Comparing RRT Modalities: Does It Matter What You Use If The Job Is Done? Sean M Bagshaw, MD, MSc Division of Critical Care Medicine University of Alberta
Disclosure Consulting: Alere, Baxter, Gambro, Spectral Diagnostics, Otsuka Speaking: Alere, Gambro, Otsuka
Does It Matter if the Job is Done?
Continuous OR Intermittent?
Continuous OR Intermittent? WRONG QUESTION!
CRRT SLED IHD
Azotemic/Uremic Control 120 100 CVVH IHD SLED BUN (mg/dl) 80 60 40 20 0 0 1 2 3 4 5 6 7 Time (day) Liao et al Artif Organs 2003
Urea (mmol/l) Azotemic/Uremic Control 35 30 25 20 15 10 1 2 3 4 5 6 7 8 9 10 Day CRRT IHD Mehta et al KI 2001
Volume Homestasis/Removal Variable IHD SLED CRRT Duration 3-5 6-8 20-24 Obligatory Intake 3500 ml 3500 ml 3500 ml Urine output 100 100 100 Balance +3400 ml +3400 ml +3400 ml Fluid removal (per hr) 1000 ml 2000 ml 3000 ml 4000 ml 200-350 400-600 600-1000 800-1300 125-150 250-350 375-500 500-650 40-50 83-100 125-150 150-200
Mean %FO Volume Homeostasis Days Bouchard et al KI 2009
Systemic Hemodynamics Therapeutic goals during RRT: Avoid rapid/large fluid compartment shifts Avoid intravascular depletion Avoid hypotension/decreases in cardiac output Avoid precipitation of arrhythmic episodes Avoid new/further ischemic injury to kidney Augustine et al AJKD 2004; Manns et al NDT 1997
Hemodynamic Tolerance Study Odds ratio (95% CI) No. of events CRRT IRRT john (2001) 0.55 ( 0.12, 2.55) 9/20 6/10 gasparovic (2003) 0.19 ( 0.01, 4.11) 50/52 52/52 augustine (2004) 0.21 ( 0.07, 0.66) 5/40 16/40 vinsonneau (2006) 0.83 ( 0.54, 1.28) 61/175 72/184 Overall 0.66 ( 0.45, 0.96) 125/287 146/286 Large ΔMAP associated with renal recovery.1.25.5 1 2 4 8 Odds ratio Favours CRRT Favours IRRT Bagshaw et al CCM 2007
IHD sessions complicated by hypotension ~ 17.5% Instability during IHD can delay initiation or lead to suboptimal sessions
Hemodiaf Study IHD sessions complicated by hypotension ~ 39% Instability during IHD can delay initiation or lead to suboptimal sessions
Selby et al AJKD 2006
Myocardial Stunning Variable Odds Ratio p UF volume 1L 5.1 0.007 UF volume 1.5L 11.6 UF volume 2L 26.2 Max SBP Reduction 10 mmhg 1.8 0.002 Max SBP Reduction 20 mmhg 3.3 Max SBP Reduction 30 mmhg 6.0 Burton et al CJASN 2009
Anticoagulation/Bleeding Risk OR 1.03; 95% CI, 0.59-1.80 Rabindranath et al Cochrane 2007
Specific ICU Subgroups Septic shock/multi-organ failure Fulminant hepatic failure (FHF) Brain injury (TBI, stroke, meningitis) Refractory congestive heart failure Post-cardiac surgical shock
Fulminant Hepatic Failure Subgroup Davenport et al IJAO 1989; Davenport et al Contrib Nephrol 1991
Hounsfield Units Hounsfiled Units Brain Injured Patients Intermittent Continuous 60 50 * 60 50 40 40 30 30 20 20 10 10 0 0 4 24 Time (hrs) 0 0 4 24 Time (hrs) Grey White Grey White Ronco et al J Nephrol 1999
Does Modality Impact Survival? Study Odds ratio (95% CI) No. of events CRRT IRRT simpson (1993) 0.50 ( 0.21, 1.20) 46/65 48/58 kierdorf (1994) 0.81 ( 0.36, 1.82) 29/48 34/52 john (2001) 1.00 ( 0.19, 5.24) 14/20 7/10 mehta (2001) 1.89 ( 1.01, 3.52) 54/84 40/82 gasparovic (2003) 1.67 ( 0.74, 3.78) 37/52 31/52 augustine (2004) 0.89 ( 0.35, 2.29) 27/40 28/40 uehlinger (2005) 0.91 ( 0.45, 1.85) 34/70 28/55 vinsonneau (2006) 0.95 ( 0.61, 1.48) 118/175 126/184 lins (unpublished) 0.83 ( 0.53, 1.31) 100/172 90/144 Overall 0.99 ( 0.78, 1.26) 459/726 432/677.1.25.5 1 2 4 8 Odds ratio Favours CRRT Favours IRRT Bagshaw et al CCM 2007; Rabindranath et al Cochrane 2007; Pannu et al JAMA 2008
Does Modality Impact Survival? SHARF 4 Trial: 9 centres in Belgium 316 critically ill patients with AKI (SCr 177 µmol/l) Lins et al NDT 2008
RCT Design: Limitations No standardization of RRT practice Under-powered (sample size estimates) Selection bias: Exclusion of patients with hemodynamic instability Lack of CRRT machine availability Lack of trained personnel and/or institutional expertise
RCT Design: Bias Failure of randomization/baseline differences Inadequate concealment Variations in applied RRT technology (i.e. CAVH) Protocol modifications High cross-over between therapies (10-38%)
RCT Data: Generalizability Trials performed over 2 decades No standardized application of RRT Cross-over - how can ITT analyses be interpreted? Selected trials excluded CKD Selected trials excluded hemodynamic instability Are the patients in these RCTs truly representative of our ICU population?
Does Modality Impact Recovery? Study Odds ratio (95% CI) No. of events CRRT IRRT mehta (2001) 0.50 ( 0.10, 2.42) 26/30 39/42 augustine (2004) 1.25 ( 0.24, 6.44) 5/13 4/12 uehlinger (2005) 1.38 ( 0.08, 23.17) 36/37 26/27 vinsonneau (2006) 0.29 ( 0.01, 7.25) 67/68 77/77 Overall 0.76 ( 0.28, 2.07) 134/148 146/158.1.25.5 1 2 4 8 Odds ratio Favours CRRT Favours IRRT Bagshaw et al CCM 2007
Recovery to RRT independence Does Modality Impact Recovery? 1.8 CRRT.6 IRRT.4.2 0 89% vs. 65%; OR 3.33 (95% CI, 1.9-6.0), p<0.0001 0 20 40 60 80 100 Days Uchino et al IJAO 2007
Does Modality Impact Recovery? ESKD: 8.3% vs. 16.5% Adjusted-OR 2.6 (95% CI, 1.5-4.3) Bell et al ICM 2007
Does Modality Impact Recovery? Schneider et al ISICEM 2012 [Abstract]
ATN vs RENAL: Mortality Variable ATN RENAL All-patients n=1124 n=1508 Mortality 90 day (%) 44.7 Mortality 60 day (%) 52.5 SOFA score 3 or 4 (%) 36.9 70.0 Mortality 90 day (%) 47.5 Mortality 60 day (%) 79.8 * Survivors
ATN vs RENAL: Recovery Variable ATN RENAL *RRT dependence 28 day 45.2 13.3 *RRT dependence 60 day 24.6? *RRT dependence 90 day? 5.6
RRT-free days ATN vs RENAL: RRT-Free Days 25 20 15 17 10 5 0 6.5 ATN RENAL
ATN and RENAL? Possible explanations for the disparity: Chance/spurious finding Differences in patient characteristics Differences in timing of intervention Differences in RRT bundle of care Differences in processes of care Any combination of above Are they important?
SLED/EDD Rationale: Lower solute/uf clearances Longer treatment duration SLED/EDD aims to mimic CRRT Conclusion: SLED/EDD is a viable alternative to CRRT Logistically more simple Less expensive Marshall et al KI 2001; Marshall et al NDT 2004; Kielstein et al AJKD 2004; Berbece et al KI 2006
SLED/EDD Observational single centre case-series: 37 critically ill patients (sepsis/cancer) intolerant of IHD 145 SLED sessions SLED details: Prescription: BFR ~ 200 ml/min, dialysate ~ 100 ml/hr Delivery: 10.4 hrs; dp-kt/v 1.36 (n=9) Results Proportion Sessions (%) Session Stopped Early 34.5 Vasopressors Increased >50 Hypotensive Episodes 17 Blood Circuit Clotting 26 Marshall et al KI 2001
SLED/EDD Phase II RCT 39 critically ill patients Oliguric AKI EDD (12 hr) vs. CRRT EDD by single-pass No differences: Hemodynamic tolerance Small-solute clearance UF volume Kielstein et al AJKD 2004
SLED/EDD Parameter CVVH EDD P Urea Removal (g) 73.1 71.8 NS Creatinine Removal (g) 1.20 1.18 NS B2M Removal (g) 0.29 0.15 <0.01 Kielstein et al AJKD 2004
Middle/Large MW Clearance 6 5 CVVH IHD SLED 4 b2m (mg/dl) 3 2 1 0 0 1 2 3 4 5 6 7 Time (day) Liao et al Artif Organs 2003
SLED/EDD Observational single centre non-randomized pilot study: 23 critically ill patients requiring HD received SLED (165 sessions) 11 critically ill patients received CRRT (209 days) Parameter SLED (n=23) CRRT (n=11) Treatment Days (Median) 6 13 RRT Time (hrs/day) 7.5 21.3 APACHE II score 24.4 26.3 Hypotension (% sessions) 14 - EKR (ml/min) 28 29 Cost/wk (CDN$) 1431 2607-3089 Berbece et al KI 2006
[HCO3] BE SLED/EDD Acid/Base Balance 29 Serum Bicarbonate 8 Base Excess 27 6 25 23 4 21 2 19 17 15 0 10 24 48 72 Time (hrs) 0-2 -4 0 10 24 48 72 Time (hrs) CVVH EDDf CVVH EDDf Baldwin et al IJAO 2007; Baldwin et al ICM 2007
CRRT (n=86) SLED (n=39) p SOFA score 15.7 14.0 <0.001 MAP (mmhg) 74.1 (10.0) 76.4 (13.1) 0.34 Vasopressors (n, %) 62 (72.1) 19 (48.7) 0.01 UF Volume/session (ml) 1823 (1464) 1915 (1302) 0.74 MAP > 20% (n, %) 16 (18.6) 15 (38.5) 0.02 Vasopressors (n, %) 34 (39.5) 10 (25.6) 0.13 Unstable sessions (n, %) 43 (50.0) 22 (56.4) 0.51 Fieghen et al BMC Nephrol 2010
SLED in VA/NIH ATN Trial Stratification to RRT modality by csofa score: Score >2 allocated to CRRT/SLED (55%) Score 2 allocated to IHD (45%) CRRT represented >95% of treatments Supported by additional observational studies/trials CRRT is the Standard of care for hemodynamically unstable patients Clinicians do not yet believe SLED/EDD is equivalent to CRRT (or have little experience) ATN Trial NEJM 2008; Ronco et al Crit Care 2008; Uchino et al IJAO 2007; Bell et al ICM 2007
Health Technology Evaluation HTA ~ Assumptions: Accurate/current outcome data Accurate/current costing data Homogenous worldwide RRT practice No differences in long-term outcomes Bottomline ~ CRRT vs. IRRT: Higher cost/treatment or /treatment day Expenses for materials (i.e. fluids, anticoagulation, equipment) Per patient treatment no difference Shorter duration AKI and need for RRT RRT modality choice should never be driven by cost alone Mehta et al KI 2002; Vitale et al J Nephrol 2003; Manns et al CCM 2003; Tonelli et al, 2007 Available: wwwcadha.ca
Best (RRT Modality) Practice? When selecting RRT modality: Recognize the spectrum +/- shifts that occur in in patients with critical illness +AKI transition What are the Needs of the Patient? Hemodynamic stability? Acid/base control? Volume homeostasis? What Are the Current Goals of Therapy? CRRT (as initial modality) higher likelihood of renal recovery
CRRT SLED IHD
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