SLED - CRRT Online

Comparing RRTModalities: Does ItMatter What You Use IfThe Job Is Done?Sean M Bagshaw, MD, MScDivision of Critical Care MedicineUniversity of Alberta

Disclosure• Consulting:– Alere, Baxter, Gambro, SpectralDiagnostics, 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 Control120100CVVHIHDSLEDBUN (mg/dL)8060402000 1 2 3 4 5 6 7Time (day)Liao et al Artif Organs 2003

Urea (mmol/L)Azotemic/Uremic Control3530252015101 2 3 4 5 6 7 8 9 10DayCRRT IHDMehta et al KI 2001

Volume Homestasis/RemovalVariable IHD SLED CRRTDuration 3-5 6-8 20-24Obligatory Intake 3500 mL 3500 mL 3500 mLUrine output 100 100 100Balance +3400 mL +3400 mL +3400 mLFluid removal (per hr)1000 mL2000 mL3000 mL4000 mL200-350400-600600-1000800-1300125-150250-350375-500500-65040-5083-100125-150150-200

Mean %FOVolume HomeostasisDaysBouchard 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 kidneyAugustine et al AJKD 2004; Manns et al NDT 1997

Hemodynamic ToleranceStudyOdds ratio(95% CI)No. of eventsCRRT IRRTjohn (2001) 0.55 ( 0.12, 2.55) 9/20 6/10gasparovic (2003) 0.19 ( 0.01, 4.11) 50/52 52/52augustine (2004) 0.21 ( 0.07, 0.66) 5/40 16/40vinsonneau (2006) 0.83 ( 0.54, 1.28) 61/175 72/184Overall 0.66 ( 0.45, 0.96) 125/287 146/286Large ΔMAPassociated with↓ renal recovery.1 .25 .5 1 2 4 8Odds ratioFavours CRRT Favours IRRTBagshaw et al CCM 2007

IHD sessions complicated by hypotension ~ 17.5%Instability during IHD can delay initiation or leadto suboptimal sessions

Hemodiaf StudyIHD sessions complicated by hypotension ~ 39%Instability during IHD can delay initiation or leadto suboptimal sessions

Selby et al AJKD 2006

Myocardial StunningVariable Odds Ratio pUF volume 1L 5.1 0.007UF volume 1.5L 11.6UF volume 2L 26.2Max SBP Reduction 10 mmHg 1.8 0.002Max SBP Reduction 20 mmHg 3.3Max SBP Reduction 30 mmHg 6.0Burton et al CJASN 2009

Anticoagulation/Bleeding RiskOR 1.03; 95% CI, 0.59-1.80Rabindranath 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 SubgroupDavenport et al IJAO 1989; Davenport et al Contrib Nephrol 1991

Hounsfield UnitsHounsfiled UnitsBrain Injured PatientsIntermittentContinuous6050*6050404030302020101000 4 24Time (hrs)00 4 24Time (hrs)GreyWhiteGreyWhiteRonco et al J Nephrol 1999

Does Modality Impact Survival?StudyOdds ratio(95% CI)No. of eventsCRRT IRRTsimpson (1993) 0.50 ( 0.21, 1.20) 46/65 48/58kierdorf (1994) 0.81 ( 0.36, 1.82) 29/48 34/52john (2001) 1.00 ( 0.19, 5.24) 14/20 7/10mehta (2001) 1.89 ( 1.01, 3.52) 54/84 40/82gasparovic (2003) 1.67 ( 0.74, 3.78) 37/52 31/52augustine (2004) 0.89 ( 0.35, 2.29) 27/40 28/40uehlinger (2005) 0.91 ( 0.45, 1.85) 34/70 28/55vinsonneau (2006) 0.95 ( 0.61, 1.48) 118/175 126/184lins (unpublished) 0.83 ( 0.53, 1.31) 100/172 90/144Overall 0.99 ( 0.78, 1.26) 459/726 432/677.1 .25 .5 1 2 4 8Odds ratioFavours CRRT Favours IRRTBagshaw 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 institutionalexpertise

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 instabilityAre the patients in these RCTs trulyrepresentative of our ICU population?

Does Modality Impact Recovery?StudyOdds ratio(95% CI)No. of eventsCRRT IRRTmehta (2001) 0.50 ( 0.10, 2.42) 26/30 39/42augustine (2004) 1.25 ( 0.24, 6.44) 5/13 4/12uehlinger (2005) 1.38 ( 0.08, 23.17) 36/37 26/27vinsonneau (2006) 0.29 ( 0.01, 7.25) 67/68 77/77Overall 0.76 ( 0.28, 2.07) 134/148 146/158.1 .25 .5 1 2 4 8Odds ratioFavours CRRT Favours IRRTBagshaw et al CCM 2007

Recovery to RRT independenceDoes Modality Impact Recovery?1.8CRRT.6IRRT.4.2089% vs. 65%; OR 3.33(95% CI, 1.9-6.0), p

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: MortalityVariable ATN RENALAll-patients n=1124 n=1508Mortality 90 day (%) 44.7Mortality 60 day (%) 52.5SOFA score 3 or 4 (%) 36.9 70.0Mortality 90 day (%) 47.5Mortality 60 day (%) 79.8* Survivors

ATN vs RENAL: RecoveryVariable ATN RENAL*RRT dependence 28 day 45.2 13.3*RRT dependence 60 day 24.6 ?*RRT dependence 90 day ? 5.6

RRT-free daysATN vs RENAL: RRT-Free Days2520151710506.5ATNRENAL

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 durationSLED/EDD aims to mimic CRRT• Conclusion:– SLED/EDD is a viable alternative to CRRT– Logistically more simple– Less expensiveMarshall 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 34.5Vasopressors Increased >50Hypotensive Episodes 17Blood Circuit Clotting 26Marshall 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 volumeKielstein et al AJKD 2004

SLED/EDDParameter CVVH EDD PUrea Removal (g) 73.1 71.8 NSCreatinine Removal (g) 1.20 1.18 NSB2M Removal (g) 0.29 0.15

Middle/Large MW Clearance65CVVHIHDSLED4b2M (mg/dL)32100 1 2 3 4 5 6 7Time (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)ParameterSLED(n=23)CRRT(n=11)Treatment Days (Median) 6 13RRT Time (hrs/day) 7.5 21.3APACHE II score 24.4 26.3Hypotension (% sessions) 14 -EKR (mL/min) 28 29Cost/wk (CDN$) 1431 2607-3089Berbece et al KI 2006

[HCO3]BESLED/EDD – Acid/Base Balance29Serum Bicarbonate8Base Excess276252342121917150 10 24 48 72Time (hrs)0-2-40 10 24 48 72Time (hrs)CVVHEDDfCVVHEDDfBaldwin et al IJAO 2007; Baldwin et al ICM 2007

CRRT(n=86)SLED(n=39)pSOFA score 15.7 14.0 20% (n , %) 16 (18.6) 15 (38.5) 0.02↑ Vasopressors (n, %) 34 (39.5) 10 (25.6) 0.13Unstable sessions (n, %) 43 (50.0) 22 (56.4) 0.51Fieghen 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 hemodynamicallyunstable patients• Clinicians do not yet believe SLED/EDD is equivalent toCRRT (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 dayExpenses for materials (i.e. fluids, anticoagulation, equipment)◦Per patient treatment – no differenceShorter duration AKI and need for RRT• RRT modality “choice” should never be driven by costaloneMehta 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 inpatients with critical illness +AKI → transition• What are the Needs of the Patient?• Hemodynamic stability? Acid/base control? Volumehomeostasis?• What Are the Current Goals of Therapy?• CRRT (as initial modality) → higherlikelihood of renal recovery

CRRT SLED IHD

Thank You For Your Attention!DiscussionQuestions?