© 2008 Universitair Ziekenhuis Gent RENAL REPLACEMENT THERAPY IN PATIENTS WITH SEPSIS AND ACUTE KIDNEY INJURY Prof. Dr. Raymond Vanholder University Hospital Ghent Belgium

22 © 2008 Universitair Ziekenhuis Gent TIMING START RRT TYPE OF STUDYNPARAMETEREFFECT ES Gettings et al, 1999Retrospective243BUN 76+ Guerin et al, 2000Prospective Observational post hoc 510Time after admission0 Bouman et al, 2002RCT*, 4 arms106Fixed time point (12 hrs) vs. classical parameters 0 Elahi et al, 2004Retrospective64UO vs. other**+ Demirkiliç et al, 2004Retrospective61UO vs. other**+ Liu et al, 2006Observational243BUN 760 unadj + adj Piccinni et al, 2006Retrospective80Septic shock+ ES: Early Start; BUN: Blood Urea Nitrogen; UO: urine output; + favors ES; 0 neutral *: early vs. late low vol ( 72L/d) no late comparator; **: UO <100 mL/d to start vs. other parameters (K, crea) irrespective of UO Gettings et al, Intens Care Med, 1999; Guerin et al, Am J Resp CCM, 2000; Bouman et al, CCM, 2002; Elahi et al, Eur J Cardio- thor Surg, 2004; Demirkiliç et al, J Card Surg, 2004; Liu et al, Clin JASN 2006 ; Piccinni et al, Intens Care Med 2006

33 © 2008 Universitair Ziekenhuis Gent C. Bouman, Crit Care Med, 30: ; 2002 Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial Bouman, Catherine S. C. MD; Oudemans-van Straaten, Heleen M. MD, PhD; Tijssen, Jan G. P. MD, PhD; Zandstra, Durk F. MD, PhD; Kesecioglu, Jozef MD, PhD From the Departments of Intensive Care (CSCB) and Clinical Epidemiology (JGPT), Academic Medical Center, Amsterdam, The Netherlands; the Department of Anesthesiology, Cardiothoracic and Neurosurgical Intensive Care Unit, University Medical Center, Utrecht, The Netherlands (JK); and the Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (HMOvS, DFZ). Address requests for reprints to: Catherine S. C. Bouman, MD, Academic Medical Center, Department of Intensive Care, Meibergdreef 9, Amsterdam NL-1105 AZ, The Netherlands.

44 © 2008 Universitair Ziekenhuis Gent V. Seabra et al, AJKD, 52: ; 2008

55 © 2008 Universitair Ziekenhuis Gent IMPACT ON MORTALITY V. Seabra et al, AJKD, 52: ; 2008

66 © 2008 Universitair Ziekenhuis Gent V. Seabra et al, AJKD, 52: ; 2008 IMPACT ON RECOVERY RENAL FUNCTION

77 © 2008 Universitair Ziekenhuis Gent V. Seabra et al, AJKD, 52: ; 2008 ABSTRACT Background Some studies have suggested that early institution of renal replacement therapy (RRT) might be associated with improved outcomes in patients with acute renal failure (ARF). Study Design A systematic review and meta-analysis of randomized controlled trials and cohort comparative studies to assess the effect of early RRT on mortality in patients with ARF. Setting & Population Hospitalized adult patients with ARF. Selection Criteria for Studies We searched several databases for studies that compared the effect of early and late RRT initiation on mortality in patients with ARF. We included studies of various designs. Intervention Early RRT as defined in the individual studies. Outcomes The primary outcome measure was the effect of early RRT on mortality stratified by study design. The pooled risk ratio (RR) for mortality was compiled using a random-effects model. Heterogeneity was evaluated by means of subgroup analysis and meta-regression. Results We identified 23 studies (5 randomized or quasi-randomized controlled trials, 1 prospective and 16 retrospective comparative cohort studies, and 1 single-arm study with a historic control group). By using meta-analysis of randomized trials, early RRT was associated with a nonsignificant 36% mortality risk reduction (RR, 0.64; 95% confidence interval, 0.40 to 1.05; P = 0.08). Conversely, in cohort studies, early RRT was associated with a statistically significant 28% mortality risk reduction (RR, 0.72; 95% confidence interval, 0.64 to 0.82; P < 0.001). The overall test for heterogeneity among cohort studies was significant (P = 0.005). Meta-regression yielded no significant associations; however, early dialysis therapy was associated more strongly with lower mortality in smaller studies (n < 100) by means of subgroup analysis. Limitations Paucity of randomized controlled trials, use of variable definitions of early RRT, and publication bias preclude definitive conclusions. Conclusion This hypothesis-generating meta-analysis suggests that early initiation of RRT in patients with ARF might be associated with improved survival, calling for an adequately powered randomized controlled trial to address this question.

88 © 2008 Universitair Ziekenhuis Gent Vinsonneau et al, Lancet, 368, , 2006

99 © 2008 Universitair Ziekenhuis Gent MOST RECENT STUDIES IHDCVVHDP Survival Day %38.9%0.65 Day 60 (1ary EP)32.5%32.6%0.98 Day %28.5%0.95 RRT duration (d) Length ICU stay (d) Length hosp stay (d) Vinsonneau et al, Lancet, 368, , 2006

10 © 2008 Universitair Ziekenhuis Gent R. L. Lins et al, NDT, advance access published October 14, 2008

11 © 2008 Universitair Ziekenhuis Gent R. L. Lins et al, NDT, advance access published October 14, 2008 THE SHARF STUDY

12 © 2008 Universitair Ziekenhuis Gent Bagshaw et al, Crit Care Med, 36: ; 2008 Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: A meta-analysis Bagshaw, Sean M. MD, MSc; Berthiaume, Luc R. MD; Delaney, Anthony MBBS, MSc; Bellomo, Rinaldo MD From the Division of Critical Care Medicine, University of Alberta Hospital, University of Alberta, Edmonton, Alberta, Canada (SMB); Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia (SMB, RB); Departments of Critical Care Medicine and Community Health Sciences, Calgary Health Region and University of Calgary, Calgary, Alberta, Canada (LRB); and Intensive Care Unit, Royal North Shore Hospital, and Northern Clinical School, University of Sydney, Sydney, NSW, Australia (AD).

13 © 2008 Universitair Ziekenhuis Gent W. Van Biesen et al, Crit Care Med, 36: ; 2008 A tantalizing question: Ferrari or Rolls Royce? A meta-analysis on the ideal renal replacement modality for acute kidney injury at the intensive care unit Van Biesen, Wim MD, PhD; Lameire, Norbert MD, PhD; Vanholder, Raymond MD, PhD Renal Division; Department of Internal Medicine; University Hospital Ghent; Ghent, Belgium

14 © 2008 Universitair Ziekenhuis Gent FACTORS AFFECTING CHOICE Labor intensity Cost Availability of machines Availability of SLEDD as alternative

15 © 2008 Universitair Ziekenhuis Gent Extended Daily Dialysis: what? Offering the choice between the advantages of a IHDF-monitor (high efficiency, low cost, high precision of UF control) in combination with the advantages of CRRT (extended treatment, smooth metabolic control) in a modular fashion, using one single type of dialysis machine Dialysis monitor with: Water treatment module Reverse osmosis unit Hemofiltration capacity Dialysate flow adjustment

16 © 2008 Universitair Ziekenhuis Gent TOTAL NUMBER, DURATION, AND MEDIAN NUMBER OF TREATMENTS PERFORMED Kumar et al. Am J Kidney Dis 36: ,2000

17 © 2008 Universitair Ziekenhuis Gent COMPARISON OF MAP DURING EDD VS. CVVH. Kumar et al, AJKD, 36, , 2000 P=NS

18 © 2008 Universitair Ziekenhuis Gent PERCENTAGE OF TREATMENT DAYS REQUIRING INOTROPIC SUPPORT % of treatment days Kumar et al, AJKD, 36, , 2000

19 © 2008 Universitair Ziekenhuis Gent SINGLE PASS BATCH HEMODIALYSIS SYSTEM (GENIUS): PREPARATION OF DIALYSIS WATER AND DIALYSATE

20 © 2008 Universitair Ziekenhuis Gent CUMULATIVE ULTRAFILTRATION VOLUME AND MEAN ARTERIAL PRESSURE DURING 18H OF EXTENDED HIGH-FLUX HD USING THE GENIUS SYSTEM Lonnemann et al, NDT, 15, , 2000

21 © 2008 Universitair Ziekenhuis Gent R. Busund et al, Int Care Med, 28: ; 2002 PF: signif younger & less mechanical ventilation

22 © 2008 Universitair Ziekenhuis Gent J. Tumlin et al, JASN, 19: ; 2008

23 © 2008 Universitair Ziekenhuis Gent Schiffl et al, NEJM, 346: ; 2002

24 © 2008 Universitair Ziekenhuis Gent P. Honore et al, Crit Care Med, 28: ; 2000 Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock Honore, Patrick, Jamez, Jean, Wauthier, Michel, Lee, Patrice, Dugernier, Thierry, Pirenne, Bruno, Hanique, Genevieve, Matson, James From the Departments of Intensive Care Medicine (Drs. Honore, Dugernier, and Pirenne) and Nephrology (Drs. Jamez and Wauthier), St-Pierre Hospital, Ottignies, Belgium; the Department of Clinical Research and Pediatric Critical Care (Drs. Lee and Matson), Dallas Hospital, Dallas, TX; and the Department of Internal Medicine and Biostatistics (Dr. Hanique), Nivelles Hospital, Nivelles, Belgium

25 © 2008 Universitair Ziekenhuis Gent C. Ronco et al, The Lancet, 256: 26-30; 2000

26 © 2008 Universitair Ziekenhuis Gent P. Saudan et al, KI, 70: ; 70

27 © 2008 Universitair Ziekenhuis Gent C. Bouman, Crit Care Med, 30: ; 2002 Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial Bouman, Catherine S. C. MD; Oudemans-van Straaten, Heleen M. MD, PhD; Tijssen, Jan G. P. MD, PhD; Zandstra, Durk F. MD, PhD; Kesecioglu, Jozef MD, PhD From the Departments of Intensive Care (CSCB) and Clinical Epidemiology (JGPT), Academic Medical Center, Amsterdam, The Netherlands; the Department of Anesthesiology, Cardiothoracic and Neurosurgical Intensive Care Unit, University Medical Center, Utrecht, The Netherlands (JK); and the Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (HMOvS, DFZ). Address requests for reprints to: Catherine S. C. Bouman, MD, Academic Medical Center, Department of Intensive Care, Meibergdreef 9, Amsterdam NL-1105 AZ, The Netherlands.

28 © 2008 Universitair Ziekenhuis Gent Palevsky et al, NEJM, 359, 1: 7-20; 2008 Intensive vs less intensive therapy Intermittent hemodialysis (hemodynamically stable) Intensive: daily except Sunday Less intensive: alternate days except Sunday Sustained low-efficiency dialysis (hemodynamically unstable) Intensive: daily except Sunday Less intensive: alternate days except Sunday Continuous renal replacement therapy (hemodynamically unstable) Intensive: 35 mL/h/kgBW substitution Less intensive: 20 mL/h/kgBW substitution

29 © 2008 Universitair Ziekenhuis Gent Palevsky et al, NEJM, 359, 1: 7-20; 2008 KAPLAN–MEIER PLOT OF CUMULATIVE PROBABILITIES OF DEATH CUMULATIVE PROBABILITY OF DEATH FROM ANY CAUSE IN THE ENTIRE STUDY COHORT

30 © 2008 Universitair Ziekenhuis Gent COMMENTS Standard IHD more efficient than in Schiffl et al Hemodiafiltration Shifts among therapies possible Kt/V not a validated parameter of adequacy in AKI More adequate treatment may also have negative impact REAL-LIFE STUDIES

31 © 2008 Universitair Ziekenhuis Gent SINGLE PASS BATCH HEMODIALYSIS SYSTEM (GENIUS): PREPARATION OF DIALYSIS WATER AND DIALYSATE

32 © 2008 Universitair Ziekenhuis Gent GENIUS R S. Eloot et al, NDT, 22: ; 2007

33 © 2008 Universitair Ziekenhuis Gent Eloot et al, KI, 73: RESULTS: TOTAL SOLUTE REMOVAL TSR

34 © 2008 Universitair Ziekenhuis Gent PERCENTAGE CHANGE VS. 4 HRS Eloot et al, KI, 73:

35 © 2008 Universitair Ziekenhuis Gent COMMENTS Standard IHD more efficient than in Schiffl et al Hemodiafiltration Shifts among therapies possible Kt/V not a validated parameter of adequacy in AKI More adequate treatment may also have negative impact REAL-LIFE STUDIES

36 © 2008 Universitair Ziekenhuis Gent ANTIBIOTIC CONCENTRATION AND SLEDD Kielstein et al, NDT, in press MIC 90

37 © 2008 Universitair Ziekenhuis Gent PRACTICE PATTERNS IN THE MANAGEMENT OF ACUTE RENAL FAILURE IN THE CRITICALLY ILL PATIENT: AN INTERNATIONAL SURVEY RICCI et al. Nephrol Dial Transpl, 21: 690–696, 2006

38 © 2008 Universitair Ziekenhuis Gent COMMENTS Standard IHD more efficient than in Schiffl et al Hemodiafiltration Shifts among therapies possible Kt/V not a validated parameter of adequacy in AKI More adequate treatment may also have negative impact REAL-LIFE STUDIES

39 © 2008 Universitair Ziekenhuis Gent CONCLUSIONS At this moment, there are no definite data favoring an earlier start of RRT than the conventional criteria There is no difference in outcome between intermittent an continuous dialysis strategies Although under well controlled circumstances, intensified strategies seem to improve outcome, under real life circumstances this difference seems to disappear