Continuous Renal Replacement Therapy (Pittsburgh Critical Care Medicine)

Continuous Renal Replacement Therapy This page intentionally left blank Continuous Renal Replacement Therapy Edited...

Author: John Kellum | Rinaldo Bellomo | Claudio Ronco

406 downloads 1549 Views 6MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

Continuous Renal Replacement Therapy

This page intentionally left blank

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.


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.


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


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


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


Part 1

Theory


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 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.


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


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


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


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


Heparin

CHAPTER 2

Bubble trap

15

Pressure monitoring


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


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.


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.


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


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


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.


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


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.


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.


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


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

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


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.


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.

37

Key references


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


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 30 mL/h Creatinine clearance 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.


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).


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.


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).


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


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 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 (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).


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


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.


• 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 • •

• • •

• • • •


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. •


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


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


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


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.


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


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


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


(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.


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.


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


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. •


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. •


92

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 (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


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 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.

98

CHAPTER 11


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

99

Introduction

The circuit and the prescription CHAPTER 12

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.

101

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).


102

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.

CHAPTER 12

Methods and approach

103

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.


104

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


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.


Summary

105

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.


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

107

Introduction

The membrane: size and material CHAPTER 13

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.


109

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”)


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)


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.


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.

113

Continuous hemodialysis


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


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


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.

119

Summary


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.

121

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


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


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.


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


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).

127

Conclusions


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.

129

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.


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.

132

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


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.


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.

139

Heparin dose Filter hour


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

140

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.


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


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.


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. 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.


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 (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


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


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.


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.


Part 3

Special situations


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 and 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.

161

Dwell volume


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


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


165

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.


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 ( 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.

183

Efficiency of adsorption

Sorbents CHAPTER 23

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.

184

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.

Sorbents CHAPTER 23

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.

Sorbents CHAPTER 23

187

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.

Sorbents CHAPTER 23

188

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

189

Introduction

Hybrid therapies CHAPTER 24

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


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.

191

Blood flow


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

192

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

>300 300 100 >300 200 >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

193

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


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.


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.

195

Suggested readings


Part 4

Organizational issues


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.

199

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.

203

• Organizing structure in patient care

The ICU environment CHAPTER 25

204

• 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).

205

Kimberly Whiteman and Frederick J. Tasota

Patient care quality and teamwork CHAPTER 26

206

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.


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


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 •


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.


210

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.


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.

211

Suggested readings


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.

215

•


• 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.


•

CHAPTER 27

•

217

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


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.

218

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


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


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.


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


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


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.


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.


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.


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


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


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

236

CHAPTER 29

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.


237

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


238

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.

239

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.

Machines for CRRT

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.


240

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


Figure 29.9 Detailed front view of the Aquarius machine.

241

Figure 29.8 The Aquarius machine.


242

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.


High-volume hemofiltration

243

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.


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.

244

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.


References

245

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.


246

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

247

Introduction

Quality assurance for CRRT CHAPTER 30

248

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

CHAPTER 30

Q.A. item

249

Table 30.1 Quality indicators associated with RRT

Quality assurance for CRRT CHAPTER 30

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.

CHAPTER 30

Key references

251

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.


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).

253

Introduction

Educational resources CHAPTER 31

254

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.


255

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. •


256

• •

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.


257

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. •


258

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.

Educational resources

Abstract

CHAPTER 31

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).

259

balance and anticoagulation errors. • Mentored experience with CRRT where expert nurses provide an extended


RRT and multidisciplinary team Standards Nurses Policies and documents

Technicians Physicians

RRT education

Pharmacy Patient care: RRT

Suppliers Teachers

AUDIT

260

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/

Educational resources

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.

CHAPTER 31

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.

261

Suggested readings


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.

262

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

263

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

264

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

265

nutrition, 194 water considerations, 194

Continuous Renal Replacement Therapy (Pittsburgh Critical Care Medicine)

Renal Failure and Replacement Therapies (Competency-Based Critical Care)

Clinical Critical Care Medicine

Pediatric Critical Care Medicine

Small Animal Critical Care Medicine

Critical Care Medicine: The Essentials

Hormone Replacement Therapy

Hormone Replacement Therapy

Hormone Replacement Therapy

Advanced renal care

Handbook of Critical Care Drug Therapy

Core Topics in Critical Care Medicine

Perioperative and Critical Care Medicine: Educational Issuess

Core Topics in Critical Care Medicine

Critical Care Medicine: The Essentials 3rd edition

Review of Pulmonary and Critical Care Medicine

Core Topics in Critical Care Medicine

Harrison's Pulmonary and Critical Care Medicine

Core Topics in Critical Care Medicine

Critical Care Medicine Just the Facts

Intensive and Critical Care Medicine: WFSICCM World Federation of Societies of Intensive and Critical Care Medicine

Hormone Replacement Therapy: Conventional Medicine and Natural Alternatives, Your Guide to Menopausal Health-Care Choices

Historical Aspects of Critical Illness and Critical Care Medicine, An Issue of Critical Care Clinics

Critical Care

Critical Care Nursing Care Plan

Hormone Replacement Therapy and the Menopause

Manual Medicine Therapy

Gene Therapy for Renal Diseases and Transplantation

Renal Cell Cancer: Diagnosis and Therapy

Islet Transplantation and Beta Cell Replacement Therapy

Manipulative Therapy: Musculoskeletal Medicine

Continuous Renal Replacement Therapy (Pittsburgh Critical Care Medicine)

Renal Failure and Replacement Therapies (Competency-Based Critical Care)

Clinical Critical Care Medicine

Pediatric Critical Care Medicine

Small Animal Critical Care Medicine

Critical Care Medicine: The Essentials

Hormone Replacement Therapy

Hormone Replacement Therapy

Hormone Replacement Therapy

Advanced renal care

Handbook of Critical Care Drug Therapy

Core Topics in Critical Care Medicine

Perioperative and Critical Care Medicine: Educational Issuess

Core Topics in Critical Care Medicine

Critical Care Medicine: The Essentials 3rd edition

Review of Pulmonary and Critical Care Medicine

Core Topics in Critical Care Medicine

Harrison's Pulmonary and Critical Care Medicine

Core Topics in Critical Care Medicine

Critical Care Medicine Just the Facts

Intensive and Critical Care Medicine: WFSICCM World Federation of Societies of Intensive and Critical Care Medicine

Hormone Replacement Therapy: Conventional Medicine and Natural Alternatives, Your Guide to Menopausal Health-Care Choices

Historical Aspects of Critical Illness and Critical Care Medicine, An Issue of Critical Care Clinics

Critical Care

Critical Care Nursing Care Plan

Hormone Replacement Therapy and the Menopause

Manual Medicine Therapy

Gene Therapy for Renal Diseases and Transplantation

Renal Cell Cancer: Diagnosis and Therapy

Islet Transplantation and Beta Cell Replacement Therapy

Manipulative Therapy: Musculoskeletal Medicine

Recommend Documents