i CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT) IN CRITICALLY ILL PATIENTS WITH ACUTE RENAL FAILURE (ARF) TAN HAN KHIM MBBS (Singapore), MRCP (UK), FAMS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF MEDICINE (MD) DEPARTMENT OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2003 ii Acknowledgements This thesis would not have been completed without the advice and assistance from numerous individuals I am deeply grateful to Dr Rinaldo Bellomo, Professor of Medicine, University of Melbourne and Director of Intensive Care Research, Department of Intensive Care, Austin and Repatriation Medical Centre (A&RMC), Heidelberg, Melbourne, Victoria, Australia, and Professor Woo Keng Thye, Emeritus Consultant, Department of Renal Medicine, Singapore General Hospital (SGH) They have inspired me to undertake medical research through their own academic and scientific accomplishments I would like to thank Professor Evan Lee Jon Choon, Head of Division of Nephrology, Department of Medicine, National University Hospital (NUH), who gave me much invaluable advice on the preparation of this thesis I would also like to thank my critical care colleagues at the Department of Intensive Care, Austin and Repatriation Medical Centre (A&RMC) where I spent a one year Fellowship in Critical Care Nephrology, sponsored by the Singapore Ministry of Health (MOH) under the Health Manpower Development Plan (HMDP) from October 1998 to October 1999 They taught me about the principles and practice of critical care medicine and were as follows: Drs Geoff Gutteridge, Graeme Hart, Jonathan Buckmaster, Laurie Doolan, William Silvester, Louise Cole and, last but not least Ian Baldwin This thesis would also not have been possible without the generous help of the nursing, laboratory, paramedical and auxiliary staff of Monash Medical Centre (MMC), Clayton, and those of the Austin and Repatriation Medical Centre (A&RMC), Heidelberg, both centres in Victoria, Australia Funding for the studies was generously supported by the following sources, with corresponding studies enumerated next to the funding sources: (1) Austin and Repatriation Medical Centre Intensive Care Research Fund: This fund supported the study in Chapter 3.1 (2) Austin Hospital Anaesthesia and Intensive Care Trust Fund: This fund supported the study in Chapters 3.3 (3) Austin and Repatriation Medical Centre Anaesthesia and Intensive Care Trust Fund: This fund supported the studes in Chapter 3.5 and 4.2 Locally, I wish to thank all my nephrology teachers and senior nephrology colleagues: Drs Lina Choong Hui Lin, Vathsala Anantharaman, Wong Kok Seng and Grace Lee It is from them that I learnt about clinical nephrology Finally, I am especially grateful to my parents for my upbringing, my wife for her kind understanding at home and my children for their patience and unconditional affection for me A special thanks also goes to Ms Irene Ow who provided excellent secretarial assistance during the preparation of this thesis iv Table of Contents Page Preface Title Page Acknowledgements iv Summary vii List of Abbreviations x List of Figures xiv List of Tables xix Publications arising from material in the thesis 1.1 ii Table of contents Chapter i xxii Introduction Acute renal failure (ARF) in critically ill patients 1.1.1 Acute renal failure (ARF)-related clinical syndromes 1.1.2 Pathophysiology of acute renal failure (ARF) 1.1.3 The immune system in multi-organ failure (MOF)/acute renal failure (ARF) 1.1.4 1.1.5 1.2 Vasoactive molecules Oxidant injury Medical management of acute renal failure 1.2.1 Volume replacement 1.2.2 Vasopressor agents 1.2.3 Diuretics 1.2.4 Atrial natriuretic peptide (ANP) 1.2.5 Low dose theophylline 1.2.6 1.2.7 Growth factors 1.2.8 1.3 N-acetylcysteine (NAC) Fenoldopam Acute renal replacement therapy 1.3.1 Acute peritoneal dialysis 1.3.2 Acute intermittent haemodialysis (IHD) versus Continuous renal replacement therapy (CRRT) (1) Patient survival (2) Physiological parameters (3) Biochemical parameters (4) Haemodynamic status (5) Dialytic adequacy (6) Membrane biocompatibility (7) ARRT modality choice 1.3.3 Isolated ultrafiltration (UF), slow continuous ultrafiltration (SCUF) and slow, low-efficiency dialysis (SLED) 1.3.4 Chapter 2.1 Molecular Adsorbent Recirculating System (MARS) Continuous Renal Replacement Therapy (CRRT): CRRT in severe renal failure 2.1.1 Background 2.1.2 Technique 2.1.3 Machines and Solutions 2.1.4 CRRT circuit surveillance 2.1.5 Circuit patency I: Anticoagulatory factors 2.1.6 Circuit patency II: Physico-mechanical factors 2.1.7 Other metabolic effects of CRRT 2.1.8 2.2 Clinical impact CRRT-derived Blood Purification Techniques 2.2.1 2.2.2 Chapter 3.1 Membrane plasma filtration (PF) 2.2.3 2.3 High-Volume Haemofiltration (HVHF) Coupled plasma filtration-adsorption (CPFA) Aims of CRRT Thesis Biochemical Effects of CRRT Ionised serum calcium and phosphate concentrations during acute renal failure (ARF): intermittent haemodialysis (IHD) versus continuous haemodiafiltration (HDF) 3.2 The acid-base effects of continuous haemofiltration with lactate or bicarbonate buffered replacement fluids 3.3 Electrolyte mass balance during CVVH: lactate versus bicarbonate buffered replacement fluids 3.4 High protein intake during continuous haemodiafiltration: Impact on amino acids and nitrogen balance Chapter 4.1 CRRT Technique I: Physico-mechanical Factors Possible strategies to prolong filter life during haemofiltration: Three controlled studies 4.2 Ex-vivo evaluation of vascular catheters for continuous haemofiltration 4.3 Platelet loss across the haemofilter during continuous haemofiltration Chapter 5.1 CRRT Technique II: Anticoagulation Continuous veno-venous haemofiltration without anticoagulation in high-risk patients 5.2 A prospective study of thromboelastography (TEG) and filter life during continuous veno-venous haemofiltration (CVVH) Chapter 6.1 Clinical Impact of CRRT Early and intensive continuous haemofiltration for severe renal failure after cardiac surgery Chapter References vii Summary Acute renal failure (ARF) is a common complication in critically ill patients Severe ARF is associated with high mortality Different pathogenetic factors contribute to its development Precipitating factors include severe sepsis, hypotension, drug nephrotoxicity and hypovolaemia To prevent ARF and to promote recovery, standard ICU care has a central role To this end, ensuring adequate circulatory volume and systemic and organ perfusion pressures are vital Given that there are hitherto no renal-specific, diseasemodifying pharmacological agent capable of “curing” ARF, much of the progress in the clinical management of ARF has been in the area of acute renal replacement therapy (ARRT) This includes intermittent haemodialysis (IHD), slow, low efficiency dialysis (SLED), continuous renal replacement therapy (CRRT) and Molecular Adsorbent Recirculating System (MARS) MARS has been used for both liver and renal dialysis However, CRRT remains an important treatment modality in critically ill patients, especially haemodynamically unstable ones Central to its optimal use is an understanding of its clinical effects in critically ill ICU patients Such information complements knowledge of the course and characteristics of major critical illnesses and would make the interpretation of clinical and laboratory data more meaningful Moreover, technical factors affecting the optimal operation of CRRT systems are also pertinent Frequent system “downtimes” potentially reduce the overall dialytic dose delivered This thesis is therefore focussed on three main aspects of CRRT: (1) Biochemical effects in terms of electrolyte and acid-base regulation, (2) Technique in terms of understanding both the anticoagulatory and nonanticoagulatory or physico-mechanical factors affecting CRRT operational integrity, and (3) the clinical impact of CRRT utilisation in terms of the effects of timing of initiation and dialytic intensity on patient outcome in a group of critically ill post-cardiosurgical patients To this end, we performed a study to understand the relative effects of IHD and continuous venovenous haemodiafiltration (CVVHDF) on serum ionised calcium and phosphate concentrations in critically ill patients (Chapter 3.1) In addition, a prospective, randomised, double cross-over comparative study of the effects of continuous venovenous haemofiltration (CVVH) on acid-base status using proprietary lactate- and bicarbonatebuffered haemofiltration (HF) replacement fluids was also conducted (Chapter 3.2) Another study looked at the kinetics of electrolyte elimination from the blood compartment during CVVH and whether blood-to-effluent movement of electrolytes is influenced by the nature of the buffer (lactate- versus bicarbonate) used in the HF replacement fluid (Chapter 3.3) Given that many critically ill patients are catabolic, intensive nutritional support may be indicated However, such regimens may exacerbate the uraemic milieu in ARF A study was performed to determine if CRRT could ameliorate the uraemic effects of a high protein nutritional regimen and also to delineate the specific effects of CRRT on individual amino acid losses in the ultrafiltrate and their corresponding serum concentrations (Chapter 3.4) CRRT technique is concerned with the factors that contribute to a patent extracorporeal blood circuit, the natural tendency of which is to clot spontaneously in the absence of adequate antithrombotic factors/agents Such clotting, if frequent, compromises dialytic adequacy of the treatment These technical factors can be divided into two main categories: (1) Non-anticoagulatory or physico-mechanical factors, and (2) Anticoagulatory strategies Individual studies addressing specific aspects of these two broad categories are detailed in Chapter – CRRT Technique I and Chapter – CRRT Technqiue II, respectively Three different physical strategies were studied: haemofilter geometry, site of heparin anticoagulation in the extracorporeal circuit (EC), and surface area of haemofilter (Chapter 4.1) Larger surface area and flat-plate haemofilters were studied to see if they were associated with longer circuit lifespans Similarly, exclusive administration of heparin anticoagulant pre-filter was compared with simultaneous pre-filter and direct air-bubble chamber heparin administration to determine if there was any significant prolongation of CVVH circuit lifespan with the latter intervention Another critical component of the EC is the central venous, dual-lumen dialysis catheter An ex-vivo experiment was conducted using different proprietary dialysis catheters under standard conditions to determine blood flow resistivities (Chapter 4.2) This may provide objective data about catheter performance and guide their selection for use Given that blood is in contact with the artificial plastic surface of the EC during its passage through the circuit, blood-circuit interactions can occur These may result in quantitative and qualitative changes of leucocytes, erythrocytes and platelets, which can also be deranged by the critical illness complex per se A study of the quantitative effect of the AN69 haemofilter on platelets was therefore performed (Chapter 4.3) Changes in platelet counts in such patients can then be interpreted more accurately in terms of whether it is due to underlying disease and/or filter membrane per se Anticoagulation is the mainstay of ensuring EC patency in clinical practice Accordingly, different anticoagulants, modes of administration, and various anticoagulation protocols have evolved for clinical use in CRRT All are associated with some degree of bleeding risk which would be greatly increased in patients who are already at high bleeding risk On the other hand, omitting anticoagulant was considered impractical since this was thought to result in frequent circuit clotting Our study of CVVH without standard heparin anticoagulation observed that such an approach is compatible with circuit lifespans comparable to those of anticoagulated circuits (Chapter 5.1) Another aspect of anticoagulation relates to monitoring of its intensity It is recognised that standard laboratory indices of anticoagulation not accurately correlate with circuit lifespan Circuits can still clot despite an adequate level of anticoagulation Measurements of the actual process of clot formation using thromboelastography (TEG) was explored to see if TEG-derived variables of physical clot formation provided more accurate correlation with circuit patency/clotting (Chapter 5.2) 10 250 Nimmo GR, Mackenzie SJ, Walker S, Nicol M, Grant IS Acid-base responses to high-volume haemofiltration in the critically ill Nephrol Dial Transplant 1993;8:854857 251 Thomas AN, Guy JM, Kishen R, Geraghty IF, Bowles BJM, Vadgama P Comparison of lactate and bicarbonate buffered haemofiltration fluids : use in critically ill patients Nephrol Dial Transplant 1997;12:1212-1217 252 Levraut J, 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Publications arising from material in the thesis 1.1 ii Table of contents Chapter i xxii Introduction Acute renal failure (ARF) in critically ill patients 1.1.1 Acute renal failure (ARF) -related clinical... also noted in patients with ARF There was a higher incidence of acute gastrointestinal tract (GIT) bleeding in patients with ARF Such bleeding was in turn associated with greatly increased mortality