–24-hourly 5–20 mg 6–24-hourly 0.5–1 mg 6–24-hourly

IV

Infusion

250–500 mg IV 5–80 mg 6–24-hourly 5–20 mg 6–24-hourly 0.5–2 mg 6–24-hourly

1–10 mg/h 1–5 mg/h 1–5 mg/h

Indications, timing, and patient selection CHAPTER 6

40

volume input—even if true oliguria is not present. Furthermore, most authorities recommend therapy before volume overload becomes clinically manifest, and thus RRT may be used to “create space” for additional ﬂuids (e.g., nutritional support, antibiotics) that are scheduled to be administered. There is a controversy regarding the role of diuretics in the setting of volume overload secondary to acute renal failure (ARF). While most clinicians will attempt diuretics prior to initiation of RRT, there is a wide variation as to how long or intense such a trial will be or how the success will be deﬁned. Although it is obviously desirable to avoid RRT, there is little evidence to suggest that diuretics can be successful in achieving this goal and even the available evidence suggests potential harm. Importantly, attempts to increase urine output with diuretics should only be directed toward treatment of volume overload or hyperkalemia, not oliguria per se. Large observational studies have failed to show beneﬁt from diuretics in critically ill patients with oliguria, and some studies have shown harm. Diuretic therapy A loop diuretic such as furosemide is given in a dose of 20–40 mg intravenously. If this dose is ineffective, a higher dose can be tried within 30–60 minutes. Higher doses may be needed if the patient has previously received diuretic therapy (see Table 6.2). If boluses doses of 80 mg every 6 hours are infective, an infusion may be started (1–5 mg/h IV). A thiazide diuretic such as chlorothiazide (250–500 mg IV) or metolazone (10–20 mg PO) can be used in conjunction with a loop diuretic to improve diuresis. In general, there is no point in continuing diuretic therapy if it is not effective; loop diuretics in particular may be nephrotoxic. Discontinue all diuretics prior to initiating RRT. Azotemia Azotemia, the retention of urea and other nitrogenous waste products, results from a reduction in glomerular ﬁltration rate (GFR) and is a cardinal feature of kidney failure. However, like oliguria, azotemia represents not only disease but also a normal response of the kidney to extracellular volume depletion or a decreased renal blood ﬂow. Conversely, a “normal” GFR in the face of volume depletion could only be viewed as renal dysfunction. Thus, changes in urine output and GFR are neither necessary nor sufﬁcient for the diagnosis of renal pathology. Yet, no simple alternative for the diagnosis currently exists. Azotemia is also a biochemical marker of the uremic syndrome, a condition caused by a diverse group of toxins that are normally excreted but build up in the circulation and in the tissues during renal failure. The clinical manifestations of the uremic syndrome are shown in the Table 6.2. Although uremic symptoms correlate with the level of urea in the blood, the relationship between blood urea nitrogen (BUN) and uremic symptoms is not consistent across individuals or even within a given individual at different times. Thus, there is no threshold level of BUN that deﬁnes uremia or provides a speciﬁc indication for RRT. Instead, the provision of RRT and, indeed, decisions

Complication(s)

Mechanism(s)

Cardiovascular

Volume overload

Electrolyte and acid-base

Hyponatremia, hyperkalemia, acidosis, azotemia

Gastrointestinal

Impaired nutrient absorption, GI bleeding, abdominal compartment syndrome Anemia, platelet dysfunction

Salt/water retention Edema, heart failure, hypertension Impaired free water Hypotension, impaired excretion, chloride glucose metabolism, decreased muscle accumulation protein synthesis, cardiac dysrhythmias Nausea, vomiting, Bowel edema, platelet dysfunction, decreased mucosal/ intestinal absorption, volume overload increased intra-abdominal pressures

Immune Nervous Respiratory

Infections, immune suppression Encephalopathy Pleural effusions, pulmonary edema

Decreased erythropoietin, decreased von Wilibrand’s factor Impaired neutrophil function Uremic toxins, hyponatremia Volume overload, decreased oncotic pressure, ? direct uremic toxicity

Anemia, bleeding

Infection, sepsis Asterixis, delirium, coma Pleural effusion, pulmonary edema, respiratory failure

regarding timing and intensity should be individualized to patients on the basis of clinical factors and not solely on the basis of biochemical markers. Hyperkalemia Hyperkalemia may be severe and can be life threatening. The risks of hyperkalemia are greatest when it develops rapidly, where serum concentrations in excess of 6 mmol/L may produce cardiac dysrhythmias. The earliest electocardiographic sign of hyperkalemia is peaking of the T waves. This ﬁnding is associated with cardiac irritability and should prompt emergent treatment. Temporary management of severe hyperkalemia (while preparing for RRT) includes intravenous calcium chloride (10 mL of 10% solution) to reduce cardiac irritability and a combination of insulin (10 units IV) and dextrose (50 mL D50) given together over 20 minutes to shift potassium intracellularly (blood glucose should be monitored). Metabolic acidosis Renal failure causes metabolic acidosis by retention of various acid anions (e.g., phosphate, sulfate) as well as from renal tubular dysfunction resulting in hyperchloremic acidosis. Clinical manifestations range from acute alterations

41

Hematological

Clinical features

Indications, timing, and patient selection

System

CHAPTER 6

Table 6.2 Manifestations of renal failure

Indications, timing, and patient selection CHAPTER 6

42

in inﬂammatory cell function to chronic changes in bone mineralization. Mild alterations can be managed using oral sodium bicarbonate or calcium carbonate. RRT is effective in removing acids as well as correcting plasma sodium and chloride balance and is generally targeted at maintaining an arterial pH > 7.30.

“Nonrenal” indications So-called nonrenal indications for RRT are to remove various dialyzable substances from the blood. These substances include drugs, poisons, contrast agents, and cytokines.

Drug and toxin removal Blood puriﬁcation techniques have long been used for removal of various dialyzable drugs and toxins. A list of common drugs and toxins that can be readily removed using RRT is shown in Table 6.3. The majority of poisoning cases do not require treatment with RRT. Indeed, the drugs or toxins that are most commonly responsible for poisoning-related fatalities are not amenable to RRT (e.g., acetaminophen, tricyclic antidepressants, short-acting barbiturates,

Table 6.3 Common poisonings treated with RRT Substance Methanol

Extracorporeal method Hemodialysis

Isopropanol

Hemodialysis

Ethylene glycol

Hemodialysis

Lithium

IHD/CRRT

Salicylate

IHD/CRRT

Theophylline

IHD/CRRT/ hemoperfusion

Valproic acid

IHD/CRRT/ hemoperfusion

Comments RRT should be continued until the serum methanol concentration is < 25 mg/dL and the anion-gap metabolic acidosis and osmolal gap are normal. Rebound may occur up to 36 hours. RRT effectively removes isopropanol and acetone, although it is usually unnecessary except in severe cases (prolonged coma, myocardial depression, renal failure). RRT should be continued until the ethylene glycol level is <20 mg/dL and metabolic acidosis or other signs of systemic toxicity have been resolved. Rebound may occur up to 24 hours. IHD removes lithium faster but rebound is a signiﬁcant problem and can be addressed effectively with CRRT. Both IHD/CRRT have been reported in the management of salicylate poisoning. RRT should be continued until clinical improvement and a plasma level < 20 mg/L is obtained. Rebound may occur. At supratherapeutic drug level plasma proteins become saturated, and the fraction of unbound drug increases substantially and becomes dialyzable.

Note: Other treatments are also required for many of these substances.

Indications, timing, and patient selection CHAPTER 6

stimulants, and “street drugs”). In general, the size of the molecule and the degree of protein binding determines the degree to which the substance can be removed (smaller, nonprotein bound substances are easiest to remove). Continuous renal replacement therapy (CRRT) may be effective in removing substances with higher degrees of protein binding and is sometimes used to remove substances with very long plasma half-lives. Techniques such as sorbent hemoperfusion may also be used for this indication and are discussed further in Chapter 23. The role of CRRT in the management of acute poisonings is not well established. There is relatively lower drug clearance per unit of time compared to intermittent hemodialysis (IHD) but CRRT has a distinct advantage in hemodynamically unstable patients who are unable to tolerate the rapid solute and ﬂuid losses associated with IHD or even other techniques such as hemoperfusion. CRRT may also be effective for the slow, continuous removal of substances with large volumes of distribution, a high degree of tissue binding, or for substances that are prone to “rebound phenomenon” (e.g., lithium, procainamide, and methotrexate). In such cases, CRRT may even be used as adjuvant therapy with IHD or hemoperfusion. RRT has been used to remove radio-contrast agents for many years, but the purpose of this treatment has changed over time. In the past, ionic, high-osmolar contrast was used for imaging studies, and RRT was often used to remove these substances and to remove ﬂuid in patients with renal failure who were at risk of congestive heart failure from the large osmotic load. These patients could not excrete the contrast and would develop pulmonary edema after contrast administration. In more recent years, nonionic, low-osmolality, or even iso-osmolar agents have been developed, and the risk of pulmonary edema has decreased signiﬁcantly. However, all radio-contrast agents are nephrotoxic and CRRT is being advocated by some experts to help prevent so-called contrast nephropathy. Standard IHD has been shown to remove radio-contrast agents but does not appear to prevent contrast nephropathy. Despite less efﬁciency in removing contrast, CRRT has been shown to result in less contrast nephropathy, particularly when it has begun prior to or in conjunction with contrast administration (see Table 6.4). However, the effect is controversial and most centers do not currently offer RRT for prevention of contrast nephropathy.

Cytokines Many endogenous mediators of sepsis can be removed using continuous venovenous hemoﬁltration (CV VH) or continuous veno-venous hemodiaﬁltration (CV VHDF) (dialysis is not able to remove these mediators). This observation has prompted many investigators to attempt to use CV VH as an adjunctive therapy in sepsis. While it remains controversial as to whether CV VH offers additional beneﬁt in patients with renal failure and sepsis, available evidence does not support a role of CV VH for the removal of cytokines in patients without

43

Contrast agents

Indications, timing, and patient selection CHAPTER 6

44

Table 6.4 Methods to reduce contrast nephropathy Saline

IV 0.9% (154 mEq/L)

Dosinga 1 mL/kg/h begun 12 hours or 3 mL/kg/h begun 1 hour prior to procedure and 1 mL/kg/h continuing 6 hours after procedure

NaHCO3 in water

150 mEq/L

1 mL/kg/h begun 12 hours or 3 mL/kg/h begun 1 hour prior to procedure and 1 mL/kg/h continuing 6 hours after procedure beginning 24 hours before and continuing 24 hours after procedure

Oral

N-acetylcysteine

1200 mg every 1200 mg every 12 hours 12 hours

: a Dosing ranges are provided as a general guide only—none of the above agents are approved for this indication.

renal failure. If CV VH is capable of removing cytokines, the effect of standard “renal dose” CV VH appears to be small. However, some individuals appear to respond with improved hemodynamics, especially to higher doses of CV VH (also see Chapter 7).

Key studies Lee PT, Chou KJ, Liu CP, et al. Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am Coll Cardiol. 2007;50:1015-1020. Mehta RL, Pascual MT, Soroko S, et al; PICARD Study Group. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA. 2002;288:2547-2553. Uchino S, Doig GS, Bellomo R, et al; B.E.S.T. Kidney Investigators. Diuretics and mortality in acute renal failure. Crit Care Med. 2004;32:1669-1677.

Timing of RRT When to initiate RRT The simplest answer to the question “when should RRT be started?” would be when the indications discussed above are met. Numerous attempts have been made to reach a consensus on timing of RRT. The Acute Dialysis Quality Initiative (ADQI) ﬁrst addressed this issue in 2000 but was unable to reach consensus beyond stating that a patient is considered to require RRT when he or she has “an acute fall of GFR and has developed, or is at risk of, clinically significant solute imbalance/toxicity or volume overload.” In essence this amounts to saying that RRT should begin when a patient has “symptomatic” ARF. What constitutes symptomatic ARF is a matter of clinical judgment and how “at risk”

An even more difﬁcult question to answer than when to start is when to stop RRT. Again the simplest answer would be “when renal function has recovered,” but two problems exist with this simple answer. First, it is not always easy to determine when renal function has recovered and it is also unclear what amount of recovery should be sought prior to cessation of therapy. In essence the question is not dissimilar to so-called weaning from mechanical ventilation and very little is actually known about how and when “weaning” from RRT should occur. One approach that was used in the largest trial of dialysis intensity published to date used the rule described in Table 6.5.

Key studies Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury is associated with hospital mortality in critical ill patients: A cohort analysis. Crit Care. 2006;10:R73. Kellum JA, Mehta RL, Levin A, et al; AKIN. Development of a clinical research agenda for acute kidney injury using an international, interdisciplinary, three-step modiﬁed Delphi process. Clin J Am Soc Nephrol. 2008;3:887-894.

Table 6.5 Assessment for recovery of renal function if urine volume > 30 mL/h Creatinine clearance <12 mL/min 12–20 mL/min >20 mL/min

Management of RRT Continuation of RRT Clinician’s judgment Discontinuation of RRT

Note: 6 hours’ timed urine collections obtained for assessment of creatinine clearance.

Indications, timing, and patient selection CHAPTER 6

When to stop RRT

45

is interpreted. Most, but not all, experts advise that RRT should begin before clinical complications occur, but it is often difﬁcult to know exactly when such a point occurs. For example, subtle abnormalities in platelet function can begin early in acute kidney injury (AKI) prior to when most clinicians would begin RRT. Observational studies of AKI using RIFLE criteria have provided two important pieces of information: ARF (stage F by RIFLE) is common among critically ill patients (10%–20% of ICU patients) and is associated with a 3- to10-fold increase in the risk of death prior to discharge. Given the profound increase in the risk of death, many investigators have asked why more patients do not receive RRT, yet many patients with ARF recover renal function without ever receiving RRT. Should these patients receive RRT? Current evidence is insufﬁcient to answer this question, but given the low rates of complications associated with CRRT, and high risk of death associated with AKI, consideration should be given to starting therapy early (e.g., when F criteria is present rather than waiting for complications to occur).

Indications, timing, and patient selection CHAPTER 6

46

Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury. N Engl J Med. 2008; EPub May 20. Uchino S, Bellomo R, Morimatsu H, et al. Continuous renal replacement therapy: a worldwide practice survey. Intensive Care Med. 2007;33(9):1563-1570. Uchino S, Bellomo R, Morimatsu H, et al. Discontinuation of Continuous Renal Replacement Therapy: A Prospective Multi-center Observational study. Crit Care Med, In press.

Patient selection for CRRT Which patients should receive CRRT? Once the decision is made to initiate RRT the question of which modality (intermittent vs. continuous) arises. The following considerations inﬂuence the choice of modality, although, strictly speaking, there are few absolute indications for one modality over the other. • Hemodynamic stability: CRRT is preferred for patients with or at risk for hypotension. In practice, this usually means patients who require vasopressor support either at baseline or as a result of treatment. The ARF trial network (ATN) study demonstrated that hypotension is extremely common with IHD. • Intracranial hypertension: This is an absolute indication for CRRT. IHD induces much greater ﬂuid shifts and is therefore contraindicated in patients with increased intracranial pressure. • Severe volume overload and high obligatory ﬂuid intake: Even hemodynamically stable patients with severe volume overload or patients with mild ﬂuid overload but high daily ﬂuid requirements (usually for medications and nutritional support) may be more effectively managed with CRRT. For example, it is unusual to remove more than 3–4 L of volume in a 4-hour dialysis session. Yet it is quite common to remove 200–300 mL/h (5–7 L per day) or even more with CRRT. • Mechanical ventilation: For patients who are unable to tolerate weaning trials on nondialysis days, CRRT (or daily dialysis) may be better. • High protein turnover/catabolic patients: For some critically ill patients it may be difﬁcult to control solute with alternate day dialysis. Patient with very high predialysis BUN may be better treated with CRRT. • Hyperkalemia: When rapid solute clearance is necessary, such as in severe hyperkalemia, intermittent therapy is generally preferred. CRRT is usually quite effective for hyperkalemia, but intermittent therapy will be somewhat faster.

Chapter 7

Extended indications for continuous renal replacement therapy Rinaldo Bellomo and Ian Baldwin

Continuous renal replacement therapy (CRRT) was developed to deal with the issue of offering a form of renal replacement therapy (RRT) that was better suited to the needs of critically ill patients than intermittent hemodialysis (IHD), and this remains the primary reason for its use in the intensive care unit (ICU). However, with increasing use, it has become clear that CRRT can be applied to the treatment of other conditions relevant to critical illness. Such situations are described as “extended indications” because they extend the reach of CRRT beyond the simple treatment of acute kidney injury (AKI). Although such extended indications are not supported by evidence from large multicenter, randomized, controlled trials, many studies have provided sufﬁcient evidence to justify the use of CRRT outside the simple replacement of lost renal function.

Key terms Blood puriﬁcation: This term refers to the use of extracorporeal therapies such as CRRT for the treatment of a variety of conditions (drug overdose, liver failure, volume overload, diuretic resistant cardiac failure, severe sepsis) for which a biological rationale exists for their application. Soluble mediators: This term refers to molecules (mostly small- to medium-sized peptides) that participate in the pathogenesis of the inﬂammatory and counterinﬂammatory response seen after major body injury or infection. These molecules are water soluble and therefore potentially removable by CRRT. Many of these molecules are referred to with the term “cytokines.” Humoral theory of sepsis: This term refers to a particular framework of biological thinking used to explain the clinical manifestations of severe sepsis. According to this theory, the clinical syndrome of severe sepsis or septic shock is due to the excessive release into the blood stream of cytokines. This ideological framework provides the rationale for using CRRT in sepsis.

47

Introduction

Extended indications for CRRT CHAPTER 7

High-volume hemoﬁltration (HVHF): This term refers to a technique of CRRT where the amount of ﬂuid removed and replaced is much higher than the typical 2–3 L/h and reaches values of 6–10 L/h. The goal of such therapy is to increase the intensity of blood puriﬁcation to address not just any renal dysfunction, but also any humoral components of sepsis (cytokines) whose removal from the circulation may be desirable (see Figures 7.1 and 7.2). High-cutoff hemoﬁltration: This term refers to the use of special ﬁlters with larger pore size to increase CRRT’s ability to remove soluble mediators in patients with sepsis. Middle-molecular weight molecules: This term refers to all molecules that are >500 daltons in molecular weight but less than albumin in size. These molecules,

P < 0.017

600 500

*

48

ng/mL

400 *

300 200 100 0 0

2

6 Time (h)

8

20

Figure 7.1 Impact of high-volume hemoﬁltration (HVHF) on C3a levels (triangles) compared with standard Continuous veno-venous hemoﬁltration (CVVH) (diamonds).

P < 0.017

30

ng/mL

25

*

20 15

* HFHV CVVH

*

10 5 0 0

2

6 Time (h)

8

20

Figure 7.2 Impact of high-volume hemoﬁltration (HVHF) on C3a levels compared with standard Continuous veno-venous hemoﬁltration (CVVH).

Free drug concentration: This term refers to the percentage or amount of a given drug that is not protein bound. This concept is important because, in case of drug overdose with a water soluble drug (e.g., lithium or sodium valproate), it is only the free drug that is available for removal by CRRT. Diuretic resistance: This term refers to conditions where marked edema (anasarca) develops despite intensive, high-dose, multiple diuretic-based attempts to remove excess ﬂuid.

Extended indications for CRRT

Adsorption: This term refers to the removal of molecules from the circulation not by means of diffusion or convection but rather by means of binding of the molecules to the spongy layer of the ﬁltering membrane. Such removal is one of the mechanisms by which CRRT can remove cytokines from blood.

CHAPTER 7

if water soluble, can, theoretically, be removed by CRRT. Because of their size, they are more efﬁciently removed by convection than by diffusion. Many of these molecules are soluble mediators/cytokines.

CRRT can be used to achieve its logical clinical goals in extended indications using different methods. For example, if the issue at stake is that of ﬂuid removal with a degree of inevitably accompanying uremia, standard CRRT can be used to lower the urea concentration while aiming for a signiﬁcant negative ﬂuid balance of –200 to –400 mL/h. With this approach, large amounts of ﬂuid can be removed from patients with diuretic resistant ﬂuid overload. If the patient has severe sepsis or septic shock and the goal of therapy is to remove soluble mediators, then either HVHF or high-cutoff hemoﬁltration can be applied. HVHF requires high blood ﬂows (>300 mL/min) in order to avoid either excessive predilution (if the replacement ﬂuid is administered before the ﬁlter) or excessive hemoconcentration within the ﬁlter (if the replacement ﬂuid is administered after the ﬁlter). If HVHF is used, attention must be paid to ﬂuid balance and to phosphate levels. This is because relatively minor errors in ﬂuid balance can cause problems when 10 L of ﬂuids are exchanged every hour and because the rapid removal of phosphate will inevitably lead to hypophosphatemia. If high-cutoff hemoﬁltration is used, special ﬁlter membranes are necessary. HVHF may also be used to remove a water-soluble free toxic drug like lithium or sodium valproate at higher efﬁciency than standard CRRT. If this is done, such therapy is best followed by a spell of standard CRRT to avoid the so-called rebound in plasma concentration that follows the cessation of a high-efﬁciency treatment of blood. In some case, CRRT can be used to control body temperature in situations like malignant hyperthermia or severe fever due to infection or cerebral injury. In such cases, replacement ﬂuid is not warmed prior to administration or can even be cooled prior to administration.

49

Methods, techniques, and approach

Extended indications for CRRT CHAPTER 7

50

Practical considerations The choice to apply CRRT in the techniques described earlier is entirely based on clinical judgment and a view that the possible beneﬁts of therapy are greater than its risks. This requires that those applying CRRT for extended use should have a very high level of clinical competence in this ﬁeld so that the treatment can be applied with minimal risk. This requirement particularly applies to HVHF, which requires adequate machines, accurate ﬂuid balance monitoring, frequent monitoring of electrolytes and phosphate, and attention to body temperature. The risks are much less with severe diuretic refractory ﬂuid overload, especially when secondary to advanced cardiac failure. In such patients, the typical desired ﬂuid removal (10–15 L ) can be achieved over 24–48 hours by means of a steady negative ﬂuid balance of –300 mL/h. This is easily executed, as it is commonplace during CRRT for acute renal failure (ARF) in any case. For water-soluble drugs with limited or little protein binding and with limited volumes of distribution (< 0.5 L/kg), in case of serious life-threatening intoxication, CRRT (perhaps initially at high volume and then once the levels are within a safe range, at standard volumes) also appears justiﬁed, biologically sound, and relatively safe. CRRT has now been used as an adjunctive treatment for the following: • Sepsis • Controlling body temperature not responding to conventional approaches • Decreasing the inﬂammatory response associated with cardiac arrest • Achieving or maintaining acid-base homeostasis in patients with severe academia • Removing radiocontrast and attenuating renal injury in patients at risk of radiocontrast nephropathy • Correcting anasarca of different etiology • Preventing massive ﬂuid overload in patients receiving large amounts of clotting factors • Attenuating the inﬂammatory response associated with prolonged cardiopulmonary bypass • Correcting sodium disturbances in patients with limited renal function Once all the potential biological, physiological, and clinical effects of CRRT are appreciated, logical use of this therapy outside the ﬁeld of CRRT is inevitable.

Summary CRRT has the ability to affect multiple biological and clinical targets. Once such ability is appreciated and the technique is mastered, CRRT becomes a tool that can be easily applied to situations outside the simple need for RRT. CRRT can lower body temperature, remove ﬂuid, deliver large amounts of buffer, remove water-soluble drugs, affect the inﬂammatory and counterinﬂammatory systems,

Extended indications for CRRT

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. Bellomo R, Baldwin I, Ronco C. Extracorporeal blood puriﬁcation for sepsis and systemic inﬂammation: its biologic rational. Contrib Nephrol. 2001;132:367-374. Bellomo R, Baldwin I, Ronco C. High-volume hemoﬁltration. Curr Opin Crit Care. 2000; 6:442-445. Bellomo R, Baldwin I, Ronco C. Rationale for extracorporeal blood puriﬁcation therapies in sepsis. Curr Opin Crit Care. 2000;6:446-450. Cruz DN, Perazella MA, Bellomo R, et al. Extracorporeal blood puriﬁcation therapies for prevention of radiocontrast-induced nephropathy. Am J Kidney Dis. 2006;48:361-371. Haase M, Bellomo R, Baldwin I, et al. Hemodialysis membrane with a high-molecular weight cutoff and cytokine levels in sepsis complicated by acute renal failure: a phase I randomized trial. Am J Kidney Dis. 2007;50:296-304. Kellum JA, Bellomo R, Mehta R, Ronco C. Blood puriﬁcation in non-renal critical illness. Blood Purif. 2003;21:6-13.

CHAPTER 7

Key references

51

modulate electrolyte concentration, and allow the rapid administration of large amounts of blood products without the associated development of ﬂuid overload. Once these properties are appreciated, extended indications for CRRT simply become logical physiological interventions similar to those achieved with mechanical ventilation.

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Chapter 8

Dose adequacy and assessment Zaccaria Ricci and Claudio Ronco

Approximately 5%–6% of critically ill patients admitted to intensive care unit (ICU) develop severe acute kidney injury (AKI), and more than 70% of them receive renal replacement therapy (RRT). The mortality rate for severe AKI has exceeded 50% over the past three decades, and it represents an independent risk factor for mortality of critically ill patients. Strategies to improve patient outcome in AKI may include optimization of delivered RRT dose.

Theoretical aspects of renal replacement therapy dose The conventional view of RRT dose is that it is a measure of the quantity of blood puriﬁed by “waste products and toxins” achieved by means of renal replacement. The operative measure of RRT dose is the elimination amount of a representative marker solute: • The marker solute, however, does not represent all the solutes that accumulate during AKI because kinetics and volume of distribution are different for each solute. • The removal of marker solute during RRT is not necessarily representative of the removal of other solutes. A signiﬁcant body of data suggests that single solute marker assessment of the dose of dialysis appears to have a clinically meaningful relationship with patient outcome and, therefore, clinical utility. The amount (dose) of delivered RRT can be described by various terms: efﬁciency, intensity, frequency, and clinical efﬁcacy.

53

Introduction

Dose adequacy and assessment CHAPTER 8

54

• Efﬁciency of RRT is represented by the concept of clearance (K), that is, the

volume of blood cleared of a given solute over a given time (it is generally expressed as volume over time: mL/min, mL/h, L/h, L/24 h, etc.). K does not reﬂect the overall solute removal rate (mass transfer) but rather its value normalized by the serum concentration: even when K remains stable over time, the removal rate will vary if the blood levels of the reference molecule change. During RRT, K depends on solute molecular size, transport modality (convection or diffusion), and circuit operational characteristics [blood ﬂow rate (QB), ultraﬁltration rate (QF), dialysate ﬂow rate (QD), hemodialyzer type and size]. QB, as a variable in delivering RRT dose, is mainly dependent on vascular access and operational characteristics of utilized machines in the clinical setting. During convective techniques, QF is strictly linked to QB by ﬁltration fraction (the fraction of plasma water that is removed from blood by ultraﬁltration), because it is recommended to keep QF below 0.5 * QB. During diffusive techniques, when QD/QB ratio exceeds 0.3, it can be estimated that dialysate will not be completely saturated by blood diffusing solutes. In the absence of a speciﬁc solute, clearances of urea and creatinine blood levels are used to guide treatment dose. During ultraﬁltration, the driving pressure jams solutes, such as urea and creatinine, against the membrane and into the pores, depending on membrane sieving coefﬁcient (SC) for that molecule. SC expresses a dimensionless value and is estimated by the ratio of the concentration of the solutes in the ﬁltrate divided by that in the plasma water or blood. An SC of 1.0, as is the case for urea and creatinine, demonstrates complete permeability and a value of 0 reﬂects complete rejection. Molecular size over approximately 12 kDa and ﬁlter porosity are the major determinants of SC. The K during convection is measured by the product of QF times the SC. Thus, there is a linear relationship between K and QF, the SC being the changing variable for different solutes. During diffusion, an analog linear relationship depends on the diffusibility of a solute across the membrane. As a rough estimate, we showed that during continuous slow efﬁciency treatments, urea K can be considered as a direct expression of QF and QD. K can be normally used to compare the treatment dose during each dialysis session, but it cannot be employed as an absolute dose measure to compare treatments with different time schedules. For example, K is typically higher in intermittent hemodialysis (IHD) than continuous renal replacement therapy (CRRT) and sustained low efﬁciency daily dialysis (SLEDD). This is not surprising, since K represents only the instantaneous efﬁciency of the system. However, mass removal may be greater during SLEDD or CRRT. For this reason, the information about the time span during which K is delivered is fundamental to describe the effective dose of dialysis (intensity). • Intensity of RRT can be deﬁned by the product “clearance x time” (Kt: mL/ min * 24 h, L/h * 4 h, etc.). Kt is more useful than K in comparing various RRTs. However, it does not take into account the size of the pool of solute which needs to be cleared. This requires the dimension of efﬁcacy.

Practical aspects of RRT dose Tables 8.1 and 8.2 show a potential ﬂow chart that could be followed each time an RRT prescription is indicated. • Urea volume of distribution V (L): patient’s body weight (kg) * 0.6. • Estimated fractional clearance (Kt/VCALC): KCALC (mL/min) * prescribed treatment time (min)/V (mL).

Dose adequacy and assessment CHAPTER 8

administration of a given treatment dose to a given patient. It can be described as a fractional clearance of a given solute (Kt/V) where V is the volume of distribution of the marker molecule in the body. Kt/V is a dimensionless number (e.g., 50 mL/min * 24h/45 L = 3 L/h * 24h/45 L = 72 L/45 L = 1.6) and it is an established measure of dialysis dose correlating with medium term (several years) survival in chronic hemodialysis patients. Urea is typically used as a marker molecule in end-stage kidney disease to guide treatment dose (the volume of distribution of urea (VUREA) is generally considered as equal to patient total body water, which is 60% of patient body weight), and a Kt/VUREA of at least 1.2 is currently recommended for IHD treatments. However, Kt/VUREA application to patients with AKI has not been rigorously validated due to a major uncertainty about VUREA estimation. Some authors have suggested to express dose as K indexed to patient body weight as an operative measure of daily CRRT: it is now suggested to deliver no less than 20 mL/kg/h * 24 h: if the simpliﬁcation discussed above (K = mL/h = QF or QD) can be considered acceptable, this CRRT dose might be expressed in a 70 kg patient as about 1500 mL/h or 36 L/day of continuous venovenous hemoﬁltration (CV VH: QF * kg * 24 h) or dialysis (CV VHD: QD * kg * 24 h). Interestingly, applying Kt/ VUREA dose assessment methodology in such a 70 kg patient, the dosage of 20 mL/kg/h * 24 h would be equivalent to a Kt/V of 0.8. Many authors showed the potential beneﬁts of higher RRT doses. However, it has been shown that during a continuous therapy a K less than 2 L/h will almost deﬁnitely result insufﬁcient in an adult septic (hypercatabolic) critically ill patient. Furthermore, it is usually necessary to proscribe a higher dose (e.g., 25–30 mL/kg/h) to ensure that delivery is never less than the 20 mL/kg/h ﬂoor. Nevertheless, so far, several clinical trials have failed to show a “one-size ﬁts all” prescription for RRT, and dialysis dose should always be tailored to each patient. The most important point is to never “underdialize” patients. • Other parameters include acid-base control, tonicity control, potassium control, magnesium control, calcium and phosphate control, intravascular volume control, extravascular volume control, temperature control, and the avoidance of unwanted side effects associated with the delivery of solute control. These aspects of dose are not currently addressed by any attempt of measure, but should be considered when discussing the prescription of RRT.

55

• Efﬁcacy of RRT is the effective solute removal outcome resulting from the

Dose adequacy and assessment CHAPTER 8

Table 8.1 RRT prescription Clinical variables Fluid balance

Adequacy and dose

Acid-base

56

Electrolyte

Timing Protocol

Operational variables Net ultraﬁltration

Setting

A continuous management of negative balance (100–300 mL/h) is preferred in hemodynamically unstable patients. A complete monitoring (CVC, S-G, arterial line, EKG, pulse oxymeter) is recommended. Clearance/modality 2000–2500 mL/h K (or 25–30 mL/kg/h) for CRRT; consider ﬁrst CVVHDF. If IHD is selected, a minimum dose of 1.2 Kt/V delivered at least 3 times per week. Note that a 4–5 hour prescription is usually necessary and monitoring of delivered Kt/V is recommended. Solution buffer Bicarbonate buffered solutions are preferable to lactate buffered solutions in case of lactic acidosis and/or hepatic failure. Dialysate/replacement Consider solutions without K+ in case of severe hyperkalemia. Manage accurately MgPO4. Schedule Early and intense RRT is suggested. Staff/machine Well-trained staff should routinely utilize RRT monitors according to predeﬁned institutional protocols.

Note: CVC = central venous catheter; S-G = Swan Ganz catheter; EKG = electrocardiogram; CRRT = continuous renal replacement therapy; CVVHDF = continuous veno-venous hemodiaﬁltration; IHD = intermittent hemodialysis.

• 25 mL/kg/h roughly correspond to a Kt/V of 1.0. • Filtration fraction calculation (postdilution): QREP/QB * 100; ﬁltration fraction

calculation (predilution): QREP/QB + QREP * 100. • QB: blood ﬂow rate; QREP: replacement solution ﬂow rate; QUF: ultraﬁltration

ﬂow rate (QUF: QREP + QNET); QNET: patient’s net ﬂuid loss; QDO: dialysate solution ﬂow rate.

RRT dose delivery: continuous or intermittent In its original conceivement, K is utilized to evaluate renal function among disparate individuals whose kidneys, however, are operating 24 hours per day and urea/creatinine blood levels are at steady state. For this reason, the concept of K is easily applicable to continuous treatments, and its utilization to describe intermittent therapies’ efﬁciency is a sort of “adaptation.” • K is typically higher in IHD than in CRRT and SLEDD. • However, mass removal may be greater during SLEDD or CRRT because the K is applied for 12/24 hours (Table 8.3).

CV VH predilution

Always keep ﬁltration fraction < 20% (QB must be 5 times QREP) KCALC = QUF / Filtration fraction [1 + (QREP/QB)] computation changes (keep <20%)

CV VHD

KCALC = QDO

Keep QB at least thrice Qd

CV VHDF postdilution (~50% convective and diffusive K)

KCALC = QREP + QDO

Consider both notes of CVVH and CVVHD

Value of Q in order to obtain 25 mL/kg/h QREP: 25 mL/min or 2000 mL/h

For a QB of 180 mL/min: QREP: 30 mL/min or 2500 mL/h QDO: 25 mL/min or 2000 mL/h QREP: 15 mL/min + QDO: 10 mL/min

Value of Q in order to obtain a Kt/V of 1 QREP: 29 mL/min or 1750 mL/h

For a QB of 200 mL/min: QREP: 35 mL/min or 2100 mL/h QDO: 29 mL/min or 1750 mL/h QREP: 14 mL/min replacement solution + QDO: 15 mL/min

Table 8.3 Comparison of intermittent hemodialysis and continuous renal replacement therapy efﬁciency K (mL/min) Urea start (mg/dL) Urea end (mg/dL) Treatment time (min) Total K (K*time) Urea removed (g)

CRRT 35 110 90 1440 50.5 25

IHD 200 110 30 240 48 18

• From a physiological point of view, even if a continuous and an intermittent

therapy were prescribed in order to provide exactly the same marker solute removal, still they could not be comparable: during continuous treatments, where a relatively low K is applied, a slow but prolonged removal of solutes approaches a pseudosteady state slope (Figure 8.1). In highly intermittent therapies, the intensive K, limited to 4–6 hours per day, thrice a week, causes the saw tooth slope in solute removal and the eventual rebound during the time span without treatment: these peaks and valleys of solutes, bicarbonate, electrolytes, plasma osmolarity, and volemia are not physiological and might

Dose adequacy and assessment

Notes

CHAPTER 8

CV VH postdilution

Estimated urea clearance (KCALC) KCALC = QREP

57

Table 8.2 Example of a possible prescription for a continuous treatment in a 70-kg patient (VUREA: 42 L) during an ideal session of 24 hours (t: 1440 minutes). Net ultraﬁltration (patient ﬂuid loss) is considered zero in KCALC for simplicity

IHD 100 BUN (mg/dL)

Dose adequacy and assessment CHAPTER 8

120

80 60 CVVH

40 SLED

20 0

0

6

12

18 24 30 36 42 Hours of treatment

48

54

58

Figure 8.1 Blood urea nitrogen (BUN) patterns over time for intermittent hemodialysis (IHD), continuous venovenous hemoﬁltration (CVVH), and slow low-efﬁciency dialysis (SLED).

have a detrimental impact on patients’ hemodynamics as well as electrolyte, acid base, and other “osmoles” balance. • Furthermore, in the case of IHD, the intercompartmental transmittance (Kc), that is, the variable tendency of different tissues to “release” a solute into the bloodstream, is much more relevant than during slow efﬁciency treatments. Different prescriptions may lead to almost equivalent ﬁnal daily delivery of K. Nonetheless, continuous therapies seem to achieve a ﬁnal better urea control due to the different “physiology” of solute removal (slow, steady, prolonged, and independent from tissues intercompartmental transmittance). According to recent international surveys on clinical practice patterns, 80% centers administer CRRT, 17% use intermittent RRT (IRRT), and a few minority apply peritoneal dialysis (PD). Interestingly, in many centers intermittent techniques are utilized together with continuous ones, thus evidencing possibility of multiple prescriptions and practices. Nonetheless, after years of debate, scientiﬁc literature is not able to draw conclusions on how RRT delivery modalities may impact clinical outcomes. Many papers have been published on this issue and they must be analyzed critically. Many randomized controlled trials compared intermittent and continuous RRT, providing so far only conﬂicting and puzzling results. Basing on actual scientiﬁc evidence, the Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock recently concluded that, during AKI, CV VH and IHD should be considered equivalent.

Key references Lameire N, van Biesen W, Van Holder R, Colardijn F. The place of intermittent hemodialysis in the treatment of acute renal failure in the ICU patient. Kidney Int. 1998;53(suppl 66):S110-S119. Ricci Z, Bellomo R, Ronco C. Dose of dialysis in acute renal failure. Clin J Am Soc Nephrol. 2006;1:380-388. 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. The VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359:7-20. Uchino S, Bellomo R, Kellum JA, et al; BEST Kidney Investigators Writing Committee. Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury. Int J Artif Organs. 2007;30:281-292. Uchino S, Kellum JA, Bellomo R, et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients a multinational, multicenter study. JAMA. 2005;294:813-818.

Dose adequacy and assessment CHAPTER 8

As concluded by the Acute Dialysis Quality Initiative (ADQI) workgroup in 2001, delivered clearance should be monitored during all renal supportive therapies. No recommendations can be made for speciﬁc dialysis dosing for patients with speciﬁc diseases at this time. A minimum dose of RRT, however, needs to be delivered for AKI: • The best evidence to date supports the delivery of at least 20 mL/kg/h for CV VH, CV VHD, or CV VHDF. Usually this will require the prescribed dose of 25–30 mL/kg/h. At present, there is no evidence of harm in increasing the dose up to 35 mL/kg/h (2–2.5 L/h): this might be beneﬁcial in terms of solute control in selected patients. • 1.2 Kt/V delivered IHD on alternate days—typically prescribed dose is approximately 1.4 Kt/V for alternate day dosing. • For alternate day IHD, isolated ultraﬁltration can be used for volume control as needed on nondialysis days. • It should also be recommended that the prescription should exceed that calculated to be “adequate” because of the known gap between prescribed and delivered dose. • If a solute-based approach to the concept of dose seems too restrictive, although operatively relatively simple, other dimensions of adequacy of RRT or RRT dose remain unexplored but likely to be important: blood volume control, acid-base control, tonicity control.

59

Conclusions

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Chapter 9

Acid-base and electrolyte disorders John A. Kellum

An important principle in the management of electrolytes with continuous renal replacement therapy (CRRT) is that “you get what you replace.” With hemoﬁltration, all electrolytes are freely removed (sieving coefﬁcients near 1) and, thus, over time and assuming no large intake or other losses, plasma concentrations will approach those of the replacement ﬂuid. The rate at which electrolytes change is determined by how different the plasma concentration is relative to that in the replacement ﬂuid and the rate of ﬂuid replacement delivered. Similar principles exist for continuous hemodialysis with one exception: phosphate. Although the phosphate molecule is not large, it behaves as if it were a much larger molecule. As a consequence, phosphate is removed much more slowly with dialysis (diffusion) compared to ﬁltration (convection). For this reason, patients receiving dialysis may still require phosphate binders whereas those receiving hemoﬁltration frequently require phosphate replacement. It should be noted that plasma electrolyte concentrations often don’t reﬂect whole body stores, whereas high or low plasma concentrations still may induce symptoms and deleterious physiological and metabolic effects. In particular, K+, the primary intracellular cation, exhibits only a loose association between plasma and intracellular concentrations (see below). Plasma Mg2+ concentrations bear almost no relation to total body stores, and persistent hypokalemia may be the only clue to total body Mg2+ deﬁciency. Electrolyte losses, as well as electrolyte intake, should be considered in prescribing CRRT. An important source of exogenous K+ is from transfusions of banked blood. Blood transfusions are also an important cause of hypocalcemia owing to the citrate anticoagulation used in blood banking. Important sources of electrolyte loss are shown in Table 9.1. Speciﬁc ﬂuid prescribing information for both continuous veno-venous hemoﬁltration (CVVH) and continuous veno-venous hemodialysis (CVVHD) is found in Chapter 14.

61

Electrolyte management

Acid-base and electrolyte disorders CHAPTER 9

62

Table 9.1 Electrolyte losses • Large nasogastric aspirate, vomiting • Sweating • Polyuria • Diarrhea • Ascitic drainage

Na+, Cl− Na+, Cl− Na+, Cl−, K+, Mg2+ Na+, Cl−, K+, Mg2+ Na+, Cl−, K+

Source: From Kellum JA, Gunn SR, eds. Oxford American Handbook of Critical Care. New York: Oxford University Press; 2008.

Dysnatremias Continuous renal replacement therapy (CRRT) is rarely required as primary therapy for dysnatremias, but patients with renal failure frequently develop dysnatremia, and care must be taken to correct sodium according to the rate at which the abnormality has developed and in response to the nature of the symptoms present. In general dysnatremias that develop slowly should be treated slowly, whereas rapidly occurring dysnatremias demand rapid correction. Severe symptoms also require rapid treatment, although correction will be partial, at ﬁrst, in the case of chronic conditions. Finally volume status should be considered in the treatment plan.

Hypernatremia Hypernatremia is manifest by thirst, lethargy, coma, seizures, muscular tremor and rigidity, and an increased risk of intracranial hemorrhage. Thirst usually occurs when the plasma sodium rises 3–4 mmol/L above normal. Lack of thirst is associated with central nervous system disease (see Table 9.2). Rate of correction • If hyperacute (<12 h), correction should be rapid. • Otherwise, aim for gradual correction of plasma sodium levels (over 1–3 days), particularly in chronic cases (>2 days’ duration), to avoid cerebral edema through sudden lowering of osmolality. A rate of plasma sodium lowering <0.7 mmol/h has been suggested. Low or normal total body Na (water loss) • Reduce Na concentration in replacement ﬂuid or dialysate (see Chapter 14 for speciﬁc ﬂuids). • Give water replacement PO in addition to changes in CRRT ﬂuids. • Even ﬂuid balance (or even ﬂuid gain with replacement ﬂuid) until total body water is normalized. • In the case of central diabetes insipidus (CDI), restrict salt and give thiazide diuretics. Complete CDI will require desmopressin (10 µg bid intranasally or 1–2 µg bid IV), whereas partial CDI may require desmopressin but often responds to drugs that increase the rate of antidiuretic hormone (ADH) secretion or end-organ responsiveness to ADH, for example, chlorpropamide, hydrochlorthiazide.

Etiology

Urine

Low total body Na

Renal losses: diuretic excess, osmotic diuresis (glucose, urea, mannitol) Extra-renal losses: excess sweating

[Na+] >20 mmol/L iso- or hypotonic

Normal total body Na

Increased total body Na

Renal losses: diabetes insipidus Extra-renal losses: respiratory and renal insensible losses Conn’s syndrome, Cushing’s syndrome, excess NaCl, hypertonic NaHCO3

[Na+] <10 mmol/L hypertonic [Na+] variable hypo-, iso- or hypertonic [Na+] variable hypertonic [Na+] >20 mmol/L iso- or hypertonic

Acid-base and electrolyte disorders

Type

CHAPTER 9

Table 9.2 Causes of hypernatremia

• In the case of nephrogenic diabetes insipidus (DI), manage by a low salt diet

and thiazides. High dose desmopressin may be effective. Consider removal of causative agents, for example, lithium. Increased total body Na (Na gain) • Reduce Na concentration in replacement ﬂuid or dialysate (see Chapter 14 for speciﬁc ﬂuids). • Remove ﬂuid to achieve even, or in the case of hypervolemia, net negative, ﬂuid balance.

Hyponatremia Hyponatremia may cause nausea, vomiting, headache, fatigue, weakness, muscular twitching, obtundation, psychosis, seizures, and coma. Symptoms depend on the rate as well as the magnitude of fall in the plasma [Na+] (see Table 9.3). Rate and degree of correction • Rate and degree of correction depend on how rapidly the condition has developed and whether the patient is symptomatic. Hyponatremia that has developed over more than 48 h is considered “chronic.” • In CHRONIC ASYMPTOMATIC hyponatremia correction should not exceed 4 mmol /24 h and the rate of correction should not exceed 0.3 mmol/L/h. • In CHRONIC SYMPTOMATIC (e.g., seizures, coma) hyponatremia correction should be 1–1.5 mmol/L/h until symptoms resolve and then correction should be as per asymptomatic cases. • In ACUTE hyponatremia (<48 h) the ideal rate of correction is controversial, although elevations in plasma Na+ can be faster, but <20 mmol/L/day.

63

Source: Kellum JA, Gunn SR, eds. Oxford American Handbook of Critical Care. New York: Oxford University Press; 2008.

Acid-base and electrolyte disorders CHAPTER 9

64

• A plasma Na+ of 125–130 mmol/L is a reasonable target for initial correc-

tion of both acute and chronic states. Attempts to achieve eunatremia rapidly should be avoided. • Neurological complications, for example, central pontine myelinolysis, are related to the degree of correction and (in chronic hyponatremia) the rate. Premenopausal women are at highest risk for this complication. Extracellular ﬂuid (ECF) volume excess • If symptomatic (e.g., seizures, agitation), 100 mL aliquots of hypertonic (1.8%) saline can be given, with plasma levels being checked every 2–3 h. • If symptomatic and edematous, ﬂuid removal on CRRT can be done in addition to hypertonic saline. Plasma levels should be checked every 2–3 h. With custom replacement ﬂuid or dialysate, the Na concentration can be increased somewhat, but hypertonic dialysis or replacement ﬂuid is not recommended. • If not symptomatic, water should be restricted to 1–1.5 L/day. If hyponatremia persists, inappropriate ADH [syndrome of inappropriate antidiuretic hormone secretion (SIADH)] secretion should be considered. • If SIADH is likely, isotonic saline should be given and demeclocycline should be considered. Extracellular ﬂuid (ECF) volume depletion • If symptomatic (e.g., seizures, agitation), give isotonic (0.9%) saline. Consider hypertonic (1.8%) saline initially especially if acute. • If asymptomatic, use isotonic (0.9%) saline. • Maintain even ﬂuid balance on CRRT. General points • Equations that calculate excess water are unreliable. It is safer to monitor plasma sodium levels closely. • Hypertonic saline may be dangerous, especially in the elderly and those with impaired cardiac function. • Use isotonic solutions for reconstituting drugs, parenteral nutrition, and so on (i.e., avoid hypotonic ﬂuids). • Hyponatremia may intensify the cardiac effects of hyperkalemia. • A true hyponatremia may occur with a normal osmolality in the presence of abnormal solutes, for example, ethanol, ethylene glycol, glucose.

Causes of inappropriate ADH secretion • • • • • • •

Neoplasm, for example, lung, pancreas, lymphoma Most pulmonary lesions Most central nervous system lesions Surgical and emotional stress Glucocorticoid and thyroid deﬁciency Idiopathic Drugs, for example, chlorpropamide, carbamazepine, narcotics

Urine [Na+]

Renal losses: diuretic excess, osmotic diuresis (glucose, urea, mannitol), renal tubular acidosis, salt-losing nephritis, mineralocorticoid deﬁciency Extra-renal losses, vomiting, diarrhea,: burns, pancreatitis Water intoxication (NB postoperative, TURP syndrome), inappropriate ADH secretion, hypothyroidism, drugs(e.g., carbamazepine, chlorpropamide), glucocorticoid deﬁciency, pain, stress. Acute and chronic renal failure

>20 mmol/l

Nephrotic syndrome, cirrhosis, heart failure

<10 mmol/l

Modest ECF volume excess (no edema)

ECF volume excess (edema)

<10 mmol/l >20 mmol/l

>20 mmol/l

Source: Kellum JA, Gunn SR, eds. Oxford American Handbook of Critical Care. New York: Oxford University Press; 2008.

Potassium and magnesium Both K+ and Mg2+ are primarily intracellular cations; their total body concentrations depend on the balance between intake and excretion, while their plasma concentrations are determined by total body stores as well as by their distribution across cell membranes. In the case of K+, plasma pH and [Na+] also affect the plasma concentration. Excretion is primarily controlled by the kidneys, although both cations are excreted in the feces as well.

Hyperkalemia Hyperkalemia may cause dangerous arrhythmias, including cardiac arrest. Arrhythmias are more closely related to the rate of rise of potassium than the absolute level. Clinical features such as paresthesia and areﬂexic weakness are not clearly related to the degree of hyperkalemia but usually occur after ECG changes (tall “T” waves, ﬂat “P” waves, prolonged PR interval and wide QRS). Causes • Reduced renal excretion (e.g., renal failure, adrenal insufﬁciency, diabetes, potassium sparing diuretics) • Intracellular potassium release (e.g., acidosis, rapid transfusion of old blood, cell lysis including rhabdomyolysis, hemolysis, and tumor lysis • Potassium poisoning Management CRRT is effective in removing K+, although standard hemodialysis can remove K+ faster. Ancillary therapy may also be required particularly in emergency situations (see Chapter 6).

Acid-base and electrolyte disorders

Etiology

ECF volume depletion

CHAPTER 9

Type

65

Table 9.3 Causes of hyponatremia

Acid-base and electrolyte disorders CHAPTER 9

66

Hypokalemia Typical manifestations of hypokalemia include the following: • Arrhythmias (SVT, VT, and Torsades de Pointes) • ECG changes (ST depression, “T” wave ﬂattening, “U” waves) • Constipation • Ileus • Weakness Causes • Inadequate intake • Gastrointestinal losses (e.g., vomiting, diarrhea, ﬁstula losses) • Renal losses (e.g., diabetic ketoacidosis; Conn’s syndrome; secondary hyperaldosteronism; Cushing’s syndrome; renal tubular acidosis; metabolic alkalosis; hypomagnesemia; drugs including diuretics, steroids, theophyllines) • Hemoﬁltration losses • Potassium transfer into cells (e.g., acute alkalosis, glucose infusion, insulin treatment, familial periodic paralysis) Management Potassium replacement should be intravenous with ECG monitoring when there is a clinically signiﬁcant arrhythmia (20 mmol over 30 min, repeated according to levels). Slower intravenous replacement (20 mmol over 1 h) should be used where there are clinical features without arrhythmias. Oral supplementation (to a total intake of 80–120 mmol/day, including nutritional input) can be given where there are no clinical features.

Hypomagnesemia Magnesium is primarily an intracellular ion involved in the production and utilization of energy stores and in the mediation of nerve transmission. Low plasma levels, which do not necessarily reﬂect either intracellular or whole body stores, may thus be associated with features related to these functions: • Confusion, irritability • Seizures • Muscle weakness, lethargy • Arrhythmias • Symptoms related to hypocalcemia and hypokalemia, which are resistant to calcium and potassium supplementation, respectively Normal plasma levels range from 1.7–2.4 mg/dL; severe symptoms do not usually occur until levels drop below 1.0 mg/dL. Causes • Excess loss, for example, diuretics, other causes of polyuria (including poorly controlled diabetes mellitus), severe diarrhea, prolonged vomiting, large nasogastric aspirates

Hypermagnesemia Symptomatic hypermagnesemia rarely occurs even in severe renal failure except as a consequence of a large magnesium load (in which it may occur even with intact renal function) (see Table 9.4). However, patients with renal failure may develop severe hypermagnesemia when exposed to magnesium containing antacids or laxatives, even in usual therapeutic dosages. Thus, these agents are contraindicated in patients with severe renal failure. Most cases of hypermagnesemia are mild (<3.6 mg/dL, or 1.5 mmol/L) and asymptomatic. However, three types of symptoms may be seen when the plasma magnesium concentration exceeds 4.8 mg/dL (2 mmol/L): neuromuscular, cardiovascular, and hypocalcemia. Causes • IV magnesium infusion (typically as treatment for preeclampsia) • Oral ingestion (e.g., laxative, epsom salts) • Magnesium enemas

Table 9.4 Relationship of plasma magnesium and clinical symptoms Plasma [Mg2+] 4.8–7.2 mg/dL (2–3 mmol/L) 7.3–12 mg/dL (3–5 mmol/L) >12 mg/dL (>5 mmol/L)

Deep tendon reﬂexes Diminished

Other symptoms/signs Nausea, ﬂushing, headache, lethargy, and drowsiness

Absent

Somnolence, hypocalcemia, hypotension, bradycardia, and ECG changes

Absent

Muscle paralysis, respiratory paralysis, complete heart block, and cardiac arrest.

Acid-base and electrolyte disorders

Management • For severe, symptomatic hypomagnesemia, 10 mmol of magnesium sulphate can be given IV over 3–5 min. This can be repeated once or twice as necessary. • In less acute situations or for asymptomatic hypomagnesemia, 1–2 g MgSO4 solution can be given over 1–2 h and repeated as necessary, or according to repeat plasma levels. • A continuous IV infusion can be given; however, this is usually reserved for therapeutic indications where supranormal plasma levels (4–5 mg/dL) of magnesium are sought, for example, treatment of supraventricular and ventricular arrhythmias, preeclampsia, and eclampsia. • Oral magnesium sulfate has a laxative effect and may cause severe diarrhea.

CHAPTER 9

malabsorption syndromes

67

• Inadequate intake, for example, starvation, parenteral nutrition, alcoholism,

Acid-base and electrolyte disorders CHAPTER 9

Management Peritoneal dialysis, hemodialysis, and CRRT have been used effectively to lower the plasma magnesium concentration in patients with severe symptomatic hypermagnesemia, usually in the setting of renal failure complicated by exogenous magnesium loading. Hemodialysis with its higher ﬂow rates works more rapidly, lowering magnesium levels to the nontoxic range usually within 3–4 h. CRRT is typically slower and peritoneal dialysis is usually reserved for milder cases in patients receiving chronic peritoneal dialysis. Exchange transfusion has been effective in neonatal hypermagnesemia. While awaiting dialysis in a patient with severe symptoms, intravenous calcium can be given as a magnesium antagonist. The usual dose is 100–200 mg of elemental calcium over 5–10 min.

Calcium and phosphate

68

Ca2+ and PO43– are often considered together in patients with renal failure as a common complication of chronic disease is renal osteodystophy or bone mineral disease, which leads to hypocalcemia and hyperphosphatemia.

Hypocalcemia Symptoms of hypocalcemia usually appear when total plasma calcium levels are less than 8 mg/dL and the ionized fraction is below 0.8 mmol/L. • Tetany (including carpopedal spasm) • Muscular weakness • Hypotension • Perioral and peripheral paresthesia • Chvostek and Trousseau’s signs • Prolonged QT interval • Seizures Causes • Associated with hyperphosphatemia: • Renal failure • Rhabdomyolysis • Hypoparathyroidism (including surgery), pseudohypoparathyroidism • Associated with low/normal phosphate: • Critical illness including sepsis, burns • Hypomagnesemia • Pancreatitis • Osteomalacia • Overhydration • Massive blood transfusion (citrate binding)

Management • If respiratory alkalosis is present, adjust ventilator settings or, if spontaneously hyperventilating and agitated, calm ± sedate. Rebreathing into a bag may be beneﬁcial. • Administer 1 g of calcium chloride or 3 g of calcium gluconate (270 mg of elemental calcium) IV infusion over 30–60 min. • If symptomatic, give 5–10 mL 10% calcium chloride or 15–20 mL 10% calcium gluconate solution over 10–15 min. Repeat as necessary. • Correct hypomagnesemia or hypokalemia if present. • If asymptomatic and in renal failure or hypoparathyroid, consider enteral/ parenteral calcium supplementation and vitamin D analogues. • If hypotensive or cardiac output is decreased following administration of a calcium antagonist, give 5–10 mL 10% calcium chloride solution over 2–5 min.

Acid-base and electrolyte disorders

ized plasma calcium fraction and induce clinical features of hypocalcaemia

CHAPTER 9

• Hyperventilation and the resulting respiratory alkalosis may reduce the ion-

Among all causes of hypercalcemia, hyperparathyroidism and malignancy are the most common, accounting for greater than 90% of cases. Symptoms of hypercalcemia usually do not become apparent until the total (ionized + unionized) plasma levels >13 mg/dL (normal range 8.5–10.5 mg/dL). Symptoms depend on the patient’s age, the duration and rate of increase of plasma calcium, and the presence of concurrent medical conditions. Signs and symptoms of hypercalcemia may include the following: • Nausea, vomiting, weight loss, pruritus • Abdominal pain, constipation, acute pancreatitis • Muscle weakness, fatigue, lethargy • Depression, mania, psychosis, drowsiness, coma • Polyuria, renal calculi, renal failure • Cardiac arrhythmias Causes • Malignancy (e.g., myeloma, bony metastatic disease, hypernephroma) • Hyperparathyroidism • Granulomatous disease (e.g., sarcoidosis, tuberculosis) • Excess intake of calcium, vitamin A, or vitamin D • Drugs (e.g., thiazides, lithium) • Immobilization • Rarely, thyrotoxicosis, Addison’s disease Management • Identify and treat cause where possible.

69

Hypercalcemia

Acid-base and electrolyte disorders CHAPTER 9

Table 9.5 Drug dosage Diuretics Steroids Pamidronate Calcitonin

Furosemide 10–40 mg IV 2–4 h (may be increased to 80–100 mg IV every 1–2 h) Hydrocortisone 100 mg qid IV or prednisolone 40–60 mg PO for 3–5 days 15–60 mg slow IV bolus 3–4 U/kg IV followed by 4U/kg SC bd

• Carefully monitor hemodynamic variables, urine output, and ECG morphology •

• •

70

•

•

•

with frequent estimations of plasma Ca2+, PO43–, Mg2+, Na+, and K+. Intravascular volume repletion—this inhibits proximal tubular reabsorption of calcium and may lower plasma Ca2+ by 1–2 mg/dL. It should precede diuretics or any other therapy. Isotonic saline is typically used. Calciuresis—after adequate intravascular volume repletion, a forced diuresis with furosemide plus 0.9% saline (6–8 L/day) may be attempted. Steroids can be effective for hypercalcemia related to hematological cancers (lymphoma, myeloma), vitamin D overdose, and sarcoidosis (see Table 9.5). Calcitonin has the most rapid onset of action with a nadir often reached within 12–24 h. Its action is limited (usually does not decrease plasma Ca2+ by more than 2–3 mg/dL), usually short-lived, and rebound hypercalcemia may occur. Biphosphonates (e.g., pamidronate) and IV phosphate should only be given after other measures have failed in view of their toxicity and potential complications. CRRT or hemodialysis may be indicated particularly early on if the patient is in established oligoanuric renal failure ± ﬂuid overloaded. • CRRT or hemodialysis without calcium in the dialysis or replacement ﬂuid are both effective therapies for hypercalcemia, although are usually considered treatments of last resort. RRT may be indicated in patients with severe malignancy-associated hypercalcemia and renal failure or heart failure, in whom hydration cannot be safely administered. • The use of CRRT or hemodialysis in patients with hypercalcemia but without renal failure may require modiﬁcation of the composition of dialysis solutions. In one case report, hemodialysis with a dialysis solution containing 4 mg/dL of phosphorus resulted in rapid correction of all abnormalities in a patient in whom medical therapy had failed to reverse hypercalcemia, mental status changes, and hypophosphatemia due to primary hyperparathyroidism.

Hypophosphatemia Hypophosphatemia is often asymptomatic even when severe (<1 mg/dL). Symptoms may include muscle weakness (including respiratory muscles and can be associated with inability to wean from mechanical ventilation) rhabdomyolysis, paresthesias, hemolysis, platelet dysfunction, and cardiac failure.

Hyperphosphatemia Hyperphosphatemia itself does not produce symptoms. The major concern for hyperphosphatemia is the high circulating levels of parathyroid hormone (PTH) that result, and, in turn, its role in the development of renal osteodystrophy and possibly in other uremic complications as well. High levels of plasma Ca2+, PO43– together may cause calcinosis (soft tissue calciﬁcations) especially if the plasma Ca × PO4 product is chronically >70. Causes There are three general circumstances, alone or in combination, in which hyperphosphatemia occurs:

1. Massive acute phosphate load (e.g., tumor lysis, rhabdomyolysis) 2. Renal failure 3. Increased phosphate reabsorption (hypoparathyroidism, acromegaly, familial tumoral calcinosis, bisphosphonate therapy, vitamin D toxicity) Management The approach to therapy differs in acute and chronic hyperphosphatemia. Acute severe hyperphosphatemia with symptomatic hypocalcemia can be life-threatening. The hyperphosphatemia usually resolves within 6–12 h if renal function is intact. Phosphate excretion can be increased by saline infusion, although this can further reduce the serum calcium concentration by dilution. CRRT or hemodialysis is often indicated in patients with symptomatic hypocalcemia, particularly if renal function is impaired. Unlike other electrolytes, phosphate is removed more efﬁciently with CRRT (in hemoﬁltration mode) compared to hemodialysis. This is because PO43– acts in solution as a larger molecule and is more difﬁcult to remove with diffusion (dialysis) compared to convection (ﬁltration).

Acid-base and electrolyte disorders CHAPTER 9

Management Mild hypophosphatemia may be treated with PO phosphate supplements. In severe and symptomatic cases 20–40 mmol of NaPO4 or KaPO4 should be given by intravenous infusion over 6 h and repeated according to the plasma phosphate level.

71

Causes • Critical illness • Inadequate intake • Loop diuretic therapy (including low-dose dopamine) • Parenteral nutrition levels fall rapidly during high-dose intravenous glucose therapy, especially with insulin • Alcoholism • Hyperparathyroidism

Acid-base and electrolyte disorders CHAPTER 9

72

Pseudohyperphosphatemia Spurious hyperphosphatemia may result from interference with the analytical methods. Causes • Hyperglobulinemia, hyperlipidemia, hemolysis, and hyperbilirubinemia • Liposomal amphotericin B

Key Study Leehey DJ, Ing TS. Correction of hypercalcemia and hypophosphatemia by hemodialysis using a conventional, calcium-containing dialysis solution enriched with phosphorus. Am J Kidney Dis. 1997 Feb;29(2):288-290.

General acid-base management Increased intake, altered production, or impaired/excessive excretion of acid or base leads to derangements in blood pH. With time, respiratory and renal adjustments correct the pH toward normality by altering the plasma levels of PCO2 or strong ions (Na+, Cl− ).

Increased intake • Acidosis: chloride administration (e.g., saline), aspirin overdose • Alkalosis: NaHCO3 administration, antacid abuse, buffered replacement ﬂuid

(hemoﬁltration) Altered production • Increased acid production: lactic acidosis, diabetic ketoacidosis Altered excretion • Hypercapnic respiratory failure, permissive hypercapnia • Alkalosis: vomiting, large gastric aspirates, diuretics, hyperaldosteronism, corticosteroids • Acidosis: diarrhea, small bowel ﬁstula, urethroenterostomy, renal tubular acidosis, renal failure, distal renal tubular acidosis, acetazolamide

General management principles • Correct (where possible) the underlying cause, for example, hypoperfusion • Use NaCl infusion for vomiting-induced alkalosis; insulin, Na+, and K+ in dia-

betic ketoacidosis • Correct pH in speciﬁc circumstances only, for example, NaHCO3 in renal

failure • Avoid large volume saline-based ﬂuids. Consider lacted Ringer’s solution or

hetastarch in balanced electrolyte solution (Hextend) for ﬂuid resuscitation.

citrate anticoagulation) and are amenable to correction with CRRT. • Correction of plasma pH occurs because of change in plasma strong ion differ-

ence and to a small extent, change in weak acid concentration. • “Rules of thumb” for pH correction with CRRT:

The standard base access (SBE) quantiﬁes the change in plasma strong ion difference (SID) required to restore pH to 7.4 for a pCO2 of 40 mm Hg (e.g., SBE –10 indicates that the SID must be increased by 10 mEq/L to fully correct the acid-base abnormality). • To increase SID increase Na+ or decrease Cl– and or lactate. • To decrease SID decrease Na+ or increase Cl–. • Do not change Na+ beyond the normal range (135–145 mEq/L). • Use “buffer” (bicarbonate or lactate) to increase the difference between Na+ and Cl– in the dialysate or replacement ﬂuid. • Typically, undertake correction of half the abnormality and then reassess. • Avoid “over correction” of acid-base abnormalities particularly in cases of metabolizable acid anions (e.g., lactate, ketones) (see metabolic acidosis).

73

•

Acid-base and electrolyte disorders

• Acid-base abnormalities may be caused by improper use of CRRT (e.g., during

CHAPTER 9

CRRT management

Metabolic acidosis A reduced arterial blood pH with a reduced strong ion difference and a base deﬁcit > 2 mEq/L. Outcome in critically ill patients has been linked to the severity and duration of metabolic acidosis and hyperlactatemia.

Causes • Lactic acidosis. Can be due to tissue hypoperfusion, for example, circulatory

• • • •

shock. The anion gap (or strong ion gap) is increased with lactic and other organic acids and poisons. Anaerobic metabolism contributes, in part, to this metabolic acidosis; however other cellular mechanisms are involved and may be more important. May be seen with increased muscle activity (e.g., post seizure, respiratory distress). Lung lactate release seen in acute lung injury. High sustained levels suggest tissue necrosis, for example, bowel, muscle. Hyperchloremia, for example, excessive saline infusion. Ketoacidosis—high levels of β-hydroxybutyrate and acetoacetate related to uncontrolled diabetes mellitus, starvation, and alcoholism. Renal failure—accumulation of organic acids, for example, sulphuric. Drugs—in particular, aspirin (salicylic acid) overdose, acetazolamide (carbonic anhydrase inhibition), ammonium chloride. Vasopressor agents may be implicated, possibly by inducing regional ischemia or, in the case of epinephrine, accelerated glycolysis.

Acid-base and electrolyte disorders CHAPTER 9

• Ingestion of poisons, for example, paraldehyde, ethylene glycol, methanol. • Cation loss, for example, severe diarrhea, small bowel ﬁstulae, large ileostomy

losses.

Causes of lactic acidosis Sepsis Acute lung injury Diabetes mellitus Drugs, for example, phenformin, metformin, alcohols Circulatory shock, for example, septic shock, hemorrhage, heart failure Glucose-6-phosphatase deﬁciency Hematological malignancy Hepatic failure Renal failure Short bowel syndrome (d-lactate) Thiamine deﬁciency

74

Clinical features • Dyspnea • Hemodynamic instability • A rapidly increasing metabolic acidosis (over minutes to hours) is not due to

renal failure. Other causes, particularly severe tissue hypoperfusion, sepsis, or tissue necrosis should be suspected when there is associated systemic deterioration

General management • The underlying cause should be identiﬁed and treated where possible. • Ventilation support (increase minute volume in controlled mechanical ventila-

tion) to help normalize the arterial pH. • Reversal of the metabolic acidosis is generally an indication of successful

therapy. An increasing base deﬁcit suggests that the therapeutic maneuvers in operation are either inadequate or wrong. • The beneﬁts of buffers such as Carbicarb and THAM (tris-hydroxymethylaminomethane) remain unproved.

CRRT management • Urgent CRRT/hemodialysis may be necessary, particularly if renal function is

also impaired. • Lactate and ketones are easily removed by CRRT, but they are also metabo-

lized rapidly once the underlying metabolic derangement is reversed. CRRT is rarely the primary therapy for lactic or ketoacidosis.

An increased arterial blood pH with an increased strong ion difference and base excess > 2 mEq/L caused either by loss of anions or gain of cations. As the kidney is usually efﬁcient at regulating the strong ion difference, persistence of a metabolic alkalosis usually depends on either renal impairment or a diminished extracellular ﬂuid volume with severe depletion of K+ resulting in an inability to reabsorb Cl– in excess of Na+. • The patient is usually asymptomatic, though, if spontaneously breathing, will hypoventilate. • A metabolic alkalosis will cause a left shift of the oxyhemoglobin curve, reducing oxygen availability to the tissues. • If severe (pH > 7.6), may result in encephalopathy, seizures, altered coronary arterial blood ﬂow, and decreased cardiac inotropy.

Causes • Loss of total body ﬂuid, Cl–, usually due to

diuretics large nasogastric aspirates, vomiting Secondary hyperaldosteronism with potassium chloride (KCl) depletion Use of hemofiltration replacement fluid containing excess buffer (e.g., lactate) Renal compensation for chronic hypercapnia. This can develop within 1–2 weeks. Although more apparent when the patient hyperventilates, or is hyperventilated to normocapnia, an overcompensated metabolic alkalosis can occasionally be seen in the chronic state (i.e., a raised pH in an otherwise stable long-term hypercapnic patient) Excess administration of sodium bicarbonate Excess administration of sodium citrate (large blood transfusion) Drugs, including laxative abuse, corticosteroids Rarely, Cushing’s, Conn’s, Bartter’s syndrome • •

• • •

• • • •

Acid-base and electrolyte disorders CHAPTER 9

Metabolic alkalosis

75

Use standard or slightly more alkaline dialysate or replacement ﬂuid— avoid increasing SID by >5 mEq/L as rapid change in lactate or ketones will result in overshoot alkalosis. • Hyperchloremia does not self-correct in a patient with anuric renal failure. Apart from diet, GI losses, and intracellular shifts, the kidney is the primary regulator of plasma electrolytes. • CRRT is effective in correcting hyperchloremic acidosis. • Decrease Cl– in dialysate or replacement ﬂuid by the same interval as the standard base excess (SBE), for example, for SBE-10, decrease Cl– by 10 mEq/L. •

Acid-base and electrolyte disorders CHAPTER 9

Management • Replacement of ﬂuid, Cl– (i.e., give 0.9% saline), and K+ losses are often sufﬁcient

to restore acid-base balance. • With distal renal causes related to hyperaldosteronism, addition of spironolac-

tone can be considered. • Active treatment is rarely necessary. If so, administer 150 mL of 1.0 N HCl in 1

L sterile water using a central line. Infuse at a rate not greater than 1 mL/kg/h. Alternatives include ammonium chloride PO or, if volume overloaded with intact renal function, acetazolamide 500 mg IV or PO q8h. • Compensation for a long-standing respiratory acidosis, followed by correction of acidosis, for example, with mechanical ventilation, will lead to an uncompensated metabolic alkalosis. This usually corrects with time though treatments such as acetazolamide can be considered. Mechanical “hypoventilation,” that is, maintaining hypercapnia, can also be considered.

CRRT management

76

• CRRT is not generally required for management of metabolic alkalosis itself

but in patients receiving CRRT principles of management of metabolic alkalosis mirror those described above for metabolic acidosis. • If hypernatremia, decrease Na+ in dialysate or replacement ﬂuid. • Increase Cl– concentration in dialysate or replacement ﬂuid (increase concentration by the interval of the SBE). • Metabolic alkalosis can result from regional citrate anticoagulation, particularly if the concentrations of Na+ and Cl– are not adjusted. The Cl– concentration should be increased; if using hypertonic sodium citrate, Na+ concentration in dialysate/replacement ﬂuid should be decreased. • Avoid citrate and Ca2+ “dose spirals;” reduce citrate rather than increasing Ca2+ to avoid citrate overdosing.

Part 2

Practice

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Chapter 10

Choosing a renal replacement therapy in acute kidney injury Jorge Cerdá and Claudio Ronco

Continuous renal replacement therapies (CRRT) are continuous forms of renal functional replacement used to manage acute kidney injury (AKI) in the critically ill patient. Depurative mechanisms include convection, diffusion, and membrane adsorption utilizing high-ﬂux highly permeable biocompatible dialysis membranes. Simultaneous infusion of replacement ﬂuid permits ﬂuid removal without intravascular contraction and better hemodynamic stability, metabolic control to almost normal parameters, and removal of large-size toxins and cytokines. Moreover, CRRT allows better long-term clearance of small and middle molecules than other dialysis modalities. This chapter focuses on the different modalities of CRRT and brieﬂy reviews both the basic concepts and the newest approaches to the management of the critically ill patient with AKI. Nowadays, most of AKI occurs in the intensive care units (ICU) and is associated with elevated morbidity and mortality. The following are characteristics of the “ideal” treatment modality of AKI in the ICU: • Preserves homeostasis • Does not increase comorbidity • Does not worsen patient’s underlying condition • Is inexpensive • Is simple to manage • Is not burdensome to the ICU staff CRRT has made possible the delivery of renal replacement therapy (RRT) to these hemodynamically unstable patients and has permitted a conceptual shift from “renal replacement” to “renal support” therapies, with “renal” and “nonrenal” [such as sepsis, acute respiratory distress syndrome (ARDS)] applications. The hemodynamic stability of the critically ill patient is the main determinant of the most appropriate dialysis modality (Table 10.1). When choosing the modality of RRT most appropriate for each patient, multiple considerations must be kept in mind (Table 10.2).

79

Introduction

Choosing a RRT in AKI CHAPTER 10

Table 10.1 Indications for speciﬁc renal replacement therapies Therapeutic goal

Hemodynamics

Preferred therapy

Fluid removal

Stable Unstable Stable Unstable

Intermittent isolated UF Slow continuous UF Intermittent hemodialysis CRRT Convection: CAVH, CV VH Diffusion: CAVHD, CV VHD Both: CAVHDF, CV VHDF Intermittent hemodialysis Intermittent hemodialysis CRRT CRRT CRRT

Urea clearance

Severe hyperkalemia Severe metabolic acidosis Severe hyperphosphoremia Brain edema

Stable/unstable Stable Unstable Stable/unstable Unstable

80

Table 10.2 Considerations in renal replacement therapy for AKI Consideration

Components

Varieties

Dialysis modality

Intermittent hemodialysis

Daily, every other day, SLED AV, VV

Continuous renal replacement therapies Dialysis biocompatibility Dialyzer performance Dialysis delivery

Peritoneal dialysis Membrane characteristics Efﬁciency Flux Timing of initiation Intensity of dialysis Adequacy of dialysis

Early, late Prescription vs. delivery Dialysis dose

In addition to the patient’s hemodynamic stability, the choice between the various renal replacement modalities rests on solute clearance goals, volume control, and anticoagulation (Table 10.3). This discussion will focus on CRRT modalities and review the basic concepts and the newest approaches to this technology and its application in the ICU. We intend to discuss convective and diffusive depurative mechanisms and address the use of membrane adsorption as an additional method of large molecule removal. Previous chapters have discussed the fundamental operational characteristics of CRRT. Recently, the Acute Dialysis Quality Initiative (ADQI) published a consensus on ﬂuid and volume management, which is relevant to the present discussion.

Use in hemodynamically unstable patients

Solute clearance

Volume control

Anticoagulation

PD IHD IHF Intermittent IHF Hybrid techniques CV VH CV VHD CV VHDF

Yes Possible Possible Possible

++ ++++ +++ ++++

++ +++ +++ +++

No Yes/no Yes/no Yes/no

Possible

++++

++++

Yes/no

Yes Yes Yes

+++/++++ +++/++++ ++++

++++ ++++ ++++

Yes/no Yes/no Yes/no

Choosing a RRT in AKI

Modality

CHAPTER 10

Table 10.3 Advantages and disadvantages of various renal replacement modalities

Arterio-venous or veno-venous blood circuits Arterio-venous (AV) systems are not used except in emergent situations when veno-venous (VV) systems are not available. AV system limitations include arterial damage, blood ﬂow dependency on systemic hemodynamics, and insufﬁcient dialysis dose.

Choice of continuous renal replacement therapy modality The different modalities of CRRT (Figure 10.1) are deﬁned by the main mechanism with which clearance is achieved: simple diffusion (continuous hemodialysis, CV VHD), convection (continuous hemoﬁltration, CV VH), or a combination of both (continuous hemodiaﬁltration, CV VHDF). These different modalities differ in the magnitude of the clearance achieved by convection or diffusion, as well as by the vascular access and the need for ﬂuid replacement (hemoﬁltration) (Table 10.4). Given the absence of evidence of superiority among the different CRRT modalities, the choice rests on the available equipment (membranes, pump systems) and appropriate dialysate, cost, and conceptual considerations.

81

Notes: HDF = hemodiaﬁltration; CVVH = continuous veno-venous hemoﬁltration; CVVHD = continuous veno-venous hemodialysis; CVVHDF = continuous veno-venous hemodiaﬁltration; IHD = intermittent hemodialysis; IHF = intermittent hemoﬁltration; PD = peritoneal dialysis. Modiﬁed from Davenport.

82

CHAPTER 10

Choosing a RRT in AKI

Modalities of CRRT CVVH

SCUF Blood in

Blood in

V UFC

Uf

Uf

V

D

QB = 100–200 mL/min QF = 10 –30 mL/min QD = 10–30 mL/min K = 20 – 50 L/24 h

Blood in

V

Blood in Plasma

QB = 100–200 mL/min Can be coupled with CVVH or CVVHDF

Figure 10.1 Modalities of CRRT.

V

QB = 100–200 mL/min PF = 20–30 mL/min Can be coupled with CVVH or CVVHDF

CPFA

Adsorbent

Plasmafilter

D

QB = 100 – 200 mL/min QF = 2 – 8 mL/min QD = 50 – 200 mL/min K = 40 – 60 L/24 h Diffusion + Convection (Back Filtration)

CHP Blood in

QB = 100–200 mL/min QF = 2–4 mL/min QF = 10–30 mL/min K = 15–45 L/24 h

CPF–PE V

UFC

V D

CVVHDF–SLED

R Blood in

Blood in UF+D

Blood in

V

QB = 100–200 mL/min QF = 10–30 mL/min K = 15–45 L/24 h

QB = 100 mL/min QF = 2–8 mL/min

CVVHDF

CVVHD

R

Plasmafilter

HVHF V

Adsorbent

QB = 100–200 mL/min PF = 20 –30 mL/min Can be coupled with CVVH or CVVHD/F

R

Blood in

V Uf

QB = 200 –300 mL/min QF = 50 – 100 mL/min K = 60 – 120 L/24 h

Clearance

mechanism

Vascular access

Fluid replacement

SCUF CAVH CV VH CAVHD CV VHD CAVHDF CV VHDF CAVHFD CV VHFD

Convection + ++++ ++++ + + +++ +++ ++ ++

Diffusion ++++ ++++ +++ +++ ++++ ++++

Large vein Artery and vein Large vein Artery and vein Large vein Artery and vein Large vein Artery and vein Large vein

0 +++ +++ +++ +/0 ++ ++ +/0 +/0

Choosing a RRT in AKI

Technique

CHAPTER 10

Table 10.4 Modalities of continuous renal replacement therapy

Dialysis membranes for CRRT The main features of convective treatments are the following: • High-ﬂux membranes • High permeability to water • High permeability to low and middle molecular weight (MW) solutes (1000–12,000 dalton) • High “biocompatibility” Dialysis devices are designated as the following: • “Dialyzers” working predominantly in diffusion with a countercurrent ﬂow of blood and dialysate • “Hemoﬁlters” working prevalently in convection • Newer designs allowing powerful simultaneous convection and diffusion (highﬂux dialysis, hemodiaﬁltration) It is a widespread opinion that convective treatments like high-ﬂux hemodialysis, hemodiaﬁltration, and hemoﬁltration offer a clinical advantage over standard dialysis, when considering physiological outcomes. The crucial point is that up until now none of the studies have been able to demonstrate superiority of these techniques on morbidity, mortality, and quality of life.

83

Notes: CAVH = continuous arterio-venous hemoﬁltration; CAVHD = continuous arterio-venous hemodialysis; CAVHDF = continuous arterio-venous hemodiaﬁltration; CAVHFD = continuous arteriovenous high-ﬂux hemodialysis; CV VH = continuous veno-venous hemoﬁltration; CV VHD = continuous veno-venous hemodialysis; CV VHDF = continuous veno-venous hemodiaﬁltration; CV VHFD = continuous veno-venous high-ﬂux hemodialysis; SCUF = slow continuous ultraﬁltration; 0 = not required; + = negligible; ++ = some; +++ = marked; ++++ = major.

Choosing a RRT in AKI CHAPTER 10

84

Comparison between CRRT and other renal replacement modalities Continuous renal replacement therapy techniques offer better long-term clearance of small and middle molecules than intermittent hemodialysis (IHD) or slow low efﬁciency dialysis (SLED): • An 8% and 60% higher small solute clearance comparing CV VH with SLED and IHD respectively. • Effective azotemic control with CRRT and SLED but pronounced concentration peaks and poor time-averaged azotemic control with IHD. • More pronounced differences in the middle-molecule range of solutes, with superior middle-molecule clearance with CV VH compared with SLED or IHD. • The superior middle and large molecule removal for CV VH is due to combination of convection and continuous operation. • While on CRRT beta-2 microglobulin plasma concentration achieved steady state after 3 days, using SLED or IHD plasma concentration actually increases steadily, thus reﬂecting the inability of the latter modalities to clear large and middlemolecular weight toxins. The importance of the clearance of larger compounds is suggested by two treatment trials (Ronco et al. [1] study and an earlier CRRT study) correlating convective dose (i.e., ultraﬁltration rate) with survival. Large molecular clearance may have contributed substantially to the salutary effect of higher doses in these therapies. More recently, Saudan et al. [2] have shown that the addition of diffusion to convective clearance resulted in further improvement in patient outcome. Because the daily IHD versus every other day IHD study by Schifﬂ et al. [3] was performed with high-ﬂux dialyzers, the clearance of compounds signiﬁcantly larger than urea may have played a role in the improved survival among the patients dialyzed daily. In spite of these suggestive ﬁndings, there is no ﬁrm evidence that enhanced removal of mid or high molecular weight in patients leads to better patient outcomes (see below).

Convection and diffusion Convection-based replacement techniques (hemoﬁltration and hemodiaﬁltration) using high-ﬂux membrane ﬁlters are aimed at maximizing the removal of so-called medium and high molecularweight solutes (higher than 1000 kDa up to several thousand kDa), as opposed to the so-called low molecular weight toxins.

Hemoﬁltration • Predominantly convective technique • Removes larger quantities of hydrophilic MW compounds than diffusion • Leads to greater cytokine removal by adsorption and convection

Hemodiaﬁltration • Utilizes partially hydrophilic high-ﬂux membranes • Membranes that have high sieving coefﬁcient and reduced wall thickness com-

bine diffusion and convection • Accurate ultraﬁltration (UF) control systems make safe large-volume removal

possible • Newer machines permit separate control of dialysate and UF/reinfusion • Online production of ultrapure dialysate and replacement ﬂuid has made it

Choosing a RRT in AKI

strated to beneﬁt patient outcome

CHAPTER 10

• Removal of inﬂammatory mediators has been postulated but not demon-

With current CRRT machines, solute exchanges can be obtained by convection, diffusion, or both, with easier and more precise control over each component of the therapy. Blood (QB), dialysate (QD), and ultraﬁltrate (QUF) ﬂow rates can be controlled accurately with integrated pumps, and greater dialysate or convective ﬂows—and therefore greater diffusive and convective solute ﬂuxes can be achieved. During CRRT, diffusion is limited by QD, in contrast to IHD; the addition of convection may improve the clearances or middle molecular weight solutes.

Diffusion • The diffusivity of a solute, whether in solution or in an extracorporeal mem-

brane, is, inversely proportional to its molecular weight: as solute molecular weight increases, diffusion becomes a relatively inefﬁcient dialytic removal mechanism and the relative importance of convection increases. • Diffusion occurs whenever a concentration gradient (dc) exists for solutes not restricted in diffusion by the porosity of the membrane. • Diffusion ﬂux is also inﬂuenced by the characteristics of the membrane including the following: • Surface area (A) • Thickness (dx) • The temperature of the solution (T) • Diffusion coefﬁcient of the solute (D) The diffusion ﬂux of a given solute (Jx) will therefore result from the equation: Jx = D . T . A (dc/dx)

(1)

Other factors may inﬂuence the ﬁnal clearance values, including protein binding or electrical charges in the solute. Increased convection may contribute to greater solute transport, especially in the higher molecular weight range.

85

possible to deliver safe and less costly treatments

Choosing a RRT in AKI CHAPTER 10

Convection Convection requires movement of ﬂuid across the membrane driven by a transmembrane pressure gradient (TMP). The ﬂuid transport is deﬁned as ultraﬁltration and can be described by the equation: Jf = Kf . TMP

(2)

where Kf is the coefﬁcient of hydraulic permeability of the membrane and TMP = (PB – PUF) – S, where PB is the hydrostatic pressure of blood, PUF is the hydrostatic pressure of ultraﬁltrate or dialysate, and S is the oncotic pressure of plasma proteins. The convective ﬂuid of a solute x will therefore depend on the following: • The amount of ultraﬁltration (Jf) • The concentration of the solute in plasma water (Cb) • The sieving characteristics of the membrane for the solute (S): Jx = Jf Cb (1–V) = Jf Cb S

(3)

86

The sieving coefﬁcient (S) is regulated by the reﬂection coefﬁcient of the membrane V according to the equation S=1–V

(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 expected from a simple theoretical calculation.

Predilution or postdilution In hemoﬁltration, replacement ﬂuid can be infused either before the hemoﬁlter (“predilution”) or after the hemoﬁlter (“postdilution”). Postdilution CV VH is a purely convective therapy. The three primary determinants of solute clearance are as follows: 1. Ultraﬁltration rate 2. Membrane sieving coefﬁcient 3. Dilution mode Convection occurs by “solvent drag”: solutes are swept (dragged) across the membrane in association with ultraﬁltered plasma water, such that K = QF . SC

(5)

where K is clearance (mL/min), QF is ultraﬁltration rate (mL/min), and SC is sieving coefﬁcient. For small solutes, as SC approaches unity, clearance equals the ultraﬁltration rate in postdilution. In postdilution CV VH, ﬁltration fraction (FF), the ratio of ultraﬁltration rate (QUF) to plasma water ﬂow rate is a limiting factor determined by blood ﬂow (QB) rate and patient hematocrit (Htc): QUF FF = ___________ QB(1 – Htc)

(6)

Predilution mode has been introduced as an useful adjunct to prevent clotting of the extracorporeal circuit and to extend ﬁlter life, especially during high-volume CRRT, where ﬁltration fraction would otherwise reach values greater than 0.3 and induce clotting and protein encroachment of the membranes. Predilution CRRT allows freedom from the constraints in blood ﬂow and ﬁltration rate imposed by predilution. For small solutes dissolved in the water of the blood passing through the hemoﬁlter, clearance equals

Choosing a RRT in AKI

(7)

where QBW is blood water ﬂow rate and QS is the substitution (replacement) ﬂuid rate. At a given QF value, • predilution is always less efﬁcient than postdilution CV VH with respect to ﬂuid utilization, • while predilution attenuates hemoconcentration-related effects, it simultaneously reduces the efﬁciency of the treatment, • the larger the QS is relative to QBW, the smaller the entire fraction and the greater the loss of efﬁciency relative to postdilution.

Importance of achieving a high blood ﬂow (QB) In CV VH, given the direct relationship between QS and QF, great efforts are needed toward increasing the blood ﬂow beyond that used traditionally in CRRT, usually close to 150 mL/min or less. In predilution mode, to attain doses of 35 mL/kg/h as described by Ronco et al., it is necessary to achieve blood ﬂows of 250 mL/min or higher, given that the decrease in efﬁciency inherent to predilution mode can be as high as 35% to 40%–45% for urea and creatinine respectively when QB is 125–150 mL/min and QS is ﬁxed at 75 mL/min. Utilizing modeling analysis, Clark et al. [4] have shown that • as patient’s weight increases, for low blood ﬂow rates substitution ﬂuid rates required to achieve this dose are impractically high in the majority of patients weighing more than 70 kg, • to achieve the dose target, the high ultraﬁltration required determines high replacement ﬂuid infusion rates, which in turn have a substantial dilutive effect on solute concentrations at low blood ﬂows,

87

K = QF . SC . [QBW/(QBW + QS)]

CHAPTER 10

Clinical practice indicates that an FF greater than 0.3 should be avoided because of hemoconcentration and protein-membrane interaction. • Greater ultraﬁltration rates require larger blood ﬂows to avoid elevated FF and ﬁlter clotting and coating with accumulated proteins. • As higher blood ﬂows are usually difﬁcult to reach with the temporary dialysis catheters and hemodynamic conditions commonly prevalent among critically ill patients, reaching the higher doses recently demonstrated to affect survival are difﬁcult to reach in postdilution mode.

Choosing a RRT in AKI CHAPTER 10

Interaction between convection and diffusion

88

• conversely, higher blood ﬂows allow the delivery of higher doses without loss

of efﬁciency. Brunet et al. [5] studied the diffusive and convective solute clearances during CV VHDF at various dialysate and ultraﬁltration rates. They demonstrated that convection is more effective than diffusion in removing middle molecular weight solutes during CRRT, and that high convective ﬂuxes should be applied if the goal is to remove middle molecules more efﬁciently. At the slow ﬂow rates normally utilized in CRRT, there is no interaction between diffusive and convective clearances. Recent studies have shown that the addition of a diffusive component to dialysis “dose” resulted in improved survival. Up until recently, dose data were mainly limited to diffusion and convection [1]. The results of Ronco et al. led to the deﬁnition of a “standard dose” of CRRT of 35 mL/kg/h, which was applied indiscriminately to diffusive and convective continuous modalities. More recently, Palevsky et al. [6], utilizing a combined diffusive and convective modality (predilution CV VHDF) or IHD depending on hemodynamic stability, failed to demonstrate a beneﬁcial effect of such dose, as discussed elsewhere (see Chapter 8). It must be emphasized that the study by Palevsky et al. was not designed to evaluate the different RRT modalities, but rather to evaluate the effects of dose on survival and renal recovery function. • The premise of those studies is that dose is a solute clearance-related parameter. • The studies were not designed to enable a determination of which toxin class increased clearance led to better survival. Although small solute clearance is a possible explanation, substantial clearance of relatively large molecular weight toxins may also explain the survival beneﬁt in the high dose arm of the Ronco study. Based on the dosing scheme of normalizing efﬂuent ﬂow rate to body weight, other forms of CRRT such as CV VHD and CV VHDF may provide equivalent or nearly equivalent small solute clearances as postdilution CV VH, but for a given efﬂuent ﬂow rate, the diffusive component of these therapies limits their ability to clear larger molecular weight toxins relative to hemoﬁltration. Consequently, extrapolating Ronco’s data to other forms of CRRT, especially for dosing purposes, should be done with caution.

Nutrition and outcome Better management of volume and body ﬂuid composition is easily achieved with CRRT. Given the importance of nutrition on the outcome of critically ill patients with AKI, CRRT could offer a theoretical advantage over IHD in this setting.

Choosing a RRT in AKI CHAPTER 10

Older and very recent studies have consistently shown that the main advantage of continuous modalities is greater hemodynamic stability. In their recently published study, Palevsky et al. [6] chose CRRT (CV VHDF) as the modality of choice for hemodynamically unstable patients, a decision that reﬂects current practice in the United States. In their study, although hemodynamically “stable” patients were allocated to IHD, hypotension occurred more frequently among patients treated with IHD than CRRT and may have had an impact on their lower rate of recovery of renal function. CRRT is associated with better tolerance to ﬂuid removal because of the following reasons: • The rate of ﬂuid removal is much slower in CRRT than in IHD. • The main determinant of hemodynamic instability during RRT is the maintenance of intravascular compartment volume. • The volume of that compartment is the result of the balance between convective removal of ﬂuid (ultraﬁltration) from plasma and the rate of replenishment from the interstitium. • Therefore, whenever the UF rate exceeds the rate of interstitium-toplasma ﬂow (reﬁlling), the patient will experience hypovolemia and hemodynamic instability. • In IHD rapid diffusion of urea creates a plasma-to-interstitium and interstitium-to-cell osmotic gradient that drives water to the interstitium and to the intracellular compartment, such that plasma volume decreases and cell edema (including neuronal edema) occurs. • With CRRT, the slower rate of urea clearance allows for equalization of urea concentrations between compartments and, therefore, lessened water shifts and cell edema. • This is particularly important in patients with intracranial hypertension, such as head trauma and severe liver failure. • A decrease in core temperature and peripheral vasoconstriction has been shown to decrease hypotensive episodes and may play a role in hemodynamic stability. • With either pre- or postdilution hemoﬁltration, the magnitude of sodium removal is less than the amount of sodium removed with hemodialysis, a factor that may contribute to better cardiovascular stability in hemoﬁltration. • Although hypovolemia is the ﬁrst step in dialysis-related hypotension, the ultimate arterial pressure response to hypovolemia is the result of a complex interplay between active and passive mechanisms, including decreased venous vessel capacity to sustain cardiac ﬁlling, increased arterial vascular resistances to ensure organ perfusion, and increased myocardial contractility and heart rate to maintain cardiac stroke volume. Any factor interfering with one or more of these compensatory mechanisms may foster cardiovascular instability.

89

Hemodynamic stability

Choosing a RRT in AKI CHAPTER 10

90

In this context, it is possible that convective removal of inﬂammatory mediators could contribute to hemodynamic stability, especially in the early phases of septic shock (see below).

Hemoﬁltration of large molecules • Middle molecules

Mostly of peptides and small proteins with molecular weight in the range of 1000 to 600,000 daltons. • Accumulate in renal failure and contribute to the uremic toxic state. • Beta-2 microglobulin, with a molecular weight of 11,000 dalton, is considered representative of these middle molecules. • Cannot be well cleared by low-ﬂux dialysis. • High-ﬂux dialysis will clear middle molecules partly by internal ﬁltration (convection); the convective component of high-ﬂux dialysis can be enhanced in a predictable way by hemodiaﬁltration. In the past decade, it has been postulated that high convective dose therapies improve the management of sepsis. • Severe sepsis and septic shock are the primary causes of multiple organ dysfunction syndrome (MODS), the most frequent cause of death in intensive care unit patients. • Many water-soluble mediators with pro- and antiinﬂammatory action such as TNF, IL-6, IL-8, and IL-10 play a strategic role in septic syndrome. • In intensive care medicine, blocking any one mediator has not led to a measurable outcome improvement in patients with sepsis. • CRRT is a continuously acting therapy, which removes in a nonselective way pro- and antiinﬂammatory mediators. The “peak-concentration hypothesis” is the concept that cutting peaks of soluble mediators through continuous hemoﬁltration may help restore homeostasis. This latter development proposes to use increased volume exchanges in hemoﬁltration or the combined use of adsorbent techniques. • High-volume hemoﬁltration (HVHF): • A variant of CV VH that requires higher surface area hemoﬁlters and ultraﬁltration volumes of 35 to 80 mL/kg/h. • Provides higher clearance for middle/high molecular weight solutes than simple diffusive transport (CV VHD) or convection-based transport at lower volumes (CV VH). • Associated with practical difﬁculties including machinery, replacement ﬂuid availability and cost, and accurate monitoring systems to maintain safety. • Studies utilizing this technique have shown preliminary evidence of beneﬁt, but none of the studies are randomized trials of adequate statistical power to demonstrate effect conclusively. • Alternative technologies have utilized high cutoff hemoﬁlters with increased effective pore size. •

Choosing a RRT in AKI

References

91

1. 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. 2. Saudan P, Niederberger M, DeSeigneux S, et al. Adding a dialysis dose to continuous hemoﬁltration increases survival in patients with acute renal failure. Kidney Int. 2006;70:1312-1317. 3. Schifﬂ H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. New England Journal of Medicine. 2002;346:305-310. 4. Clark WR, Turk JE, Kraus MA, Gao D. Dose determinants in continuous renal replacement therapy. Artif Organs. 2003;27(9):815-220. 5. 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. American Journal of Kidney Diseases. 1999;34:486-492. 6. Palevsky PM, Zhang JH, O’Connor TZ, et al., The VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7-20.

Suggested readings Cerda J, Bagga A, Kher V, Chakravarthi RM. The contrasting characteristics of acute kidney injury in developed and developing countries. Nat Clin Pract Nephrol. 2008;4(3):138–153.

CHAPTER 10

Drawbacks of such porous membranes include the loss of essential proteins such as albumin. • Plasmaﬁltration coupled with adsorption (CPFA) has been recently utilized in septic patients • In coupled plasma ﬁltration adsorption (CPFA), plasma is separated from blood and the plasma is circulated through a sorbent bed; blood is subsequently reconstituted and dialyzed with standard techniques, thus achieving normalization of body ﬂuid composition and increased removal of proteinbound solutes and high molecular weight toxins. • Recently, evidence has been obtained that very high-volume hemoﬁltration applied in pulses may improve the hemodynamic stability of septic patients in septic shock, but failed to show consistently improved survival. Larger multicentric evidence will be necessary before such techniques are widely implemented. If beneﬁt is demonstrated, the use of very high volume hemoﬁltration will require special equipment and very capable nursing able to manage such large volumes (i.e., up to 5–6 L/h) of ultrapure replacement ﬂuid without error. •

Choosing a RRT in AKI CHAPTER 10

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Cerda, J, Cerdá M, Kilcullen P, Prendergast J. In severe acute kidney injury, a higher serum creatinine is paradoxically associated with better patient survival. Nephrol Dial Transplant. 2007;22(10):2781-2784. Cerda J, Lameire N, Eggers P. Epidemiology of acute kidney injury. Clin J Am Soc Nephrol. 2008;3(3):881-886. Clark WR, Ronco C. Continuous renal replacement techniques. Contrib Nephrol. 2004;144:264-277. Cruz D, Bellomo R, Kellum JA, de Cal M, Ronco C. The future of extracorporeal support. Crit Care Med. 2008;36(suppl 4):S243-252. Davenport A. Renal replacement therapy in acute kidney injury: which method to use in the intensive care unit? Saudi J Kidney Dis Transpl. 2008;19(4):529-536. Gibney N, Cerda J, Davenport A, et al. Volume management by renal replacement therapy in acute kidney injury. Int J Artif Organs. 2008;31(2):145-155. Kellum JA, Cerda J, Kaplan LJ, Nadim MK, Palevsky PM. Fluids for prevention and management of acute kidney injury. Int J Artif Organs. 2008;31(2):96-110. Lameire N, Biesen WV, Vanholder R. Dialysing the patient with acute renal failure in the ICU: the emperor’s clothes? Nephrol Dial Transplant. 1999;14(11):2570-2573. Murray P, Hall J. Renal replacement therapy for acute renal failure. Am J Respir Crit Care Med. 2000;162(3 Pt 1):777-781. Palevsky PM, Bunchman T, Tetta C. The Acute Dialysis Quality Initiative—part V: operational characteristics of CRRT. Adv Ren Replace Ther. 2002;9(4):268-272. Ronco C. Recent evolution of renal replacement therapy in the critically ill patient. Crit Care. 2006;10(1):123-131. Ronco C, Inguaggiato P, D’Intini V. The role of extracorporeal therapies in sepsis. J Nephrol. 2003;16(suppl 7):S34-41. Ronco C, Tetta C. Extracorporal blood puriﬁcation: more than diffusion and convection. Does this help? Curr Opin Crit Care. 2007;13(6):662-667.

Chapter 11

Vascular access for continuous renal replacement therapy

Renal replacement therapy (RRT) remains a cornerstone for the management of patients with severe acute kidney injury (AKI). The efﬁcacy of RRT depends on a reliable vascular access. In critically ill patients, continuous renal replacement therapy (CRRT) is usually performed with a temporary dialysis catheter (TDC), which can be employed in any patient, easily inserted at the bedside, and used immediately after insertion. Malfunction of the catheter is frequently due to insufﬁcient blood ﬂow rates, repeated clotting of the extracorporeal circuit, and shortened dialysis time.

Type of catheter The demands on TDC are manifold, including sufﬁcient rigidity to insert the catheter and maintain patency, enough ﬂexibility to prevent kinking, thromboresistent, and resistant to bacterial invasion. Different types of TDC are available, but CRRT is usually performed with a dual-lumen catheter inserted into a central vein (see Figure 11.1). A septum in the catheter separates the two lumina and prevents cross ﬂow. The two lumina can be arranged side by side or in a concentric manner (coaxial). To minimize the recirculation rate, the tips on the catheter are staged. Frequently, the return tip will be longer than the intake tip with a gap of more than 3 cm separating the two oriﬁces. The choice of the right catheter length is crucial for both upperbody (i.e., internal jugular vein) and lower-body (i.e., femoral vein) access sites, since recirculation will occur if the catheter length is not long enough. The two most frequently used blood-compatible materials for dialysis catheters are silicone and polyurethane. The advantage of silicone is that it is soft and ﬂexible and resistant to most chemicals. However, due to the mechanical properties, silicone catheters are more difﬁcult to insert and compression of the lumen may lead to mechanical failure. On the other hand the danger of endothelial damage or venous perforation is lower. Polyurethane is comparable to

93

Alexander Zarbock and Kai Singbartl

Vascular access for CRRT

B

C

D

94

CHAPTER 11

A

Figure 11.1 Type of catheters used for continuous renal replacement therapy (CRRT): (A) All catheters used for acute CRRT today have tapered tips. Blood is usually removed through the side holes, located at some distance from the tip (approx. 3 cm). (B) The Mahurkar acute dialysis catheter has a so-called “double-D design” that allows blood to be withdrawn through one side of the catheter (intake lumen, “dark grey”) and returned through the other side (return lumen, “light grey”). (C) The “Circle C” catheter represents a variation of the Mahurkar catheter. Blood is removed through the outer cylindrical lumen and later returned through the inner cylindrical lumen. Here, the internal surface area is greater than that of the double-D catheter, and therefore resistance to blood ﬂow is greater. (D) Uldall concentric duallumen catheter. This catheter had an outer surface with side holes in all directions for intake of blood and a concentric inner lumen for blood return through the tip.

silicone with respect to biocompatibility but displays a higher tensile strength. Polyurethane catheter can be extruded with a thinner wall resulting in a larger inner diameter and subsequently a higher ﬂow rate, compared to silicon catheters with the same outer diameter. The advantage of polyurethane catheters is that they have thermoplastic properties, being rigid during placement but softening when soaked at body temperature. The use of polyurethane catheters are often recommended, because it has been shown that this material is associated with reduced bacterial colonization [2].

Vascular access site and implementation General consideration • The insertion site of the catheter depends on the patient’s characteristics (e.g.,

previous surgery, local infection, coagulopathy, and body habitus), the availability of the insertion site, the skills/experience of the operator, and the risks of site-speciﬁc complications. • Due to catheter-related bloodstream infection, nontunneled and noncuffed catheters can be used for short-term RRT (<3 weeks), but tunneled (5–10 cm subcutaneous course) and cuffed catheters should be used if the duration of the RRT is anticipated to be more than 3 weeks [2].

Site of insertion Jugular vein Insertion in the right internal jugular vein (IJV) is preferred over the left IJV because of the increased blood ﬂow and reduced complication rate. Femoral vein The femoral vein is often preferred because of easy and fast accessibility. Transient dialysis catheters in the femoral vein have for a long time been thought to be associated with the highest infection rate. However, a recently conducted multicenter study demonstrated that femoral catheterization is only associated with an increased infection rate in patients with a high body mass index (>28.4) [5]. However, femoral TDCs drastically limit patient mobilization and increase recirculation rates [6,7]. Subclavian vein In critically ill patients, the insertion of a central venous catheter (CVC) in the subclavian vein is preferred because of the low infection rate [8]. However, in patients who develop ESRF and may need permanent vascular access for dialysis, the insertion of a TDC in the subclavian vein is not recommended because it is associated with higher rates of central venous stenosis, excluding the ipsilateral arm for future dialysis access [9–11]. Therefore, the subclavian vein should be reserved for a very short-term use or if there is no other alternative [2,8].

Complications Primary complications • Insertion-related complications are arterial puncture, pneumothorax,

hemothorax, air embolism, arrhythmias, pericardial tamponade, and retroperitoneal hemorrhage. Most of these complications can be reduced by using ultrasound guidance. • A reduced blood ﬂow, frequently indicated by increased intake and/or return pressures in the CRRT circuit, are often due to malpositioning, kinking during insertion, or other mechanical problems. Improper catheter tip placement is a common cause of reduced blood ﬂow and malfunction. Femoral catheters

Vascular access for CRRT

tion whenever possible. This approach can increase the overall success rate while reducing the rate of complications, for example, hemothorax, pneumothorax, and catheter-related infections [2,3]. • Preexisting grafts and ﬁstulae in patients with end-stage renal failure (ESRF) should not be used as vascular access sites for TDCs, as these catheters can lead to permanent vessel or graft wall damage [4].

CHAPTER 11

catheter-related bloodstream infections (CRBSI). • Ultrasound guidance is recommended to be used for central vein catheteriza-

95

• TDCs should be inserted using stringent sterile precautions in order to reduce

Vascular access for CRRT CHAPTER 11

should be inserted in the inferior vena cava, and jugular and subclavian catheters should be placed at the junction of the superior vena cava and the right atrium. Malfunction of catheters in the superior vena cava is further decreased when the tip of the catheters is located in the right atrium, which is safe only with silicone catheters. • Another problem is the inefﬁciency of CRRT due to recirculation of blood from the return to the intake part of the catheter. This problem arises when the ﬂow generated by the extracorporeal circuit exceeds the ﬂow in the vein. Recirculation rates are normally <5% and dependent on design, length, and insertion site of the catheter as well as the blood ﬂow in the CRRT circuit.

Secondary complications • Infection •

96

•

• • • •

•

•

In ICU patients risk factors for CRBSI include the following: catheter material, elective versus urgent insertion, the frequency of manipulation, the number of infusion ports, the operator’s experience, insertion site, indwelling time, and the severity of the underlying illness. Contamination of TDCs can occur as follows: Extraluminal contamination (migration of skin ﬂora along the external surface of the catheter into the bloodstream), hematogenous contamination (seeding from another focus of infection), and intraluminal contamination (dominant mechanism in longer-dwelling catheters, contamination of the catheter hub through contaminated infusate). The most frequent bacteria are coagulase-negative staphylococci, staphylococcus aureus, enterococci, gram-negative bacteria, and yeast. TDCs should be used for RRT only. The use of trisodium citrate compared to heparin as a catheter-locking solution reduces catheter-related infections [12]. The use of antibiotic-impregnated catheters prevents CRBSI [13], but a general recommendation for using these catheters cannot be given due to the emergence of allergic reactions and bacterial resistance. If a clinical suspicion of CRBSI exists, empiric systemic antibiotics appropriate for the suspected organisms should be started after cultures have been taken. After receiving the blood culture results, antibiotic treatment should be tailored to the speciﬁc organism. A positive result in the culture of the catheter tip necessitates the removal of the catheter and insertion of a new catheter at a new site. However, if an infection at the side of puncture, pocket infection of tunneled catheters, or CRBSI with clinical signs of sepsis exists, the catheter has to be removed immediately.

• •

• • •

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•

Depending on the diagnostic method, the incidence of catheter-related thrombosis may be as high as 33%–67% [14]. Catheter-related thrombosis may occur as a thrombus adherent to the vessel wall or formation of a ﬁbrin sleeve around the catheter. Catheter-related thrombosis can lead to life-threatening complications, such as right heart thromboembolism (RHTE) and pulmonary embolism. Nonmobile RHTE originate from the tip of a catheter in the right atrium. Mobile RHTE represent dislodged thrombi from deep venous thromboses in both upper and lower extremities. During interdialytic periods, the catheter can be ﬁlled with an anticoagulant (citrate or heparin) to prevent intraluminal thrombosis. Risk factors for catheter-related thrombosis are listed in Table 11.1. In critically ill patients the incidence of catheter-related thrombosis is higher for femoral and jugular than subclavian catheters. The risk of catheter-related thrombosis and subsequently the risk of catheter-related infection can be reduced by administering anticoagulants or using anticoagulant-bonded catheters.

Vascular access for CRRT

•

CHAPTER 11

• Thrombosis

Table 11.1 Risk factors for TDC thrombosis Patient-related Hypercoagulable statesa Thrombophilic statesa,b Age > 64b Underlying malignancya,b Dehydrationb Impaired tissue perfusionb Absent prophylaxis/ treatmentb

Catheter-related Polyurethane/polyvinyl cathetersb Additional central venous catheters simultaneouslyb Traumatic insertionb Distal placementa

Site-related Femoral or internal jugular siteb Subclavian sitea

Source: Modiﬁed after Burns KEA, McLaren A. A critical review of thromboembolic complications associated with central venous catheters. Can J Anesth. 2008;55:532–541. Notes: a Associated with RHTE; bAssociated with central venous thrombosis.

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Vascular access for CRRT

References 1. Wentling AG, Hemodialysis catheters: materials, design and manufacturing. Contrib Nephrol. 2004;142:112-127. 2. NKF-K/DOQI. Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis. 2001;37(suppl 1):S137-S181. 3. Karakitsos D, Labropoulos N, De Groot E, et al. Real-time ultrasound-guided catheterisation of the internal jugular vein: a prospective comparison with the landmark technique in critical care patients. Crit Care. 2006;10:R162. 4. Davenport A, Mehta S. The Acute Dialysis Quality Initiative—part VI: access and anticoagulation in CRRT. Adv Ren Replace Ther. 2002;9:273-281. 5. Parienti JJ, Thirion M, Megarbane B, et al. Femoral vs jugular venous catheterization and risk of nosocomial events in adults requiring acute renal replacement therapy: a randomized controlled trial. JAMA. 2008;299:2413-2422. 6. Leblanc M, Fedak S, Mokris G, Paganini EP. Blood recirculation in temporary central catheters for acute hemodialysis. Clin Nephrol. 1996;45(5):315-319. 7. Little MA, Conlon PJ, Walshe JJ. Access recirculation in temporary hemodialysis catheters as measured by the saline dilution technique. Am J Kidney Dis. 2000;36:1135-1139. 8. Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Infect Control Hosp Epidemiol. 2002;23:759-769. 9. 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. 10. Schillinger F, Schillinger D, Montagnac R, Milcent T. Post catheterisation vein stenosis in haemodialysis: comparative angiographic study of 50 subclavian and 50 internal jugular accesses. Nephrol Dial Transplant. 1991;6:722-724. 11. Trerotola SO, Kuhn-Fulton J, Johnson MS, Shah H, Ambrosius WT, Kneebone PH. Tunneled infusion catheters: increased incidence of symptomatic venous thrombosis after subclavian versus internal jugular venous access. Radiology. 2000;217:89-93. 12. Weijmer MC, van den Dorpel MA, Van de Ven PJ, et al; CITRATE Study Group. Randomized, clinical trial comparison of trisodium citrate 30% and heparin as catheter-locking solution in hemodialysis patients. J Am Soc Nephrol. 2005;16:2769-2777. 13. Chatzinikolaou I, Finkel K, Hanna H, et al. Antibiotic-coated hemodialysis catheters for the prevention of vascular catheter-related infections: a prospective, randomized study. Am J Med. 2003;115:352-357. 14. Burns KEA, McLaren A. A critical review of thromboembolic complications associated with central venous catheters. Can J Anesth. 2008;55:532-541.

Chapter 12

The circuit and the prescription Rinaldo Bellomo and Ian Baldwin

The prescription of continuous renal replacement therapy (CRRT) requires an understanding of the circuit and the ﬁlter and their properties in order to deliver physiologically logical treatment. It also requires an understanding of the different processes of solute removal (diffusion and convection) and the importance of ﬁltration fraction on ﬁlter performance and ﬁlter life. Finally, it requires an understanding of the different patterns of solute removal achieved with continuous hemoﬁltration compared with hemodiaﬁltration and, in turn, compared with hemodialysis. This understanding allows the application of a particular circuit setting, which, in turn, deﬁnes a signiﬁcant component of the ﬁnal prescription. Both physician and nurses need to understand these principles to practice CRRT safely and effectively.

Key terms Hemoﬁltration (CV VH): This term refers to the removal of plasma water (the solvent) across a semipermeable membrane by means of the application of a transmembrane pressure (Figure 12.1). This transmembrane pressure can derive form the rate of blood ﬂow through the ﬁlter containing the membrane or from a negative pressure (typically generated by a peristaltic pump) applied to the nonblood side of the membrane. This process leads to solute removal as it follows the solvent across the membrane (solvent drag). This process is known as convection. Hemodialysis (CV VHD): This term refers to the removal of solute across a semipermeable membrane by means of the application of a concentration gradient. This concentration gradient derives form the relationship between the rate of blood ﬂow through the ﬁlter and the rate of ﬂow of a toxin-free electrolyte containing ﬂuid (dialysate) on the nonblood side of the membrane (Figure 12.2). This process leads to solute removal as solutes move from plasma water (high

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100

CAVH–CVVH CAVH A

QB = 50 – 100

R

High perm.

V

QF = 8–12 mL/min

CVVH V

QB = 150–200 High perm.

R V

QF = 20–25 mL/min

Figure 12.1 Diagram of a continuous arterio-venous hemoﬁltration (CAVH) or continuous veno-venous hemoﬁltration (CV VH) circuit. A = artery; V = vein; R = replacement ﬂuid; QB = blood ﬂow; QF = ultraﬁltrate ﬂow; high per = high permeability ﬁlter.

CAVHD–CVVHD CAVHD A

QB = 50 – 100 Low perm.

V

Do Di QD = 8–15 mL/min QD = 2–3 mL/min CVVHD V

QB = 150–200 Low perm. Do

V

Di

QD = 20–35 mL/min QF = 2–5 mL/min Figure 12.2 Diagram of a continuous arterio-venous hemodialysis (CAVHD) or continuous veno-venous hemodialysis (CV VHD) circuit. A = artery; V = vein; R = replacement ﬂuid; QB = blood ﬂow; QF = ultraﬁltrate ﬂow; QD = dialysate ﬂow rate; DO = dialysate outﬂow port; DI = dialysate inﬂow port; low perm = low permeability ﬁlter.

CAVHDF–CVVHDF CAVHDF A

QB = 50 – 100

R

High perm.

Do

V

Di

QD = 15–20 mL/min QF = 8–12 mL/min CVVHDF V

QB = 150–200 High perm.

Do

R V

Di

QD = 10 –20 mL/min QF = 10–20 mL/min Figure 12.3 Diagram of a continuous arterio-venous hemodiaﬁltration (CAVHDF) or continuous veno-venous hemodiaﬁltration (CVVHDF) circuit. A = artery; V = vein; R = replacement ﬂuid; QB = blood ﬂow; QF = ultraﬁltrate ﬂow; QD = dialysate ﬂow rate; DO = dialysate outﬂow port; DI = dialysate inﬂow port; high perm = high permeability ﬁlter.

The circuit and the prescription

Filtration fraction (FF): This term refers to the fraction of plasma that is ﬁltered across the semipermeable membrane. For example, if blood ﬂow through the ﬁlter is 150 mL/min and the hematocrit is 33%, plasma ﬂow is 100 mL/min. If the ﬁltration rate is 25 mL/min (1.5 L/h), then the FF is 25%. FF above 25% are associated with increased hemoconcentration (signiﬁcant increases in hematocrit, platelet count, and concentration of proteins within the ﬁlter) which, in turn, increase the likelihood of ﬁlter clotting and lead to the formation of layers of protein on the ﬁltering membrane (“caking” or “concentration polarization”). These changes decrease membrane permeability.

CHAPTER 12

Hemodiaﬁltration (CV VHDF): This term refers to the removal of solute across a semipermeable membrane by means of the application of both a concentration gradient and a transmembrane pressure (Figure 12.3). This treatment combines hemoﬁltration and hemodialysis (convection and diffusion) in a way that can be determined by prescription.

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concentration) to the dialysate (concentration equal to zero). This process is known as diffusion. Middle-sized molecules (>500 daltons) are not removed by diffusion as effectively as they are by convection. This may affect antibiotic clearance (e.g., vancomycin, which is approximately 1100 daltons in molecular weight, is removed with convection but not diffusion).

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Replacement ﬂuid: It is an electrolyte-containing, buffer-containing ﬂuid that is given to replace the losses of plasma water induced by hemoﬁltration or hemodiaﬁltration. Dialysate: It is an electrolyte-containing, buffer-containing ﬂuid that is given to provide a concentration gradient across the membrane to enable diffusive solute clearance. Typically, the same ﬂuid can be used as dialysate and as replacement ﬂuid. Predilution: This term refers to the administration of replacement ﬂuid into the circuit before the ﬁlter. This choice of preﬁlter administration has two effects. First it dilutes the concentration of solutes entering the ﬁlter in a way that is proportional to the relationship between ﬂuid administration and plasma ﬂow (if the replacement ﬂuid ﬂow rate is 25 mL/min and the plasma ﬂow rate is 100 mL/min, the dilution effect is 25% and the serum creatinine and urea will be 25% less when entering the ﬁlter. This will decrease the efﬁciency of solute removal) and, second, it will stop any hemoconcentration. This effect on hemoconcentration has been shown to prolong ﬁlter life and thereby decrease “off-time.” As a consequence, despite its diminished efﬁciency, predilution leads to similar solute control and decreased ﬁlter clotting. Postdilution: This term refers to the administration of replacement ﬂuid into the circuit after the ﬁlter. This choice of postﬁlter administration has two effects. First it avoids any dilution of the concentration of solutes entering the ﬁlter and, second, it will lead to hemoconcentration as described under the term FF. This effect on hemoconcentration has been shown to decrease ﬁlter life and, thereby, increase “off-time.” As a consequence, despite its greater efﬁciency, postdilution does not appear to have signiﬁcant advantages. Efﬂuent: This term refers to the waste ﬂuid generated by CRRT. This ﬂuid can be straight ultraﬁltrate in CV VH, spent dialysate in CV VHD, or a combination of both in CV VHDF. Circuit pressure measurements: The functioning of the circuit can be monitored by the measurements of pressures at various points along it. Pressure can be monitored before the ﬁlter, after the ﬁlter, and on the ultraﬁltrate/spent dialysate side of the membrane. At blood ﬂows of 200 mL/min, common preﬁlter pressures of 130–160 mm Hg can be expected (depending on ﬁlter size, design, hematocrit etc.). The pressure fall across the ﬁlter would typically be expected to be 30–40 mm Hg with a postﬁlter (or “inﬂow”) pressure of 110–120 mm Hg. The ultraﬁltrate/dialysate side of the membrane may initially register a positive pressure as the peristaltic pump retards spontaneous ﬁltration in a new ﬁlter. Over time, as the ﬁlter “ages” and the membrane clots, a negative pressure develops as the pump now actively “sucks” ﬂuid across the membrane. The transmembrane pressure (average pressure on the blood side of the membrane minus the pressure on the ultraﬁltrate side of the membrane) can be used as a measure of progressive ﬁlter clotting. If pressure is measured before the blood pump, this is typically negative (usually in the range of 50–70 mm Hg) and

Practical considerations For many machines, CRRT circuits are typically already set up for a particular modality. Thus, once an intensive care unit (ICU) clinician group has chosen a machine and the modality they wish to apply to patients, then the appropriate circuit is used during the machine setup. When this is not the case, appropriately designed tubing is typically provided that can be connected to achieve the necessary circuit design inclusive of pressure pod connections. The circuit is then primed with a crystalloid solution (in neonates or small children the circuit prime might require blood or a blood-albumin mix) and connected with the vascular access catheter. The outﬂow lumen of the access catheter (“arterial” lumen) is typically labeled in red. The inﬂow lumen of the catheter is typically labeled in blue (“venous” lumen). If CV VHDF is being implemented, the bag containing ﬂuid is connected with peristaltic ﬂuid pumps, which can deliver some of the ﬂuid in the predilution position as replacement ﬂuid (typically 50%) and also deliver some of the ﬂuid (the other 50%) in a countercurrent direction to blood on the nonblood side of the membrane. However, some machines and circuit design prohibit predilutional CV VHDF because of the reduced diffusive clearance. Finally, the efﬂuent port of the ﬁlter is connected with tubing to another peristaltic pump that sets the efﬂuent ﬂow rate. This is typically greater than the sum of the replacement ﬂuid ﬂow rate and the dialysate ﬂow rate to ensure

The circuit and the prescription

There is no evidence to suggest that choosing CRRT based on hemoﬁltration over hemodiaﬁltration or over hemodialysis leads to clinically important differences in outcomes. There is a clear difference, however, in terms of the nature of solute removal with convection (ﬁltration) leading to essentially equal small solute removal but much greater middle molecular weight solute removal. It is unclear, however, whether this effect matters pathophysiologically or clinically. Because of such uncertainty, physicians and nurses choose a particular approach in a given unit (typically based on local tradition, comfort, ease of operation etc.) and apply it consistently to all patients. Epidemiological data suggest that continuous veno-venous hemodiaﬁltration (CV VHDF) with replacement ﬂuid delivered in predilution mode may be the most common approach to CRRT worldwide, followed by continuous veno-venous hemoﬁltration (CV VH) also with predilution. The delivery of the actual dose is more important than the choice of modality (see Chapter 8). The dose depends not only on modality but also on the size of the patient and the rate of efﬂuent generation.

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Methods and approach

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reﬂects the suction pressure applied to the outﬂow lumen of the vascular access catheter by the blood pump. High negative (>100 mm Hg) pressures suggest vascular access malfunction.

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Table 12.1 Prescription for CVVHDF (100 mL/h negative ﬂuid balance) Patient

H. Jones

Technique Med. record no. 678945 CVVHDF

Replacement ﬂuid rate 900 mL/h

Dialysate ﬂow rate

Efﬂuent ﬂow rate

Comments

900 mL/h

2000 mL/h (25 mL/kg/h) 100 mL/h ﬂuid loss

Start pump at 20 mL/min and increase to 200 mL/ min over >5 min.

some ﬂuid removal, which will compensate for additional ﬂuids (nutrition, drugs, blood products) that the patient may be receiving. Once all tubing is connected, the blood pump can be started. This is best done at low ﬂows (especially for patients who require vasopressor support) because, at the start, blood is removed and crystalloid administered to replace it. This results in the equivalent of acute venesection or “bleed” equal to the volume of the circuit (close to 150 mL in adults) before blood can both leave and enter the patient at an equivalent rate. Accordingly, the blood pump is best set at 20–30 mL/min until the full circuit is primed with blood. Once that has happened, gentle increases of 20–30 mL/min are appropriate until the target ﬂow is achieved. After the blood path has been “set,” the therapy (dialysate ﬂow, replacement ﬂuid ﬂow, and efﬂuent generation) can begin. A possible prescription for such therapy is summarized in Table 12.1.

Expected outcomes, potential problems, cautions, and beneﬁts If the principles of circuit design and function are understood and if the consequences of different techniques are appreciated and if the impact of choosing predilution versus postdilution are clear, then the physician can prescribe a logical approach to starting and delivering CRRT and the nurse can conduct CRRT with insight and expertise. This combination of knowledge and expertise inevitably leads to safe and effective delivery of CRRT. This leads to the following beneﬁts: (1) reliable and safe control of uremia; (2) adequate ﬁlter life and costing; (3) full control of ﬂuid balance; and (4) minimal technical problems. The clinical outcome is a patient in whom CRRT goes on silently and problem-free in the background in a way that is similar to successful mechanical ventilation. Problems may appear to arise in speciﬁc circumstances. However, understanding of the basics will help to deal with the problems successfully and rapidly. For example, ﬁlter life may be short. If so, assessment of the circumstances surrounding ﬁlter loss should allow prevention of similar events: Was the patient

The extracorporeal circuit used for CRRT has key components that, if understood clearly, allow physicians to prescribe physiologically logical therapy and nurses to conduct smooth, safe, and problem-free treatment. Appreciation of the consequence of choosing a particular technique is important. Understanding of the impact of predilution and postdilution on solute clearance and ﬁltration fraction is similarly important. A clear and logical understanding of pressure measurements along the CRRT circuit is extremely useful in troubleshooting and in making the correct etiological diagnosis when the circuit fails. To conduct CRRT without such knowledge and understanding will likely make the treatment less safe for the patient, less effective in terms of uremic control, and a burden for nurses to develop expertise.

Key references Baldwin I, Bellomo R, Koch B. A technique for the monitoring of blood ﬂow during continuous hemoﬁltration. Intensive Care Med. 2002;28:1361-1364. Baldwin I, Tan HK, Bridge N, Bellomo R. Possible strategies to prolong ﬁlter life during hemoﬁltration: three controlled studies. Ren Fail. 2002;24:839-848. Bellomo R. Choosing a therapeutic modality: hemoﬁltration vs. hemodialysis vs. hemodiaﬁltration. Semin Dial. 1996;9:88-92. Fealy N, Baldwin I, Bellomo R. The effect of circuit “down-time” on uraemic control during continuous veno-venous haemoﬁltration. Crit Care Resuscitation. 2002;4:170-172. Tan HK, Bridge N, Baldwin I, Bellomo R. Ex-vivo evaluation of vascular catheters for continuous hemoﬁltration. Ren Fail. 2002;24:755-762. 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. Intensive Care Med. 2003;29:1672-1678.

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Summary

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agitated and ﬂexing the hip in the presence of a femoral vascular access catheter? If so, acute blockage to ﬂow may have been responsible. Was the outﬂow pressure very negative (–120 mm Hg) from the very start of the therapy ? If so, vascular access dysfunction/clotting should be suspected. Was the transmembrane pressure low (90–100 mm Hg) at the start but increased progressively over 4–5 hours of therapy? If so, rapidly progressive ﬁlter clotting should be suspected and the circuit anticoagulation approach reviewed. Did the postﬁlter pressure rise while the transmembrane pressure did not change much? If so, one should suspect postﬁlter obstruction in the air chamber, where clot can frequently form. All of these diagnostic thoughts are logical and derive from understanding the circuit and its components.

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Chapter 13

The membrane: size and material Zhongping Huang, Jeffrey J. Letteri, Claudio Ronco, and William R. Clark

The ﬁlter membrane in a continuous renal replacement therapy (CRRT) extracorporeal circuit is vitally important for several reasons. Because it has the largest degree of exposure to blood of all circuit components, the membrane is the most important determinant of the circuit’s overall biocompatibility. In addition, membrane characteristics determine both the solute removal and water permeability properties of a CRRT ﬁlter. This chapter addresses the key clinical issues related to CRRT membrane performance and biocompatibility.

Hollow ﬁber membranes used for CRRT: biometrical considerations As opposed to chronic hemodialysis, for which cellulosic membranes continue to be used commonly, membrane comprising CRRT ﬁlters are almost exclusively synthetic. Synthetic membranes were developed essentially in response to concerns related to the narrow scope of solute removal and the pronounced complement activation associated with unmodiﬁed cellulosic dialyzers. The AN69 membrane, a copolymer of acrylonitrile and an anionic sulfonate group, was ﬁrst employed in ﬂat sheet form in a closed-loop dialysate system in the early 1970s for chronic hemodialysis. Since that time, a number of other synthetic membranes have been developed, including polysulfone, polyamide, polymethylmethacrylate, polyethersulfone, and polyarylethersulfone/polyamide. As is the case in chronic hemodialysis, all of these membranes either have been used or currently are being used in a CRRT application. Synthetic membranes are manufactured polymers that are classiﬁed as thermoplastics. In fact, for most of the synthetic membranes, the renal market represents only a small fraction of their entire industrial utilization. Having wall thickness values of at least 20 µm, synthetic membranes tend to be thicker than their cellulosic counterparts and, from a structural perspective, they may be

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108

symmetric (e.g., AN69, polymethylmethacrylate) or asymmetric (e.g., polysulfone, polyamide, polyethersulfone, polyamide/polyarylethersulfone). In the latter category, a very thin “skin” (approximately 1 µm) contacting the blood compartment lumen acts primarily as the membrane’s separative element with regard to solute removal. The structure of the remaining wall thickness (“stroma”), which determines the thermal, chemical, and mechanical properties, varies considerably among the different synthetic membranes. Although biocompatibility encompasses several different considerations, complement activation traditionally has been the primary parameter used for comparisons of different membranes. As suggested earlier, synthetic membranes as a class result in less complement activation than do cellulosic membranes. Because complement activation is roughly proportional to the balance between hydrophilicity (which promotes complement activation) and hydrophobicity (which attenuates complement activation), the relatively hydrophobic nature of synthetic membranes is a beneﬁt in this regard. Another distinguishing feature of synthetic membranes is their propensity to adsorb plasma proteins. As discussed in more detail below, exposure of an extracorporeal membrane to blood results in the instantaneous adsorption of a protein layer (“secondary membrane”), which modiﬁes the native membrane’s permeability properties. The composition of this secondary membrane is dominated by relatively high molecular weight proteins that have the highest plasma concentrations, such as albumin, immunoglobulins, and ﬁbrinogen. However, certain membranes also possess the speciﬁc capability to remove low molecular weight (LMW) proteins, such as anaphylatoxins and other inﬂammatory mediators including cytokines, in signiﬁcant amounts by adsorption. With respect to adsorptive removal of LMW proteins, the AN69 membrane (a component of extracorporeal circuits used with the Prisma and Prismaﬂex CRRT systems) has been studied most widely. Previous investigations have had several ﬁndings. First, while overall secondary membrane formation occurs at the “nominal” (nonpore) membrane surface, the bulk of LMW protein adsorption occurs within the membrane’s internal pore structure. Second, the removal of some LMW proteins by AN69 ﬁlters occurs exclusively by adsorption, even though the molecular weights of such compounds theoretically would allow transmembrane removal. Third, adsorptive removal of LMW proteins by AN69 ﬁlters is a saturable phenomenon, usually within the ﬁrst 60–90 minutes of use of a particular ﬁlter. Subsequent to saturation, the removal of a speciﬁc compound may effectively cease or continue to occur by a “breakthrough” transmembrane mechanism.

Relationship between ultraﬁltration rate and transmembrane pressure in CRRT Extracorporeal membranes used for dialysis are classiﬁed according to their ultraﬁltration coefﬁcient as high ﬂux or low ﬂux. However, considerable

Region of TMP–independent filtration (concentr. polarizat. control)

Filtration rate

Pure water filtration

Region of formation of concentration polarization

Region of TMP–independent filtration (membrane control)

Transmembrane pressure

Figure 13.1 Fundamental relationship between ultraﬁltration rate and transmembrane pressure during ultraﬁltration under different operating conditions. Reprinted from Goehl H, Konstantin P. Membranes and ﬁlter for hemoﬁltration. In: Henderson LW, Quellhorst EA, Baldamus CA, Lysaght MJ, eds. Hemoﬁltration, 1st ed. Berlin: Springer-Verlag Publishers; 1986,73-85. With kind permission of Springer Science and Business Media.

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confusion currently exists regarding the exact meaning of ﬂux. The hydraulic ﬂux of a membrane is the volumetric rate (normalized to surface area) at which ultraﬁltration occurs. The clinical parameter used to characterize the water permeability of a speciﬁc dialyzer is the ultraﬁltration coefﬁcient (KUF: mL/h/mm Hg). The KUF of a ﬁlter is usually derived from in vitro experiments in which bovine blood is ultraﬁltered at varying transmembrane pressure (TMP). The membrane characteristic having the largest impact on water permeability is the pore size, such that ultraﬁltrate ﬂux is roughly proportional to the fourth power of the mean membrane pore radius. As such, small changes in pore size have a very large effect on water permeability. The method by which KUF is determined can be derived from Figure 13.1, in which the relationship between ultraﬁltration ﬂow rate (QUF) and TMP is shown for a particular CRRT ﬁlter operated under different conditions. The line in the left part of the ﬁgure represents the relationship between these two parameters for a “virgin” ﬁlter (i.e., no prior exposure to blood or other protein-containing solution) when the test ﬂuid is also an aqueous solution. The slope of the line represents the KUF of the ﬁlter for these operating conditions. This strictly linear relationship can be contrasted with the nature of the curve in the right part of the ﬁgure. The curved line in the right part of the ﬁgure deﬁnes a ﬁlter’s QUF versus TMP relationship under the condition of ultraﬁltration of blood. As the ﬁgure indicates, two distinct regions of this curve can be identiﬁed: a region controlled by the permeability of the ﬁlter membrane itself (“membrane control”)

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110

and a region controlled by the effects of the secondary membrane on ﬁlter performance. (Note that the term “concentration polarization,” which is used in the ﬁgure, is essentially synonymous with secondary membrane for the purpose of this discussion.) The membrane control region of the curve occurs at relatively low TMP values and is linear. Similar to the situation of aqueous ultraﬁltration with a virgin ﬁlter, the slope of the line in this region is the KUF of the ﬁlter. The lower slope (i.e., lower KUF) of the right-hand curve is a direct result of the permeability reduction resulting from the secondary membrane. As TMP increases, the curve eventually plateaus in the region of secondary membrane control at a certain maximum QUF where further increases in TMP result in no further increase in QUF. In terms of clinical operation of a ﬁlter, the plateau portion of the curve is to be avoided because of the high likelihood of impaired performance or premature clotting of the ﬁlter. As mentioned previously, ﬁlter KUF is a value that is speciﬁc to a certain set of ﬂow operating conditions, including blood ﬂow rate (QB). Blood ﬂow rate inﬂuences the nature of the right-hand curve in two ways. First, as QB increases, the slope of the curve in the linear (low TMP) region increases. Effectively, this means to achieve a certain QUF, a lower TMP is required. The second way in which QB inﬂuences the nature of these curves is its effect on the maximum achievable (plateau) QUF such that an increase in QB results in a corresponding increase in plateau QUF. The explanation for these phenomena is related to the effect of higher QB in preserving ﬁlter membrane function. Speciﬁcally, as QB increases, a greater shear force is applied to the proteins comprising the secondary membrane. In this way, the secondary membrane is disrupted and its negative impact on membrane permeability is blunted.

Effect of secondary membrane formation on solute permeability in CRRT The adsorbed protein layer comprising the secondary membrane also reduces the effective solute permeability of a CRRT membrane by “plugging” or blocking of a certain percentage of membrane pores. The effect of this process on solute permeability for a polyamide membrane is shown in Figure 13.2. In this ﬁgure, percent rejection (which is essentially equal to 1—sieving coefﬁcient), is plotted against solute molecular weight. Results for both a protein-containing ﬂuid (plasma) and a protein-free ﬂuid (saline) are shown. For a test solute with a molecular weight of 5000 daltons, the percent rejection in saline is 0% (i.e., the sieving coefﬁcient is 1.0). On the other hand, for that same solute, the percent rejection in plasma is approximately 60% (sieving coefﬁcient of 0.4). The adsorptive tendency of a particular membrane varies according to the operating conditions employed. Postdilution tends to promote protein adsorption

% Rejection

80

Plasma

60 Saline

40 20 0 0

2000 3000

5000

10,000

20,000

Figure 13.2 Effect of secondary membrane formation on the sieving properties of a polyamide ﬁlter membrane. From Feldhoff P, Turnham T, Klein E. Effect of plasma proteins on the sieving spectra of hemoﬁlters. Artif Organs. 1984;8:186-192, copyright © 1984 International Center for Artiﬁcial Organs and Transplantation. Reproduced with permission of Blackwell Publishing Ltd.

CHAPTER 13

because protein concentrations are higher within the membrane ﬁbers (due to hemoconcentration). On the other hand, as mentioned previously, higher blood ﬂow rates work to attenuate this process because the shear effect created by the blood disrupts the binding of proteins to the membrane surface.

111

Log [molecular weight]

The membrane: size and material

100

Membrane surface area effects in CRRT Early in the era of veno-venous CRRT, typical blood and efﬂuent ﬂow rates were less than 150 mL/min and 1.5 L/h, respectively. In this context, ﬁlters with surface areas in the range of 0.3–0.5 m2 could generally provide desired solute clearances at acceptable ﬁlter operating conditions. However, as blood and ﬂuid ﬂow rates have increased substantially over the years with the goal of increasing delivered CRRT dose, ﬁlter membrane surface area requirements have also increased. For adequate ﬁlter operation, the surface area required to provide an efﬂuent-based CRRT dose target of 35 mL/kg/h is approximately 1.0 m2 and may be as high as 1.5 m2 in some larger size patients treated with efﬂuent rates greater than 4 L/h.

Continuous hemoﬁltration As discussed above, the choice of operating conditions for a hemoﬁltration procedure should avoid operation of the ﬁlter in the secondary membrane-limited region of the QUF versus TMP curve. The clinical corollary of this is the need to select a ﬁlter with a surface area that is adequate to support the operating conditions chosen. In Figure 13.3, the relationship between QUF and QB for three theoretical hemoﬁlters of 0.3 m2, 1.0 m2, and 1.5 m2 at constant TMP is shown. In general, these curves have similar contours with an initial linear region at

Ultrafiltration rate (L/hr)

The membrane: size and material CHAPTER 13

112

Membrane surface area (m2) 1.5

1.0 B

High QUF

C 0.3

Low QUF

A

Blood fow rate (mL/min) Figure 13.3 Relationship between ultraﬁltration rate and blood ﬂow rate for theoretical hemoﬁlters of different surface area. (See text for explanation of operating conditions corresponding to points A, B, and C.)

relatively low blood ﬂow rates followed eventually by a plateau or quasi-plateau region at relatively high blood ﬂow rates. Both the slope of the linear phase and the maximum (plateau) QUF for each curve are directly proportional to membrane surface area at a given TMP. At a low blood ﬂow rate (e.g., 75 mL/min), all three ﬁlters can generate a relatively low QUF (e.g., 1.5 L/h) at the same TMP, as denoted by point A on the graph. However, when the clinical goal is a higher QUF (e.g., 4.0 L/h), a 0.3 m2 ﬁlter is not adequate as the plateau QUF for this ﬁlter falls below the desired value. On the other hand, the higher QUF is in the operating range of both of the larger ﬁlters for the TMP that has been chosen. However, the 1.5 m2 ﬁlter can achieve this ﬁltration rate at a lower blood ﬂow rate (point B) compared to the 1.0 m2 ﬁlter (point C). An analogous point is that, for a given blood ﬂow rate, ﬁlter membrane surface area is inversely proportional to the TMP required to achieve a certain ultraﬁltration rate. The general relationship between ultraﬁltration rate and blood ﬂow rate during hemoﬁltration, as described in Figure 13.3, is explained by the phenomenon of ﬁltration pressure equilibrium. In this situation, hydrostatic pressure driving ﬁltration out of the blood compartment is balanced by the oncotic pressure opposing ﬁltration in this direction. When a scenario of ﬁltration pressure equilibrium situation occurs for a ﬁlter, surface area is relatively unimportant since the additional surface area is not used for ﬁltration. The corollary is that the beneﬁt of higher surface area on ﬁltration rate can only be achieved if higher blood ﬂow rates are used.

Clearance or effluent rate (mL/min)

Effluent Urea Cr Ur P

45 40 35 30 25 20 15 10 5 0

B2-M

0

500

1000

1500

2000

2500

Dialysate flow rate (mL/h) Figure 13.4 Relationship between solute clearance and dialysate ﬂow rate for a 0.9 m2 ﬁlter in continuous veno-venous hemodialysis. Abbreviations: Cr: creatinine; Ur: urate; P: phosphate; and B2M: beta2-microglobulin. Reprinted from 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, copyright 1999, with permission from Elsevier.

The membrane: size and material CHAPTER 13

Relative to conventional hemodialysis, in which solute clearance is primarily dictated by blood ﬂow rate and membrane surface area, efﬂuent dialysate ﬂow rate is the primary determinant of solute clearance in continuous veno-venous hemodialysis (CV VHD). At least with respect to small solute clearance, saturation of the efﬂuent indicates optimal utilization of the prescribed dialysate volume. If such saturation is not achieved, the most likely explanation is a ﬁlter of inadequate membrane surface area. When CV VHD is performed with a relatively small surface area ﬁlter (< 0.5 m2), saturation of the dialysate is only achieved at relatively low dialysate ﬂow rates. For a 0.4 m2 AN69 ﬁlter, Bonnardeaux et al. showed saturation of the efﬂuent dialysate for urea, and creatinine is preserved only up to a dialysate ﬂow rate (QD) of approximately 16.7 mL/min (1 L/h). For QD values in the 2–3 L/h range (33.3–50 mL/min), although an increase in QD resulted in an increase in clearance, a divergence between the urea/creatinine clearance and the efﬂuent ﬂow rates was observed, indicating nonsaturation of the efﬂuent dialysate. Of course, the greater the degree of nonsaturation, the more inefﬁcient is the procedure. A more contemporary study involving a larger surface area AN69 ﬁlter (0.9 m2) demonstrates clearly the important effect of surface area on preserving dialysate saturation (Figure 13.4). For this larger ﬁlter, preservation of efﬂuent dialysate saturation was achieved essentially over the entire QD range, the only exception being B2M. The high molecular weight of this compound (approximately 200 times that of urea) severely limits its diffusive capabilities and, therefore, its ability to saturate the dialysate.

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Continuous hemodialysis

The membrane: size and material CHAPTER 13

114

Summary In this chapter, an overview of membranes used for CRRT has been provided. The major characteristics of hollow ﬁber membranes inﬂuencing both biocompatibility and solute and water removal have been discussed. It is hoped that this information will help provide clinicians with a rational approach to the prescription of CRRT from the perspective of the extracorporeal membrane.

References Bonnardeaux A, Pichette V, Ouimet D, Geadeh 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. 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. Clark WR, Hamburger RJ, Lysaght MJ. Effect of membrane composition and structure on performance and biocompatibility in hemodialysis. Kidney Int. 1999;56:2005-2015. Clark WR, Macias WL, Molitoris A, Wang NHL. Plasma protein adsorption to highly permeable hemodialysis membranes. Kidney Int. 1995;48:481-488. Feldhoff P, Turnham T, Klein E. Effect of plasma proteins on the sieving spectra of hemoﬁlters. Artif Organs. 1984;8:186–192. Goehl H, Konstantin P. Membranes and ﬁlter for hemoﬁltration. In: Henderson LW, Quellhorst EA, Baldamus CA, Lysaght MJ, eds. Hemoﬁltration. 1st ed. Berlin: SpringerVerlag; 1986:73.

Chapter 14

Fluids for continuous renal replacement therapy Paul M. Palevsky and John A. Kellum

Considerable variability exists in the prescription of ﬂuids for continuous renal replacement therapy (CRRT), both dialysate and replacement ﬂuid. In general, since electrolytes will diffuse across the dialysis membrane in both directions, there is little practical difference in the composition of dialysate and replacement ﬂuid, and many commercial dialysis ﬂuids are used off-label as replacement ﬂuid. When using both dialysis and hemoﬁltration (CVVHDF), it is usually convenient to use standard dialysate and customize the replacement ﬂuid as necessary. The Acute Dialysis Quality Initiative (ADQI) has published a series of recommendations of ﬂuids for CRRT. These recommendations are summarized below.

Electrolyte composition Available evidence shows the following: 1. Sodium is generally kept at an isonatric (physiologic) concentration except when special prescriptions are used in combination with some citrate anticoagulation protocols or during management of hypo- or hypernatremia. 2. Chloride, potassium, magnesium, and anion needs are variable in different clinical situations. 3. Phosphate—Hypophosphoremia due to increased clearance and intracellular shifts due to refeeding are common in CRRT, and may place patients at risk of complications including rhabdomyolysis. 4. Glucose—Maintenance of normoglycemia has been shown to be associated with lesser mortality in the critically ill patient. 5. Trace elements, including water-soluble metals, micronutrients, aminoacids, and folate are lost during CRRT. Recommendations from ADQI: 1. Sodium: Physiological concentrations should be used except when using citrate anticoagulation. In the latter circumstances, adjustments may be

115

General considerations

Fluids for CRRT CHAPTER 14

2.

3.

4.

116

5.

6.

necessary, given the variable contents of sodium in different citrate solutions. Adjustment of the sodium concentration of ﬂuids may also be necessary in patients with hypo- or hypernatremia in order to achieve an appropriate controlled correction of the serum sodium concentration. Chloride, potassium, magnesium, and anions: These should be present in replacement ﬂuid and/or dialysate in concentrations tailored to patient need and anticoagulation procedures. Calcium: It should be present in replacement ﬂuids and dialysate. It should be at approximately physiological concentrations (corresponding to the normal blood ionized calcium). Augmented levels may be necessary in the setting of severe hypocalcemia and reduced levels in the setting of hypercalcemia. Very low or no calcium should be used when citrate is used as an anticoagulant, although intravenous calcium infusion to maintain normal serum ionized calcium concentration is then necessary. Phosphate: To avoid hypophosphoremia, phosphate should be provided either as a supplement in the CRRT ﬂuids (replacement ﬂuid or dialysate) or as a nutritional supplement once hyperphosphatemia, if present, has resolved. Glucose: To avoid hyperglycemia, glucose can either be absent or present at physiological concentration in replacement ﬂuids and dialysate. The use of ﬂuids with supraphysiological glucose concentrations should be avoided. Trace elements: Losses of trace elements (water-soluble metals, micronutrients, aminoacids, and folate) must be appropriately replaced.

Buffer composition Lactate versus bicarbonate Both lactate and bicarbonate ions have been used in replacement ﬂuid and dialysate for CRRT. Historically, lactate has been preferentially used as a buffer due to the instability of bicarbonate-based solutions when stored over prolonged periods of time. This problem has recently been overcome, allowing commercial availability of bicarbonate-based ﬂuids. Controlled (though not all randomized) trials have suggested that lactate and bicarbonate buffered solutions have a similar efﬁcacy for correction of metabolic acidosis during CRRT. However, recent studies showed better control of metabolic acidosis with bicarbonate as compared to lactate. Blood levels of lactate are generally higher when lactate is used as a buffer and may confuse the clinical interpretation of these measurements. It is not clear whether this hyperlactatemia is associated with morbidity. Depending on tissue redox status and substrate availability, lactate is either metabolized back to pyruvate and into the citric acid cycle, resulting in proton buffering, or into glucose by gluconeogenesis. Potential concerns with excessive lactate accumulation are hemodynamic compromise, increased urea generation, and cerebral

Acetate

Fluids for CRRT CHAPTER 14

dysfunction. Hyperlactatemia may develop in situations of impaired lactate clearance including liver failure and tissue hypoperfusion. This hyperlactatemia can be expected to be more pronounced if lactate-buffered solutions are used during high-volume hemoﬁltration. Accumulation of the d-isomer of lactate may also be a concern as the d-isomer constitutes 50% of the total lactate contents of racemic mixtures. As d-lactate is nonmetabolizable by humans, it may accumulate, contributing to severely elevated lactatemia and associated with neurologic impairment. In the intermittent hemodialysis (IHD) literature, acetate has been shown to be associated with impaired myocardial contractility and decreased cardiac function. This anion has been rarely used as a buffer in CRRT. Used primarily for its anticoagulant properties, citrate serves as an effective buffer. Scant evidence is available on the use of citrate exclusively as a buffer in CRRT. Importantly, citrate metabolism is often impaired in liver failure or muscle hypoperfusion, both situations posing risk of hypercitratemia when citrate is utilized. Hypercitratemia carries the risk of decreased ionized extracellular calcium concentration. Importantly, blood products contain citrate as an anticoagulant; massive blood or plasma product transfusions are associated with high citrate loads, which accumulate when citrate is simultaneously used as an anticoagulant and/or a buffer. Low concentrations of citrate are present in some commercial dialysate solutions for IHD. Complications of citrate toxicity have not been associated with these agents. Recommendations from ADQI: 1. Bicarbonate is an effective buffer and is currently the preferred organic buffer in commercially manufactured solutions. 2. Lactate-buffered solutions are safe and efﬁcacious in the majority of patients, but these solutions may be hazardous whenever lactate clearance is impaired, such as in liver failure patients or patients with severe tissue hypoperfusion. d-lactate should be removed from lactate-containing solutions, which should consist almost exclusively of l-Lactate. 3. There is insufﬁcient data to evaluate the use of acetate-buffered solutions in CRRT. However, limited evidence does not support its use compared to lactate or bicarbonate, given the risks of cardiac depression. 4. The metabolism of sodium citrate used for regional anticoagulation during CRRT generates three moles of bicarbonate per mole of citrate and functions as an efﬁcacious organic buffer. Use of citrate in the setting of decreased citrate clearance or when patients receive large doses of citrate during massive transfusions should be done with individualized adjustment of citrate dose and with close monitoring of plasma ionized calcium levels.

117

Citrate

Fluids for CRRT CHAPTER 14

Fluid prescriptions during permissive hypercapnia In patients with acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) on lung protecting ventilator strategies, the resulting respiratory acidosis can be partially or completely compensated by elevation of plasma bicarbonate with CRRT. The decision about the level to which acidemia should be corrected is controversial, but most authors recommend avoiding severe acidosis (pH < 7.20).

118

Example ﬂuid orders for CRRT Keeping in mind that, after a period of equilibration, plasma composition will approach the electrolyte composition of the dialysate or replacement ﬂuid used (with the exception of bicarbonate) the standard composition of CRRT ﬂuids will be physiological. Table 14.1 shows that the usual range of composition for a standard dialysate or replacement ﬂuid is close to the usual range for plasma electrolytes. Bicarbonate is higher in these ﬂuids compared to plasma because plasma contains albumin, a weak acid, which serves as an endogenous buffer. The same solutions can be used for either dialysis or hemoﬁltration. Example A might be appropriate for a patient with relatively stable electrolyte and acidbase status. Example B might be more appropriate for a hyperkalemic patient. Occasionally severe abnormalities in electrolyte and acid-base balance call for more drastic changes in ﬂuid prescription from the standard composition. For example, a patient with severe acidosis and hyperkalemia might require a potassium-free solution with higher concentration of bicarbonate. One liter of sterile water with three “ampoules” of sodium bicarbonate (each ampoule of 8.4% solution contains 50 mEq both sodium and bicarbonate) produces a near isotonic solution of 150 mEq/L of sodium and 150 mEq/L of bicarbonate. If this solution is used as replacement ﬂuid, it should only be temporary and should be done only with close monitoring. In continuous veno-venous hemodiaﬁltration (CVVHDF) mode, it is often Table 14.1 Example ﬂuids for CRRT

Sodium Potassium Chloride Calcium Magnesium Bicarbonate Lactate Glucose

Custom dialysate/replacement ﬂuid 140–150 mEq/L 0–5 mEq/L As needed to achieve charge balance 0–3.5 mEq/L 0.5–1.5 mEq/L 22–45 mEq/L 0–5 mEq/L 100–120 mg/dL

Example A

Example B

140 mEq/L 4 mEq/L 113 mEq/L 2.5 mEq/L 1.5 mEq/L 32 mEq/L 3 mEq/L 110 mg/dL

140 mEq/L 2 mEq/L 112 mEq/L 3.5 mEq/L 1.0 mEq/L 32 mEq/L 3 mEq/L 110 mg/dL

Correct electrolyte formulation by repeat testing as needed should be assured, given that serious errors have been reported when local pharmacies compound without regular monitoring of composition. When dialysis ﬂuids are compounded locally, appropriate monitoring of RRT ﬂuid composition must be assured. Most established CRRT programs are switching to commercially prepared ﬂuids.

Fluids for CRRT

Fluid compounding

CHAPTER 14

convenient to choice a standard solution for dialysate (e.g., Example A) and, when necessary, a custom solution for replacement ﬂuid. After the patient’s metabolic status stabilizes, the replacement ﬂuid can be switched to standard as well.

Both lactate and bicarbonate are able to correct metabolic acidosis in most CRRT patients; however, correction of acidosis may not be as efﬁcient with lactate as with equimolar bicarbonate. Worsening hyperlactatemia has been noted when lactate was used in patients with lactic acidosis or liver failure. The clinical relevance of this ﬁnding is unknown. Thus, bicarbonate is the preferred buffer, especially in patients with lactic acidosis and/or liver failure and in high-volume hemoﬁltration. However, lactate is an effective buffer in most CRRT patients. Citrate used as an anticoagulant has also been effectively used as a buffer in CRRT. When citrate is used as an anticoagulant, the concentrations of other buffers need to be adjusted or eliminated, depending on the speciﬁc regimen used, to minimize the risk of iatrogenic metabolic alkalosis. Monitoring of plasma pH and ionized calcium is required.

Key references Davenport A. Replacement and dialysate ﬂuids for patients with acute renal failure treated by continuous veno-venous haemoﬁltration and/or haemodiaﬁltration. Contrib Nephrol. 2004;144:317-328. Kellum JA, Cerda J, Kaplan LJ, Nadim MK, Palevsky PM. Fluids for prevention and management of acute kidney injury. Int J Artif Organs. 2008; 31(2):96-110. Kellum JA, Mehta R, Angus DC, Palevsky P, Ronco C; ADQI Workgroup. The First International Consensus Conference on Continuous Renal Replacement Therapy. Kidney Int. 2002; 62(5):1855-1863. Kierdorf H, Leue C, Heintz B, Riehl J, Melzer H, Sieberth HG. Continuous venovenous hemoﬁltration in acute renal failure: is a bicarbonate- or lactate-buffered substitution better? Contrib Nephrol. 1995;116:38-47. Leblanc M, Moreno L, Robinson OP, Tapolyai M, Paganini EP. Bicarbonate dialysate for continuous renal replacement therapy in intensive care unit patients with acute renal failure. Am J Kidney Dis. 1995;26(6):910-917.

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Chapter 15

Alarms and troubleshooting Zaccaria Ricci, Ian Baldwin, and Claudio Ronco

Technical expertise is mandatory for administration and management of continuous renal replacement therapy (CRRT), which is conceived to run for 24 hours a day in the intensive care unit (ICU). Routine clinical practice of CRRT may challenge physicians and nurses with several practical problems that can be of clinical and technical nature. Circuit pressure monitoring, setting and responding to alarms, and default safety features of modern CRRT machines allow effective and safe therapy delivery in critically ill patients. It should be never forgotten, however, that the human-machine interface can fail and is not a perfect system.

Training Intensive care unit (ICU) physicians and nurses involved in prescription and delivery of CRRT operate safely and best with protocols and deﬁned procedures. The following is a list of key aims for training and education: • An educational program providing theoretical content is necessary. • A training program for practical skills speciﬁc to using CRRT is also necessary with a connection to the theory. • All training should be sequenced, providing a logical ﬂow to embrace the cycle of use from preparation of a CRRT machine, patient connection and management during use, and then cessation of treatment—disconnection. • Programs need to be continuous and repeated owing to the ongoing technological developments and high staff turnover. • A simple simulator can be achieved by placing a double lumen access catheter into a 5 L saline bag—simulating the patient. • It is desirable to have the majority of staff working at a “competent” level with small groups at the “novice” and “expert” levels. Novice practitioners can also be assisted and supervised by expert colleagues.

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Introduction

Alarms and troubleshooting CHAPTER 15

122

Vascular access Veno-venous CRRT rely on the use of a temporary double lumen catheter, typically inserted into one of the central veins (femoral, subclavian, or jugular). Ideal catheter type, size, and site of insertion are determined by local hospital policies; however, success can be achieved with many variations, and no controlled data are available to reﬂect “best” practice. Catheters should be easy to insert and remove or be guide wire exchanged, allow a wide range of blood ﬂows, minimize recirculation phenomena, and reduce decubitus and infection episodes. Key considerations for access catheter use are as follows: • Catheter type and size: Double lumen catheters as a general rule can be classiﬁed into short (about 15 cm) and long (more than 20 cm), small (less than 11 Fr) and big (more than 13 Fr). The catheter lumen design proﬁle varies, but all designs can obstruct by contact with vessel walls and/or kinking due to body positional changes during nursing. • Catheter site: Jugular venous catheterization access does not appear to reduce the risk of infection compared with femoral access, except among adults with a high body mass index, and may have a higher risk of hematoma. The site of catheter placement should depend on clinician skill, the presence of other central venous catheters, and the risk of bleeding. Insertion of the catheter to the right atrium promotes reliable and higher blood ﬂow rate use. • Catheter trouble-shooting: a malfunctioning catheter is suspected when CRRT monitor pressure alarms occur as low “arterial” or high “venous.” The catheter could be guide-wire exchanged; however this is not always successful to resolve the problem and a new site insertion is necessary. Swapping over the connections to the CRRT circuit may also resolve the catheter malfunction but creates a recirculation of blood. This may not be of clinical consequence when solute levels are in control and can allow treatment to continue when ﬂuid balance is the key goal, and a new access catheter insertion is not easily done.

Circuit pressures Modern technology CRRT machines allow continuous pressure measurement and display for both operator (human) and “smart software” (machine) interpretation. This requires measurement from several different points in the circuit. • Machine inlet (negative) pressure and return (positive) pressure depends mostly on the performance of vascular access relative to programmed blood ﬂow rate and patient position. • Inlet of the ﬁlter: This pressure indicates the resistance of blood that is pumped into the ﬁlter. The gradient of ﬁlter inlet and catheter return is deﬁned as “drop pressure” (DP) and is generally automatically calculated by all modern monitors. DP indicates the capacity of blood to ﬂow through the membrane.

CHAPTER 15

new or spontaneous UF occurs. When the ﬁlter pores are reduced in size and number due to clotting, UF starts being sucked by the pump and the UF port pressure value becomes negative. • Inlet of ﬁlter pressure, catheter return pressure, and UF port pressure are used in software calculation of transmembrane pressure (TMP) indicating the capacity of the ﬁlter ultraﬁltering blood. • This amount of information, integrated with friendly user operator interface, are optimized in different monitors with different setups and displays: in our opinion, the optimal machine keeps record of circuit pressures during the last 24 hours of the treatment (or more) and possibly provides graphs and trends of all recorded pressures, and a “log ﬁle” of alarms or errors when they occurred, along with the remedy or operator response at the time. This information is a useful audit of the system in use.

Alarms and troubleshooting

• Ultraﬁltration (UF) port pressure: Its value can be positive when the ﬁlter is

Understanding how alarms systems work on CRRT machines is useful for troubleshooting. In general, alarms used in biomedical equipment are classiﬁed according to severity of problem and urgency for attention. They range from “advisory” messages, with no immediate error to “crisis” indicating danger and automatic shutdown. In addition, alarms can be “latched,” where, if a measured parameter is breached. despite self-correction, the machine will pause operation with the alarm sounding until resetting. Or, the alarm can be “unlatched,” where, if a breached parameter creates an alarm but the situation self corrects, the alarm stops and the machine restarts automatically. For example, with CRRT machine technology, low arterial pressure alarm is an unlatched alarm, but air detection is latched, representing the potential severity of each. Most new machines provide default settings for many alarms; sometimes these can be altered. It is useful for the staff to know the default settings or the policy within the ICU for where common alarms are set. Alarms set too widely will create unsafe use of the machine. Figure 15.1 outlines this concept of alarm classiﬁcation.

The clogging circuit All circuits clot, sooner or later, and they generally need change of all the components of the extracorporeal circuit. The ﬁrst issue to address in order to optimize management of circuit clotting is prevention: performing an “elective” change, before the circuit clots completely, leading to progressive anemia. A scheduled change to a new extracorporeal circuit also allows a reduced time off therapy (downtime).

123

Alarm systems

Alarms and troubleshooting CHAPTER 15

Latched

Requires correction, will not reset, use alarm silence

Unlatched

Self correction, then reset without intervention

Advisory alarm

Message to operator, futrue intervention

Warning alarm

Message to operator, intervention now:

Crisis alarm

Message to operator, machine stop

124

Figure 15.1 Classiﬁcation of biomedical devices and alarms.

In order to identify and recognize circuit clotting the following “signs” are proposed: • Dark streaks through the hollow ﬁbers of ﬁlters indicates a degree of ﬁlter clotting that is proportional with the total amount of clotted ﬁbers. This sign should be kept under constant observation but does not herald imminent ﬁlter failure. • TMP rapid increase (before it reaches machine alarm threshold) is an important sign of hollow ﬁbers failure, especially during hemo/ultraﬁltration. There is not an absolute value to be aware of but >250 mm Hg is commonly considered indicative of substantial membrane clotting; however, this also depends on machine setup and ﬁlter size. The trend curve of TMP should be observed by the operators because a rapid increase in a short time frame suggests a threshold of membrane surface area clotting and total failure imminent. • DP rapid increase (before it reaches machine alarm threshold) is another important sign of ﬁlter clotting, and it works as a reliable indication either during dialysis and hemo/ultraﬁltration. Again, there is not an absolute value to be aware of (it generally depends on machine setup and ﬁlter size), whereas the trend curve of DP should be monitored by the operators. • Experience can also teach the ICU staff that different components in different machines are particularly susceptible to early clotting and should be strictly monitored. • The venous drip chamber (bubble trap) may be a site of circuit clotting during continuous runs. Two mechanisms seem to be responsible for clot formation: blood-air interface and blood stagnation in the chamber. Modiﬁcations of these chambers, derived from traditional intermittent therapies, have been

Fluid balance errors The possibility of making ﬂuid balance errors during CRRT has been identiﬁed since the beginning of this modality of treatment. The advent of automated

Alarms and troubleshooting

Treatment failure due to circuit clotting has been acknowledged as the major problem in CRRT delivery. Some general measures can be recommended in order to increase ﬁlter life and to achieve an average session length of at least 20 hours. • Blood ﬂow should be ideally prescribed and maintained between 150 and 200 mL/min. If poor vascular access does not allow such ﬂow rate, blood ﬂow below 100 mL/min should not be accepted and vascular access should be optimized. • Administration of replacement ﬂuids before the ﬁlter may prolong ﬁlter function. Alternatively, if postdilution hemoﬁltraiton is the institutional preferred CRRT modality, when TMP is rapidly increasing, a switch to predilution hemoﬁltration, hemodialysis, or hemodiaﬁltration can be tried (if the utilized machine allows such intra-therapy changes). • If heparin is the administered anticoagulant, the infusion of dilute solutions (10 IU/mL) at a greater rate will improve the efﬁcacy of anticoagulation. In these patients, antithrombin III levels should be monitored, and maintained at supernormal levels (> 100%). Activated clotting time or other methods of bedside anticoagulation measure are strongly recommended and, if necessary, small heparin boluses might be indicated. • Flushing circuits with normal saline once per shift or when clogging is suspected may allow better visual detection of clot formation in the circuit and sometimes small decreases of circuit pressures. However, the routine ﬂushing of the circuits is not recommended in all cases because of the limited efﬁcacy and because of the ﬂuid administered to patients when doing this frequently. Troubleshooting for speciﬁc events, however, must be decided at the moment and the rapidity of intervention is based on adequate staff training, optimal material choice, and correct CRRT machine setup and/or therapy prescription. Quick interventions reduce circuit failure and downtime, increase system accuracy, and especially prevent prolonged cessation or slowing of blood ﬂow, which is the most common cause of clotting.

CHAPTER 15

Management of clogging circuit

125

designed and new deareation chambers without air-blood contact are now available. Keeping the chamber full with a small air space and stopping foaming or splashing of blood ﬂow may also be preventative of clotting.

Alarms and troubleshooting CHAPTER 15

126

machines has partially overcome this problem. Nevertheless, there are conditions and operation modes in which the potential for ﬂuid balance errors is still present. The precision of delivery of the prescribed renal replacement therapy is dependent on the training of the operators, the clarity of the orders, the familiarity with the equipment, and its ﬂuid measurement accuracy. Third-generation machines control ﬂuid ﬂows by accurate pump-scales feedback: 30 gm (30 mL) per hour is the accepted error for each pump, and an alarm warns the operator if this limit is exceeded; furthermore, some monitors are designed to correct a previous error in the next 60 minutes, further increasing accuracy of the system. When the therapy is interrupted by a pressure alarm, it automatically restarts if the pressure level normalizes within few seconds. In spite of several educational efforts, however, misunderstandings are still possible on common terms such as “ﬂuid exchange rate,” “ultraﬁltration,” “ﬂuid loss,” “ﬂuid balance,” “weight loss rate,” and “patient negative.” Improvements in commercial machines for safety and accuracy of ﬂuid balance, the way alarms can be overridden, or the occasional addition of external components to the overall ﬂuid balance can easily affect the ﬁnal result and make ﬂuid balance signiﬁcantly different from that prescribed. In particular, users who override scale alarms without solving the cause of the alarm (possible error in ﬂuid balance typically occurs when a replacement ﬂuid bag is clamped) may dramatically impact patient ﬂuid balance. In fact, if an alarm appears on the machine, one can override it without major problems: these may occur when multiple override commands are operated without identifying the problem and solving it adequately. For this reason some monitors, by default, accept a limited numbers of overrides per hour, automatically stopping the therapy if the limit is exceeded. In general, ﬂuid balance errors can easily be avoided not only by a correct and careful adherence to the protocols of use of the current CRRT machines, but also by the compliance to prescriptions and programmed controls during therapy. Potential ﬂuid balance errors, not detected by the machine or due to inadvertent prescription of additional ﬂuids (diluted drugs, nutrition increase, need for high volumes of blood derivates) should be always considered. • Physical assessment of the patient and hemodynamic monitor should be constant (especially when CRRT is delivered in semi-intensive care (high dependency units). • A ﬂuid balance chart should be updated hourly. This will help to correctly interpret patients’ total ﬂuid balance. • Never forget to check and possibly record machine information on “effectively delivered net UF” and not just reporting on clinical chart the “prescribed UF”: they can differ signiﬁcantly due to systematic small errors of the machine (after 24 hours they can be highly multiplied) but, above all, they are caused by all unreported interruptions needed for troubleshooting.

Alarm/problem Too low arterial pressure alarm

Possible causes 1. Kinked or clamped line 2. Clotted line 3. Access device against vessel wall 4. Hypovolemia

High venous pressure alarm

1. Kinked or clamped line 2. Clotted line 3. Positional vascular access obstruction 1. Line separation or disconnection from patient (very rare!) 2. Circuit kinked or clamped before pressure sensor 3. Clot excluding pressure sensor 4. Blood pump speed relatively too slow with respect to catheter performance 1. Clogging hemoﬁlter 2. Kinked or clamped hemoﬁltration/ dialysis line 3. Blood ﬂow too slow for UF setting 1. Presence of small air bubbles (often due to bicarbonate - CO2 coming from hemoﬁltration bags) 2. Line disconnection at arterial access 3. Turbulence close to air sensor 1. Efﬂuent or hemoﬁltration/dialysis bags moving or incorrectly hanged. 2. Kinking in efﬂuent or hemoﬁltration/dialysis bags 3. Machine occasional error 4. Machine systematic error (if more than 10 times without reason in 3 hours)

Arterial (or venous) line disconnection alarm

Increasing TMP

Air in the circuit

Fluid balance error

Actions 1. Remove kinking 2. Declot access 3. Consider limbs switching 4. Stop UF, decrease blood ﬂow rate 1. Remove kinking 2. Declot access 3. Consider limbs switching 1. Check circuit and patient and, if no disconnection is present, override alarm 2. Declamp line 3. Evaluate for circuit change 4. Increase set blood ﬂow rate

1. Evaluate for circuit change 2. Declamp line 3. Increase blood ﬂow speed, check UF setting 1. Follow instruction for degassing 2. Stop session 3. Override alarm

1. Wait for bags, stop or reposition them on scales 2. Remove line kinking 3. Override 4. Change machine and do not reuse it before technical assistance

Alarms and troubleshooting

Table 15.1 Troubleshooting checklist

CHAPTER 15

With any health care technology, it is easy to focus on management of the machinery and lose sight of the patient. It is, therefore, invaluable to always have a problem-oriented approach to patients. Constant technical training and checklists are useful for all users and considered mandatory for novice practitioners (Table 15.1).

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Conclusions

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128

It should be noted that modern CRRT machines include, for each occurring alarm during treatment, an online “real time” alarm page with clear and simple explanations describing the causes and remedy for alarms. This is very useful to operators, but rarely read and used as a learning tool due to the hurry and perceived urgency of the event.

Suggested readings Acute Dialysis Quality Initiative, www.adqi.org (accessed July 10, 2009) Baldwin I. Training, Management and Credentialing for CRRT in ICU. Am J Kidney Dis, 1997;30(5)(suppl 4):S112-S116. Bellomo R, Baldwin I, Ronco C, Golper T. Atlas of hemoﬁltration. WB Saunders, Philadelphia, PA: Harcourt Publishers Limited; 2002. Parienti JJ, Thirion M, Mégarbane B, and the Members of the Cathedia Study Group. Femoral vs jugular venous catheterization and risk of nosocomial events in adults requiring acute renal replacement therapy: a randomized controlled trial. JAMA. 2008;299:2413-2422. Ricci Z, Bonello M, Salvatori G, et al. Continuous renal replacement technology: from adaptive technology and early dedicated machines towards ﬂexible multipurpose machine platforms. Blood Purif. 2004;22:269-276. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Contributions to Nephrology. Karger Publishers; 2007. Ronco C, Bellomo R, La Greca G. Blood Puriﬁcation in Intensive Care. Contributions to Nephrology. Basel: Karger Publishers; 2002. Ronco C, Bellomo R. Critical Care Nephrology. Dordrecht: Kluwer Academic Publishers; 1st ed.; 1998. Ronco C, Ricci Z, Bellomo R, Baldwin I, Kellum J. Management of ﬂuid balance in CRRT: a technical approach. Int J Artif Organs. 2005;28:765-776.

Chapter 16

Nonanticoagulation strategies to optimize circuit function in renal replacement therapy Ian Baldwin

Anticoagulant drugs such as heparin and citrate can be effective in preventing clotting in the extracorporeal circuit. Not all patients can be administered these agents due to risk of bleeding. Renal replacement therapies can be done without anticoagulation. In centres with a large surgical case load, anticoagulation may only be used in approximately 50% of all treatments. In all treatments, and particularly when anticoagulation is not used, strategies to maintain blood ﬂow in the renal replacement therapy (RRT) circuit are useful in preventing clotting.

Deﬁnitions—key terms associated with optimising circuit function in renal replacement therapy Filter life: The “ﬁlter life” is deﬁned as the time (hour, minute) from the commencement of blood ﬂow through the hemoﬁlter until the time when the blood is unable to pass through the hemoﬁlter due to clot formation and obstruction in the hemoﬁlter. Predilution: The administration of replacement ﬂuid into the blood pathway prior to its entry into the hemoﬁlter (preﬁlter delivery, see Figure 16.1). Access catheter: Often referred to as a Vascath (vascular access catheter), which is also a trade name; Vascath. A plastic tubing device with two lumens placed percutaneously in a large vein of the body for the purpose of drawing blood into an RRT circuit and returning it to the patient. Access failure: Obstruction in the catheter such that blood aspiration and or ﬂush is not adequate for RRT to function.

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Introduction

Nonanticoagulation strategies CHAPTER 16

CVVH predilution Membrane

Replacement fluid Blood pump

Waste pump

Pump

Heater

Waste collection Patient

130

Figure 16.1 Schematic diagram for continuous veno-venous hemoﬁltration indicating premembrane ﬂuids administration or predilution.

Blood Pump speed: Flow of blood setting for RRT in mL/min. Filtration fraction: Describes a relationship between the blood ﬂow through the hemoﬁlter and the amount of plasma water removed from the blood within the hemoﬁlter. An increased ﬁltration fraction means hemoconcentration and potential clotting and cell clogging of the hemoﬁlter ﬁbers. P-in: Pressure (mm Hg) measured in the RRT circuit before the hemoﬁlter. An increase in this pressure reﬂects hemoﬁlter clotting. Transmembrane Pressure (TMP): A measure of pressure across the hemoﬁlter as a result of pressure measurements taken before (P-in), after the hemoﬁlter (P-venous), and in the ﬁltration pathway (P-Uf). P-venous – P-in/2 + P-Uf = TMP. Arterial pressure: Pressure in the RRT circuit between the access catheter outﬂow connection and the blood pump is a negative pressure reﬂecting blood being drawn from the patient. Blood ﬂow reduction: A blood ﬂow less than set or prescribed, related to access catheter outﬂow failure and insufﬁcient stroke volume of the roller pump tubing. It is associated with increasing negative arterial pressure, and often without operator awareness as pump rotations remain stable. Venous chamber clotting: Clot formation in the circuit bubbles trap chamber, found in the section of tubing between the hemoﬁlter and the access catheter return line. Air-blood interface: A pocket of gas above the level of blood in the venous chamber. This provides an exposure of blood to this gas thought to promote clotting. The gas is initially air on starting RRT, but becomes carbon dioxide when

The access catheter type and site: Large size, 13.5–15.0 Fg, side-by-side lumen conﬁguration (see Figure 16.2). Tip placement close to the right atrium on chest X-ray. Femoral site functions well in most patients. Test access patency by aspiration and ﬂush for each circuit connection. Access failure can cause reduced blood ﬂow with pump failure due to inadequate pump tubing segment reﬁll (see Figure 16.3). The operator will be unaware this is occurring and premature clotting will result. Blood ﬂow rate setting: 150–200 mL/min. Flow must be adequate for the ﬂuid removal rate (see ﬁltration fraction error). Incorrect blood ﬂow and ﬂuid removal rate ratio (ﬁltration fraction) causes membrane hemoconcentration with an increase in clotting and cell clogging of the membrane. Flow too fast can cause turbulence at resistance points, cell and plasma separation, and clot formation. Flow too slow causes cell slugging and sticking to surfaces. Membrane size and type: The membrane needs to be adequate for the blood ﬂow and ﬂuids removal settings. In adults it is commonly between 1.0 and 1.4 m2. Different membrane composition may affect clot potential. Where clotting occurs frequently with one type of membrane composition, use an alternative.

Vascular access catheter design profiles Side by side: Double ‘‘D’’

Inner and outer lumen: Coaxial

Side by side: Double ‘‘O’’ Figure 16.2 Schematic diagram indicating three different vascular access catheter proﬁles. Side-by-side proﬁle can provide best blood ﬂow.

Nonanticoagulation strategies

Circuit preparation: Use saline solution to expel all air; avoid excessive tapping to remove air bubbles. Use of bicarbonate ﬂuids may increase bubbles during priming. Addition of heparin may prevent clotting by coating plastic and membrane surfaces.

CHAPTER 16

Key areas for attention to maintain blood ﬂow and reduce clotting

131

bicarbonate ﬂuids are used as substitution solution and heated liberating carbon dioxide gas.

Nonanticoagulation strategies

After forward compression, the tubing behind the rotating wheel will reexpand and refill with blood from the access catheter (A).

Patient access catheter (A)

If patient access restricts flow, the tubing may not adequately refill and may remain partially collapsed. Output of the next pump stroke is reduced. Blood may also pass backwards through the occlusion gap before the compression stroke of the alternate wheel.

QB

Gap QF

QB backwards flow

Flow reduction is therefore related to patient access, the revolutions per min. of the roller, (affecting refill time) the occlusion gap, and tubing reexpansion properties. QF backwards flow

Figure 16.3 Schematic diagram with description for how blood ﬂow may fail when the access catheter is inadequate and pump tubing fails to recoil and reﬁll reducing stroke volume. From Tamari Y, Lee-Sensiba K, Leonard EF, Tortolani A. A dynamic method for setting roller pumps nonocclusively reduces hemolysis and predicts retrograde ﬂow. ASAIO J. 1997;43:39-52. Reprinted with permission of Wolters Kluwer Health.

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CHAPTER 16

Roller pumps. Why they may not deliver the desired blood flow!

Substitution fluids administration site: Replacement fluids given before the membrane dilute the blood and reduce clot development in the membrane (predilution). Understanding the “air-bubble trap” chamber: The bubble trap collects bubbles that enter the circuit before blood returns to the patient. CO2 bubbles cause most of this and occur frequently when using heated bicarbonate solutions. The gas and blood interface, along with surface movement, causes cell smearing on the chamber walls. Adjustment of the blood level high in the chamber may reduce this by reducing blood splashing on the surface. Postdilution ﬂuids into the chamber can create a ﬂuid layer on top of the blood level, possibly reducing clot development (see Figure 16.4). Training and education for staff: Staff training and education has a direct relationship to success and therefore circuit life. Machine alarms “troubleshooting,” recognizing access failure, and use of anticoagulation are the key areas for education and training.

Summary Clotting in the circuit during continuous renal replacement therapy (CRRT) can be prevented by paying attention to circuit preparation with air and bubble removal and addition of heparin into the circuit with priming, circuit connection to a large Fg vascular access catheter with side-by-side lumen conﬁguration,

Gas space

Clot: cross-section Keep level to here

CHAPTER 16

Splashing of blood on entry to chamber causing clotting as cells stick to chamber walls

Nonanticoagulation strategies

Blood entry

133

Figure 16.4 Schematic diagram of a typical bubble trap on the return or venous limb of the RRT circuit. Blood level needs to be high to reduce gas and blood interface and minimize cell splashing on surface of blood level. Cells stick to chamber walls and create clot development.

pumping blood at 200 mL/min, use of a larger surface area membrane in the adult, premembrane substitution ﬂuids administration, and keeping the blood level in the venous bubble trap high. Nursing training and “troubleshooting” ability is also vital to prevent clotting due to delayed alarms correction and skilled use of technology.

Key references Baldwin I, Tan HK, Bridge N, Bellomo R. Possible strategies to prolong circuit life during hemoﬁltration: three controlled studies. Ren Fail. 2002;24(6):839-848. Baldwin I, Bellomo R. The relationship between blood ﬂow, access catheter and circuit failure during CRRT; a practical review. Contributions to Nephrology. 2004;144:203-213. Baldwin I, Bellomo R, Koch W. Blood Flow reductions during continuous renal replacement therapy and circuit life. Intensive Care Med. 2004;30:2074-2079. Baldwin I. Training management and credentialing for CRRT in critical care. Am J Kidney Dis. 1997;30(5)(suppl 4):S112-S116. Baldwin IC, Elderkin TD. CV VH in intensive care. Nursing perspectives. New Horiz. 1995;3(4):738-747. Canaud B, Formet C, Raynal N, et al. Vascular access for extracorporeal renal replacement therapy in the intensive care unit. Contributions to Nephrology. 2004;144:291-307. Egi M, Naka T, Bellomo R, et al. A comparison of two citrate anticoagulation regimens for continuous veno-venous hemoﬁltration. J Artif Organs. 2005;28(12):1211-1218.

Nonanticoagulation strategies CHAPTER 16

134

Lavaud S, Paris B, Maheut H, et al. Assessment of the heparin-binding AN69 ST hemodialysi membrane: II. clinical studies without heparin administration. ASAIO J. 2005;51(4): 348-351. Oudemans-Van Straaten HM, Wester JPJ, de Pont ACJM, Schetz MRC. Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Med. 2006;32:188-202. Schetz M. Anticoagulation for continuous renal replacement therapy. Current Opinion in anaesthesiology. 2001;14:143-149. 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(4):94-98. Webb AR, Mythen MG, Jacobsen D, Mackie IJ. Maintaining blood ﬂow in the extracorporeal circuit: haemostasis and anticoagulation. Intensive Care Med. 1995;21:84-93.

Chapter 17

Anticoagulation Rinaldo Bellomo and Ian Baldwin

Continuous treatment suggests extracorporeal blood ﬂow without clotting. This is not a realistic aim. However, drugs blocking normal coagulation pathways can prevent or delay clotting such that sufﬁcient treatment time is achieved, and importantly patient blood is returned before complete circuit obstruction. Anticoagulation primarily refers to the use of agents that prevent blood from clotting after contact with the plastic and artiﬁcial surfaces in the extracorporeal circuit (EC). Heparin is most commonly used as an anticoagulant for renal replacement therapy (RRT). Citrate is routinely used to prevent clotting by chelating calcium and preventing its action as a cofactor. Administration of anticoagulant drugs during RRT requires speciﬁc knowledge and the application of monitoring protocols to ensure safety and effectiveness. This chapter provides a brief clinical guide to such treatments.

Deﬁnitions and key terms associated with anticoagulation during continuous renal replacement therapy Filter life: The term “ﬁlter life” refers to the time from the commencement of blood ﬂow through the ﬁlter until the time when the blood is unable to pass through it due to clot formation and obstruction. Circuit life: An equivalent term for ﬁlter life. It is probably a more correct term as some circuits develop obstruction to adequate blood ﬂow because of clot elsewhere in the circuit and not in the ﬁlter itself. Air trap (or bubble trap): A component of circuit, which is typically located after the ﬁlter and which aims to prevent air entering the circuit and embolizing into the blood of the patient.

135

Introduction

Anticoagulation CHAPTER 17

Anticoagulant: A term used to describe any agent given with the aim of decreasing the tendency of blood to clot. Heparin: The most common drug used to prevent blood clotting within the circuit. Heparin is administered to prevent clot formation when extracorporeal blood ﬂow is required. It can be administered at various doses, from “low dose” (5 units/kg/h) to simply decrease the coagulability of the circuit to “full dose” [to achieve an activated partial thromboplastin time (APTT) between 1.5 to 2.5 times the normal value] to achieve both circuit and patient anticoagulation. Low molecular weight heparin (LMWH): A drug that is a modiﬁcation of the heparin molecule and that can also be used to achieve circuit anticoagulation during CRRT. It can be given as a single subcutaneous dose once a day. Various types of LMWH exist and some can accumulate in patients with kidney failure. LMWH can only be partially reversed by protamine.

136

Protamine: A drug given to bind heparin and reverse its anticoagulant effect. The typical effective ratio for full blockade is 1 mg of protamine to 100 international units of heparin. Protamine can be given to reverse the effect of heparin within the circuit before blood is returned to the patient. Warfarin (coumadin): A drug used to anticoagulate blood in the chronic setting. Although uncommon in the ICU, several patients may be admitted to the ICU with acute kidney injury and require CRRT while still under the effects of this agent. In some of these cases, such effects may be used to advantage as a form of circuit anticoagulation. INR: International normalized ratio for the prothrombin time. This test is used to measure and monitor the degree of anticoagulation achieved with warfarin. It is frequently prolonged in patients with liver disease and may be used to guide the (lack of) need for additional anticoagulant treatment in such patients. Prostacyclin: A drug that interferes with platelet aggregation and can be used as a continuous infusion to retard circuit clotting during CRRT. Activated partial thromboplastin time (APTT): A laboratory test used to monitor the degree of anticoagulation achieved with heparin. Citrate: (See Chapter 18 for details.) A molecule administered to chelate (bind) calcium in the EC blood and make it unavailable as a cofactor to the clotting process. Citrate is then metabolized by the liver into CO2. The calcium lost into the dialysate or ultraﬁltrate together with citrate is then replaced by a separate infusion of calcium. Citrate acts as both an anticoagulant and a buffer. The amount given is sufﬁcient to inhibit clotting within the circuit but, typically, does not have an effect on systemic anticoagulation. Bolus dose: Drug administration aimed at achieving therapeutic blood levels quickly. A continuous infusion at a lower dose is then provided to maintain this level.

Anticoagulation

Newer anticoagulants: More recently new anticoagulants have been developed and found to be effective and safe for human use. They include the pentasaccharides and the thrombin inhibitors. There is limited information on their use for circuit anticoagulation. In patients receiving invasive cardiac procedures, glycoprotein IIb/IIIa inhibitors are often used to prevent coronary vessel clotting. These agents may also affect the lack of need for circuit anticoagulation in some patients. In Japan, circuit anticoagulation is commonly achieved with a protease inhibitor called nafamostat mesylate, which is not available in other countries.

CHAPTER 17

Heparin coating: Administering the drug heparin into the circuit priming solution with the aim of preventing clotting due to blood contact with plastic surfaces where the heparin has coated the surface.

Orgaran: This drug is a low molecular weight glycosaminoglycan, which can be used to anticoagulate the circuit in the presence of the heparin-induced thrombocytopenia thrombosis syndrome (HITTS).

Regional anticoagulation: Any anticoagulation of the circuit but not of the patient. This might include the use of citrate with separate administration of calcium and the use of heparin with the administration of protamine to reverse its effect before the blood is returned to the patient.

Key areas for attention when administering an anticoagulant for the prevention of circuit clotting • Develop a bedside protocol for anticoagulant use. Keep this simple and read-

ily available for reference as a chart or computer page. • Develop your own expertise with this protocol. • If the circuit clots, this can be replaced. If the patient bleeds, a more seri-

ous and adverse outcome may occur. To lose a ﬁlter to protect a patient is entirely acceptable. To lose a patient in order to protect a ﬁlter is not. • Often the circuit clots not because anticoagulation is suboptimal or inadequate but rather because of poor quality vascular access, poor attention to optimal machine operation, and sudden changes in patient position that alter catheter function, decrease blood ﬂow, and induce clotting through stasis. To respond to such events by increasing anticoagulant dose is dangerous and unwise. For every clotting event, an appropriate diagnostic assessment is necessary in order to implement rational measure to prevent it the next time around.

137

No anticoagulation: In patients considered at high risk of bleeding because of recent major surgery, low platelet count, abnormal clotting tests or any combination of these can receive CRRT without the administration of any anticoagulant drug.

Anticoagulation CHAPTER 17

Practical considerations using heparin anticoagulation • It is not necessary to use full heparin anticoagulation to perform CRRT; many

patients have altered clotting as a result of critical illness. • After major surgery and with epidural use, no anticoagulation for the ﬁrst

24–48 hours postoperatively or citrate anticoagulation may be a safer option. • CRRT machines include a syringe device for concentrated anticoagulant drug

• • • •

138

• •

• • • •

•

preparation. If a dilute preparation is used, an intravenous pump used widely in the ward promotes safety as all staff will be familiar with its operation. Use of dilute preparation administered by volumetric pump minimizes accidental bolus and syringe “lag” when changing syringe once it is empty. Make the heparin infusion preparation simple in terms of calculation of dose. Heparin at 10,000 IU in a 1000 mL bag = 10 IU/mL. Label and identify this infusion as “for CRRT only.” Use a heparin preparation different to those used for other anticoagulation prescriptions (e.g., following thrombosis or embolism). Use a dosing chart or table (see Table 17.1) based on body weight for initial bolus dose and consideration of the daily clotting proﬁle for the patient. Start the treatment using the dosing table as a guide, then increase heparin if circuit life is poor. If ﬁlter life is less than 8 hours for the ﬁrst circuit consider increasing the dose. A ﬁlter life of 20–24 hours is common using heparin. A dose of 5–10 IU/kg/h given preﬁlter is a common starting dose for the ﬁrst treatment circuit. The ﬂuid volume used to administer the anticoagulation must be included in the ﬂuid balance calculations. Administer the anticoagulant into the circuit before blood enters the membrane in “preﬁlter” position. Check and assess the patient for evidence of spontaneous bleeding, urine, faeces, wounds, punctures sites, and mucus membranes. Do not check the patient clotting time (APPT) too frequently and make inappropriate infusion adjustments. Check after the ﬁrst 6 hours. After that, 12 hourly monitoring is probably adequate in most cases unless signiﬁcant clinical changes have taken place. After stabilization, daily monitoring is adequate. If patient anticoagulation is the goal, APTT monitoring may need to be more frequent. If circuit anticoagulation is the goal, APTT monitoring is performed not to titrate heparin infusion but rather to ensure there is no unnecessary or excessive patient anticoagulation. Chart the dose of heparin given each hour on bedside observation charts/ computers and the ﬁlter consecutive hours of function next to this. This provides an instant ability to assess ﬁlter life associated with heparin dosing (see Table 17.2).

Anticoagulation

Table 17.1 Heparin dosing guide for bolus and infusion Heparin anticoagulation

• All circuits primed with 5000 U heparin (1st bolus) • Patients to have at least two of the following: INR

APTT

Plts

d1.5

d40s

t150

Heparin 35 IU/kg*5 U kg/h

t1.5 d2.5

t40s

d150 t60

No bolus

t2.5

t60s

d60

CHAPTER 17

2nd bolus Heparin 70 IU/kg*10 U kg/h

Nil other

Table 17.2 ICU charting aligning heparin dose each hour with accompanying ﬁlter “life” 500 7

500 8

500 9

500 10

// clotted

750 1

750 2

Summary Anticoagulants can delay or prevent circuit clotting. However, they increase the risk of bleeding. Accordingly, their use should be based on a careful assessment of the likely risks and beneﬁts in a given patient. Heparin is commonly used in hospitals. Typically, doctors and nurses understand its risks and beneﬁts well and have established expertise with this drug. Heparin, however, is not always necessary and CRRT can be done without using it, particularly in the patient at high risk of bleeding. Heparin can be reversed with protamine if necessary. Use of a standard dilute preparation, administration preﬁlter via a common infusion device, reference to a dosing chart speciﬁc for CRRT, ongoing review of the patient and of his/her clotting proﬁle all promote safe circuit anticoagulation. No other approaches to circuit anticoagulation have yet been convincingly shown to be superior to heparin, although citrate anticoagulation is also highly effective. Whatever the choice of approach to anticoagulation, the physician and nurse must remain vigilant of changes in the patient’s risk proﬁle and make a frequent and thoughtful assessment of what approach to circuit anticoagulation is best at any given time in a given patient.

Key references Fealy N, Baldwin I, Johnstone M, Egi M, Bellomo R. A pilot controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemoﬁltration. Int J Artif Organs. 2007;30:281-292.

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Heparin dose Filter hour

Anticoagulation CHAPTER 17

Naka T, Egi M, Bellomo R, et al. Commercial low-citrate anticoagulation haemoﬁltration in high risk patients with frequent ﬁlter clotting. Anaesth Intensive Care. 2005;33:601-608. Tan HK, Baldwin I, Bellomo R. Hemoﬁltration without anticoagulation in high-risk patients. Intensive Care Med. 2000;26:1652-1657. Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R. Continuous hemoﬁltration without anticoagulation. ASAIO J. 2004;50:76-80.

Other suggested readings

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Joannidis M, Oudemans-van Straaten HM. Clinical review: Patency of the circuit in continuous renal replacement therapy. Crit Care. 2007;11(4):218. Mehta RL. Anticoagulation during continuous renal replacement therapy. ASAIO J. 1994 Oct-Dec;40(4):931-935.

Chapter 18

Regional citrate anticoagulation Nigel Fealy

An alternative to systemic methods of extracorporeal circuit anticoagulation is the application of a “regional technique” using citrate. A regional technique such as citrate anticoagulation reduces the hemorrhagic risk of systemic anticoagulation by providing selective anticoagulation within the extracorporeal system. Regional citrate anticoagulation (RCA) involves the infusion of citrate into the blood circuit, which combines (chelates) with ionized calcium to form citrate– calcium complexes. This decreases the level of circulating calcium in the circuit and prevents coagulation of blood. Ionized calcium is an important cofactor in multiple steps of the clotting cascade. Calcium, therefore, that is bound to citrate will not participate in the clotting cascade, leading to clotting inhibition.

Deﬁnitions Extracorporeal circuit (EC)—The path for blood ﬂow outside the body. Includes the plastic tubing carrying the blood to the hemoﬁlter from the access catheter and from the hemoﬁlter back to the body via the access catheter. Filter life or functional life of the EC—The passage of blood through the EC, particularly the hemoﬁlter, initiates blood clotting. The clotting of blood is a slow but inevitable process delayed by factors known and unknown. Blood coagulation is thought to be a main factor in this process. The time period before the blood is unable to pass through the hemoﬁlter due to clot formation and obstruction in the hemoﬁlter is the ﬁlter life. This is generally synonymous with EC life or circuit life. Anticoagulation—It is the administration of a substance that prevents coagulation, that is, it stops blood from clotting. Anticoagulant therapies interfere with humoral coagulation or platelet activation and have varying impact on systemic coagulation.

141

Introduction

Regional citrate anticoagulation CHAPTER 18

142

Systemic anticoagulation—Where an anticoagulant is administered and has a direct effect on the patient’s ability to activate the clotting cascade within the body. The agent leads to increased clotting times of the patients themselves. Some anticoagulants are administered into the EC circuit but also have a direct effect on the patient’s ability to clot blood. Circuit anticoagulation—The aim of anticoagulation is to prevent clot formation within the EC circuit and hemoﬁlter, with little or no impact on the patient’s ability to start the clotting process. Regional anticoagulation–Where a high level of anticoagulation is provided to the EC circuit only while the patient receives no drug. Usually the anticoagulant is administered into the circuit and an “antidote” is administered to reverse the effects of the anticoagulant before blood returns to the body.

Method It is important to understand some aspects of calcium physiology and distribution in blood (Figure 18.1). When citrate is infused into the blood circuit, it combines with ionized calcium (IC) to form citrate–calcium complexes (nonionized). This reduces the level of ionized calcium in the extracorporeal circuit, which in turn leads to the inhibition of clotting in the circuit. The target for circuit ionized calcium level to prevent or retard clotting is generally between 0.25 and 0.4 mmol/L. There is no systemic anticoagulation because of the following reasons: • There is signiﬁcant loss of the citrate–calcium complexes as they cross the semipermeable membrane of the hemofilter (dialyzer) into the ultraﬁltrate (UF).

(IC) Ionized calcium, (~ 50%) 1.1–1.3 mmol/L (TC) Total calcium 2.2–2.6 mmol/L (PBC) Protein bound calcium (~ 40% 0.95–1.2 mmol/L

(CC) Complex calcium (~ 10%) Calcium phosphate, salts ~ 0.05 mmol/L Figure 18.1 Calcium distribution in plasma and normal lab ranges.

Practical considerations Key areas that need attention to maintain metabolic and electrolyte balance are as follows: • In addition to acting as an anticoagulant, citrate acts as a buffer following liver metabolism. One mmol of citrate yields three mmol of bicarbonate when metabolized. Potentially, when higher doses of citrate are administered, this could lead to an increase in serum bicarbonate levels (metabolic alkalosis). • The amount of citrate lost in the ultraﬁltrate will vary with ﬁltrate ﬂow (both UF rate and amount of ﬂuid removal), and, therefore, the amount of buffer entering the systemic circulation may vary (metabolic acidosis). • When trisodium citrate is used, there is an increase in the sodium load to the patient, increasing the risk of hypernatremia. • If the patient is not able to metabolize citrate–calcium complexes due to liver dysfunction or via the skeletal muscle pathway, then citrate may accumulate and no buffer is generated. In addition, hypocalcaemia may also result.

Regional citrate anticoagulation CHAPTER 18

are delivered to the patient are diluted with the patient’s blood and rapidly metabolized by liver, kidney, and muscle cells to form bicarbonate (1 citrate ion = 3 bicarbonate ions). • During this metabolism of the citrate–calcium complexes, calcium liberated from the complex contributes to the normalization of calcium levels. • Serum ionized calcium levels lost in the UF are replaced by the administration of a calcium infusion systemically to restore normal levels (normal serum ionized calcium level ~ 1.1–1.3 mmol/L) A variety of citrate protocols or regimens exist for the prescription for continuous renal replacement therapy (CRRT) using both continuous venovenous hemoﬁltration (CV VH) and continuous veno-venous hemodiaﬁltration (CV VHDF) as the mode of therapy. Often protocols are hospital speciﬁc requiring pharmacy or custom-made solutions (substitution and dialysate) to implement the technique. These prescriptions vary according to mode, pre- or postdilution, different citrate solutions, and different approaches for monitoring and adjustment of acid-base balance. In CRRT, there are three major forms of citrate administration. First is 4% trisodium citrate, second is acid citrate dextrose solution (ACD-A), and third is citrate-containing replacement solution. These different approaches can also vary with respect to the mode of CRRT—a pure diffusive method (CV VHD), a diffusive and convective method (CV VHDF), and pure convective method (CV VH). As previously described, there are many descriptions and protocols for the delivery of citrate anticoagulation in the clinical setting. A description of protocols for CV VHDF and CV VH can be seen in Figures 18.2 and 18.3.

143

• Any citrate or citrate–calcium complexes that remain in the venous line and

Regional citrate anticoagulation CHAPTER 18

144

QE = QR + QFR + QD

QB 100–150 mL/min

Dialysate: 4L bag Na+ 140 mmol/L Cl– 118.5 mmol/L HCO3– 25 mmol/L K+ 4.0 mmol/L Mg 0.58 mmol/L Rate: 1000–2500 mL/h QD Patient iCa2+ 1.1–1.3 mmol/L

QR PF iCa2+ (0.25–0.5mmol/L) Prefilter fluid: 4L bag 0.5% Trisodium citrate Citrate 18 mmol/L Na+ 140 mmol/L Rate: 1000–2000 mL/h

Ca2+ Gluconate 38.75 mmol/L Initial rate: 60 mL/h

Figure 18.2 Continuous veno-venous hemodiaﬁltration (CV VHDF). University of Alabama at Birmingham CV VHDF protocol (A. Tolwani, 2005). QB = blood ﬂow; QE = efﬂuent ﬂow; QR = replacement; QFR = ﬂuid removal; QD = dialysate ﬂow. Modiﬁed from Tolwani A, Prendergast M, Speer R, Stofan B, Willie K. A practical citrate anticoagulation continuous venovenous hemodiaﬁltration protocol for metabolic control and high solute clearance. Clinical Journal of the American Society of Nephrologists. 2005;1:79-87.

• In addition to binding calcium to form calcium–citrate complexes, magnesium

is also bound and freely ﬁltered across the membrane, potentially leading to a reduction in serum magnesium levels. Therefore, when prescribing a citrate-based anticoagulation regimen, metabolic monitoring should be a priority. Regular monitoring of pH, serum and circuit iCa, serum bicarbonate, and sodium and magnesium levels should be an essential element of any unit based protocol. Depending on the method used a local protocol should be developed to monitor, report, and treat any metabolic derangements that may occur as a result of utilizing a citrate-based anticoagulation regimen. There are numerous descriptions and reports available for the monitoring of electrolytes, acid-base balance, and anticoagulation in RCA.

Summary With regional citrate anticoagulation, ﬁlter life is prolonged or equal to that of standard systemic heparin anticoagulation. The major advantage is that adequate

Patient iCa2+ 1.1–1.3 mmol/L

Prefilter fluid: 5 L bag Sodium citrate Citrate 14 mmol/L Na+ 140 mmol/L Rate: 2000 mL/h

Ca2+ Chloride + Mg+(210 mL) Ca2+ 70 mmol/L Mg+ 35 mmol/L Initial rate: 12mL/h (Ca2+ = 4 mmol/h)

Regional citrate anticoagulation

QB 200 mL/min

CHAPTER 18

QE = QR + QFR

anticoagulation can be achieved for CRRT without the need for systemic anticoagulation and the associated risks of bleeding in critically ill patients. The choice of citrate protocol will depend largely on the citrate solution available, mode of therapy used (CV VH, CV VHDF), and method chosen for citrate delivery (infusion, replacement solution). RCA requires, however, the development of unit-based protocols that are easy, safe, and practical in the clinical setting. With these protocols in place, RCA is a safe and practical alternative strategy for anticoagulation in CRRT.

Key references Abramson S, Niles J. Anticoagulation for continuous renal replacement therapy. Current Opinion in Nephrology and Hypertension. 1999;8:701-707. Amanzadeh J, Reilly Jr R. Anticoagulation for continuous renal replacement therapy. Seminars in Dialysis. 2006;19(4):311-316. Cointault O, Kamar N, Bories P, et al. Regional citrate anticoagulation in continuous venovenous haemodiafiltration using commercial solutions. Nephrology Dialysis Transplantation. 2003;19(1):171-178. Fealy N, Baldwin I, Johnstone MJ, Egi M, Bellomo R. A pilot randomized controlled crossover study comparing regional heparinization to regional citrate anticoagulation for continuous venovenous hemoﬁltration. International Journal of Artiﬁcial Organs. 2007;30(4):301-307.

145

Figure 18.3 Continuous veno-venous hemoﬁltration (CV VH). Department of intensive care, Austin hospital CV VH protocol. QB = blood ﬂow; QE = efﬂuent ﬂow; QR = replacement; QFR = ﬂuid removal.

Regional citrate anticoagulation CHAPTER 18

146

Kutsogiannis DJ, Mayers I, Chin W, Gibney R. Regional citrate anticoagulation in continuous venovenous hemoﬁltration. American Journal of Kidney Diseases. 2007;35:802-811. Oudemans-van Straaten HM, Wester J, de Pont A, Schetz M. Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Medicine. 2006;32:188-202. Tolwani A, Prendergast M, Speer R, Stofan B, Willie K. A practical citrate anticoagulation continuous venovenous hemodiaﬁltration protocol for metabolic control and high solute clearance. Clinical journal of the American Society of Nephrologists. 2005;1:79-87.

Chapter 19

Drug dosing in continuous renal replacement therapy

The use of continuous renal replacement therapy (CRRT) in intensive care patients is increasing. Typically, CRRT is used in the critically ill patient because it provides continuous removal of solutes and ﬂuid, which results in decreased ﬂuctuations in electrolytes and ﬂuid balance with reduced hemodynamic instability as compared to conventional intermittent hemodialysis (IHD). While there is still debate regarding the optimal use and application of renal replacement therapy (RRT) in the intensive care unit (ICU), it is important to recognize the impact that RRT may have on medications used to treat the critically ill. More precisely, it is important to understand the numerous variables that affect drug dosing in the critically ill patient receiving RRT. Among those variables are differences between available renal replacement therapies, pharmacokinetic and pharmacodynamic changes that occur in the critically ill, and physiochemical properties that affect drug dosing and clearance in this patient population.

Continuous renal replacement therapy properties As discussed in Chapter 10 and 12, CRRT can be applied utilizing various techniques and methods. Differences among CRRT techniques that affect solute and medication clearance include mechanism of solute clearance, vascular access, ﬁlter membrane properties, and ﬂow rates for blood, ultraﬁltration, and dialysis ﬂuid.

CRRT techniques The three main techniques of clearance utilized are hemodialysis, hemoﬁltration, and hemodiaﬁltration. Each technique varies in mechanism of solute clearance (i.e., convection or diffusion) and need for ﬂuid replacement (see Table 19.1). In addition, each technique can be applied using either arterio-venous or veno-venous access. However, veno-venous methods are generally preferred, given the reduced risk of complications and the ability to generate consistent and higher solute clearance rates.

147

Kimberly A. Maslonek, Kelly A. Killius, and John A. Kellum

Drug dosing in CRRT CHAPTER 19

Table 19.1 CRRT techniques Technique

Clearance mechanism

Replacement ﬂuid 0

SCUF

Convection +

Diffusion

CV VH

++++

CV VHD

+

++++

+/0

CV VHDF

+++

+++

++

+++

Note: SCUF = slow continuous ultraﬁltration; CV VH = continuous veno-venous hemoﬁltration; CV VHD = continuous veno-venous hemodialysis; CV VHDF = continuous veno-venous hemodiaﬁltration

148

• Hemodialysis utilizes passive diffusion of solutes across a concentration gra-

dient with countercurrent dialysis ﬂuid. Only molecules of small molecular weight (<500 dalton) are readily removed during diffusion. Replacement ﬂuid is not required. • Hemoﬁltration utilizes convection, where solutes and plasma water are driven through a membrane with a pressure gradient, resulting in higher solute removal and the formation of an ultraﬁltrate. As long as the solute is smaller than the pore size cutoff for the membrane used, particle size or molecular weight has little inﬂuence on solute removal during convection methods. However, replacement ﬂuid, which can be administered before or after blood ﬁltration, is required due to the large volume of ultraﬁltrate formed during this process. • Hemodiaﬁltration is a combination of diffusion and convection. Solute and volume removal involve a countercurrent dialysis ﬂuid and pressure gradient. Replacement ﬂuids are required to support higher ultraﬁltration rates. • Slow continuous ultraﬁltration (SCUF) is a method of ﬂuid removal without dialysis or replacement ﬂuid. SCUF is not appropriate for patients with renal failure since it provides only very limited solute clearance. SCUF is usually employed for temporary volume removal in patients with at least some renal function (e.g., congestive heart failure). As such drug dosing does not typically require adjustment for patients receiving SCUF. In general, drug removal may be expected to be greater with CRRT compared to IHD, and when replacement ﬂuids are administered after ﬁltration. Drug clearance with CRRT may vary greatly depending on the particular physicochemical properties of each compound and the CRRT device characteristics and operating conditions.

Filter properties Filters used in RRT differ in a number of properties including, but not limited to, permeability, membrane composition, and surface area. While no one membrane is recommended, it is important to note their differences and to understand that different ﬁlters may result in signiﬁcant differences in solute or drug removal.

Membrane composition Intermittent hemodialysis (IHD) ﬁlters are composed of cellulose or syntheticbased materials, while the most common materials employed in CRRT ﬁlters are synthetics, including polyacrylonitrile, polyamide, and polysulfone. Again, while no one ﬁlter is considered optimal, ﬁlters composed of synthetic material are favored over those that are cellulose based because they are generally considered more biocompatible. Other considerations include differences in permeability and their varying effect on the SC of many drugs. In general, larger pore sizes or “high-ﬂux” membranes generally result in greater drug clearances especially for larger molecules.

Flow rates Although variation exists depending on which mode of therapy is provided (e.g., CV VH vs. CV VHD) and which membranes are used, in general, higher ﬂow rates (blood ﬂow, dialysate ﬂow, ultraﬁltration ﬂow) result in increased solute removal. Hence, for medications removed by CRRT, increased ﬂow rates will result in a need to increase drug dosing or to shorten dosing intervals.

Patient properties Critically ill patients may have alterations in their pharmacokinetic parameters that can affect drug clearance and disposition (see Table 19.2). With regard to medication dosing in IHD and CRRT, the most relevant patient changes can occur in volume of distribution, protein binding, metabolism, and elimination.

Drug dosing in CRRT CHAPTER 19

SC = CUF/CP SC = 0; no passage through ﬁlter SC = 1; pass freely through ﬁlter SC = Sieving coefﬁcient, CUF = concentration of medication in ultraﬁltrate, CP = concentration of medication in plasma The SC is available for some medications in published literature. Otherwise, it can be calculated by obtaining medication concentrations.

149

Membrane permeability Membrane permeability differs on the basis of the type of RRT used. Conventional low-ﬂux dialysis (IHD) ﬁlters have smaller pore size and are inefﬁcient at removing molecules > 500 dalton. Conversely, ﬁlters that are used in CRRT have increased pore size and are effective in removing molecules up to 50,000 dalton. The ability of a drug or solute to pass through a ﬁlter membrane is expressed as the sieving coefﬁcient (SC). Medications with SC that approach unity (SC = 1) are able to freely pass through the ﬁlter and will require increased dosing or interval changes.

Drug dosing in CRRT CHAPTER 19

150

Table 19.2 Patient factors affecting drug levels Factor Hypervolemia Hypoalbuminemia Organ dysfunction

Effects Increases Vd and decreases absorption Increases unbound fraction Decreases drug clearance

Effect on drug levels Decreases Increases Increases

• Volume of distribution: It may be altered in critically ill patients, with either an

•

•

• •

increase or decrease in total body water and intravascular volume. Increases in volume of distribution have been reported in patients with edema, ascites, pleural effusions, mediastinitis, hypoalbuminemia, and postsurgical drainage. Hypervolemic patients may require higher doses for medications with large volumes of distribution, with the opposite being true for hypovolemic patients. As ﬂuid removal is accomplished with CRRT, volume of distribution will decrease for many drugs. This may paradoxically result in a need to decrease dosing as severely volume overloaded patients are brought back toward their premorbid weight. Drug absorption: In the case of transdermal, subcutaneous, and oral administration drug absorption can also be signiﬁcantly affected by volume overload and by peripheral and intestinal edema. As edema is reduced with CRRT, drug absorption may increase. Protein binding: In the critically ill patients may be affected by several variables including, but not limited to, acid-base disturbances and alterations in protein concentrations. Acid-base abnormalities will adversely affect protein binding. Studies performed in the critically ill show that a decrease in the concentration of albumin or an increase in the concentration of alpha-1-acid glycoprotein can occur. Given that only the unbound fraction of a medication is able to diffuse across a ﬁlter membrane, shifts in protein concentrations or acid-base status can affect the amount of unbound drug (active drug) available in the body. These changes can ultimately affect the amount of drug available for removal by RRT. Importantly, protein binding is in dynamic equilibrium. Because of its continuous nature, CRRT results in signiﬁcantly greater removal of drugs with increased protein binding compared to IHD. Metabolism: Assessment of other organ function is essential to determine the potential for accumulation of metabolites as well as parent compounds. Elimination: The application of CRRT is more likely to increase the clearance of renally eliminated medications than those that undergo nonrenal clearance mechanisms. In addition, the existence of residual renal function must also be considered as this may further enhance drug clearance in a patient undergoing CRRT. Furthermore, ﬂuid removal by CRRT may result in changes in drug elimination by other organs.

Molecular weight Medications with a small molecular weight (<500 dalton) are effectively cleared by conventional low-ﬂux hemodialysis and CRRT, while only CRRT is capable of removing larger molecules (up to the pore size cutoff of the membrane, typically 20,000–50,000 dalton). Drugs of larger molecular size, therefore, are more likely to be removed by CRRT methods and may require increased or more frequent dosing. For example, vancomycin (1400 dalton) is not easily removed by IHD but has signiﬁcantly greater clearance through more open membranes even during diffusive therapy (continuous hemodialysis).

Drug dosing in CRRT

There are a number of intrinsic properties that affect the ability of any drug to be removed by RRT. These properties include molecular size, volume of distribution, protein binding, and elimination mechanisms (renal vs. nonrenal clearance).

CHAPTER 19

Drug properties

The degree to which any drug is bound to protein will affect its ability to be cleared by CRRT or dialysis (see Table 19.3). Drugs that are bound to proteins form large complex molecules (>50,000 dalton) and are not readily removed by IHD or CRRT. Unbound medications are more likely to pass through a dialysis ﬁlter and require increased dosing or dosing interval changes.

Volume of distribution Drugs that have a small volume of distribution are generally hydrophilic and limited to vascular space since they are unable to pass through plasma membranes. Most hydrophilic agents are renally eliminated as unchanged drug. Therefore, Table 19.3 Relative sieving coefﬁcients and protein binding of select drugs Drug Acyclovir Amphotericin Ampicillin Cefoxitin Ceftazidime Ciproﬂoxacin Cyclosporine Diazepam

SC +++ + ++ ++ +++ ++ ++ 0

PB Very low Very high Low High Very low Low Very high Very high

Drug Digoxin Ganciclovir Gentamicin Imipenem Oxacillin Phenytoin Piperacillin Vancomycin

SC +++ +++ ++ +++ 0 + ++ ++

PB Low Very low Very low Low Very high High Low Very low

Note: SC = sieving coefﬁcient; PB = protein binding; Drugs with high SCs and low protein binding are easily removed by CRRT. Drugs with low or near 0 SCs cannot be removed by RRT; drugs with high protein binding will be removed only to a small extend with CRRT and not at all with IHD.

151

Protein binding

Drug dosing in CRRT CHAPTER 19

medications with a low volume of distribution are more readily removed by RRT and may require increased or more frequent dosing. Examples include beta-lactams, glycopeptides, and aminoglycosides, with the exception of ceftriaxone and oxacillin. Both undergo primary biliary elimination and are therefore largely unaffected by CRRT despite their hydrophilic status. Conversely, lipophilic medications, which are able to freely cross plasma membranes and sequester into tissues, typically have high volumes of distribution and undergo hepatic metabolism. Medications with large volumes of distribution are less available to pass through the RRT circuit for clearance and are less affected by renal clearance changes (extracorporeal or residual). Dose adjustments are generally not necessary for drugs with large volumes of distribution in IHD. However, CRRT may have a greater impact on drug removal because the increased duration of therapy increases the likelihood that drug will redistribute from tissue to vascular space and be available for clearance. Examples include macrolides, ﬂuoroquinolones, tetracyclines, chloramphenicols, and rifampins, with the exception of levoﬂoxacins and ciproﬂoxacins. Both undergo renal elimination and may be removed by RRT despite their lipophilic nature.

152

Elimination Medications that are cleared renally will likely require increased dosing during RRT. In addition, dosing requirements may be further increased in patients with residual renal function receiving CRRT.

Pharmacodynamic principles Appropriate dosing of antimicrobial agents in patients receiving RRT is imperative in order to avoid therapeutic failure, increased resistance, or adverse effects, and must include pharmacodynamic considerations. In brief, antimicrobial efﬁcacy has been deﬁned in pharmacodynamic terms to be either time dependent or concentration dependent.

Concentration-dependent antimicrobial The efﬁcacy of concentration-dependent antimicrobials is primarily related to the peak of minimum inhibitory concentration (MIC) (Cmax/MIC) and the area under the curve (AUC) to MIC (AUC/MIC) ratios. Concentration-dependent antimicrobials include ﬂuoroquinolones, metronidazole, and aminoglycosides. AUC/MIC ratios >100 have been suggested for gram-negative organisms and >30 for gram-positive organisms. Cmax/MIC ratios of 10–12 have been shown to provide clinical efﬁcacy and prevent the development of resistance. Concentration-dependent agents exhibit postantibiotic effects against grampositive and gram-negative organisms; therefore, allowing concentrations to fall below the MIC is permissible. Concentration-dependent medications typically require increased doses to achieve adequate peak or area under the curve MIC ratios (see Figure 19.1).

MBC

Drug dosing in CRRT

Bacterial regrowth

CHAPTER 19

Bacteriostatic

Plasma concentration

Bactericidal

B MIC C

A

Figure 19.1 Time-varying plasma concentration and relation to minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Curve A represents a typical relationship while B represents a decreased clearance and C represents increased clearance. Time-dependent killing is most affected by increasing drug clearance. When possible, medication adjustments based on appropriately drawn serum levels is desired.

Time-dependent antimicrobial The efﬁcacy of time-dependent antimicrobials is primarily related to the duration of time that the drug concentration exceeds the MIC (T>MIC ratio) or by maintaining the minimum plasma concentration above the MIC (Cmin>MIC). Time-dependent agents include beta-lactams, glycopeptides, oxazolidinones, and azole antifungals. Maximum efﬁcacy is thought to be achieved by maintaining the Cmin at 4 to 5 times the MIC. Troughs below the MIC must be avoided in time-dependent agents as the majority (with the exception of carbepenems) lacks a postantibiotic effect against gram-negative organisms. Time-dependent medications will require more frequent dosing to achieve adequate time above the MIC.

Dosing recommendations There are multiple limitations with regard to dosing recommendations for CRRT. Included is the limited number of studies available that evaluate the effect of CRRT on drug disposition in the critically ill. Those studies that do exist primarily involve the investigation of antimicrobial agents and vary in their study design, method of CRRT, and study population, making it difﬁcult to generalize

153

Time

Drug dosing in CRRT CHAPTER 19

Table 19.4 Antibiotic dosing recommendations Dosing for CrCl 30 mL/min but not on RTT 500 mg–1 g Q 24 h

Conventional IHD (Kt/V 1.2 QOD)

Ciproﬂoxacin

500 mg oral or 400 mg IV Q 24 h

Gentamicina

24-hour dosing

250–500 mg oral or 200–400 mg IV after* each dialysis 30% removal occurs during 4 hours of HD; administer dose after* dialysis and follow levels

Piperacillintazobactam

Decrease dose by 30% and administer every 6 h 15–20 mg/kg Q 24 h

2.25 g every 8–12 h with additional dose of 0.75 g after each dialysis 10–15 mg/kg after each treatment

Drug

Cefepime

154

Vancomycinb

1 g load; 500 mg Q 24 h (given after dialysis)

CRRT (CVVH at 25 mL/ kg/h) 1–2 g Q 12 h (consider continuous infusion of 2–4 g/24 h) 250–500 mg oral or 200–400 mg IV Q 12 h 24-hour dosing

4.5 g every 8 h

15–20 mg/kg Q 24 h

Notes: a Should always be guided by therapeutic drug levels; b For concentration-dependent antimicrobials some authorities recommend higher IV dosing administered 1 hour before IHD.

data to all patients. In addition, there exists inconsistency across drug information resources. Many of the drug information resources offer adjustments for IHD or early forms of CRRT that are not applicable to the newer forms of CRRT that provide higher clearance rates. Table 19.4 provides dosing recommendations for some common antimicrobial agents based on available literature. Limitations to these recommendations are as cited above. Drug clearance is highly dependent on the method of renal replacement, ﬁlter type, and ﬂow rate. Appropriate dosing requires close monitoring of pharmacological response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (for a typical sized adult patient) and should not supersede clinical judgment: When available, therapeutic drug monitoring should be applied to optimize drug therapy and limit adverse effects.

Key references Joy MS, Matzke GR, Armstrong DK, Marx MA, Zarowitz BJ. A primer on continuous renal replacement therapy for critically ill patients. Ann Pharmacother. 1998;32:362-375. Pea F, Viale P, Falanut M. Antimicrobial therapy in critically ill patients. Clin Pharmacokinet. 2005;44(10):1009-10034.

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155

Pea F, Viale P, Pavan F, Falanut M. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet. 2007; 46(12):997-1038. Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill patients receiving continuous renal replacement therapy. Clin Infect Dis. 2005;41:1159-66.

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Part 3

Special situations

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Chapter 20

Renal replacement therapy in children Michael L. Moritz

There are various options for renal replacement therapy (RRT) in children. The type of RRT largely depends on the child’s size, the reason for initiating therapy, and the equipment and expertise available at an institution. Acute RRT is not nearly as often performed in children as it is in adults, and not all RRT’s are available at each pediatric center. Peritoneal dialysis is the most widely available RRT, performed at almost all pediatrics centers. Hemodialysis is also widely available, but many centers do not have the expertise or equipment to dialyze infants or neonates. Continuous veno-venous hemoﬁltration (CV VH) is becoming more available at pediatric center, but is primarily offered at large pediatric tertiary care centers. RRT in the large child or adolescent (> 50 kg) is no different than in adults. The focus of this section will be to discuss RRT, as it pertains to infants and small children. A complete discussion of renal replacement therapies can be found elsewhere in this manual.

Indications The most common reasons for initiated acute RRT in children are similar to adults: acute renal failure, sepsis, multisystem organ failure, solid organ transplants, and bone marrow transplants There are some reasons for initiating RRT in children that are different than adults, such as postoperative congenital heart disease repair, urea cylcle disorders, and hemolytic uremic syndrome.

Peritoneal dialysis Peritoneal dialysis (PD) remains an attractive form of RRT for a variety of reasons. PD catheters are relatively easy to insert and can be placed in, virtually, any sized child. It is an inexpensive therapy that does not require sophisticated dialysis equipment or highly trained personnel. Acute PD is primarily performed following postoperative complex congenital heart disease repair. PD is a better

159

Renal replacement therapy in children

Renal replacement therapy in children CHAPTER 20

160

option than CV VH in these children due to their small size and also because PD does not require vascular access or systemic anticoagulation. Many cardiac centers will place a PD catheter at the time of cardiac repair and initiate PD if there is oliguria, ﬂuid overload, or metabolic derrangements.

Contraindications to PD There are only a few contraindications to PD. A gastrostomy tube, ileostomy, colostomy, and vesicostomy are not contraindications to PD. A ventriculo-peritoneal shunt is a relative contraindication to PD, but should only be initiated by experienced dialysis personnel. Contraindications to PD: • Recent abdominal surgery ( 5–7 days) • Abdominal drains • Abdominal wall defects • Communication between abdomen and thorax • Extensive abdominal adhesion • Peritoneal membrane failure • Ventriculo-peritoneal shunt

PD access A single-cuff acute Tenckoff catheter is the most common catheter used for acute PD in children. The catheters can be either straight or coiled. The catheters come in three sizes—infant, pediatric, and adult. Pediatric and adult catheters have the same internal diameter, but only differ in length. Selection of acute Tenckoff PD catheter: • <3 kg infant catheter • >3 and <20 kg pediatric catheter • 20 kg adult catheter

Apparatuses for PD Acute PD is easy to initiate. Manual PD can be initiated with a “Y-set” that connects to the PD catheter. One end of the Y is connected to the dialysate solution and the other end is connected to a drain bag. Manual PD can then be initiated. A burretrol will be required to deliver small dwell volumes in such cases. A specially manufactured manual dialysis set called “Daily-Nate” is available for performing manual PD in small infants. Dialy-Nate is a closed system with a graded burretrol to deliver small volumes, a drain bag, multiple connectors for dialysate, and an optional heating coil. An automated “cylcler” can be used in large sized infants. The minimal volume that can be delivered by a cylcler is 60 mL. It is best to use a cylcler when a dwell volume of 100 mL or greater is used.

Acute PD prescription There are various components to writing an acute PD prescription. The list below describes a typical prescription to initiate PD. Below is an explanation of each component of the dialysis prescription.

The dialysate solution is referred to by the dextrose concentration as 1.5%, 2.5%, or 4.25%. Dialysate is hyperosmolar in relationship to the plasma. Uremic toxins, electrolytes, and water are removed from the patient via diffusion into the peritoneum. • A 1.5% dialysate solution is the standard concentration for initiating PD. • The dextrose concentration can be increased if additional ﬂuid removal is required. • 200 units of heparin per liter are usually added to the dialysate to prevent ﬁbrin clots. • Heparin does not cross the peritoneal. • 2–4 mEq/L of heparin can be added to the dialysate if hypokalemia develops.

Renal replacement therapy in children

Dialysate

CHAPTER 20

Initial PD prescription: • 1.5% Dextrose + 200 units of heparin per liter • 10 mL/kg dwell volume • Continuous hourly exchanges

Acute PD is initiated at a low dwell volume to prevent leakage of dialysate around the catheter from higher intraperitoneal volume. The dwell volume can be progressively increased over time to improve clearance. • PD is initiated at a dwell volume of 10 mL/kg. • The dwell volume can be progressively increased over 2 weeks to up to 40 mL/kg.

Dwell time • Acute PD is usually initiated with hourly exchanges • 20–30 minute exchanges can be used if

PD is initiated within 24 hours of catheter placement, aggressive ﬂuid removal is needed, • there is severe hyperkalemia. • Acute PD is usually continuous. • Intermittent PD of 8–10 hours can be done when dwell volumes > 30 mL/kg are achieved. • •

Complications There are a variety of complications associated with peritoneal dialysis. Below are the key aspects to a variety of complications: • Leakage of ﬂuid around the PD catheter • Interrupt PD for 24–48 hours. • Resume at a reduced dwell volume. • Consider administering ﬁbrin glue to the exit site.

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Dwell volume

Renal replacement therapy in children CHAPTER 20

162

• Peritonitis: Cloudy ﬂuid, abdominal pain, fever; peritoneal cell count: >100 µL,

>50% neutrophils • Send peritoneal ﬂuid for culture. • Treat with intraperitoneal antibiotics. • PD does not have to be discontinued. • Problems with ﬁlling and draining • Check catheter placement on abdominal X-ray. • Treat constipation. • Consider increasing dwell volume. • Change position of the patient. • Add heparin to dialysate if ﬁbrin is present. • Consider using tissue plasminogen activator (TPA) in PD catheter. • Omentum may be wrapped around catheter.

Hemodialysis Hemodialysis (HD) is a widely available RRT in most pediatric centers. It can be successfully performed in infants 2 kg, and in even smaller neonates by very experienced personal. Infant and neonatal HD requires special equipment and modiﬁcations in the dialysis prescription due to the small blood volume of these patients. An adult dialysis prescription with adult lines and dialyzers are not appropriate for children < 40 kg.

Acute hemodialysis access Reliable vascular access is critical for doing HD or CV VH in children. Various sizes of HD catheters are available for children (Table 20.1). Dialysis is usually performed through a double lumen hemodialysis catheter. In neonates, HD can be performed through umbilical lines or through a radial arterial line and a single lumen central venous catheter.

Dialysis blood lines and dialyzers Dialysis blood lines and dialyzers come in a variety of sizes. The exact blood volume differs between manufacturers. Selecting an appropriate blood line and dialyzer is critical to dialyzing children (Table 20.2). • The surface are of the dialyzer should be approximately the same as the body surface area of the child. • The extracorporeal volume (ECV) of the blood line and dialyzer should not exceed 10% of the patients blood volume (8 mL/kg). • If the ECV exceeds 10% of the blood volume, prime the lines with 5% albumin or whole blood (hematocrit 30%–35%).

3–6 kg 6– 30 kg > 30 kg

Table 20.2 Examples of appropriate dialysis prescriptions for children Patient size Wt (kg), BSA (m2) 4.0, 0.3 10.0, 0.5 30.0, 1.0

Blood lines, volume (mL) Neonatal, 20 Small pediatric, 44 Large pediatric, 79

Dialyzer, volume (mL), surface ares (m2) a F3, 28, 0.4 F3, 28, 0.4 a F5, 63, 1.0

QB (mL) Priming volume (mL), blood volume (%) 48, 15 12–40 48, 6 30–100 142, 6 100–300

Note: aF3 and F5 are manufactured by Fresenius.

Blood ﬂow (QB) • First dialysis treatment should be 3–5 mL/kg. • Subsequent dialysis treatments can be as much as 10 mL/kg.

Time Dialysis is extremely efﬁcient in small children due to the small volume of distribution. • A 3-hour dialysis treatment is usually sufﬁcient for children < 50 kg.

Ultraﬁltration • Ultraﬁltration should not exceed 5%–7% of body weight in a 3-hour treatment.

Anticoagulation • • • •

30–50 units/kg loading dose 10 units/kg hourly Heparin-free dialysis can be done with high blood ﬂows and saline ﬂushes. Lock catheters with 1:1000 unit of heparin per liter.

Renal replacement therapy in children

Catheter size 3.5 Fr or 5 Fr umbilical artery catheter 5 Fr umbilical venous catheter 5 Fr single lumen venous catheters Radial arterial line 7 Fr double lumen dialysis catheter 7 Fr double lumen dialysis catheter 8, 9 Fr double lumen dialysis catheter 10, 11, 11.5 Fr double lumen dialysis catheter

CHAPTER 20

Patient size Neonate < 3 kg

163

Table 20.1 Vascular access in children

Renal replacement therapy in children CHAPTER 20

164

Continuous veno-venous hemoﬁltration (CV VH) The principles of CV VH are the same for children as adults. CV VH is technically more difﬁcult in small children than hemodialysis due to the larger priming volume of the system. The minimum priming volume for the Aquarius system by Baxter, the System One by NxStage, and the Prisma system by Gambro is 75 mL, 83 mL, and 93 mL respectively. CV VH should not be attempted in children < 10 kg unless the center has signiﬁcant experience with children of this size. Initiating CV VH in small children and infants can produce signiﬁcant hemodynamic instability. Below are general principles to follow when initiating CV VH.

Blood pressure The initiation of CV VH should be delayed if there is severe hypotension and hemodynamic instability. CV VH can usually be initiated successfully if the mean arterial pressure is >50 mm Hg.

Vascular access At least a 7 Fr double lumen hemodialysis catheter should be used for CV VH in children as the minimum blood for most CV VH machines is 30 mL/h. The 7 Fr catheters are prone to kinking and may need to be replaced often (Table 20.1).

Extracorporeal volume The priming volume (PV) for the CV VH system usually exceeds 10% of the blood volume in children < 10 kg. • Calculate the ECV of the CV VH circuit. • The child’s hematocrit should be 30% prior to initiating CV VH. • If the PV exceeds 8 mL/kg, prime the system with whole blood.

Blood ﬂow • 3–5 mL/kg/h

Dialysate-replacement ﬂuid ﬂow rate The choice of using CV VH or CV VHD is center speciﬁc and there is no clear advantage of one over the other in pediatrics. There are no speciﬁc CV VH solution for children. Accusol, Prismasate, Normocarb, Nxstage, or a pharmacy made solution have all been used successfully. The dialysis ﬂow in children has been adapted from what has been used in adults and adjusted to body surface area (BSA). The most widely accepted dialysate rate is 2L/1.73 m2/h. In the authors opinion, excellent clearance and metabolic control can be obtained with ﬂow rates much lower than this.

Anticoagulation Both heparin and citrate anticoagulation have been used successfully in children and the principles are the same as those for adults. Heparin anticoagulation typically requires a 30– 50 units/kg loading dose followed by a 10–20 units/kg/h

Renal replacement therapy in children CHAPTER 20

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maintenance dose to keep to the activated clotting time (ACT) 180–240 seconds or an activated partial thromboplastin time (APTT) of 60–80 seconds. Heparin anticoagulation should be avoided if the patient is immediately postoperative, if there is active bleeding, or if the patient is systemically anticoagulated. The protocol for regional citrate anticoagulation is mostly same as that for adults. The ACD-A citrate ﬂow rate is 1.5 times the blood ﬂow rate to keep the postﬁlter ionized calcium 0.2–0.4 mm. The calcium chloride (20 mg/mL) infusion rate is 0.1 times the ACD-A ﬂow rate to keep the systemic ionized calcium 1. 0–1.3. The adjustments made to the ACD-A and calcium chloride ﬂow rate to maintain the appropriate ionized calcium will be 50% less for children less then 20 kg.

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Chapter 21

Therapeutic plasma exchange in critical care medicine Joseph E. Kiss

Therapeutic plasma exchange (TPE) is the automated removal of a patient’s plasma and its replacement (exchange) with a suitable alternative ﬂuid such as a solution containing albumin or fresh frozen plasma. Its intended use is not only depletion of pathogenic, large molecular weight substances (>30–50,000 daltons) present in blood plasma, but also replacement of depleted normal/ beneﬁcial substances. Smaller molecular weight compounds are not efﬁciently removed by TPE, but may be effectively removed by alternative extracorporeal techniques such as hemoﬁltration (<20–30,000 daltons) or dialysis (<500–600 daltons).

The decision to utilize TPE The rational use of TPE is based on the following considerations: • What is the pathophysiological role of the target macromolecule in the clinical disorder? Is there an evidence of acute toxicity caused by the substance? Is the patient resistant to the usual medical and/or pharmacologic therapy or does the clinical urgency demand more immediate action? • Can the substance be efﬁciently removed by TPE? Generally, this applies to large molecules with relatively long half-lives (reduced synthetic rate). • Is there evidence that reduction in levels of the offending substance is associated with improved clinical outcomes? Clinical consultation with the appropriate provider of TPE services is recommended to address these issues and to provide management guidance, as outlined in Table 21.1. Note, the American Society for Apheresis (ASFA) has published comprehensive evidence-based indications on the use of TPE in speciﬁc disease categories (Szczepiorkowski ZM. Clinical applications of therapeutic apheresis: an evidence-based approach. 4th ed. J Clin Apher. 2007;22:96-105). The classiﬁcation system and examples of substances removed are shown in Table 21.2 and 21.3.

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Principles

Therapeutic plasma exchange CHAPTER 21

Table 21.1 Decision making in therapeutic plasma exchange Rationale Technical issues Management plan Endpoint

Considerations Disease pathogenesis, published efﬁcacy, and quality of evidence Vascular access, volume of plasma to process, replacement solution Timing (emergent, urgent), number, and frequency of treatments Clinical and/or laboratory response

Table 21.2 Consensus indications for plasma exchange ASFA category I

Interpretation Standard acceptable therapy

Remarks Proven in controlled trials

II

Available evidence supports efﬁcacy

III

Available evidence suggests efﬁcacy but is inconclusive Ineffective in controlled trials

Case series, second line, adjunctive therapy Anecdotal data, for example case reports

IV

168

Table 21.3 Clinical examples where plasma exchange is used Substances removed Autoantibodies Alloantibodies Immunoglobulins causing hyperviscosity Cryoglobulins Protein-bound toxins

Clinical examples Goodpasture’s syndrome (antiglomerular basement membrane autoantibodies) Solid organ transplant (e.g., anti-HLA) Waldenstrom’s macroglobulinemia

ASFA category I

Cryoglobulin-associated skin ulceration, renal dysfunction Amanita (mushroom) poisoning

I

Substances replenished Thrombotic thrombocytopenic ADAMTS13 purpura (TTP) (von-Willebrand factor cleaving protease) Coagulation factors Hepatic failure

II I

II I III

Management guidelines for TPE The extent of removal of a substance during TPE depends on the volume of the patient’s plasma removed in relation to total plasma volume, the distribution of the substance between the intravascular and extravascular compartments, and how rapidly the substance reequilibrates between compartments. The plasma volume (PV) is calculated as PV = total blood volume x [1–hematocrit (HCT)]. In adults, the total blood volume may be estimated as 70 mL/kg. Therefore, for a 70-kg man with HCT of 0.45 the PV = 4900 mL x 0.55, or 2695 mL.

1 PV = 65% removal 1.5 PV = 75% • 2 PV = 87% • 3 PV = 95% • IgM—80% intravascular (efﬁciently depleted due to limited reequilibration) • IgG—both intravascular (40%) and in tissues (removal less efﬁcient, redistribution into plasma postapheresis over 24–48 hour period) •

Note: The volume processed during TPE procedures is often “capped” at 1.5 PV because of the minimal additional effect of increasing the procedure time above this level, i.e., there is only 12% additional removal/ replacement going from 1.5 to 2.0 PV.

A one-compartment model best describes the kinetics of removal in TPE. The rate of removal is not linear but curvilinear, that is very steep during the more efﬁcient early stages of the exchange, then leveling off during the latter stages of the procedure as more of the replacement ﬂuid and less of the original patient’s plasma is exchanged. During a TPE procedure, removal of immunoglobulin M (IgM) and ﬁbrinogen, which are located predominantly in the intravascular compartment (~80%), is more complete than removal of immunoglobulin G (IgG) because only ~40% of this protein is intravascular. From a practical standpoint, IgM-mediated disorders require fewer TPE treatments to achieve a similar level of removal than IgG-mediated disorders. Lower-molecular-weight compounds that are highly diffusible (i.e., have a large volume of distribution) or are regulated actively in the plasma (such as calcium or potassium) are removed much less efﬁciently by TPE. After being depleted by TPE, the return of a substance toward baseline levels is governed by a balance of synthesis, catabolism, and reequilibration between compartments. Variability in these factors, as well as the binding characteristics of the substance, relates to the overall efﬁcacy of a course of treatment. Table 21.4 depicts the proportion of an idealized compound that is removed based on the kinetic model.

Apheresis devices Two general types of instrumentation may be used to perform TPE: centrifugalbased and membrane-based ﬁltration.

Centrifugal cell separators Centrifugal separation relies on the application of gravitational force to separate blood elements according to density. In order from lightest to heaviest, whole blood components may be separated into plasma (S.G. 1.025 to 1.029), platelets 1.040, lymphocytes (S.G. 1.070), granulocytes (S.G. 1.087 to 1.092), and red blood cells (S.G. 1.093 to 1.096). Centrifugal cell separators operate either

Therapeutic plasma exchange

•

CHAPTER 21

• Efﬁciency:

169

Table 21.4 Removal of a substance by TPE

Therapeutic plasma exchange CHAPTER 21

by discontinuous (alternates blood collection and reinfusion sequentially) or continuous ﬂow. Continuous ﬂow devices achieve greater efﬁciency by simultaneously collecting and reinfusing processed blood components. In a typical TPE channel conﬁguration, the whole blood is withdrawn from the patient by means of an inlet pump. To prevent clotting, it is immediately mixed with an anticoagulant solution at a preset ratio, typically 10 to 14 parts of whole blood to 1 part of ACD-A (a citrate dextrose solution). The blood then enters the separation chamber, where an interface is established to separate the blood into component layers. The heavier cellular elements settle to the outside of the channel, while the lighter plasma remains at the inner aspect. The plasma is siphoned off through the plasma-out tube, while the cellular components are removed through the RBC return tube. Typical ﬂow rates for therapeutic plasma exchange range from 60 to 95 mL/min, depending upon patient size, patient tolerance of side effects, and type of replacement solution being used.

170

Anticoagulation Most centrifugal cell separators employ citrate anticoagulants; protocols are also available for using heparin alone or heparin and citrate in combination. Use of citrate avoids potential bleeding risks of systemic anticoagulation; however, the hypocalcemia induced by citrate has certain potentially serious toxicities, including seizures and depression of cardiac function. For this reason, manufacturers of apheresis instrumentation have designed controls that regulate the maximum amount of citrate that can be infused. The maximum AC infusion rate is based on the average patient’s ability to metabolize citrate under normal physiological conditions. However, many patients, such as those with liver failure, have a reduced clearance of citrate. Therefore, individual factors need to be considered.

Priming of the extracorporeal circuit A saline prime is used in the external tubing and channel of the apheresis instrument in order to avoid hypotension due to a sudden volume deﬁcit. The extracorporeal volume (ECV) or “dead space volume” within the TPE circuit varies among different machines, ranging between 170 to 250 mL. Dilution of an adult’s RBC mass by this volume is negligible, however, it may be substantial for a child. Red blood cell prime methods have been developed to minimize the effects of hemodilution.

Membrane ﬁltration cell separators Membrane ﬁltration technology is an extension of the use of synthetic biocompatible membranes employed in hemodialysis, ultraﬁltration, and hemoﬁltration. The membrane is permeable to large molecular weight proteins but excludes cellular elements, including platelets. Pore sizes ranging from 0.2 to 0.6 microns allow passage of proteins with molecular weight ranges of more than 500,000 daltons. Membrane ﬁlters that are currently used have sieving coefﬁcients of

Adverse effects of TPE Serious complications such as infection, thrombosis, pneumothorax, and hematoma formation are often related to the need for central venous access. Overall 3%–8% of TPE procedures may be associated with adverse reactions (Table 21.5). Most of these are easily recognized and treated. Severe reactions such as cardiac or respiratory arrest, and mortality (1–2/10,000 procedures) are rare. The more serious consequences are seldom due to the TPE procedure itself.

Citrate toxicity One part of acid citrate dextrose (ACD) solution is added to fourteen parts of whole blood immediately after withdrawal from patient. This prevents clotting in the apheresis machine. The citrate ions bind ionized calcium, resulting in transient hypocalcemia. Plasma products add to this side effect because of high citrate concentration. • Symptoms • Perioral tingling • Vibration sensation • Numbness and tingling in extremities • Nausea and emesis • May progress to muscle spasms, tetany, and seizure activity

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171

0.9–1.0. This implies that the protein composition of the ﬁltrate and the plasma are nearly identical, even for very large molecules such as IgM. Cellulose diacetate, polyethylene, polypropylene, polyvinylchloride, and other synthetic materials are used to make membrane ﬁlters. After the addition of anticoagulant, the patient’s blood is pumped through either a parallel plate or hollow ﬁber ﬁlter at a continuous ﬂow rate between 50 and 200 mL/min. The efﬁciency of ﬁltration is determined by several parameters including the blood ﬂow rate, composition and physical characteristics of the membrane, transmembrane pressure, geometry of the blood ﬂow path, as well as the physical and chemical nature of the plasma proteins. A typical device features an anticoagulant syringe pump (usually employing heparin as the anticoagulant of choice), a blood pump, replacement ﬂuid pump, and efﬂuent pump. Blood is directed to the plasma ﬁlter by means of the blood pump. The hemoconcentrated blood leaves the plasma ﬁlter through the return line, where it is combined with replacement ﬂuid and returned to the patient. The efﬂuent side of the plasma ﬁlter leads to a waste bag. Studies comparing centrifugal and membrane ﬁltration have found them to be similar with respect to safety and efﬁciency. TPE is not as rapid with membrane separators. Although use of systemic heparin anticoagulation may avoid some side effects of citrate, systemic heparinization is disadvantageous in some patients, such as those with coagulopathy.

Therapeutic plasma exchange CHAPTER 21

Table 21.5 Adverse events and frequency Event b

Overall rate Speciﬁc reaction rates Transfusion reactions (primarily due to plasma replacement) Citrate related nausea and/or vomiting, paresthesias Hypotensionc Vasovagal nausea and/or vomiting Pallor and/or diaphoresis Tachycardia Respiratory distress Tetany or seizure

Frequencya (%) 3–8 1.6 1.2 1.0 0.5 0.5 0.4 0.3 0.2

Notes: a Approximate rate based on published literature; b Higher rate associated with TPE in which plasma is used; c Autonomic dysfunction with hypotension is seen especially in patients treated for neurological conditions, including Guillain-Barre syndrome and chronic idiopathic demyelinating polyneuropathy (CIDP).

• Management

Decrease inlet ﬂow (blood withdrawal) rate (or pause machine) Calcium gluconate infusion—in adults 10 mL 10% (1 gm) in 250 mL 0.9% saline solution may be added to albumin replacement ﬂuid (not plasma). • Calcium chloride infusion—in adults, this is 3x more potent and acts faster than calcium gluconate because the ions dissociate immediately. Monitor patient q 15–30 min with [Ca 2+] levels. Vasovagal reactions: Generally manifested by sudden hypotension and bradycardia, diaphoresis, lightheadedness, and occasionally nausea and emesis. TPE is temporarily halted and legs are elevated to increase venous return. Reaction is usually self-limited but may progress to loss of consciousness. Bolus NSS, 200–400 mL may be given. Hypotension: Acute volume loss is prevented by priming the apheresis circuit with replacement ﬂuid. Despite simultaneous replacement, patients such as those with autonomic neuropathy are sensitive and become hypotensive. These kind of patients generally respond to bolus saline, 200–400 mL. Allergic reactions: Mainly due to plasma proteins; rarely albumin or residual ethylene oxide sterilization of disposable plastic. Hemolysis: Very rare. Suspect use of hypotonic crystalloid solution or mechanical cause (kinked tubing) or patient red blood cell abnormality. Depletion of clotting factors: Prolonged prothrombin time and international normalized ratio (PT/INR), and/or activated partial thromboplastin time (APTT) that occurs with daily serial TPE using non-plasma replacement or cryodepleted plasma (see Table 21.6). TPE especially depletes ﬁbrinogen—longer

172

• •

•

•

• • •

Advantages

Disadvantages

Viral inactivation Ease of use Reactions rare All proteins replaced

High cost Most proteins not replaced

Low cost Viral Safety Ease of use Slow catabolism

No proteins replaced Hypotensive reactions Dosage limit

Single-donor plasmaa

6% Hetastarch

High cost Inconvenientb Citrate reactions Urticaria Viral infection risk

Therapeutic plasma exchange

Fluid 5% Albumin

CHAPTER 21

Table 21.6 Colloid replacement ﬂuids used in TPE

half-life (90 hours), slower recovery rate than other coagulation factors (3–4 days to return to normal). • Usually not manifest with every-other-day plasma exchanges • Treatment: Decrease frequency of procedures or use plasma or cryoprecipitate (donor exposure risk) • Transfusion-transmitted diseases (when plasma is used)—rare • Ace inhibitors • Symptoms: Flushing (vasodilation), hypotension, dyspnea, watery diarrhea. • Prekallikrein activator (an activator of bradykinin) is present in albumincontaining replacement solutions • Ace is identical to kininase ii—bradykinin degradation inhibited • Prevention: Withhold ace inhibitors at least 24 hours before procedure.

173

Note: TPE, therapeutic plasma exchange; a Fresh-frozen plasma or cryoprecipitate-poor plasma; b Must be thawed prior to use; must match patient ABO type.

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Chapter 22

MARS: molecular adsorbent recirculating system Nigel Fealy and Rinaldo Bellomo

Molecular adsorbent recirculating system (MARS) is an artiﬁcial liver support system aimed at the removal of toxins in patients suffering from acute liver failure (ALF) or acute on chronic liver failure (AoCLF). MARS is performed through an additional circuit attached to a standard extracorporeal circuit (continuous renal replacement circuit), which uses albumin as a dialysis medium. Using albumin as carrier molecule, toxins are adsorbed onto speciﬁc sorbents. Most potential liver toxins such as bilirubin, ammonia, fatty acids, hydrophobic bile acids, and nitric oxide use albumin as their transport protein and, as a result, appear to be more effectively removed by an albumin-enriched dialysate. This albumin dialysate is regenerated online by passage through a second hemodialyser and two sorbent columns (charcoal and anion exchanger).

Deﬁnitions Acute liver failure (ALF)—is a syndrome in which rapid loss of metabolic and synthetic liver function leads to the hepatic encephalopathy and multiorgan failure in patients with no previous history of liver disease. Acute on chronic liver failure (AoCLF)—is a syndrome that occurs in patients with long-standing liver failure and cirrhosis of the liver where there is an acute decompensation of their disease process. Albumin dialysis—is a form of artiﬁcial liver support where normal serum albumin is used as a component of the dialysate as a basis for more effective protein-bound toxin removal. Artiﬁcial liver support—is any device designed to speciﬁcally purify blood form liver-related toxins. The role of these devices is to remove toxins, which may be responsible for hepatic encephalopathy and multiorgan failure secondary to liver failure.

175

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Molecular adsorbent recirculating system CHAPTER 22

176

Bioartiﬁcial liver support—is any form of liver support that uses ﬁlters impregnated with human or porcine liver cells (hepatocytes) to perform the three main functions of the liver: detoxiﬁcation, biosynthesis, and regulation. Dialysis—is the separation of substances across a semipermeable membrane on the basis of particle size and/or concentration gradients. Extracorporeal circuit—is the path for blood ﬂow outside the body. It includes the plastic tubing carrying the blood to the dialyzer from the access catheter and from the dialyzer back to the body via the access catheter. Liver support devices—are any man-made devices that are used to purify blood in the setting of liver failure. This term encompasses both artiﬁcial and bioartiﬁcial liver support systems.

Method The MARS treatment kit consists of an albumin hemodialyser, a standard hemodialyser, an activated carbon adsorber, and an anion exchanger. The circuit is ﬁlled with 500 mL of 20% human albumin solution. Albumin acts as dialysate and is pumped through a hollow ﬁber membrane (MARS ﬂux dialyzer) countercurrent to blood [Figure 22.1 (A)]. Water-soluble substances diffuse into the albumin solution whilst albumin-bound toxins move by physicochemical interactions between plasma, albumin molecules bound to the dialysis side of the membrane, and the circulating albumin solution. Toxin-carrying albumin is then passed through another hemodialyzer countercurrent to a standard buffered dialysis solution where diffusive clearance of water-soluble substances occurs [Figure 22.1 (B)]. A concentration gradient is maintained by the circulation of the albumin solution and disposal of the albumin-bound toxins by passage through activated charcoal [Figure 22.1 (C)] and anion exchange columns [Figure 22.1 (D)] (see Figures 22.1 and 22.2).

Practical considerations The MARS treatment is achieved by the combined use of a stand-alone continuous renal replacement therapy (CRRT) machine or hemodialysis machine and the MARS albumin pump and monitor unit. The MARS albumin pump and monitor unit [Figure 22.3 (A)] is placed in series with a standard continuous veno-venous hemodialysis (CV VHD) circuit [Figure 22.3 (B)]. Depending on the external CRRT or dialysis machine used, the CRRT machine may act as a blood pump and dialysate controller or is more integrated for MARS use as with the Prisma and Prismaﬂex platforms. As with other renal replacement therapies, suitable vascular access is a key factor in achieving the prescribed treatment dose. The use of anticoagulation should be considered carefully. Often patients with ALF have some degree of autoanticoagulation and do not require anticoagulants to maintain MARS or CRRT circuits. Often the difﬁculty in treating patients with ALF is in determining

B

Figure 22.1 Extracorporeal and albumin dialysis circuit [molecular adsorbent recirculating system (MARS) monitor]. A = MARS ﬂux dialyzer; B = standard high ﬂux hemodialyzer; C = activated charcoal; D = anion exchange column

A MARS Monitor

Dialyser 1

Dialyser 2

Albumin intermediate circuit

V

QB = 150 –200 mL/min QA = 200 mL/min QD = 33 mL/min (2L/h)

CRRT machine

Ion exchange Activated charcoal resin cartiridge cartidge Dialysate

Figure 22.2 Schematic representation of a molecular adsorbent recirculating system (MARS) circuit. A = outﬂow lumen of dialysis catheter; V = inﬂow lumen of dialysis catheter; QB = blood ﬂow; QA = albumin ﬂow; QD = dialysate ﬂow

Molecular adsorbent recirculating system

A

CHAPTER 22

C

177

D

A

178

CHAPTER 22

Molecular adsorbent recirculating system

B

Figure 22.3 Molecular adsorbent recirculating system (MARS) with Prisma continuous renal replacement therapy (CRRT) machine. A = MARS unit; B = Prisma CRRT machine

when to institute the MARS therapy, duration of therapy (intermittent vs. continuous), and when to cease the therapy. Table 22.1 outlines one set of recommendations for the use of MARS in ALF. After three days of consecutive intermittent or continuous treatments there is an expectation that the patient with ALF or AoCLF will have signiﬁcant improvement both clinically and biochemically. At present there is insufﬁcient data to demonstrate a survival beneﬁt when MARS is instituted in patients with ALF or AoCLF. However, there is evidence to suggest that MARS’ impacts favorably on the complications of liver failure. MARS appears to improve several clinical parameters such as hemodynamic status, bilirubin levels, bile acid levels, encephalopathy, pruritus, and renal function. The effect of improving these parameters in patients with liver failure is to provide time for either liver regeneration or to bridge the patient safely to liver transplantation. A consideration when applying the therapy is modiﬁcation of antibiotics and drug therapy. Theoretically, removal of both water-soluble and albumin-bound drugs is achieved during the MARS therapy and, therefore, adjustment of drug therapy and therapeutic drug level monitoring should be undertaken. The exposure of blood to an extracorporeal circuit initiates the coagulation cascade and may deplete clotting factors and lower the platelet count. In

Source: Adapted from Phua J, Hoe Lee K. Liver support devices. Curr Opin Crit Care. 2008;14:208-215.

patients with an already impaired coagulation state, observation of bleeding and investigation of platelet count should be undertaken during treatments and prior to recommencement of MARS therapy.

Summary The MARS treatment is a technically feasible therapeutic option for liver support in the intensive care environment. However, the setup is labor intensive compared to CRRT. The treatment option at present is currently limited to intensive care units (ICU) in specialist referral centers where highly skilled nurses are available as required to institute and maintain the therapy. MARS represents the most frequently used liver support therapy at present. It appears to allow for the safe removal of albumin-bound as well as water-bound toxic substances in patients with AoCLF and ALF. At present many physicians believe that the therapy is a useful adjunct to bridge patients to transplantation and/or potentially support patients to spontaneous recovery. As reports of clinical and biochemical improvements in patients continue to emerge, there will be an ongoing interest in these types of therapies.

Molecular adsorbent recirculating system CHAPTER 22

Start criteria Rising total bilirubin > 300 µmol/L and one of the following: 1. Hepatic encephalopathy of grade II or greater 2. Hepatorenal syndrome Intermittent MARS treatment 6–8 h of treatment with intermittent hemodialysis Use when hemodynamically stable and no evidence of cerebral edema Anticoagulation—none, heparin, or citrate (risk of citrate accumulation) Blood ﬂow rate (QB) at 250 mL/min Albumin ﬂow rate (QA) at 250 mL/min Continuous MARS treatment 24 h of treatment with continuous veno-venous hemodialysis Use when hemodynamically unstable or evidence of cerebral edema Anticoagulation—none, heparin, or citrate (risk of citrate accumulation) Blood ﬂow rate (QB) at 180–200 mL/min Albumin ﬂow rate (QA) at 180–200 mL/min Stop criteria Plan for at least 3 days of MARS treatment Stop when 1. total bilirubin is less than 200 µmol/L; 2. resolution of hepatic encephalopathy.

179

Table 22.1 Guidelines for the use of MARS in liver failure

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Key references Boyle M, Kurtovic J, Bihari D, Riordan S, Steiner C. Equipment review: the molecular adsorbent recirculating system (MARS). Crit Care. 2004;8(4):280-286. Cruz D, Bellomo R, Kellum J, de Cal M, Ronco C. The future of extracorporeal support. Crit Care Med. 2008;36(4):S243-S252. Evenpoel P, Laleman W, Wilmer A, et al. Prometheus versus molecular adsorbent recirculating system: comparison of efﬁciency in two different liver detoxiﬁcation devices. Arch Ortop. 2006;30(4):276-284. Fealy N, Baldwin I, Boyle M. The molecular adsorbent recirculating system (MARS). Aust Crit Care. 2005;18(3):96-102. Mitzner S. Albumin dialysis: an update. Curr Opin Nephrol Hypertens. 2007;16:589–595. Phua J, Hoe Lee K. Liver support devices. Curr Opin Crit Care. 2008;14:208-215. Stadlbauer V, Jalan R. Acute liver failure: liver support therapies. Curr Opin Crit Care. 2007;13:215-221.

Chapter 23

Sorbents

Over the years, the possibility of removing solutes from blood to obtain blood puriﬁcation has mainly focused on classic hemodialysis. However, the characteristics of some solutes that make their removal difﬁcult and the limited efﬁciency of some dialysis membranes have spurred a signiﬁcant interest in the use of further mechanisms of solute removal such as adsorption. Materials with high capacity of adsorption (sorbents) have been utilized for about 50 years in extracorporeal blood treatments of acute poisoning or uremia. With the recognition of the role of cytokines in systemic inﬂammatory response syndrome (SIRS) and sepsis, and the fact that most cytokines are poorly removable by conventional diffusive or convective blood puriﬁcation modalities, treatment of sepsis based on sorbent technique has recently been explored.

Removal of target substances by sorbent in sepsis Endotoxin: Endotoxin is a lipopolysaccharide (LPS) and an outer membrane molecule essential for virtually all gram-negative bacteria. It is generally considered a major causative agent in shock states related to gram-negative bacteria infection. LPS will bind to LPS-binding protein (LBP) and be transferred to bind to surface molecule cluster of differentiation (CD) 14 when it enters into blood, presented in aggregate form or monomeric form. The signal of LPS combination with CD14 will be relayed by Toll-like receptor (TLR) to activate the nuclear factor NB(NF-NB) and produce multiple cytokines. Superantigen: Superantigen (SAg), which is a secreted production of gram-positive bacteria, plays an important role in activating and regulating the innate immune system, SAg is also known to be associated with toxic-shock like state in grampositive bacterial infection. Unlike conventional antigen, SAg bypasses normal antigen processing steps, binds directly as an intact protein to major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells and T cell receptor, and activates many more T cells than conventional

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Dehua Gong and Claudio Ronco

Sorbents CHAPTER 23

antigen. SAg is the most powerful T cell mitogen ever discovered. Activated T cells then producte and release massive proinﬂammatory cytokines. Cytokines: Activation of immune system is almost present in all critically ill patients, particularly in patients with infection. In the early stage of immune activation, there is a production and release of many proinﬂammatory mediators, especially tumor necrosis factor-D (TNF-D), interleukin -6 (IL-6), IL-1, and IL-8. These cytokines augment the body response to the pathogen and result in systemic adaptation. At the same time antiinﬂammatory mechanism is also initiated, including production of IL-10, transforming growth factor-E and IL-13. If the over-responsiveness of immune system is still uncontrolled and persists for a period, the tissue damage and organ failure will occur, and the antiinﬂammatory effect will overweigh the proinﬂammatory effect, leading to immunoparalysis.

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Selectivity of sorbent used for the removal of target substance According to the selectivity of target substance removal, sorbents can be divided into the following three groups: • Unselective porous particles: These kind of sorbents consist of paramount porous polymers, such as resin or activated charcoal (AC). Sorbents exist in granules, spheres, cylindrical pellets, ﬂakes, and powder. They are solid particles with single particle diameter between 0.05 cm and 1.2 cm. Surface area to volume ratio is extremely high in sorbent particles, which varies from 300 to 1200 m2/g. They can also be deﬁned as the following:(1) macroporous = pore size > 500 Å (50 nm); (2) mesoporous = pore size 20–500 Å; and (3) microporous = pore size < 20 Å. Usually they adsorb molecules onto their surface unspeciﬁcally by Van der Waals forces, electrostatic attraction, or hydrophobic afﬁnity. Because molecules adsorbed onto the porous surface of sorbent must ﬁrst pass through the pores, manipulating the pore size can to some extent control the molecules for removal. • Relative selective adsorption: The recent advancement of technique makes it possible to develop many new sorbents by immobilizing a ligand speciﬁc to a certain group of substances onto matrix ﬁbers or particles. This kind of sorbents include Lixelle, CTR adsorber (Kaneka Corporation, Osaka, Japan), and CYT-860 (Toray Industries Inc., Tokyo, Japan). They employ hydrogen bond or hydrophobic interaction between ligand moiety and protein chemical groups to enhance protein adsorption capacity, and employ designed pore size distribution to specify the molecular weight of protein that can be adsorbed. Superantigenadsorbing device, which is prepared from a polystyrene-based composite ﬁber reinforced with polypropylene, is recently undergoing investigation. • Selective adsorption: Sorbents made by immobilization of more speciﬁc ligands onto matrix can target the adsorption on one certain substance or limit the adsorption within a very narrow range. Adsorber composed of polymyxin

Sorbents CHAPTER 23

B-immobilized ﬁbers (PMX) has been used for adsorption of endotoxins in sepsis. Adsorbers based on macroporous beads immobilized with human serum albumin such as MATISSE also aim at endotoxins adsorption. The microspheres-based detoxiﬁcation system provides a platform in which anti-TNF D antibody is immobilized onto microparticles with diameter range of 1–10 um. This system is designed to adsorb serum TNF D in early stage of sepsis.

When a liquid mixture is brought into contact with a microporous solid, adsorption of certain components in the mixture takes place on the internal surface of the solid. The maximum extent of adsorption occurs when equilibrium is reached. No theory for predicting adsorption curves is universally embraced. Instead, laboratory experiments must be performed at ﬁxed temperature (separation processes are energy intensive and affecting entropy) for each liquid mixture and adsorbent to provide data for plotting curves called adsorption isotherms (Figure 23.1). Adsorption isotherms can be used to determine the amount of adsorbent required to remove a given amount of solute from the solvent. Another measure of the efﬁciency of the unit is obtained by using marker molecules to determine the so-called mass transfer zone. The mass transfer zone is the portion of the cartridge length that goes from a fully saturated sorbent to a completely unsaturated condition. Mass transfer zone determination also helps to deﬁne the design of the unit and the expected time of efﬁciency before saturation. However, both adsorption isotherms and mass transfer zone are not a clinical practical parameter to evaluate a sorbent’s adsorptive capacity. Extraction ratio

Amount adsorbed

Adsorption isotherm

Equilibrium concentration Figure 23.1 Typical example of an adsorption isotherm.

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Efﬁciency of adsorption

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is often used to reﬂect the removal ability of a sorbent, which is deﬁned as the reduction ratio of solute concentration in blood or plasma after a single pass through the sorbent. The factors other than the sorbent per se also have impacts on extraction ratio, including blood or plasma ﬂow rate, target solute burden in blood, and so on. In one treatment session, dynamic monitor of extraction ratio may reﬂect the saturation status of the sorbent. Another clinical useful parameter for demonstration of the removal effect of sorbent is reduction ratio of solute by a single session of treatment. However, the fact that both of these parameters cannot accurately reﬂect the removal ability of a sorbent makes the comparison between different sorbent difﬁcult.

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Biocompatibility of sorbents The concept of sorbent biocompatibility may have three meanings: ﬁrst, the sorbent must be resistant and must not release any harmful substances into the body. Second, the contact of sorbent with plasma or blood will not induce activation of complement, immune system, and hemostasis system, nor result in hematological abnormality such as hemolysis, leucopenia, and thrombocytopenia. Third, the adsorption will not result in unwanted loss, such as albumin loss. However, so far no one sorbent fully reaches all these requirements. Commercial sorbent column usually contains a sieving device that allows free passage of blood but retains particles or their fragments, in order to prevent dissemination of small particles in the body. Some systems also have a built-in monitor device to detect the possible detached microparticles in blood. Blood-surface reaction depends on sorbent surface ﬂatness and materials. Sometimes, surface-coating technique is used to improve sorbent biocompatibility, while in expense of adsorption efﬁciency. Another way to improve biocompatibility is plasma adsorption, in which only plasma pass through sorbent, blood cells are separated from plasma and bypass the sorbent, and ﬁnally blood is reconstituted after an extracorporeal single pass treatment. However, addition of plasma separator will make the procedure more complex. Researches on materials with high molecular weight and polymers provide the hope for emergence of new type of sorbent with good biocompatibility, especially, the new sorbent with high selectivity of adsorption and least unwanted loss.

Typical modalities of utilization of sorbents Typical modalities for the utilization of sorbents in extracorporeal therapies are represented in Figure 23.2. • Hemoperfusion (HP): HP is a technique in which the sorbent is placed in direct contact with blood in an extracorporeal circulation. It has a very simple circuit, but requires an extremely biocompatible sorbent and adequate anticoagulation of extracorporeal circuit (EC). For materials such as charcoal that

Blood in

CHAPTER 23

Blood out

Sorbents

Sorbent

A

B Sorbent

Hemodiafilter

Blood in

Blood out

Dialysate out

Dialysate in

C Hemofilter

Hemodiafilter Blood out

185

Blood in

Sorbent Dialysate out

D

Plasmafilter

Dialysate in

Hemodiafilter

Blood in

Blood out

Sorbent Dialysate out

Dialysate in

Figure 23.2 Possible modes of application of sorbents: (A) hemoperfusion (HP). (B) The sorbent unit is placed in series before the hemodialyzer (hemoperfusion-hemodialysis = HPHD). (C) The sorbent unit is placed online in the ultraﬁltrate produced from a hemoﬁlter. The hemoﬁlter is placed in series with the hemodialyzer. The system is used for online hemodiaﬁltration in chronic patients and it is deﬁned as paired ﬁltration dialysis with sorbent (HFR). (D) The sorbent unit is placed online in the plasmaﬁltrate produced from a plasmaﬁlter. The plasmaﬁlter is placed in series with the hemodiaﬁlter. The system is used for critically ill patients with septic shock and it is deﬁned as coupled plasmaﬁltration adsorption (CPFA).

has poor biocompatibility, it has to be coated before its use in HP. More recently, synthetic polymers have been introduced with remarkable capacity for adsorption and better biocompatibility.

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186

• Hemoperfusion coupled with hemodialysis (HPHD): Sorbents have also been

used in conjunction with hemodialysis (hemoperfusion-hemodialysis = HPHD). In such a case the sorbent is placed in the circuit just before the dialyzer, expecting that the following dialysis will keep desired temperature or correct other abnormalities induced by the sorbent (e.g., acidosis). This modality is mostly utilized for the removal of molecules, such as beta-2 microglobulin, that are poorly removed by dialysis. Another approach consists of the use of sorbents in “uncoated” form. These, however, cannot be placed in direct contact with whole blood and they are used for the treatment online of the ultraﬁltrate or the plasmaﬁltrate. • Double chamber hemodiaﬁltration (HFR): In these systems, plasma water is separated from whole blood and, after passing through the sorbent, it is reinfused into the blood circuit reconstituting whole blood structure. This technique has mostly been used in chronic dialysis as a particular form of hemodiaﬁltration. • Coupled plasma ﬁltration adsorption (CPFA): Continuous plasmaﬁltration adsorption is a modality of blood puriﬁcation in which plasma is separated from the whole blood and circulated in a sorbent cartridge. After circulating the plasma in the sorbent unit, it is returned to the blood circuit and the whole blood undergoes hemoﬁltration or hemodialysis. The rationale consists in the attempt to combine the advantages of adsorption and hemoﬁltration or hemodialysis techniques in solutes elimination. This technique has mostly been used in septic patients showing speciﬁc advantages of blood puriﬁcation, restoration of hemodynamics, and immunomodulation. In another technique using uncoated sorbents [detoxiﬁcation plasmaﬁltration (DTPF) HemoCleanse, Inc., West Lafayette, IN], a hemodiabsorption mechanism is associated with a push-pull plasmaﬁltration system (a suspension of powdered sorbents surrounding 0.5 micros plasma ﬁlter membranes). Bidirectional plasma ﬂow (at 80–100 mL/min) across the plasmaﬁltration membrane not only provides direct contact between plasma proteins and powdered sorbents, but also helps in the clearance of cytokines. A major criticism may be raised concerning the removal of beneﬁcial substances or drugs by the mechanism of adsorption. In an in vitro experiment, a hydrophobic resin sorbent was investigated for the adsorptive properties of different most-commonly used antibiotics. Except for Vancomycin, where a modest removal can be observed, the blood levels of other antibiotics such as Tobramycin or Amikacin tend to remain stable over time.

Sorbents in sepsis Conventional blood puriﬁcation has been evidenced as less effective in the removal of pathogenic factors and mediators involved in the process of sepsis.

Suggested readings Bellomo R, Tetta C, Ronco C. Coupled plasma ﬁltration adsorption. Intensive Care Med. 2003;29(8):1222-1228. Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885-891. Cruz DN, Perazella MA, Bellomo R, et al. Effectiveness of polymyxin B-immobilized ﬁber column in sepsis: a systematic review. Crit Care. 2007;11(2):R47 Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis. 2008;8:32-43. Ronco C, Tetta C. Extracorporeal blood puriﬁcation: more than diffusion and convection. Does this help? Curr Opin Crit Care. 2007;13:662-667. Ronco C, Brendolan A, Dan M, et al. Adsorption in sepsis. Kidney Int Suppl. 2000;76: S148-S155.

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This fact has aroused many innovative approaches such as high-volume hemoﬁltration, the use of superpermeable membranes, as well as sorbent-based membranes. HP using polymyxin B-immobilization adsorber (PMX) is on purpose of eliminating serum endotoxins, with a reported reduction ratio of endotoxins after single treatment as 27%–33%. The impact on cytokines and other mediators still remains controversial. A recent systematic review shows that HP with PMX appears to have favorable effects on MAP, dopamine use, PaO2/FiO2 ratio, and mortality. Experience from Japanese practice suggests the blood ﬂow rate at 80–100 mL/min for a duration of 2 hours. Possible indication is the patients fulﬁlling all the following three conditions: • Endotoxemia or suspected gram-negative infection • SIRS • Septic shock, which necessitates vasopressor therapy Other endotoxins adsorbers such as albumin-based sorbents have showed a trend of improvement of clinical outcome and are waiting for further clinical trials. Coupled plasma ﬁltration adsorption (CPFA) is aimed at nonselective removal of soluble mediators involved in the septic shock. Limited amount of clinical studies showed a beneﬁcial effect on the function of hemodynamics and monocytes. Novel sorbents are recently developing for enhanced and more selective removal of cytokines including Lixelle, CTR adsorber, and CYT-860. Animal experiments have shown the ability of cytokines removal and improvement of animal survival in sepsis models. Adsorbers targeting on speciﬁc removal of superantigens and TNFD are also limited in animal experiments. These novel sorbents may soon be clinically available.

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Ronco C, Brendolan A, d’Intini V, et al. Coupled plasma ﬁltration adsorption: rationale, technical development and early clinical experience. Blood Purif. 2003;21(6):409-416. Sakata H, Yonekawa M, Kawamura A. Blood puriﬁcation therapy for sepsis. Transfus Apher Sci. 2006 Dec;35(3):245-251. Shimizu T, Endo Y, Tsuchihashi H, et al. Endotoxin apheresis for sepsis. Transfus Apher Sci. 2006 Dec;35(3):271-282. Sriskandan S, Altmann DM. The immunology of sepsis. J Pathol. 2008;214:211-223. Tsuchida K, Yoshimura R, Nakatani T, et al. Blood puriﬁcation for critical illness: cytokines adsorption therapy. Ther Apher Dial. 2006 Feb;10(1):25-31.

Chapter 24

Hybrid therapies Dinna N. Cruz and Claudio Ronco

Hybrid therapy is any renal replacement therapy (RRT) modality for critically ill patients that combines the therapeutic advantages of continuous renal replacement therapy (CRRT) with the logistic and cost advantages of intermittent hemodialysis (IHD). Similar to the term “CRRT,” hybrid therapy is an umbrella term encompassing various speciﬁc “discontinuous” RRT modalities. Other terms which have been used in the literature are “sustained low efﬁciency (daily) dialysis” (SLEDD), “sustained low efﬁciency (daily) diaﬁltration” (SLEDD-f), “extended daily dialysis” (EDD), “prolonged intermittent renal replacement therapy” (PIRRT), “go slow dialysis,” and “accelerated veno-venous hemoﬁltration” (AVVH). General features of hybrid therapies include (1) use of standard equipment from ESRD programs, including machinery, dialyzers, extracorporeal blood circuitry, and online ﬂuid production for dialysate and ﬁltrate replacement; (2) intentionally “discontinuous” therapy (i.e., intended duration is less than 24 hours); (3) longer treatment duration than conventional IHD. Solute and ﬂuid removal are slower than conventional IHD, but faster than conventional CRRT, thereby allowing “scheduled down time” without compromise in total daily dialysis dose. Solute removal is largely diffusive, but variants with a convective component, such as SLEDD-f and AVVH, are possible.

Brief Orders Session length: 6–18 h Blood ﬂow: 70–350 mL/min Dialyzer: Synthetic biocompatible membrane, either low or high ﬂux

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Introduction

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Dialysis solution composition: Session length < 8 h: Sodium: 135–145 mEq/L, potassium: 2–3 mEq/L, bicarbonate: 28–32 mEq/L, calcium: 1.5–2.5 mEq/L Session length t 8 h: Sodium: 135–145 mEq/L, potassium: 4 mEq/L, bicarbonate: 24–28 mEq/L, calcium: 1.5–2.5 mEq/L Phosphate: see text Dialysis solution ﬂow rate: 70–300 mL/min Substitution ﬂuid ﬂow rate (for SLEDDf): 100 mL/min (with QD 200 mL/min)

190

Fluid removal: Determined by clinical need Anticoagulation orders: Unfractionated heparin 1000–2000 units as bolus, then continuous infusion 500–1000 units/hour to keep activated partial thromboplastin time (aPTT) 1.5 times control Regional citrate anticoagulation (many protocols exist) Timing of treatment: Diurnal or nocturnal

The following references refer to citrate protocols with hybrid therapies: Clark JA, Schulman G, Golper TA. Safety and efﬁcacy of regional citrate anticoagulation during 8-hour sustained low-efﬁciency dialysis. Clin J Am Soc Nephrol. 2008;3:736. Finkel KW, Foringer JR. Safety of regional citrate anticoagulation for continuous sustained low efﬁciency dialysis (C-SLED) in critically ill patients. Ren Fail. 2005;27:541. Morath C, Miftari N, Dikow R, et al. Sodium citrate anticoagulation during sustained low efﬁciency dialysis (SLED) in patients with acute renal failure and severely impaired liver function. Nephrol Dial Transplant. 2008;23:421. Schneider M, Liefeldt L, Slowinski T, Peters H, Neumayer HH, Morgera S. Citrate anticoagulation protocol for slow extended hemodialysis with the Genius dialysis system in acute renal failure. Int J Artif Organs. 2008;31:43.

Details of prescription Session length A number of factors help determine the prescribed duration of the RRT session. One of these is tolerance to ultraﬁltration. Patients who are less

Hybrid therapies CHAPTER 24

hemodynamically stable will fare better with slower ultraﬁltration rates and longer treatments. Machine-related issues may also play a role, in conjunction with dialysate ﬂow rates. For instance, for most single-pass HD machines, a single canister of dialysate concentrate would last approximately 5–6 hours with a dialysate ﬂow of 300 mL/min, or 16–17 hours at a dialysate ﬂow of 100 mL/ min. When the Fresenius 2008H is not equipped with CRRT software, the session length cannot be set beyond 8 hours and will give frequent alarms once treatment duration exceeds the set time. In the case of a batch system such as the Fresenius Genius machine, a 75 L tank of dialysate will last approximately 18 hours, with a dialysate ﬂow of 70 mL/min, and a 90 L tank about 8–12 hours at dialysate ﬂows of 150–200 mL/min. Blood flows used in the literature generally range from 70–350 mL/min. Interestingly, in a recent publication describing AVVH, the blood ﬂow rate was set at 400 mL/min as vascular access permitted in an ICU population in which 79% of patients were on vasopressors. Only 5% of treatments were terminated early due to patient instability. Although it is a common practice to prescribe a lower blood ﬂow in intensive care unit (ICU) patients to improve cardiovascular stability, presumably by decreasing clearance and associated solute and ﬂuid shifts, this may be less relevant during hybrid therapy. When dialysate ﬂow is signiﬁcantly lower than blood ﬂow, as is often the case during hybrid therapy, dialysate is saturated with solute. Therefore, lowering the blood ﬂow would not materially reduce solute and ﬂuid shifts. On the other hand, the downside of a low blood ﬂow is a propensity for clotting in the extracorporeal circuit. Therefore, some experts recommend that maximizing blood ﬂow as tolerated by the catheter to improve circuit patency.

Dialysis solution composition As with all RRT in the ICU, the dialysate solution composition should be customized to patient needs. With prolonged treatments, a lower bicarbonate level may be preferable to avoid inducing alkalosis. In acidotic patients, a more “standard” bicarbonate bath of 35 mEq/L may be used initially, and subsequently adjusted after the initial acidosis has been corrected. Hypophosphatemia may occur during hybrid therapy, particularly when performed daily, and phosphate levels should be monitored. To avoid this problem, one may add phosphate to the dialysate by adding 45 mL of ﬂeet phospho-soda to 9.5 L of bicarbonate bath (ﬁnal concentration 0.8 mmol/L) after the ﬁrst few days of therapy. Alternatively, instead of manipulating the dialysate concentration, one may give phosphate supplementation, approximately 0.1–0.2 mmol/kg/day. For online production of dialysate, special attention to water treatment is recommended. This is discussed later in this chapter.

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Blood ﬂow

Hybrid therapies CHAPTER 24

Dialysis solution ﬂow rate (variable) Dialysate ﬂow rates as reported in the literature range from 70 to 300 mL/min. In general, the shorter the duration of RRT, for instance 6–10 hours, the higher the dialysate ﬂow rate, for example, 300 mL/min, and vice versa. It is also, in part, determined by individual machine capabilities. Most machines frequently used for hybrid therapies do not require any adjustment for dialysate ﬂow t 300 mL/ min. Minor changes in setting while in service mode are done with the Fresenius 2008H, while some improvisation is necessary for the 4008H and the Gambro 200S Ultra (Table 24.1). In the case of the Fresenius Genius system, a single roller pump with two pump segments circulate blood and dialysate in either a 1:1 or 1:2 ratio.

Fluid removal Net ultraﬁltration rate is determined by patient need and hemodynamic stability. When the Fresenius 2008H is not provided with speciﬁc CRRT software, there is

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Table 24.1 Hybrid therapy using various hemodialysis machines Machine

QD (mL/min)

Comments

Fresenius 2008H

> 300

No adjustment needed

100

Activate “slow dialysis” option while in service mode To avoid persistent low dialysate temperature alarms, recalibrate temperature control to 37° while in service mode

Fresenius 4008E/H

>300 <300

Fresenius 4008K

>300 100 >300 200 >300 <300 >300 100

Fresenius 4008S ARrT Plus Fresenius Genius Gambro 200S Ultra

To quickly optimize conductivity, set QD at 500 mL/min initially, run for 5 minutes until conductivity stabilizes, then set at 100 mL/min No adjustment needed Possible with use of an external ﬂow meter and additional tubing to create a bypass No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed Run in hemoﬁltration mode. Set QR at 100 mL/min Instead of infusing, run replacement ﬂuid as dialysate in countercurrent fashion

Substitution ﬂuid ﬂow rate (for SLEDD-f) The ability to achieve and maintain greater convective clearance of middle molecular weight solutes has potentially important therapeutic implications in critically ill patients with acute kidney injury (AKI) and inﬂammatory or septic states. In this context, the principally diffusive solute clearance during SLEDD may be perceived as a disadvantage of this modality with respect to CRRT. A convective component can be added to the therapy with the use of adjunctive hemoﬁltration (SLEDD-f). Online production of ultrapure ﬂuid for reinfusion is similar to the process during hemodiaﬁltration in chronic dialysis. In hybrid therapies, SLEDD-f has been performed primarily with the Fresenius 4008S ARrT-Plus. Online-produced substitution ﬂuid is not yet approved by the Federal Drug Administration in the United States, but the technique is widely used elsewhere. A speciﬁc variant of hybrid therapies utilizing convection that has been reported in the United States is AVVH. This technique uses prepared replacement ﬂuid packaged in bags, with an infusion rate of 4000mL/h (67 mL/min) for 9 hours.

Hybrid therapies

Unfractionated heparin is the most commonly used anticoagulant, in regimens similar to those used for conventional intermittent HD. Heparin-free treatments are possible with the use of periodic saline ﬂushes, but such treatments are nevertheless complicated by clotting of the extracorporeal circuit in a substantial proportion of cases. Clinical evidence suggests that the incidence of clotting may be slightly less with the Fresenius Genius machine, possibly related to the absence of the air-trap chamber. In hybrid therapies using convection, such as SLEDD-f and AVVH, infusion of replacement ﬂuid in predilution mode helps abrogate ﬁlter clotting but also decreases effective clearance. There have been several descriptions of successful use of regional citrate anticoagulation for hybrid therapies for both single pass and batch machines. Two regimens involve the use of custom calcium-free dialysate in conjunction with 4% sodium citrate solution in the arterial line. Calcium chloride is infused into the venous line. The reader is referred to the original articles for details. An alternative for or patients with heparin-induced thrombocytopenia is the direct thrombin inhibitor argatroban. In the absence of liver failure, a bolus of 250 mcg is given, followed by an infusion of 2 mcg/kg during the treatment. Dialysate containing citric acid as buffer (citrisate) is now commercially available in the United States. There has been one report of reduced extracorporeal circuit clotting with its use for IHD in the critical care setting; however, further study is warranted before its use can be recommended, particularly with hybrid therapies.

CHAPTER 24

Anticoagulation orders

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a mandatory lower limit of 70 mL/h, below which frequent low transmembrane pressure (TMP) alarms may occur.

Hybrid therapies CHAPTER 24

Timing of treatment Hybrid therapies may be performed during the day or at night. The rationale for nocturnal programs include unrestricted patient access for diagnostic and therapeutic procedures during the day as well as greater availability of HD machines at night. Potential disadvantages would be safety issues and the need for trouble shooting at a time when there is lower stafﬁng ratio. Daytime treatments are recommended in the early phases when establishing a new hybrid therapy program, until such time as medical and nursing personnel are familiar and comfortable with the procedures.

Miscellaneous

194

Water considerations When high-ﬂux membranes are used for dialysis, signiﬁcant backﬁltration may occur such that, even in the absence of direct infusion, solute and water movement from the dialysate into the patient occurs in signiﬁcant amounts. Endotoxin in the dialysate is of speciﬁc concern, and backﬁltration of such may potentially further aggravate proinﬂammatory processes already ongoing in critically ill patients. Although deﬁnitive evidence is lacking, the use of ultrapure water for dialysate is prudent for all online ﬂuid-generating therapies. On the other hand, use of ultrapure water is obligatory for online production of replacement ﬂuid in hybrid therapies utilizing convection, that is SLEDD-f. It is therefore mandatory for hybrid therapy programs to have an appropriate water quality assurance program in place. Standard water treatment entails bedside tap water being passed through the following three membrane ﬁlters: (1) a 10µ ﬁlter to remove granulates and large particles; (2) activated charcoal to adsorb carbon, chloramines, and organic contaminants; and (3) a 1µ ﬁlter to remove small particles. The latter is particularly prone to bacterial contamination due to removal of chloramines. Water is then treated by reverse osmosis. The ﬁnal step is further puriﬁcation by a two (Fresenius) or three-step (Gambro) ultraﬁltration process to produce ultrapure water ready for mixing with electrolyte and bicarbonate concentrate. Water produced during this process as well as water obtained from the tap pretreatment must undergo a regular schedule of chemical, microbiological, chlorine/chloramines, and endotoxin assessment. Such veriﬁcation of water quality is a paramount safety feature of hybrid therapies.

Nutrition Although albumin loss in the dialysate is minimal in patients treated with SLEDD, intradialytic amino acid losses are approximately 1 g/h, and cumulative losses may be substantial with prolonged therapy. Expert opinion recommends that enteral or parenteral diet prescription must be augmented with protein 0.2 g/kg/ day for the duration of therapy to offset these losses.

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Fliser D, Kielstein JT. A single-pass batch dialysis system: an ideal dialysis method for the patient in intensive care with acute renal failure. Curr Opin Crit Care. 2004;10:483-492. Gashti CN, Salcedo S, Robinson V, Rodby RA. Accelerated venovenous hemoﬁltration: early technical and clinical experience. Am J Kidney Dis. 2008;51:804-810. Hall JA, Shaver MJ, Marshall MR, K. CD, Golper TA. Daily 12-hour sustained low-efﬁciency hemodialysis (SLED). A nursing perspective. Blood Purif. 1999;17:36-42. Kielstein JT, Kretschmer U, Ernst T, et al. Efﬁcacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study. Am J Kidney Dis. 2004;43:342-349. 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. Kumar VA, Yeun JY, Depner TA, Don BR. Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal failure: a two-year single center report. Int J Artif Organs. 2004;27:371-379. Marshall M, 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;19:875-877. 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; 60:777-782. Marshall MR, Golper TA, Shaver MJ, Alam MG, Chatoth DK. Urea kinetics during sustained low-efﬁciency dialysis in critically ill patients requiring renal replacement therapy. Am J Kidney Dis. 2002;39:556-562. Naka T, Baldwin I, Bellomo R, Fealy N, Wan L. Prolonged daily intermittent renal replacement therapy in ICU patients by ICU nurses and ICU physicians. Int J Artif Organs. 2004;27:380-388. Tu A, Ahmad S. Heparin-free hemodialysis with citrate-containing dialysate in intensive care patients. Dial Transplant. 2000;29:620-627.

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Part 4

Organizational issues

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Chapter 25

The ICU environment Younghoon Kwon

The purpose of this chapter is to help one understand the unique environment of the intensive care unit (ICU) and therefore facilitate multidisciplinary team approach in the care of critically ill patients.

Monitoring With modern technology and a high nurse-to-patient ratio, ICU provides an optimal setting for close monitoring of the physiological changes in the patient and, therefore, empowers to identify condition that requires urgent intervention. Notes: Data derived from the monitoring system in the ICU may not be always useful unless it is interpreted in the context of individual clinical problem and coupled with therapeutic approaches.

Support One of the main functions of the ICU is to temporally support failing organs until they partially or fully recover. Some of the examples of organ support modalities are pharmacological agents (vasopressor, inotropes), intraaortic balloon pump, ventricular assisted devices for cardiovascular support, mechanical ventilator for respiratory support, and dialysis for renal support. Notes: It is important to recognize the limitations and potential harm these supporting tools can cause.

Prevention Patients in the ICU are susceptible to develop various complications not only from ongoing underlying disease process itself but also from iatrogenic complications from therapy directed to treat the disease. Notes: Concept of “do not harm” should be emphasized in the ICU. Recently, many efforts have been made to reduce avoidable complications and errors in the ICU by implementing structured approach such as using a standardized checklist.

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Purpose of the ICU care

The ICU environment CHAPTER 25

Organized structure of the ICU ICU Stafﬁng The ICU multidisciplinary team consists of the following members: Intensivist: A specialist who is trained in the care of critically ill patients and certiﬁed by one of several medical specialty boards, including internal medicine, anesthesiology, or surgery. One major role of intensivist is to assume leadership in multidisciplinary team and to coordinate the care provided by different consultants. ICUs where patients are managed or comanaged by intensivist have reduced mortality.

200

Primary or consulting physician: Primary physician, who is knowledgeable with the history of the patient, contributes greatly to continuity of care that is often forgotten in the ICU. Consulting physicians provide speciﬁc advice in patient care from their unique perspectives. Critical care nurse: A nurse with additional training in critical care. As a bedside clinician, they are capable of assessing patient’s condition on a minute-to-minute basis and thus are on the frontline of patient care. Due to this nature, it is usually through them that the patient’s progress is updated to other professionals. Nationwide there is an increasing shortage of skilled and experienced critical care nurses. Respiratory therapist: Respiratory therapist plays an integral part in airway management and ventilator management. They are experts in assessing the needs of respiratory treatment such as use of oxygen and bronchodilator and in implementing them. They are also proven to be effective at weaning patients from mechanical ventilation. Clinical pharmacist: Clinical pharmacists on rounds provide invaluable information about dosing drugs and adverse drug interaction. It has been shown that clinical pharmacists’ involvement in a multidisciplinary team positively impacts patient care and results in cost savings to an institution. Other members of the team: Mid-level practitioner (nurse practitioner or physician assistant), clinical nutritionist, speech therapist, physical therapist, occupational therapist, clerk, social worker, pastoral care worker, and so forth.

ICU models (physician stafﬁng) Open unit: The primary attending physician continues to direct primary responsibility for the provision of critical care services and consults a specialist trained in critical care (intensivist) if necessary (e.g., general surgeon consults intensivist for ventilator management of the patient). Closed unit: Intensivist assumes primary responsibility for the provision of critical care services in collaboration with primary attending physician (e.g., intensivist works closely with neurosurgeon in postoperative management of a patient).

Various types of ICU have been developed in order to focus on specialized care for different groups of patient population (Table 25.1). Specialized ICU teams can gain signiﬁcant experience by working with many patients who share a limited number of diagnoses. However, as many patients have preexisting comorbidities and present with multiple medical issues, there are much overlaps of patient population throughout different types of ICU. While large tertiary care centers tend to have a number of different types of ICU, small community hospitals tend to have one or two ICU that are usually mixed medical/surgical ICU.

The ICU environment

Specialized ICU

CHAPTER 25

Notes: There exists spectrum of variety of models between the two. While the open unit model may provide better continuity of care, closed unit model offers much better accessibility of the physician to patients, which can be crucial in the care of ICU patients. There have been many observational studies that supported improved outcome when closed unit model or high intensity (mandatory consultations with intensive care physician) was adopted.

Organizational challenges Shortage of workforce: Demand is rising with ever increasing number of aging population, increasing use of modern technology, and with standard physician stafﬁng model, which leapfrog initiative recently proposed. Complex stafﬁng and uncertain communication: There exists some degree of ambiguity in leadership and in the role of each member of multidisciplinary team.

Economical challenge High cost: High cost due to increasing patient population, increasing use of expensive technologies, and frequently inappropriate use of resources.

Ethical challenge End of life care: Deﬁning the level of care, more speciﬁcally, making decision about withholding or withdrawing life supporting therapy is one of the most challenging issues that patients, their surrogates, and clinicians face.

Approach to critical care Organizational approach • Building infrastructure • •

Ensure all necessary resources (i.e., staff, equipment, and supplies) are available. Develop optimal physical environment in which critical care is delivered.

201

Challenges of the ICU environment

ICU Type

Common admitting diagnosis

General mixed Med/ Surgery ICU

All critically ill patients

Medical ICU

Sepsis Acute respiratory failure (AFR) Hypovolemia Liver failure Gastrointestinal bleeding Acute pancreatitis Diabetic ketoacidosis Intoxication Acute myocardial infarction Acute congestive heart failure Hypertensive emergency Postoperative care—High risk general surgery Trauma Postoperative care—Cardiothoracic surgery Coronary artery bypass graft Heart valve surgery Postoperative care—Neurosurgery Subarachnoid hemorrhage Stroke Acute neuromuscular failure

Medical intensivist (pulmonary & critical care or critical care specialist)

Burn All pediatric critical illness—medical and surgical Related to prematurity or neonatal critical illness

Intensivist/surgeon Pediatric intensivist/ surgeon Neonatologist

CHAPTER 25

The ICU environment

Table 25.1 Types of specialized intensive care unit

Coronary care unit (CCU)

202

Surgical ICU Trauma ICU Cardiothoracic ICU

Neurological ICU

Burn ICU Pediatric ICU Neonatal

Primary physician in charge Intensivist

Cardiologist

Intensivist/surgeon Intensivist/surgeon Intensivist/cardiothoracic surgeon

Intensivist/neurologist/ neurosurgeon

Notes: Many variations exist in physician stafﬁng in the ICU depending on the model each ICU and hospital employs. “Intensivist” refers to a physician who, by training or experience, provides care for the critically ill in a role broader than that provided by a consultant specialist and can be an internist (a physician trained in internal medicine or one of the medical subspecialties of internal medicine), anesthesiologist, surgeon, or pediatrician.

• Implementing a multidisciplinary team (Figure 25.1)

Ultimate goal is to work together as a team to provide highest quality of care to patients. • Good communication based on the spirit of collaboration and trust between team members is a key to success. • Creating collaborative culture •

Between team members Between team members and patient/family

Care giver

Collegial interdisciplinary team interaction Open minded Collaborative Trusting

Supporting staff

System to improve quality of care and patient safety

The ICU environment

Leadership Communication and coordination

CHAPTER 25

Patient centered multidisciplinary team approach

Figure 25.1 Four factors to create ideal intensive care unit (ICU) environment. Well-organized multidisciplinary approach can improve patient outcome.

•

• •

Adopt established guidelines and protocols that have proven to improve patient outcome, and implement them based on the needs and modify, if necessary, according to unique environment of the individual ICU. Establish standard operating procedures for protocol implementation to increase efﬁciency and reduce errors. Ensure continuous quality improvement and training.

Clinical approach Rules: Always practice evidence-based critical care • Construct a thorough problem list. • Evaluate a patient with a systematic approach to include all organs or systems of a patient. • Identify the main problem that led the patient to the ICU and reevaluate the problem as time goes by. • Attend to any newly developed problem and speculate potential problems that may occur due to patient’s prolonged stay in the ICU. • Formulate a hypothesis to examine pathophysiology of patient’s main problems. • Deﬁne overall goals of ICU care (patient oriented). • Institute diagnostic test and intervention to test the formulated hypothesis. • Employ appropriate diagnostic tests relevant to the hypothesis. • Use invasive diagnostic procedures rationally and only when it can effectively guide the therapy. • Interpret data within the context of patient’s pertinent problem. • Seek the least intensive intervention to achieve goals of ICU care.

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• Organizing structure in patient care

The ICU environment CHAPTER 25

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• Observe and monitor patient’s progress. • • •

Focus on the patient’s overall clinical condition rather than on data. Pay attention to potential complication associated with intervention. Monitor complications that arise from critical illness (e.g., sepsis, acute renal failure (ARF), deep vein thrombosis, decubitus ulcer, anemia, malnutrition etc.).

Simple observation and prevention of complication is often the best strategy.

Outcome measures in the ICU Assessment of severity of illness: Several scoring systems have been designed as a tool to assess severity of disease and prognosis in critically ill patients. Common variables include age, vital sign, organ function, and chronic medical illness. Their utility in predicting outcome is imperfect; however, they provide useful foundation in quality management and research. Commonly used scoring systems are as follows: • APACHE (acute physiologic and chronic health evaluation) • SAPS (simpliﬁed acute physiologic score) • MPM (mortality prediction model)

Suggested reading Hales BM, Pronovost PJ. The checklist—a tool for error management and performance improvement. Crit Care. 2006;21(3):231-235. Pronovost PJ, Angus DC, Dorman T, Robinson KA, Dremsizov TT, Young TL. Physician staffing patterns and clinical outcomes in critically ill patients. JAMA. 2002;288:2151-2162. Kane SL, Weber RJ, Dasta JF. The impact of critical care pharmacists on enhancing patient outcomes. Intensive Care Med. 2003;29(5):691-698. Kollef MH, Schuster DP. Predicting intensive care unit outcome with scoring systems. Underlying concepts and principles. Crit Care Clin. 1994;10(1):1-18.

Chapter 26

Patient care quality and teamwork

Quality patient care with successful outcomes depends on effective care delivery and requires a multifaceted approach to support a continuous renal replacement therapy (CRRT) program. To that end, the Acute Dialysis Quality Initiative (ADQI) was established in 2000 to provide direction for the appropriate medical management of complicated patients with acute kidney injury (AKI) by • establishing evidence-based statements, • promoting consensus related to best practice, • standardizing treatments for critically ill patients, • facilitating research. Those healthcare team members who are involved in the provision of direct patient care also need to consider how the delivery is best accomplished. The three components of Donabedian’s classic model of quality healthcare (structure, process, and outcome) can be used to conceptualize the complex environment encompassing CRRT care delivery (see Figure 26.1).

Structure

Process

Education Machine Organizational commitment

Teamwork Policies Staffing Treatment

Outcome

Renal recovery Deliver prescribed dose Cost

Structure = Characteristics of care givers and the organizational setting Process = Interactions between care givers and patients Outcome = Change in patient condition as a result of health care

Figure 26.1 Donabedian model of quality healthcare adapted for continuous renal replacement therapy (CRRT).

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Kimberly Whiteman and Frederick J. Tasota

Patient care quality and teamwork CHAPTER 26

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Structure incorporates the characteristics of the healthcare providers and the physical and organizational setting in which they deliver care. The core of the CRRT healthcare team is composed of the renal physician, the intensivist, and the ICU nurse. • Characteristics of the healthcare providers include their educational preparation. As previously discussed, adequate didactic learning and hands-on training for nurses is critical. Physicians with expertise in different disciplines, including renal medicine and critical care medicine, must also be educated to understand clinical indications for and how to prescribe and manage patients on CRRT. For most members of the team, the addition of a CRRT program to the hospital requires integration of a signiﬁcant repertoire of knowledge and clinical skills. Other disciplines, including, but not limited to pharmacy and respiratory, need to be included. Finally, family and patient education materials should be developed to provide basic information to the recipients of care. • The physical setting is the actual patient care area where the treatments are prepared and delivered. For example, dialysate and replacement solutions might be compounded in the pharmacy or commercially prepared solutions dispensed by the pharmacy. The physical setting in the pharmacy may be a determinant of whether to compound or purchase commercially prepared dialysate and replacement bags. Another example might be that the availability of space in the room or presence of dialysis drains may inﬂuence the choice of CRRT machine used. • Machines selected for treatment, their advantages, and limitations are a part of the structure of a CRRT program. Product currently on the market varies as to the types of treatment that can be prescribed and how efﬁciently prescribed treatments can be delivered. Company speciﬁcations for the machines, available from the manufacturer, determine how quickly pumps can be run and their accuracy. • Organizational commitment to a CRRT program is absolutely necessary during start-up to provide monies for machines, supplies, training, support services, and education. Routine and continually evolving needs, like machine maintenance or replacement, require continued resource deployment to sustain the program. Costs for disposable kits and commercially prepared dialysate solutions accrue on an ongoing basis. Organizations also need to commit to coordinate multiple hospital departments in order to expedite care. Pharmacy, laboratory, central supply, and housekeeping are all affected by a CRRT program. For instance, if the hospital chooses to have pharmacy dispense a commercial dialysate solution, the work load of the pharmacy will increase with each additional patient receiving treatment. Process in Donabedian’s model is deﬁned as the interactions between healthcare providers themselves and between healthcare workers and patients. Successful CRRT programs require collaboration and teamwork between numerous disciplines, especially between the renal and intensive care physicians and the ICU nurses. CRRT policies and procedures, stafﬁng, and treatment selection are other processes that affect quality care.

Patient care quality and teamwork CHAPTER 26

between disciplines. One model utilizes a multidisciplinary CRRT work group. Members of the group should include representation from renal and intensive care physicians, the nurse educator for CRRT, ICU managers, and staff nurses with ad hoc members included as needed. At the start of a program, the work group should decide who is accountable for each aspect of care and how the different interested parties should interact with one another. As the program evolves, the members can then use meeting times to share information and solve problems. Cooperation and sharing of expertise, leadership, and responsibilities between work group members can expedite problem solving and implementation of clinical changes. • Policies and procedures should be in place to guide practitioners. Some suggestions for policies include the following: • Initiation, maintenance, and termination of treatment policies should be based on evidence. The published guidelines of American Nephrology Nurses Association can provide a basis for procedures (see www.annanurse. org). In the work group model, the renal dialysis expert can coordinate seeking out the latest evidence and initiating care recommendations. • Accountability for patient care between the renal dialysis nurses and ICU nurses varies in different practice settings. Some centers have renal dialysis nurses responsible for machine priming, initiating, and terminating treatment. Most frequently, in these models the ICU nurse maintains the treatment, completes the intake and output, and performs basic troubleshooting. The renal dialysis nurse is available for troubleshooting more complicated problems. At the other end of the spectrum, some centers have the ICU bedside nurse assume total responsibility for every aspect of care related to CRRT. For this reason, careful delineation of the roles for renal dialysis and ICU nurses needs to be done prior to the start of a program. • Documentation requirements, especially accurate documentation of intake and output, are a vital aspect of CRRT patient care. Charting models range from extensive ﬂow sheets to a simplistic model of documenting only the amount of ﬂuid removed from the patient. • When CRRT is discontinued, there needs to be a method in place to discontinue any ﬂuids, medications, and laboratory tests appropriate only during the treatment. For instance, replacement ﬂuid that remains on the medication administration record and is administered after CRRT is discontinued can quickly cause problems with ﬂuid overload. • Electronic medical record programmers need to understand how the intake and output should be calculated to ensure accurate accounting of ﬂuids without double entry or charting. Double charting can occur when replacement or ﬂuid volumes from the CRRT machine are recorded as intake and/or efﬂuent is recorded as output and the actual patient ﬂuid removal is also recorded as output.

207

• Teamwork and collaboration can be achieved through open communications

Patient care quality and teamwork CHAPTER 26

208

Management of emergency situations should be planned before beginning a program and reviewed periodically. During a cardiac arrest, some centers routinely turn the ﬂuid removal rate to zero but continue blood circulation through the system. Others routinely return the blood if time permits, clamp all the lines, and discontinue treatment. Another option is to decide how to handle a patient on CRRT in cardiac arrest on an individual basis. Whatever the model, all members of the healthcare team need to know the expectations for CRRT management during an emergency. • Interruption of treatments for off-unit interventions should be kept to a minimum to achieve maximum beneﬁt from CRRT. Coordination of testing between hospital departments can eliminate the need to discontinue treatments for long periods of time or numerous times per day for testing and interventions off the unit. • Physician accountability for who writes CRRT orders should be determined by the physician groups and clearly communicated to the nursing staff and pharmacy. Some areas for determination of physician accountability include who completes the following: — Writing initial and daily CRRT orders — Inserting a temporary dialysis catheter and insuring placement — Making changes to the orders based on changes in patient condition • Responsibility for cleaning and storage of machines between patients is an important process to have in place. Centers for Disease Control Guidelines and hospital-speciﬁc infection control measures for equipment should be used to provide a consistent and effective standard for cleaning. • Nursing care demands created by a critically ill patient on CRRT can sometimes be daunting. Therefore, stafﬁng requirements and assignments should ultimately be determined by the patient’s condition and the skills of the available nursing staff. Consider 1:1 nurse patient ratios for inexperienced CRRT nurses. Depending on the severity of illness of the patients, an experienced CRRT nurse may be able to manage a 1:2 nurse patient ratio. As previously mentioned, several models of nursing care delivery exist in practice. The workload of the bedside nurse and, for many centers, the renal dialysis nurse also increases with the initiation of a CRRT program. Consider who will assume responsibility for the following tasks: • Setup, priming, and takedown of circuits and/or machines • Initiation and termination of treatment • Patient monitoring during treatments • Troubleshooting at the bedside • Emergency procedures for rapid termination of treatment As with any new skill, nurses who are unfamiliar with a procedure will require more support and time than experienced nurses. Other decisions that affect •

Patient care quality and teamwork CHAPTER 26

209

nurse stafﬁng are determined by the processes chosen for obtaining supplies, dialysate, and replacement ﬂuids and other necessary equipment. Each of the various commercially available RRT machines has its own set of implications for nurse interventions and time commitment. Clinical choices should make sense for your organization, with quality patient care central to decision making. Choices of machines and intensity of treatments may also affect stafﬁng needs. Treatments that utilize anticoagulation protocols such as heparin and citrate require more extensive monitoring of patients and laboratory results than treatments without anticoagulation. However, treatments provided with no anticoagulation may also lead to increased incidence of clotting and impact nursing time. • Treatment selection can dictate slight variations to the care process. For instance, CVVH treatments require the preparation and administration of large volumes of replacement ﬂuid, while CVVHD utilizes no replacement ﬂuid. Knowledge of the available treatments and how to perform each efﬁciently and effectively are necessary to appropriately deliver care. Program outcomes of a positive nature are the result of careful delivery of CRRT medical and nursing care. The ultimate goal of therapy is to have complete recovery of renal function with no residual damage. In order to achieve that outcome it is necessary not only to deliver care based on the best currently available evidence but also to ensure that the care is delivered as planned. Other outcomes include the rate of discharge from the ICU or the cost of treatment. Examples of short-term outcome measures are the number of hours on treatment per day and achievement of prescribed ﬂuid balance or dose. Risk management reports can be used to track clinical error rates with an outcome goal of minimal or zero errors, depending on the variable of interest. Monitoring quality is a vital aspect of any CRRT program. A multidisciplinary work group model can be used to monitor and evaluate care delivery and facilitate implementing subsequent changes in practice. Initiatives should be directed toward each of the three components of quality healthcare: structure, process, and outcomes. These might include the following: • Structure • Standard monitoring of educational programming for physicians and nurses that could include a posttest or participation in a simulation. • Clinical competency programs to insure a minimal level of performance for all nurses caring for patients on CRRT or to systematically review high-risk/ low-incidence problems. • Machine utilization, repair, and maintenance schedules of machines can be reviewed to look for patterns. Reviewing a history of alarm conditions can give insight into issues with care. • Recommendations for classes and educational materials can be obtained through trends in the literature, clinical experiences, or risk management reports.

Patient care quality and teamwork CHAPTER 26

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Effectiveness of programs to disseminate new information or a practice change to include whether the information is — getting to the proper people. — being implemented into practice. — resulting in the expected clinical outcome. • Process • Knowledge of and/or compliance with policies and procedures can often be a problem for both new and experienced users. As with any policy, periodic clinical updates relating to seldom used skills may be necessary. • Exploration of machine alarm histories or obtaining a summary of calls to clinical support lines can provide information related to gaps in care giver knowledge that may need to be addressed. • Accuracy of documentation can be audited and interventions planned based on any deﬁciencies. • Care interruptions, for example off-unit testing, barriers to care delivery and lack of support, should be reviewed periodically. Interventions to help the staff provide a maximum number of hours of treatment per day can be trialed and evaluated. • Standardized order sets can be developed to minimize the chance of error. Collaboration with the pharmacy to determine the types of ﬂuids being ordered and standardization of commercially prepared bags can help to decrease compounding errors. • Outcomes • Renal recovery rates can be measured and benchmarked against published renal recovery rates for similar patients. • The dose prescribed should be compared to the delivered dose and the reason for discrepancies should be determined. • Cost of treatment can be evaluated both in comparison to hemodialysis, other centers who perform CRRT, and/or complications related to or prevented as a result of the treatment. •

Summary Caring for patients with CRRT is complex and requires the collaboration of a highly skilled team. Care delivery can be addressed using the structure, process, and outcome components involved in treatment. The implementation of a successful CRRT program and continued vigilance in all aspects of care related to it provide an effective support to patients with AKI and facilitate optimal recovery of renal function for this population.

Patient care quality and teamwork CHAPTER 26

Acute dialysis quality initiative home page. http://www.adqi.net/. Accessed November 30, 2008. Baldwin I. Continuous renal replacement therapy: keeping pace with changes in technology and technique. Blood Purif. 2002;20(3):269-274. Donabedian A. Evaluating the quality of medical care. Milbank Q. 1966;44(3 Pt. 2): 691-729. Donabedian A. The Quality of Care: How can it be assessed? JAMA. 1988;260(12): 1743-1748. Kellum JA, Bellomo R, Ronco C. Acute Dialysis Quality Initiative (ADQI): Methodology. Int J Artif Organs. 2008;31(2):90-93. Kelly DL. Applying Quality Management in Healthcare: A Systems Approach. 2nd ed. Chicago and Washington DC: Health Administration Press and AUPHA Press; 2006. Mehta R,Martin R. Initiating and implementing a continuous renal replacement therapy program: requirements and guidelines. Semin Dial. 1996;9:80-87. Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R. Continuous is not continuous: the incidence and impact of circuit “down-time” on uraemic control during continuous veno-venous haemoﬁltration. Intensive Care Med. 2003;29(4):575-578.

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Suggested readings

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Chapter 27

Organizational aspects: developing policies and procedures for continuous renal replacement therapies Jorge Cerdá

Considerations in renal replacement therapy for acute renal failure • Dialysis modality

Intermittent hemodialysis (IHD): daily, alternate day, sustained low efﬁciency daily dialysis (SLEDD) • CRRT: continuous veno-venous hemoﬁltration (CV VH), continuous venovenous hemodialysis (CV VHD), continuous veno-venous hemodiaﬁltration (CV VHDF) • Peritoneal dialysis Dialysis biocompatibility • Membranes Dialyzer performance • Efﬁciency • Flux Dialysis delivery • Timing of initiation • Intensity of dialysis: prescription versus delivery • Adequacy of dialysis: dose of dialysis Fluid removal • Maintenance of daily ﬂuid balance • Treatment of ﬂuid overload •

• •

•

•

213

This chapter deals with the process of developing a continuous renal replacement therapy (CRRT) program and how to avoid the pitfalls that frequently confront newly growing CRRT programs (Table 27.1).

Organizational aspects CHAPTER 27

Table 27.1 Indications for speciﬁc renal replacement therapies Therapeutic goal Fluid removal Urea clearance

Severe hyperkalemia Severe metabolic acidosis Severe hyperphosphatemia Brain edema

Hemodynamicsa Stable Unstable Stable Unstable

Stable/Unstable Stable Unstable Stable/Unstable Unstable

Preferred therapy Intermittent isolated ultraﬁltration Slow continuous ultraﬁltration Intermittent hemodialysis CRRT: Convection: CVVH Diffusion: CVVHD Both: CVVHDF Intermittent hemodialysis Intermittent hemodialysis CRRT CRRT CRRT

214

Note: aIn general, stable patients are those not requiring vasopressor therapy

Implementing CRRT: requirements for a successful program In our experience and that of others, ﬁve items that appear critical to success are the following: • Motivation and involvement of a physician leader (usually a nephrologist) • Motivation and involvement of nursing education • Educated nursing staff • Standardized protocols and orders • Continuing education with (re)certiﬁcation The care team must include the following: • Nurses (critical care and/or nephrology) • Physicians (nephrology and critical care, other subspecialties) • Pharmacists • Nutritionists The following factors affect the performance of the CRRT program: • Clear delineation of nursing responsibilities (setup, initiation, monitoring, troubleshooting) • Clear delineation of physician responsibilities and interaction • Formal and continuous education • Standardized and updated protocols • Continuous quality improvement and innovation

Forces in the development of a CRRT program • Driving forces

Previous positive experiences/outcomes Key staff resources: “champions” • Administration and physician support • Improved patient outcomes • Knowledgeable critical care and nephrology nurses • Restraining forces • Negative patient outcomes • Unclear/unrealistic expectations • Control: who is in charge? • Staff inertia — “Big ships” are sometimes harder to steer • Resource availability and costs — Personnel — Equipment

Organizational aspects

Policies, procedures, and personal interaction must clearly establish right from the start of the program as to who is in control of the technique and its application, and who is authorized to write orders and modify patient management, in agreement with the other members of the patient care team. Who is in charge of the procedure varies widely across the world and across the different models of ICU (closed or open format).

CHAPTER 27

Notes

•

Notes Driving forces. Previous positive experiences and improvement in patient outcomes will facilitate the development of the program. A point person—generally a nephrologist—will “champion” the idea and gather enough nursing, physician, and administration support. A knowledgeable group of critical care and nephrology nurses is essential. Restraining forces. Given the severity of disease of the patients involved, initial negative patient outcomes are common and become potential hindrances in the growth of the program. “Negative” outcomes are intimately associated with unclear or unrealistic expectations. Clear general goals for the program and evaluable goals for the individual patient will frequently avoid this problem and facilitate quality assurance measurements. In particular, we have seen ﬂedgling programs begin by treating the sickest patients with highest expected mortality. Outcomes in such cases are predictably poor, leading to negative staff impressions of the overall efﬁcacy of the therapy.

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•

Organizational aspects CHAPTER 27

• Hospital factors

216

In large institutions, staff inertia is an important restraining force. Conversely, in smaller institutions, unavailability of personnel and equipment may severely interfere with the success of the program.

Factors affecting the development of a CRRT program Size and type Nature of services provided • Number of — ICU beds — ARF patients in the ICU/year — ARF patients dialyzed in the ICU/year • Mission • Commitment of administration • Dialysis services • ICU stafﬁng • Level of ICU • Resources available • ICU staff support • Nephrology staff support • Dedicated budget • ICU staff education, training, and support • Equipment decisions • Ease of use • Accuracy of measures • Affordability • Clinical support versus technical support • Staff education and quality improvement • Staff — Education — Clinical Support — Competency • Patient — Early identiﬁcation — Response to treatment — Untoward events — Vascular access • System • •

1. Hospital factors The size and type of hospital and the nature of the services provided have a clear impact on the program. Larger hospitals with an active surgical program including cardiac and vascular surgery are more likely to generate a greater number of critical patients in need of CRRT. The size of the ICU is generally related to the size of these programs and has an important impact on resource availability. In addition, whatever the size of the hospital, its “mission” usually has an important bearing on the growth of the program, as it determines the commitment of administration to—at least—a trial of the technique.

2. Patient factors Prior to initiation of the program, the team must measure the number of acute renal failure (ARF) cases in the ICU per year, and the number of patients dialyzed during that interval and estimate the number of CRRT procedures per year. Previous experience demonstrates that in order to maintain the staff proﬁcient in CRRT, it is necessary to treat a minimum of 8–10 yearly patients, with gaps between procedures not longer than 8 weeks. Overall, at least 12 CRRT procedures should be performed per year, each procedure lasting a minimum of 5 to 7 days.

3. Resources available A recent national survey in the United States has shown that while hemodialysis nurses perform 90% of the acute IHD, approximately 50% of the CRRT patients are cared jointly by hemodialysis and ICU nurses. In 30% of the institutions, the ICU nurse alone performs CRRT. In the majority of institutions, available resources include ICU and nephrology staff support and a dedicated budget. Initial education, training, and ongoing support are essential for resource development. More recent international surveys show signiﬁcant variation in the distribution of physician and nursing responsibilities, with almost exclusively critical care-driven models in Asia and Australia/New Zealand, mixed responsibility in Europe, and higher nephrology involvement in the United States.

Organizational aspects

•

CHAPTER 27

•

217

Stafﬁng Supplies • Equipment Outcome — Patient goal achieved — Patient outcomes • Survival • Renal function status — Staff satisfaction — Costs •

Organizational aspects CHAPTER 27

Which nurses should be selected? The desirable nurses are the critical thinkers, the problem-solvers, and those who enjoy challenge. Generally, these nurses see technology as a means to improve care and are able to “think in action.”

4. Equipment decisions The main factors to consider include ease of use and accuracy of measures. Although at the start less expensive, simpler equipment may appear preferable, in the long term more reliable and accurate equipment may not only ensure success but also be less costly. Better blood pump systems and tubing, appropriate biocompatible membranes, and access, by ensuring long-lasting ﬁlters, may result in savings that overcome the initial expense. Furthermore, more complex and less reliable equipment will be more costly in nursing personnel and, by requiring 1:1 nursing at all times, severely interfere with resource availability. Moreover, at the time of purchasing, a clear distinction must be made between clinical and technical support. Rapid-response clinical support by knowledgeable nurses is most desirable on a 24 hour a day, seven days a week basis.

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5. Staff education and quality improvement Where available, nephrology nurses provide valuable education on dialysis and access management. For critical care nurses unfamiliar with the procedure, such know-how will ﬂatten an otherwise steep learning curve. ICU-based critical care nurse specialists are essential to the education of the ICU staff, by placing CRRT in the appropriate context of overall patient care. In addition, ICU-based education establishes an all-important “ownership” of the procedure. In a gradual fashion, ICU nurses learn that rather than merely adding another piece of equipment to an already cluttered bedside, CRRT provides virtually complete control of nutrition, hemodynamics, ﬂuid, electrolytes, and acid-base management that facilitates rather than complicates patient support. Pharmacists must be part of the group from the start, and nutritionists must understand the new requirements of CRRT patients. Most commonly, these patients have different, and sometimes opposite, needs to those of patients on IHD.

Sources of ﬂuid balance and dialysis errors • Inappropriate prescription • Operator error • Machine error

Recommendations for preventing complications during ultraﬁltration with hybrid/CRRT modalities • All operators of intermittent or continuous renal replacement machines should

be appropriately trained and certiﬁed initially and on a periodical basis.

Notes When a new procedure is initiated, it is necessary to evaluate the process and its outcomes. The major question is whether this therapy make a difference. The improvement process begins at the inception of the program and examines staff, patient, and system issues as well as clinical outcomes. Staff education, clinical support, and competency are ongoing. Patient outcomes are measured in three domains: achievement of goal of therapy, patient survival, and preservation of renal function. Outcome evaluation must include staff satisfaction. System and ﬁnancial concerns are also monitored. Analysis of data includes periodic revision of orders, ﬂow sheets, protocols, education, ﬁlter and circuits, anticoagulation, and equipment.

Role of the nephrologist The nephrologist who treats critically ill patients with ARF must change from a focused to a global role in patient care. By his or her ability to achieve continuous effective metabolic, ﬂuid, and electrolyte control, the nephrologist in charge of CRRT must continuously interact and agree with all the other practitioners involved. The nephrologist must have a solid presence in the ICU, and not only needs to be aware of the problems affecting his patients but also become “a part of the team,” a recognizable presence that solves problems reliably and is seen by ICU staff as a relevant practitioner in that environment. The nephrologist participates in modality and equipment decisions, ﬂuid management (volume and composition), and dose of dialysis prescription, anticoagulation, nutrition, and drug adjustment in continuous collaboration with the other members of the patient care team. Moreover, the nephrologist is key in the decisions on treatment initiation and discontinuation. Continuous measurement of severity of disease by widely accepted scoring systems is desirable to evaluate patient outcomes and quality assurance. In this important ﬁeld of medicine, where critical care and nephrology overlap, the size of the practice and the scope of knowledge is so wide that the evolution of a new subspecialty, critical care nephrology, is justiﬁed (see also Chapter 25).

Financial considerations Characteristics of the “ideal” treatment modality of ARF in the ICU: • Preserves homeostasis

Organizational aspects

umes during CRRT, as well as pre- and posttreatment weights and ultraﬁltration loss for intermittent therapies.

CHAPTER 27

of overriding machine alarms. • Intensive care and dialysis units should record hourly and total efﬂuent vol-

219

• All operators of such machines must be aware of the potential complications

Organizational aspects CHAPTER 27

220

• • • • •

Does not increase comorbidity Does not worsen patient’s underlying condition Is inexpensive Is simple to manage Is not burdensome to the ICU staff

Is CRRT more expensive than IHD? • Depends on what you count: • Use of personnel — 1:1 versus 1:2 nursing; dialysis nurses involved or not • Equipment: — Initial expense: type of machine — Filter life — Replacement and dialysis ﬂuids: pharmacy costs • Lab costs • Respirator days, ICU length of stay Other modiﬁers of cost: • Predetermined changes of extracorporeal circuit • Scheduled changes • Minimal ﬁltrate to blood urea nitrogen concentration (FUN/BUN) ratio (generally 0.8) • Anticoagulation • Filter survival • Replacement solutions • Labs • Cost increases when higher amounts of therapy are delivered: • IHD: personnel costs increase • CRRT: replacement solutions and dialysate Areas of potential cost reduction in CRRT: • Dialyzers • Type of membrane • Access (MAJOR) • Anticoagulation (MAJOR) • Personnel • ICU alone versus nephrology/ICU collaboration • Dialysate and replacement ﬂuids • Service, support • Appropriateness of treatment/patient selection

Suggested readings Bell M, Swing, Granath F, Schön S, Ekbom A, Martling CR. Continuous renal replacement therapy is associated with less chronic renal failure than intermittent hemodialysis after acute renal failure. Intensive Care Med. 2007;33(5):773-780. Bellomo R, Cole L, Reeves J, Silvester W. Renal replacement therapy in the ICU: the Australian experience. Am J Kidney Dis. 1997;5(suppl 4):S80-S83. Bellomo R, Cole L, Reeves J, Silvester W. Who should manage CRRT in the ICU? The intensivists’ viewpoint. Am J Kidney Dis. 1997;30(5)(suppl 4):S109-S111. Bellomo R, Ronco C. Acute renal failure in the intensive care unit: adequacy of dialysis and the case for continuous therapies. Nephrol Dial Transpl. 1996;11:424-428. Benner P, Clinical wisdom and interventions in critical care: a thinking-in-action approach. 1999 Clark WR, Letteri JJ, Uchino S, Bellomo R, Ronco C. Recent clinical advances in the management of critically ill patients with acute renal failure. Blood Purif. 2006;24(5–6): 487-498. Gibney N, Cerda J, Davenport A, et al. Volume management by renal replacement therapy in acute kidney injury. Int J Artif Organs. 2008;31:145-155. Kellum JA, Cerda J, Kaplan LJ, Nadim MK, Palevsky PM. Fluids for the prevention and management of acute kidney injury. Int J Artif Organs. 2008;31:96-110. Martin RK. Who should manage CRRT in the ICU? The nursing viewpoint. Am J Kidney Dis. 1997;30(suppl 4):S105-S108. Martin RK, Jurschak J. Nursing management of continuous renal replacement therapy. Semin Dial. 1996;9(2):192-199. Mehta RL. Acute renal failure in the intensive care unit: Which outcomes should we measure? Am J Kidney Dis. 1996;5(suppl 3):S74-S80. Mehta RL. Indications for dialysis in the ICU: Renal replacement vs. renal support. Blood Purif. 2001;19(2):227-232. Mehta RL, Lettieri JM; National Kidney Foundation Council on Dialysis. Current status of renal replacement therapy for acute renal failure: a survey of US nephrologists. Am J Nephrol. 1999;19:377-382.

Organizational aspects CHAPTER 27

Several recent articles suggest CRRT is superior to IHD with respect to “renal recovery.” Implications go far beyond than just “hard” endpoint of renal recovery: • Need for chronic dialysis impairs quality of life • If stay in ICU can be reduced this will have major impact on hospital budget • Patient dependent on chronic dialysis will consume signiﬁcant health care resources and have an impact on community health care budget

221

Notes

Organizational aspects CHAPTER 27

222

Mehta RL, Martin RL. Initiating and implementing a continuous renal replacement therapy program. Semin Dial. 1996;9(2):80-87. Monson P, Mehta RL. Nutritional considerations in continuous renal replacement therapies. Semin Dial. 1996;9:152-160. Paganini EM, Tapolyai M, Goormastic M, et al. 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(5)(suppl 3):S81-S89. Paganini EP. Continuous renal replacement therapy: A nephrological technique, managed by nephrology. Semin Dial. 1996;9:200-203. Ronco C and Bellomo R. Critical care nephrology: the time has come. Nephrol Dial Transplant. 1998;13:264-267. Silvester W, Bellomo R, Cole L. Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Critical Care Med. 2001;29(10):1910-1915. Uchino S, Bellomo R, Kellum JA et al. Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury. Int J Artif Organs. 2007;30(4):281-292. Uchino S, Bellomo R, Morimatsu H, et al. Continuous renal replacement therapy: a worldwide survey. Intensive Care Med. 2007;33(9):1563-1570.

Chapter 28

Documentation, billing, and reimbursement for continuous renal replacement therapy Kevin W. Finkel

Many critically ill patients with acute or chronic renal failure are unable to tolerate intermittent hemodialysis because of hemodynamic instability and are treated with various modalities of continuous renal replacement therapy (CRRT). In these patients, thorough documentation and correct coding is essential for timely and appropriate reimbursement. The billing codes that are typically utilized in this setting are the subject of this chapter and are summarized in Table 28.1.

Billing codes Initial inpatient consultations—new or established patients (CPT codes 99251–99255) New or established hospitalized patients who are seen for an initial consultation are billed under the CPT codes 99251–99255. In order to meet the requirements for proper documentation, there must be a written request for the consultation, and the results of the consultation must be made available to the requesting physician. This requirement is easily met with either a written or dictated note in the inpatient medical record. The level of service billed (level 5 being highest) is based on the complexity of the particular patient supported by the appropriate documentation. It is likely that most, if not all, patients in the intensive care unit (ICU) who require CRRT will be ill enough to justify a level 5 visit. There are three components to medical documentation: the history, physical exam, and decision making. For a level 5 initial consultation, all three components must be detailed and medically complex. Documentation for a level 5 consultation requires comprehensive history (chief complaint, four elements of the history of present illness, a 10-point review of systems, and complete past,

223

Introduction

Documentation, billing, and reimbursement CHAPTER 28

224

Table 28.1 Billing codes CPT 99251–99255: Initial inpatient consultations—new or established patients CPT 99221–99223: Initial hospital care for a new or established patient CPT 99291–99292: Critical care services CPT 90945: Procedure other than hemodialysis (e.g., peritoneal, hemoﬁltration) with single physician evaluation CPT 90947: Procedure other than hemodialysis requiring repeated evaluations, with or without substantial revision of the dialysis prescription CPT 99231–99233: Subsequent hospital follow-up

family, and social histories), comprehensive physical exam (vital signs plus examination of nine organ systems), and highly complex decision making (extensive number of diagnoses or treatment options, complex data, and high risk to the patient).

Initial hospital care for a new or established patient (CPT codes 99221–99223) If a patient is admitted under the direct care of the physician who will also provide CRRT then the initial evaluation can be billed under the CPT codes 99221–99223. The level of service billed (level 3 being the highest) is based on the complexity of the particular patient supported by the appropriate documentation. It is likely that most, if not all, patients admitted to the ICU will be ill enough to justify a level 3 visit. As with a level 5 initial consultation, documentation requires a comprehensive history and physical exam, and complex decision making with extensive number of diagnoses or treatment options, complex data, and high risk to the patient.

Critical care services (CPT codes 99291–99292) Initial and subsequent care of the critically ill patient may be billed with the critical care services CPT codes of 99291 and 99292. Such patients should be critically ill, usually with multiple organ failure. Documentation must explicitly state that the patient is critically ill and should include such factors as the degree of hemodynamic instability and its treatment. Critical care service is a timedependent CPT code: the ﬁrst 30 to 74 minutes of critical care is billed as 99291; the code 99292 is used for each additional 30 minutes. The total critical care time must be documented in the medical record. Multiple physicians may bill for critical care if the services involve multiple organ system (unrelated diagnoses) but the actual period of billing cannot overlap, so it is best to document the actual time periods spent at the patient’s bedside. Also, no more than a total of 3 hours of critical care time can be billed in a single 24-hour period.

Continuous dialysis/CRRT (CPT codes 90945 and 90947) CRRT can be billed for on the initial day of patient encounter and subsequent days with the CPT codes 90945 and 90947 [procedure other than hemodialysis

CPT codes 99231–99233 are used to bill for subsequent hospital follow-up. Most critically ill patients will qualify for a level 3 (highest severity) service. Documentation for a level 3 follow-up requires that two of the three components of the chart note be detailed. This requirement is most commonly met with a detailed physical exam (vital signs plus examination of seven organ systems) and highly complex decision making.

Dialysis catheters and modiﬁers for multiple procedures Placement of temporary dialysis catheters (CPT code 36556) can be billed at any time. It is billed with a 25 modiﬁer linked to the evaluation and management (E&M) CPT code billed the same day (initial or follow-up codes). For example, if a patient is billed for subsequent hospital follow-up (99233) and a dialysis catheter is also placed on that day, then 99233.25 and 36556 are billed. The 25 modiﬁer is linked to the E&M code and signiﬁes that there is a signiﬁcant and separately identiﬁable procedure. When multiple procedures are done on the same day, then a 51 modiﬁer is also used. The 51 modiﬁer is linked to all procedures after the ﬁrst. For example, on the initial hospital day, if a physician performs a consultation, places a temporary dialysis catheter, and sees the patient after CRRT is initiated, then all three encounters can be billed: 99255.25 (Initial Consult with a signiﬁcant and separately identiﬁable procedure); 36556 (placement of a temporary dialysis catheter); and 90945.51 (CRRT with multiple procedures).

Initial patient evaluation The initial evaluation of a patient in the ICU by a consultant can be billed by CPT codes 99251–99255 based on the complexity of the particular patient supported by the appropriate documentation. If on the day of consultation CRRT is

Documentation, billing, and reimbursement CHAPTER 28

Subsequent hospital follow-up (CPT codes 99231–99233)

225

(e.g., peritoneal, hemoﬁltration)]. In order to bill for continuous dialysis, it must be clearly stated in the medical record that the patient was seen during dialysis. Code 90945 [procedure other than hemodialysis (e.g., peritoneal, hemoﬁltration) with single physician evaluation] is billed if only one visit is required. However, ICU patients usually require multiple reassessments throughout the day. Whether or not there is a change in the dialysis prescription, as long as there is appropriate documentation of the need for multiple assessments, then 90947 (procedure other than hemodialysis requiring repeated evaluations, with or without substantial revision of the dialysis prescription) can be billed. The medical record should include such factors as the degree of hemodynamic instability, changes in acid base status, and change in replacement ﬂuid. Documentation of the degree of hemodynamic instability is necessary to be properly reimbursed for CRRT procedures. When more than one visit to the bedside is needed it is appropriate to bill 90947.

Documentation, billing, and reimbursement CHAPTER 28

226

performed, and the consultant is present for a portion of the CRRT procedure, then a bill for CRRT (90945 or 90947) can also be charged with a 25 modiﬁer (signiﬁcant and separately identiﬁable procedure). However, after the initial evaluation, subsequent dialysis days allow only billing for one CPT code (continuous dialysis, subsequent hospital follow-up, or critical care) because E&M is built into dialysis codes. If a patient is admitted to the physician who will also provide CRRT care, then CPT codes 99221–99223 (initial hospital care for a new or established patient) can be used along with CRRT codes (90945 or 90947) on the initial day with the appropriate documentation and the 25 modiﬁer. As an alternative to the initial CPT codes for consultation or inpatient admission, a critical care code (99291–99292) may be used.

Subsequent hospital days In the daily follow-up of patients on CRRT, the CPT codes 90945 and 90947 are traditionally used. Since these codes (as opposed to other procedure codes) include an E&M component, it is improper to separately bill a follow-up or critical care code and a CRRT code. In all cases, after the initial day of evaluation, subsequent billing can only be a single CPT code, either CRRT, subsequent hospital follow-up, or critical care. As per the guidelines of the Centers for Medicare and Medicaid Services (CMS), if both CRRT and another E&M service is billed on subsequent hospital days then—pay only the dialysis service and deny any other evaluation and management service. Choosing to bill for CRRT, subsequent follow-up, or critical care is at the physician’s discretion.

Relative value units The relative value unit (RVU) is the common scale by which practically all physician services are measured. CMS and most other insurers use RVU values to determine the reimbursement rate for services after incorporating geographic and other factors. The resource-based relative value scale (RBRVS) assigns a relative value to each CPT code relative to all of the other CPT codes. The RBRVS was developed for CMS, and in 1992, Medicare established its standardized physician payment schedule based on the RBRVS. RVUs are determined by committees of the American Medical Association. The committee members come from all medical specialties and include representatives from other health professions, including nursing. The committee assigns a relative value after hearing testimony from specialty groups on how many hours or minutes it takes to perform a procedure, the level of skill required, the level of education/training required, and the practice expense associated with a procedure.

RVU 5.17 5.48 4.96 1.61 2.16

227

There are three components to a relative value—practice expense, work, and malpractice. Each component is adjusted geographically using three separate geographic practice cost indexes (GPCI). This relative value is then multiplied by a single nationally uniform “conversion factor” to arrive at a monetary value. The CMS conversion factor for 2008 is approximately $38/RVU. Depending on the contract, insurance ﬁrms may pay at or above Medicare rates. For example, a level 5 initial inpatient consultation has an RVU of 5.17 that reimburses approximately $196. Actual RVU levels are subject to change, but Table 28.2 lists those for common CPT codes.

Documentation, billing, and reimbursement

CPT Code 99255 (Initial consult) 99291 (Critical care 30–74 minutes) 99223 (Initial inpatient admission) 90945 (Single CRRT) 90947 (Repeat CRRT)

CHAPTER 28

Table 28.2 RVU associated with common CPT codes

Summary • Thorough documentation and correct coding are essential for timely and

appropriate reimbursement. • New patients can be billed as initial inpatient consults, initial hospital care, or

critical care services. • If on the day of consultation or admission CRRT is performed, and the phy-

• • •

•

•

sician is present for a portion of the CRRT procedure, then a bill for CRRT can also be charged with a 25 modiﬁer (signiﬁcant and separately identiﬁable procedure). Multiple procedures can be billed with the 51 modiﬁer attached to all procedure after the ﬁrst. After the initial day of evaluation, subsequent billing can only be a single CPT code, either CRRT, subsequent hospital follow-up, or critical care. As per the guidelines of CMS, if both CRRT and another E&M service is billed on subsequent hospital days then—pay only the dialysis service and deny any other evaluation and management service. The RVU is the common scale by which practically all physician services are measured. CMS and most other insurers use RVU values to determine the reimbursement rate for services after incorporating geographic and other factors. The CMS conversion factor for 2008 is approximately $38/RVU.

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Chapter 29

Machines for continuous renal replacement therapy Claudio Ronco

In 1977, Peter Kramer introduced for the ﬁrst time a simple therapy called continuous arterio-venous hemoﬁltration (CAVH) [1]. In the following years, CAVH represented an important alternative to hemodialysis or peritoneal dialysis, especially in those patients where severe clinical conditions precluded the traditional forms of renal replacement [2]. CAVH enabled small centers not equipped with hemodialysis facilities to perform acute renal replacement therapy (RRT). The technique, however, rapidly displayed its limitations and, despite a good ﬂuid control, urea clearance could not exceed 15 L/24 h. Since most critically ill patients are severely catabolic, the amount of urea removed frequently resulted in an insufﬁcient control of blood urea levels and inadequate blood puriﬁcation. For this reason, Geronemus and Schneider, in 1984, introduced the use of continuous arterio-venous hemodialysis (CAVHD) [3]. The treatment was similar to CAVH, but a low permeability membrane could be employed and a countercurrent dialysate ﬂow was provided to increase urea removal by the addition of diffusion. A daily urea clearance in the range of 24–26 L could be achieved with CAVHD. In the same days, we applied the same concept to a highly permeable hollow ﬁber hemodiaﬁlter, and we ﬁrstly described the treatment called continuous arterio-venous hemodiaﬁltration (CAVHDF) [4]. In this treatment, the high convection rates combined with the countercurrent dialysate ﬂow allowed increased removal of small and large molecules. One of the major limitations imposed by the arterio-venous approach was the unstable performance of the circuit due to possible reductions of extracorporeal blood ﬂow secondary to the patient’s hypotension, or line kincking and ﬁlter clotting. This frequently resulted in treatment interruptions, reduced daily clearance, and treatment failure [5]. On the other hand, the perception of continuous renal replacement therapy (CRRT) had changed over time and, by the late eighties, CRRT had become more and more accepted in the intensive care units (ICUs) as a standard form of therapy [6]. Therefore, owing to the development of reliable double-lumen venous catheters and a new generation

229

Introduction

CRRT technology evolution

hno

Evolution

Machines for CRRT CHAPTER 29

230

of blood pump modules for continuous therapies, the use of CAVH started to decline and the more efﬁcient continuous veno-venous hemoﬁltration (CV VH) or continuous veno-venous hemodiaﬁltration (CV VHDF) became the golden standard [7–8]. CV VH can be performed in postdilution mode, reaching daily clearances for urea in the range of 36–48 L. When predilution is performed, the requirement of heparin may be remarkably reduced and ultraﬁltration can be increased up to 48–70 L/24 h. Since predilution decreases the effective concentration of the solute in the ﬁltered blood, the amount of solute removal is not proportional to the amount of ultraﬁltration and it must be scaled down by a factor depending on the percent of predilution versus blood ﬂow. The increased amount of ﬂuid exchanged per day in CV VH lead to the development of automated blood modules equipped with blood leak detectors, pressure alarms, and pressure drop measurement in the dialyzer [9]. However, despite the achievement of higher efﬁciency, safety and reliability were still questionable in these machines that were basically derived from hemodialysis blood modules and were never designed as self-standing units for CRRT. In most cases, volumetric pumps were added to a blood module to achieve ultraﬁltration and replacement ﬂuid volume control. This approach is still in use in several units and it is deﬁned as adaptive technology. Adaptive technology may be very effective but it presents the risk of operating with components that are not interconnected and therefore they are not completely safe according to the standards of an integrated machine [9]. For this reason a full spectrum of CRRT machines has been developed over the years following a pathway of development and evolution in technology (Figure 29.1).

s of

res rog

ec TT

logy

CRR

P

CAVH Years

1977

CVVH-D 1985

CVVHDF 1989

HVHF 2004

?

Figure 29.1 Evolution of continuous renal replacement therapy technology over the years.

Multifiltrate

Prismaflex

BM 25

Prisma

Diapact CRRT

HF 400

Aquarius

Equa-Smart

Hygeia plus

Performer LRT

Figure 29.2 The various continuous renal replacement therapy machines available in the market.

Machines for CRRT CHAPTER 29

The modern history of CRRT is characterized by the development of complete CRRT machines designed speciﬁcally for acute renal replacement in intensive care patients (Figure 29.2). These machines are all equipped with integrated safety alarms, ﬂuid balancing controls, and connected blood modules with the possibility to perform CV VH, CV VHD, and CV VHDF. Such machines can now achieve a smooth conduction of the renal replacement treatment in the ICU and they can perform continuous as well as intermittent renal replacement therapies with increased levels of efﬁciency. Blood ﬂows up to 500 mL/min and dialysate/replacement ﬂuid ﬂow rates in the same ranges are leading to urea clearances that may reach levels close to standard hemodialysis machines. At the same time, the highly permeable membranes utilized in CRRT systems achieve improved clearances of the larger molecular weight solutes. Due to the higher blood and dialysate ﬂow rates achievable in the system, higher surface areas can now be utilized and more efﬁcient treatments can be carried out. The ﬂuid control is achieved via gravimetric or volumetric control systems, which drive peristaltic pumps both for ultraﬁltration and reinfusion. The priming procedures are simpliﬁed because of the step-by-step online help and the self-loading preassembled tubing sets.

231

Machines for continuous renal replacement therapy

Machines for CRRT CHAPTER 29

232

The new machines are also equipped with a friendly user interface: this leads to an increased conﬁdence of the personnel with the therapy while constant levels of efﬁciency can be obtained without major problems or complications [10]. In Table 29.1, we report a comparative prospect in which different features are analyzed in each single different machine. It can be noted that the level of blood and dialysate ﬂow ranges is varying from one to another, but it has been dramatically increased in comparison to the ﬁrst generation of machines. Some of the new machines present operational conditions similar to those utilized for chronic hemodialysis. This provides the possibility of using the machine for different treatments and purposes. Most machines work either in pure convection or in diffusion, or in combined mode. Again the most recent machines have the capability to perform treatments with high exchange volumes such as high-volume hemoﬁltration. In these circumstances, the presence of an adequate warmer for the substitution ﬂuid is very important to maintain thermal balance. In this ﬁeld, online monitors for thermal balance and for blood volume determination are available on the market, but they are integrated in the machines only in isolate cases [11–12]. New machines are equipped with preset disposable circuits or with easy instruction for the rinsing/priming phase of the therapy. The friendly user interface plays an important role in the selection of the therapy mode and the smooth conduction of the entire session. This makes these machines well suited for the use in intensive care units where the experience of the personnel may not be as wide as in the dialysis setting. The presence of an increased number of pressure sensors in the machines renders the monitoring of the treatment easier and accurate. In particular, the measurement of the end-to-end pressure drop in the dialyzer allows for the monitoring of the patency of the blood compartment and permits to identify early signs of clotting or dialyzer malfunction. In some machine, the pressure transducers are designed to prevent the contact of blood with air and the lines are constructed with special membrane buttons that transmit the pressure values to the sensor without air-to-blood interface. The measurement of net ﬁltration and the balance between ultraﬁltration and reinfusion is done with one or two scales in different machines. Most of these systems also operate in continuous hemodialysis to achieve the desired balance between the dialysate inlet and the dialysate outlet. A remarkable accuracy is observed in most cases. The metabolic control of acute renal failure (ARF) generally requires at least 30 L of urea clearance per day and positive outcomes have considered a dose above 35 mL/kg/h as adequate, although some evidence may suggest that doses between 20 and 35 mL/kg/h can be equally safe. The combination of diffusion and convection has shown that satisfactory clearances of small, medium, and large molecules can generally be achieved. Furthermore, in case of sepsis, patients may present increased levels of substances in the middle molecular weight range (500–5000 dalton), such as chemical mediators of the humoral response to endotoxin. In this case the treatment should control not only urea and other waste products, but also the circulating levels of these proinﬂammatory substances [13]. To achieve such a complex task, high convective rates may be required [14].

Table 29.1 Characteristics of recent CRRT machines Heparin

0–165

Heater management (Liters) 10 L

Printer sensors

Scales Possible techniques RS-332 P

Y

Y

Pre Post pre-post

4

no Y

2

(IHD-IHDF)-IHF, PEXPAP SCUF-CVVHCVVHD-CVVHFD Pediatric Tx

30–500

0–150

16 L

no

no Pre Post

2

no Y

2

Y

no Pre Post

4

no Y

1

10 L

Y

Y

Pre Post

3

Y Y

3

SCUF-CVVH-CVVHDPEX Pediatric TX (QB = 5–150 mL/min) IHD-IHFD-IHF, PEX-PAP SCUF-CVVH-CVVHDCVVHFD SCUF-CVVH-CVVHDCVVHDF-PEXPedi-tric Tx

3

10–500

5–400

25 L

Medica

2*

5–400

0–150

FMC-NA

1+3**

0–500

0–300

open

Y

Y

Pre Post

3

Volumetric

IHD-IHFD, SLED-SCUFCVVHD Pediatric Tx

0–400

0–75

25 L

no

Y

Pre Post

3

1

0–450

0–200

12 L

no

Y

Pre Post Pre-Post

4

no Y no no no Y

Bellco

2***

SCUF-CVVH-CVVHD CVVHD-PEX IHD-IHFD-IHF, PEX, SCUF-CVVH-CVVHDSCCHFD-CVVHDFPediatric Tx

Infomed

4

Company

Pumps

QB

QD (mL/min)

Fluid (mL/min)

Aquarius

Ew L S Baxter

4

0–450

BM 25

Ew L S Baxter

3

Diapact

B. Braun

Equa-Smart

2008H 2008K Multimat B HF 400

Reinfusion Pump

233

2

CHAPTER 29

Machines for CRRT

234

CHAPTER 29

Machines for CRRT

Table 29.1 Continued Company

Pumps

QB

QD (mL/min)

Fluid (mL/min)

Heater management (Liters)

Heparin

Hygela plus

Kimal

4

0–500

0–65

4L

Y

Y

Performer

Rand

4****

5–500

0–500

20 L

Y

Y

Prisma

Gambro

4

0–180

0–40

5L

Blood warmer

Y

Pre Post Pre-Post

4

no Y

3

Multiﬁltrate FMC

4

0–500

0–70

24 L

Y in-line

Y

Pre Post Pre Post

4

No Y

4

Prismaﬂex

5

0–450

0–133

15 L

Y in-line

Y

Pre Post Pre-BP

5

no Y

4

Gambro

Reinfusion Pump

Pre Post Pre-Post Pre Post Pre Post

4 4

Printer sensors

Scales Possible techniques RS-332 P

Y Y Y Y

Volumetric 1

SCUF-CVVH-CVVHD CVVHDF-PEX IHD-IHFD-IHF, PEXPAP-SCUF-CVVHCVVHD-CVVHFDCVVHDF SCUF-CVVH-CVVHDCVVHFDCVVHDF-PEX SCUF-CVVH-HV-HF CVVHD-CVVHFDCVVHDF PEX SCUF-CVVH-HV-HF CVVHD-CVVHFDCVVHDF PEX

Notes: * 2 pumps + 2 intelligent clamps; ** the 3 pumps for dialysate and ﬂuid replacement are positioned inside the hydraulic circuit of the monitor; *** every pump runs two tubing segments; **** the machine is equipped with thermal sensors.

Technical characteristics of common CRRT machines The Prisma The Prisma machine (Gambro-Sweden) has been the ﬁrst integrated equipment speciﬁcally designed for CRRT. The machine features a preassembled cartridge including lines and the dialyzer. Tubing loading as well as the priming procedure is automatic. The presence of four pumps and three independent scales allows performing all the CRRT techniques. Blood ﬂows can vary from 0 to 180 mL/min while

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235

In these conditions the necessary rate of convection can be obtained in continuous hemoﬁltration, in continuous hemodiaﬁltration (in this case four pumps are required), or in continuous high-ﬂux hemodialysis with continuous dialysate volume control (three pumps are required and a reliable UF control system). In HDF, dialysate outlet ﬂow exceeds the volume of inlet dialysate volume and the required ultraﬁltration, and for this reason a substitution ﬂuid is required. In high-ﬂux dialysis substitution ﬂuid is not required and the balance is obtained by a mechanism of internal backﬁltration. Warmed dialysate is delivered at a programmed ﬂow rate and the second pump regulates the dialysate outlet ﬂow rate and net ultraﬁltration with a continuous volume control. In some machines this treatment has been performed in recirculation mode and it has been deﬁned as continuous high-ﬂux dialysis because of the ﬁltration–backﬁltration mechanism similar to that of high-ﬂux dialysis in chronic hemodialysis [15]. Once the patient’s dry weight has been achieved, the circuit may operate at zero net ﬁltration using sterile dialysate at various ﬂows (50–200 mL/min). With relatively high-volume hemoﬁltration (2–3 L/h), hemodiaﬁltration or high-ﬂux dialysis, the clearance of small and large molecules is improved. If performed continuously, the treatments can provide weekly Kt/V in the range of 7 to 10, thus resulting in a treatment efﬁciency much higher than that achieved with other intermittent dialysis therapies [16]. At the same time, signiﬁcant amount of proinﬂammatory mediators can be removed, leading to an improved hemodynamic stability [17]. Besides the number of the pumps, an important feature of CRRT machines is the operator interface. The wide color screen of some machines allows an easy access to the required information and online help for most of the functions (Figure 29.2). The issue of collecting the treatment data is an important one and almost all the machines are now equipped with an RS32 computer post that allows a complete extraction of data and the possibility of exporting the data to populate a spreadsheet or a database. Some machines are even equipped with built-in printers with automatic printing of the data at the end of the session. The transportability of the machine is an important aspect to be considered since these treatments may be performed in different sites of the same hospital or even outside, especially in peripheral units or disaster areas. The structure of the machines is including, in most of the cases, a practical trolley with an easy movement of the equipment.

Machines for CRRT

The Prismaﬂex machine The new “Prismaﬂex machine” (Gambro-Sweden) like all new-generation platforms for CRRT, presents new features, speciﬁcally designed to perform therapies with high ﬂuid volume exchange (HVHF), nowadays supposed to be effective in ARF, sepsis, and multiple organ dysfunction syndrome (MODS). The machine features ﬁve pumps [blood, dialysate, preblood-pump replacement solution (PBP), postblood-pump replacement solution, and efﬂuent], four scales (efﬂuent, dialysate and two for replacement solutions), and a disposable set with preconnected high ﬂow dialysers and ﬂuid circuitry. The machine allows performing a complete spectrum of therapies [slow continuous ultraﬁltration (SCUF), CV VH, CV VHD, CV VHDF, therapeutic plasma exchange (TPE/PEx), and hemoperfusion (HP)]. Three different

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dialysate ﬂow ranges between 0 and 40 mL/min. The ﬂuid handling capacity is 5 L. Pre, post, and simultaneous pre-post dilution modes are available (Figure 29.3).

Figure 29.3 The Prisma machine.

Figure 29.4 The Prismaﬂex machine and its blood circuit.

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preconnected kits with different surface area dialysers for adult treatments are available: the M100 (the same of the Prisma set with AN69 membrane), the HF 1000, and the HF 1400 (Figure 29.4), which have a larger surface (0.60, 1.00, and 1.40 m2 respectively), useful specially in high-volume therapies. The last two have also different membranes (polyarylthersulphone-PAES). Contrary to previous conﬁguration in the classic Prisma machine, here the blood inlet is at the bottom of the dialyser, facilitating priming procedure and elimination of air bubbles from the blood compartment. The innovative technical solution of two pinch valves provides the possibility of varying the ratio between pre- and postdilution with different simultaneous infusion rates. This ratio can also be changed during therapy. Pre- or postdilution mode can also be selected for CV VHDF modality. Heparin syringe pump has been designed to accommodate different types and sizes of syringes. Another innovative feature is now present in the Prismaﬂex machine: the ﬁfth pump. This pump delivers pre-blood-pump (PBP) ﬂuid infusion, and it makes possible to use citrate for circuit anticoagulation. This feature, in fact, allows citrate infusion just after the connection between the arterial access and the blood line. The blood pump is bigger than in the earlier version and it allows blood ﬂows within a range of 10–450 mL/min (depending on the ﬁlter in use). Fluid ﬂow rate allows a maximum ﬂuid handling of 8000 mL/h: both in hemoﬁltration and in hemodiaﬁltration. If PBP replacement solution is used, ﬂuxes can be further increased: in this case the blood pump is able to automatically adjust its rotational speed in order to maintain the prescribed blood ﬂow, which otherwise would be relatively decreased by the scaling down factor induced by PBP infusion. Total

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efﬂuent delivery is from 0 to 10000 mL/h, allowing a maximum ultraﬁltration of 2000 mL/h combined with the maximum dialysate/reinfusate ﬂow rate. All these schemes are clearly designed to meet the issue of high-volume hemoﬁltration. Prismaﬂex software controls ﬂuid ﬂows by an accurate pump-scales feedback: 30 g/h is the accepted error for each pump and an alarm warns the operator if this limit is exceeded. The accuracy warranty is further ensured by an end-of-treatment set up, in case of scale damage or need for calibration. When the therapy is interrupted by a pressure alarm, it automatically restarts if the pressure level normalizes within few seconds (i.e., during coughs or inadvertent line kinking due to patients movements). Scales have become four parallel sliding “drawers” positioned below the monitor, and are able to shift-out and allow easy and backsafe collection of ﬂuid bags. One of the most frequent concerns, the de-aerating chamber clots, has been challenged by an innovative design: the chamber is connected by a line to a pressure sensor that is able to adjust chamber blood level through a pump; a reversed cone inside the chamber makes the blood run into the return line with a whirling movement, which reduces stagnant ﬂows; furthermore when replacement solution is reinfused post ﬁlter, it is poured directly on top of this cone, in order to create a ﬂuid layer between air and blood. Sets are completed with efﬂuent collection bags of 9 L (Figure 29.5). This makes the application of high-volume therapies much more feasible without generating

Figure 29.5 The Prismaﬂex machine and its dialysate-ultraﬁltrate collecting bags.

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The Diapact machine (B.Braun, Melsungen) is derived from a series of prototypes called ECU (emergency case units). The system presents three pumps with a wide range of blood ﬂows (10–500 mL/min) and dialysate ﬂows (5–400 mL/min) (Figure 29.6). Fluid handling and ultraﬁltration control is gravimetric with one scale (Figure 29.7). Dialysate is warmed and the heparin pump is included. Reinfusion can be performed either in pre- or postdilution mode during hemoﬁltration.

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The Diapact CRRT

CHAPTER 29

an excessive workload of ICU nurses. The colored monitor displays pressures and ﬂows in the ﬁrst page and complete graphs and event lists in other history pages. A PCMCIA card allows to download these data into laptop computers. Among the new features, ﬁlters with modiﬁed and treated surface (ST 60, ST 100, ST 150) are today available with various surface area in different kits.

Figure 29.6 The Diapact machine.

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Figure 29.7 Details of the Diapact machine: screen, pumps, scales, and heater.

The machine is particularly suited for continuous high-ﬂux dialysis with possibility of operating either in single pass or in recirculation mode.

The Aquarius/Accura The Aquarius/Accura machine (Edwards Life Sciences, USA) is a modern machine for CRRT (Figure 29.8). The system includes four pumps and two scales with a possibility of performing all the CRRT techniques (Figure 29.9). The blood ﬂow can be varied from 0 to 450 mL/min while the dialysate ﬂow rate ranges between 0 and 165 mL/min. The system includes a preassembled tubing set and a wide color screen with a friendly user interface. The priming procedure is automatic. Fluid heater and the heparin pump are included in the machine. Two independent scales allow for an accurate and continuous ﬂuid balancing while four-pressure sensors help to monitor the extracorporeal circuit function. Pre, post, and simultaneous pre-post dilution modes are available. A remarkable ﬂexibility and versatility characterize the machine.

The 2008H/K The 2008H/K machine (Fresenius Medical Care, Walnut Creek, USA) is basically a standard hemodialysis machine that has been adapted to CRRT and mostly to slow low efﬁciency dialysis (SLED) by modifying the software and the

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Figure 29.9 Detailed front view of the Aquarius machine.

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Figure 29.8 The Aquarius machine.

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operational parameters (Figure 29.10). The machine is equipped with a blood pump plus three pumps for dialysate that are internal. Blood ﬂow can vary from 0 to 500 mL/min while the dialysate ﬂow in CRRT mode can be set at three ﬁxed values of 100, 200, and 300 mL/min. Dialysate is warmed and the heparin pump is built-in. The system does not include a reinfusion pump, and therefore hemoﬁltration techniques cannot be performed. The ultraﬁltration control is open-volumetric. Other machines, as depicted in Figure 29.2, are available in the world but they are not imported in the United States. This is a matter in which evolution is continuous and changes may occur every day. We did not intend to be complete in the description of all available machines but rather to describe some models as an example of CRRT technology. Therefore, the fact that our list may be

Figure 29.10 Fresenius machine utilized for SLED.

Recent experimental ﬁndings [18] have demonstrated the beneﬁcial impact of increasing the volume of ultraﬁltration during continuous hemoﬁltration therapy. Hemodynamic improvement has been observed in the experimental animal injected with endotoxin. Although the possibility of preventing the septic shock syndrome in humans by this technique has not been proven yet, in a controlled randomized trial we could demonstrate a clear reduction of the required dose of norepinephrine in septic patients treated with 6 L/h. The treatment seems to be promising and further investigation should include the possible use of larger surface areas as well as the use of more open membranes. To perform high-volume hemoﬁltration (HVHF) however, a clear deﬁnition of the operational ranges of the technique and a precise description of the technical requirements imposed by this form of therapy are deﬁnitely needed. According to present clinical practice, CV VH is generally performed with an average ultraﬁltration rate between 1 and 2 L/h. Above the value of 50 L per day, the amount of ultraﬁltration begins to be considered “high” and the treatment can be deﬁned as HVHF. There are, however, two ways to perform HVHF: (1) the standard CV VH treatment schedule is maintained and the rate of ultraﬁltration is maintained at 3–4 L/h; (2) the standard CV VH therapy is maintained overnight, but during few hours of the day, a large amount of ultraﬁltration is produced at rates above 6 L/h. In both cases the amount of ultraﬁltration exchanged per day may exceed 60 L. To perform this treatment several requirements must be fulﬁlled and, above all, a deep knowledge of the mechanism of transmembrane ultraﬁltration in the hemoﬁlters should be understood. High-volume hemoﬁltration (HVHF) requires large hemoﬁlters to accomplish the task of achieving a daily ﬂuid exchange in the range of 60–100 L. While in the treatment schedule (a) hemoﬁlters of 1.0 m2 can be utilized, for the schedule (b), hemoﬁlters in the range of 1.6–2 m2 are needed. In all these ﬁlters, high-ﬂux membranes are utilized. AN69, polysulfone, or polyamide membranes are generally employed with a permeability coefﬁcient between 30 and 40 mL/h/mmHg x m2. These membranes have solutes sieving coefﬁcients close to 1 in a wide spectrum of molecular weights. Therefore, in most cases, clearance value equals the amount of ultraﬁltration achieved. There may be some exception to this rule. One case is when the sieving coefﬁcient is less than 1 for a given solute. In other cases, there may be a reduction in the permeability of the membrane due to concentration polarization and secondary layer formation by the proteins.

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incomplete does not mean that we suggest or prefer one model against another. For a more detailed description of the machines, setup and troubleshooting, purchase and maintenance, we suggest that the nearest agent of the chosen company be contacted.

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This is most likely to occur in the presence of high ﬁltration fractions or in the case of long-term utilization of the hemoﬁlter (more than 24 h). Finally, clearance may be reduced by the presence of predilution, that is, in the case of administration of the substitution ﬂuid into the arterial line to replace ultraﬁltration. This reduces the oncotic pressure of plasma proteins and increases ultraﬁltration, but the efﬁciency of the system may be reduced by the parallel reduction in the concentration of the solutes in the incoming blood. Furthermore, since the availability of large quantities of substitution ﬂuid may be limited, new trends suggest the use of online production of replacement solutions by machines with built-in step ﬁltration techniques. These are already utilized in the chronic setting and they may become soon a practical approach for the patient undergoing HVHF.

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Special treatments and plasma therapies Based on the assumption that higher clearances may be required to remove proinﬂammatory mediators from the circulating blood, the other possible approach other than HVHF is that of utilizing a largely porous membrane. For this purpose we have recently employed a system that includes a continuous plasma ﬁltration and a subsequent reinfusion of the ﬁltered plasma into the venous line, after passage on a cartridge of uncoated carbon or speciﬁc resins [19, 20]. The system has offered interesting results in vitro and it is now utilized in a prospective randomized study in septic patients to evaluate the capacity of removing proinﬂammatory mediators and to reduce the pharmacological requirement of amines in the patient. This represents the latter treatment that can be included in the large list of techniques identiﬁed with the name of CRRT. More therapies are today emerging by utilizing the principle of CRRT for plasma exchange, plasma adsorption techniques, immunoadsorption techniques, therapy of support in liver failure conditions, and regional therapy for cancer. All these therapies will require further reﬁnement and studies, but they may well become part of the family of CRRT, especially in those cases when a continuous and prolonged extracorporeal treatment is indicated. In these cases, the modern machines are able to accomplish the difﬁcult tasks of performing complex and combination therapies. This is mostly done by built-in speciﬁc software that assigns a speciﬁc role to each pump and each component in the circuit.

Future trends The evolution in the technology of CRRT has only partially followed the more sophisticated evolution that took place in the equipment for chronic hemodialysis patients. In such patients, the increased morbidity and the progressively increased age require a gentle and carefully monitored hemodialysis therapy. To achieve such results, online monitoring techniques including urea sensors,

1. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. Arteriovenous hemoﬁltration: a new and simple method for treatment of over hydrated patients resistant to diuretics. Klin Wocherr-Scrift. 1997;55:1121-1122. 2. Ronco C, Burchardi H. Management of acute renal failure in the critically ill patient. In: Pinsky MR, Dhaunaut JFA, eds. Pathophysiobiologic Foundations of Critical Care. Baltimore: Williams and Wilkins; 1993;630-676. 3. Geronemus R, Schneider N. Continuous arterio-venous hemodialysis: a new modality for treatment of acute renal failure. Trans ASAIO. 1984;30:610-613. 4. Ronco C. Arterio-venous hemodiaﬁltration (AVHDF): a possible way to increase urea removal during CAVH. Int J of Artif Organs. 1985 8:61-62. 5. Ronco C, Bellomo R. Complications with continuous renal replacement therapies. Am J Kidney Dis. 1996;28(5)(suppl 3):100-104. 6. Ronco C. Continuous renal replacement therapies for the treatment of acute renal failure in intensive care patients. Clin Nephrol. 1993;4:187-198. 7. Ronco C, Bellomo R. Continuous renal replacement therapy: evolution in technology and current nomenclature. Kidney Int. 1998;53(suppl 66):S160-S164. 8. Ronco C, Bellomo R. Critical Care Nephrology. Dordrecht, The Netherlands: Kluwer Academic Publishers; 1998. 9. Ronco C, Brendolan A, Bellomo R. Current technology for continuous renal replacement therapies. In: Ronco C, Bellomo R, ed. Critical Care Nephrology. Dordrecht: Kluwer Academic Publishers; 1998,1269-1308. 10. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous venovenous haemoﬁltration on outcomes of acute renal failure. A prospective randomised trial. The Lancet. 2000;356:26-23. 11. Ronco C, Brendolan A, Bellomo R. On-Line monitoring in continuous renal replacement therapies. Kidney Int.1999;56(suppl 72):S8-S14. 12. Rahmati S, RoncoF, Spittle M, et al. Validation of the Blood Temperature Monitor for Extracorporeal Thermal Energy Balance during in vitro Continuous Hemodialysis. Blood Purif. 2001;19:245-250. 13. Ronco C, Ghezzi P, Bellomo R. New perspective in the treatment of acute renal failure. Blood Purif. 1999;17:166-172. 14. 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.

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temperature sensors, blood volume sensors, and teledialysis or biofeedback systems have been developed . All these systems are not yet implemented in the current CRRT machines or in some cases they are just partially utilized. The online monitoring techniques are, however, under scrutiny for the possible beneﬁts in the critically ill patients, and future trends may indeed include the development of machines equipped with these technologies.

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15. Ronco C. Continuous renal replacement therapies in the treatment of acute renal failure in intensive care patients. Part 1: Theoretical aspects and techniques. Nephrol Dial Transplant. 1994;9(Suppl 4):191-200. 16. Bellomo R, Ronco C. Continuous versus intermittent renal replacement therapy in the intensive care unit. Kidney Int. 1998;53(suppl 66):S125-S128. 17. Tetta C, Mariano F, Ronco C, Bellomo R. Removal and generation of inﬂammatory mediators during continuous renal replacement therapies. In: Ronco C, Bellomo R, ed. Critical Care Nephrology. Dordrecht: Kluwer Academic Publishers; 1998,1239-1248. 18. 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. 19. Tetta C, Cavaillon JM, Schulze M, et al. Removal of cytokines and activated complement components in an experimental model of continuous plasma ﬁltration coupled with sorbent adsorption. Nephrol Dial Transplant. 1998;13: 1458-1464. 20. Tetta C, Bellomo R, Brendolan A, et al. Use of adsorptive mechanisms in continuous renal replacement therapies in the critically ill. Kidney Int. 1999;56(S72):S15-S19.

Chapter 30

Quality assurance for continuous renal replacement therapies Ian Baldwin and Rinaldo Bellomo

There are different clinical parameters that can reﬂect the successful use of continuous renal replacement therapy (CRRT) and the successful achievement of relevant therapeutic goals. The major goals of CRRT include the achievement of desired toxic solute clearance, acid-base homeostasis, electrolyte balance, appropriate ﬂuid removal and balance, and temperature control. These goals should ideally be achieved in a timely and cost-effective manner. Establishing and maintaining a unit CRRT database is useful to gauge success, compare unit performance to that of others, and to review progress or change over time to detect potentially useful trends in performance. This quality improvement process is useful in respect of the changing clinical context, personnel changes and training requirements, new devices and CRRT machines, and access devices and technical variations in prescription for anticoagulation and ﬂuid balance. Data collection can be in the form of a speciﬁc “snap shot” assessment over a short period (e.g., 1 month) or continuous.

Deﬁnitions—key terms associated with CRRT and quality monitoring Filter life: Filter life is deﬁned as the time from the commencement of blood ﬂow through the ﬁlter until the time when the blood is unable to pass through the hemoﬁlter due to clot formation and obstruction. This is a useful variable for monitoring of the quality of CRRT. Collection of ﬁlter life is an important process and is a desirable, simple, and practical way of assessing the combined quality of access care, nursing care, and circuit anticoagulation. Off time (or down time): The time interval when no renal replacement therapy (RRT) is in progress, although expected and prescribed to be. It can be expressed as number of hours/day or as a percentage of each 24-hour period. Off time is

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commonly associated with circuit clotting due to the preparation time for a new circuit. Sometimes it is due to procedures outside the intensive care unit (ICU) or physical therapy and mobilization in some patients. As off time decreases the time that therapy is applied, it has adverse consequences on solute control and ﬂuid removal. Off time associated with ﬁlter clotting is a particularly good measure of quality in relation to the management of CRRT. A long mean off time period/day (>25%) is often an indicator of limited quality in CRRT circuit care. On time: Effective treatment time where RRT is in progress, equal to ﬁlter life, and can be expressed as a percentage of a 24-hour period. This is the mirror image of off time and can similarly be used as a marker of quality of CRRT circuit care. Adverse event: An unexpected and undesirable outcome secondary to CRRT. For CRRT this may be premature ﬁlter clotting and obstruction with blood loss, patient bleeding with excessive anticoagulation, hypovolaemia due to incorrect ﬂuid balance settings, arrhythmias due to inappropriate electrolyte or volume management, hypotension due to incorrect ﬂuid management or too rapid initiation of therapy, and other similar unwanted complications of CRRT. Snapshot data: Data collected to measure clinical care or outcomes over a short period, designed to provide a quick picture that might be suggestive of a long-term behavior, trends, or outcomes. Catheter tip culture: Assessment of a catheter tip (e.g., access catheter) for microbiological culture to identify the presence of catheter colonization. Consumables (disposables): Components that together make a functioning system and, in the case of CRRT, a circuit. Commonly, disposable plastic pieces connecting together are known as disposables or consumables. Common useful quality measures are listed next as well as summarized in Table 30.1. Below, we discuss some important aspects of quality improvement (see Table 30.2). 1. Daily review of patient’s biochemistry and ﬂuid balance for adequate volume control is vital. This would appear as an obvious quality activity. However, a bedside review is useful, particularly where prescribing physicians and nurses change frequently for the same patient over many days. Fluid balance needs to be assessed to see if inputs exceed ﬂuid loss. Fluid removed by the treatment does not necessarily mean a neutral or negative patient balance has been achieved. This is an important process to clarify in bedside discussions and treatment prescriptions to ensure that goals are being achieved. Adequate written and formal documentation of ﬂuid management goals and ﬂuid balance is mandatory. 2. Number of patients treated, duration of each treatment, and days of treatment for each patient are the most important and necessary data. Some ICU database schedules capture this already. However, a review of these data is useful for a team providing CRRT. Individual treatment data can be maintained on bedside charts/computers and is very helpful in monitoring

Solutes, urea, and creatinine should be declining or stable each day. Fluid loss is usually required and each day should achieve this considering all ﬂuids inputs and losses, and not the machine alone. An accurate patient weight is useful. Number of Useful data for justifying staff levels, budgeting, patterns in prescribing, patients treated and number of machines in use. The time Can reﬂect differences over 24-h periods, stafﬁng changes, training, and without treatment medical review. May also reﬂect inadequate dosing and under treatment, if excessive. Errors and Frequent mistakes reﬂect a need to change policy or additional training, adverse events resource development. For example, ﬂuid balance mistakes may suggest misunderstanding in orders and how clinicians interpret ﬂuid loss. Is this machine loss or patient net loss? Access catheters How many access catheters are being used, are they being replaced used frequently? Such data can suggest a need to change methods, use new design, and/or maintenance and care routines. For example, this may relate to management of the device when not used, dressing, and securing. Cost of Useful to have up-to-date knowledge of this to determine average cost for consumables each patient and wastage, to make quick estimates when considering new and alternative products. The total cost of all consumables and the number of patients treated annually indicates the cost per patient. Note: Q.A. = Quality Assurance.

Table 30.2 List of CRRT problems and appropriate responses Problem Frequent ﬁlter clotting

Long ‘off time’ Errors in ﬂuid balance Patient on high vasopressor therapy and hypotension

Unexplained fever or leukocytosis Swollen limb distal to catheter

Response Review choice and placement of vascular access catheter, review anticoagulation policies, review nurse training–nurse machine interface. Review nurse training. Emphasize need to prime circuit efﬁciently. See above responses to frequent ﬁlter clotting. Optimize physician and nurse education. Accurately chart ﬂuid balance and ensure clarity of medical prescription of desired ﬂuid balance. Develop and use a CRRT prescription orders sheet. Initiate CRRT slowly. Begin with slow blood ﬂow (20–30 mL/ min) for up to 5 min until the circuit is ﬁlled with blood and blood is returning to the patient. Slowly increase blood pump ﬂow to desired rate by 20–50 mL/min increments. Initiate ﬂuids therapy only after blood ﬂow is at desired level. If necessary increase vasopressor drug therapy by 10%–20% before the start of CRRT and return it to baseline levels once therapy has been established. Examine vascular access site. Consider removal of catheter (guidewire exchange preferred as initial step). Consider deep venous thrombosis. Perform ultrasound. If large clot present, initiate anticoagulation. Do not immediately remove catheter as this can trigger lethal embolism.

Quality assurance for CRRT

Clinical comment

Daily review

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Q.A. item

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Table 30.1 Quality indicators associated with RRT

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3.

250

4.

5.

6.

success and failure in a patient. Sequential, progressive charting of a treatment, with each new treatment starting again at hour “1,” achieves this and provides a quick assessment for time “on treatment” or ﬁlter life. A common ﬁlter life using CRRT across all patients in the ICU is a median of 20 consecutive hours. The mean value is often skewed by outlying data: one very long or short treatment. The time without treatment or “off time” in each patient is the time where no RRT is functioning or the “off time” is a useful measure of efﬁciency, as solute levels will increase with increasing “off time.” There are many reasons for extended periods without CRRT being applied despite a continuous prescription. However, these data can reﬂect inefﬁcient practices, lack of nursing staff and skill, delayed medical review, the frequent need for out-of-ICU diagnostics, and bad policies. Such data are often not reported. However, publications indicate that an off time of approximately 5 hours for each 24 hours may be common. Errors, adverse events and mistakes, speciﬁc alarm events, and machine repairs are relatively common. Although many mistakes and malfunctions are not reported or lack surrounding context data, these data provide useful feedback to the CRRT team. Such data must be managed with sensitivity and used to improve CRRT in a constructive manner, avoiding individuals being targeted. Frequent identical events reﬂect a need to change and modify policy. Where many CRRT machines exist, naming each machine makes tracking of machines and repairs or failures easier. Access catheters used and microbiology associated with use. Access devices can be overlooked as separate from therapy. The number used and type and site of insertion provide useful data. A database with information on such devices, site of insertion, time of insertion, date of insertion, person who inserted the device, and complications related to insertion or subsequent catheter colonization or infection or vessel thrombosis are very useful in monitoring the safety and quality of catheter management. Cost of consumables–circuits. This information provides feedback for managers and helps with decision making on purchasing and supply contracts.

Summary Collection and review of patient’s daily biochemistry, ﬁlter life, and time without treatment, all provide useful measures of CRRT quality. Biochemistry should reﬂect solute reduction, ﬁlter life should be approximately 20 hours, and time without treatment minimal. Reviewing adverse events, machine repairs, simple mistakes, and errors is necessary to prevent serious harm during CRRT. Such information helps guide better education and policy development. Cost data can be a measure of success as increasing costs will be associated with inefﬁcient treatments, access catheter malfunction, and poor ﬁlter life. The safety and quality of CRRT are highly dependent on the collection of quality improvement

Quality assurance for CRRT

Baldwin I. Factors affecting circuit patency and ﬁlter life. Contrib Nephrol. 2007;156: 178-184. Baldwin I, Bellomo R. Relationship between blood ﬂow, access catheter and circuit failure during CRRT. A practical review. Contrib Nephrol. 2004;144:203-213. Baldwin I, Bellomo R, Koch B. Blood ﬂow reductions during continuous renal replacement therapy and circuit life. Intensive Care Med. 2004 Nov;30(11):2074-2079. Baldwin I, Tan HK, Bridge N, Bellomo R. Possible strategies to prolong circuit life during hemoﬁltration: three controlled studies. Ren Fail. 2002 Nov;24(6):839-848. Ronco C, Ricci Z, Bellomo R, Baldwin I, Kellum J. Management of ﬂuid balance in CRRT: a technical approach. Int J Artif Organs. 2005 Aug;28(8):765-776. Tan HK, Bridge N, Baldwin I, Bellomo R. An ex-vivo evaluation of vascular catheters for continuous hemoﬁltration. Ren Fail. 2002 Nov;24(6):755-762. 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(4):c94-c98.

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data as outlined above. If this is not done, the quality and safety of CRRT are seriously undermined and patients are exposed to the risk of major complications.

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Chapter 31

Educational resources Ian Baldwin and Kimberly Whiteman

Continuous renal replacement therapy (CRRT) requires a signiﬁcant commitment to ongoing education and training. New machines for CRRT are automated for the priming and preparation sequence; however they continue to be challenging for learners to master and operate safely. In addition, ﬂuid balance and anticoagulation regimens can be a source of mistakes without adequate nurse education and training. It is also important to recognize that suppliers’ operating manuals for machines are not always suitably prepared for the clinical environment, and idiosyncrasies of clinical patient care when using a machine need to be developed and taught locally. The application of theoretical frameworks into psychomotor clinical knowledge for the extracorporeal circuit (EC) is a challenge for the nursing instructor and is best achieved using a variety of approaches. This recognizes that people learn in different ways and may need different experiences to gain knowledge and clinical skills. Instructional methods can include video review; system simulation exercises; circuit set up using suitable abstract models, such as drawing board exercises or computer diagrams; priming practice with nonsterile circuits on machines when not in use; bedside instruction; and ﬁnally “live” patient care experience(s) with and without supervision. The educational needs can be divided into introductory competency development and ongoing continuing education.

Introductory education: theory and practical training Theory must accompany practical training. Nurse caring for CRRT patients need to know the science behind treatments and how to safely operate the equipment. In addition, education about ﬂuid balance and anticoagulation regimes helps to eliminate errors. A one-day seminar with guest speakers for theory in the morning and practical machine activities in the afternoon is useful for groups of 8–12 nurses (see Figure 31.1).

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Figure 31.1 The continuous renal replacement therapy (CRRT) classroom for theory using standard lecture set.

Theory can be taught as a lecture set with course handout notes and current journal references. Suggested lectures include the following: • Acute kidney injury (AKI) and critical illness • Begin the course with a review of AKI and historical treatments such as hemodialysis and peritoneal dialysis. Include and emphasize that treatments should be initiated as soon as possible after the placement of the temporary dialysis catheter. Standard safety measures with central lines such as radiographic conﬁrmation of line placement should be complete prior to treatment initiation. Emphasize the need for immediate treatment of patients with severe electrolyte imbalances and not to wait for initiation of CRRT. For example, patients with high potassium levels should be treated with standard regimes like insulin and glucose or sodium polystyrene sulphonate (kayexylate) until CRRT can be started. • Theory of solvent and solute removal • Describe the principles of ultraﬁltration, diffusion, and convection. Discuss clearance of ﬂuid and small molecules as the goal of treatment. Drug levels can also be affected by CRRT. • Types of CRRT: SCUF, CV VH, CV VHD, CV VHDF • Use diagrams and drawings to discuss the hemoﬁlter and each of the four possible treatments.

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In diffusive techniques the hemoﬁlter is a dialyzer with hollow ﬁbers inside. The blood ﬂows through the center of the hollow ﬁbers. The dialysate ﬂows around the hollow ﬁbers. Generally, the blood and ﬂuid ﬂow in opposite directions, called countercurrent ﬂow. • The ﬂuids ﬂow path varies slightly depending on the treatment. It is important that class participants understand that the dialysate ﬂuid does not directly enter the blood stream. Dialysate ﬂows around the hollow ﬁbers, diffusion occurs, and waste is drained directly into the efﬂuent bag or dialysis drain along with the patient’s ﬂuid removed during treatment. Depending on the manufacturer, replacement ﬂuids might enter the blood stream before or after the ﬁlter or both. They may also be added in a separate intravenous line. • The blood path for all CRRT modalities is that the blood is pulled from the patient, enters the ﬁlter through tubing that is color-coded red (access), exits the ﬁlter, and is returned to the patient in lines color-coded blue (return). • Fluids and ﬂuid balance • Review the dialysis principles and blood and ﬂuid ﬂow used in each of the four types of CRRT. 1. SCUF: ultraﬁltration 2. CV VH: convection and ultraﬁltration 3. CV VHD: diffusion and ultraﬁltration 4. CV VDF: diffusion and convection • Discuss the components of net ﬂuid balance for any given period of time. — Net ﬂuid balance = All ﬂuids in – All ﬂuids out — Generally the goal for ﬂuid balance will be zero or a negative number • Each day the nursing staff should be made aware of the ﬂuid balance goals set for the patient. Periodically, throughout each shift, check to see if the ﬂuid balance goals are being achieved. • Review examples of clinical situations where blood transfusions or new orders for large volumes of antibiotics affect the net negative balance. • Review any site-speciﬁc protocols for achieving net negative goals. This might include a standing order to call the physician if the net negative ﬂuid balance goals are not met or a protocol to increase ﬂuid removal rates with blood transfusions. • Manufacturers vary with regard to what ﬂuids are automatically calculated into the machine ﬂuid balance and what ﬂuids need to be added separately. This is important for calculating the intake and output and machine pump rates and can be repeated during the documentation session. • Anticoagulation protocol and potential complications • Discuss the reason for anticoagulation and review any site-speciﬁc protocols for administration and monitoring. •

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• •

If citrate is used, review ionized calcium monitoring, signs and symptoms of hypocalcemia and hypercalcemia and calcium replacement protocol. If heparin is used, review protamine reversal protocols, prothrombin time (PT), and international normalization ratio (INR) normal values.

Other course materials may include the following: • Excerpts from the manufacturer’s operator manual reprinted with permission. • References, lectures, and course material may also be placed on computers or intranet sites for reference. • Hospital policy or protocol documents. They are an essential reference. As with many areas of intensive care machine management, a multidisciplinary consensus policy is useful as a “baseline” reference point for learners. Some new learners prefer a bulleted list of the descriptive steps and pictures in lieu of the procedure, which can be long once rationale is added. • Emergency procedures to be followed in the case of cardiac arrest. Consider duplicating this content in the practical part of the course, possibly with an explanation with the theory and a scenario with the practical experience.

Practical experience After formal lectures, participants in a one-day class should be given some time to work with the machine that will be used in clinical treatment. The following components are suggestions for practical experience. For small classes use a sequential model. For larger classes breakout sessions with a ﬁnal demonstration of how to put all the steps together can help to save time and keep the participants engaged: • Machines and extracorporeal circuit setup • In a controlled classroom environment, each nurse should be given the opportunity to set up and prime a machine. In larger classes, work in pairs. Allow the nurses time to read on-screen directions and help screens. • Care and maintenance of temporary dialysis catheter • Have the temporary dialysis catheters used in the clinical areas at your site available in class for participants to handle and view. • Discuss catheter placement. Catheters ( e.g., 15–20 cm) placed in the right internal jugular vein have the most direct path to the right atria and tend to have the best ﬂow. Left internal jugular and femoral veins can also be used. Longer catheters (e.g., 24 cm) are used in the femoral vein only. This length catheter is unsuitable for jugular or subclavian use. The subclavian site is generally used last to preserve its integrity in case a semipermanent dialysis catheter might need to be inserted later.

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Review the ﬂow through the double-lumen dialysis catheter. This lumen is color-coded red and is sometimes referred to as the “access” line. Blood is returned through the blue lumen or “return” that exits at the distal end of the catheter. This design prevents recirculation of clean blood through the circuit. • When CRRT is interrupted or discontinued, the temporary dialysis catheter is capped. End caps that will not accommodate needle or IV entry are preferred. Often an anticoagulant, such as heparin, is instilled in the lumens. Lumens should be clearly labeled with the type and dose of anticoagulant. Consider placing a label or barrier over the end caps as a physical reminder to personnel that anticoagulant is present and needs to be withdrawn before use. • Entrance into the temporary dialysis catheter and dressing changes should be performed using aseptic technique and should follow hospital policies for dressings and sterile procedures. • Two “online” sources of evidence-based practice for renal dialysis nurses can be helpful in developing policies and procedures about temporary dialysis catheters: — American Nephrology Nurses Association (ANNA) at www.annanurse.org — National Kidney Foundation Kidney Disease Outcomes Quality Initiative at www.kidney.org/Professionals/kdoqi • Nursing care of a patient on CRRT including troubleshooting of the machine, the temporary dialysis catheter, and patient. Use the acronym P-A-C-E for troubleshooting: • Patient—Look at the patient ﬁrst. Coughing, patient positioning, and movement can sometimes set off alarms. • Access refers to the temporary dialysis catheter. Check for a blood return and ﬂow before use and for patency, kinks, or clamps when alarms occur. Consider teaching a standard access troubleshooting sequence. An example is given below: — Release kinks in the catheter. — Reposition the patient. — Reposition the catheter. — Attempt to ﬂush the catheter. • Circuit is the disposable ﬁlter and tubing. Clots or gas bubbles can cause alarms. Teach participants to remove bubbles from lines following the manufacturer’s guidelines. • E quipment failure or power outages can cause a disruption in care. Emergency procedures for equipment failure should be developed and reviewed in class. • Alarm conditions • Common alarm conditions can easily be simulated in the classroom setting. •

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Suggested alarms that should be simulated in class include access and return line kinks, air in line and alarms that require nursing intervention such as ﬂuids bag changing and ﬂuid balance settings. • Nursing staff should be aware that repeated alarms should be thoroughly investigated. Consider a “three strikes” policy that requires nurses to seek help if unable to remedy an alarm on the third try (see Figure 31.2). • Termination of treatment • Review the sequence for termination of treatment. Consider combining this with a scenario that includes ﬂushing the temporary dialysis catheter, instilling anticoagulant, and labeling. • If desired, develop a protocol for recirculation or temporary disconnection for off-unit interventions, such as in radiology, or in the operating room. • Documentation • Documentation of the intake and output is critical for managing ﬂuid balance. Whenever possible, use actual tools that will be used for documentation at the bedside in class. Use several hours of data for intake and output numbers and check that all participants are able to complete the charting accurately. •

Learning environment Offer a variety of practical approaches for learning. Develop methods for teaching CRRT that appeal to a variety of learning styles including the following: • Video instruction for review or individual learning. Some manufacturers provide videos for their products. • Cue cards or quick reference charts that can be kept with the machine after class. • Troubleshooting tutorials to include common alarm conditions and potential complications of treatment including hypothermia, air embolism, and frequent ﬁlter clotting.

Alarm sounds

If alarm resets: Continue CRRT.

Figure 31.2 Troubleshooting tree.

If same alarm ×3 and patient is stable: Continue CRRT. Seek help.

If same alarm × 3 and patient is unstable: Discontinue CRRT. Seek help.

Unsterile circuit prepared with RRT machine. Use saline bag as patient. Use resuscitation mannequin as patient. Simulation Patient care with supervision and teacher support.

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Abstract

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Training sequence Discussion using white-board and circuit diagram or sketch.

“Live” experience Figure 31.3 Suggested learning sequence useful in continuous renal replacement therapy (CRRT) training.

• Case exemplars that include common errors in clinical practice including ﬂuid

time for practical learning. This varied approach to learning can link together the sequence of abstract discussion, simulation, and then “live” experience (see Figure 31.3.).

Assessment of learning Quiz, demonstrations of key skills by the participants, or other measurements of learning should be developed. Participation in a debrieﬁng session after troubleshooting simulations or live experience can help with development of critical thinking skills. Observation of clinical practice can be evaluated following the formal class day either by the instructor or by CRRT clinical experts on the units. Encourage learners to describe their understanding of alarms and problems in addition to their suggested remedy to demonstrate their understanding. This is in contrast to simply correcting the problem each time.

CRRT champion Following initial training, bedside experts are necessary to sustain a program. A nurse instructor or experienced clinical nurse on staff is necessary to “champion” CRRT and link together education and clinical implementation. The CRRT champion will need to be able to work with other disciplines within the organization and with the manufacturer to coordinate care of patients. Periodic updates to standards and policies need to be completed and disseminated (see Figure 31.4).

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balance and anticoagulation errors. • Mentored experience with CRRT where expert nurses provide an extended

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RRT and multidisciplinary team Standards Nurses Policies and documents

Technicians Physicians

RRT education

Pharmacy Patient care: RRT

Suppliers Teachers

AUDIT

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Figure 31.4 The continuous renal replacement therapy (CRRT) educator is central to others involved and “champion” for this specialized aspect of nursing in the ICU.

Competency and ongoing education Nurses will be exposed to patients on CRRT at varying levels depending upon medical practice and patient care needs. The CRRT educator or champion should plan for programs to ensure ongoing competence of staff. Quality and risk management reports as well as manufacturer changes to machine hardware and software can be used to develop periodic competency updates for clinical staff. As with the introductory stage of learning, competency and continuing CRRT education may be enhanced by using simulation or scenarios. Competency can be done on a yearly or as-needed basis. Consider the development of an advanced CRRT user program or unit-based expert development program. This program could include more in-depth troubleshooting and current trends in practice taken from the literature.

Online educational resources Online educational resources can be accessed to keep abreast of current trends and network with other CRRT professionals. The following web sites can be used as an introduction to online CRRT communities: • Acute Dialysis Quality Initiative: http://www.adqi.net/ • Adult CRRT: http://www.crrtonline.com/ • Pediatric CRRT: http://www.pCRRT.com/

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Skilled application of CRRT in the ICU is a specialized area of knowledge for nurses. As with mechanical ventilation and cardiac support devices, it takes time to learn the “language,” make sense of the treatment prescription, and master the machines that are used to provide treatment. Theory, abstract learning, simulation, and live experience with supervision, all facilitate learning and the development of clinical expertise. An experienced nurse champion who has been educated in the care of patients on CRRT is an effective way to achieve this in a busy ICU environment. Education and stafﬁng to support a CRRT program helps to assure positive patient outcomes.

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Summary

Alspach JG, ed. Core Curriculum for Critical Care Nursing. 6th ed. St. Louis: Saunders Elsevier; 2006. Baldwin I. Training management and credentialing for CRRT in critical care. Am J Kidney Dis. 1997;30(5)(suppl 4):S112-S116. Bashaw S, Baldwin I, Fealy N, Bellomo R. Fluid balance error in continuous renal replacement therapy: a technical note. Int J Artif Organs. 2007;30(5):435-440. Clevenger K. Setting up a continuous venovenous hemoﬁltration educational program. Crit Care Nurs Clin North Am. 1998;10(2):235-244. Dirkes S, Hodge K. Continuous renal replacement therapy in adult ICU patients: history and current trends. Crit Care Nurse. 2007;27(2):61-80. Jones S. Heat loss and continuous renal replacement therapy. AACN Clin Issues. 2004;15(2):223-230. Langford S, Slivar S, Tucker SM, Bourbonnais FF. Exploring CRRT practices in ICU: a survey of Canadian hospitals. Dynamics. 2008;19(1):18-23. Rauen CA. Using simulation to teach critical thinking skills. Crit Care Nurs Clin North Am. 2001;13(1):93-103. Talbot TL, Rosenthal CH, Strider VC. Collaborative development of a patient simulator for educating nurses in hemoﬁltration therapies. Biomed Instrum Technol. 1994;28(4): 271-281. Wiegand LM, Carlson K, eds. AACN Procedure Manual for Critical Care. 5th ed. St. Louis: Elsevier Saunders; 2005.

Glossary of terms Deﬁnitions—key terms associated with training and education for CRRT. Abstract CRRT model: An activity using concepts with readily available representative materials and some aspects of simulation to prepare for real life events. Examples of an abstract CRRT model include simple cutout pictures of CRRT machines and components rather than the machine itself.

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Suggested readings

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Competency: The ability to perform a task or skill within a set time with no mistakes. An example is the ability to recognize an error and ﬁx that error demonstrates the level of competency. Education: A process providing instruction and information for analysis and knowledge development, responding to cognition. Lecture cluster: A series of lectures designed and presented in sequence. Used where information is sensitive to logical ﬂow in learning from simple to complex. Live experience: Undertaking tasks and applying knowledge previously learned in a simulation or education process in a real nonartiﬁcial situation. CRRT simulation: An activity patterned after real life events in order for learners to develop knowledge without fear of mistakes, and seek feedback while developing or demonstrating competency. Training: A process in order for learners to obtain psychomotor skills required to perform a task.

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Troubleshooting: Recognizing an error and applying remedies to correct the error with effect.

Index

A Abdominal compartment syndrome, 6–7, 8 Accelerated veno-venous hemoﬁltration (AVVH), 191, 193 Access catheter, 129, 249, 250 femoral, 36 type and site, 131 vascular, 23, 103, 131 Acid-base and electrolyte disorders, in CRRT, 61–76 acid-base management, 72–73 calcium, 68–72 dysnastremias, 62–65 electrolyte management, 61, 62 magnesium, 65–68 metabolic acidosis, 73–75 metabolic alkalosis, 75–76 phosphate, 68–72 potassium, 65–68 Acid citrate dextrose (ACD), 165, 171 Activated charcoal, 176, 182, 194 Acute kidney injury (AKI), 3–9, 205, 254 classiﬁcation of, 3, 4 clinical consequences, 9, 9 etiology of, 5–6 hypotension, 6 incidence and progression, 4–5 management of, 7–8 postoperative, 6 renal replacement therapy for, 79–91 risk factors of, 5 sepsis-induced, 5 volume-responsive, 5 Adsorption, 49, 108 coupled plasma ﬁltration, 91, 185, 186, 187 efﬁciency of, 183–184 immunoadsorption, 244 membrane, 80 plasma, 244 relative selective, 182 selective, 182–183 AKI. See Acute kidney injury Alarms and troubleshooting, in CRRT, 121–128 alarm systems, 123, 124 circuit pressure, 122–123 clogging circuit, 123–125 ﬂuid balance errors, 125–126 training, 121 troubleshooting checklist, 127 Albumin dialysis, 175 Anticoagulation, 135–139, 141, 254–255 administering, 137 herapin, considerations, 138–139

orders, 193 regional citrate, 141–145 Antimicrobials concentration-dependant, 152, 153 dosing recommendations, 154 time-dependant, 153 Apheresis devices, 169–171 anticoagulation, 170 centrifugal cell separators, 169–170 extracorporeal circuit, priming, 170 membrane ﬁltration cell separators, 170–171 Aquarius/Accura CRRT, 164, 231, 233, 240, 241 Argatroban, 193

B Baxter CRRT, 164, 231, 233, 240, 241 Billing codes, for CRRT, 223–225, 224 continuous dialysis/CRRT, 224–225 critical care services, 224 dialysis catheters and modiﬁers, for multiple procedures, 225 initial hospital care–new or established patients, 224 initial inpatient consultations– new or established patients, 223–224 initial patient evaluation, 225–226 subsequent hospital days, 226 subsequent hospital ﬂow-up, 225 Bioartiﬁcial liver support, 176 Biocarbonate, 116–117 Blood ﬂow maintenance, in extracorporeal circuit, 131–132 “air-bubble trap” chamber, 132 access catheter size and type, 131, 131 circuit preparation, 131 membrane size and type, 131 rate, setting, 131 substitution ﬂuids administration site, 132 training and education for staff, 132 Bubble trap. See Air trap

C Calcium, 68–72, 116 Calcium chloride, 193 Catheter-related bloodstream infections (CRBSI), 96

Catheters access, 23, 36, 129, 131, 249, 250 dialysis billing codes for, 225 silicone, 93 site, 122 size, 122 troubleshooting, 122 types of, 93–94, 94, 122 CAVH. See Continuous arteriovenous hemoﬁltration CAVHD. See Continuous arteriovenous hemodialysis CAVHDF. See Continuous arteriovenous hemodiaﬁltration Children, RRT in, 159–165 continuous veno-venous hemoﬁltration, 164–165 hemodialysis, 162–163 indications, 159 peritoneal dialysis, 159–162 Chloride, 115, 116 Citrate, 117, 136 toxicity, during TPE, 171–173 Continuous arterio-venous hemodiaﬁltration (CAVHDF), 101, 229 Continuous arterio-venous hemodialysis (CAVHD), 100, 229. See also Hemodialysis Continuous arterio-venous hemoﬁltration (CAVH), 100, 229. See also Hemoﬁltration Continuous veno-venous hemodiaﬁltration (CVVHDF), 20, 21, 101, 144, 230, 254 and CVVH, comparison, 31, 31 prescription for, 104 and solute transfer, 30–31 Continuous veno-venous hemodialysis (CVVHD), 20, 21, 100, 229, 254 Continuous veno-venous hemoﬁltration (CVVH), 12, 13, 14, 19–20, 20, 100, 145, 230, 254. See also Hemoﬁltration in children, 164–165 access, 164 anticoagulation, 164–165 blood ﬂow, 164 blood pressure, 164 dialysate-replacement ﬂuid ﬂow rate, 164 extracorporeal volume, 164 and CVVHDF, comparison, 31, 31 and solute transfer, 29–30 Contrast agents, 43 Convection, 19, 24, 28–29, 84, 86, 99 and diffusion, interaction, 88

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Note: Page numbers in italics refer to ﬁgures and tables.

INDEX

Coumadin. 136 Coupled plasma ﬁltration adsorption (CPFA), 91, 185, 186, 187 CRRT program, development of, 213–221, 214 factors affecting, 216–218 ﬁnancial considerations, 219–221 ﬂuid balance and dialysis errors, sources of, 218 forces in, 215–216 nephrologist, role of, 219 requirements for, 214–215 untraﬁltration with hybrid/CRRT recommendations for preventing complications during, 218–219 Cytokines, 182

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D Dialysate, 102 Dialysis, 176 albumin, 175 catheter billing codes for, 225 continuous, 224–225 errors, 218 membranes, 83 peritoneal, 159–162 slow low efﬁciency, 23, 23, 240 solution composition, 191 solution ﬂow rate, 192 Dialyzer, 24 Diapact CRRT, 239–240, 239, 240 Diffusion, 24, 27–28, 84, 85, 99, 101 and convection, interaction, 88 Diuretic therapy, 39, 40 Donabedian model, of quality healthcare, 205–210, 205 Dose adequacy and assessment, of RRT, 53–59 delivery, continuous and intermittent, 56–58 practical aspects, 55–56 prescription, 56 theoretical aspects, 53–55 Drug adsorption, 150 Drug dosing, in CRRT, 147–154 drug properties, 151–152 elimination, 152 molecular weight, 151 protein binding, 151, 151 volume of distribution, 151–152 ﬁlter properties, 148–149 membrane composition, 149 membrane permeability, 149 ﬂow rates, 149 patient properties, 149–150, 150 pharmacodynamic principles, 152–153 concentration-dependant antimicrobials, 152, 153 time-dependant antimicrobials, 153 recommendations, 153–154 antimicrobials, 154 techniques, 147–148, 148 Drug/toxin removal, 42–43

E Education, 261. See also Educational resources introductory, 253–256 ongoing, 260 Educational resources, 253–261. See also Education competency, 260 CRRT champion, 259, 260 learning assessment, 259 learning environment, 258–259, 259 ongoing education, 260 online, 260 practical experience, 256–258, 258 theory and practical training, 253–256 Efﬂuent, 33–34, 102 Endotoxin, 181, 194 Extended indications, for CRRT, 47–51 considerations, 50 methods, 49 Extracorporeal circuit (EC), 23, 141, 176 blood ﬂow maintenance in, 131–132 “air-bubble trap” chamber, 132 access catheter, 131, 131 circuit preparation, 131 membrane size and type, 131 rate, setting, 131 staff training, 132 substitution ﬂuids administration site, 132

F Filter. See Dialyzer Filter life, 129, 135, 141, 247 Filtration fraction, 101, 130 Fluid balance, 34, 34–35, 254 Fluid management, in CRRT, 33–36 beneﬁts, 36 considerations, 35 expected outcomes, 35 ﬂuid balance, 34 problems, 35–36 Fluids, 115–119, 254 buffer composition, 116–117 compounding, 119 electrolyte composition, 115–116 example, 118–119 prescription during permissive hypercapnia, 118 Fresenius CRRT, 191–193, 240, 242–243, 242

G Gambro CRRT, 192, 235–239, 237, 238 Glomerular disease, 6, 8 Glucose, 115, 116

H Hemodiaﬁltration, 85, 101, 148 continuous arterio-venous, 101, 229

continuous veno-venous, 20, 21, 26, 30–31, 31, 101, 104, 230 double chamber, 185, 186 Hemodialysis, 99, 148 in children, 162–163 access, 162, 163 anticoagulation, 163 blood ﬂow, 163 dialysis blood lines and dialyzers, 162, 163 time, 163 ultraﬁltration, 163 continuous arterio-venous, 100, 229 continuous veno-venous, 20, 21, 100, 229 electrolyte management in, 61 and surface area, 113 Hemoﬁltration, 84–85, 99, 148 accelerated veno-venous, 191, 193 adjunctive, 193 in children, 164–165 access, 164 anticoagulation, 164–165 blood pressure, 164 bloodﬂow, 164 dialysate-replacement ﬂuid ﬂow rate, 164 extracorporeal volume, 164 continuous arterio-venous, 11, 100, 229 continuous veno-venous, 12, 13, 14, 19–20, 20, 29–30, 31, 31, 100, 145, 164–165, 230 electrolyte management in, 61 high-cutoff, 48, 48, 49 high-volume, 48, 48, 49, 90, 243–244 of large molecules, 90–91 postdilution, 86–87 predilution, 87 surface area effects of membrane in, 111–112 Hemolytic uremic syndrome, 6 Heparin, 12, 96, 125, 131, 135, 136, 161, 230, 237 anticoagulation, 138, 139, 164–165, 171 coating, 137 low molecular weight, 136 unfractionated, 190, 193 High-cutoff hemoﬁltration, 48, 48, 49 High-volume hemoﬁltration (HVHF), 48, 48, 49, 90, 243–244. See also Hemoﬁltration Hybrid therapies, 189–195 brief orders, 189–194 anticoagulation orders, 193 blood ﬂow, 191 dialysis solution composition, 191 dialysis solution ﬂow rate, 192 ﬂuid removal, 192–193 session length, 190–191 substitution ﬂuid ﬂow rate, 193 timing of treatment, 194 features of, 189

I Intensive care unit (ICU) approach to critical care clinical, 203–204 organizational, 201–203, 203 outcome measures, 204 closed unit, 200 environment, challenges of, 201 monitoring, 199 open unit, 200 prevention, 199 specialized, 201, 202 stafﬁng, 200–201 support, 199 Intermittent hemodialysis (IHD), 22, 22, 89, 117 and CRRT, comparison between, 57 Interstitial nephritis, 8

L Lactate, 116–117 Lactic acidosis causes, 74

M MARS. See Molecular adsorbent recirculating system MATISSE, 183 Membrane, in CRRT, 107–114 composition, 149 hollow ﬁber, 107–108 permeability, 149 secondary membrane formation, on solute permeability, 110–111, 111 surface area effects, 111–113 in hemoﬁltration, 111–112 in hemodialysis, 113 synthetic, 107–108 ultraﬁltration rate and transmembrane pressure, relationship, 108–110, 109 Metabolic acidosis, 41–42, 73–75 causes, 73–74 clinical features, 74 CRRT management, 74–75 management, 74 Metabolic alkalosis, 75–76 causes, 75 CRRT management, 74–75

N NxStage CRRT, 164

P Peritoneal dialysis (PD) in children, 159–162 access, 160 apparatuses for, 160 complications, 161–162 contradictions to, 160 dialysate, 161 dwell time, 161 dwell volume, 161 prescription, 160–161 Phosphate, 68–72, 115, 116 Plasma exchange, 244 Polymyxin B-immobilized ﬁbers (PMX), 182–183, 187 Postdilution, 22, 86–87, 102 Potassium, 65–68, 115, 116 Predilution, 22, 87, 102, 129 Prisma CRRT, 235–236, 236 Prismaﬂux CRRT, 236–239, 237, 238 Prostacyclin, 136 Protamine, 136 Protein binding, 150, 151

Q Quality assurance, for CRRT, 247–251

R Regional anticoagulation, 137, 142 Regional citrate anticoagulation (RCA), 141–145 method, 142–143 considerations, 143–144 Replacement ﬂuid, 102 Rhabdomyolysis, 6 RIFLE Criteria, 3–5, 4

S SCUF. See Slow continuous ultraﬁltration (SCUF) Sepsis humoral theory, 47 sorbents in, 186–187 target substances removal by, 181–182 Sepsis-induced AKI, 5 Sieving coefﬁcient, 27 Slow continuous ultraﬁltration (SCUF), 148, 254 Slow low efﬁciency dialysis (SLED), 23, 23, 240 Sodium, 115–116 System One, 164

INDEX

management, 76 Molecular adsorbent recirculating system (MARS), 175–179 method, 176–179, 177 guidelines, 179 with Prisma continuous renal replacement therapy (CRRT) machine, 178 Multiorgan support therapy (MOST), 14–16

T Theraperutic plasma exchange (TPE), 167–173 adverse effects, 171–173 apheresis devices, 169–171 anticoagulation, 170 centrifugal cell separators, 169–170 extracorporeal circuit, priming, 170 membrane ﬁltration cell separators, 170–171 principles, 167–169 management guidelines for, 168–169 rationale for, 167, 168 Training, 261 Transmembrane pressure (TMP), 109–110, 130 Troubleshooting, 121–128, 261 catheters, 122 checklist, 127

V Vascath (vascular access catheter), 23, 103, 129, 131. See also Access catheter; Catheters Vascular access, for CRRT, 93–97, 122 catheter types, 93–94, 94 complications primary, 95–96 secondary, 96–97 site and implementation, 94–95

W Warfarin, 136

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nutrition, 194 water considerations, 194