When to start CRRT during ECMO? Matthew L. Paden, MD Associate Professor of Pediatric Critical Care Director, Pediatric ECMO

Disclosures Everything in ECMO is off label use I’m a believer…

When do YOU start CRRT during ECMO? On every pediatric respiratory patient at initiation of ECMO, regardless of creatinine/UOP.

When to start CRRT during ECMO? No one knows.

Concomitant ECMO and CRRT Question Evidence Optimal population for therapy? None What indication? Survey results about what people are doing Timing of initiation? Expert opinion, ELSO Guidelines Optimal mode of therapy? Optimal method of therapy? (Device vs. in-line) Optimal dose of therapy? Effectiveness of therapy? (URR, Kt/V) Outcome? 4 single center reports, Registry data

Objectives Discuss why it might be helpful Discuss what people are doing Review the small amount of outcome literature Discuss where future work needs to be done

Why CRRT Could Provide Potential Benefit on ECMO Treatment of Acute Kidney Injury which is common Impact on Reducing Inflammatory Response of ECMO/Underlying Disease Process Impact on Decreasing Fluid Overload

AKI Prevalence in ECMO Neonates - 25% (Askenazi 2011) ELSO registry ~8000 non-cardiac neonates Congenital diaphragmatic hernia - 71% (Gadepalli 2011) Congenital hearts - 72% (Smith 2009) Pediatric respiratory - 63% (ELSO DB 2011) AKI on ECMO is associated with increased mortality, controlling for confounders (Askenazi 2012) AKI on adult ECMO: OR 12.1 (2.5-59) AKI on pediatric ECMO: OR 24.0 (4.2-137)

CRRT Associated with Increased Risk of Death in Pediatric ECMO ELSO Registry (1998-2008) Adjusting for other risk factors: Patients with AKI and CRRT had higher mortality Neonates (25% AKI incidence) OR with AKI: 3.2 OR with RRT: 1.9 Children (46% AKI incidence) OR with AKI: 1.7 OR with RRT: 2.5 Therapies to prevent/ameliorate AKI and optimize RRT could improve outcomes -Askenazi et al., Pediatr Crit Care Med, 2011

Impact of ECMO on Inflammation Circulation of blood across synthetic surfaces escalates a pro-inflammatory response (already activated by disease) Early elevation of TNF-alpha, IL-1beta, IL-6, IL-8 within 3-4 hours post-ECMO cannulation; associated with lung changes (Fortenberry et al., J Peds 1996; Massoudy et al., Chest 2001)

CRRT Decreases Cytokine mRNA Expression in VV ECMO-Healthy Pig Model -Shen et al. (Nanjing U), Inflammation, 2013

Improvement in ECMO-Induced Mitochondrial Dysfunction with CRRT in Healthy Pigs -Shen et al. (Nanjing U), Inflammation, 2013

CRRT Modulates Renal Inflammatory Cytokines During ECMO Porcine model Control, sham vs. VV ECMO, ECMO+CRRT CRRT addition decreased renal TNF, IL-1, IL-6 expression Decreased Nf-KB transcription gene expression TNF- a Nf-KB -Hu Yimin et al., (Nanjing), J Cardiothoracic Surgery 2013

Fluid Overload and Outcome Strong body of evidence showing fluid overload is associated with: Acute kidney injury Increased mortality Increased ventilator days Increased ICU LOS In both children and adults Conservative fluid approach (fluid restriction, diuretics) associated with improved ventilator days, ICU LOS (FACTT Trial, NEJM 2006)

ELSO Guidelines …spontaneous or pharmacologic diuresis should be instituted until patient is close to dry weight and edema has cleared. This will enhance recovery from heart or lung failure and decrease the time on ECLS. The goal of fluid management is to return the extracellular fluid volume to normal (dry weight) and maintain it there. As with all critically ill patients, full caloric and protein nutritional support is essential.

ELSO Guidelines The hourly fluid balance goal should be set and maintained until normal extracellular fluid volume is reached (no systemic edema, within 5% of “dry” weight). Renal replacement therapy use to enhance fluid removal allowing adequate nutritional support is often performed. Despite the literature surrounding fluid overload (>10%) as a risk factor for death, review of the ELSO registry also finds that use of renal replacement therapy is also a risk factor for poor outcome. Even if acute renal failure occurs with ECLS, resolution in survivors occurs in >90% of patients without need for long-term dialysis.

So we should do it, but how do we do it? No guidance.

In-line hemofiltration during ECMO Hemofilter placed post-pump, preoxygenator Returns pre-pump Control UF with IV pump’s resistance Measure UF with urometer Deliver replacement fluids/dialysate with IV pump

Advantages of in-line hemofiltration Cheap Does not require stand alone machine Only need dialysis filter, IV pumps, and urometer No need for dialysis/CRRT trained nurse Can provide SCUF, CVVH, CVVHD Smaller addition of extracorporeal volume compared to stand alone CRRT device

Disadvantages of in-line hemofiltration Creates a shunt Pump flow ≠ delivered flow Less effective with diffusive techniques Incredibly inaccurate fluid control IV pump error rates – between 2 -12.5% ECMO conditions – 34 mL/hour (>800 mL/day) difference between prescribed and actual ultrafiltration.

Pediatric ECMO / In-line CRRT Warning Sucosky et al., J Med Devices (2), 2008 IV pumps Your I/O’s are not accurate Delivers less replacement fluid than ordered. 10 kg child with 300 mL/hour UF rate – negative 288 mL per day (28 ml/kg) 45 kg adolescent with 2000 ml/hour UF rate – negative 1.9 L/day (42 ml/kg)

Using a CRRT device during ECMO CRRT device placed pre-pump Returns pre-pump UF controlled by CRRT device

Advantages of CRRT device Engineered to provide CRRT * Provides multiple modalities of therapy More accurate fluid balance control than in-line hemofiltration No shunt

Disadvantages of CRRT device Not engineered to provide CRRT on ECMO Alarm modes Default access pressure alarms are usually negative Accuracy Better than inline over time, but still can be a problem over short time periods -30 -10 -5 -40 35 10 Hourly Fluid Balance

CRRT outcomes NOT on ECMO ppCRRT (344 multicenter patients) overall survival 58% (Symons ClinJAmSocNeph 2007) MODS 51% survival (Goldstein Kid Int 2005) <10 kg 43% (Askenazi J Peds 2012) Multiple other single center reports 40-55% survival

RRT/ECMO Outcomes – ELSO Registry Survival Neonatal respiratory 2696/5319 (51%) Pediatric respiratory 1010/2498 (40%) Adult respiratory 815/1781 (46%) Cardiac 0-30d 527/2198 (24%) Cardiac 31d – 364d 364/1210 (30%) Cardiac 1y-16 y 437/1094 (40%) Cardiac >16 y 366/1386 (26%)

Concomitant ECMO and RRT – Neo/Peds Author (year) Patient population Number of patients Survivors Outcome reported Bartlett (1986) Neonates 10 2 Not reported Weber (1990) 43 8 Sell (1987) Neo/Ped 6 “Normal renal function at discharge” Adolph (1991) Pediatric 3 N/A Weber (1998) 38 “No survivors with renal injury at discharge” Swaniker (2000) 18 Meyer (2001) 35 15 *** Paden (2011) 154 68

Concomitant ECMO/CRRT Renal Outcomes University of Michigan 35 CRRT/ECMO patients – 15 survivors (43%) 14/15 (93%) with full renal recovery at D/C Wegeners – ultimately transplanted Children’s Healthcare of Atlanta 154 CRRT/ECMO patients - 68 survivors (44%) 65/68 (96%) with full renal recovery at D/C 1 nosocomial enterococcus sepsis at transfer – normal 1 month later 2 primary renal disease (Wegeners/polyangiitis) – Cr 13.7/6.5 One ultimately transplanted / one with elevated Cr, no RRT

ECMO and CRRT Outcome Reporting Under reporting in the literature Medical literature survivors – 161 ELSO Registry survivors – 6215 2.6% of all survivors Biased towards bad outcomes Medical literature - 28% survival of 567 patients ELSO Registry – 40% survival of 15,486 patients Highly biased to a few centers experience 83% of the medical literature patients come from 3 centers 201 centers reporting to ELSO in 2012

KIDMO Multiple centers – Michigan, UAB, Vanderbilt, Cincinnati, Emory, McGill Standard definition of AKI (KDIGO modification of AKIN) 2007-2014 Analysis of ~900 patients

AKI is common

AKI - longer ECMO and increased mortality

Fluid overload at ECMO initiation

Peak Fluid overload

More in depth review of the topic http://cjasn.asnjournals.org/content/7/8/1328.long

Angelica Hale