Dallas 2015 TFQO: Anne-Marie Guerguerian # 97 EVREV1: Anne-Marie Guerguerian # 97 EVEREV2: Ericka Fink # 83 Taskforce: PEDS Peds 407 : ECMO for pediatric cardiac arrest

Dallas 2015 COI Disclosure specific to this systematic review Anne-Marie Guerguerian # 97 Commercial/industry None Potential intellectual conflicts None Ericka Fink # 83 Commercial/industry None Potential intellectual conflicts None

Dallas CoSTR “ECPR may be beneficial for infants and children with cardiac arrest if they have heart disease amenable to recovery or transplantation and the arrest occurs in a highly supervised environment such as an ICU with existing clinical protocols and available expertise and equipment to rapidly initiate ECPR. There is insufficient evidence for any specific threshold for CPR duration beyond which survival with ECPR is unlikely. ECPR may be considered in cases of environmentally induced severe hypothermia (temperature 30°C) for pediatric patients with out-of-hospital cardiac arrest if the appropriate expertise, equipment, and clinical protocols are in place.”

Dallas 2015 C2015 PICO Population: infants and children in cardiac arrest in the in-hospital setting Intervention: does the use of ECMO with resuscitation (ECPR) Comparison: compared to standard resuscitative treatment (resuscitation without the use of ECMO) Outcomes: Critical (9): survival to 180 days with good neurological outcome Critical (7): survival to hospital discharge Important (5): survival to intensive care discharge

Dallas 2015 Inclusion/Exclusion Included: studies with infants or children populations, with cardiac arrest where comparative interventional or observational studies designs were available. Excluded: studies without a comparator group (case series, case reports), studies that did not report separate outcomes for infants and children, studies reporting cardiopulmonary arrest in out- of-hospital such as in the context of drowning events.

Dallas Proposed Treatment Recommendations - 1 We suggest ECMO with resuscitation (ECPR) compared to standard resuscitation without ECMO for infants and children with cardiac disease with in- hospital cardiac arrest (weak recommendation, very low quality evidence) in settings that allow for the resources, systems, and expertise to optimize the use of ECMO during resuscitation.

Dallas Proposed Treatment Recommendations -2 We recommend that there is insufficient evidence to suggest for or against the routine use of ECMO with resuscitation (ECPR) in comparison to standard resuscitation without ECMO in infants and children in general with in-hospital cardiac arrest (weak recommendation, very low quality evidence).

Dallas 2015 Articles found & Data Set selected The search yielded a total of 2834 citations. Of these, five observational studies were included for bias assessment. Two additional studies’ data were retrieved, the public dataset used in Moler 2009, p 2259, and author query to Doherty 2009, p 1492; unpublished analysis of the former was selected.

Dallas 2015 Risk of Bias in published studies non-RCT StudyYearPageDesignPopulation IHCA subjectsIndustryEligibilityExposure/OutcomeConfoundingFollow up De Mos Retrospective cohortIHCA91noLowHigh Wu Retrospective + prospective single center cohort study IHCA316nonLow Ortmann Retrospective registryIHCA cardiac disease1274noLowHighLowHigh Lowry National administrative registry IHCA & ECMO same day9000noHigh high Odegard Retrospective single centerIHCA Cath lab only70noLow High Public dataset 2015NA Retrospective multicenter cohort study IHCA selected491noLow HighLow

Dallas 2015 Evidence profile table - 1 Quality assessment№ of patientsEffect QualityImportance № of studies Study design Risk of bias Inconsistency Indirect- ness Impreci- sion Other considera -tions ECPR Standard resuscita- tion Relative 95% CI Absolute 95% CI Critical outcome: Survival at 180 days with good neurological outcome or follow up at one year as reported in Wu et al 2009 p 443: 1 Wu 2009 Retro & prospective single center cohort – outcome at one year SeriousNot seriousSeriousNo serious Residual confounding 12/6439/ % CI 0.67 to % CI to 0.13 Very LowCritical

Dallas 2015 Evidence profile table - 2 Quality assessment№ of patientsEffect QualityImportance № of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsECPR Standard resuscitation Relative 95% CI Absolute 95% CI Critical outcome: Survival to hospital discharge 5 studiesObservationalSerious Not serious Residual confounding Very LowCritical De Mos 2006 p1209 Retrospective cohort single center SeriousNot seriousSerious Residual confounding 2/521/86 RR % CI 0.53 to % CI to 0.59 LowCritical Wu 2009 p443 Retrospective and prospective single center cohort Not serious SeriousNot seriousResidual confounding 16/6450/252 RR % CI 0.77 to % CI to 0.17 LowCritical Ortmann 2011 p 2329 Registry, multicenter, Surgical and Medical Cardiac Not serious SeriousNot seriousResidual confounding but adjusted odds ratio of survival reported Unadjusted Not reported Surgical Cardiac OR %CI 1.3 to 4.5 p Medical Cardiac OR %CI 1.4 to 5.8 p Not estimatedLowCritical Lowry 2013 p 1422 National administrative dataset (KID Inpatient Database) Serious Residual confounding but propensity matched odds ratio of survival reported Propensity matched 34.1% Propensity matched 43.3% Propensity matched OR % CI 0.4 to 1.3 Not estimatedVery lowCritical Odegard 2013 p 175 Retrospective cohort single center (cardiac interventional diagnostic unit) Serious Residual confounding 10/1845/ % CI 0.48 to % CI to 0.06 Very LowCritical Public datasetRetrospective multicenter cohort study Very seriousSeriousNot seriousSeriousResidual confounding 19/38206/ % CI 0.78 to % CI to 0.21 Very LowCritical

Dallas 2015 Proposed Consensus on Science statements -1 In infants and children with in-hospital cardiac arrest for the critical outcome of survival at 180 days with favorable outcome we have identified no difference in outcomes, with very low quality evidence (downgraded for indirectness and imprecision) from an observational study (Wu 2009, p443) with RR 1.21 (95% CI ) at one year, and very low quality evidence from unpublished secondary data analyses from another study's public dataset (Moler 2009, p2259) with RR 0.74 (95% CI ) on hospital discharge (downgraded for serious risk of bias with residual confounding).

Dallas 2015 Proposed Consensus on Science statements -2 In infants and children with in-hospital cardiac arrest for the critical outcome of survival to hospital discharge, we identified very low quality evidence from five observational studies (Wu 2009, p443; De Mos 2006, p1209; Ortmann 2011, p2329; Lowry 2013, p1422, Odegard 2014, p175) (downgraded for indirectness, inconsistency, and residual confounding) and very low quality evidence from an unpublished analysis of a public dataset (RR %CI ; used in Moler 2009, p2259) showing no benefit, or some benefit among children with cardiac diseases (downgraded for residual confounding) (Ortmann 2011, p 2329; Lowry 2013, p 1422).

Dallas Proposed Treatment Recommendations - 1 We suggest ECMO with resuscitation (ECPR) over standard resuscitation without ECMO for infants and children with cardiac disease with in-hospital cardiac arrest (very low quality evidence) in settings that allow for the resources, systems, and expertise to optimize the use of ECMO during resuscitation.

Dallas Proposed Treatment Recommendations -2 We recommend that there is insufficient evidence to suggest for or against the routine use of ECMO with resuscitation (ECPR) in comparison to standard resuscitation without ECMO in infants and children in general with in-hospital cardiac arrest (weak recommendation, very low quality evidence).

Dallas 2015 Knowledge Gaps -1 Comparative studies in pediatric in-hospital cardiac arrest or out-of-hospital cardiac arrest receiving resuscitation with and without ECMO are lacking. 1.The quality of CPR i.e., quality of perfusion of cerebral and systemic circulations, during ECMO cannulation has not been studied in the pediatric resuscitation setting. 2.The optimal timing of initiation of ECMO cannulation during pediatric resuscitation measures has been not studied - both minimal interval and maximal interval. The optimal timing of ECMO initiation during resuscitation measures of select populations such as deep hypothermic out-of-hospital arrest, pulmonary emboli, and high risk complex congenital heart disease (e.g., in single ventricle physiology) has not been studied. 3.The anatomical preferred location for ECMO cannulation during resuscitation for optimal neuro and cardio-protection has not been studied.

Dallas 2015 Knowledge Gaps -2 4.The effect of co-interventions delivered during ECMO initiation and circulatory support is not reported in the pediatric in-hospital cardiac arrest population; such interventions that warrant further evaluation are the following: temperature targeted therapy, hypothermia therapy and rate of rewarming, blood flow rate on reperfusion, oxygenation and carbon dioxide targets, hemodilution (associated with crystalloid circuit prime), hemofiltration, concurrent mechanical ventilation, inotropes and vasoactives strategies, steroids. 5.Studies incorporating functional outcomes are urgently needed. 6.Alternatives to patient-level-randomization study designs to evaluate benefit are urgently needed. Several enters have adopted the use of ECMO in resuscitation as standard practice in pediatric in-hospital cardiac arrest in selected pediatric populations. Random allocation of ECMO for resuscitation at an individual patient level presents several challenges which decreases the feasibility of traditional randomized control trials designs and suggests that alternatives need to be considered to minimize bias in order to compare interventions and generate clinical evidence to inform practice. 7.Studies on the ethical frameworks applied or informed consent processes used with ECMO for resuscitation are also missing.

Dallas 2015 Additional comments – Resources and costs We found in one study that studied the costs associated with in-hospital charges in children with cardiopulmonary events and found that these were different and increased with the use of ECMO compared to no ECMO ( Lowry 2013, p 1422).

Dallas 2015 Next Steps This slide will be completed during Task Force Discussion (not EvRev) and should include: Consideration of interim statement Person responsible Due date