1. Dallas 2015 TFQO: Vinay Nadkarni #375 EVREV 1: Vinay Nadkarni #375 EVREV 1: Dave Kloeck #126 Taskforce: Paeds Paed 424: Vasopressors in Paediatric cardiac arrest

2. Dallas 2015 COI Disclosure (specific to this systematic review) Vinay Nadkarni COI#375 Commercial/industry Nil Potential intellectual conflicts Nil Dave Kloeck COI#126 Commercial/industry Nil Potential intellectual conflicts Nil

3. Dallas 2015 2010 CoSTR In adult and pediatric patients with cardiac arrest (prehospital [OHCA] or in hospital [IHCA])(P),does the use of vasopressin or vasopressin+epinephrine (I)compared with standard treatment recommendations(C), improve outcome (e.g.,ROSC, survival to hospital discharge, or survival with favorable neurologic outcome) (O)? New question specific to Paeds – PICO edited to read - Infants and children in cardiac arrest (P), does use of NO vasopressor (epinephrine, vasopressin, combination of vasopressors) (I), compared with ANY use of vasopressors (C), change survival to 180 days with good neurological outcome, survival to hospital discharge, ROSC (O)?

4. Dallas 2015 C2015 PICO Population: Infants and children in cardiac arrest Intervention: Does the use of NO vasopressor (epinephrine, vasopressin, combination of vasopressors) Comparison: Compared with ANY use of vasopressors Outcomes: Survival to 180 days with good neurological outcome (9 – Critical) Survival to hospital discharge (6 – Important) ROSC (5 – Important)

5. Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions: (all studies) Infants and paediatrics Animals – paediatric and infant Number of articles initially identified = 1360 narrowed down to 10 articles Number finally included in Evidence Profile tables RCTs = 0 non-RCTs = 2 Excluded = 8 Later in review process – 1 adult RCT identified to answer the PICO question (ALS #788)– included into SoF but downgraded heavily for indirectness

6. Dallas 2015 #ALS 788

7. Dallas 2015 2015 Proposed Treatment Recommendations None We suggest no change to current practise in using vasopressors for paediatric cardiac arrest Strength of evidence is very low with very serious downgrades in quality assessment for inconsistency, indirectness, imprecision and risk of bias

8. Dallas 2015 Risk of Bias in studies Non-RCT bias asssesment StudyYearDesign Total Patients Population Industry Funding Eligibility Criteria Exposure/Outcome Confounding Follow up Kevin Enright 2012Non-RCT9Paediatric-OHCANoLowHigh Low Ronald Diekmann 1995Non-RCT65Paediatric-OHCANoLowHigh Low RCT bias assessment StudyYearDesign Total Patients Population Industry Funding Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias Ian Jacobs2011RCT534Adults - OHCANoLow High – 67 pts (11%) post randomization excl Low High – 989 consecutive cases, of which 601 randomized (unexplained) & trial terminated early due to lack of enthusiasm by providers

9. Dallas 2015 Evidence profile table

10. Dallas 2015 Evidence profile table

11. Dallas 2015 Proposed Consensus on Science statements For the critical outcome of “survival with good neurological outcome” we have identified very low quality evidence (downgraded for indirectness, imprecision, inconsistency and high risk of bias) from two pediatric out of hospital case series observational studies including 74 patients suggesting uncertain benefit. (Enright, 2012, 336 & Diekmann, 1995, 901)(Pooled unadjusted OR 8.3 95% CI 1.49 – 47.13). For the important outcome of “survival to hospital discharge” we have identified very low quality evidence (downgraded for indirectness, imprecision, inconsistency and high risk of bias) from two pediatric out of hospital case series observational studies including 74 patients suggesting uncertain benefit. (Enright, 2012, 336 & Diekmann, 1995, 901) (Pooled unadjusted OR 5.5 95% CI 1.2 – 25.8).

12. Dallas 2015 Proposed Consensus on Science statements For the important outcome of “ROSC” we have identified very low quality evidence (downgraded for indirectness, imprecision, inconsistency and high risk of bias) from two pediatric out of hospital case series observational studies including 74 patients suggesting uncertain benefit. (Enright, 2012, 336 & Diekmann, 1995, 901) (Pooled unadjusted OR 6.7 95% CI 1.5 to 29.7). Note: (See Adult PICO question #788) For all critical and important outcomes, we reviewed and considered a single underpowered ADULT out-of-hospital cardiac arrest RCT that provided very low quality evidence (downgraded for extreme indirectness, imprecision and risk of bias) comparing Standard Dose Epinephrine to placebo (Jacobs, 2011, 1138). For the critical outcome “good neurological outcome” and important outcome of “survival to discharge”, there was uncertain benefit or harm of standard dose epinephrine compared to placebo. For the important outcomes of “Survival to Hospital Admission” and “ROSC”, there was possible benefit of standard dose epinephrine compared to placebo.

13. Dallas 2015 Draft Treatment Recommendations For paediatrics in cardiac arrest we suggest no change in the current approach. Therefore no change in the current practice of using vasopressors for paediatric cardiac arrest. Strength of evidence is very low with very serious downgrades in quality assessment for inconsistency, indirectness, imprecision and risk of bias

14. Dallas 2015 Knowledge Gaps If adult studies suggest that vasopressor administration is associated with improved ROSC, but worse survival to hospital discharge and neurological outcome then prospective studies of placebo vs epinephrine/vasopressors for paediatric cardiac arrest would be indicated. Are there selected resuscitation circumstances (e.g. pulmonary hypertension, myocarditis, imminent ECPR rescue) where the administration of vasopressors is not indicated?

15. Dallas 2015 Next Steps Task force discussion – TR not appropriate and needs better wordsmithing  proposal below: There is insufficient evidence of benefit or harm from using no vasopressors compared to any vasopressors to treat infants and children in cardiac arrest. Until specific studies of this question, We suggest providers continue to use epinephrine for pediatric cardiac arrest as per their current council-specific practice