terapia renal continua

Continuous Renal Replacement Therapy

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Continuous Renal Replacement TherapyEdited by

John A. KellumProfessor and Vice ChairDepartment of Critical Care MedicineUniversity of PittsburghPittsburgh, Pennsylvania

Rinaldo BellomoProfessor of MedicineDirector of Intensive Care ResearchMelbourne UniversityMelbourne, Australia

Claudio RoncoProfessor of Clinical Nephrology and MedicineDirector, Department of NephrologySt. Bortolo HospitalVicenza, Italy

12010

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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 hemofi ltration. 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 2009616.6’14—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 misapplica-tion of material in this work.

10 9 8 7 6 5 4 3 2 1Printed in the United States of Americaon 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.

vii

Signifi cant advances have occurred in the care of patients with acute kidney injury. Continuous renal replacement therapy (CRRT) has become the stan-dard 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 expe-rienced CRRT providers, to enrich existing expertise, and to achieve a better understanding of this powerful treatment. Our ultimate goal is to improve out-comes for patients with acute kidney injury through teamwork and education.

John A. KellumRinaldo Bellomo

Claudio Ronco2009

Preface

Abbreviations xiiiContributors xvii

Part 1 Theory 1 The critically ill patient with acute kidney injury

Aditya Uppalapati and John A. Kellum 3 2 History and rationale for continuous renal

replacement therapy Ilona Bobek and Claudio Ronco 11

3 Terminology and nomenclatureIan Baldwin and Rinaldo Bellomo 19

4 Basic principles of solute transportZhongping Huang, Jeffrey J. Letteri, Claudio Ronco, and William R. Clark 25

5 Principles of fl uid managementRinaldo Bellomo and Sean M. Bagshaw 33

6 Indications, timing, and patient selectionJohn A. Kellum 39

7 Extended indications for continuous renal replacement therapy Rinaldo Bellomo and Ian Baldwin 47

8 Dose adequacy and assessmentZaccaria Ricci and Claudio Ronco 53

9 Acid-base and electrolyte disordersJohn A. Kellum 61

Part 2 Practice 10 Choosing a renal replacement therapy

in acute kidney injury Jorge Cerdá and Claudio Ronco 79

11 Vascular access for continuous renal replacement therapyAlexander Zarbock and Kai Singbartl 93

12 The circuit and the prescriptionRinaldo Bellomo and Ian Baldwin 99

Contents

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ON

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TS 13 The membrane: size and material

Zhongping Huang, Jeffrey J. Letteri, Claudio Ronco, and William R. Clark 107

14 Fluids for continuous renal replacement therapyPaul M. Palevsky and John A. Kellum 115

15 Alarms and troubleshootingZaccaria Ricci, Ian Baldwin, and Claudio Ronco 121

16 Nonanticoagulation strategies to optimize circuit function in renal replacement therapy Ian Baldwin 129

17 AnticoagulationRinaldo Bellomo and Ian Baldwin 135

18 Regional citrate anticoagulationNigel Fealy 141

19 Drug dosing in continuous renal replacement therapy Kimberly A. Maslonek, Kelly A. Killius, and John A. Kellum 147

Part 3 Special Situations 20 Renal replacement therapy in children

Michael L. Moritz 159 21 Therapeutic plasma exchange in critical care medicine

Joseph E. Kiss 167 22 MARS: molecular adsorbent recirculating system

Nigel Fealy and Rinaldo Bellomo 175 23 Sorbents

Dehua Gong and Claudio Ronco 181 24 Hybrid therapies

Dinna N. Cruz and Claudio Ronco 189

Part 4 Organizational issues 25 The ICU environment

Younghoon Kwon 199 26 Patient care quality and teamwork

Kimberly Whiteman and Frederick J. Tasota 205 27 Organizational aspects: developing policies

and procedures for continuous renal replacement therapiesJorge Cerdá 213

xiC

ON

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TS 28 Documentation, billing, and reimbursement for

continuous renal replacement therapyKevin W. Finkel 223

29 Machines for continuous renal replacement therapyClaudio Ronco 229

30 Quality assurance for continuous renal replacement therapiesIan Baldwin and Rinaldo Bellomo 247

31 Educational resources Ian Baldwin and Kimberly Whiteman 253

Index 263

xiii

Abbreviations

AC Activated Charcoal ACD Acid Citrate Dextrose ACE Angiotensin-Converting EnzymeACT Activated Clotting TimeADQI Acute Dialysis Quality InitiativeAKI Acute Kidney InjuryAKIN Acute Kidney Injury NetworkAoCLF Acute on Chronic Liver Failure APACHE Acute Physiology and Chronic Health EvaluationaPTT Activated Partial Thromboplastin TimeARDS Acute Respiratory Distress SyndromeARF Acute Renal FailureASFA American Society for Apheresis AV VH Accelerated Venovenous Hemofi ltrationBUN Blood Urea NitrogenCAVH Continuous Arterio-Venous Hemofi ltrationCAVHD Continuous Arterio-Venous HemodialysisCAVHDF Continuous Arterio-Venous Hemodiafi ltrationCDI Central Diabetes Insipidus CPFA Coupled Plasma Filtration and AdsorptionCRBSI Catheter-Related Bloodstream InfectionsCRRT Continuous Renal Replacement TherapyCVC Central Venous CatheterCV VH Continuous Veno-Venous Hemofi ltrationCV VHD Continuous Veno-Venous HemodialysisCV VHDF Continuous Veno-Venous Hemodiafi ltrationDP Drop PressureEC Extracorporeal CircuitECLS Extracorporeal Lung Support SystemECU Emergency Case UnitsECV Extracorporeal Volume EDD Extended Daily DialysisESRF End-Stage Renal Failure

xiv

ABB

REV

IAT

ION

S GFR Glomerular Filtration RateGPCI Geographic Practice Cost Indexes HF Hemofi ltrationHFR Double Chamber Hemodiafi ltration HITTS Heparin Induced Thrombocytopenia Thrombosis SyndromeHP HemoperfusionHPHD Hemoperfusion Coupled with Hemodialysis HVHF High-Volume Hemofi ltrationICU Intensive Care UnitIHD Intermittent HemodialysisIJV Internal Jugular VeinINR International Normalization Ratio LMW Low Molecular WeightMODS Multiple Organ Dysfunction SyndromeMOST Multi-Organ Support TherapyMPM Mortality Prediction ModelNSAID Nonsteroidal Antiinfl ammatory DrugPD Peritoneal DialysisPIRRT Prolonged Intermittent Renal Replacement TherapyPT Prothrombin Time PTH Parathyroid Hormone RBRVS Resource-Based Relative Value Scale RCA Regional Citrate Anticoagulation RHTE Right Heart ThromboembolismRIFLE Risk, Injury, Failure, Loss, and End-Stage Kidney DiseaseRRT Renal Replacement TherapyRVU Relative Value Unit SAg SuperantigenSAPS Simplifi ed Acute Physiologic ScoreSBE Standard Base Access SC Sieving Coeffi cientSCrt Serum CreatinineSCUF Slow Continuous Ultrafi ltrationSID Strong Ion Difference SIRS Systemic Infl ammatory Response Syndrome SLED Slow Low Effi ciency DialysisSLEDD Sustained Low Effi ciency Daily Dialysis

xvA

BBR

EVIA

TIO

NS

SLEDD-f Sustained Low Effi ciency (Daily) Diafi ltrationSOFA Sepsis-Related Organ Failure AssessmentTDC Temporary Dialysis CatheterTLR Toll-Like ReceptorTMP Transmembrane PressureTNF Tumor Necrosis FactorTPE Therapeutic Plasma Exchange UF Ultrafi ltration

xvii

Contributors

Sean M. Bagshaw, MDAssistant ProfessorDivision of Critical Care MedicineUniversity of Alberta HospitalUniversity of AlbertaEdmonton, Canada

Ian Baldwin, RNClinical Educator Department of Intensive Care Austin HospitalDepartment of Nursing and Health SciencesRMIT UniversityMelbourne, Australia

Rinaldo Bellomo, MDProfessor of MedicineDirector of Intensive Care ResearchDepartment of Intensive CareMelbourne UniversityMelbourne, Australia

Ilona Bobek, MDNephrologistDepartment of Nephrology, Dialysis and TransplantationSan Bartolo HospitalVicenza, Italy

Jorge Cerdá, MD, FACP, FASNClinical Associate Professor of MedicineAlbany Medical College and Capital District Renal PhysiciansAlbany, New York

William R. Clark, MDVice President, Medical Strategy and Therapy DevelopmentGambro Renal ProductsLakewood, Colorado

Assistant Clinical Professor of Medicine Nephrology DivisionIndiana University School of MedicineIndianapolis, Indiana

Dinna N. Cruz, MD, MPHNephrologistDepartment of Nephrology, Dialysis and TransplantationSan Bortolo HospitalInternational Renal Research Institute VicenzaVicenza, Italy

Nigel Fealy, RNClinical Nurse EducatorDepartment of Intensive CareAustin HospitalHeidelberg, Australia

Kevin W. Finkel, MD, FACP, FASNProfessor and DirectorDivision of Renal Diseases and HypertensionUniversity of Texas Medical School at HoustonHouston, Texas

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CO

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S Dehua Gong, MDAssociate ProfessorResearch Institute of NephrologyJinling HospitalNanjing University School of MedicineNanjing, P.R.China

Zhongping Huang, PhDAssistant ProfessorDepartment of Mechanical EngineeringWidener UniversityChester, Pennsylvania

John A. Kellum, MDProfessor of Critical Care Medicine, Medicine, Bioengineering, and Clinical and Translational SciencesVice Chair of ResearchDepartment of Critical Care MedicineUniversity of Pittsburgh School of MedicinePittsburgh, Pennsylvania

Kelly A. Killius, PharmD, BCPSClinical Pharmacy Specialist, Emergency MedicineBoston Medical CenterBoston, Massachusetts

Joseph E. Kiss, MDAssociate Professor of MedicineDepartment of MedicineDivision of Hematology/OncologyPittsburgh, Pennsylvania

Younghoon Kwon, MDStaff IntensivistHealth East Care SystemSaint Paul, Minnesota

Jeffrey J. Letteri, BS, CHTDirector DevelopmentGambro, Inc.Lakewood, Colorado

Kimberly A. Maslonek, PharmDClinical PharmacistCardiothoracic and Surgical ICUUniversity of Pittsburgh Medical Center PresbyterianPittsburgh, Pennsylvania

Michael L. Moritz, MDAssociate Professor of PediatricsDivision of NephrologyChildren's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania

Paul M. Palevsky, MDProfessor of MedicineUniversity of Pittsburgh School of MedicinePittsburgh, Pennsylvania

Zaccaria Ricci, MDConsultantIntensive Care UnitDepartment of Pediatric Cardiac SurgeryBambino Gesù Children’s HospitalRome, Italy

Claudio Ronco, MDDirectorDepartment of Nephrology, Dialysis and TransplantationSan Bortolo HospitalVicenza, Italy

Kai Singbartl, MD, EDICAssistant Professor of Critical Care Medicine and AnesthesiologyDepartment of Critical Care MedicineUniversity of PittsburghPittsburgh, Pennsylvania

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SFrederick J. Tasota, RN, MSN, CCRNCritical Care Advanced Practice NurseUniversity of Pittsburgh Medical Center PresbyterianPittsburgh, Pennsylvania

Aditya Uppalapati, MDResidentInternal MedicineUniversity of Pittsburgh Medical CenterMcKeesport, Pennsylvania

Kimberly Whiteman, RN, MSN, CCRNAdvanced Practice Nurse EducatorUniversity of Pittsburgh Medical Center PresbyterianPittsburgh, Pennsylvania

Alexander Zarbock, MDResidentDepartment of Anesthesiology and Critical Care MedicineUniversity of MuensterMuenster, Germany

Part 1

Theory

3

Chapter 1

The critically ill patient with acute kidney injuryAditya Uppalapati and John A. Kellum

The terms acute kidney injury (AKI) and acute renal failure (ARF) are not syn-onymous. 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 in-tervention, 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 defi ned as renal function inadequate to clear the waste products of metabolism despite the absence of or correction of hemody-namic 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 glomer-ular fi ltration. 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).

Classifi cation

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.

Oliguria

Classifi cation

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Incidence and etiology of acute kidney injury

The classifi cation system includes separate criteria for serum creatinine and urine output. The criteria, which lead to the worst classifi cation, defi ne the stage of AKI. Note that RIFLE-F is present even if the increase in serum creatinine (SCrt) is less than threefold, so long as the new SCrt is <4.0 mg/dL in the setting of an acute increase of at least 0.5 mg/dL. The fi gure shows that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specifi city). In contrast, at the bottom, the cri-teria are strict and therefore specifi c, but some patients will be missed.

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

Incidence and etiology of acute kidney injury

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—defi nition, outcome measures, animal models, fl uid 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 defi ne “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.

Creatinine criteria

RiskHigh

sensitivity

Highspecificity

Injury

Failure

Loss

ESRD

Urine output criteria

Increased creatininex 1.5*

Persistent ARF = complete loss ofrenal function > 4 weeks

End stage renal disease

Olig

uria

Increased creatinine x2

Increased creatinine x3 or creatinine ≥4mg/dL(Acute rise of ≥0.5 mg/dL)

UO < 0.5mL/kg/hx 6 h

UO < 0.5mL/kg/hx 12 h

UO < 0.3mL/kg/hx 24 h or Anuria x12 h

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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.

Risk factors for AKIRisk factors for developing AKI as defi ned by RIFLE criteria are as follows:

Sepsis•

Increasing age, especially age > 62 years•

Race—Black patients for developing RIFLE-F•

Greater severity of illness as per Acute Physiology and Chronic Health •

Evaluation (APACHE) III or Sepsis-related Organ Failure Assessment (SOFA) scoresPreexisting 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•

Etiology of AKI Clinical features may suggest the cause of AKI and dictate further investigation. AKI is common in the critically ill, especially in patients with sepsis and other forms of systemic infl ammation (e.g., major surgery, trauma, burns), but other causes must be considered. In sepsis, the kidney often has a normal histological appearance.

Volume-responsive AKIIt is estimated that as many as 50% of cases of AKI are “fl uid responsive,” and the fi rst step in managing any case of AKI is to ensure appropriate fl uid resuscitation. However, volume overload is a key factor contributing to the mortality attrib-utable to AKI, so ongoing fl uid administration to nonfl uid responsive patients should be discouraged. In general, fl uid resuscitation should be guided by hemo-dynamic monitoring.

Sepsis-induced AKISepsis is a primary cause or contributing factor in more than 50% of cases of AKI, which includes cases severe enough to require renal replacement therapy (RRT). Patients with sepsis, including those outside the ICU, develop AKI at rates as high as 40%. Septic shock appears to be an important factor in the development of sepsis-induced AKI; however, patients without overt shock do not appear to be any less likely to develop AKI.

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HypotensionHypotension is an important risk factor for AKI, and many patients with AKI have sustained at least one episode of hypotension. Treating fl uid-responsive AKI with fl uid 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 fl ow actually increases with norepinephrine in animals with sepsis.

Postoperative AKIRisk 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 infl ammation.

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

nephritis, or renal tubular obstruction. In patients with AKI, all potential neph-rotoxins 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 fea-•

tures (e.g., hypertension, purpura, arthralgia, vasculitis) are all suggestive of glomerular disease. Renal biopsy or specifi c blood tests (e.g., Goodpasture’s syndrome, vasculitis) are required to confi rm diagnosis and guide appropriate treatment.Hemolytic uremic syndrome—suggested by hemolysis, uremia, thrombocyto-•

penia, and neurological abnormalities. Crystal nephropathy—suggested by the presence of crystals in the urinary •

sediment. Microscopic examination of the crystals confi rms 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 renog-•

raphy. 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 fl ow is fur-ther reduced by hemodynamic instability or locally via drug therapy [e.g., non-steroidal antiinfl ammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors]. Renal vein obstruction may be due to thrombosis or ex-ternal compression (e.g., raised intra-abdominal pressure).Abdominal compartment syndrome—suggested by oliguria, a fi rm abdomen •

on physical examination, and increased airway pressures (secondary to up-ward pressure on the diaphragms). Diagnosis is likely when sustained increased

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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.

NephrotoxinsTable 1.1 lists some common nephrotoxins.

Key referencesBellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure—defi nition, outcome measures, animal models, fl uid 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 multina-tional, multicenter study. JAMA. 2005;294:813-818.

Management of AKI

Identifi cation and correction of reversible causes of AKI is critical. All cases re-quire careful attention to fl uid management and nutritional support.

Urinary tract obstructionLower 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 managementFluid-responsive AKI may be reversible in its early stage. Careful fl uid manage-ment 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.

Management of AKI

Table 1.1 Common nephrotoxinsAllopurinol Organic solvents

Aminoglycosides Paraquat

Amphotericin Pentamidine

Furosemide Radiographic contrast

Herbal medicines Sulfonamides

Heavy metals Thiazides

NSAIDs

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Glomerular diseaseSpecifi c therapy in the form of immunosuppressive drugs may be useful after diagnosis has been confi rmed.

Interstitial nephritisAcute 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 specifi city 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 syndromeAbdominal compartment syndrome is a clinical diagnosis in the setting of in-creased 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 infl uence the amount of intra-abdominal pressure that can be tolerated. Surgical decompression is the only defi nitive therapy and should be undertaken before irreversible end-organ damage occurs.

Renal replacement therapyCRRT 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 suffi cient. 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 incom-plete 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).

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Clinical consequences of AKI

Until recently it was assumed that patients with AKI died not because of AKI it-self but because of their underlying disease. Several studies, however, have doc-umented 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.

Clinical consequences of AKI

Table 1.2 Clinical consequences of AKISystem Mechanisms ComplicationsElectrolyte disturbances

1. Hyponatremia 2. Hyperkalemia

1. CNS (see below)2. Malignant arrhythmias

Acid-base(decreased chloride excretion, accu-mulation of organic anions like PO4, decreased albumin l decreased buffering)

1. Downregulation of Beta receptors, increased iNOS

2. Hyperchloremia3. Impairing the insulin resistance4. Innate immunity

1. Decreased cardiac output, blood pressure

2. Lung, Intestinal injury, decreases gut barrier function

3. Hyperglycemia, increased protein break down

4. See below

Cardiovascular 1. Volume overload 1. Congestive heart failure2. Secondary hypertension

Pulmonary 1. Volume overload, decreased oncotic pressure

2. Infi ltration and activation of lung neutrophils by cytokines

3. Uremia

1. Pulmonary edema, pleural effusions

2. Acute lung injury3. Pulmonary hemorrhage

Gastrointestinal 1. Volume overload2. Gut ischemia and reperfusion

injury

1. Abdominal compartment syndrome

2. Acute gastric and duodenal ulcerlbleeding; impaired nutrient absorption

Immune 1. Decreased clearance of oxidant stress

2. Tissue edema3. White cell dysfunction

1. Increased risk of infection2. Delayed wound healing

Hematological 1. Decreased synthesis of RBC increased destruction of RBC, blood loss

2. Decreased production of erythro-poietin, von willebrand’s factor

1. Anemia2. Bleeding

Nervous system 1. Secondary hepatic failure, malnutrition, altered drug metabolism

2. Hyponatremia, acidosis3. Uremia

1. Altered mental status2. Seizures, impaired

consciousness, coma3. Myopathy, neuropathyl

prolonged length on mechanical ventilation

Pharmacokinetics and dynamics

1. Increased volume of distribution2. Decreased availability, albumin binding, elimination

1. Drug toxicity or under dosing

11

Chapter 2

History and rationale for continuous renal replacement therapyIlona Bobek and Claudio Ronco

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 1980sSevere sepsis was considered to be the underlying disease leading to ARF, and earlier ARF occurred frequently after abortions; however, ARFs epidemio-logical 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 signifi cantly increased. •

There was evidence of longer stay with possibility of better outcomes in ICU.•

Change in the pathogenesis of ARFMain factors that are currently considered to be responsible for ARF are as follows:

Shock•

Perfusion disturbances•

Hypoxia•

Medical demand/necessity for CRRT

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Chronology/cornerstones of CRRT

1960sThe idea of CRRT was born, but resources and technology were not available. Most ARF cases were treated with peritoneal dialysis (PD) because hemodi-alysis (HD) was diffi cult to perform and it was not tolerated by intensive care patients.

1970sHenderson played an important role in developing the technical groundwork for hemofi ltration (HF). Isolated ultrafi ltration (UF) and the use of convection for solute removal was experimentally established.

1977First description of an arterio-venous hemofi ltration 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 ultrafi ltrate, providing an effective method for elimination of both fl uid and solutes.

Heparin could be added before and fluid could be reinfused after the fi ltration. Continuous arterio-venous hemofi ltration (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 fl uid removal•

Limitations of CAVH: Low effi ciency 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•

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

Chronology/cornerstones of CRRT

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Figure 2.1 The concept from Peter Kramer and Lee Henderson of continuous fi ltration and the fi rst patient treated with continuous arterio-venous hemofi ltration in Vicenza, 1978.

Substitutionslösung

Heparin

Bubbletrap

Venous return clamp

Graduatedcylinder

Blood pump

Ultrafilter

To dialyzer

Venous return line

Po A

BPo

Pr

Pi

(1)

(2)

(2) (3)Ultrafiltrate

clamp

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

Minifilters

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1980sNumerous technical and methodical improvements in CRRT have contributed to the following:

Changes in arterio-venous technique:Different types of catheters to obtain adequate blood fl ow•

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 fi ltration fraction•

Changes in fi lter geometry and in the structure of fi ber; an entire family of •

diafi lters was created to fulfi l the hemodynamic requirementsImplementation of CAVHD; to increase the effi cacy, dialyses fl uid was fi ltered •

through the external port of the fi lterCombination of hemofiltration and hemodialysis, that is, CAVHDF was •

performedReplacement of the arterio-venous techniques by the pump-driven veno-

venous techniques:Introduction of CVVH, employing blood pump to further increase effi ciency •

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

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

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

1990–2000Establishment of new technologies, modalities, and adequate dose of CRRT.

Adoptive technology •

Machines specifi cally 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 presentMultiorgan support therapyPatients 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

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Figure 2.3 The fi rst neonate treated in the world with continuous arterio-venous hemofi ltra-tion (CAVH) and a special minifi lter (Vicenza, 1984).

Bloodpump

Pressure monitoring

Bubble trapHeparin

Reinfusionpump

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

1985 1989

Years

CRRT evolution

Evol

utio

n

Progress of CRRT

2004 ?1977

the severity of physiological disorders. The proper goal of extracorporeal blood purifi cation 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 sup-portive therapy in sepsis and liver failure were established, such as high-volume

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

SCUF

CRRT

LiverSupport - HVHFCPFA - CAST

ECLS

M.O.S.T

hemofi ltration (HVHF), coupled plasma fi ltration and adsorption (CPFA), bioartifi cial liver, and endotoxin removal strategies.

Acute dialysis quality initiative Acute dialysis quality initiative (ADQI) is an ongoing process that seeks to pro-duce 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 fl uids during high-volume hemofi ltration, intracorporeal microfl uidics and technology for plasma separation, intracorporeal ultrafi ltration plasma water extraction, bio-artifi cial tubulus, new sorbent techniques, nanotechnology, and wearable/trans-portable 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 fl ex-ibility in parameters and prescription such that it can be used to respond to

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

Key references

Henderson LW, Besarab A, Michaels A, Bluemle LW. Blood purifi cation by ultrafi ltration and fl uid replacement (Diafi ltration). Trans ASAIO. 1967;13:216-222.

Henderson LW. Peritoneal ultrafi ltration dialysis: enhanced urea transfer using hypertonic peritoneal fl uid. JCI 1966;45:950-961.

Kellum JA, Mehta R, Angus DC, Palevsky P, Ronco C; ADQI Workgroup. The fi rst inter-national 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 hemofi ltration: 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 veno-venous haemofi ltration 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.

19

Chapter 3

Terminology and nomenclatureIan Baldwin and Rinaldo Bellomo

Introduction

As with any specialized fi eld of therapy, specifi c 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 in-tensity or “dose” of treatment.

In addition, there are also specifi c 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.

Defi nitions and relevant key terms

Continuous renal replacement therapy (CRRT)Continuous renal replacement therapy is a general term referring to any extra-corporeal blood purifi cation 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 hemofi ltration (CV VH)Continuous veno-venous hemofi ltration 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 ultrafi ltration. The ultrafi ltrate 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 purifi cation is called convection. The fl uid loss is

Introduction

Defi nitions and relevant key terms

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replaced in part or completely with appropriate replacement solutions to achieve blood purifi cation 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 fl uid, which contains appropriate plasma electrolytes, into the nonblood side of the membrane and in a direction coun-tercurrent to that of blood (Figure 3.2). As this fl uid (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 hemodiafi ltration (CV VHDF) Continuous veno-venous hemodiafi ltration is a technique of CRRT that com-bines 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 (hemo-fi ltration, hemodialysis, and hemodiafi ltration) whereby the patient’s blood pressure (instead of pump) drives blood through a fi lter, 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 purifi cation is otherwise

Figure 3.1 Continuous veno-venous hemofi ltration (CVVH) circuit. In this circuit, the re-placement fl uid is being delivered before the fi lter in predilution mode.

CVVH

Membrane

Blood pump

Replacementfluid

HeaterWaste collection Patient

PumpPump

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

CVVHD

Blood pump

Patient

Pump

Dialysate

Heater

Spentdialysate

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

CVVHDF

Blood pump

Pump

Replacementfluid

Patient

Pump

Dialysate

Heater

Heater

Diafiltrate/waste

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 hemofi ltration would be abbreviated as CAVH. These techniques have all been abandoned in developed countries in favor of veno-venous techniques.

For all techniques, fl uid balance is maintained by the difference between fl uid input (dialysate and/or replacement fl uid or both) and output (spent dialysate and/or ultrafi ltrate or both). Both input and output can be regulated by pumps.

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If output is greater than input, there is a negative fl uid balance, which can be reg-ulated in intensity as deemed necessary.

PredilutionPredilution is the administration of replacement fl uid into the patient’s blood before its entry into the hemofi lter (prefi lter delivery).

PostdilutionPostdilution is the administration of replacement fl uid into the patient’s blood after its exit from the hemofi lter (postfi lter delivery).

Intermittent hemodialysis (IHD)Intermittent hemodialysis is a term that describes a diffusive blood purifi ca-tion 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 fl ow 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 pro-vide a dialysate fl uid for high fl ow use (Figure 3.4). Prescription is commonly for 3–4 hours per session with the frequency and intensity of such sessions regu-lated in response to perceived clinical need. Ultrafi ltration can also be achieved to remove fl uid by applying a negative pressure on the dialysate side of the membrane. This allows the removal of excess fl uid as clinically estimated.

Figure 3.4 Intermittent hemodialysis circuit. Tap water is further purifi ed 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.

Waste

Heater

R.O. K+

HCO3-

Electrolytes IHDTap water

Bloodpump

Patient

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Slow low effi ciency dialysis (SLED)Slow low effi ciency dialysis is a dialysis treatment equivalent in nature to IHD but where dialysate and blood fl ow rates are reduced to provide a less effi cient clearance rate but with an extended time of treatment (e.g., 8–12 hours in-stead 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 fi ltration (EDDf) are also used to describe these respective techniques.

Extracorporeal circuit (EC)Extracorporeal circuit is the path for blood fl ow outside the body. The EC includes the plastic tubing carrying the blood to the fi lter (or hemofi lter or dia-lyzer) from the vascular access catheter and from the fi lter back to the body via the access catheter again.

Vascular access catheterVascular access catheter is a device inserted into a central vein to allow blood to be pumped in and out of a fi lter. 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 outfl ow 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 fl ows between 150 and 300 mL/min can be typically achieved through such catheters.

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 fl ow rates are lower than that for intermittent hemodialysis.

Waste

Heater

R.O. K+

HCO3-

Electrolytes SLED(f)Tap water

Fluidpump

Bloodpump

Patient

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DiffusionDiffusion is a term that describes a type of solute transport across a semiper-meable 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.

ConvectionConvection is a term that describes a type of solute transfer across a semi-permeable membrane in which solute is transported together with a solvent by means of a process (fi ltration) that occurs in response to a transmembrane pressure gradient.

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

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 fur-ther help one understand the mechanisms and principles involved in achieving blood purifi cation 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-defi nition, outcome measures, animal models, fl uid 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 Hemofi ltration. London: WB Saunders; 2001:11-14.

Bellomo R. Choosing a therapeutic modality: hemofi ltration vs. hemodialysis vs. hemodia-fi ltration. Semin Dial. 1996;9:88-92.

Ronco C, Bellomo R. A nomenclature of continuous renal replacement therapies. Contrib Nephrol. 1995;116:28-33.

Summary

25

Introduction

Renal replacement therapy (RRT) is required in a signifi cant percentage of patients developing acute kidney injury (AKI) in an intensive care unit (ICU) set-ting. 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 fi ltration. 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 fi lter performance in CRRT

Clearance Quantifi cation of dialytic solute removal is complicated by the confusion relating to the relationship between clearance and mass removal for different therapies. By defi nition, 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 fl ows for determin-ing 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 con-centration 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

Introduction

Characterization of fi lter performance in CRRT

Chapter 4

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

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

QACA QCCV

QECE

CA

QECE QDQR

Mass removal rate

Blood concentrationClearance

Filter

=

=

ddi

Figure 4.2 Solute clearance in CRRT.

CVVHD/CVVHDF

K = E·QD

Postdilution CWH

Predilution CWH

K = S·QUF

K = S·QUF·QBW

QBW + QR

Concentration in effluent dialysate/diafiltrate

Concentration in blood

Concentration in blood

Concentration in filtrateS =

E =(

(

(

)

)

)

is estimated by measuring the actual amount of solute appearing in the effl uent. The mass removal rate is the product of the effl uent fl ow rate (QE) and the effl uent concentration of the solute (CE).

In continuous veno-venous hemodialysis (CV VHD) and continuous veno-venous hemodiafi ltration (CV VHDF), the effl uent is dialysate and diafi ltrate, 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 effl uent saturation. The benchmark for effi ciency in these therapies is the volume of fl uid (dialysate and/or replacement fl uid) required to achieve a certain solute clear-ance target (see below).

Clearance in postdilution CV VH is the product of the SC (see below) and the ultrafi ltration rate (QUF). For small solutes like urea and creatinine, the SC is

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essentially 1 (under normal fi lter operation). Therefore, small solute clearance in postdilution CV VH essentially is equal to the QUF. On the other hand, estima-tion 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 fi lter. 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 fl ow rate (QB) to the sum of QB and the replacement fl uid rate (QRF). (The actual blood fl ow parameter, QBW, is blood water fl ow rate.) In essence, the dilution factor can be viewed as a measure of the extent to which predilution differs from postdilution for a specifi c combination of QB and QUF.

Sieving coeffi cientWhen a dialyzer is operated as an ultrafi lter (i.e., ultrafi ltration with no dialysate fl ow, e.g., CV VH), solute mass transfer occurs almost exclusively by convection. Convective solute removal is primarily determined by membrane pore size and treatment ultrafi ltration rate. Mean pore size is the major determinant of a dia-lyzer’s ability to prevent or allow the transport of a specifi c solute. The sieving coeffi cient (SC) represents the degree to which a particular membrane permits the passage of a specifi c solute:

SC = CUF/CP [2]

In this equation, CUF and CP are the solute concentrations in the ultrafi ltrate and the plasma (water), respectively.

Irrespective of membrane type, all fi lters in the “virgin” state have small sol-ute SC values of 1, and these values are typically not reported by dialyzer manu-facturers. 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 coeffi cient (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 fl uid. In actual clinical practice, nonspecifi c 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

DiffusionDiffusion 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

Transmembrane solute removal mechanisms

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from the region of higher concentration into the region of lower concentra-tion (Figure 4.3). In reality, molecules present a random movement. However, since they tend to reach the same concentration in the available space occu-pied 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 infl uenced by the following:

Membrane characteristics: surface area, thickness, porosity•

Solute diffusion coeffi cient (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 fi nal clearance value. Conversely, con-vection may result in a measured clearance value that is signifi cantly greater than the value based on a “pure” diffusion assumption. Diffusion is an effi cient 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.

ConvectionConvection is the mass transfer mechanism associated with ultrafi ltration 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

Figure 4.3 Mechanisms of diffusion and convection.

Diffusion is solute transport across a semipermeable membrane—molecules move froman area of higher to an area of lower concentration

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

Effectiveness less dependent onmolecular size

Best for small molecule clearance

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with the ultrafi ltrated plasma water. This movement of plasma water is a conse-quence of a transmembrane pressure (TMP) gradient. Quantitatively, the ultra-fi ltration fl ux (JF), defi ned as the ultrafi ltration rate normalized to membrane surface area, can be described by

JF = KF TMP [3]

In this equation, KF is the membrane-specifi c hydraulic permeability (units: mL/h/mmHg/m2) and TMP is a function of both the hydrostatic and oncotic pressure gradients. Convective fl ux of a given solute is a function mainly of the following parameters:

Ultrafi ltration 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 fi nal observed SC is smaller than that expected from a simple theoretical calculation. As noted above, nonspe-cifi c 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 mem-brane pores.

Postdilution fl uid replacement tends to accentuate secondary membrane effects because protein concentrations are increased within the membrane fi bers (due to hemoconcentration). On the other hand, higher blood fl ow 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-fl ux membranes are utilized and the prevalent mechanism of solute transport is convection. Ultrafi ltration rates in excess of the amount required for volume control are prescribed, requiring partial or total replace-ment of ultrafi ltrate losses with reinfusion (replacement) fl uid. As described in greater detail elsewhere, replacement fl uid can either be infused before the fi lter (predilution) or after the fi lter (postdilution). Postdilution hemofi ltration is inherently limited by the attainable blood fl ow rate and the associated fi ltration 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 signifi cantly before the blood enters into the hemofi lter. This effective reduction in the red cell and protein content of the blood attenuates the secondary membrane and concentration

Kinetic considerations for different CRRT techniques

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polarization phenomena described above, resulting in improved mass transfer. Predilution also favorably impacts mass transfer due to the augmented fl ow in the blood compartment because prefi lter mixing of blood and replacement fl uid occurs. This achieves a relatively high membrane shear rate, which also reduces solute-membrane interactions. Finally, predilution may also enhance mass trans-fer for some compounds by creating concentration gradients that induce solute movement out of red blood cells.

However, the major drawback of predilution hemofi ltration is its relatively low effi ciency, resulting in relatively high replacement fl uid requirements to achieve a given solute clearance. In a group of patients treated with a “traditional” blood fl ow rate for CRRT, the effi ciency loss associated with predilution has recently been quantifi ed. Troyanov et al. demonstrated the signifi cant negative effect on effi ciency when a relatively low QB (less than 150 mL/min) is used with a relatively high QUF and QRF in predilution CV VH. This specifi c combination of QB = 125–150 mL/min and QUF = 4.5 L/h (75 mL/min) is associated with a loss of effi ciency of 30%–40% relative to postdilution for several different solutes. In other words, to achieve the same solute clearance, 30%–40% more replacement fl uid 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 ultrafi ltration rate in postdilution is very remote at such a low blood fl ow rate, as this would require a fi ltration fraction in excess of 50%. This condition is likely to lead to very short-term fi lter patency.

In CV VHDF, a high-fl ux hemodiafi lter is used, and the operating principles of hemodialysis and hemofi ltration 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, ultrafi ltration is obtained in excess of the desired fl uid loss from the patient. The ultrafi ltrate is partially or totally replaced with reinfusion fl uid, either in predilution or postdilution mode. Later-generation CRRT machines allow a combination of predilution and postdilu-tion with the aim of combining the advantages of both reinfusion techniques. Information from the chronic hemodiafi ltration literature suggests that a combi-nation 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 specifi c set of CV VHDF operating conditions, namely blood fl ow rate, dialysate fl ow rate, ultrafi ltration rate, and fi lter type.

Due to the markedly lower fl ow 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 hemodiafi ltration (HDF). In the latter application, diffusion and convection interact in such a manner that total solute removal is signifi cantly less than what is expected if the individ-ual components are simply added together. On the other hand, in CV VHDF

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the small solute concentration gradient along the axial length of the fi lter (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 diffusion-related change in small solute concentrations along the fi lter 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 2-microglobulin (B2M) clearance at a “traditional” blood fl ow rate of 125 mL/min. The study compared clear-ances at the same effl uent rate over an effl uent 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 effl uent rate increased. These results are consistent with the “penalizing” effect of predilution, which is especially pronounced at low blood fl ow rates. For B2M, the results are contrary to the “conventional wisdom,” which would suggest that a purely con-vective 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 effl uent rates (greater than 3.5 L/h). Until the impact of higher blood fl ow 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 effi cient way.

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 haemofi ltration at various ultrafi ltration fl ow rates using Multifl ow-100 and HF1000 fi lters. Nephrol Dial Transplant. 2003;18:961-966. Reprinted by permission of Oxford University Press.

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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 fi lter function is characterized have been reviewed clinically. In addition, the fundamental mechanisms for solute and fl uid 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 ultrafi ltration fl ow rates. Am J Kidney Dis. 1999;34:486-492.

Clark WR, Turk JE, Kraus MA, Gao D. Dose determinants in continuous renal replace-ment 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. Ultrafi ltration rate as dose surrogate in pre-dilution hemofi ltration. Int J Artif Organs. 2007;30:124-132.

Troyanov S, Cardinal J, Geadah D, et al. Solute clearances during continuous venvenous haemofi ltration at various ultrafi ltration fl ow rates using Multifl ow-100 and HF1000 fi lters. Nephrol Dial Transplant. 2003;18:961-966.

Summary

33

The control and optimization of fl uid balance is a clinically important compo-nent of continuous renal replacement therapy (CRRT). Inadequate fl uid removal is associated with peripheral edema and vital organ edema (i.e., pulmonary edema). Such edema can retard weaning from mechanical ventilation or com-prise wound healing. Fluid overload has been identifi ed as an independent pre-dictor of increased mortality in critically ill patients and is clearly undesirable. Similarly, excessive fl uid removal may contribute to hypovolemia with increased doses of vasopressor drug therapy, exposing the patients to the risks of unneces-sary beta and alpha receptor stimulation. Hypovolemia may induce hypotension and, thereby, possibly aggravate organ injury and, specifi cally, retard or block renal recovery. Accordingly, careful clinical assessment of the patient’s fl uid status and careful prescription of CRRT to optimize fl uid balance, together with frequent review of such assessment and prescription, represent a key aspect of best practice in the fi eld of CRRT.

Patient fl uid balance: This term refers to the total balance over a 24-hour period of fl uids administered (intermittent drugs, continuous infusion of drugs, blood, blood products, nutrient solutions, additional fl uids) and measurable fl uids re-moved (drainage from chest or abdomen, urine—if present, blood loss, and excess fl uid removed by the CRRT machine).

Machine (CRRT) fl uid balance: This term refers to the total balance over a 24-hour period of fl uids administered by the CRRT machine (dialysate or replacement fl uid or both depending on the technique and any additional anticoagulant infu-sion) and fl uids removed by the CRRT machine (spent dialysate or ultrafi ltrate or both depending on the technique).

Effl uent: It is the total amount of fl uid discarded by the machine. In continuous veno-venous hemofi ltration (CV VH), this is the same as ultrafi ltrate. In contin-uous veno-venous hemodialysis (CV VHD), this is equal to the spent dialysate + any additional ultrafi ltrate generated by the machine. In continuous veno-venous

Introduction

Chapter 5

Principles of fl uid managementRinaldo Bellomo and Sean M. Bagshaw

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hemodiafi ltration (CV VHDF), this is the same as the sum of spent dialysate and ultrafi ltrate discarded by the machine (also called spent ultradiafi ltrate).

Dry weight: This is the patient’s normal/optimal weight before the onset of ill-ness. 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 fl uid in the extracellular compartment. In the subcutaneous tissue, it can be detected by the phenom-enon of pitting of the skin under pressure. In the lungs, if signifi cant, it can be detected by radiography.

Assessment of fl uid status: This term refers to the clinical process of estimating the patient’s intravascular and extravascular fl uid status. Such assessment is com-plex and imperfect. It requires consideration of vital signs, invasive and noninva-sive hemodynamic measurements, information of fl uid balance and body weight, and radiological information. Such assessment is necessary to guide fl uid balance prescription during CRRT.

Approach to fl uid balance during CRRT

The prescription of CRRT-related fl uid management and its integration into overall patient fl uid management can be assisted by a specifi c order chart (Table 5.1) for the machine fl uid balance.

The above order chart will tell the nurse how to set the machine and how to achieve the planned hourly fl uid balance. However, in the intensive care unit (ICU), the fl uid 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 specifi cation for the duration of change and the reasons (Table 5.2).

The fl uid balance prescription related to the machine can be usefully related to the patient and a fl uid balance prescription describing the overall patient fl uid balance goal for a 12-hour time period is useful for informing the nurse what the broad goals of fl uid therapy are in a given patient. This may be expressed in an additional prescription attached to the previous machine fl uid balance chart (Table 5.3).

Approach to fl uid balance during CRRT

Table 5.1 Example Order ChartTechnique Dialysate

fl ow rateReplacement fl uid fl ow rate

Effl uent fl ow rate

Anticoagulant infusion fl ow rate

Machine fl uid balance

CV VHDF 1000 mL/h 1000 mL/h 2300 mL/h 100 mL/h –200 mL/h

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Practical considerations

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 fl uid bal-ance on an hourly basis and its correct fi nal addition of fl uid 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 benefi ts

The expected outcome of a systematic process for the prescription, delivery, and monitoring of fl uids 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 fl uid 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 fi lter clotting or an out-of-ICU procedure or investigation). Under such cir-cumstances, the fl uid 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


Expected outcomes, potential problems,cautions, and benefi ts

Table 5.3 Example Order Chart 3Patient Medical

record number

Overall fl uid balance from midnight to 12:00 (noon)

Overall fl uid balance from 12:00 (noon) to midnight

Right atrial pressure notifi cation range

Name 00123 –1000 mL –1000 mL/h <6 or >15 mmHg

Table 5.2 Example Order Chart 2Technique Dialysate

fl ow rateReplacement fl uid fl ow rate


Anticoagulant infusion fl ow rate

Machine fl uid balance

CV VHDF 1000 mL/h 1000 mL/h 2600 mL/h 100 mL/h –500 mL/h(for 2 hours only during FFP treatment)

Note: FFP = Fresh frozen plasma

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fl uid removal fails to occur (assuming fl uid balance of 200mL/h). Moreover, dur-ing this off-time, patients may be administered additional fl uid that will counter earlier fl uid 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 fl uid removal during the ensuing 12 or 24 hours, which safely com-pensates for the off-time by increasing the hourly fl uid removal by, for example, an extra 100 mL/h. Due consideration needs to be paid to specifi c patients where such fl uid removal may be problematic. However, typically, machine fl uid removal rates of 300–400 mL/h are well tolerated in fl uid-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 fl exion 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 substi-tution fl uids 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 fl uid balance goals. It is often prudent to prescribe a greater fl uid loss than desired to compensate for these factors. Most machines allow the operator to check what the actual fl uid removal achieved was over a given time period. Such checks should be done to ensure that the correct fl uid removal is entered into the fl uid balance calculations; many nursing protocols mandate fl uid balance check each hour particularly for inexperienced nurses.

The benefi ts of such continuous monitoring of fl uid 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 fl uid status, and competent and detailed machine operation.

Conclusion

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

Conclusion

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Key references

Bagshaw SM, Baldwin I, Fealy N, Bellomo R. Fluid balance error in continuous renal re-placement 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 infl uence 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 fl uid overload on outcome in critically ill patients with acute kidney injury. Crit Care. 2008;12:169.

39

Indications for renal replacement therapy

Indications for renal replacement therapy (RRT) fall into two broad categories, so-called “renal” (i.e., to specifi cally 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 indicationsThe manifestations of acute kidney disease (as discussed in Chapter 1 and sum-marized in Table 6.1) include oliguria, (leading to volume overload), azotemia (leading to a host of clinical complications), hyperkalemia, and metabolic aci-dosis. 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 overloadVolume overload usually occurs in the setting of oliguria, but it may occur simply because urine output is insuffi cient to maintain fl uid balance in the face of large

Indications for renal replacement therapy

Chapter 6

Indications, timing, and patient selectionJohn A. Kellum

Table 6.1 Diuretic dosingOral IV Infusion

Metolazone 10–20 mg qd

Chlorothiazide 250–500 mg IV

Furosemide 20–40 mg 6–24-hourly 5–80 mg 6–24-hourly 1–10 mg/h

Torsemide 5–20 mg 6–24-hourly 5–20 mg 6–24-hourly 1–5 mg/h

Bumetanide 0.5–1 mg 6–24-hourly 0.5–2 mg 6–24-hourly 1–5 mg/h

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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 fl uids (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 defi ned. Although it is obviously desirable to avoid RRT, there is little evidence to sug-gest 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 benefi t 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.

AzotemiaAzotemia, the retention of urea and other nitrogenous waste products, results from a reduction in glomerular fi ltration 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 fl ow. 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 suffi cient 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 defi nes uremia or provides a spe-cifi c indication for RRT. Instead, the provision of RRT and, indeed, decisions

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Table 6.2 Manifestations of renal failureSystem Complication(s) Mechanism(s) Clinical features

Cardiovascular Volume overload Salt/water retention Edema, heart failure, hypertension

Electrolyte and acid-base

Hyponatremia, hyperkalemia, acidosis, azotemia

Impaired free water excretion, chloride accumulation

Hypotension, impaired glucose metabolism, decreased muscle protein synthesis, cardiac dysrhythmias

Gastrointestinal Impaired nutrient absorption, GI bleeding, abdominal compartment syndrome

Bowel edema, platelet dysfunction, volume overload

Nausea, vomiting, decreased mucosal/ intestinal absorption, increased intra-abdominal pressures

Hematological Anemia, platelet dysfunction

Decreased erythropoietin, decreased von Wilibrand’s factor

Anemia, bleeding

Immune Infections, immune suppression

Impaired neutrophil function

Infection, sepsis

Nervous Encephalopathy Uremic toxins, hyponatremia

Asterixis, delirium, coma

Respiratory Pleural effusions, pulmonary edema

Volume overload, decreased oncotic pressure, ? direct uremic toxicity

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.

HyperkalemiaHyperkalemia 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 fi nding is associated with car-diac 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 acidosisRenal 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

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in infl ammatory 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 chlo-ride balance and is generally targeted at maintaining an arterial pH > 7.30.

“Nonrenal” indicationsSo-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 removalBlood purifi cation 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 RRTSubstance Extracorporeal

methodComments

Methanol Hemodialysis 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.

Isopropanol Hemodialysis RRT effectively removes isopropanol and acetone, although it is usually unnecessary except in severe cases (prolonged coma, myocardial depression, renal failure).

Ethylene glycol Hemodialysis RRT should be continued until the ethylene glycol level is <20 mg/dL and metabolic acidosis or other signs of systemic toxicity have been resolved. Rebound may occur up to 24 hours.

Lithium IHD/CRRT IHD removes lithium faster but rebound is a signifi cant problem and can be addressed effectively with CRRT.

Salicylate IHD/CRRT Both IHD/CRRT have been reported in the management of salicylate poisoning.

Theophylline IHD/CRRT/ hemoperfusion

RRT should be continued until clinical improvement and a plasma level < 20 mg/L is obtained. Rebound may occur.

Valproic acid IHD/CRRT/ hemoperfusion

At supratherapeutic drug level plasma proteins become saturated, and the fraction of unbound drug increases substantially and becomes dialyzable.

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

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stimulants, and “street drugs”). In general, the size of the molecule and the degree of protein binding determines the degree to which the substance can be removed (smaller, nonprotein bound substances are easiest to remove). Continuous renal replacement therapy (CRRT) may be effective in removing substances with higher degrees of protein binding and is sometimes used to remove substances with very long plasma half-lives. Techniques such as sorbent hemoperfusion may also be used for this indication and are discussed further in Chapter 23.

The role of CRRT in the management of acute poisonings is not well estab-lished. There is relatively lower drug clearance per unit of time compared to intermittent hemodialysis (IHD) but CRRT has a distinct advantage in hemody-namically unstable patients who are unable to tolerate the rapid solute and fl uid losses associated with IHD or even other techniques such as hemoperfusion. CRRT may also be effective for the slow, continuous removal of substances with large volumes of distribution, a high degree of tissue binding, or for sub-stances that are prone to “rebound phenomenon” (e.g., lithium, procainamide, and methotrexate). In such cases, CRRT may even be used as adjuvant therapy with IHD or hemoperfusion.

Contrast agentsRRT has been used to remove radio-contrast agents for many years, but the purpose of this treatment has changed over time. In the past, ionic, high-osmolar contrast was used for imaging studies, and RRT was often used to remove these substances and to remove fl uid in patients with renal failure who were at risk of congestive heart failure from the large osmotic load. These patients could not excrete the contrast and would develop pulmonary edema after contrast ad-ministration. In more recent years, nonionic, low-osmolality, or even iso-osmo-lar agents have been developed, and the risk of pulmonary edema has decreased signifi cantly. However, all radio-contrast agents are nephrotoxic and CRRT is being advocated by some experts to help prevent so-called contrast nephrop-athy. Standard IHD has been shown to remove radio-contrast agents but does not appear to prevent contrast nephropathy. Despite less effi ciency in removing contrast, CRRT has been shown to result in less contrast nephropathy, partic-ularly when it has begun prior to or in conjunction with contrast administration (see Table 6.4). However, the effect is controversial and most centers do not currently offer RRT for prevention of contrast nephropathy.

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

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

Key studiesLee PT, Chou KJ, Liu CP, et al. Renal protection for coronary angiography in advanced

renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am Coll Cardiol. 2007;50:1015-1020.

Mehta RL, Pascual MT, Soroko S, et al; PICARD Study Group. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA. 2002;288:2547-2553.

Uchino S, Doig GS, Bellomo R, et al; B.E.S.T. Kidney Investigators. Diuretics and mortality in acute renal failure. Crit Care Med. 2004;32:1669-1677.

Timing of RRT

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

Timing of RRT

Table 6.4 Methods to reduce contrast nephropathyOral IV Dosinga

Saline 0.9% (154 mEq/L)

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

NaHCO3 in water 150 mEq/L 1 mL/kg/h begun 12 hours or 3 mL/kg/h begun 1 hour prior to procedure and 1 mL/kg/h continuing 6 hours after procedure

N-acetylcysteine 1200 mg every 12 hours

1200 mg every 12 hours

beginning 24 hours before and continuing 24 hours after procedure

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

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is interpreted. Most, but not all, experts advise that RRT should begin before clinical complications occur, but it is often diffi cult 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 impor-tant 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 insuffi cient 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).

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

Key studiesHoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury is associated

with hospital mortality in critical ill patients: A cohort analysis. Crit Care. 2006;10:R73.

Kellum JA, Mehta RL, Levin A, et al; AKIN. Development of a clinical research agenda for acute kidney injury using an international, interdisciplinary, three-step modifi ed Delphi process. Clin J Am Soc Nephrol. 2008;3:887-894.

Table 6.5 Assessment for recovery of renal function if urine volume > 30 mL/hCreatinine clearance Management of RRT

<12 mL/min Continuation of RRT

12–20 mL/min Clinician’s judgment

>20 mL/min Discontinuation of RRT

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

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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 world-wide 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 (inter-mittent vs. continuous) arises. The following considerations infl uence 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 hy-potension. 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 fl uid shifts and is therefore contraindicated in patients with in-creased intracranial pressure.Severe volume overload and high obligatory fl uid intake• : Even hemodynamically stable patients with severe volume overload or patients with mild fl uid over-load but high daily fl uid requirements (usually for medications and nutritional support) may be more effectively managed with CRRT. For example, it is un-usual 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 diffi cult 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.

Patient selection for CRRT

47

Introduction

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 suffi cient evidence to justify the use of CRRT outside the simple replacement of lost renal function.

Key terms

Blood purifi cation: This term refers to the use of extracorporeal therapies such as CRRT for the treatment of a variety of conditions (drug overdose, liver fail-ure, 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 infl ammatory and counter-infl ammatory response seen after major body injury or infection. These mol-ecules 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 frame-work provides the rationale for using CRRT in sepsis.

Introduction

Key terms

Chapter 7

Extended indications for continuous renal replacement therapyRinaldo Bellomo and Ian Baldwin

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High-volume hemofi ltration (HVHF): This term refers to a technique of CRRT where the amount of fl uid 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 purifi cation 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 hemofi ltration: This term refers to the use of special fi lters 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,

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

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Figure 7.2 Impact of high-volume hemofi ltration (HVHF) on C3a levels compared with stan-dard Continuous veno-venous hemofi ltration (CVVH).

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

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 fi ltering membrane. Such removal is one of the mechanisms by which CRRT can remove cytokines from blood.

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 (ana-sarca) develops despite intensive, high-dose, multiple diuretic-based attempts to remove excess fl uid.

Methods, techniques, and approach

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 fl uid removal with a degree of inevitably accompanying uremia, standard CRRT can be used to lower the urea concentration while aiming for a signifi cant negative fl uid balance of –200 to –400 mL/h. With this approach, large amounts of fl uid can be removed from patients with diuretic resistant fl uid 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 hemofi ltration can be applied. HVHF requires high blood fl ows (>300 mL/min) in order to avoid either excessive predilution (if the replacement fl uid is administered before the fi lter) or excessive hemo-concentration within the fi lter (if the replacement fl uid is administered after the fi lter). If HVHF is used, attention must be paid to fl uid balance and to phos-phate levels. This is because relatively minor errors in fl uid balance can cause problems when 10 L of fl uids are exchanged every hour and because the rapid removal of phosphate will inevitably lead to hypophosphatemia. If high-cutoff hemofi ltration is used, special fi lter membranes are necessary. HVHF may also be used to remove a water-soluble free toxic drug like lithium or sodium val-proate at higher effi ciency 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-effi ciency treatment of blood. In some case, CRRT can be used to control body temperature in situ-ations like malignant hyperthermia or severe fever due to infection or cerebral injury. In such cases, replacement fl uid is not warmed prior to administration or can even be cooled prior to administration.

Methods, techniques, and approach

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The choice to apply CRRT in the techniques described earlier is entirely based on clinical judgment and a view that the possible benefi ts 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 fi eld so that the treatment can be applied with minimal risk. This requirement particularly applies to HVHF, which requires adequate machines, accurate fl uid balance monitoring, frequent monitoring of electrolytes and phosphate, and attention to body temperature. The risks are much less with severe diuretic refractory fl uid overload, especially when secondary to advanced cardiac failure. In such patients, the typical desired fl uid removal (10–15 L ) can be achieved over 24–48 hours by means of a steady negative fl uid 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 intoxica-tion, CRRT (perhaps initially at high volume and then once the levels are within a safe range, at standard volumes) also appears justifi ed, 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 infl ammatory 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 nephropathyCorrecting anasarca of different etiology•

Preventing massive fl uid overload in patients receiving large amounts of clot-•

ting factorsAttenuating the infl ammatory response associated with prolonged cardiopul-•

monary bypassCorrecting 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 fi eld 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 fl uid, deliver large amounts of buffer, remove water-soluble drugs, affect the infl ammatory and counterinfl ammatory systems,


Summary

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

Key references

Bellomo R, Baldwin I, Cole L, Ronco C. Preliminary experience with high-volume hemofi l-tration in human septic shock. Kidney Int. 1998;53(suppl 66):S182-S185.

Bellomo R, Baldwin I, Ronco C. Extracorporeal blood purifi cation for sepsis and systemic infl ammation: its biologic rational. Contrib Nephrol. 2001;132:367-374.

Bellomo R, Baldwin I, Ronco C. High-volume hemofi ltration. Curr Opin Crit Care. 2000;6:442-445.

Bellomo R, Baldwin I, Ronco C. Rationale for extracorporeal blood purifi cation therapies in sepsis. Curr Opin Crit Care. 2000;6:446-450.

Cruz DN, Perazella MA, Bellomo R, et al. Extracorporeal blood purifi cation 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 purifi cation in non-renal critical illness. Blood Purif. 2003;21:6-13.

53

Introduction

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 purifi ed by “waste products and toxins” achieved by means of renal replacement.

The operative measure of RRT dose is the elimination amount of a represen-tative marker solute:

The marker solute, however, does not represent all the solutes that accumu-•

late 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 signifi cant 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: effi ciency, intensity, frequency, and clinical effi cacy.

Introduction

Theoretical aspects of renal replacement therapy dose

Chapter 8

Dose adequacy and assessmentZaccaria Ricci and Claudio Ronco

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Effi ciency 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 refl ect 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 fl ow rate (QB), ultrafi ltration rate (QF), dialysate fl ow 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 clini-cal setting. During convective techniques, QF is strictly linked to QB by fi ltra-tion fraction (the fraction of plasma water that is removed from blood by ultrafi ltration), 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 specifi c solute, clearances of urea and creatinine blood levels are used to guide treatment dose. During ultrafi ltration, the driving pressure jams solutes, such as urea and creatinine, against the membrane and into the pores, depending on membrane sieving coeffi cient (SC) for that molecule. SC expresses a dimensionless value and is estimated by the ratio of the con-centration of the solutes in the fi ltrate divided by that in the plasma water or blood. An SC of 1.0, as is the case for urea and creatinine, demonstrates com-plete permeability and a value of 0 refl ects complete rejection. Molecular size over approximately 12 kDa and fi lter 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 chang-ing variable for different solutes. During diffusion, an analog linear relation-ship depends on the diffusibility of a solute across the membrane. As a rough estimate, we showed that during continuous slow effi ciency 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 differ-ent time schedules. For example, K is typically higher in intermittent hemodi-alysis (IHD) than continuous renal replacement therapy (CRRT) and sustained low effi ciency daily dialysis (SLEDD). This is not surprising, since K represents only the instantaneous effi ciency 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 defi ned 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 effi cacy.

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Effi cacy of RRT is the effective solute removal outcome resulting from the •

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 dis-tribution 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 simplifi cation 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 hemofi ltration (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 benefi ts of higher RRT doses. However, it has been shown that during a continuous therapy a K less than 2 L/h will almost defi nitely result insuffi cient 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 fl oor. Nevertheless, so far, several clinical trials have failed to show a “one-size fi ts 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 con-•

trol, magnesium control, calcium and phosphate control, intravascular volume control, extravascular volume control, temperature control, and the avoid-ance 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.

Practical aspects of RRT dose

Tables 8.1 and 8.2 show a potential fl ow 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/V• CALC): KCALC (mL/min) * prescribed treat-ment time (min)/V (mL).

Practical aspects of RRT dose

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25 mL/kg/h roughly correspond to a Kt/V of 1.0. •

Filtration fraction calculation (postdilution): Q• REP/QB * 100; fi ltration fraction calculation (predilution): QREP/QB + QREP * 100.Q• B: blood fl ow rate; QREP: replacement solution fl ow rate; QUF: ultrafi ltration fl ow rate (QUF: QREP + QNET); QNET: patient’s net fl uid loss; QDO: dialysate so-lution fl ow rate.

RRT dose delivery: continuous or intermittent

In its original conceivement, K is utilized to evaluate renal function among dis-parate 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’ effi ciency 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).

RRT dose delivery: continuous or intermittent

Table 8.1 RRT prescriptionClinical variables Operational

variablesSetting

Fluid balance Net ultrafi ltration 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.

Adequacy and dose Clearance/modality 2000–2500 mL/h K (or 25–30 mL/kg/h) for CRRT; consider fi rst 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.

Acid-base Solution buffer Bicarbonate buffered solutions are preferable to lactate buffered solutions in case of lactic acidosis and/or hepatic failure.

Electrolyte Dialysate/replacement Consider solutions without K+ in case of severe hyperkalemia. Manage accurately MgPO4.

Timing Schedule Early and intense RRT is suggested.

Protocol Staff/machine Well-trained staff should routinely utilize RRT monitors according to predefi ned institutional protocols.

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

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

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

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

Estimated urea clearance (KCALC)

Notes Value of Q in order to obtain 25 mL/kg/h

Value of Q in order to obtain a Kt/V of 1

CV VH postdilution

KCALC = QREP Always keep fi ltration fraction < 20% (QB must be 5 times QREP)

QREP: 25 mL/min or 2000 mL/h

QREP: 29 mL/min or 1750 mL/h

CV VH predilution

KCALC = QUF /[1 + (QREP/QB)]

Filtration fraction computation changes (keep <20%)

For a QB of 180 mL/min:QREP: 30 mL/min or 2500 mL/h

For a QB of 200 mL/min:QREP: 35 mL/min or 2100 mL/h

CV VHD KCALC = QDO Keep QB at least thrice Qd

QDO: 25 mL/minor 2000 mL/h

QDO: 29 mL/min or 1750 mL/h

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

KCALC = QREP + QDO

Consider both notes of CVVH and CVVHD

QREP: 15 mL/min + QDO: 10 mL/min

QREP: 14 mL/min replacement solution + QDO: 15 mL/min

Table 8.3 Comparison of intermittent hemodialysis and continuous renal replacement therapy effi ciency

CRRT IHDK (mL/min) 35 200

Urea start (mg/dL) 110 110

Urea end (mg/dL) 90 30

Treatment time (min) 1440 240

Total K (K*time) 50.5 48

Urea removed (g) 25 18

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have a detrimental impact on patients’ hemodynamics as well as electrolyte, acid base, and other “osmoles” balance. Furthermore, in the case of IHD, the intercompartmental transmittance (Kc), •

that is, the variable tendency of different tissues to “release” a solute into the bloodstream, is much more relevant than during slow effi ciency treatments.

Different prescriptions may lead to almost equivalent fi nal daily delivery of K. Nonetheless, continuous therapies seem to achieve a fi nal better urea control due to the different “physiology” of solute removal (slow, steady, prolonged, and independent from tissues intercompartmental transmittance).

According to recent international surveys on clinical practice patterns, 80% centers administer CRRT, 17% use intermittent RRT (IRRT), and a few minority apply peritoneal dialysis (PD). Interestingly, in many centers intermittent tech-niques are utilized together with continuous ones, thus evidencing possibility of multiple prescriptions and practices. Nonetheless, after years of debate, scien-tifi c literature is not able to draw conclusions on how RRT delivery modalities may impact clinical outcomes. Many papers have been published on this issue and they must be analyzed critically.

Many randomized controlled trials compared intermittent and continuous RRT, providing so far only confl icting and puzzling results. Basing on actual sci-entifi c evidence, the Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock recently concluded that, during AKI, CV VH and IHD should be considered equivalent.

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Conclusions

As concluded by the Acute Dialysis Quality Initiative (ADQI) workgroup in 2001, delivered clearance should be monitored during all renal supportive ther-apies. No recommendations can be made for specifi c dialysis dosing for patients with specifi c diseases at this time. A minimum dose of RRT, however, needs to be delivered for AKI:

The best evidence to date supports the delivery of at least 20 mL/kg/h for •

CV VH, CV VHD, or CV VHDF. Usually this will require the prescribed dose of 25–30 mL/kg/h. At present, there is no evidence of harm in increasing the dose up to 35 mL/kg/h (2–2.5 L/h): this might be benefi cial in terms of solute control in selected patients.1.2 Kt/V delivered IHD on alternate days—typically prescribed dose is approx-•

imately 1.4 Kt/V for alternate day dosing. For alternate day IHD, isolated ultrafi ltration can be used for volume control •

as needed on nondialysis days.It should also be recommended that the prescription should exceed that cal-•

culated to be “adequate” because of the known gap between prescribed and delivered dose. If a solute-based approach to the concept of dose seems too restrictive, •

although operatively relatively simple, other dimensions of adequacy of RRT or RRT dose remain unexplored but likely to be important: blood volume control, acid-base control, tonicity control.

Key references

Lameire N, van Biesen W, Van Holder R, Colardijn F. The place of intermittent he-modialysis in the treatment of acute renal failure in the ICU patient. Kidney Int. 1998;53(suppl 66):S110-S119.

Ricci Z, Bellomo R, Ronco C. Dose of dialysis in acute renal failure. Clin J Am Soc Nephrol. 2006;1:380-388.

Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofi ltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000;356:26-30.

The VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359:7-20.

Uchino S, Bellomo R, Kellum JA, et al; BEST Kidney Investigators Writing Committee. Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury. Int J Artif Organs. 2007;30:281-292.

Uchino S, Kellum JA, Bellomo R, et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients a multina-tional, multicenter study. JAMA. 2005;294:813-818.

Conclusions

61

Electrolyte management

An important principle in the management of electrolytes with continuous renal replacement therapy (CRRT) is that “you get what you replace.” With hemofi l-tration, all electrolytes are freely removed (sieving coeffi cients near 1) and, thus, over time and assuming no large intake or other losses, plasma concentrations will approach those of the replacement fl uid. The rate at which electrolytes change is determined by how different the plasma concentration is relative to that in the replacement fl uid and the rate of fl uid replacement delivered.

Similar principles exist for continuous hemodialysis with one exception: phos-phate. Although the phosphate molecule is not large, it behaves as if it were a much larger molecule. As a consequence, phosphate is removed much more slowly with dialysis (diffusion) compared to fi ltration (convection). For this reason, patients receiving dialysis may still require phosphate binders whereas those receiving hemofi ltration frequently require phosphate replacement.

It should be noted that plasma electrolyte concentrations often don’t refl ect whole body stores, whereas high or low plasma concentrations still may induce symptoms and deleterious physiological and metabolic effects. In particular, K+, the primary intracellular cation, exhibits only a loose association between plasma and intracellular concentrations (see below). Plasma Mg2+ concentra-tions bear almost no relation to total body stores, and persistent hypokalemia may be the only clue to total body Mg2+ defi ciency.

Electrolyte losses, as well as electrolyte intake, should be considered in pre-scribing CRRT. An important source of exogenous K+ is from transfusions of banked blood. Blood transfusions are also an important cause of hypocalcemia owing to the citrate anticoagulation used in blood banking. Important sources of electrolyte loss are shown in Table 9.1.

Specifi c fl uid prescribing information for both continuous veno-venous hemo-fi ltration (CVVH) and continuous veno-venous hemodialysis (CVVHD) is found in Chapter 14.

Electrolyte management

Chapter 9

Acid-base and electrolyte disordersJohn A. Kellum

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Dysnatremias

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

HypernatremiaHypernatremia is manifest by thirst, lethargy, coma, seizures, muscular tremor and rigidity, and an increased risk of intracranial hemorrhage. Thirst usually occurs when the plasma sodium rises 3–4 mmol/L above normal. Lack of thirst is associated with central nervous system disease (see Table 9.2).

Rate of correctionIf hyperacute (<12 h), correction should be rapid.•

Otherwise, aim for gradual correction of plasma sodium levels (over 1–3 •

days), particularly in chronic cases (>2 days’ duration), to avoid cerebral edema through sudden lowering of osmolality. A rate of plasma sodium lowering <0.7 mmol/h has been suggested.

Low or normal total body Na (water loss)Reduce Na concentration in replacement fl uid or dialysate (see Chapter 14 •

for specifi c fl uids). Give water replacement PO in addition to changes in CRRT fl uids. •

Even fl uid balance (or even fl uid gain with replacement fl uid) until total body •

water is normalized.In the case of central diabetes insipidus (CDI), restrict salt and give thiazide •

diuretics. Complete CDI will require desmopressin (10 µg bid intranasally or 1–2 µg bid IV), whereas partial CDI may require desmopressin but often responds to drugs that increase the rate of antidiuretic hormone (ADH) se-cretion or end-organ responsiveness to ADH, for example, chlorpropamide, hydrochlorthiazide.

Dysnatremias

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

Na+, Cl−

Na+, Cl−

Na+, Cl−, K+, Mg2+

Na+, Cl−, K+, Mg2+

Na+, Cl−, K+

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

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

and thiazides. High dose desmopressin may be effective. Consider removal of causative agents, for example, lithium.

Increased total body Na (Na gain)Reduce Na concentration in replacement fl uid or dialysate (see Chapter 14 •

for specifi c fl uids). Remove fl uid to achieve even, or in the case of hypervolemia, net negative, •

fl uid balance.

HyponatremiaHyponatremia may cause nausea, vomiting, headache, fatigue, weakness, mus-cular twitching, obtundation, psychosis, seizures, and coma. Symptoms depend on the rate as well as the magnitude of fall in the plasma [Na+] (see Table 9.3).

Rate and degree of correctionRate and degree of correction depend on how rapidly the condition has de-•

veloped and whether the patient is symptomatic. Hyponatremia that has de-veloped over more than 48 h is considered “chronic.” In CHRONIC ASYMPTOMATIC hyponatremia correction should not exceed •

4 mmol /24 h and the rate of correction should not exceed 0.3 mmol/L/h.In CHRONIC SYMPTOMATIC (e.g., seizures, coma) hyponatremia correc-•

tion should be 1–1.5 mmol/L/h until symptoms resolve and then correction should be as per asymptomatic cases. In ACUTE hyponatremia (<48 h) the ideal rate of correction is controversial, •

although elevations in plasma Na+ can be faster, but <20 mmol/L/day.

Table 9.2 Causes of hypernatremiaType Etiology Urine

Low total body Na

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

[Na+] >20 mmol/Liso- or hypotonic

[Na+] <10 mmol/Lhypertonic

Normal total body Na

Renal losses: diabetes insipidusExtra-renal losses: respiratory and renal insensible losses

[Na+] variablehypo-, iso- or hypertonic[Na+] variablehypertonic

Increased total body Na

Conn’s syndrome, Cushing’s syndrome, excess NaCl, hypertonic NaHCO3

[Na+] >20 mmol/Liso- or hypertonic

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

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

tion of both acute and chronic states. Attempts to achieve eunatremia rapidly should be avoided.Neurological complications, for example, central pontine myelinolysis, are re-•

lated to the degree of correction and (in chronic hyponatremia) the rate. Premenopausal women are at highest risk for this complication.

Extracellular fl uid (ECF) volume excessIf symptomatic (e.g., seizures, agitation), 100 mL aliquots of hypertonic (1.8%) •

saline can be given, with plasma levels being checked every 2–3 h.If symptomatic and edematous, fl uid removal on CRRT can be done in add-•

ition to hypertonic saline. Plasma levels should be checked every 2–3 h. With custom replacement fl uid or dialysate, the Na concentration can be increased somewhat, but hypertonic dialysis or replacement fl uid is not recommended. If not symptomatic, water should be restricted to 1–1.5 L/day. If hyponatremia •

persists, inappropriate ADH [syndrome of inappropriate antidiuretic hormone secretion (SIADH)] secretion should be considered.If SIADH is likely, isotonic saline should be given and demeclocycline should •

be considered.

Extracellular fl uid (ECF) volume depletionIf symptomatic (e.g., seizures, agitation), give isotonic (0.9%) saline. Consider •

hypertonic (1.8%) saline initially especially if acute.If asymptomatic, use isotonic (0.9%) saline.•

Maintain even fl uid balance on CRRT.•

General pointsEquations that calculate excess water are unreliable. It is safer to monitor •

plasma sodium levels closely.Hypertonic saline may be dangerous, especially in the elderly and those with •

impaired cardiac function. Use isotonic solutions for reconstituting drugs, parenteral nutrition, and so on •

(i.e., avoid hypotonic fl uids).Hyponatremia may intensify the cardiac effects of hyperkalemia.•

A true hyponatremia may occur with a normal osmolality in the presence of •

abnormal solutes, for example, ethanol, ethylene glycol, glucose.

Causes of inappropriate ADH secretionNeoplasm, for example, lung, pancreas, lymphoma•

Most pulmonary lesions•

Most central nervous system lesions•

Surgical and emotional stress•

Glucocorticoid and thyroid defi ciency•

Idiopathic•

Drugs, for example, chlorpropamide, carbamazepine, narcotics•

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Potassium and magnesium

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

HyperkalemiaHyperkalemia may cause dangerous arrhythmias, including cardiac arrest. Arrhythmias are more closely related to the rate of rise of potassium than the absolute level. Clinical features such as paresthesia and arefl exic weakness are not clearly related to the degree of hyperkalemia but usually occur after ECG changes (tall “T” waves, fl at “P” waves, prolonged PR interval and wide QRS).

CausesReduced renal excretion (e.g., renal failure, adrenal insuffi ciency, diabetes, po-•

tassium sparing diuretics)Intracellular potassium release (e.g., acidosis, rapid transfusion of old blood, •

cell lysis including rhabdomyolysis, hemolysis, and tumor lysis Potassium poisoning•

ManagementCRRT is effective in removing K+, although standard hemodialysis can remove K+ faster. Ancillary therapy may also be required particularly in emergency situ-ations (see Chapter 6).

Potassium and magnesium

Table 9.3 Causes of hyponatremiaType Etiology Urine [Na+]

ECF volume depletion

Renal losses: diuretic excess, osmotic diuresis (glucose, urea, mannitol), renal tubular acidosis, salt-losing nephritis, mineralocorticoid defi ciency

>20 mmol/l

Extra-renal losses, vomiting, diarrhea,: burns, pancreatitis

<10 mmol/l

Modest ECF volume excess (no edema)

Water intoxication (NB postoperative, TURP syndrome), inappropriate ADH secretion, hypothyroidism, drugs(e.g., carbamazepine, chlorpropamide), glucocorticoid defi ciency, pain, stress.

>20 mmol/l

Acute and chronic renal failure >20 mmol/l

ECF volume excess (edema)

Nephrotic syndrome, cirrhosis, heart failure <10 mmol/l

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

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HypokalemiaTypical manifestations of hypokalemia include the following:

Arrhythmias (SVT, VT, and • Torsades de Pointes)ECG changes (ST depression, “T” wave fl attening, “U” waves)•

Constipation•

Ileus•

Weakness•

CausesInadequate intake•

Gastrointestinal losses (e.g., vomiting, diarrhea, fi stula losses)•

Renal losses (e.g., diabetic ketoacidosis; Conn’s syndrome; secondary hyperal-•

dosteronism; Cushing’s syndrome; renal tubular acidosis; metabolic alkalosis; hypomagnesemia; drugs including diuretics, steroids, theophyllines)Hemofi ltration losses•

Potassium transfer into cells (e.g., acute alkalosis, glucose infusion, insulin •

treatment, familial periodic paralysis)

ManagementPotassium replacement should be intravenous with ECG monitoring when there is a clinically signifi cant arrhythmia (20 mmol over 30 min, repeated according to levels). Slower intravenous replacement (20 mmol over 1 h) should be used where there are clinical features without arrhythmias. Oral supplementation (to a total intake of 80–120 mmol/day, including nutritional input) can be given where there are no clinical features.

HypomagnesemiaMagnesium is primarily an intracellular ion involved in the production and utili-zation of energy stores and in the mediation of nerve transmission. Low plasma levels, which do not necessarily refl ect either intracellular or whole body stores, may thus be associated with features related to these functions:

Confusion, irritability•

Seizures•

Muscle weakness, lethargy•

Arrhythmias•

Symptoms related to hypocalcemia and hypokalemia, which are resistant to •

calcium and potassium supplementation, respectively

Normal plasma levels range from 1.7–2.4 mg/dL; severe symptoms do not usu-ally occur until levels drop below 1.0 mg/dL.

CausesExcess loss, for example, diuretics, other causes of polyuria (including poorly •

controlled diabetes mellitus), severe diarrhea, prolonged vomiting, large na-sogastric aspirates

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

malabsorption syndromes

ManagementFor severe, symptomatic hypomagnesemia, 10 mmol of magnesium sul-•

phate can be given IV over 3–5 min. This can be repeated once or twice as necessary.In less acute situations or for asymptomatic hypomagnesemia, 1–2 g MgSO• 4 solution can be given over 1–2 h and repeated as necessary, or according to repeat plasma levels.A continuous IV infusion can be given; however, this is usually reserved for •

therapeutic indications where supranormal plasma levels (4–5 mg/dL) of mag-nesium are sought, for example, treatment of supraventricular and ventricular arrhythmias, preeclampsia, and eclampsia.Oral magnesium sulfate has a laxative effect and may cause severe diarrhea.•

HypermagnesemiaSymptomatic hypermagnesemia rarely occurs even in severe renal failure except as a consequence of a large magnesium load (in which it may occur even with intact renal function) (see Table 9.4). However, patients with renal failure may develop severe hypermagnesemia when exposed to magnesium containing ant-acids or laxatives, even in usual therapeutic dosages. Thus, these agents are con-traindicated in patients with severe renal failure. Most cases of hypermagnesemia are mild (<3.6 mg/dL, or 1.5 mmol/L) and asymptomatic. However, three types of symptoms may be seen when the plasma magnesium concentration exceeds 4.8 mg/dL (2 mmol/L): neuromuscular, cardiovascular, and hypocalcemia.

CausesIV magnesium infusion (typically as treatment for preeclampsia)•

Oral ingestion (e.g., laxative, epsom salts)•

Magnesium enemas•

Table 9.4 Relationship of plasma magnesium and clinical symptomsPlasma [Mg2+] Deep tendon

refl exes Other symptoms/signs

4.8–7.2 mg/dL(2–3 mmol/L)

Diminished Nausea, fl ushing, headache, lethargy, and drowsiness

7.3–12 mg/dL(3–5 mmol/L)

Absent Somnolence, hypocalcemia, hypotension, bradycardia, and ECG changes

>12 mg/dL(>5 mmol/L)

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

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ManagementPeritoneal dialysis, hemodialysis, and CRRT have been used effectively to lower the plasma magnesium concentration in patients with severe symptomatic hypermagnesemia, usually in the setting of renal failure complicated by exogen-ous magnesium loading. Hemodialysis with its higher fl ow rates works more rapidly, lowering magnesium levels to the nontoxic range usually within 3–4 h. CRRT is typically slower and peritoneal dialysis is usually reserved for milder cases in patients receiving chronic peritoneal dialysis. Exchange transfusion has been effective in neonatal hypermagnesemia.

While awaiting dialysis in a patient with severe symptoms, intravenous cal-cium can be given as a magnesium antagonist. The usual dose is 100–200 mg of elemental calcium over 5–10 min.

Calcium and phosphate

Ca2+ and PO43– are often considered together in patients with renal failure as a

common complication of chronic disease is renal osteodystophy or bone min-eral disease, which leads to hypocalcemia and hyperphosphatemia.

HypocalcemiaSymptoms of hypocalcemia usually appear when total plasma calcium levels are less than 8 mg/dL and the ionized fraction is below 0.8 mmol/L.

Tetany (including carpopedal spasm)•

Muscular weakness•

Hypotension•

Perioral and peripheral paresthesia•

Chvostek and Trousseau’s signs•

Prolonged QT interval•

Seizures•

CausesAssociated with hyperphosphatemia:•

Renal failure•

Rhabdomyolysis•

Hypoparathyroidism (including surgery), pseudohypoparathyroidism•

Associated with low/normal phosphate:•

Critical illness including sepsis, burns•

Hypomagnesemia•

Pancreatitis•

Osteomalacia•

Overhydration•

Massive blood transfusion (citrate binding)•

Calcium and phosphate

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

ized plasma calcium fraction and induce clinical features of hypocalcaemia

ManagementIf respiratory alkalosis is present, adjust ventilator settings or, if spontaneously •

hyperventilating and agitated, calm ± sedate. Rebreathing into a bag may be benefi cial.Administer 1 g of calcium chloride or 3 g of calcium gluconate (270 mg of •

elemental calcium) IV infusion over 30–60 min.If symptomatic, give 5–10 mL 10% calcium chloride or 15–20 mL 10% calcium •

gluconate solution over 10–15 min. Repeat as necessary.Correct hypomagnesemia or hypokalemia if present.•

If asymptomatic and in renal failure or hypoparathyroid, consider enteral/•

parenteral calcium supplementation and vitamin D analogues.If hypotensive or cardiac output is decreased following administration of a •

calcium antagonist, give 5–10 mL 10% calcium chloride solution over 2–5 min.

HypercalcemiaAmong all causes of hypercalcemia, hyperparathyroidism and malignancy are the most common, accounting for greater than 90% of cases.

Symptoms of hypercalcemia usually do not become apparent until the total (ionized + unionized) plasma levels >13 mg/dL (normal range 8.5–10.5 mg/dL). Symptoms depend on the patient’s age, the duration and rate of increase of plasma calcium, and the presence of concurrent medical conditions. Signs and symptoms of hypercalcemia may include the following:

Nausea, vomiting, weight loss, pruritus •

Abdominal pain, constipation, acute pancreatitis•

Muscle weakness, fatigue, lethargy•

Depression, mania, psychosis, drowsiness, coma•

Polyuria, renal calculi, renal failure•

Cardiac arrhythmias•

CausesMalignancy (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.•

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

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 ± fl uid overloaded. CRRT or hemodialysis without calcium in the dialysis or replacement fl uid •

are both effective therapies for hypercalcemia, although are usually consid-ered treatments of last resort. RRT may be indicated in patients with se-vere 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 modifi cation of the composition of dia-lysis solutions. In one case report, hemodialysis with a dialysis solution containing 4 mg/dL of phosphorus resulted in rapid correction of all abnor-malities in a patient in whom medical therapy had failed to reverse hyper-calcemia, mental status changes, and hypophosphatemia due to primary hyperparathyroidism.

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

Table 9.5 Drug dosageDiuretics Furosemide 10–40 mg IV 2–4 h (may be increased to

80–100 mg IV every 1–2 h)

Steroids Hydrocortisone 100 mg qid IV or prednisolone 40–60 mg PO for 3–5 days

Pamidronate 15–60 mg slow IV bolus

Calcitonin 3–4 U/kg IV followed by 4U/kg SC bd

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CausesCritical illness•

Inadequate intake•

Loop diuretic therapy (including low-dose dopamine)•

Parenteral nutrition levels fall rapidly during high-dose intravenous glucose •

therapy, especially with insulinAlcoholism•

Hyperparathyroidism•

ManagementMild 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 phos-phate level.

HyperphosphatemiaHyperphosphatemia itself does not produce symptoms. The major concern for hyperphosphatemia is the high circulating levels of parathyroid hormone (PTH) that result, and, in turn, its role in the development of renal osteodystrophy and possibly in other uremic complications as well. High levels of plasma Ca2+, PO4

3– together may cause calcinosis (soft tissue calcifi cations) especially if the plasma Ca × PO4 product is chronically >70.

CausesThere are three general circumstances, alone or in combination, in which hyper-phosphatemia occurs:

Massive acute phosphate load (e.g., tumor lysis, rhabdomyolysis)1. Renal failure 2. Increased phosphate reabsorption (hypoparathyroidism, acromegaly, fa-3. milial tumoral calcinosis, bisphosphonate therapy, vitamin D toxicity)

ManagementThe approach to therapy differs in acute and chronic hyperphosphatemia. Acute severe hyperphosphatemia with symptomatic hypocalcemia can be life-threat-ening. 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 hemodi-alysis is often indicated in patients with symptomatic hypocalcemia, particularly if renal function is impaired. Unlike other electrolytes, phosphate is removed more effi ciently with CRRT (in hemofi ltration mode) compared to hemodial-ysis. This is because PO4

3– acts in solution as a larger molecule and is more diffi -cult to remove with diffusion (dialysis) compared to convection (fi ltration).

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PseudohyperphosphatemiaSpurious hyperphosphatemia may result from interference with the analytical methods.

CausesHyperglobulinemia, hyperlipidemia, hemolysis, and hyperbilirubinemia•

Liposomal amphotericin B•

Key StudyLeehey 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 intakeAcidosis: chloride administration (e.g., saline), aspirin overdose•

Alkalosis: NaHCO• 3 administration, antacid abuse, buffered replacement fl uid (hemofi ltration)

Altered productionIncreased acid production: lactic acidosis, diabetic ketoacidosis•

Altered excretionHypercapnic respiratory failure, permissive hypercapnia•

Alkalosis: vomiting, large gastric aspirates, diuretics, hyperaldosteronism, •

corticosteroidsAcidosis: diarrhea, small bowel fi stula, urethroenterostomy, renal tubular •

acidosis, renal failure, distal renal tubular acidosis, acetazolamide

General management principlesCorrect (where possible) the underlying cause, for example, hypoperfusion•

Use NaCl infusion for vomiting-induced alkalosis; insulin, Na• +, and K+ in dia-

betic ketoacidosisCorrect pH in specifi c circumstances only, for example, NaHCO• 3 in renal failureAvoid large volume saline-based fl uids. Consider lacted Ringer’s solution or •

hetastarch in balanced electrolyte solution (Hextend) for fl uid resuscitation.

General acid-base management

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

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) quantifi es 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 fl uid. Typically, undertake correction of half the abnormality and then reassess. •

Avoid “over correction” of acid-base abnormalities particularly in cases of me-•

tabolizable acid anions (e.g., lactate, ketones) (see metabolic acidosis).

Metabolic acidosis

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

CausesLactic 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 sei-zure, 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 impli-cated, possibly by inducing regional ischemia or, in the case of epinephrine, accelerated glycolysis.

Metabolic acidosis

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Ingestion of poisons, for example, paraldehyde, ethylene glycol, methanol.•

Cation loss, for example, severe diarrhea, small bowel fi stulae, large ileostomy •

losses.

Causes of lactic acidosis

SepsisAcute lung injuryDiabetes mellitusDrugs, for example, phenformin, metformin, alcoholsCirculatory shock, for example, septic shock, hemorrhage, heart failure Glucose-6-phosphatase defi ciencyHematological malignancyHepatic failureRenal failureShort bowel syndrome (d-lactate)Thiamine defi ciency

Clinical featuresDyspnea•

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 managementThe underlying cause should be identifi ed 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 defi cit suggests that the therapeutic maneuvers in operation are either inadequate or wrong.The benefi ts of buffers such as Carbicarb and THAM (tris-hydroxymethyl-•

aminomethane) remain unproved.

CRRT managementUrgent 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.

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Use standard or slightly more alkaline dialysate or replacement fl uid—•

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 fl uid by the same interval as the stan-

dard base excess (SBE), for example, for SBE-10, decrease Cl– by 10 mEq/L.

Metabolic alkalosis

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 effi cient at regulating the strong ion difference, persistence of a metabolic alkalosis usually depends on either renal impairment or a diminished extracellular fl uid 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 fl ow, and decreased cardiac inotropy.

CausesLoss of total body fl uid, Cl•

–, usually due todiuretics•

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 hyper-ventilated to normocapnia, an overcompensated metabolic alkalosis can oc-casionally 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

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ManagementReplacement of fl uid, Cl•

– (i.e., give 0.9% saline), and K+ losses are often suffi cient 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 uncompen-sated 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 managementCRRT is not generally required for management of metabolic alkalosis itself •

but in patients receiving CRRT principles of management of metabolic alkal-osis mirror those described above for metabolic acidosis.

If hypernatremia, decrease Na• + in dialysate or replacement fl uid.

Increase Cl• – concentration in dialysate or replacement fl uid (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 fl uid should be decreased.

Avoid citrate and Ca• 2+ “dose spirals;” reduce citrate rather than increasing

Ca2+ to avoid citrate overdosing.

Part 2

Practice

79

Introduction

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-fl ux highly permeable biocompatible dialysis membranes. Simultaneous infusion of replacement fl uid permits fl uid removal without intravascular contraction and better hemodynamic stability, meta-bolic 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 briefl y 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 associ-ated 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 “non-renal” [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, mul-tiple considerations must be kept in mind (Table 10.2).

Introduction

Chapter 10

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

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Table 10.1 Indications for specifi c renal replacement therapiesTherapeutic goal Hemodynamics Preferred therapy

Fluid removal Stable Intermittent isolated UF

Unstable Slow continuous UF

Urea clearance Stable Intermittent hemodialysis

Unstable CRRT

Convection: CAVH, CV VH

Diffusion: CAVHD, CV VHD

Both: CAVHDF, CV VHDF

Severe hyperkalemia Stable/unstable Intermittent hemodialysis

Severe metabolic acidosis Stable Intermittent hemodialysis

Unstable CRRT

Severe hyperphosphoremia Stable/unstable CRRT

Brain edema Unstable CRRT

Table 10.2 Considerations in renal replacement therapy for AKIConsideration Components Varieties

Dialysis modality Intermittent hemodialysis Daily, every other day, SLED

Continuous renal replacement therapies

AV, VV

Peritoneal dialysis

Dialysis biocompatibility Membrane characteristics

Dialyzer performance Effi ciency

Flux

Dialysis delivery Timing of initiation Early, late

Intensity of dialysis Prescription vs. delivery

Adequacy of dialysis 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 consen-sus on fl uid and volume management, which is relevant to the present discussion.

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KI81Arterio-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 arte-rial damage, blood fl ow dependency on systemic hemodynamics, and insuffi cient dialysis dose.

Choice of continuous renal replacement therapy modality

The different modalities of CRRT (Figure 10.1) are defi ned by the main mecha-nism with which clearance is achieved: simple diffusion (continuous hemodialy-sis, CV VHD), convection (continuous hemofi ltration, CV VH), or a combination of both (continuous hemodiafi ltration, 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 fl uid replacement (hemofi ltration) (Table 10.4).

Given the absence of evidence of superiority among the different CRRT modalities, the choice rests on the available equipment (membranes, pump sys-tems) and appropriate dialysate, cost, and conceptual considerations.

Arterio-venous or veno-venous blood circuits

Choice of continuous renal replacement therapy modality

Table 10.3 Advantages and disadvantages of various renal replacement modalitiesModality Use in

hemodynamically unstable patients

Solute clearance

Volume control Anticoagulation

PD Yes ++ ++ No

IHD Possible ++++ +++ Yes/no

IHF Possible +++ +++ Yes/no

Intermittent IHF

Possible ++++ +++ Yes/no

Hybrid techniques

Possible ++++ ++++ Yes/no

CV VH Yes +++/++++ ++++ Yes/no

CV VHD Yes +++/++++ ++++ Yes/no

CV VHDF Yes ++++ ++++ Yes/no

Notes: HDF = hemodiafi ltration; CVVH = continuous veno-venous hemofi ltration; CVVHD = continuous veno-venous hemodialysis; CVVHDF = continuous veno-venous hemodiafi ltration; IHD = intermittent hemodialysis; IHF = intermittent hemofi ltration; PD = peritoneal dialysis. Modifi ed from Davenport.

CHAPTER 10 Choosing a RRT in AKI82

Figure 10.1 Modalities of CRRT.

Modalities of CRRT

SCUF

CVVHDF CVVHDF–SLED CPF–PE

UFC

Blood in Blood in

CVVH CVVHD

Blood inUFC Uf

QB = 100 mL/min QF = 2–8 mL/min QB = 100–200 mL/min QF = 10–30 mL/min K = 15–45 L/24 h

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

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

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

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

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

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

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)

V

V

V V

R

V

Uf

R

DV

DV

UF+DBlood in

Blood inAdsorbent

Adsorbent

Plasmafilter

Plasmafilter

Blood in Blood in

Plasma

Blood in Blood in

CHP CPFA HVHF

Uf DV

V

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KI83Dialysis membranes for CRRT

The main features of convective treatments are the following:High-fl ux 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 fl ow of •

blood and dialysate“Hemofi lters” working prevalently in convection•

Newer designs allowing powerful simultaneous convection and diffusion (high-•

fl ux dialysis, hemodiafi ltration)

It is a widespread opinion that convective treatments like high-fl ux hemodialysis, hemodiafi ltration, and hemofi ltration 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.

Table 10.4 Modalities of continuous renal replacement therapyTechnique Clearance mechanism Vascular access Fluid replacement

Convection DiffusionSCUF + - Large vein 0

CAVH ++++ - Artery and vein +++

CV VH ++++ - Large vein +++

CAVHD + ++++ Artery and vein +++

CV VHD + ++++ Large vein +/0

CAVHDF +++ +++ Artery and vein ++

CV VHDF +++ +++ Large vein ++

CAVHFD ++ ++++ Artery and vein +/0

CV VHFD ++ ++++ Large vein +/0

Notes: CAVH = continuous arterio-venous hemofi ltration; CAVHD = continuous arterio-venous hemodialysis; CAVHDF = continuous arterio-venous hemodiafi ltration; CAVHFD = continuous arterio-venous high-fl ux hemodialysis; CV VH = continuous veno-venous hemofi ltration; CV VHD = continuous veno-venous hemodialysis; CV VHDF = continuous veno-venous hemodiafi ltration; CV VHFD = continuous veno-venous high-fl ux hemodialysis; SCUF = slow continuous ultrafi ltration; 0 = not required; + = negligible; ++ = some; +++ = marked; ++++ = major.

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Comparison between CRRT and other renal replacement modalitiesContinuous renal replacement therapy techniques offer better long-term clear-ance of small and middle molecules than intermittent hemodialysis (IHD) or slow low effi ciency 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 concentra-•

tion 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 combi-•

nation 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 refl ecting 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., ultrafi ltration rate) with survival. Large molecular clear-ance 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-fl ux dialyzers, the clearance of compounds signifi cantly larger than urea may have played a role in the improved survival among the patients dialyzed daily. In spite of these suggestive fi ndings, there is no fi rm evi-dence that enhanced removal of mid or high molecular weight in patients leads to better patient outcomes (see below).

Convection and diffusionConvection-based replacement techniques (hemofi ltration and hemodiafi ltra-tion) using high-fl ux membrane fi lters 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.

Hemofi ltrationPredominantly convective technique•

Removes larger quantities of hydrophilic MW compounds than diffusion•

Leads to greater cytokine removal by adsorption and convection•

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Removal of infl ammatory mediators has been postulated but not demon-•

strated to benefi t patient outcome

Hemodiafi ltrationUtilizes partially hydrophilic high-fl ux membranes•

Membranes that have high sieving coeffi cient and reduced wall thickness com-•

bine diffusion and convectionAccurate ultrafi ltration (UF) control systems make safe large-volume removal •

possibleNewer machines permit separate control of dialysate and UF/reinfusion•

Online production of ultrapure dialysate and replacement fl uid has made it •

possible to deliver safe and less costly treatments

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 ultrafi ltrate (QUF) fl ow rates can be controlled accurately with integrated pumps, and greater dialysate or con-vective fl ows—and therefore greater diffusive and convective solute fl uxes 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.

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

brane, is, inversely proportional to its molecular weight: as solute molecu-lar weight increases, diffusion becomes a relatively ineffi cient 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 fl ux is also infl uenced by the characteristics of the membrane includ-•

ing the following:Surface area (A)•

Thickness (dx)•

The temperature of the solution (T)•

Diffusion coeffi cient of the solute (D)•

The diffusion fl ux of a given solute (Jx) will therefore result from the equation:

Jx = D . T . A (dc/dx) (1)

Other factors may infl uence the fi nal clearance values, including protein bind-ing or electrical charges in the solute. Increased convection may contribute to greater solute transport, especially in the higher molecular weight range.

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ConvectionConvection requires movement of fl uid across the membrane driven by a trans-membrane pressure gradient (TMP). The fl uid transport is defi ned as ultrafi ltra-tion and can be described by the equation:

Jf = Kf . TMP (2)

where Kf is the coeffi cient of hydraulic permeability of the membrane and TMP = (PB – PUF) – , where PB is the hydrostatic pressure of blood, PUF is the hydro-static pressure of ultrafi ltrate or dialysate, and is the oncotic pressure of plasma proteins.

The convective fl uid of a solute x will therefore depend on the following:The amount of ultrafi ltration (Jf)•

The concentration of the solute in plasma water (Cb)•

The sieving characteristics of the membrane for the solute (S):•

Jx = Jf Cb (1– ) = Jf Cb S (3)

The sieving coeffi cient (S) is regulated by the refl ection coeffi cient of the mem-brane according to the equation

S = 1 – (4)

In clinical practice, however, because plasma proteins and other factors modify the original refl ection coeffi cient of the membrane, the fi nal observed sieving coeffi cient is smaller than expected from a simple theoretical calculation.

Predilution or postdilutionIn hemofi ltration, replacement fl uid can be infused either before the hemofi lter (“predilution”) or after the hemofi lter (“postdilution”).

Postdilution CV VH is a purely convective therapy. The three primary deter-minants of solute clearance are as follows:

Ultrafi ltration rate1. Membrane sieving coeffi cient2. Dilution mode3.

Convection occurs by “solvent drag”: solutes are swept (dragged) across the membrane in association with ultrafi ltered plasma water, such that

K = QF . SC (5)

where K is clearance (mL/min), QF is ultrafi ltration rate (mL/min), and SC is siev-ing coeffi cient. For small solutes, as SC approaches unity, clearance equals the ultrafi ltration rate in postdilution. In postdilution CV VH, fi ltration fraction (FF), the ratio of ultrafi ltration rate (QUF) to plasma water fl ow rate is a limiting factor determined by blood fl ow (QB) rate and patient hematocrit (Htc):

QUF FF = ___________ (6) QB(1 – Htc)

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Clinical practice indicates that an FF greater than 0.3 should be avoided because of hemoconcentration and protein-membrane interaction.

Greater ultrafi ltration rates require larger blood fl ows to avoid elevated FF •

and fi lter clotting and coating with accumulated proteins.As higher blood fl ows are usually diffi cult 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 diffi cult to reach in postdilution mode.

Predilution mode has been introduced as an useful adjunct to prevent clotting of the extracorporeal circuit and to extend fi lter life, especially during high-volume CRRT, where fi ltration 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 fl ow and fi l-tration rate imposed by predilution. For small solutes dissolved in the water of the blood passing through the hemofi lter, clearance equals

K = QF . SC . [QBW/(QBW + QS)] (7)

where QBW is blood water fl ow rate and QS is the substitution (replacement) fl uid rate.

At a given QF value,predilution is always less effi cient than postdilution CV VH with respect to •

fl uid utilization,while predilution attenuates hemoconcentration-related effects, it simulta-•

neously reduces the effi ciency of the treatment,the larger the Q• S is relative to QBW, the smaller the entire fraction and the greater the loss of effi ciency relative to postdilution.

Importance of achieving a high blood fl ow (QB)In CV VH, given the direct relationship between QS and QF, great efforts are needed toward increasing the blood fl ow 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 fl ows of 250 mL/min or higher, given that the decrease in effi ciency 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 fi xed at 75 mL/min.

Utilizing modeling analysis, Clark et al. [4] have shown thatas patient’s weight increases, for low blood fl ow rates substitution fl uid 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 ultrafi ltration required determines high •

replacement fl uid infusion rates, which in turn have a substantial dilutive effect on solute concentrations at low blood fl ows,

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

of effi ciency.

Brunet et al. [5] studied the diffusive and convective solute clearances during CV VHDF at various dialysate and ultrafi ltration rates. They demonstrated that convection is more effective than diffusion in removing middle molecular weight solutes during CRRT, and that high convective fl uxes should be applied if the goal is to remove middle molecules more effi ciently.

Interaction between convection and diffusionAt the slow fl ow 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 defi nition of a “standard dose” of CRRT of 35 mL/kg/h, which was applied indiscriminately to diffusive and convec-tive 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 benefi cial 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 benefi t in the high dose arm of the Ronco study.

Based on the dosing scheme of normalizing effl uent fl ow 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 effl uent fl ow rate, the diffusive component of these therapies limits their ability to clear larger molecular weight toxins relative to hemofi ltration. Consequently, extrapolating Ronco’s data to other forms of CRRT, especially for dosing pur-poses, should be done with caution.

Nutrition and outcomeBetter management of volume and body fl uid 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.

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Hemodynamic stabilityOlder and very recent studies have consistently shown that the main advan-tage 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 refl ects 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 fl uid removal because of the following reasons:

The rate of fl uid removal is much slower in CRRT than in IHD.•

The main determinant of hemodynamic instability during RRT is the main-•

tenance of intravascular compartment volume.The volume of that compartment is the result of the balance between con-•

vective removal of fl uid (ultrafi ltration) from plasma and the rate of replen-ishment from the interstitium.Therefore, whenever the UF rate exceeds the rate of interstitium-to-•

plasma fl ow (refi lling), the patient will experience hypovolemia and hemo-dynamic instability.

In IHD rapid diffusion of urea creates a plasma-to-interstitium and interstiti-•

um-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 hemofi ltration, the magnitude of sodium •

removal is less than the amount of sodium removed with hemodialysis, a fac-tor that may contribute to better cardiovascular stability in hemofi ltration.Although hypovolemia is the fi rst step in dialysis-related hypotension, the ul-•

timate 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 fi lling, 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.

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

Hemofi ltration of large moleculesMiddle 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 consid-•

ered representative of these middle molecules.Cannot be well cleared by low-fl ux dialysis.•

High-fl ux dialysis will clear middle molecules partly by internal fi ltra-•

tion (convection); the convective component of high-fl ux dialysis can be enhanced in a predictable way by hemodiafi ltration.

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 dys-•

function syndrome (MODS), the most frequent cause of death in intensive care unit patients.Many water-soluble mediators with pro- and antiinfl ammatory 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 measur-•

able outcome improvement in patients with sepsis.CRRT is a continuously acting therapy, which removes in a nonselective way •

pro- and antiinfl ammatory mediators. The “peak-concentration hypothesis” is the concept that cutting peaks of soluble mediators through continuous hemofi ltration may help restore homeostasis.

This latter development proposes to use increased volume exchanges in hemofi ltration or the combined use of adsorbent techniques.

High-volume hemofi ltration (HVHF):•

A variant of CV VH that requires higher surface area hemofi lters and ultra-•

fi ltration 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 diffi culties including machinery, replacement fl uid •

availability and cost, and accurate monitoring systems to maintain safety.Studies utilizing this technique have shown preliminary evidence of benefi t, •

but none of the studies are randomized trials of adequate statistical power to demonstrate effect conclusively.Alternative technologies have utilized high cutoff hemofi lters with increased •

effective pore size.

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Drawbacks of such porous membranes include the loss of essential pro-•

teins such as albumin.Plasmafi ltration coupled with adsorption (CPFA) has been recently utilized in •

septic patientsIn coupled plasma fi ltration adsorption• (CPFA), plasma is separated from blood and the plasma is circulated through a sorbent bed; blood is subse-quently reconstituted and dialyzed with standard techniques, thus achieving normalization of body fl uid composition and increased removal of protein-bound solutes and high molecular weight toxins.

Recently, evidence has been obtained that very high-volume hemofi ltration •

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 benefi t is demonstrated, the use of very high volume hemofi ltration 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 fl uid without error.

References

1. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G. Effects of different doses in continuous veno-venous haemofi ltration 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 contin-uous hemofi ltration 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 replace-ment therapy. Artif Organs. 2003;27(9):815-220.

5. Brunet S, Leblanc M, Geadah D, Parent D, Courteau S, Cardinal J. Diffusive and convec-tive solute clearances during continuous renal replacement therapy at various dialysate and ultrafi ltration fl ow 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.

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Cerda, J, Cerdá M, Kilcullen P, Prendergast J. In severe acute kidney injury, a higher serum creatinine is paradoxically associated with better patient survival. Nephrol Dial Transplant. 2007;22(10):2781-2784.

Cerda J, Lameire N, Eggers P. Epidemiology of acute kidney injury. Clin J Am Soc Nephrol. 2008;3(3):881-886.

Clark WR, Ronco C. Continuous renal replacement techniques. Contrib Nephrol. 2004;144:264-277.

Cruz D, Bellomo R, Kellum JA, de Cal M, Ronco C. The future of extracorporeal support. Crit Care Med. 2008;36(suppl 4):S243-252.

Davenport A. Renal replacement therapy in acute kidney injury: which method to use in the intensive care unit? Saudi J Kidney Dis Transpl. 2008;19(4):529-536.

Gibney N, Cerda J, Davenport A, et al. Volume management by renal replacement therapy in acute kidney injury. Int J Artif Organs. 2008;31(2):145-155.

Kellum JA, Cerda J, Kaplan LJ, Nadim MK, Palevsky PM. Fluids for prevention and manage-ment 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: opera-tional 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 purifi cation: more than diffusion and convection. Does this help? Curr Opin Crit Care. 2007;13(6):662-667.

93

Renal replacement therapy (RRT) remains a cornerstone for the management of patients with severe acute kidney injury (AKI). The effi cacy 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 insuffi cient blood fl ow rates, repeated clotting of the extracorporeal circuit, and shortened dialysis time.

Type of catheter

The demands on TDC are manifold, including suffi cient rigidity to insert the catheter and maintain patency, enough fl exibility to prevent kinking, thrombore-sistent, 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 fl ow. 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 orifi ces. The choice of the right catheter length is crucial for both upper-body (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 cath-eters are silicone and polyurethane. The advantage of silicone is that it is soft and fl exible and resistant to most chemicals. However, due to the mechanical properties, silicone catheters are more diffi cult to insert and compression of the lumen may lead to mechanical failure. On the other hand the danger of endo-thelial damage or venous perforation is lower. Polyurethane is comparable to

Type of catheter

Chapter 11

Vascular access for continuous renal replacement therapyAlexander Zarbock and Kai Singbartl

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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 fl ow rate, compared to silicon cath-eters with the same outer diameter. The advantage of polyurethane catheters is that they have thermoplastic properties, being rigid during placement but soft-ening 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 considerationThe insertion site of the catheter depends on the patient’s characteristics (e.g., •

previous surgery, local infection, coagulopathy, and body habitus), the avail-ability of the insertion site, the skills/experience of the operator, and the risks of site-specifi c complications.Due to catheter-related bloodstream infection, nontunneled and noncuffed •

catheters can be used for short-term RRT (<3 weeks), but tunneled (5–10 cm subcutaneous course) and cuffed catheters should be used if the duration of the RRT is anticipated to be more than 3 weeks [2].

Vascular access site and implementation

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 fl ow is greater. (D) Uldall concentric dual-lumen 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.

A B

C D

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

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

tion whenever possible. This approach can increase the overall success rate while reducing the rate of complications, for example, hemothorax, pneumo-thorax, and catheter-related infections [2,3].Preexisting grafts and fi stulae 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].

Site of insertion

Jugular veinInsertion in the right internal jugular vein (IJV) is preferred over the left IJV because of the increased blood fl ow and reduced complication rate.

Femoral veinThe femoral vein is often preferred because of easy and fast accessibility. Transient dialysis catheters in the femoral vein have for a long time been thought to be associated with the highest infection rate. However, a recently conducted multicenter study demonstrated that femoral catheterization is only associated with an increased infection rate in patients with a high body mass index (>28.4) [5]. However, femoral TDCs drastically limit patient mobilization and increase recirculation rates [6,7].

Subclavian veinIn 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 complicationsInsertion-related complications are arterial puncture, pneumothorax, •

hemothorax, air embolism, arrhythmias, pericardial tamponade, and retroper-itoneal hemorrhage. Most of these complications can be reduced by using ultrasound guidance.A reduced blood fl ow, 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 fl ow and malfunction. Femoral catheters

Complications

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should be inserted in the inferior vena cava, and jugular and subclavian cath-eters 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 ineffi ciency of CRRT due to recirculation of blood •

from the return to the intake part of the catheter. This problem arises when the fl ow generated by the extracorporeal circuit exceeds the fl ow in the vein. Recirculation rates are normally <5% and dependent on design, length, and insertion site of the catheter as well as the blood fl ow in the CRRT circuit.

Secondary complicationsInfection•

In ICU patients risk factors for CRBSI include the following: catheter mate-•

rial, elective versus urgent insertion, the frequency of manipulation, the number of infusion ports, the operator’s experience, insertion site, indwell-ing time, and the severity of the underlying illness.Contamination of TDCs can occur as follows: Extraluminal contamination •

(migration of skin fl ora along the external surface of the catheter into the bloodstream), hematogenous contamination (seeding from another focus of infection), and intraluminal contamination (dominant mechanism in longer-dwelling catheters, contamination of the catheter hub through contaminated infusate).The most frequent bacteria are coagulase-negative staphylococci, staphylo-•

coccus aureus, enterococci, gram-negative bacteria, and yeast.TDCs should be used for RRT only.•

The use of trisodium citrate compared to heparin as a catheter-locking •

solution reduces catheter-related infections [12].The use of antibiotic-impregnated catheters prevents CRBSI [13], but a •

general recommendation for using these catheters cannot be given due to the emergence of allergic reactions and bacterial resistance.If a clinical suspicion of CRBSI exists, empiric systemic antibiotics appropri-•

ate for the suspected organisms should be started after cultures have been taken. After receiving the blood culture results, antibiotic treatment should be tailored to the specifi c organism.A positive result in the culture of the catheter tip necessitates the removal •

of the catheter and insertion of a new catheter at a new site. However, if an infection at the side of puncture, pocket infection of tunneled catheters, or CRBSI with clinical signs of sepsis exists, the catheter has to be removed immediately.

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Thrombosis•

Depending on the diagnostic method, the incidence of catheter-related •

thrombosis may be as high as 33%–67% [14].Catheter-related thrombosis may occur as a thrombus adherent to the ves-•

sel wall or formation of a fi brin sleeve around the catheter.Catheter-related thrombosis can lead to life-threatening complications, •

such as right heart thromboembolism (RHTE) and pulmonary embolism. Nonmobile RHTE originate from the tip of a catheter in the right atrium. Mobile RHTE represent dislodged thrombi from deep venous thromboses in both upper and lower extremities.During interdialytic periods, the catheter can be fi lled with an anticoagulant •

(citrate or heparin) to prevent intraluminal thrombosis.Risk factors for catheter-related thrombosis are listed in Table 11.1.•

In critically ill patients the incidence of catheter-related thrombosis is higher •

for femoral and jugular than subclavian catheters.The risk of catheter-related thrombosis and subsequently the risk of cath-•

eter-related infection can be reduced by administering anticoagulants or using anticoagulant-bonded catheters.

Table 11.1 Risk factors for TDC thrombosisPatient-related Catheter-related Site-relatedHypercoagulable statesa Polyurethane/polyvinyl

cathetersbFemoral or internal jugular siteb

Thrombophilic statesa,b Additional central venous catheters simultaneouslyb

Subclavian sitea

Age > 64b Traumatic insertionb

Underlying malignancya,b Distal placementa

Dehydrationb

Impaired tissue perfusionb

Absent prophylaxis/treatmentb

Source: Modifi ed after Burns KEA, McLaren A. A critical review of thromboembolic complications associated with central venous catheters. Can J Anesth. 2008;55:532–541.

Notes: a Associated with RHTE; bAssociated with central venous thrombosis.

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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 cath-eterisation 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 anti-coagulation 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 cathe-ters 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 intravas-cular 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 jug-ular 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 cathe-ter-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.

99

Introduction

The prescription of continuous renal replacement therapy (CRRT) requires an understanding of the circuit and the fi lter 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 fi ltration fraction on fi lter per-formance and fi lter life. Finally, it requires an understanding of the different pat-terns of solute removal achieved with continuous hemofi ltration compared with hemodiafi ltration and, in turn, compared with hemodialysis. This understanding allows the application of a particular circuit setting, which, in turn, defi nes a sig-nifi cant component of the fi nal prescription. Both physician and nurses need to understand these principles to practice CRRT safely and effectively.

Key terms

Hemofi ltration (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 de-rive form the rate of blood fl ow through the fi lter 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 semi-permeable membrane by means of the application of a concentration gradient. This concentration gradient derives form the relationship between the rate of blood fl ow through the fi lter and the rate of fl ow of a toxin-free electrolyte containing fl uid (dialysate) on the nonblood side of the membrane (Figure 12.2). This process leads to solute removal as solutes move from plasma water (high

Introduction

Key terms

Chapter 12

The circuit and the prescriptionRinaldo Bellomo and Ian Baldwin

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Figure 12.1 Diagram of a continuous arterio-venous hemofi ltration (CAVH) or continuous veno-venous hemofi ltration (CV VH) circuit. A = artery; V = vein; R = replacement fl uid; QB = blood fl ow; QF = ultrafi ltrate fl ow; high per = high permeability fi lter.

CAVH

CVVH

CAVH–CVVH

AV

R

VV

R

QB = 50–100

QB = 150–200

QF = 20–25 mL/min

QF = 8–12 mL/min

High perm.

High perm.

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 fl uid; QB = blood fl ow; QF = ultrafi ltrate fl ow; QD = dialysate fl ow rate; DO = dialysate outfl ow port; DI = dialysate infl ow port; low perm = low permeability fi lter.

CAVHD

Do Di

Do Di

CVVHD

CAVHD–CVVHD

AV

VV

QB = 50–100

QB = 150–200

QD = 20–35 mL/min QF = 2–5 mL/min

QD = 8–15 mL/min QD = 2–3 mL/min

Low perm.

Low perm.

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

Hemodiafi ltration (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 hemofi ltration and hemodialysis (convection and diffusion) in a way that can be determined by prescription.

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

Figure 12.3 Diagram of a continuous arterio-venous hemodiafi ltration (CAVHDF) or con-tinuous veno-venous hemodiafi ltration (CV VHDF) circuit. A = artery; V = vein; R = replacement fl uid; QB = blood fl ow; QF = ultrafi ltrate fl ow; QD = dialysate fl ow rate; DO = dialysate outfl ow port; DI = dialysate infl ow port; high perm = high permeability fi lter.

CAVHDF

Do Di

Do Di

CVVHDF

CAVHDF–CVVHDF

AV

R

R

VV

QB = 50–100

QB = 150–200



High perm.

High perm.

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Replacement fl uid: It is an electrolyte-containing, buffer-containing fl uid that is given to replace the losses of plasma water induced by hemofi ltration or hemodiafi ltration.

Dialysate: It is an electrolyte-containing, buffer-containing fl uid that is given to provide a concentration gradient across the membrane to enable diffusive solute clearance. Typically, the same fl uid can be used as dialysate and as replacement fl uid.

Predilution: This term refers to the administration of replacement fl uid into the circuit before the fi lter. This choice of prefi lter administration has two effects. First it dilutes the concentration of solutes entering the fi lter in a way that is proportional to the relationship between fl uid administration and plasma fl ow (if the replacement fl uid fl ow rate is 25 mL/min and the plasma fl ow rate is 100 mL/min, the dilution effect is 25% and the serum creatinine and urea will be 25% less when entering the fi lter. This will decrease the effi ciency of solute removal) and, second, it will stop any hemoconcentration. This effect on hemoconcentra-tion has been shown to prolong fi lter life and thereby decrease “off-time.” As a consequence, despite its diminished effi ciency, predilution leads to similar solute control and decreased fi lter clotting.

Postdilution: This term refers to the administration of replacement fl uid into the circuit after the fi lter. This choice of postfi lter administration has two effects. First it avoids any dilution of the concentration of solutes entering the fi lter and, second, it will lead to hemoconcentration as described under the term FF. This effect on hemoconcentration has been shown to decrease fi lter life and, thereby, increase “off-time.” As a consequence, despite its greater effi ciency, postdilution does not appear to have signifi cant advantages.

Effl uent: This term refers to the waste fl uid generated by CRRT. This fl uid can be straight ultrafi ltrate 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 fi lter, after the fi lter, and on the ultrafi ltrate/spent dial-ysate side of the membrane. At blood fl ows of 200 mL/min, common prefi lter pressures of 130–160 mm Hg can be expected (depending on fi lter size, design, hematocrit etc.). The pressure fall across the fi lter would typically be expected to be 30–40 mm Hg with a postfi lter (or “infl ow”) pressure of 110–120 mm Hg. The ultrafi ltrate/dialysate side of the membrane may initially register a pos-itive pressure as the peristaltic pump retards spontaneous fi ltration in a new fi lter. Over time, as the fi lter “ages” and the membrane clots, a negative pres-sure develops as the pump now actively “sucks” fl uid across the membrane. The transmembrane pressure (average pressure on the blood side of the mem-brane minus the pressure on the ultrafi ltrate side of the membrane) can be used as a measure of progressive fi lter clotting. If pressure is measured before the blood pump, this is typically negative (usually in the range of 50–70 mm Hg) and

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

Methods and approach

There is no evidence to suggest that choosing CRRT based on hemofi ltration over hemodiafi ltration or over hemodialysis leads to clinically important differ-ences in outcomes. There is a clear difference, however, in terms of the nature of solute removal with convection (fi ltration) 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 hemodiafi ltration (CV VHDF) with replacement fl uid delivered in predilution mode may be the most common approach to CRRT worldwide, followed by continuous veno-venous hemofi ltration (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 effl uent generation.


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, appropri-ately 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 outfl ow lumen of the access catheter (“arterial” lumen) is typically labeled in red. The infl ow lumen of the catheter is typically labeled in blue (“venous” lumen). If CV VHDF is being implemented, the bag con-taining fl uid is connected with peristaltic fl uid pumps, which can deliver some of the fl uid in the predilution position as replacement fl uid (typically 50%) and also deliver some of the fl uid (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 clear-ance. Finally, the effl uent port of the fi lter is connected with tubing to another peristaltic pump that sets the effl uent fl ow rate. This is typically greater than the sum of the replacement fl uid fl ow rate and the dialysate fl ow rate to ensure

Methods and approach


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some fl uid removal, which will compensate for additional fl uids (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 fl ows (especially for patients who require vasopressor support) because, at the start, blood is re-moved 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 fl ow is achieved. After the blood path has been “set,” the therapy (dialysate fl ow, replacement fl uid fl ow, and effl uent genera-tion) can begin.

A possible prescription for such therapy is summarized in Table 12.1.


If the principles of circuit design and function are understood and if the con-sequences of different techniques are appreciated and if the impact of choos-ing 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 follow-ing benefi ts: (1) reliable and safe control of uremia; (2) adequate fi lter life and costing; (3) full control of fl uid 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 specifi c circumstances. However, under-standing of the basics will help to deal with the problems successfully and rap-idly. For example, fi lter life may be short. If so, assessment of the circumstances surrounding fi lter loss should allow prevention of similar events: Was the patient


Table 12.1 Prescription for CVVHDF (100 mL/h negative fl uid balance)

Patient Med. record no.

Technique Replace-ment fl uid rate

Dialysate fl ow rate


Comments

H. Jones 678945 CVVHDF 900 mL/h 900 mL/h 2000 mL/h(25 mL/kg/h)100 mL/h fl uid loss

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

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agitated and fl exing the hip in the presence of a femoral vascular access cath-eter? If so, acute blockage to fl ow may have been responsible. Was the outfl ow pressure very negative (–120 mm Hg) from the very start of the therapy ? If so, vascular access dysfunction/clotting should be suspected. Was the transmem-brane pressure low (90–100 mm Hg) at the start but increased progressively over 4–5 hours of therapy? If so, rapidly progressive fi lter clotting should be suspected and the circuit anticoagulation approach reviewed. Did the postfi lter pressure rise while the transmembrane pressure did not change much? If so, one should suspect postfi lter 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.

Summary

The extracorporeal circuit used for CRRT has key components that, if under-stood 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 impor-tant. Understanding of the impact of predilution and postdilution on solute clearance and fi ltration fraction is similarly important. A clear and logical under-standing of pressure measurements along the CRRT circuit is extremely use-ful 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 ure-mic control, and a burden for nurses to develop expertise.

Key references

Baldwin I, Bellomo R, Koch B. A technique for the monitoring of blood fl ow during contin-uous hemofi ltration. Intensive Care Med. 2002;28:1361-1364.

Baldwin I, Tan HK, Bridge N, Bellomo R. Possible strategies to prolong fi lter life during hemofi ltration: three controlled studies. Ren Fail. 2002;24:839-848.

Bellomo R. Choosing a therapeutic modality: hemofi ltration vs. hemodialysis vs. hemodia-fi ltration. 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 haemofi ltration. Crit Care Resuscitation. 2002;4:170-172.

Tan HK, Bridge N, Baldwin I, Bellomo R. Ex-vivo evaluation of vascular catheters for con-tinuous hemofi ltration. 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 Hemofi ltration. Intensive Care Med. 2003;29:1672-1678.

Summary

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Introduction

The fi lter membrane in a continuous renal replacement therapy (CRRT) extra-corporeal circuit is vitally important for several reasons. Because it has the larg-est 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 perme-ability properties of a CRRT fi lter. This chapter addresses the key clinical issues related to CRRT membrane performance and biocompatibility.

Hollow fi ber membranes used for CRRT: biometrical considerations

As opposed to chronic hemodialysis, for which cellulosic membranes continue to be used commonly, membrane comprising CRRT fi lters are almost exclu-sively 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 unmodifi ed cellulosic dialyzers. The AN69 membrane, a copolymer of acrylonitrile and an anionic sulfonate group, was fi rst employed in fl at sheet form in a closed-loop dialysate system in the early 1970s for chronic hemodialysis. Since that time, a number of other syn-thetic 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 classifi ed as ther-moplastics. In fact, for most of the synthetic membranes, the renal market rep-resents 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

Introduction

Hollow fi ber membranes used for CRRT: biometrical considerations

Chapter 13

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

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symmetric (e.g., AN69, polymethylmethacrylate) or asymmetric (e.g., polysul-fone, polyamide, polyethersulfone, polyamide/polyarylethersulfone). In the latter category, a very thin “skin” (approximately 1 µm) contacting the blood compart-ment 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 consider-ably 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 benefi t 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 modifi es the native membrane’s permeability properties. The composition of this secondary membrane is dom-inated by relatively high molecular weight proteins that have the highest plasma concentrations, such as albumin, immunoglobulins, and fi brinogen. However, certain membranes also possess the specifi c capability to remove low molecular weight (LMW) proteins, such as anaphylatoxins and other infl ammatory media-tors including cytokines, in signifi cant amounts by adsorption.

With respect to adsorptive removal of LMW proteins, the AN69 membrane (a component of extracorporeal circuits used with the Prisma and Prismafl ex CRRT systems) has been studied most widely. Previous investigations have had several fi ndings. First, while overall secondary membrane formation occurs at the “nom-inal” (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 fi lters 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 fi lters is a satura-ble phenomenon, usually within the fi rst 60–90 minutes of use of a particular fi l-ter. Subsequent to saturation, the removal of a specifi c compound may effectively cease or continue to occur by a “breakthrough” transmembrane mechanism.

Relationship between ultrafi ltration rate and transmembrane pressure in CRRT

Extracorporeal membranes used for dialysis are classifi ed according to their ultrafi ltration coeffi cient as high fl ux or low fl ux. However, considerable

Relationship between ultrafi ltration rate and transmembrane pressure in CRRT

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confusion currently exists regarding the exact meaning of fl ux. The hydraulic fl ux of a membrane is the volumetric rate (normalized to surface area) at which ultrafi ltration occurs. The clinical parameter used to characterize the water per-meability of a specifi c dialyzer is the ultrafi ltration coeffi cient (KUF: mL/h/mm Hg). The KUF of a fi lter is usually derived from in vitro experiments in which bovine blood is ultrafi ltered at varying transmembrane pressure (TMP). The membrane characteristic having the largest impact on water permeability is the pore size, such that ultrafi ltrate fl ux 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 ultrafi ltration fl ow rate (QUF) and TMP is shown for a particular CRRT fi lter operated under different conditions. The line in the left part of the fi gure represents the relationship between these two parameters for a “virgin” fi lter (i.e., no prior exposure to blood or other protein-containing solution) when the test fl uid is also an aqueous solution. The slope of the line represents the KUF of the fi lter for these operating conditions. This strictly linear relationship can be contrasted with the nature of the curve in the right part of the fi gure. The curved line in the right part of the fi gure defi nes a fi lter’s QUF versus TMP relationship under the condition of ultrafi ltration of blood. As the fi gure indicates, two distinct regions of this curve can be identifi ed: a region con-trolled by the permeability of the fi lter membrane itself (“membrane control”)

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

Purewaterfiltration

Region ofTMP–independentfiltration(concentr. polarizat. control)

Region ofTMP–independentfiltration(membrane control)

Transmembrane pressure

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and a region controlled by the effects of the secondary membrane on fi lter performance. (Note that the term “concentration polarization,” which is used in the fi gure, is essentially synonymous with secondary membrane for the purpose of this discussion.)

The membrane control region of the curve occurs at relatively low TMP val-ues and is linear. Similar to the situation of aqueous ultrafi ltration with a virgin fi lter, the slope of the line in this region is the KUF of the fi lter. 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 fi lter, the plateau portion of the curve is to be avoided because of the high likelihood of impaired performance or prema-ture clotting of the fi lter.

As mentioned previously, fi lter KUF is a value that is specifi c to a certain set of fl ow operating conditions, including blood fl ow rate (QB). Blood fl ow rate infl uences 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 infl uences 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 fi lter membrane function. Specifi cally, 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 mem-brane 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 block-ing 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 fi gure, percent rejection (which is essentially equal to 1—sieving coeffi cient), is plotted against solute molecular weight. Results for both a protein-containing fl uid (plasma) and a protein-free fl uid (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 coeffi cient is 1.0). On the other hand, for that same solute, the percent rejection in plasma is approximately 60% (sieving coeffi cient of 0.4).

The adsorptive tendency of a particular membrane varies according to the op-erating conditions employed. Postdilution tends to promote protein adsorption

Effect of secondary membrane formation onsolute permeability in CRRT

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

Membrane surface area effects in CRRT

Early in the era of veno-venous CRRT, typical blood and effl uent fl ow rates were less than 150 mL/min and 1.5 L/h, respectively. In this context, fi lters with surface areas in the range of 0.3–0.5 m2 could generally provide desired solute clearances at acceptable fi lter operating conditions. However, as blood and fl uid fl ow rates have increased substantially over the years with the goal of increas-ing delivered CRRT dose, fi lter membrane surface area requirements have also increased. For adequate fi lter operation, the surface area required to provide an effl uent-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 effl uent rates greater than 4 L/h.

Continuous hemofi ltrationAs discussed above, the choice of operating conditions for a hemofi ltration pro-cedure should avoid operation of the fi lter in the secondary membrane-limited region of the QUF versus TMP curve. The clinical corollary of this is the need to select a fi lter 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 hemofi lters 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

Membrane surface area effects in CRRT

Figure 13.2 Effect of secondary membrane formation on the sieving properties of a poly-amide fi lter membrane. From Feldhoff P, Turnham T, Klein E. Effect of plasma proteins on the sieving spectra of hemofi lters. Artif Organs. 1984;8:186-192, copyright © 1984 International Center for Artifi cial Organs and Transplantation. Reproduced with permission of Blackwell Publishing Ltd.

100

80

60

40

20

00 2000

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5000

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region at relatively high blood fl ow 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 fl ow rate (e.g., 75 mL/min), all three fi lters 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 fi lter is not adequate as the plateau QUF for this fi lter falls below the desired value. On the other hand, the higher QUF is in the operating range of both of the larger fi lters for the TMP that has been chosen. However, the 1.5 m2 fi lter can achieve this fi ltration rate at a lower blood fl ow rate (point B) compared to the 1.0 m2 fi lter (point C). An analogous point is that, for a given blood fl ow rate, fi lter membrane surface area is inversely proportional to the TMP required to achieve a certain ultrafi ltration rate.

The general relationship between ultrafi ltration rate and blood fl ow rate dur-ing hemofi ltration, as described in Figure 13.3, is explained by the phenomenon of fi ltration pressure equilibrium. In this situation, hydrostatic pressure driving fi ltration out of the blood compartment is balanced by the oncotic pressure opposing fi ltration in this direction. When a scenario of fi ltration pressure equi-librium situation occurs for a fi lter, surface area is relatively unimportant since the additional surface area is not used for fi ltration. The corollary is that the benefi t of higher surface area on fi ltration rate can only be achieved if higher blood fl ow rates are used.

Figure 13.3 Relationship between ultrafi ltration rate and blood fl ow rate for theoretical hemofi lters of different surface area. (See text for explanation of operating conditions cor-responding to points A, B, and C.)

Membranesurface area (m2)

Blood fow rate (mL/min)

Ultr

afilt

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n ra

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/hr)

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1.0BHigh QUF

Low QUFA

C

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Continuous hemodialysisRelative to conventional hemodialysis, in which solute clearance is primarily dic-tated by blood fl ow rate and membrane surface area, effl uent dialysate fl ow rate is the primary determinant of solute clearance in continuous veno-venous he-modialysis (CV VHD). At least with respect to small solute clearance, saturation of the effl uent indicates optimal utilization of the prescribed dialysate volume. If such saturation is not achieved, the most likely explanation is a fi lter of inad-equate membrane surface area. When CV VHD is performed with a relatively small surface area fi lter (< 0.5 m2), saturation of the dialysate is only achieved at relatively low dialysate fl ow rates. For a 0.4 m2 AN69 fi lter, Bonnardeaux et al. showed saturation of the effl uent dialysate for urea, and creatinine is preserved only up to a dialysate fl ow 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 effl uent fl ow rates was observed, indicating nonsaturation of the effl uent dialysate. Of course, the greater the degree of nonsaturation, the more ineffi cient is the procedure.

A more contemporary study involving a larger surface area AN69 fi lter (0.9 m2) demonstrates clearly the important effect of surface area on preserving dialysate saturation (Figure 13.4). For this larger fi lter, preservation of effl uent dialysate saturation was achieved essentially over the entire QD range, the only exception being B2M. The high molecular weight of this compound (approxi-mately 200 times that of urea) severely limits its diffusive capabilities and, there-fore, its ability to saturate the dialysate.

Dialysate flow rate (mL/h)

Cle

aran

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fluen

t rat

e (m

L/m

in)

005

1015202530354045

500 1000 1500 2000 2500

B2-M

PUr

UreaEffluent

Cr

Figure 13.4 Relationship between solute clearance and dialysate fl ow rate for a 0.9 m2 fi lter 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 ultrafi ltration fl ow rates. Am J Kidney Dis. 1999;34:486-492, copyright 1999, with permission from Elsevier.

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Summary

In this chapter, an overview of membranes used for CRRT has been provided. The major characteristics of hollow fi ber membranes infl uencing both biocom-patibility and solute and water removal have been discussed. It is hoped that this information will help provide clinicians with a rational approach to the prescrip-tion 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 fl ow 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 ultrafi ltration fl ow 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 hemo-fi lters. Artif Organs. 1984;8:186–192.

Goehl H, Konstantin P. Membranes and fi lter for hemofi ltration. In: Henderson LW, Quellhorst EA, Baldamus CA, Lysaght MJ, eds. Hemofi ltration. 1st ed. Berlin: Springer-Verlag; 1986:73.

Summary

115

General considerations

Considerable variability exists in the prescription of fl uids for continuous renal replacement therapy (CRRT), both dialysate and replacement fl uid. 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 fl uid, and many commercial dialysis fl uids are used off-label as replacement fl uid. When using both dialysis and hemofi ltration (CV VHDF), it is usually convenient to use standard dialysate and customize the replacement fl uid as necessary. The Acute Dialysis Quality Initiative (ADQI) has published a series of recommenda-tions of fl uids for CRRT. These recommendations are summarized below.

Electrolyte composition

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

General considerations

Electrolyte composition

Chapter 14

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

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necessary, given the variable contents of sodium in different citrate solu-tions. Adjustment of the sodium concentration of fl uids may also be nec-essary in patients with hypo- or hypernatremia in order to achieve an appropriate controlled correction of the serum sodium concentration.

2. Chloride, potassium, magnesium, and anions: These should be present in replacement fl uid and/or dialysate in concentrations tailored to patient need and anticoagulation procedures.

3. Calcium: It should be present in replacement fl uids 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 hyper-calcemia. Very low or no calcium should be used when citrate is used as an anticoagulant, although intravenous calcium infusion to maintain nor-mal serum ionized calcium concentration is then necessary.

4. Phosphate: To avoid hypophosphoremia, phosphate should be provided either as a supplement in the CRRT fl uids (replacement fl uid or dialysate) or as a nutritional supplement once hyperphosphatemia, if present, has resolved.

5. Glucose: To avoid hyperglycemia, glucose can either be absent or present at physiological concentration in replacement fl uids and dialysate. The use of fl uids with supraphysiological glucose concentrations should be avoided.

6. Trace elements: Losses of trace elements (water-soluble metals, micronu-trients, aminoacids, and folate) must be appropriately replaced.

Buffer composition

Lactate versus bicarbonateBoth lactate and bicarbonate ions have been used in replacement fl uid and dial-ysate 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 commer-cial availability of bicarbonate-based fl uids. Controlled (though not all random-ized) trials have suggested that lactate and bicarbonate buffered solutions have a similar effi cacy 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 accumu-lation are hemodynamic compromise, increased urea generation, and cerebral

Buffer composition

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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 hemofi ltration. 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 accu-mulate, contributing to severely elevated lactatemia and associated with neuro-logic impairment.

AcetateIn the intermittent hemodialysis (IHD) literature, acetate has been shown to be associated with impaired myocardial contractility and decreased cardiac func-tion. This anion has been rarely used as a buffer in CRRT.

CitrateUsed 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 mus-cle 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 anti-coagulant; 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 effi cacious in the majority of

patients, but these solutions may be hazardous whenever lactate clear-ance is impaired, such as in liver failure patients or patients with severe tis-sue hypoperfusion. d-lactate should be removed from lactate-containing solutions, which should consist almost exclusively of l-Lactate.

3. There is insuffi cient 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 dur-ing CRRT generates three moles of bicarbonate per mole of citrate and functions as an effi cacious organic buffer. Use of citrate in the setting of decreased citrate clearance or when patients receive large doses of cit-rate during massive transfusions should be done with individualized adjust-ment of citrate dose and with close monitoring of plasma ionized calcium levels.

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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 con-troversial, but most authors recommend avoiding severe acidosis (pH < 7.20).

Example fl uid orders for CRRT

Keeping in mind that, after a period of equilibration, plasma composition will approach the electrolyte composition of the dialysate or replacement fl uid used (with the exception of bicarbonate) the standard composition of CRRT fl uids will be physiological. Table 14.1 shows that the usual range of composition for a standard dialysate or replacement fl uid is close to the usual range for plasma electrolytes. Bicarbonate is higher in these fl uids 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 hemofi ltration. Example A might be appropriate for a patient with relatively stable electrolyte and acid-base 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 fl uid 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 replace-ment fl uid, it should only be temporary and should be done only with close mon-itoring. In continuous veno-venous hemodiafi ltration (CV VHDF) mode, it is often

Fluid prescriptions during permissive hypercapnia

Example fl uid orders for CRRT

Table 14.1 Example fl uids for CRRTCustom dialysate/replacement fl uid

Example A Example B

Sodium 140–150 mEq/L 140 mEq/L 140 mEq/L

Potassium 0–5 mEq/L 4 mEq/L 2 mEq/L

Chloride As needed to achieve charge balance 113 mEq/L 112 mEq/L

Calcium 0–3.5 mEq/L 2.5 mEq/L 3.5 mEq/L

Magnesium 0.5–1.5 mEq/L 1.5 mEq/L 1.0 mEq/L

Bicarbonate 22–45 mEq/L 32 mEq/L 32 mEq/L

Lactate 0–5 mEq/L 3 mEq/L 3 mEq/L

Glucose 100–120 mg/dL 110 mg/dL 110 mg/dL

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

Fluid compounding

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

Summary

Both lactate and bicarbonate are able to correct metabolic acidosis in most CRRT patients; however, correction of acidosis may not be as effi cient with lac-tate 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 fi nding is unknown. Thus, bicarbonate is the preferred buffer, especially in patients with lactic acidosis and/or liver failure and in high-volume hemofi ltration. 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 specifi c 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 fl uids for patients with acute renal failure treated by continuous veno-venous haemofi ltration and/or haemodiafi ltration. Contrib Nephrol. 2004;144:317-328.

Kellum JA, Cerda J, Kaplan LJ, Nadim MK, Palevsky PM. Fluids for prevention and manage-ment 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 hemofi ltration 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.

Fluid compounding

Summary

121

Introduction

Technical expertise is mandatory for administration and management of contin-uous 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 deliv-ery 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 defi ned proce-dures. 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 specifi c to using CRRT is also necessary •

with a connection to the theory.All training should be sequenced, providing a logical fl ow to embrace the cycle •

of use from preparation of a CRRT machine, patient connection and manage-ment during use, and then cessation of treatment—disconnection.Programs need to be continuous and repeated owing to the ongoing techno-•

logical 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.

Introduction

Training

Chapter 15

Alarms and troubleshootingZaccaria Ricci, Ian Baldwin, and Claudio Ronco

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Vascular access

Veno-venous CRRT rely on the use of a temporary double lumen catheter, typi-cally 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 con-trolled data are available to refl ect “best” practice. Catheters should be easy to insert and remove or be guide wire exchanged, allow a wide range of blood fl ows, 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 classi-fi ed 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 profi le 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 fl ow rate use.Catheter trouble-shooting• : a malfunctioning catheter is suspected when CRRT monitor pressure alarms occur as low “arterial” or high “venous.” The cath-eter 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 fl uid bal-ance 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) interpre-tation. 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 fl ow rate and patient position.Inlet of the fi lter: This pressure indicates the resistance of blood that is pumped •

into the fi lter. The gradient of fi lter inlet and catheter return is defi ned as “drop pressure” (DP) and is generally automatically calculated by all modern monitors. DP indicates the capacity of blood to fl ow through the membrane.

Vascular access

Circuit pressures

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Ultrafi ltration (UF) port pressure: Its value can be positive when the fi lter is •

new or spontaneous UF occurs. When the fi lter 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 fi lter pressure, catheter return pressure, and UF port pressure are •

used in software calculation of transmembrane pressure (TMP) indicating the capacity of the fi lter ultrafi ltering 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 fi le” of alarms or errors when they occurred, along with the remedy or operator response at the time. This infor-mation is a useful audit of the system in use.

Alarm systems

Understanding how alarms systems work on CRRT machines is useful for trou-bleshooting. In general, alarms used in biomedical equipment are classifi ed 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 opera-tion with the alarm sounding until resetting. Or, the alarm can be “unlatched,” where, if a breached parameter creates an alarm but the situation self cor-rects, 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 classifi cation.

The clogging circuit

All circuits clot, sooner or later, and they generally need change of all the com-ponents of the extracorporeal circuit. The fi rst 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).

Alarm systems

The clogging circuit

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In order to identify and recognize circuit clotting the following “signs” are proposed:

Dark streaks through the hollow fi bers of fi lters indicates a degree of fi lter •

clotting that is proportional with the total amount of clotted fi bers. This sign should be kept under constant observation but does not herald imminent fi lter failure.TMP rapid increase (before it reaches machine alarm threshold) is an •

important sign of hollow fi bers failure, especially during hemo/ultrafi ltration. 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 fi lter 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 fi lter clotting, and it works as a reliable indication either during dialysis and hemo/ultrafi ltration. Again, there is not an absolute value to be aware of (it generally depends on machine setup and fi lter 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 forma-tion: blood-air interface and blood stagnation in the chamber. Modifi cations of these chambers, derived from traditional intermittent therapies, have been

Figure 15.1 Classifi cation of biomedical devices and alarms.

Latched

Unlatched

Advisory alarm

Warning alarm

Crisis alarm

Requires correction, will not reset,use alarm silence

Self correction, then reset withoutintervention

Message to operator, futrue intervention

Message to operator, intervention now:

Message to operator, machine stop

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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 fl ow may also be preventative of clotting.

Management of clogging circuit

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 fi lter life and to achieve an average session length of at least 20 hours.

Blood fl ow should be ideally prescribed and maintained between 150 and 200 •

mL/min. If poor vascular access does not allow such fl ow rate, blood fl ow below 100 mL/min should not be accepted and vascular access should be optimized.Administration of replacement fl uids before the fi lter may prolong fi lter •

function. Alternatively, if postdilution hemofi ltraiton is the institutional pre-ferred CRRT modality, when TMP is rapidly increasing, a switch to predilution hemofi ltration, hemodialysis, or hemodiafi ltration 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 effi cacy of anticoagulation. In these patients, antithrombin III levels should be monitored, and maintained at super-normal 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 fl ushing of the circuits is not recommended in all cases because of the limited effi cacy and because of the fl uid administered to patients when doing this frequently.

Troubleshooting for specifi c events, however, must be decided at the moment and the rapidity of intervention is based on adequate staff training, optimal mate-rial 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 fl ow, which is the most common cause of clotting.

Fluid balance errors

The possibility of making fl uid balance errors during CRRT has been identi-fi ed since the beginning of this modality of treatment. The advent of automated

Management of clogging circuit

Fluid balance errors

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machines has partially overcome this problem. Nevertheless, there are condi-tions and operation modes in which the potential for fl uid 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 famil-iarity with the equipment, and its fl uid measurement accuracy.

Third-generation machines control fl uid fl ows by accurate pump-scales feed-back: 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 “fl uid exchange rate,” “ultrafi ltration,” “fl uid loss,” “fl uid balance,” “weight loss rate,” and “patient negative.”

Improvements in commercial machines for safety and accuracy of fl uid balance, the way alarms can be overridden, or the occasional addition of external com-ponents to the overall fl uid balance can easily affect the fi nal result and make fl uid balance signifi cantly different from that prescribed. In particular, users who override scale alarms without solving the cause of the alarm (possible error in fl uid balance typically occurs when a replacement fl uid bag is clamped) may dra-matically impact patient fl uid 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 num-bers of overrides per hour, automatically stopping the therapy if the limit is exceeded.

In general, fl uid 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 fl uid balance errors, not detected by the machine or due to inadver-tent prescription of additional fl uids (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 fl uid balance chart should be updated hourly. This will help to correctly •

interpret patients’ total fl uid balance.Never forget to check and possibly record machine information on “effec-•

tively delivered net UF” and not just reporting on clinical chart the “prescribed UF”: they can differ signifi cantly 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.

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Conclusions

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 check-lists are useful for all users and considered mandatory for novice practitioners (Table 15.1).

Conclusions

Table 15.1 Troubleshooting checklistAlarm/problem Possible causes ActionsToo low arterial pressure alarm

1. Kinked or clamped line2. Clotted line3. Access device against vessel wall4. Hypovolemia

1. Remove kinking2. Declot access3. Consider limbs switching4. Stop UF, decrease blood

fl ow rate

High venous pressure alarm

1. Kinked or clamped line2. Clotted line3. Positional vascular access

obstruction

1. Remove kinking2. Declot access3. Consider limbs switching

Arterial (or venous) line disconnection alarm

1. Line separation or disconnection from patient (very rare!)

2. Circuit kinked or clamped before pressure sensor

3. Clot excluding pressure sensor4. Blood pump speed relatively too

slow with respect to catheter performance

1. Check circuit and patient and, if no disconnection is present, override alarm

2. Declamp line3. Evaluate for circuit change4. Increase set blood fl ow rate

Increasing TMP 1. Clogging hemofi lter2. Kinked or clamped hemofi ltration/

dialysis line3. Blood fl ow too slow for UF setting

1. Evaluate for circuit change2. Declamp line3. Increase blood fl ow speed,

check UF setting

Air in the circuit 1. Presence of small air bubbles (often due to bicarbonate - CO2 coming from hemofi ltration bags)

2. Line disconnection at arterial access

3. Turbulence close to air sensor

1. Follow instruction for degassing2. Stop session3. Override alarm

Fluid balance error 1. Effl uent or hemofi ltration/dialysis bags moving or incorrectly hanged.

2. Kinking in effl uent or hemofi ltration/dialysis bags

3. Machine occasional error4. Machine systematic error

(if more than 10 times without reason in 3 hours)

1. Wait for bags, stop or reposition them on scales

2. Remove line kinking3. Override4. Change machine and do not

reuse it before technical assistance

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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 hemofi ltration. 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 fl exible 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 Purifi cation 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 fl uid balance in CRRT: a technical approach. Int J Artif Organs. 2005;28:765-776.

129

Introduction

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 fl ow in the renal replacement therapy (RRT) circuit are useful in preventing clotting.

Defi nitions—key terms associated with optimising circuit function in renal replacement therapy

Filter life: The “fi lter life” is defi ned as the time (hour, minute) from the com-mencement of blood fl ow through the hemofi lter until the time when the blood is unable to pass through the hemofi lter due to clot formation and obstruction in the hemofi lter.

Predilution: The administration of replacement fl uid into the blood pathway prior to its entry into the hemofi lter (prefi lter 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 fl ush is not adequate for RRT to function.

Introduction

Defi nitions—key terms associated with optimising circuit function in renal replacement therapy

Chapter 16

Nonanticoagulation strategies to optimize circuit function in renal replacement therapyIan Baldwin

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130 Blood Pump speed: Flow of blood setting for RRT in mL/min.

Filtration fraction: Describes a relationship between the blood fl ow through the hemofi lter and the amount of plasma water removed from the blood within the hemofi lter. An increased fi ltration fraction means hemoconcentration and potential clotting and cell clogging of the hemofi lter fi bers.

P-in: Pressure (mm Hg) measured in the RRT circuit before the hemofi lter. An increase in this pressure refl ects hemofi lter clotting.

Transmembrane Pressure (TMP): A measure of pressure across the hemofi lter as a result of pressure measurements taken before (P-in), after the hemofi lter (P-venous), and in the fi ltration pathway (P-Uf). P-venous – P-in/2 + P-Uf = TMP.

Arterial pressure: Pressure in the RRT circuit between the access catheter out-fl ow connection and the blood pump is a negative pressure refl ecting blood being drawn from the patient.

Blood fl ow reduction: A blood fl ow less than set or prescribed, related to access catheter outfl ow failure and insuffi cient stroke volume of the roller pump tub-ing. 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 hemofi lter and the access catheter return line.

Air-blood interface: A pocket of gas above the level of blood in the venous cham-ber. This provides an exposure of blood to this gas thought to promote clot-ting. The gas is initially air on starting RRT, but becomes carbon dioxide when

Figure 16.1 Schematic diagram for continuous veno-venous hemofi ltration indicating pre-membrane fl uids administration or predilution.

CVVH predilution

Membrane

Blood pump

Replacementfluid

HeaterWaste collection

Patient

PumpWastepump

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

Key areas for attention to maintain blood fl ow and reduce clotting

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

The access catheter type and site: Large size, 13.5–15.0 Fg, side-by-side lumen confi guration (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 aspi-ration and fl ush for each circuit connection. Access failure can cause reduced blood fl ow with pump failure due to inadequate pump tubing segment refi ll (see Figure 16.3). The operator will be unaware this is occurring and premature clotting will result.

Blood fl ow rate setting: 150–200 mL/min. Flow must be adequate for the fl uid removal rate (see fi ltration fraction error). Incorrect blood fl ow and fl uid removal rate ratio (fi ltration 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 for-mation. Flow too slow causes cell slugging and sticking to surfaces.

Membrane size and type: The membrane needs to be adequate for the blood fl ow and fl uids 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.

Key areas for attention to maintain blood fl owand reduce clotting

Figure 16.2 Schematic diagram indicating three different vascular access catheter profi les. Side-by-side profi le can provide best blood fl ow.

Side by side: Double ‘‘D’’

Vascular access catheter designprofiles

Inner and outer lumen: Coaxial

Side by side: Double ‘‘O’’

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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 fl uids into the chamber can create a fl uid 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 rela-tionship 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 re-moval and addition of heparin into the circuit with priming, circuit connection to a large Fg vascular access catheter with side-by-side lumen confi guration,

Summary

Figure 16.3 Schematic diagram with description for how blood fl ow may fail when the access catheter is inadequate and pump tubing fails to recoil and refi ll 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 fl ow. ASAIO J. 1997;43:39-52. Reprinted with permission of Wolters Kluwer Health.

Roller pumps. Why they may not deliver the desired blood flow!After forward compression,the tubing behind the rotatingwheel will reexpand andrefill with blood from the accesscatheter (A).

If patient access restricts flow, the tubingmay not adequately refill and may remainpartially collapsed. Output of the nextpump stroke is reduced.Blood may also pass backwards throughthe occlusion gap before the compressionstroke of the alternate wheel.

Flow reduction is therefore related topatient access, the revolutions per min. ofthe roller, (affecting refill time) theocclusion gap, and tubing reexpansionproperties.

QB backwards flow

QB

QF

Gap

Patient access catheter (A)

QF backwards flow

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pumping blood at 200 mL/min, use of a larger surface area membrane in the adult, premembrane substitution fl uids 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 hemofi ltration: three controlled studies. Ren Fail. 2002;24(6):839-848.

Baldwin I, Bellomo R. The relationship between blood fl ow, 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 replace-ment 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 replace-ment 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 hemofi ltration. J Artif Organs. 2005;28(12):1211-1218.

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.

Splashing of bloodon entry to chambercausing clotting ascells stick to chamberwalls

Keep level to hereClot: cross-section

Blood entry

Gasspace

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Lavaud S, Paris B, Maheut H, et al. Assessment of the heparin-binding AN69 ST hemodi-alysi 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 hemofi ltration: impact on fi lter life and azotemic control. Nephron Clin Pract. 2003;94(4):94-98.

Webb AR, Mythen MG, Jacobsen D, Mackie IJ. Maintaining blood fl ow in the extracorpo-real circuit: haemostasis and anticoagulation. Intensive Care Med. 1995;21:84-93.

135

Introduction

Continuous treatment suggests extracorporeal blood fl ow without clotting. This is not a realistic aim. However, drugs blocking normal coagulation pathways can prevent or delay clotting such that suffi cient 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 artifi cial surfaces in the extracorpo-real circuit (EC). Heparin is most commonly used as an anticoagulant for renal replacement therapy (RRT). Citrate is routinely used to prevent clotting by che-lating calcium and preventing its action as a cofactor. Administration of antico-agulant drugs during RRT requires specifi c knowledge and the application of monitoring protocols to ensure safety and effectiveness. This chapter provides a brief clinical guide to such treatments.

Defi nitions and key terms associated with anticoagulation during continuous renal replacement therapy

Filter life: The term “fi lter life” refers to the time from the commencement of blood fl ow through the fi lter until the time when the blood is unable to pass through it due to clot formation and obstruction.

Circuit life: An equivalent term for fi lter life. It is probably a more correct term as some circuits develop obstruction to adequate blood fl ow because of clot elsewhere in the circuit and not in the fi lter itself.

Air trap (or bubble trap): A component of circuit, which is typically located after the fi lter and which aims to prevent air entering the circuit and embolizing into the blood of the patient.

Introduction

Defi nitions and key terms associated withanticoagulation during continuous renal replacement therapy

Chapter 17

AnticoagulationRinaldo Bellomo and Ian Baldwin

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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 fl ow 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 modifi cation of the hep-arin 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.

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 pro-cess. Citrate is then metabolized by the liver into CO2. The calcium lost into the dialysate or ultrafi ltrate together with citrate is then replaced by a separate infu-sion of calcium. Citrate acts as both an anticoagulant and a buffer. The amount given is suffi cient 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.

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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.

Newer anticoagulants: More recently new anticoagulants have been developed and found to be effective and safe for human use. They include the pentasac-charides and the thrombin inhibitors. There is limited information on their use for circuit anticoagulation. In patients receiving invasive cardiac procedures, gly-coprotein 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.

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

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

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 be-fore 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 fi lter to protect a patient is entirely acceptable. To lose a patient in order to protect a fi lter 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 fl ow, 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.

Key areas for attention when administering an anticoagulant for the prevention of circuit clotting

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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 fi rst •

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

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 acci-•

dental 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 profi le for the patient.Start the treatment using the dosing table as a guide, then increase heparin if •

circuit life is poor. If fi lter life is less than 8 hours for the fi rst circuit consider increasing the dose. A fi lter life of 20–24 hours is common using heparin. A dose of 5–10 IU/kg/h given prefi lter is a common starting dose for the fi rst treatment circuit.The fl uid volume used to administer the anticoagulation must be included in •

the fl uid balance calculations.Administer the anticoagulant into the circuit before blood enters the membrane •

in “prefi lter” 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 inap-•

propriate infusion adjustments. Check after the fi rst 6 hours. After that, 12 hourly monitoring is probably adequate in most cases unless signifi cant 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 fi lter consecutive hours of function next to this. This pro-vides an instant ability to assess fi lter life associated with heparin dosing (see Table 17.2).

Practical considerations using heparin anticoagulation

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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 benefi ts in a given patient. Heparin is commonly used in hospitals. Typically, doctors and nurses understand its risks and benefi ts 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 prefi lter via a common infusion device, reference to a dosing chart specifi c for CRRT, ongoing review of the patient and of his/her clotting profi le 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 profi le 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 hemofi ltration. Int J Artif Organs. 2007;30:281-292.

Summary

Table 17.1 Heparin dosing guide for bolus and infusionHeparin anticoagulation

All circuits primed with 5000 U heparin (1st bolus)•

Patients to have at least two of the following:•

2nd bolus INR APTT Plts

Heparin 70 IU/kg*10 U kg/h 1.5 40s 150

Heparin 35 IU/kg*5 U kg/h 1.52.5

40s 15060

No bolus 2.5 60s 60

Nil other

Table 17.2 ICU charting aligning heparin dose each hour with accompanying fi lter “life”

Heparin dose 500 500 500 500 750 750

Filter hour 7 8 9 10 // clotted 1 2

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Naka T, Egi M, Bellomo R, et al. Commercial low-citrate anticoagulation haemofi ltration in high risk patients with frequent fi lter clotting. Anaesth Intensive Care. 2005;33:601-608.

Tan HK, Baldwin I, Bellomo R. Hemofi ltration without anticoagulation in high-risk patients. Intensive Care Med. 2000;26:1652-1657.

Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R. Continuous hemofi ltration without anticoagulation. ASAIO J. 2004;50:76-80.

Other suggested readings

Joannidis M, Oudemans-van Straaten HM. Clinical review: Patency of the circuit in contin-uous 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.

141

Introduction

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 anticoagula-tion 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.

Defi nitions

Extracorporeal circuit (EC)—The path for blood fl ow outside the body. Includes the plastic tubing carrying the blood to the hemofi lter from the access catheter and from the hemofi lter back to the body via the access catheter.

Filter life or functional life of the EC—The passage of blood through the EC, par-ticularly the hemofi lter, initiates blood clotting. The clotting of blood is a slow but inevitable process delayed by factors known and unknown. Blood coagu-lation is thought to be a main factor in this process. The time period before the blood is unable to pass through the hemofi lter due to clot formation and obstruction in the hemofi lter is the fi lter life. This is generally synonymous with EC life or circuit life.

Anticoagulation—It is the administration of a substance that prevents coagula-tion, that is, it stops blood from clotting. Anticoagulant therapies interfere with humoral coagulation or platelet activation and have varying impact on systemic coagulation.

Introduction

Defi nitions

Chapter 18

Regional citrate anticoagulationNigel Fealy

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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 hemofi lter, 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 distribu-tion in blood (Figure 18.1).

When citrate is infused into the blood circuit, it combines with ionized cal-cium (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 signifi cant loss of the citrate–calcium complexes as they cross •

the semipermeable membrane of the hemofilter (dialyzer) into the ultrafi ltrate (UF).

Method

Figure 18.1 Calcium distribution in plasma and normal lab ranges.

(TC) Total calcium2.2–2.6 mmol/L

(IC) Ionized calcium, (~ 50%)1.1–1.3 mmol/L

(PBC) Protein bound calcium (~ 40%0.95–1.2 mmol/L

(CC) Complex calcium (~ 10%)Calcium phosphate, salts~ 0.05 mmol/L

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

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 ion-ized 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 veno-venous hemofi ltration (CV VH) and continuous veno-venous hemodiafi ltration (CV VHDF) as the mode of therapy. Often protocols are hospital specifi c re-quiring pharmacy or custom-made solutions (substitution and dialysate) to im-plement 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 anticoagu-lation in the clinical setting. A description of protocols for CV VHDF and CV VH can be seen in Figures 18.2 and 18.3.


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 ultrafi ltrate will vary with fi ltrate fl ow (both •

UF rate and amount of fl uid 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.


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

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

PatientiCa2+

1.1–1.3 mmol/L

PF iCa2+ (0.25–0.5mmol/L)

QB 100–150 mL/min

QE = QR + QFR + QD

QD

QR

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

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

is also bound and freely fi ltered across the membrane, potentially leading to a reduction in serum magnesium levels.

Therefore, when prescribing a citrate-based anticoagulation regimen, meta-bolic 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 anticoagula-tion 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, fi lter life is prolonged or equal to that of standard systemic heparin anticoagulation. The major advantage is that adequate

Summary

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anticoagulation can be achieved for CRRT without the need for systemic antico-agulation 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 hemofi ltration. International Journal of Artifi cial Organs. 2007;30(4):301-307.

Figure 18.3 Continuous veno-venous hemofi ltration (CV VH). Department of intensive care, Austin hospital CV VH protocol. QB = blood fl ow; QE = effl uent fl ow; QR = replacement; QFR = fl uid removal.

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)

PatientiCa2+

1.1–1.3 mmol/L

QB 200 mL/min

QE = QR + QFR

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Kutsogiannis DJ, Mayers I, Chin W, Gibney R. Regional citrate anticoagulation in continuous venovenous hemofi ltration. 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 anticoagula-tion continuous venovenous hemodiafi ltration protocol for metabolic control and high solute clearance. Clinical journal of the American Society of Nephrologists. 2005;1:79-87.

147

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 fl uid, which results in decreased fl uctuations in electrolytes and fl uid balance with reduced hemodynamic insta-bility 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 crit-ically 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, phar-macokinetic 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 tech-niques and methods. Differences among CRRT techniques that affect solute and medication clearance include mechanism of solute clearance, vascular access, fi lter membrane properties, and fl ow rates for blood, ultrafi ltration, and dialysis fl uid.

CRRT techniquesThe three main techniques of clearance utilized are hemodialysis, hemofi ltra-tion, and hemodiafi ltration. Each technique varies in mechanism of solute clear-ance (i.e., convection or diffusion) and need for fl uid 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.

Continuous renal replacement therapyproperties

Chapter 19

Drug dosing in continuous renal replacement therapyKimberly A. Maslonek, Kelly A. Killius, and John A. Kellum

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Hemodialysis• utilizes passive diffusion of solutes across a concentration gra-dient with countercurrent dialysis fl uid. Only molecules of small molecular weight (<500 dalton) are readily removed during diffusion. Replacement fl uid is not required.Hemofi ltration • utilizes convection, where solutes and plasma water are driven through a membrane with a pressure gradient, resulting in higher solute removal and the formation of an ultrafi ltrate. As long as the solute is smaller than the pore size cutoff for the membrane used, particle size or molecu-lar weight has little infl uence on solute removal during convection methods. However, replacement fl uid, which can be administered before or after blood fi ltration, is required due to the large volume of ultrafi ltrate formed during this process.Hemodiafi ltration• is a combination of diffusion and convection. Solute and vol-ume removal involve a countercurrent dialysis fl uid and pressure gradient. Replacement fl uids are required to support higher ultrafi ltration rates.Slow continuous ultrafi ltration (SCUF) • is a method of fl uid removal without dialysis or replacement fl uid. SCUF is not appropriate for patients with renal failure since it provides only very limited solute clearance. SCUF is usually employed for temporary volume removal in patients with at least some renal function (e.g., congestive heart failure). As such drug dosing does not typically require adjustment for patients receiving SCUF.

In general, drug removal may be expected to be greater with CRRT compared to IHD, and when replacement fl uids are administered after fi ltration. Drug clearance with CRRT may vary greatly depending on the particular physico-chemical properties of each compound and the CRRT device characteristics and operating conditions.

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

Table 19.1 CRRT techniquesTechnique Clearance mechanism Replacement fl uid

Convection DiffusionSCUF + 0

CV VH ++++ +++

CV VHD + ++++ +/0

CV VHDF +++ +++ ++

Note: SCUF = slow continuous ultrafi ltration; CV VH = continuous veno-venous hemofi ltration; CV VHD = continuous veno-venous hemodialysis; CV VHDF = continuous veno-venous hemodiafi ltration

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Membrane permeabilityMembrane permeability differs on the basis of the type of RRT used. Conventional low-fl ux dialysis (IHD) fi lters have smaller pore size and are inef-fi cient at removing molecules > 500 dalton. Conversely, fi lters 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 fi lter membrane is expressed as the sieving coeffi cient (SC). Medications with SC that approach unity (SC = 1) are able to freely pass through the fi lter and will require increased dosing or interval changes.

SC = CUF/CP

SC = 0; no passage through fi lterSC = 1; pass freely through fi lterSC = Sieving coeffi cient, CUF = concentration of medication in ultrafi ltrate,

CP = concentration of medication in plasma

The SC is available for some medications in published literature. Otherwise, it can be calculated by obtaining medication concentrations.

Membrane compositionIntermittent hemodialysis (IHD) fi lters are composed of cellulose or synthetic-based materials, while the most common materials employed in CRRT fi lters are synthetics, including polyacrylonitrile, polyamide, and polysulfone.

Again, while no one fi lter is considered optimal, fi lters composed of synthetic material are favored over those that are cellulose based because they are gener-ally considered more biocompatible. Other considerations include differences in permeability and their varying effect on the SC of many drugs. In general, larger pore sizes or “high-fl ux” membranes generally result in greater drug clearances especially for larger molecules.

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

Patient properties

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

Patient properties

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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, asci-tes, pleural effusions, mediastinitis, hypoalbuminemia, and postsurgical drain-age. Hypervolemic patients may require higher doses for medications with large volumes of distribution, with the opposite being true for hypovolemic patients. As fl uid removal is accomplished with CRRT, volume of distribu-tion 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 adminis-tration drug absorption can also be signifi cantly 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 vari-ables 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 fi lter 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 avail-able for removal by RRT. Importantly, protein binding is in dynamic equilib-rium. Because of its continuous nature, CRRT results in signifi cantly 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, fl uid removal by CRRT may result in changes in drug elimination by other organs.

Table 19.2 Patient factors affecting drug levels Factor Effects Effect on drug levelsHypervolemia Increases Vd and

decreases absorptionDecreases

Hypoalbuminemia Increases unbound fraction Increases

Organ dysfunction Decreases drug clearance Increases

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Drug properties

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

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

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

Volume of distributionDrugs that have a small volume of distribution are generally hydrophilic and lim-ited to vascular space since they are unable to pass through plasma membranes. Most hydrophilic agents are renally eliminated as unchanged drug. Therefore,

Drug properties

Table 19.3 Relative sieving coeffi cients and protein binding of select drugsDrug SC PB Drug SC PBAcyclovir +++ Very low Digoxin +++ Low

Amphotericin + Very high Ganciclovir +++ Very low

Ampicillin ++ Low Gentamicin ++ Very low

Cefoxitin ++ High Imipenem +++ Low

Ceftazidime +++ Very low Oxacillin 0 Very high

Ciprofl oxacin ++ Low Phenytoin + High

Cyclosporine ++ Very high Piperacillin ++ Low

Diazepam 0 Very high Vancomycin ++ Very low

Note: SC = sieving coeffi cient; 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.

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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 ceftri-axone 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 mem-branes and sequester into tissues, typically have high volumes of distribution and undergo hepatic metabolism. Medications with large volumes of distribu-tion are less available to pass through the RRT circuit for clearance and are less affected by renal clearance changes (extracorporeal or residual). Dose adjust-ments 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 redis-tribute from tissue to vascular space and be available for clearance. Examples include macrolides, fl uoroquinolones, tetracyclines, chloramphenicols, and rifampins, with the exception of levofl oxacins and ciprofl oxacins. Both undergo renal elimination and may be removed by RRT despite their lipophilic nature.

EliminationMedications 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 impera-tive in order to avoid therapeutic failure, increased resistance, or adverse effects, and must include pharmacodynamic considerations. In brief, antimicrobial effi -cacy has been defi ned in pharmacodynamic terms to be either time dependent or concentration dependent.

Concentration-dependent antimicrobialThe effi cacy 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 fl uoroquinolones, 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 effi cacy and prevent the development of resistance. Concentration-dependent agents exhibit postantibiotic effects against gram-positive 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).

Pharmacodynamic principles

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Time-dependent antimicrobialThe effi cacy of time-dependent antimicrobials is primarily related to the dura-tion 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 effi cacy is thought to be achieved by maintain-ing 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 pri-marily involve the investigation of antimicrobial agents and vary in their study design, method of CRRT, and study population, making it diffi cult to generalize

Dosing recommendations

Figure 19.1 Time-varying plasma concentration and relation to minimum inhibitory concen-tration (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

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Bactericidal Bacteriostatic

Bacterial regrowth

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data to all patients. In addition, there exists inconsistency across drug infor-mation 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 antimicro-bial agents based on available literature. Limitations to these recommendations are as cited above. Drug clearance is highly dependent on the method of renal replacement, fi lter type, and fl ow rate. Appropriate dosing requires close mon-itoring of pharmacological response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropri-ate). The following are general recommendations only (for a typical sized adult patient) and should not supersede clinical judgment: When available, therapeu-tic 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.

Table 19.4 Antibiotic dosing recommendationsDrug Dosing for CrCl

30 mL/min but not on RTT

Conventional IHD(Kt/V 1.2 QOD)

CRRT (CVVH at 25 mL/kg/h)

Cefepime 500 mg–1 gQ 24 h

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

1–2 g Q 12 h(consider continuous infusion of 2–4 g/24 h)

Ciprofl oxacin 500 mg oral or 400 mg IV Q 24 h

250–500 mg oral or 200–400 mg IV after* each dialysis

250–500 mg oral or 200–400 mg IV Q 12 h

Gentamicina 24-hour dosing 30% removal occurs during 4 hours of HD; administer dose after* dialysis and follow levels

24-hour dosing

Piperacillin-tazobactam

Decrease dose by 30% and administer every 6 h

2.25 g every 8–12 h with additional dose of 0.75 g after each dialysis

4.5 g every 8 h

Vancomycinb 15–20 mg/kgQ 24 h

10–15 mg/kg after each treatment

15–20 mg/kgQ 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.

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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

159

Renal replacement therapy in children

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 avail-able 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 hemofi ltration (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 else-where 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 trans-plants, 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 rea-sons. 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

Renal replacement therapy in children

Indications

Peritoneal dialysis

Chapter 20

Renal replacement therapy in childrenMichael L. Moritz

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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, fl uid overload, or metabolic derrangements.

Contraindications to PDThere are only a few contraindications to PD. A gastrostomy tube, ileostomy, colostomy, and vesicostomy are not contraindications to PD. A ventriculo-peri-toneal 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 accessA 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 cath-eters come in three sizes—infant, pediatric, and adult. Pediatric and adult cath-eters have the same internal diameter, but only differ in length.

Selection of acute Tenckoff PD catheter:<3 kg infant catheter •

>3 and <20 kg pediatric catheter•

#20 kg adult catheter•

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

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

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Initial PD prescription:1.5% Dextrose + 200 units of heparin per liter•

10 mL/kg dwell volume•

Continuous hourly exchanges•

DialysateThe dialysate solution is referred to by the dextrose concentration as 1.5%, 2.5%, or 4.25%. Dialysate is hyperosmolar in relationship to the plasma. Uremic toxins, electrolytes, and water are removed from the patient via diffusion into the peritoneum.

A 1.5% dialysate solution is the standard concentration for initiating PD.•

The dextrose concentration can be increased if additional fl uid removal is •

required.200 units of heparin per liter are usually added to the dialysate to prevent •

fi brin clots.Heparin does not cross the peritoneal.•

2–4 mEq/L of heparin can be added to the dialysate if hypokalemia develops.•

Dwell volumeAcute PD is initiated at a low dwell volume to prevent leakage of dialysate around the catheter from higher intraperitoneal volume. The dwell volume can be progressively increased over time to improve clearance.

PD is initiated at a dwell volume of 10 mL/kg.•

The dwell volume can be progressively increased over 2 weeks to up to 40 •

mL/kg.

Dwell timeAcute PD is usually initiated with hourly exchanges•

20–30 minute exchanges can be used if•

PD is initiated within 24 hours of catheter placement,•

aggressive fl uid removal is needed,•

there is severe hyperkalemia.•

Acute PD is usually continuous.•

Intermittent PD of 8–10 hours can be done when dwell volumes > 30 mL/kg •

are achieved.

ComplicationsThere are a variety of complications associated with peritoneal dialysis. Below are the key aspects to a variety of complications:

Leakage of fl uid around the PD catheter•

Interrupt PD for 24–48 hours.•

Resume at a reduced dwell volume.•

Consider administering fi brin glue to the exit site.•

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

>50% neutrophilsSend peritoneal fl uid for culture.•

Treat with intraperitoneal antibiotics.•

PD does not have to be discontinued.•

Problems with fi lling 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 fi brin 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 modifi cations 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 accessReliable 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 dialyzersDialysis 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%).

Hemodialysis

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Blood fl ow (QB)First dialysis treatment should be 3–5 mL/kg.•

Subsequent dialysis treatments can be as much as 10 mL/kg.•

TimeDialysis is extremely effi cient in small children due to the small volume of distribution.

A 3-hour dialysis treatment is usually suffi cient for children < 50 kg.•

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

Anticoagulation30–50 units/kg loading dose•

10 units/kg hourly•

Heparin-free dialysis can be done with high blood fl ows and saline fl ushes.•

Lock catheters with 1:1000 unit of heparin per liter.•

Table 20.1 Vascular access in childrenPatient size Catheter sizeNeonate < 3 kg 3.5 Fr or 5 Fr umbilical artery catheter

5 Fr umbilical venous catheter5 Fr single lumen venous cathetersRadial arterial line7 Fr double lumen dialysis catheter

3–6 kg 7 Fr double lumen dialysis catheter

6– 30 kg 8, 9 Fr double lumen dialysis catheter

> 30 kg 10, 11, 11.5 Fr double lumen dialysis catheter

Table 20.2 Examples of appropriate dialysis prescriptions for childrenPatient size Wt (kg), BSA (m2)

Blood lines, volume (mL)

Dialyzer, volume (mL), surface ares (m2)

Priming volume (mL), blood volume (%)

QB (mL)

4.0, 0.3 Neonatal, 20 aF3, 28, 0.4 48, 15 12–40

10.0, 0.5 Small pediatric, 44 F3, 28, 0.4 48, 6 30–100

30.0, 1.0 Large pediatric, 79 aF5, 63, 1.0 142, 6 100–300

Note: aF3 and F5 are manufactured by Fresenius.

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Continuous veno-venous hemofi ltration (CV VH)

The principles of CV VH are the same for children as adults. CV VH is techni-cally more diffi cult 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 signifi cant experience with children of this size. Initiating CV VH in small children and infants can produce signifi cant hemody-namic instability. Below are general principles to follow when initiating CV VH.

Blood pressureThe 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 accessAt 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 volumeThe 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 fl ow3–5 mL/kg/h•

Dialysate-replacement fl uid fl ow rateThe choice of using CV VH or CV VHD is center specifi c and there is no clear advantage of one over the other in pediatrics. There are no specifi c CV VH so-lution for children. Accusol, Prismasate, Normocarb, Nxstage, or a pharmacy made solution have all been used successfully. The dialysis fl ow in children has been adapted from what has been used in adults and adjusted to body sur-face 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 fl ow rates much lower than this.

AnticoagulationBoth 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

Continuous veno-venous hemofi ltration (CV VH)

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

167

Principles

Therapeutic plasma exchange (TPE) is the automated removal of a patient’s plasma and its replacement (exchange) with a suitable alternative fl uid 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/benefi cial substances. Smaller molecular weight compounds are not effi ciently removed by TPE, but may be effectively removed by alternative extracorporeal techniques such as hemofi ltration (<20–30,000 daltons) or dialysis (<500–600 daltons).

The decision to utilize TPEThe rational use of TPE is based on the following considerations:

What is the pathophysiological role of the target macromolecule in the clinical •

disorder? Is there an evidence of acute toxicity caused by the substance? Is the patient resistant to the usual medical and/or pharmacologic therapy or does the clinical urgency demand more immediate action?Can the substance be effi ciently removed by TPE? Generally, this applies to •

large molecules with relatively long half-lives (reduced synthetic rate).Is there evidence that reduction in levels of the offending substance is associ-•

ated with improved clinical outcomes?

Clinical consultation with the appropriate provider of TPE services is recom-mended to address these issues and to provide management guidance, as out-lined in Table 21.1.

Note, the American Society for Apheresis (ASFA) has published compre-hensive evidence-based indications on the use of TPE in specifi c disease cate-gories (Szczepiorkowski ZM. Clinical applications of therapeutic apheresis: an evidence-based approach. 4th ed. J Clin Apher. 2007;22:96-105). The classifi cation system and examples of substances removed are shown in Table 21.2 and 21.3.

Principles

Chapter 21

Therapeutic plasma exchange in critical care medicineJoseph E. Kiss

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Table 21.1 Decision making in therapeutic plasma exchangeConsiderations

Rationale Disease pathogenesis, published effi cacy, and quality of evidence

Technical issues Vascular access, volume of plasma to process, replacement solution

Management plan Timing (emergent, urgent), number, and frequency of treatments

Endpoint Clinical and/or laboratory response

Table 21.2 Consensus indications for plasma exchangeASFA category Interpretation RemarksI Standard acceptable therapy Proven in controlled trials

II Available evidence supports effi cacy Case series, second line, adjunctive therapy

III Available evidence suggests effi cacy but is inconclusive

Anecdotal data, for example case reports

IV Ineffective in controlled trials

Table 21.3 Clinical examples where plasma exchange is usedSubstances removed Clinical examples ASFA categoryAutoantibodies Goodpasture’s syndrome (antiglomerular

basement membrane autoantibodies)I

Alloantibodies Solid organ transplant (e.g., anti-HLA) II

Immunoglobulins causing hyperviscosity

Waldenstrom’s macroglobulinemia I

Cryoglobulins Cryoglobulin-associated skin ulceration, renal dysfunction

I

Protein-bound toxins Amanita (mushroom) poisoning IISubstances replenishedADAMTS13 (von-Willebrand factor cleaving protease)

Thrombotic thrombocytopenic purpura (TTP)

I

Coagulation factors Hepatic failure III

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

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

Table 21.4 depicts the proportion of an idealized compound that is removed based on the kinetic model.

Apheresis devices

Two general types of instrumentation may be used to perform TPE: centrifugal-based and membrane-based fi ltration.

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

Apheresis devices

Table 21.4 Removal of a substance by TPE• Effi ciency:

• 1 PV = 65% removal• 1.5 PV = 75%• 2 PV = 87%• 3 PV = 95%

• IgM—80% intravascular (effi ciently depleted due to limited reequilibration)• IgG—both intravascular (40%) and in tissues (removal less effi cient, redistribution into

plasma postapheresis over 24–48 hour period)

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

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by discontinuous (alternates blood collection and reinfusion sequentially) or continuous fl ow. Continuous fl ow devices achieve greater effi ciency by simulta-neously collecting and reinfusing processed blood components.

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

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

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

Membrane fi ltration cell separatorsMembrane fi ltration technology is an extension of the use of synthetic biocom-patible membranes employed in hemodialysis, ultrafi ltration, and hemofi ltration. The membrane is permeable to large molecular weight proteins but excludes cellular elements, including platelets. Pore sizes ranging from 0.2 to 0.6 microns allow passage of proteins with molecular weight ranges of more than 500,000 daltons. Membrane fi lters that are currently used have sieving coeffi cients of

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0.9–1.0. This implies that the protein composition of the fi ltrate and the plasma are nearly identical, even for very large molecules such as IgM. Cellulose diac-etate, polyethylene, polypropylene, polyvinylchloride, and other synthetic mate-rials are used to make membrane fi lters.

After the addition of anticoagulant, the patient’s blood is pumped through either a parallel plate or hollow fi ber fi lter at a continuous fl ow rate between 50 and 200 mL/min. The effi ciency of fi ltration is determined by several param-eters including the blood fl ow rate, composition and physical characteristics of the membrane, transmembrane pressure, geometry of the blood fl ow path, as well as the physical and chemical nature of the plasma proteins. A typical device features an anticoagulant syringe pump (usually employing heparin as the antico-agulant of choice), a blood pump, replacement fl uid pump, and effl uent pump. Blood is directed to the plasma fi lter by means of the blood pump. The hemo-concentrated blood leaves the plasma fi lter through the return line, where it is combined with replacement fl uid and returned to the patient. The effl uent side of the plasma fi lter leads to a waste bag.

Studies comparing centrifugal and membrane fi ltration have found them to be similar with respect to safety and effi ciency. TPE is not as rapid with mem-brane separators. Although use of systemic heparin anticoagulation may avoid some side effects of citrate, systemic heparinization is disadvantageous in some patients, such as those with coagulopathy.

Adverse effects of TPE

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

Citrate toxicityOne part of acid citrate dextrose (ACD) solution is added to fourteen parts of whole blood immediately after withdrawal from patient. This prevents clot-ting in the apheresis machine. The citrate ions bind ionized calcium, resulting in transient hypocalcemia. Plasma products add to this side effect because of high citrate concentration.

Symptoms•

Perioral tingling•

Vibration sensation•

Numbness and tingling in extremities•

Nausea and emesis•

May progress to muscle spasms, tetany, and seizure activity•

Adverse effects of TPE

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Management•

Decrease inlet fl ow (blood withdrawal) rate (or pause machine)•

Calcium gluconate infusion—in adults 10 mL 10% (1 gm) in 250 mL 0.9% •

saline solution may be added to albumin replacement fl uid (not plasma).Calcium chloride infusion—in adults, this is 3x more potent and acts faster •

than calcium gluconate because the ions dissociate immediately. Monitor patient q 15–30 min with [Ca 2+] levels.

Vasovagal reactions: Generally manifested by sudden hypotension and brady-•

cardia, diaphoresis, lightheadedness, and occasionally nausea and emesis. TPE is temporarily halted and legs are elevated to increase venous return. Reaction is usually self-limited but may progress to loss of consciousness. Bolus NSS, 200–400 mL may be given.Hypotension: Acute volume loss is prevented by priming the apheresis cir-•

cuit with replacement fl uid. Despite simultaneous replacement, patients such as those with autonomic neuropathy are sensitive and become hypotensive. These kind of patients generally respond to bolus saline, 200–400 mL.Allergic reactions: Mainly due to plasma proteins; rarely albumin or residual •

ethylene oxide sterilization of disposable plastic.Hemolysis: Very rare. Suspect use of hypotonic crystalloid solution or mechan-•

ical cause (kinked tubing) or patient red blood cell abnormality.Depletion of clotting factors: Prolonged prothrombin time and international •

normalized ratio (PT/INR), and/or activated partial thromboplastin time (APTT) that occurs with daily serial TPE using non-plasma replacement or cryo-depleted plasma (see Table 21.6). TPE especially depletes fi brinogen—longer

Table 21.5 Adverse events and frequencyEvent Frequencya (%)

Overall rateb 3–8

Specifi c reaction rates

Transfusion reactions (primarily due to plasma replacement) 1.6

Citrate related nausea and/or vomiting, paresthesias 1.2

Hypotensionc 1.0

Vasovagal nausea and/or vomiting 0.5

Pallor and/or diaphoresis 0.5

Tachycardia 0.4

Respiratory distress 0.3

Tetany or seizure 0.2

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

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3half-life (90 hours), slower recovery rate than other coagulation factors (3–4 days to return to normal).

Usually not manifest with every-other-day plasma exchanges•

Treatment: Decrease frequency of procedures or use plasma or cryopre-•

cipitate (donor exposure risk)Transfusion-transmitted diseases (when plasma is used)—rare•

Ace inhibitors•

Symptoms: Flushing (vasodilation), hypotension, dyspnea, watery diarrhea.•

Prekallikrein activator (an activator of bradykinin) is present in albumin-•

containing replacement solutionsAce is identical to kininase ii—bradykinin degradation inhibited•

Prevention: Withhold ace inhibitors at least 24 hours before procedure.•

Table 21.6 Colloid replacement fl uids used in TPE Fluid Advantages Disadvantages

5% Albumin Viral inactivationEase of useReactions rare

High costMost proteins not replaced

Single-donor plasmaa All proteins replaced High costInconvenientb

Citrate reactionsUrticariaViral infection risk

6% Hetastarch Low costViral SafetyEase of useSlow catabolism

No proteins replacedHypotensive reactionsDosage limit

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

175

Introduction

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

Defi nitions

Acute liver failure (ALF)—is a syndrome in which rapid loss of metabolic and synthetic liver function leads to the hepatic encephalopathy and multiorgan failure in patients with no previous history of liver disease.

Acute on chronic liver failure (AoCLF)—is a syndrome that occurs in patients with long-standing liver failure and cirrhosis of the liver where there is an acute decompensation of their disease process.

Albumin dialysis—is a form of artifi cial liver support where normal serum albumin is used as a component of the dialysate as a basis for more effective protein-bound toxin removal.

Artifi cial liver support—is any device designed to specifi cally purify blood form liver-related toxins. The role of these devices is to remove toxins, which may be responsible for hepatic encephalopathy and multiorgan failure secondary to liver failure.

Introduction

Defi nitions

Chapter 22

MARS: molecular adsorbent recirculating systemNigel Fealy and Rinaldo Bellomo

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Bioartifi cial liver support—is any form of liver support that uses fi lters impreg-nated with human or porcine liver cells (hepatocytes) to perform the three main functions of the liver: detoxifi cation, biosynthesis, and regulation.

Dialysis—is the separation of substances across a semipermeable membrane on the basis of particle size and/or concentration gradients.

Extracorporeal circuit—is the path for blood fl ow outside the body. It includes the plastic tubing carrying the blood to the dialyzer from the access catheter and from the dialyzer back to the body via the access catheter.

Liver support devices—are any man-made devices that are used to purify blood in the setting of liver failure. This term encompasses both artifi cial and bioartifi cial liver support systems.

Method

The MARS treatment kit consists of an albumin hemodialyser, a standard hemo-dialyser, an activated carbon adsorber, and an anion exchanger. The circuit is fi lled with 500 mL of 20% human albumin solution. Albumin acts as dialysate and is pumped through a hollow fi ber membrane (MARS fl ux dialyzer) countercur-rent to blood [Figure 22.1 (A)]. Water-soluble substances diffuse into the albu-min solution whilst albumin-bound toxins move by physicochemical interactions between plasma, albumin molecules bound to the dialysis side of the membrane, and the circulating albumin solution.

Toxin-carrying albumin is then passed through another hemodialyzer coun-tercurrent to a standard buffered dialysis solution where diffusive clearance of water-soluble substances occurs [Figure 22.1 (B)]. A concentration gradient is maintained by the circulation of the albumin solution and disposal of the albu-min-bound toxins by passage through activated charcoal [Figure 22.1 (C)] and anion exchange columns [Figure 22.1 (D)] (see Figures 22.1 and 22.2).

Practical considerationsThe MARS treatment is achieved by the combined use of a stand-alone con-tinuous renal replacement therapy (CRRT) machine or hemodialysis machine and the MARS albumin pump and monitor unit. The MARS albumin pump and monitor unit [Figure 22.3 (A)] is placed in series with a standard continuous veno-venous hemodialysis (CV VHD) circuit [Figure 22.3 (B)]. Depending on the external CRRT or dialysis machine used, the CRRT machine may act as a blood pump and dialysate controller or is more integrated for MARS use as with the Prisma and Prismafl ex platforms.

As with other renal replacement therapies, suitable vascular access is a key factor in achieving the prescribed treatment dose. The use of anticoagulation should be considered carefully. Often patients with ALF have some degree of autoanticoagulation and do not require anticoagulants to maintain MARS or CRRT circuits. Often the diffi culty in treating patients with ALF is in determining

Method

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

A B

CD

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

MARS Monitor

Albuminintermediate

circuit

Ion exchangeresin cartiridge

Activated charcoalcartidge

Dialysate

CRRTmachine

Dialyser 2Dialyser 1

A

V

QB = 150–200 mL/minQA = 200 mL/minQD = 33 mL/min (2L/h)

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when to institute the MARS therapy, duration of therapy (intermittent vs. con-tinuous), and when to cease the therapy.

Table 22.1 outlines one set of recommendations for the use of MARS in ALF.

After three days of consecutive intermittent or continuous treatments there is an expectation that the patient with ALF or AoCLF will have signifi cant improvement both clinically and biochemically.

At present there is insuffi cient data to demonstrate a survival benefi t when MARS is instituted in patients with ALF or AoCLF. However, there is evidence to suggest that MARS’ impacts favorably on the complications of liver failure. MARS appears to improve several clinical parameters such as hemodynamic status, bili-rubin levels, bile acid levels, encephalopathy, pruritus, and renal function.

The effect of improving these parameters in patients with liver failure is to provide time for either liver regeneration or to bridge the patient safely to liver transplantation.

A consideration when applying the therapy is modifi cation of antibiotics and drug therapy. Theoretically, removal of both water-soluble and albumin-bound drugs is achieved during the MARS therapy and, therefore, adjustment of drug therapy and therapeutic drug level monitoring should be undertaken.

The exposure of blood to an extracorporeal circuit initiates the coagula-tion cascade and may deplete clotting factors and lower the platelet count. In

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

A

B

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

Summary

The MARS treatment is a technically feasible therapeutic option for liver support in the intensive care environment. However, the setup is labor intensive com-pared to CRRT. The treatment option at present is currently limited to intensive care units (ICU) in specialist referral centers where highly skilled nurses are available as required to institute and maintain the therapy.

MARS represents the most frequently used liver support therapy at present. It appears to allow for the safe removal of albumin-bound as well as water-bound toxic substances in patients with AoCLF and ALF. At present many physicians believe that the therapy is a useful adjunct to bridge patients to transplantation and/or potentially support patients to spontaneous recovery. As reports of clini-cal and biochemical improvements in patients continue to emerge, there will be an ongoing interest in these types of therapies.

Summary

Table 22.1 Guidelines for the use of MARS in liver failureStart criteria

Rising total bilirubin > 300 µmol/L and one of the following:1. Hepatic encephalopathy of grade II or greater2. Hepatorenal syndrome

Intermittent MARS treatment6–8 h of treatment with intermittent hemodialysis Use when hemodynamically stable and no evidence of cerebral edemaAnticoagulation—none, heparin, or citrate (risk of citrate accumulation)Blood fl ow rate (QB) at 250 mL/minAlbumin fl ow rate (QA) at 250 mL/min

Continuous MARS treatment24 h of treatment with continuous veno-venous hemodialysis Use when hemodynamically unstable or evidence of cerebral edemaAnticoagulation—none, heparin, or citrate (risk of citrate accumulation)Blood fl ow rate (QB) at 180–200 mL/minAlbumin fl ow rate (QA) at 180–200 mL/min

Stop criteriaPlan for at least 3 days of MARS treatmentStop when

1. total bilirubin is less than 200 µmol/L;2. resolution of hepatic encephalopathy.

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

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Key references

Boyle M, Kurtovic J, Bihari D, Riordan S, Steiner C. Equipment review: the molecular adsorbent recirculating system (MARS). Crit Care. 2004;8(4):280-286.

Cruz D, Bellomo R, Kellum J, de Cal M, Ronco C. The future of extracorporeal support. Crit Care Med. 2008;36(4):S243-S252.

Evenpoel P, Laleman W, Wilmer A, et al. Prometheus versus molecular adsorbent recir-culating system: comparison of effi ciency in two different liver detoxifi cation devices. Arch Ortop. 2006;30(4):276-284.

Fealy N, Baldwin I, Boyle M. The molecular adsorbent recirculating system (MARS). Aust Crit Care. 2005;18(3):96-102.

Mitzner S. Albumin dialysis: an update. Curr Opin Nephrol Hypertens. 2007;16:589–595.

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

Stadlbauer V, Jalan R. Acute liver failure: liver support therapies. Curr Opin Crit Care. 2007;13:215-221.

181

Over the years, the possibility of removing solutes from blood to obtain blood purifi cation has mainly focused on classic hemodialysis. However, the character-istics of some solutes that make their removal diffi cult and the limited effi ciency of some dialysis membranes have spurred a signifi cant interest in the use of further mechanisms of solute removal such as adsorption. Materials with high capacity of adsorption (sorbents) have been utilized for about 50 years in extra-corporeal blood treatments of acute poisoning or uremia. With the recognition of the role of cytokines in systemic infl ammatory response syndrome (SIRS) and sepsis, and the fact that most cytokines are poorly removable by conventional diffusive or convective blood purifi cation modalities, treatment of sepsis based on sorbent technique has recently been explored.

Removal of target substances by sorbent in sepsis

Endotoxin: Endotoxin is a lipopolysaccharide (LPS) and an outer membrane mol-ecule essential for virtually all gram-negative bacteria. It is generally considered a major causative agent in shock states related to gram-negative bacteria infec-tion. LPS will bind to LPS-binding protein (LBP) and be transferred to bind to surface molecule cluster of differentiation (CD) 14 when it enters into blood, presented in aggregate form or monomeric form. The signal of LPS combination with CD14 will be relayed by Toll-like receptor (TLR) to activate the nuclear factor B(NF- B) and produce multiple cytokines.

Superantigen: Superantigen (SAg), which is a secreted production of gram-positive bacteria, plays an important role in activating and regulating the innate immune system, SAg is also known to be associated with toxic-shock like state in gram-positive bacterial infection. Unlike conventional antigen, SAg bypasses normal antigen processing steps, binds directly as an intact protein to major histocom-patibility complex (MHC) class II molecules on the surface of antigen-presenting cells and T cell receptor, and activates many more T cells than conventional

Removal of target substances by sorbent in sepsis

Chapter 23

SorbentsDehua Gong and Claudio Ronco

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antigen. SAg is the most powerful T cell mitogen ever discovered. Activated T cells then producte and release massive proinfl ammatory cytokines.

Cytokines: Activation of immune system is almost present in all critically ill patients, particularly in patients with infection. In the early stage of immune acti-vation, there is a production and release of many proinfl ammatory mediators, especially tumor necrosis factor- (TNF- ), interleukin -6 (IL-6), IL-1, and IL-8. These cytokines augment the body response to the pathogen and result in sys-temic adaptation. At the same time antiinfl ammatory mechanism is also initiated, including production of IL-10, transforming growth factor- and IL-13. If the over-responsiveness of immune system is still uncontrolled and persists for a period, the tissue damage and organ failure will occur, and the antiinfl ammatory effect will overweigh the proinfl ammatory effect, leading to immunoparalysis.

Selectivity of sorbent used for the removal of target substance

According to the selectivity of target substance removal, sorbents can be divided into the following three groups:

Unselective porous particles• : These kind of sorbents consist of paramount porous polymers, such as resin or activated charcoal (AC). Sorbents exist in granules, spheres, cylindrical pellets, fl akes, and powder. They are solid particles with single particle diameter between 0.05 cm and 1.2 cm. Surface area to volume ratio is extremely high in sorbent particles, which varies from 300 to 1200 m2/g. They can also be defi ned as the following:(1) macroporous = pore size > 500 Å (50 nm); (2) mesoporous = pore size 20–500 Å; and (3) microporous = pore size < 20 Å. Usually they adsorb molecules onto their surface unspecifi cally by Van der Waals forces, electrostatic attraction, or hydrophobic affi nity. Because molecules adsorbed onto the porous surface of sorbent must fi rst 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 specifi c to a certain group of substances onto matrix fi bers or particles. This kind of sor-bents 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. Superantigen-adsorbing device, which is prepared from a polystyrene-based composite fi ber reinforced with polypropylene, is recently undergoing investigation.Selective adsorption• : Sorbents made by immobilization of more specifi c ligands onto matrix can target the adsorption on one certain substance or limit the adsorption within a very narrow range. Adsorber composed of polymyxin

Selectivity of sorbent used for the removal of target substance

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B-immobilized fi bers (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 micro-spheres-based detoxifi cation system provides a platform in which anti-TNF antibody is immobilized onto microparticles with diameter range of 1–10 um. This system is designed to adsorb serum TNF in early stage of sepsis.

Effi ciency of adsorption

When a liquid mixture is brought into contact with a microporous solid, adsorp-tion 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 fi xed temperature (sep-aration 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 sol-vent. Another measure of the effi ciency 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 sor-bent to a completely unsaturated condition. Mass transfer zone determination also helps to defi ne the design of the unit and the expected time of effi ciency 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

Effi ciency of adsorption

Figure 23.1 Typical example of an adsorption isotherm.

Equilibrium concentration

Adsorption isotherm

Am

ount

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is often used to refl ect the removal ability of a sorbent, which is defi ned 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 fl ow rate, target solute burden in blood, and so on. In one treatment session, dynamic monitor of ex-traction ratio may refl ect the saturation status of the sorbent. Another clinical useful parameter for demonstration of the removal effect of sorbent is reduc-tion ratio of solute by a single session of treatment. However, the fact that both of these parameters cannot accurately refl ect the removal ability of a sorbent makes the comparison between different sorbent diffi cult.

Biocompatibility of sorbentsThe concept of sorbent biocompatibility may have three meanings: fi rst, 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 thrombocytope-nia. 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 fl atness and materials. Sometimes, surface-coating technique is used to improve sorbent biocom-patibility, while in expense of adsorption effi ciency. Another way to improve biocompatibility is plasma adsorption, in which only plasma pass through sor-bent, blood cells are separated from plasma and bypass the sorbent, and fi nally 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 anti-coagulation of extracorporeal circuit (EC). For materials such as charcoal that

Typical modalities of utilization of sorbents

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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 ultrafi ltrate produced from a hemo-fi lter. The hemofi lter is placed in series with the hemodialyzer. The system is used for online hemodiafi ltration in chronic patients and it is defi ned as paired fi ltration dialysis with sorbent (HFR). (D) The sorbent unit is placed online in the plasmafi ltrate produced from a plasmafi lter. The plasmafi lter is placed in series with the hemodiafi lter. The system is used for critically ill patients with septic shock and it is defi ned as coupled plasmafi ltration adsorption (CPFA).

Sorbent

Blood in

Blood in

Blood in

Blood in Blood out

Blood out

Blood out

Blood out

Sorbent Hemodiafilter

Hemofilter Hemodiafilter

Hemodiafilter

Dialysatein

Dialysatein

Dialysateout

Dialysateout

Dialysateout

Dialysatein

Sorbent

Sorbent

Plasmafilter

A

B

C

D

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

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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 con-sists 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 treat-ment online of the ultrafi ltrate or the plasmafi ltrate.Double chamber hemodiafi ltration (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 hemodiafi ltration.Coupled plasma fi ltration adsorption (CPFA):• Continuous plasmafi ltration adsorption is a modality of blood purifi cation in which plasma is sepa-rated 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 hemofi ltration or hemodialy-sis. The rationale consists in the attempt to combine the advantages of adsorption and hemofi ltration or hemodialysis techniques in solutes elim-ination. This technique has mostly been used in septic patients showing specifi c advantages of blood purifi cation, restoration of hemodynamics, and immunomodulation.

In another technique using uncoated sorbents [detoxifi cation plasmafi ltration (DTPF) HemoCleanse, Inc., West Lafayette, IN], a hemodiabsorption mecha-nism is associated with a push-pull plasmafi ltration system (a suspension of pow-dered sorbents surrounding 0.5 micros plasma fi lter membranes). Bidirectional plasma fl ow (at 80–100 mL/min) across the plasmafi ltration 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 benefi cial sub-stances 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 sepsisConventional blood purifi cation has been evidenced as less effective in the removal of pathogenic factors and mediators involved in the process of sepsis.

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This fact has aroused many innovative approaches such as high-volume hemo-fi ltration, the use of superpermeable membranes, as well as sorbent-based membranes.

HP using polymyxin B-immobilization adsorber (PMX) is on purpose of elim-inating 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 fl ow rate at 80–100 mL/min for a duration of 2 hours. Possible indication is the patients ful-fi lling 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 fi ltration adsorption (CPFA) is aimed at nonselective re-moval of soluble mediators involved in the septic shock. Limited amount of clinical studies showed a benefi cial 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 specifi c removal of superantigens and TNF are also limited in animal experiments. These novel sorbents may soon be clinically available.

Suggested readings

Bellomo R, Tetta C, Ronco C. Coupled plasma fi ltration 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 fi ber 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 purifi cation: more than diffusion and convection. Does this help? Curr Opin Crit Care. 2007;13:662-667.

Ronco C, Brendolan A, Dan M, et al. Adsorption in sepsis. Kidney Int Suppl. 2000;76:S148-S155.

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Ronco C, Brendolan A, d’Intini V, et al. Coupled plasma fi ltration adsorption: rationale, technical development and early clinical experience. Blood Purif. 2003;21(6):409-416.

Sakata H, Yonekawa M, Kawamura A. Blood purifi cation 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 purifi cation for critical illness: cytokines adsorption therapy. Ther Apher Dial. 2006 Feb;10(1):25-31.

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Introduction

Hybrid therapy is any renal replacement therapy (RRT) modality for critically ill patients that combines the therapeutic advantages of continuous renal replace-ment 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 specifi c “discontinuous” RRT modalities. Other terms which have been used in the literature are “sustained low effi ciency (daily) dialysis” (SLEDD), “sustained low effi ciency (daily) diafi ltration” (SLEDD-f), “extended daily dialysis” (EDD), “prolonged intermittent renal replacement therapy” (PIRRT), “go slow dialysis,” and “accelerated veno-venous hemofi ltra-tion” (AVVH).

General features of hybrid therapies include (1) use of standard equipment from ESRD programs, including machinery, dialyzers, extracorporeal blood cir-cuitry, and online fl uid production for dialysate and fi ltrate replacement; (2) intentionally “discontinuous” therapy (i.e., intended duration is less than 24 hours); (3) longer treatment duration than conventional IHD. Solute and fl uid 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 fl ow:70–350 mL/min

Dialyzer:Synthetic biocompatible membrane, either low or high fl ux

Introduction

Brief Orders

Chapter 24

Hybrid therapiesDinna N. Cruz and Claudio Ronco

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Dialysis solution composition:Session length < 8 h:

Sodium: 135–145 mEq/L, potassium: 2–3 mEq/L, bicarbonate: 28–32 mEq/L, calcium: 1.5–2.5 mEq/L

Session length 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 fl ow rate:70–300 mL/min

Substitution fl uid fl ow rate (for SLEDDf):100 mL/min (with QD 200 mL/min)

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 effi cacy of regional citrate anticoagulation

during 8-hour sustained low-effi ciency dialysis. Clin J Am Soc Nephrol. 2008;3:736.

Finkel KW, Foringer JR. Safety of regional citrate anticoagulation for continuous sustained low effi ciency 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 effi ciency 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 antico-agulation 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 lengthA number of factors help determine the prescribed duration of the RRT session. One of these is tolerance to ultrafi ltration. Patients who are less

Details of prescription

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hemodynamically stable will fare better with slower ultrafi ltration rates and longer treatments. Machine-related issues may also play a role, in conjunction with dialysate fl ow rates. For instance, for most single-pass HD machines, a sin-gle canister of dialysate concentrate would last approximately 5–6 hours with a dialysate fl ow of 300 mL/min, or 16–17 hours at a dialysate fl ow of 100 mL/min. When the Fresenius 2008H is not equipped with CRRT software, the ses-sion 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 fl ow of 70 mL/min, and a 90 L tank about 8–12 hours at dialysate fl ows of 150–200 mL/min.

Blood fl owBlood flows used in the literature generally range from 70–350 mL/min. Interestingly, in a recent publication describing AVVH, the blood fl ow 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 fl ow in intensive care unit (ICU) patients to improve cardiovascular stability, presumably by decreasing clearance and associated solute and fl uid shifts, this may be less relevant during hybrid therapy. When dialysate fl ow is signifi cantly lower than blood fl ow, as is often the case during hybrid therapy, dialysate is saturated with solute. Therefore, lowering the blood fl ow would not materially reduce solute and fl uid shifts. On the other hand, the downside of a low blood fl ow is a propensity for clotting in the extracorporeal circuit. Therefore, some experts recommend that maximizing blood fl ow as tolerated by the catheter to improve circuit patency.

Dialysis solution compositionAs with all RRT in the ICU, the dialysate solution composition should be cus-tomized to patient needs. With prolonged treatments, a lower bicarbonate level may be preferable to avoid inducing alkalosis. In acidotic patients, a more “stan-dard” 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 per-formed daily, and phosphate levels should be monitored. To avoid this problem, one may add phosphate to the dialysate by adding 45 mL of fl eet phospho-soda to 9.5 L of bicarbonate bath (fi nal concentration 0.8 mmol/L) after the fi rst few days of therapy. Alternatively, instead of manipulating the dialysate concentration, one may give phosphate supplementation, approximately 0.1–0.2 mmol/kg/day.

For online production of dialysate, special attention to water treatment is recommended. This is discussed later in this chapter.

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Dialysis solution fl ow rate (variable)Dialysate fl ow 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 fl ow 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 fl ow 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 rol-ler pump with two pump segments circulate blood and dialysate in either a 1:1 or 1:2 ratio.

Fluid removalNet ultrafi ltration rate is determined by patient need and hemodynamic stability. When the Fresenius 2008H is not provided with specifi c CRRT software, there is

Table 24.1 Hybrid therapy using various hemodialysis machinesMachine 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

To quickly optimize conductivity, set QD at 500 mL/min initially, run for 5 minutes until conductivity stabilizes, then set at 100 mL/min

Fresenius 4008E/H >300 No adjustment needed

<300 Possible with use of an external fl ow meter and additional tubing to create a bypass

Fresenius 4008K >300 No adjustment needed

100 No adjustment needed

Fresenius 4008S ARrT Plus >300 No adjustment needed

200 No adjustment needed

Fresenius Genius >300 No adjustment needed

<300 No adjustment needed

Gambro 200S Ultra >300 No adjustment needed

100 Run in hemofi ltration mode. Set QR at 100 mL/min

Instead of infusing, run replacement fl uid as dialysate in countercurrent fashion

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

Anticoagulation ordersUnfractionated 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 fl ushes, but such treatments are nev-ertheless 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 fl uid in predilution mode helps abrogate fi lter clotting but also decreases effective clearance.

There have been several descriptions of successful use of regional citrate anti-coagulation 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 avail-able 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.

Substitution fl uid fl ow 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 infl ammatory 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 adjunc-tive hemofi ltration (SLEDD-f). Online production of ultrapure fl uid for rein-fusion is similar to the process during hemodiafi ltration in chronic dialysis. In hybrid therapies, SLEDD-f has been performed primarily with the Fresenius 4008S ARrT-Plus. Online-produced substitution fl uid is not yet approved by the Federal Drug Administration in the United States, but the technique is widely used elsewhere.

A specifi c variant of hybrid therapies utilizing convection that has been reported in the United States is AVVH. This technique uses prepared replace-ment fl uid packaged in bags, with an infusion rate of 4000mL/h (67 mL/min) for 9 hours.

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Timing of treatmentHybrid therapies may be performed during the day or at night. The rationale for nocturnal programs include unrestricted patient access for diagnostic and ther-apeutic procedures during the day as well as greater availability of HD machines at night. Potential disadvantages would be safety issues and the need for trou-ble shooting at a time when there is lower staffi ng 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

Water considerationsWhen high-fl ux membranes are used for dialysis, signifi cant backfi ltration may occur such that, even in the absence of direct infusion, solute and water move-ment from the dialysate into the patient occurs in signifi cant amounts. Endotoxin in the dialysate is of specifi c concern, and backfi ltration of such may potentially further aggravate proinfl ammatory processes already ongoing in critically ill patients. Although defi nitive evidence is lacking, the use of ultrapure water for dialysate is prudent for all online fl uid-generating therapies. On the other hand, use of ultrapure water is obligatory for online production of replacement fl uid in hybrid therapies utilizing convection, that is SLEDD-f.

It is therefore mandatory for hybrid therapy programs to have an appropri-ate water quality assurance program in place. Standard water treatment entails bedside tap water being passed through the following three membrane fi lters: (1) a 10µ fi lter to remove granulates and large particles; (2) activated char-coal to adsorb carbon, chloramines, and organic contaminants; and (3) a 1µ fi lter to remove small particles. The latter is particularly prone to bacterial con-tamination due to removal of chloramines. Water is then treated by reverse osmosis. The fi nal step is further purifi cation by a two (Fresenius) or three-step (Gambro) ultrafi ltration process to produce ultrapure water ready for mixing with electrolyte and bicarbonate concentrate. Water produced during this pro-cess as well as water obtained from the tap pretreatment must undergo a regu-lar schedule of chemical, microbiological, chlorine/chloramines, and endotoxin assessment. Such verifi cation of water quality is a paramount safety feature of hybrid therapies.

NutritionAlthough 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.

Miscellaneous

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Suggested readings

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 hemofi ltration: 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-effi ciency hemodialysis (SLED). A nursing perspective. Blood Purif. 1999;17:36-42.

Kielstein JT, Kretschmer U, Ernst T, et al. Effi cacy 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 hemodi-alysis 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-effi ciency daily diafi l-tration (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-effi ciency 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 sus-tained low-effi ciency 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 replace-ment 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.

Part 4

Organizational issues

199

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.

Purpose of the ICU care

MonitoringWith modern technology and a high nurse-to-patient ratio, ICU provides an opti-mal 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.

SupportOne 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 sup-porting tools can cause.

PreventionPatients in the ICU are susceptible to develop various complications not only from ongoing underlying disease process itself but also from iatrogenic compli-cations 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.

Purpose of the ICU care

Chapter 25

The ICU environmentYounghoon Kwon

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Organized structure of the ICU

ICU Staffi ngThe ICU multidisciplinary team consists of the following members:

Intensivist: A specialist who is trained in the care of critically ill patients and cer-tifi ed by one of several medical specialty boards, including internal medicine, anesthesiology, or surgery. One major role of intensivist is to assume leader-ship in multidisciplinary team and to coordinate the care provided by different consultants. ICUs where patients are managed or comanaged by intensivist have reduced mortality.

Primary or consulting physician: Primary physician, who is knowledgeable with the history of the patient, contributes greatly to continuity of care that is often for-gotten in the ICU. Consulting physicians provide specifi c 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 usu-ally 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 man-agement and ventilator management. They are experts in assessing the needs of respiratory treatment such as use of oxygen and bronchodilator and in imple-menting them. They are also proven to be effective at weaning patients from mechanical ventilation.

Clinical pharmacist: Clinical pharmacists on rounds provide invaluable informa-tion 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 physi-cian assistant), clinical nutritionist, speech therapist, physical therapist, occupa-tional therapist, clerk, social worker, pastoral care worker, and so forth.

ICU models (physician staffi ng)Open unit: The primary attending physician continues to direct primary respon-sibility 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).

Organized structure of the ICU

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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 sup-ported improved outcome when closed unit model or high intensity (mandatory consultations with intensive care physician) was adopted.

Specialized ICUVarious 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 signifi cant experience by working with many patients who share a lim-ited number of diagnoses. However, as many patients have preexisting comor-bidities 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 hos-pitals tend to have one or two ICU that are usually mixed medical/surgical ICU.

Challenges of the ICU environment

Organizational challengesShortage of workforce: Demand is rising with ever increasing number of aging population, increasing use of modern technology, and with standard physician staffi ng model, which leapfrog initiative recently proposed.

Complex staffi ng and uncertain communication: There exists some degree of ambi-guity in leadership and in the role of each member of multidisciplinary team.

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

Ethical challengeEnd of life care: Defi ning the level of care, more specifi cally, 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 approachBuilding infrastructure•

Ensure all necessary resources (i.e., staff, equipment, and supplies) are •

available.Develop optimal physical environment in which critical care is delivered.•

Challenges of the ICU environment

Approach to critical care

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Table 25.1 Types of specialized intensive care unit ICU Type Common admitting diagnosis Primary physician in

chargeGeneral mixed Med/Surgery ICU

All critically ill patients Intensivist

Medical ICU SepsisAcute respiratory failure (AFR)HypovolemiaLiver failureGastrointestinal bleedingAcute pancreatitisDiabetic ketoacidosisIntoxication

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

Coronary care unit (CCU)

Acute myocardial infarctionAcute congestive heart failureHypertensive emergency

Cardiologist

Surgical ICU Postoperative care—High risk general surgery

Intensivist/surgeon

Trauma ICU Trauma Intensivist/surgeon

Cardiothoracic ICU Postoperative care—Cardiothoracic surgeryCoronary artery bypass graftHeart valve surgery

Intensivist/cardiothoracic surgeon

Neurological ICU Postoperative care—NeurosurgerySubarachnoid hemorrhageStrokeAcute neuromuscular failure

Intensivist/neurologist/neurosurgeon

Burn ICU Burn Intensivist/surgeon

Pediatric ICU All pediatric critical illness—medical and surgical

Pediatric intensivist/surgeon

Neonatal Related to prematurity or neonatal critical illness

Neonatologist

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 be-•

tween team members is a key to success.Creating collaborative culture•

Notes: Many variations exist in physician staffi ng 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.

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Organizing structure in patient care•

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 effi ciency and reduce errors.Ensure continuous quality improvement and training.•

Clinical approachRules: Always practice evidence-based critical care

Construct a thorough problem list.•

Evaluate a patient with a systematic approach to include all organs or sys-•

tems 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.•

Defi ne 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.•

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

System to improve quality of care and patient safety

Care giver Supporting staff

Patient centered multidisciplinary team approach

LeadershipCommunication and coordination

Between team membersBetween team members and patient/family

Collegial interdisciplinary teaminteraction

Open minded CollaborativeTrusting

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Observe and monitor patient’s progress.•

Focus on the patient’s overall clinical condition rather than on data.•

Pay attention to potential complication associated with intervention.•

Monitor complications that arise from critical illness (e.g., sepsis, acute •

renal failure (ARF), deep vein thrombosis, decubitus ulcer, anemia, malnu-trition etc.).

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

Outcome measures in the ICUAssessment 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 founda-tion in quality management and research.

Commonly used scoring systems are as follows:APACHE (acute physiologic and chronic health evaluation)•

SAPS (simplifi ed 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 staff-ing 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.

205

Quality patient care with successful outcomes depends on effective care deliv-ery and requires a multifaceted approach to support a continuous renal replace-ment therapy (CRRT) program. To that end, the Acute Dialysis Quality Initiative (ADQI) was established in 2000 to provide direction for the appropriate medi-cal 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 (struc-ture, process, and outcome) can be used to conceptualize the complex environ-ment encompassing CRRT care delivery (see Figure 26.1).

Chapter 26

Patient care quality and teamworkKimberly Whiteman and Frederick J. Tasota

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

ProcessStructure

EducationMachineOrganizationalcommitment

Teamwork PoliciesStaffingTreatment

Outcome

Renal recoveryDeliver prescribed dose Cost

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

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Structure incorporates the characteristics of the healthcare providers and the physical and organizational setting in which they deliver care. The core of the CRRT healthcare team is composed of the renal physician, the intensivist, and the ICU nurse.

Characteristics of the healthcare providers• include their educational prepara-tion. 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 under-stand 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 signifi cant 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 pre-pared 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 replace-ment bags. Another example might be that the availability of space in the room or presence of dialysis drains may infl uence 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 effi ciently prescribed treatments can be delivered. Company specifi cations for the machines, avail-able 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 mainte-nance or replacement, require continued resource deployment to sustain the program. Costs for disposable kits and commercially prepared dialysate solu-tions accrue on an ongoing basis. Organizations also need to commit to coor-dinate multiple hospital departments in order to expedite care. Pharmacy, laboratory, central supply, and housekeeping are all affected by a CRRT pro-gram. For instance, if the hospital chooses to have pharmacy dispense a com-mercial dialysate solution, the work load of the pharmacy will increase with each additional patient receiving treatment.

Process in Donabedian’s model is defi ned as the interactions between health-care providers themselves and between healthcare workers and patients. Successful CRRT programs require collaboration and teamwork between nu-merous disciplines, especially between the renal and intensive care physicians and the ICU nurses. CRRT policies and procedures, staffi ng, and treatment se-lection are other processes that affect quality care.

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Teamwork and collaboration • can be achieved through open communications 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 re-sponsibilities between work group members can expedite problem solving and implementation of clinical changes.Policies and procedures • should be in place to guide practitioners. Some sugges-tions 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 treat-ment. 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 prob-lems. 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 fl ow sheets to a simplistic model of documenting only the amount of fl uid removed from the patient.When CRRT is discontinued, there needs to be a method in place to dis-•

continue any fl uids, medications, and laboratory tests appropriate only during the treatment. For instance, replacement fl uid that remains on the medication administration record and is administered after CRRT is discon-tinued can quickly cause problems with fl uid overload.Electronic medical record programmers need to understand how the •

intake and output should be calculated to ensure accurate accounting of fl uids without double entry or charting. Double charting can occur when replacement or fl uid volumes from the CRRT machine are recorded as intake and/or effl uent is recorded as output and the actual patient fl uid removal is also recorded as output.

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Management of emergency situations should be planned before beginning •

a program and reviewed periodically. During a cardiac arrest, some centers routinely turn the fl uid removal rate to zero but continue blood circula-tion 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 benefi t from CRRT. Coordination of testing between hospital departments can eliminate the need to discontinue treat-ments 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-specifi c 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 some-times be daunting. Therefore, staffi ng requirements and assignments should ultimately be determined by the patient’s condition and the skills of the avail-able 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 work-load 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

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nurse staffi ng are determined by the processes chosen for obtaining supplies, dialysate, and replacement fl uids 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 staffi ng 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, CV VH treatments require the preparation and administration of large volumes of replacement fl uid, while CV VHD utilizes no replacement fl uid. Knowledge of the available treatments and how to perform each effi ciently 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 com-plete 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 treat-ment per day and achievement of prescribed fl uid balance or dose. Risk manage-ment 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 facili-tate 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.

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Effectiveness of programs to disseminate new information or a practice •

change to include whether the information is getting to the proper people.— being implemented into practice.— resulting in the expected clinical outcome.—

Process•

Knowledge of and/or compliance with policies and procedures can often •

be a problem for both new and experienced users. As with any policy, per-iodic 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 defi ciencies.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 fl uids 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 pre-vented 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 suc-cessful 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.

Summary

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Suggested readings

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 haemofi ltration. Intensive Care Med. 2003;29(4):575-578.

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

Considerations in renal replacement therapy for acute renal failure

• Dialysis modalityIntermittent hemodialysis (IHD): daily, alternate day, sustained low effi -•

ciency daily dialysis (SLEDD)CRRT: continuous veno-venous hemofi ltration (CV VH), continuous veno-•

venous hemodialysis (CV VHD), continuous veno-venous hemodiafi ltration (CV VHDF)Peritoneal dialysis•

Dialysis biocompatibility•

Membranes•

Dialyzer performance•

Effi ciency•

Flux•

Dialysis delivery•

Timing of initiation•

Intensity of dialysis: prescription versus delivery•

Adequacy of dialysis: dose of dialysis•

Fluid removal•

Maintenance of daily fl uid balance•

Treatment of fl uid overload•

Considerations in renal replacement therapyfor acute renal failure

Chapter 27

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

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a successful program

In our experience and that of others, fi ve 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)certifi cation•

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•

Implementing CRRT: requirements for a successful program

Table 27.1 Indications for specifi c renal replacement therapies Therapeutic goal Hemodynamicsa Preferred therapyFluid removal Stable Intermittent isolated ultrafi ltration

Unstable Slow continuous ultrafi ltration

Urea clearance Stable Intermittent hemodialysis

Unstable CRRT:

Convection: CVVH

Diffusion: CVVHD

Both: CVVHDF

Severe hyperkalemia Stable/Unstable Intermittent hemodialysis

Severe metabolic acidosis Stable Intermittent hemodialysis

Unstable CRRT

Severe hyperphosphatemia Stable/Unstable CRRT

Brain edema Unstable CRRT

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

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NotesPolicies, 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 applica-tion, 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).

Forces in the development of a CRRT program

• Driving forcesPrevious 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—

NotesDriving forces. Previous positive experiences and improvement in patient out-comes will facilitate the development of the program. A point person—gen-erally 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 fl edgling programs begin by treating the sickest patients with highest expected mortality. Outcomes in such cases are predictably poor, leading to negative staff impres-sions of the overall effi cacy of the therapy.

Forces in the development of a CRRT program

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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

• Hospital factorsSize 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 staffi ng•

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 identifi cation— Response to treatment— Untoward events— Vascular access—

System•

Factors affecting the development of a CRRT program

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Staffi ng•

Supplies•

Equipment•

Outcome•

Patient goal achieved— Patient outcomes—

Survival•

Renal function status•

Staff satisfaction— Costs—

1. Hospital factorsThe 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 com-mitment of administration to—at least—a trial of the technique.

2. Patient factorsPrior 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 dia-lyzed during that interval and estimate the number of CRRT procedures per year. Previous experience demonstrates that in order to maintain the staff pro-fi cient 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 availableA recent national survey in the United States has shown that while hemodi-alysis 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 insti-tutions, 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 signifi cant variation in the distribu-tion 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.

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Which nurses should be selected? The desirable nurses are the critical think-ers, 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 decisionsThe 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 suc-cess but also be less costly. Better blood pump systems and tubing, appropriate biocompatible membranes, and access, by ensuring long-lasting fi lters, may re-sult 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 be-tween clinical and technical support. Rapid-response clinical support by knowl-edgeable nurses is most desirable on a 24 hour a day, seven days a week basis.

5. Staff education and quality improvementWhere available, nephrology nurses provide valuable education on dialysis and access management. For critical care nurses unfamiliar with the procedure, such know-how will fl atten 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 edu-cation establishes an all-important “ownership” of the procedure. In a gradual fashion, ICU nurses learn that rather than merely adding another piece of equip-ment to an already cluttered bedside, CRRT provides virtually complete control of nutrition, hemodynamics, fl uid, 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 fl uid balance and dialysis errors

• Inappropriate prescriptionOperator error•

Machine error•

Recommendations for preventing complications during ultrafi ltration with hybrid/CRRT modalities

• All operators of intermittent or continuous renal replacement machines should be appropriately trained and certifi ed initially and on a periodical basis.

Sources of fl uid balance and dialysis errors

Recommendations for preventing complications during ultrafi ltration with hybrid/CRRT modalities

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

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

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

NotesWhen 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 fi nancial concerns are also monitored. Analysis of data includes periodic revision of orders, fl ow sheets, protocols, education, fi lter 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, fl uid, and electrolyte control, the nephrologist in charge of CRRT must continuously interact and agree with all the other practitioners in-volved. 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, fl uid man-agement (volume and composition), and dose of dialysis prescription, anticoagu-lation, 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 fi eld 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 justifi ed (see also Chapter 25).

Financial considerations

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

Role of the nephrologist

Financial considerations

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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 fl uids: pharmacy costs—

Lab costs•

Respirator days, ICU length of stay•

Other modifi ers of cost:Predetermined changes of extracorporeal circuit•

Scheduled changes•

Minimal fi ltrate 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 fl uids•

Service, support•

Appropriateness of treatment/patient selection•

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NotesSeveral 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 budgetPatient dependent on chronic dialysis will consume signifi cant health care •

resources and have an impact on community health care budget

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 man-agement 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.

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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 thera-pies. Semin Dial. 1996;9:152-160.

Paganini EM, Tapolyai M, Goormastic M, et al. Establishing a dialysis therapy/patient out-come 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 world-wide survey. Intensive Care Med. 2007;33(9):1563-1570.

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Introduction

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 essen-tial for timely and appropriate reimbursement. The billing codes that are typi-cally 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 compo-nents 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,

Introduction

Billing codes

Chapter 28

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

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family, and social histories), comprehensive physical exam (vital signs plus exam-ination 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 docu-mentation. 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, documenta-tion 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 time-dependent CPT code: the fi rst 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

Table 28.1 Billing codesCPT 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, hemofi ltration) 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

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(e.g., peritoneal, hemofi ltration)]. 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, hemofi ltration) 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 fl uid. 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.

Subsequent hospital follow-up (CPT codes 99231–99233)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 com-ponents 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 modifi ers for multiple proceduresPlacement of temporary dialysis catheters (CPT code 36556) can be billed at any time. It is billed with a 25 modifi er 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 modifi er is linked to the E&M code and signifi es that there is a signifi cant and separately identifi able procedure.

When multiple procedures are done on the same day, then a 51 modifi er is also used. The 51 modifi er is linked to all procedures after the fi rst. For exam-ple, 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 signifi cant and separately identifi able 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 sup-ported by the appropriate documentation. If on the day of consultation CRRT is

Initial patient evaluation

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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 modifi er (signifi cant and separately identifi able procedure). However, after the initial eval-uation, 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 modifi er. 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 crit-ical 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, subse-quent 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 phy-sician 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 devel-oped for CMS, and in 1992, Medicare established its standardized physician pay-ment 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 rep-resentatives from other health professions, including nursing. The commit-tee 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.

Subsequent hospital days

Relative value units

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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 fi rms may pay at or above Medicare rates. For exam-ple, 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.

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 modifi er (signifi cant and separately identifi able procedure).Multiple procedures can be billed with the 51 modifi er attached to all proce-•

dure after the fi rst.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.•

Summary

Table 28.2 RVU associated with common CPT codesCPT Code RVU99255 (Initial consult) 5.17

99291 (Critical care 30–74 minutes) 5.48

99223 (Initial inpatient admission) 4.96

90945 (Single CRRT) 1.61

90947 (Repeat CRRT) 2.16

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Introduction

In 1977, Peter Kramer introduced for the fi rst time a simple therapy called continuous arterio-venous hemofi ltration (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 fl uid 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 insuffi cient control of blood urea levels and inadequate blood purifi cation. For this reason, Geronemus and Schneider, in 1984, intro-duced 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 fl ow was provided to increase urea re-moval 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 fi ber hemodiafi lter, and we fi rstly described the treatment called continuous arterio-venous hemodiafi ltration (CAVHDF) [4]. In this treatment, the high convection rates combined with the countercurrent dialysate fl ow 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 extra-corporeal blood fl ow secondary to the patient’s hypotension, or line kincking and fi lter 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

Introduction

Chapter 29

Machines for continuous renal replacement therapyClaudio Ronco

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of blood pump modules for continuous therapies, the use of CAVH started to decline and the more effi cient continuous veno-venous hemofi ltration (CV VH) or continuous veno-venous hemodiafi ltration (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 ultrafi ltration can be increased up to 48–70 L/24 h. Since predilution decreases the effective concen-tration of the solute in the fi ltered blood, the amount of solute removal is not proportional to the amount of ultrafi ltration and it must be scaled down by a factor depending on the percent of predilution versus blood fl ow.

The increased amount of fl uid 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 effi ciency, safety and reliability were still ques-tionable 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 ultrafi ltration and replacement fl uid volume control. This approach is still in use in several units and it is defi ned as adaptive technology. Adaptive technology may be very effec-tive but it presents the risk of operating with components that are not intercon-nected 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 evolu-tion in technology (Figure 29.1).

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

1977 1985 1989 2004 ?Years

Evol

utio

n

Progress of CRRT Technology

CRRT technology evolution

CAVH CVVH-D CVVHDF HVHF

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Machines for continuous renal replacement therapy

The modern history of CRRT is characterized by the development of complete CRRT machines designed specifi cally for acute renal replacement in intensive care patients (Figure 29.2). These machines are all equipped with integrated safety alarms, fl uid 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 in-creased levels of effi ciency. Blood fl ows up to 500 mL/min and dialysate/replace-ment fl uid fl ow 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 fl ow rates achievable in the system, higher surface areas can now be utilized and more effi cient treatments can be carried out. The fl uid control is achieved via gravimetric or volumetric control systems, which drive peristaltic pumps both for ultrafi ltration and reinfusion. The priming procedures are simplifi ed because of the step-by-step online help and the self-loading preassembled tubing sets.

Machines for continuous renal replacement therapy

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

Multifiltrate Prismaflex Diapact CRRT Aquarius Equa-Smart

BM 25 Prisma HF 400 Hygeia plus Performer LRT

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The new machines are also equipped with a friendly user interface: this leads to an increased confi dence of the personnel with the therapy while constant levels of effi ciency 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 fl ow ranges is varying from one to another, but it has been dramatically increased in comparison to the fi rst 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 hemofi ltration. In these circumstances, the presence of an adequate warmer for the substitution fl uid is very important to maintain thermal balance. In this fi eld, online monitors for thermal balance and for blood volume determi-nation 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 pres-sure 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 fi ltration and the balance between ultrafi ltration 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 proinfl ammatory substances [13]. To achieve such a complex task, high convective rates may be required [14].

CHAPTER 29 Machines for CRRT233

Table 29.1 Characteristics of recent CRRT machinesCompany Pumps QB QD

(mL/min)Fluid(mL/min)

Heater manage-ment (Liters)

Heparin Reinfusion Pump

Printersensors

ScalesRS-332 P

Possible techniques

Aquarius Ew L S Baxter

4 0–450 0–165 10 L Y Y Pre Post pre-post

4 noY

2 (IHD-IHDF)-IHF, PEX-PAP SCUF-CVVH-CVVHD-CVVHFD Pediatric Tx

BM 25 Ew L S Baxter

3 30–500 0–150 16 L no no Pre Post 2 noY

2 SCUF-CVVH-CVVHD-PEX Pediatric TX (QB = 5–150 mL/min)

Diapact B. Braun 3 10–500 5–400 25 L Y no Pre Post 4 noY

1 IHD-IHFD-IHF, PEX-PAPSCUF-CVVH-CVVHD-CVVHFD

Equa-Smart Medica 2* 5–400 0–150 10 L Y Y Pre Post 3 YY

3 SCUF-CVVH-CVVHD-CVVHDF-PEX-Pedi-tric Tx

2008H2008K

FMC-NA 1+3** 0–500 0–300 open Y Y Pre Post 3 noY

Volu-metric

IHD-IHFD, SLED-SCUF- CVVHD Pediatric Tx

Multimat B Bellco 2*** 0–400 0–75 25 L no Y Pre Post 3 no 1 SCUF-CVVH-CVVHD

no CVVHD-PEX

HF 400 Infomed 4 0–450 0–200 12 L no Y Pre PostPre-Post

4 noY

2 IHD-IHFD-IHF, PEX, SCUF-CVVH-CVVHD- SCCHFD-CVVHDF-Pediatric Tx

CHAPTER 29 Machines for CRRT234

Table 29.1 Continued Company Pumps QB QD

(mL/min)Fluid(mL/min)

Heater manage-ment (Liters)

Heparin Reinfusion Pump

Printersensors

ScalesRS-332 P

Possible techniques

Hygela plus Kimal 4 0–500 0–65 4 L Y Y Pre PostPre-Post

4 YY

Volu-metric

SCUF-CVVH-CVVHDCVVHDF-PEX

Performer Rand 4**** 5–500 0–500 20 L Y Y Pre PostPre Post

4 YY

1 IHD-IHFD-IHF, PEX-PAP-SCUF-CVVH-CVVHD-CVVHFD-CVVHDF

Prisma Gambro 4 0–180 0–40 5 L Bloodwarmer

Y Pre PostPre-Post

4 noY

3 SCUF-CVVH-CVVHD-CVVHFD-CVVHDF-PEX

Multifi ltrate FMC 4 0–500 0–70 24 L Yin-line

Y Pre PostPre Post

4 NoY

4 SCUF-CVVH-HV-HFCVVHD-CVVHFD-CVVHDFPEX

Prismafl ex Gambro 5 0–450 0–133 15 L Y in-line Y Pre Post Pre-BP

5 no Y

4 SCUF-CVVH-HV-HF CVVHD-CVVHFD-CVVHDF PEX

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

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In these conditions the necessary rate of convection can be obtained in contin-uous hemofi ltration, in continuous hemodiafi ltration (in this case four pumps are required), or in continuous high-fl ux hemodialysis with continuous dialysate volume control (three pumps are required and a reliable UF control system). In HDF, dialysate outlet fl ow exceeds the volume of inlet dialysate volume and the required ultrafi ltration, and for this reason a substitution fl uid is required. In high-fl ux dialysis substitution fl uid is not required and the balance is obtained by a mechanism of internal backfi ltration. Warmed dialysate is delivered at a pro-grammed fl ow rate and the second pump regulates the dialysate outlet fl ow rate and net ultrafi ltration with a continuous volume control. In some machines this treatment has been performed in recirculation mode and it has been defi ned as continuous high-fl ux dialysis because of the fi ltration–backfi ltration mechanism similar to that of high-fl ux dialysis in chronic hemodialysis [15]. Once the patient’s dry weight has been achieved, the circuit may operate at zero net fi ltration using sterile dialysate at various fl ows (50–200 mL/min). With relatively high-volume hemofi ltration (2–3 L/h), hemodiafi ltration or high-fl ux 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 ef-fi ciency much higher than that achieved with other intermittent dialysis therapies [16]. At the same time, signifi cant amount of proinfl ammatory 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 spread-sheet 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 periph-eral 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.

Technical characteristics of common CRRT machines

The PrismaThe Prisma machine (Gambro-Sweden) has been the fi rst integrated equipment specifi cally 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 per-forming all the CRRT techniques. Blood fl ows can vary from 0 to 180 mL/min while

Technical characteristics of common CRRTmachines

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

The Prismafl ex machineThe new “Prismafl ex machine” (Gambro-Sweden) like all new-generation platforms for CRRT, presents new features, specifi cally designed to perform therapies with high fl uid volume exchange (HVHF), nowadays supposed to be effective in ARF, sepsis, and multiple organ dysfunction syndrome (MODS). The machine features fi ve pumps [blood, dialysate, preblood-pump replacement solution (PBP), post-blood-pump replacement solution, and effl uent], four scales (effl uent, dialysate and two for replacement solutions), and a disposable set with preconnected high fl ow dialysers and fl uid circuitry. The machine allows performing a complete spectrum of therapies [slow continuous ultrafi ltration (SCUF), CV VH, CV VHD, CV VHDF, therapeutic plasma exchange (TPE/PEx), and hemoperfusion (HP)]. Three different

Figure 29.3 The Prisma machine.

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Figure 29.4 The Prismafl ex machine and its blood circuit.

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 con-fi guration 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 pro-vides the possibility of varying the ratio between pre- and postdilution with dif-ferent 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 Prismafl ex machine: the fi fth pump. This pump delivers pre-blood-pump (PBP) fl uid 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 fl ows within a range of 10–450 mL/min (depending on the fi lter in use). Fluid fl ow rate allows a maximum fl uid handling of 8000 mL/h: both in hemofi ltration and in hemodiafi ltration. If PBP replacement solution is used, fl uxes 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 fl ow, which otherwise would be relatively decreased by the scaling down factor induced by PBP infusion. Total

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effl uent delivery is from 0 to 10000 mL/h, allowing a maximum ultrafi ltration of 2000 mL/h combined with the maximum dialysate/reinfusate fl ow rate. All these schemes are clearly designed to meet the issue of high-volume hemofi ltration. Prismafl ex software controls fl uid fl ows 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-treat-ment 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 back-safe collection of fl uid bags. One of the most frequent concerns, the de-aerating chamber clots, has been challenged by an innovative design: the chamber is con-nected 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 fl ows; further-more when replacement solution is reinfused post fi lter, it is poured directly on top of this cone, in order to create a fl uid layer between air and blood.

Sets are completed with effl uent 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 Prismafl ex machine and its dialysate-ultrafi ltrate collecting bags.

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an excessive workload of ICU nurses. The colored monitor displays pressures and fl ows in the fi rst 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, fi lters with modifi ed and treated surface (ST 60, ST 100, ST 150) are today available with various surface area in different kits.

The Diapact CRRTThe 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 fl ows (10–500 mL/min) and dialysate fl ows (5–400 mL/min) (Figure 29.6). Fluid handling and ultrafi ltration 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 hemofi ltration.

Figure 29.6 The Diapact machine.

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Figure 29.7 Details of the Diapact machine: screen, pumps, scales, and heater.

The machine is particularly suited for continuous high-fl ux dialysis with possi-bility of operating either in single pass or in recirculation mode.

The Aquarius/AccuraThe 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 fl ow can be varied from 0 to 450 mL/min while the dialysate fl ow 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 fl uid balancing while four-pressure sensors help to monitor the extracorporeal circuit function. Pre, post, and simultaneous pre-post dilution modes are available. A remarkable fl exibility and versatility characterize the machine.

The 2008H/KThe 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 effi ciency dialysis (SLED) by modifying the software and the

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Figure 29.8 The Aquarius machine.

Figure 29.9 Detailed front view of the Aquarius machine.

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operational parameters (Figure 29.10). The machine is equipped with a blood pump plus three pumps for dialysate that are internal. Blood fl ow can vary from 0 to 500 mL/min while the dialysate fl ow in CRRT mode can be set at three fi xed 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 hemofi ltration techniques cannot be performed. The ultrafi ltration 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 con-tinuous 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.

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incomplete does not mean that we suggest or prefer one model against another. For a more detailed description of the machines, setup and troubleshooting, purchase and maintenance, we suggest that the nearest agent of the chosen company be contacted.

High-volume hemofi ltration

Recent experimental fi ndings [18] have demonstrated the benefi cial impact of increasing the volume of ultrafi ltration during continuous hemofi ltration 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 hemofi ltration (HVHF) however, a clear defi nition of the operational ranges of the technique and a precise description of the tech-nical requirements imposed by this form of therapy are defi nitely needed.

According to present clinical practice, CV VH is generally performed with an average ultrafi ltration rate between 1 and 2 L/h. Above the value of 50 L per day, the amount of ultrafi ltration begins to be considered “high” and the treatment can be defi ned as HVHF.

There are, however, two ways to perform HVHF: (1) the standard CV VH treatment schedule is maintained and the rate of ultrafi ltration 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 ultrafi ltration is produced at rates above 6 L/h. In both cases the amount of ultrafi ltration exchanged per day may exceed 60 L.

To perform this treatment several requirements must be fulfi lled and, above all, a deep knowledge of the mechanism of transmembrane ultrafi ltration in the hemofi lters should be understood.

High-volume hemofi ltration (HVHF) requires large hemofi lters to accomplish the task of achieving a daily fl uid exchange in the range of 60–100 L. While in the treatment schedule (a) hemofi lters of 1.0 m2 can be utilized, for the schedule (b), hemofi lters in the range of 1.6–2 m2 are needed. In all these fi lters, high-fl ux membranes are utilized. AN69, polysulfone, or polyamide membranes are gen-erally employed with a permeability coeffi cient between 30 and 40 mL/h/mmHg x m2. These membranes have solutes sieving coeffi cients close to 1 in a wide spectrum of molecular weights. Therefore, in most cases, clearance value equals the amount of ultrafi ltration achieved. There may be some exception to this rule. One case is when the sieving coeffi cient 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 hemofi ltration

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This is most likely to occur in the presence of high fi ltration fractions or in the case of long-term utilization of the hemofi lter (more than 24 h). Finally, clearance may be reduced by the presence of predilution, that is, in the case of administra-tion of the substitution fl uid into the arterial line to replace ultrafi ltration. This reduces the oncotic pressure of plasma proteins and increases ultrafi ltration, but the effi ciency of the system may be reduced by the parallel reduction in the concentration of the solutes in the incoming blood. Furthermore, since the avail-ability of large quantities of substitution fl uid may be limited, new trends suggest the use of online production of replacement solutions by machines with built-in step fi ltration techniques. These are already utilized in the chronic setting and they may become soon a practical approach for the patient undergoing HVHF.

Special treatments and plasma therapies

Based on the assumption that higher clearances may be required to remove proinfl ammatory 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 fi ltration and a subsequent reinfusion of the fi ltered plasma into the venous line, after passage on a cartridge of uncoated carbon or specifi c 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 proinfl ammatory 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 identifi ed with the name of CRRT. More therapies are today emerg-ing 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 fur-ther refi nement and studies, but they may well become part of the family of CRRT, especially in those cases when a continuous and prolonged extracor-poreal treatment is indicated. In these cases, the modern machines are able to accomplish the diffi cult tasks of performing complex and combination therapies. This is mostly done by built-in specifi c software that assigns a specifi c 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 hemodi-alysis 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,

Special treatments and plasma therapies

Future trends

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temperature sensors, blood volume sensors, and teledialysis or biofeedback sys-tems 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 benefi ts in the critically ill patients, and future trends may indeed include the development of machines equipped with these technologies.

References

1. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. Arteriovenous hemofi ltration: 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 hemodiafi ltration (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 replace-ment 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 veno-venous haemofi ltration 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 replace-ment 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 quantifi cation. Kidney Int. 1998;53(suppl 66):S133-S137.

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15. Ronco C. Continuous renal replacement therapies in the treatment of acute renal failure in intensive care patients. Part 1: Theoretical aspects and techniques. Nephrol Dial Transplant. 1994;9(Suppl 4):191-200.

16. Bellomo R, Ronco C. Continuous versus intermittent renal replacement therapy in the intensive care unit. Kidney Int. 1998;53(suppl 66):S125-S128.

17. Tetta C, Mariano F, Ronco C, Bellomo R. Removal and generation of infl ammatory 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 hemofi ltration 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 comple-ment components in an experimental model of continuous plasma fi ltration 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.

247

Introduction

There are different clinical parameters that can refl ect the successful use of con-tinuous 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 fl uid 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 pro-cess 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 fl uid balance.

Data collection can be in the form of a specifi c “snap shot” assessment over a short period (e.g., 1 month) or continuous.

Defi nitions—key terms associated with CRRT and quality monitoring

Filter life: Filter life is defi ned as the time from the commencement of blood fl ow through the fi lter until the time when the blood is unable to pass through the hemofi lter due to clot formation and obstruction. This is a useful variable for monitoring of the quality of CRRT. Collection of fi lter 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

Introduction

Defi nitions—key terms associated with CRRT and quality monitoring

Chapter 30

Quality assurance for continuous renal replacement therapiesIan Baldwin and Rinaldo Bellomo

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commonly associated with circuit clotting due to the preparation time for a new circuit. Sometimes it is due to procedures outside the intensive care unit (ICU) or physical therapy and mobilization in some patients. As off time decreases the time that therapy is applied, it has adverse consequences on solute control and fl uid removal. Off time associated with fi lter 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 fi lter 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 fi lter clotting and obstruction with blood loss, patient bleeding with excessive anticoagulation, hypovolaemia due to incorrect fl uid balance settings, arrhythmias due to inappropriate electrolyte or volume management, hypotension due to incorrect fl uid management or too rapid initi-ation 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).

Daily review of patient’s biochemistry and fl uid balance for adequate 1. volume control is vital. This would appear as an obvious quality activity. However, a bedside review is useful, particularly where prescribing physi-cians and nurses change frequently for the same patient over many days. Fluid balance needs to be assessed to see if inputs exceed fl uid loss. Fluid removed by the treatment does not necessarily mean a neutral or nega-tive 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 fl uid management goals and fl uid balance is mandatory.Number of patients treated, duration of each treatment, and days of treat-2. ment 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

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Table 30.1 Quality indicators associated with RRTQ.A. item Clinical comment

Daily review Solutes, urea, and creatinine should be declining or stable each day. Fluid loss is usually required and each day should achieve this considering all fl uids inputs and losses, and not the machine alone. An accurate patient weight is useful.

Number of patients treated

Useful data for justifying staff levels, budgeting, patterns in prescribing, and number of machines in use.

The time without treatment

Can refl ect differences over 24-h periods, staffi ng changes, training, and medical review. May also refl ect inadequate dosing and under treatment, if excessive.

Errors and adverse events

Frequent mistakes refl ect a need to change policy or additional training, resource development. For example, fl uid balance mistakes may suggest misunderstanding in orders and how clinicians interpret fl uid loss. Is this machine loss or patient net loss?

Access catheters used

How many access catheters are being used, are they being replaced 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 consumables

Useful to have up-to-date knowledge of this to determine average cost for 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.

Table 30.2 List of CRRT problems and appropriate responsesProblem Response

Frequent fi lter clotting Review choice and placement of vascular access catheter, review anticoagulation policies, review nurse training–nurse machine interface.

Long ‘off time’ Review nurse training. Emphasize need to prime circuit effi ciently. See above responses to frequent fi lter clotting.

Errors in fl uid balance

Optimize physician and nurse education. Accurately chart fl uid balance and ensure clarity of medical prescription of desired fl uid balance. Develop and use a CRRT prescription orders sheet.

Patient on high vasopressor therapy and hypotension

Initiate CRRT slowly. Begin with slow blood fl ow (20–30 mL/min) for up to 5 min until the circuit is fi lled with blood and blood is returning to the patient. Slowly increase blood pump fl ow to desired rate by 20–50 mL/min increments. Initiate fl uids therapy only after blood fl ow 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.

Unexplained fever or leukocytosis

Examine vascular access site. Consider removal of catheter (guide-wire exchange preferred as initial step).

Swollen limb distal to catheter

Consider deep venous thrombosis. Perform ultrasound. If large clot present, initiate anticoagulation. Do not immediately remove catheter as this can trigger lethal embolism.

Note: Q.A. = Quality Assurance.

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success and failure in a patient. Sequential, progressive charting of a treat-ment, with each new treatment starting again at hour “1,” achieves this and provides a quick assessment for time “on treatment” or fi lter life. A common fi lter life using CRRT across all patients in the ICU is a median of 20 con-secutive 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 3. no RRT is functioning or the “off time” is a useful measure of effi ciency, as solute levels will increase with increasing “off time.” There are many reasons for extended periods without CRRT being applied despite a con-tinuous prescription. However, these data can refl ect ineffi cient 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, specifi c alarm events, and machine 4. 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 sen-sitivity and used to improve CRRT in a constructive manner, avoiding indi-viduals being targeted. Frequent identical events refl ect a need to change and modify policy. Where many CRRT machines exist, naming each ma-chine makes tracking of machines and repairs or failures easier.Access catheters used and microbiology associated with use. Access 5. devices can be overlooked as separate from therapy. The number used and type and site of insertion provide useful data. A database with informa-tion 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 man-6. agers and helps with decision making on purchasing and supply contracts.

Summary

Collection and review of patient’s daily biochemistry, fi lter life, and time without treatment, all provide useful measures of CRRT quality. Biochemistry should refl ect solute reduction, fi lter 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 ineffi -cient treatments, access catheter malfunction, and poor fi lter life. The safety and quality of CRRT are highly dependent on the collection of quality improvement

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data as outlined above. If this is not done, the quality and safety of CRRT are seri-ously undermined and patients are exposed to the risk of major complications.

Key references

Baldwin I. Factors affecting circuit patency and fi lter life. Contrib Nephrol. 2007;156:178-184.

Baldwin I, Bellomo R. Relationship between blood fl ow, access catheter and circuit failure during CRRT. A practical review. Contrib Nephrol. 2004;144:203-213.

Baldwin I, Bellomo R, Koch B. Blood fl ow 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 hemofi ltration: three controlled studies. Ren Fail. 2002 Nov;24(6):839-848.

Ronco C, Ricci Z, Bellomo R, Baldwin I, Kellum J. Management of fl uid 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 hemofi ltration. Ren Fail. 2002 Nov;24(6):755-762.

Uchino S, Fealy N, Baldwin I, Morimatsu H, Bellomo R. Pre-dilution vs. post-dilution dur-ing continuous veno-venous hemofi ltration: impact on fi lter life and azotemic control. Nephron Clin Pract. 2003;94(4):c94-c98.

253

Introduction

Continuous renal replacement therapy (CRRT) requires a signifi cant commit-ment to ongoing education and training. New machines for CRRT are auto-mated for the priming and preparation sequence; however they continue to be challenging for learners to master and operate safely. In addition, fl uid 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 knowl-edge 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 sim-ulation 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 fi nally “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 equip-ment. In addition, education about fl uid 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).

Introduction

Introductory education: theory and practicaltraining

Chapter 31

Educational resourcesIan Baldwin and Kimberly Whiteman

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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 tem-porary dialysis catheter. Standard safety measures with central lines such as radiographic confi rmation 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 sul-phonate (kayexylate) until CRRT can be started.

Theory of solvent and solute removal•

Describe the principles of ultrafi ltration, diffusion, and convection. Discuss •

clearance of fl uid 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 hemofi lter and each of the four •

possible treatments.

Figure 31.1 The continuous renal replacement therapy (CRRT) classroom for theory using standard lecture set.

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In diffusive techniques the hemofi lter is a dialyzer with hollow fi bers inside. •

The blood fl ows through the center of the hollow fi bers. The dialysate fl ows around the hollow fi bers. Generally, the blood and fl uid fl ow in op-posite directions, called countercurrent fl ow.The fl uids fl ow path varies slightly depending on the treatment. It is im-•

portant that class participants understand that the dialysate fl uid does not directly enter the blood stream. Dialysate fl ows around the hollow fi bers, diffusion occurs, and waste is drained directly into the effl uent bag or dialysis drain along with the patient’s fl uid removed during treatment. Depending on the manufacturer, replacement fl uids might enter the blood stream before or after the fi lter or both. They may also be added in a sep-arate intravenous line.The blood path for all CRRT modalities is that the blood is pulled from the •

patient, enters the fi lter through tubing that is color-coded red (access), exits the fi lter, and is returned to the patient in lines color-coded blue (return).

Fluids and fl uid balance•

Review the dialysis principles and blood and fl uid fl ow used in each of the •

four types of CRRT.SCUF: ultrafi ltration1. CV VH: convection and ultrafi ltration2. CV VHD: diffusion and ultrafi ltration3. CV VDF: diffusion and convection4.

Discuss the components of net fl uid balance for any given period of time.•

Net fl uid balance = All fl uids in – All fl uids out— Generally the goal for fl uid balance will be zero or a negative number—

Each day the nursing staff should be made aware of the fl uid balance goals •

set for the patient. Periodically, throughout each shift, check to see if the fl uid 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-specifi c protocols for achieving net negative goals. This •

might include a standing order to call the physician if the net negative fl uid balance goals are not met or a protocol to increase fl uid removal rates with blood transfusions.Manufacturers vary with regard to what fl uids are automatically calculated •

into the machine fl uid balance and what fl uids 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-specifi c proto-•

cols for administration and monitoring.

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If citrate is used, review ionized calcium monitoring, signs and symptoms of •

hypocalcemia and hypercalcemia and calcium replacement protocol.If heparin is used, review protamine reversal protocols, prothrombin time •

(PT), and international normalization ratio (INR) normal values.

Other course materials may include the following:Excerpts from the manufacturer’s operator manual reprinted with •

permission.References, lectures, and course material may also be placed on computers or •

intranet sites for reference.Hospital policy or protocol documents. They are an essential reference. As •

with many areas of intensive care machine management, a multidisciplinary consensus policy is useful as a “baseline” reference point for learners. Some new learners prefer a bulleted list of the descriptive steps and pictures in lieu of the procedure, which can be long once rationale is added.Emergency procedures to be followed in the case of cardiac arrest. Consider •

duplicating this content in the practical part of the course, possibly with an explanation with the theory and a scenario with the practical experience.

Practical experience

After formal lectures, participants in a one-day class should be given some time to work with the machine that will be used in clinical treatment. The following components are suggestions for practical experience. For small classes use a sequential model. For larger classes breakout sessions with a fi nal demonstra-tion 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 fl ow. 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.

Practical experience

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Review the fl ow 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 cath-•

eter 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 be-fore 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 di-alysis 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:

P• atient—Look at the patient fi rst. Coughing, patient positioning, and move-ment can sometimes set off alarms.A• ccess refers to the temporary dialysis catheter. Check for a blood re-turn and fl ow 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 fl ush the catheter.—

C• ircuit is the disposable fi lter and tubing. Clots or gas bubbles can cause alarms. Teach participants to remove bubbles from lines following the man-ufacturer’s guidelines.E• quipment failure or power outages can cause a disruption in care. Emergency procedures for equipment failure should be developed and reviewed in class.

Alarm conditions•

Common alarm conditions can easily be simulated in the classroom setting.•

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Suggested alarms that should be simulated in class include access and •

return line kinks, air in line and alarms that require nursing intervention such as fl uids bag changing and fl uid 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 fl ushing 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 fl uid 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 teach-ing 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 fi lter clotting.

Learning environment

Figure 31.2 Troubleshooting tree.

Alarm sounds

If alarm resets: Continue CRRT.

If same alarm × 3 and patient is stable: Continue CRRT. Seek help.

If same alarm × 3 and patient is unstable:Discontinue CRRT. Seek help.

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Case exemplars that include common errors in clinical practice including fl uid •

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

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 debriefi ng session after trou-bleshooting 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 prob-lems 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 cham-pion 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).

Assessment of learning

CRRT champion

Figure 31.3 Suggested learning sequence useful in continuous renal replacement therapy (CRRT) training.

Discussion usingwhite-board andcircuit diagram orsketch.

Training sequence

Unsterile circuit prepared withRRT machine. Use saline bagas patient. Use resuscitationmannequin as patient.

Patient care withsupervision and teachersupport.

Abstract

Simulation

“Live” experience

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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 trou-bleshooting 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/•

Competency and ongoing education

Online educational resources

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.

RRT and multidisciplinary team

Nurses

Technicians

Physicians

Pharmacy

Suppliers

TeachersAUDIT

Patient care: RRT

RRT education

Standards

Policies and documents

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Summary

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 environ-ment. Education and staffi ng to support a CRRT program helps to assure positive patient outcomes.

Suggested readings

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 replace-ment therapy: a technical note. Int J Artif Organs. 2007;30(5):435-440.

Clevenger K. Setting up a continuous venovenous hemofi ltration 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 hemofi ltration 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

Defi nitions—key terms associated with training and education for CRRT.

Abstract CRRT model: An activity using concepts with readily available represen-tative 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.

Summary

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Competency: The ability to perform a task or skill within a set time with no mistakes. An example is the ability to recognize an error and fi x that error dem-onstrates 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 fl ow in learning from simple to complex.

Live experience: Undertaking tasks and applying knowledge previously learned in a simulation or education process in a real nonartifi cial 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 devel-oping or demonstrating competency.

Training: A process in order for learners to obtain psychomotor skills required to perform a task.

Troubleshooting: Recognizing an error and applying remedies to correct the error with effect.

263

AAbdominal compartment

syndrome, 6–7, 8Accelerated veno-venous

hemofi ltration (AVVH), 191, 193Access catheter, 129, 249, 250

femoral, 36type and site, 131vascular, 23, 103, 131

Acid-base and electrolyte disorders, in CRRT, 61–76

acid-base management, 72–73calcium, 68–72dysnastremias, 62–65electrolyte management, 61, 62magnesium, 65–68metabolic acidosis, 73–75metabolic alkalosis, 75–76phosphate, 68–72potassium, 65–68

Acid citrate dextrose (ACD), 165, 171

Activated charcoal, 176, 182, 194Acute kidney injury (AKI), 3–9,

205, 254classifi cation of, 3, 4clinical consequences, 9, 9etiology of, 5–6hypotension, 6incidence and progression, 4–5management of, 7–8postoperative, 6renal replacement therapy for,

79–91risk factors of, 5sepsis-induced, 5volume-responsive, 5

Adsorption, 49, 108coupled plasma fi ltration, 91,

185, 186, 187effi ciency of, 183–184immunoadsorption, 244membrane, 80plasma, 244relative selective, 182selective, 182–183

AKI. See Acute kidney injuryAlarms and troubleshooting, in

CRRT, 121–128alarm systems, 123, 124circuit pressure, 122–123clogging circuit, 123–125fl uid balance errors, 125–126training, 121troubleshooting checklist, 127

Albumin dialysis, 175Anticoagulation, 135–139, 141,

254–255administering, 137herapin, considerations, 138–139

orders, 193regional citrate, 141–145

Antimicrobialsconcentration-dependant,

152, 153dosing recommendations, 154time-dependant, 153

Apheresis devices, 169–171anticoagulation, 170centrifugal cell separators,

169–170extracorporeal circuit, priming,

170membrane fi ltration cell

separators, 170–171Aquarius/Accura CRRT, 164, 231,

233, 240, 241Argatroban, 193

BBaxter CRRT, 164, 231, 233,

240, 241Billing codes, for CRRT, 223–225,

224continuous dialysis/CRRT,

224–225critical care services, 224dialysis catheters and modifi ers,

for multiple procedures, 225initial hospital care–new or

established patients, 224initial inpatient consultations–

new or established patients, 223–224

initial patient evaluation, 225–226subsequent hospital days, 226subsequent hospital fl ow-up, 225

Bioartifi cial liver support, 176Biocarbonate, 116–117Blood fl ow maintenance, in

extracorporeal circuit, 131–132“air-bubble trap” chamber, 132access catheter size and type,

131, 131circuit preparation, 131membrane size and type, 131rate, setting, 131substitution fl uids administration

site, 132training and education for

staff, 132Bubble trap. See Air trap

CCalcium, 68–72, 116Calcium chloride, 193Catheter-related bloodstream

infections (CRBSI), 96

Cathetersaccess, 23, 36, 129, 131, 249, 250dialysisbilling codes for, 225

silicone, 93site, 122size, 122troubleshooting, 122types of, 93–94, 94, 122

CAVH. See Continuous arterio-venous hemofi ltration

CAVHD. See Continuous arterio-venous hemodialysis

CAVHDF. See Continuous arterio-venous hemodiafi ltration

Children, RRT in, 159–165continuous veno-venous

hemofi ltration, 164–165hemodialysis, 162–163indications, 159peritoneal dialysis, 159–162

Chloride, 115, 116Citrate, 117, 136

toxicity, during TPE, 171–173Continuous arterio-venous

hemodiafi ltration (CAVHDF), 101, 229

Continuous arterio-venous hemodialysis (CAVHD), 100, 229. See also Hemodialysis

Continuous arterio-venous hemofi ltration (CAVH), 100, 229. See also Hemofi ltration

Continuous veno-venous hemodiafi ltration (CVVHDF), 20, 21, 101, 144, 230, 254

and CVVH, comparison, 31, 31prescription for, 104and solute transfer, 30–31

Continuous veno-venous hemodialysis (CVVHD), 20, 21, 100, 229, 254

Continuous veno-venous hemofi ltration (CVVH), 12, 13, 14, 19–20, 20, 100, 145, 230, 254. See also Hemofi ltration

in children, 164–165access, 164anticoagulation, 164–165blood fl ow, 164blood pressure, 164dialysate-replacement fl uid fl ow

rate, 164extracorporeal volume, 164

and CVVHDF, comparison, 31, 31

and solute transfer, 29–30Contrast agents, 43Convection, 19, 24, 28–29, 84,

86, 99and diffusion, interaction, 88

Index

Note: Page numbers in italics refer to fi gures and tables.

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Coumadin. 136Coupled plasma fi ltration

adsorption (CPFA), 91, 185, 186, 187

CRRT program, development of, 213–221, 214

factors affecting, 216–218fi nancial considerations,

219–221fl uid balance and dialysis errors,

sources of, 218forces in, 215–216nephrologist, role of, 219requirements for, 214–215untrafi ltration with hybrid/CRRTrecommendations for

preventing complications during, 218–219

Cytokines, 182

DDialysate, 102Dialysis, 176

albumin, 175catheterbilling codes for, 225

continuous, 224–225errors, 218membranes, 83peritoneal, 159–162slow low effi ciency, 23, 23, 240solution composition, 191solution fl ow rate, 192

Dialyzer, 24Diapact CRRT, 239–240, 239, 240Diffusion, 24, 27–28, 84, 85, 99,

101and convection, interaction, 88

Diuretic therapy, 39, 40Donabedian model, of quality

healthcare, 205–210, 205Dose adequacy and assessment, of

RRT, 53–59delivery, continuous and

intermittent, 56–58practical aspects, 55–56prescription, 56theoretical aspects, 53–55

Drug adsorption, 150Drug dosing, in CRRT, 147–154

drug properties, 151–152elimination, 152molecular weight, 151protein binding, 151, 151volume of distribution,

151–152fi lter properties, 148–149membrane composition, 149membrane permeability, 149

fl ow rates, 149patient properties, 149–150, 150pharmacodynamic principles,

152–153concentration-dependant

antimicrobials, 152, 153time-dependant antimicrobials,

153recommendations, 153–154antimicrobials, 154

techniques, 147–148, 148Drug/toxin removal, 42–43

EEducation, 261. See also Educational

resourcesintroductory, 253–256ongoing, 260

Educational resources, 253–261. See also Education

competency, 260CRRT champion, 259, 260learning assessment, 259learning environment, 258–259,

259ongoing education, 260online, 260practical experience, 256–258, 258theory and practical training,

253–256Effl uent, 33–34, 102Endotoxin, 181, 194Extended indications, for CRRT,

47–51considerations, 50methods, 49

Extracorporeal circuit (EC), 23, 141, 176

blood fl ow maintenance in, 131–132

“air-bubble trap” chamber, 132access catheter, 131, 131circuit preparation, 131membrane size and type, 131rate, setting, 131staff training, 132substitution fl uids administration

site, 132

FFilter. See DialyzerFilter life, 129, 135, 141, 247Filtration fraction, 101, 130Fluid balance, 34, 34–35, 254Fluid management, in CRRT, 33–36

benefi ts, 36considerations, 35expected outcomes, 35fl uid balance, 34problems, 35–36

Fluids, 115–119, 254buffer composition, 116–117compounding, 119electrolyte composition, 115–116example, 118–119prescription during permissive

hypercapnia, 118Fresenius CRRT, 191–193, 240,

242–243, 242

GGambro CRRT, 192, 235–239,

237, 238Glomerular disease, 6, 8Glucose, 115, 116

HHemodiafi ltration, 85, 101, 148

continuous arterio-venous, 101, 229

continuous veno-venous, 20, 21, 26, 30–31, 31, 101, 104, 230

double chamber, 185, 186Hemodialysis, 99, 148

in children, 162–163access, 162, 163anticoagulation, 163blood fl ow, 163dialysis blood lines and dialyzers,

162, 163time, 163ultrafi ltration, 163

continuous arterio-venous, 100, 229

continuous veno-venous, 20, 21, 100, 229

electrolyte management in, 61and surface area, 113

Hemofi ltration, 84–85, 99, 148accelerated veno-venous,

191, 193adjunctive, 193in children, 164–165access, 164anticoagulation, 164–165blood pressure, 164bloodfl ow, 164dialysate-replacement fl uid fl ow

rate, 164extracorporeal 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, 61high-cutoff, 48, 48, 49high-volume, 48, 48, 49, 90,

243–244of large molecules, 90–91postdilution, 86–87predilution, 87surface area effects of membrane

in, 111–112Hemolytic uremic syndrome, 6Heparin, 12, 96, 125, 131, 135, 136,

161, 230, 237anticoagulation, 138, 139,

164–165, 171coating, 137low molecular weight, 136unfractionated, 190, 193

High-cutoff hemofi ltration, 48, 48, 49

High-volume hemofi ltration (HVHF), 48, 48, 49, 90, 243–244. See also Hemofi ltration

Hybrid therapies, 189–195brief orders, 189–194anticoagulation orders, 193blood fl ow, 191dialysis solution composition,

191dialysis solution fl ow rate, 192fl uid removal, 192–193session length, 190–191substitution fl uid fl ow rate,

193timing of treatment, 194

features of, 189

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nutrition, 194water considerations, 194

IIntensive care unit (ICU)

approach to critical careclinical, 203–204organizational, 201–203, 203outcome measures, 204

closed unit, 200environment, challenges of, 201monitoring, 199open unit, 200prevention, 199specialized, 201, 202staffi ng, 200–201support, 199

Intermittent hemodialysis (IHD), 22, 22, 89, 117

and CRRT, comparison between, 57

Interstitial nephritis, 8

LLactate, 116–117Lactic acidosis

causes, 74

MMARS. See Molecular adsorbent

recirculating systemMATISSE, 183Membrane, in CRRT, 107–114

composition, 149hollow fi ber, 107–108permeability, 149secondary membrane formation,

on solute permeability, 110–111, 111

surface area effects, 111–113in hemofi ltration, 111–112in hemodialysis, 113

synthetic, 107–108ultrafi ltration rate and

transmembrane pressure, relationship, 108–110, 109

Metabolic acidosis, 41–42, 73–75causes, 73–74clinical features, 74CRRT management, 74–75management, 74

Metabolic alkalosis, 75–76causes, 75CRRT management, 74–75

management, 76Molecular adsorbent recirculating

system (MARS), 175–179method, 176–179, 177guidelines, 179with Prisma continuous renal

replacement therapy (CRRT) machine, 178

Multiorgan support therapy (MOST), 14–16

NNxStage CRRT, 164

PPeritoneal dialysis (PD)

in children, 159–162access, 160apparatuses for, 160complications, 161–162contradictions to, 160dialysate, 161dwell time, 161dwell volume, 161prescription, 160–161

Phosphate, 68–72, 115, 116Plasma exchange, 244Polymyxin B-immobilized fi bers

(PMX), 182–183, 187Postdilution, 22, 86–87, 102Potassium, 65–68, 115, 116Predilution, 22, 87, 102, 129Prisma CRRT, 235–236, 236Prismafl ux CRRT, 236–239, 237,

238Prostacyclin, 136Protamine, 136Protein binding, 150, 151

QQuality assurance, for CRRT,

247–251

RRegional anticoagulation, 137, 142Regional citrate anticoagulation

(RCA), 141–145method, 142–143considerations, 143–144

Replacement fl uid, 102Rhabdomyolysis, 6RIFLE Criteria, 3–5, 4

SSCUF. See Slow continuous

ultrafi ltration (SCUF)Sepsis

humoral theory, 47sorbents in, 186–187target substances removal by,

181–182Sepsis-induced AKI, 5Sieving coeffi cient, 27Slow continuous ultrafi ltration

(SCUF), 148, 254Slow low effi ciency dialysis (SLED),

23, 23, 240Sodium, 115–116System One, 164

TTheraperutic plasma exchange

(TPE), 167–173adverse effects, 171–173apheresis devices, 169–171anticoagulation, 170centrifugal cell separators,

169–170extracorporeal circuit, priming,

170membrane fi ltration cell

separators, 170–171principles, 167–169management guidelines for,

168–169rationale for, 167, 168

Training, 261Transmembrane pressure (TMP),

109–110, 130Troubleshooting, 121–128, 261

catheters, 122checklist, 127

VVascath (vascular access catheter),

23, 103, 129, 131. See also Access catheter; Catheters

Vascular access, for CRRT, 93–97, 122

catheter types, 93–94, 94complicationsprimary, 95–96secondary, 96–97

site and implementation, 94–95

WWarfarin, 136

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