1. Dallas 2015 TFQO: EVREVs: Guinsburg, Ruth COI# 00054295 McGowan, Jane COI# Taskforce: Neonatal Apgar Zero #896 In infants ≥36 weeks GA with an Apgar score of 0 for ≥ 10 minutes (P), in spite of ongoing resuscitation does continuing resuscitation (I), compared with (C), change incidence of death, death or neurocognitive impairment at 18-22 months, or survival to NICU admission (O)?

2. Dallas 2015 COI Disclosure (specific to this systematic review) EVREV COI# 00054295 Guinsburg, Ruth Commercial/industry does not have any commercial/industry or potential intellectual conflicts Potential intellectual conflicts Coordinator of Brazilian NRP; Portuguese version of Textbook on Neonatal Resuscitation & DVD-ROOM – AAP & AHA 6 th edition EVREV COI# Mc Gowan, Jane Commercial/industry Does not have any commercial/industry or potential intellectual conflicts Potential intellectual conflicts Co-author of two (one excluded) of the examined papers

3. Dallas 2015 2010 CoSTR CONSENSUS on SCIENCE: “ Available evidence, albeit from relatively small numbers of babies, suggests that babies born without a heart rate which has not returned by 10 minutes of age are likely to either die or have severe neurological disability. (LOE 4, Casalaz, 1998,F112; Jain, 1991,778). It is not known whether there was significant selection bias in many of these studies, nor indeed that the babies included in them did receive “good quality resuscitation.” One study with a large contemporary cohort of infants (some randomized to post resuscitation hypothermia) indicates that in babies born without detectable heart rate, the lack of return of spontaneous circulation after 10 minutes of age is associated with survival without severe neurological deficit in a small number of the survivors (LOE Laptook 2010 p1619). Data are not available on the number of infants who were deemed too sick for study entry or died before enrollment. These factors may have resulted in a significant overestimation of the rate of intact survival among infants with an Apgar score of 0 at 10 minutes. In all reported series, the cause of the asphyxia and the efficacy of the resuscitation process was not elucidated.”

4. Dallas 2015 2010 CoSTR TREATMENT RECOMMENDATION: “ In a newly born baby with no detectable heart rate which remains undetectable for 10 minutes, it is appropriate to then consider stopping resuscitation. The decision to continue resuscitation efforts beyond 10 minutes of no heart rate is often complex and may be influenced by issues such as the presumed etiology of the arrest, the gestation of the baby, the presence or absence of complications, and the parents’ previous expressed feelings about acceptable risk of morbidity.”

5. Dallas 2015 C2015 PICO Population: infants ≥36 weeks GA with an Apgar score of 0 or 1 for ≥ 10 minutes in spite of ongoing resuscitation Outcomes: (9 critical) death up to 22 months (9 critical) death and/or moderate / severe neurodevelopmental impairment

6. Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions/Exclusions Inclusion Criteria: Randomized studies, studies with concurrent controls or with historical controls and meta-analysis. Exclusion Criteria: Review articles, animal studies and studies that did not specifically answer the question. Unpublished studies, and studies only published in abstract form, unless accepted for publication were also excluded. 14 finally evaluated 3 RCT’s 11 observational studies

7. Dallas 2015 2015 Proposed Treatment Recommendations We suggest that, in babies with an Apgar score of zero after 10 minutes of adequate resuscitation with effective ventilation, CC and IV epinephrine, if heart rate remains undetectable, it is reasonable to withdraw support. However, the decision to continue or withdraw resuscitative efforts should be individualized at the time of resuscitation. Variables to be taken into consideration may include availability of advanced neonatal care, including therapeutic hypothermia, specific circumstances prior to delivery (e.g., known timing of the insult) and wishes expressed by the family..

8. Dallas 2015 Non-RCT bias assessment StudyYearDesignPopulation Ind Fund. Eligibility Criteria Exposure/Outco me Confounding Follow up-death Follow up-disab. Casalaz1988Obs. Retr.5 ≥34w & Apg 10=0NoHighLowUnclLowHigh Haddad2000 Obs. Retr. 16 ≥22w & Apg 10=0NoHighLowUnclLowHigh Harrington2007 Obs. Retr. 12 ≥24w & Apg 10=0NoHighLowUnclLowUncl Jain1991 Obs. Retr. 58 Apg 10=0NoHighLowUnclLowUncl Kasdorf - a (TOBY trial) 2014Obs. In RCT34 ≥36w & Apg 10=0NoUnclLow Kasdorf - b (ICE trial) 2014 Obs. In RCT 11 ≥35w & Apg 10=0NoUnclLow Kasdorf - c (NYPH) 2014Obs. Retr9 ≥36w & Apg 10=0NoHighLow Laptook2009Obs. In RCT25 ≥36w & Apg 10=0NoUnclLow Nelson2011Obs. Prosp.7 ≥24w & Apg 10=0NoUnclLowUnclLowUncl Patel2004Obs. Retr29 >36w & Apg 10=0NoHighLowUnclLowHigh Sarkar2010Obs. Retr12 ≥36w & Apg 10=0NoHighLow Uncl Thornberg1995Obs. Retr??NoHigh UnclLowHigh Risk of Bias in studies

9. Dallas 2015 Evidence profile table 1 1 Lack of blinding 2 Trial was stopped early; loss of study power for outcome Temperature<36.0°C OutcomeNo of studies Author Year 1 st page Study DesignRisk of bias* Inconsistency*Indirectness*Imprecision*Quality of evidence for outcome*** Mortality Importance (9) 9 studies Casalaz 1998, F112 Haddad 2000, 1210 Harrington 2007, 463.e1 Jain 1991, 778 Kasdorf (a) 2014, Epub Kasdorf (b) 2014, Epub Kasdorf (c) 2014, Epub Laptook 2009, 1619 Nelson 2011, 75 Patel 2004, 136 Sarkar 2013, F423 Retr cohort Retr cohort Retr cohort Retr cohort Obs/nested RCT Obs/nested RCT Retr cohort Obs/nested RCT Retr cohort Retr cohort Retr cohort Moderate Moderate Moderate Moderate Low Low Moderate Low Low Moderate Moderate Modern series (≥2009) present better outcomes in comparison to others, but all infants enrolled in these series were actively resuscitated and 60% received therapeutic hypothermia All studies directly related to the question Very small sample sizes, although event is rare LOW Mortality or severe/moderate disability at 18-24 months Importance (9) 8 studies Casalaz 1998, F112 Haddad 2000, 1210 Harrington 2007, 463.e1 Jain 1991, 778 Kasdorf (a) 2014, Epub Kasdorf (b) 2014, Epub Kasdorf (c) 2014, Epub Laptook 2009, 1619 Patel 2004, 136 Sarkar 2013, F423 Retr cohort Retr cohort Retr cohort Retr cohort Obs/nested RCT Obs/nested RCT Retr cohort Obs/nested RCT Retr cohort Retr cohort High High Moderate High Low Low Moderate LowHigh = above LOW

10. Dallas 2015 Evidence profile table 2 Studies Infants with a 10- min. Apgar of 0 & resuscitation attempted >36 w infants successfully resuscitated after a 10- minute Apgar = 0 GA (weeks) Deaths (in hospital + after discharge up 18-24 months) Severe or moderate disability at 18- 24 months Survival without disability or with minor disability Casalaz 1998, F112* 5436-423+0 = 310 Haddad 2000, 1210* unknown3>341+? = unknownunknown? Harrington 2007, 463.e1** unknown6≥ 376+0=600 Jain 1991, 778*** 5827all26+0=2610 Kasdorf (a) 2014, Epub (TOBY) -33≥ 36 ?+?+249 9 Kasdorf (b) 2014, Epub (ICE) -11≥ 352 Kasdorf (c) 2014, Epub -9≥ 360+1=135 Laptook 2009, 1619 --25≥ 36?+?=1276 Nelson 2011, 75*** -- 7 (mGA: 35.9) ≥ 246+?=unknown?? Patel 2004, 136 --29>3620+0=2081 Sarkar 2013, F423 -12≥ 367+2=930 Thornberg 1995, 927 --?>365+0=51unknown *Casalaz, Haddad and Harrington included also PT infants, but only outcomes of ≥36 infants are included in the Table. **Haddad describes 1 FT infant alive after initial hospital stay (39,3w) that was loss to follow up. **Jain and Nelson included PT infants and the articles do not allow separating PT from FT infants. In gray, studies actually included in the consensus of science

11. Dallas 2015 Proposed Consensus on Science statements In infants ≥ 36 weeks gestational age who have an Apgar score of zero after 10 minutes of effective resuscitation, what are the outcomes? For the critical outcome of death up to 22 months, low quality evidence (downgraded for risk of bias, inconsistency, indirectness and imprecision) from 6 studies encompassing 8 case series showed that 75 of 129 (58%) of infants ≥36 weeks EGA with an Apgar score of zero at 10 minutes of life died before 22 months of age (Casalaz 1998, Harrington 2007, Kasdorf 2014, Laptook 2009, Patel 2004, Sarkar 2013). For the critical outcome of death up to 22 months, 3 studies performed after 2009 that included nested observational series of cases from 3 RCTs of therapeutic hypothermia and a series of infants who received therapeutic hypothermia outside a randomized trial (moderate quality of evidence, downgraded for risk of bias) found that 46 of 90 (51%) of infants with an Apgar score of zero at 10 minutes died before 22 months of age (Kasdorf 2014, Laptook 2009, Sarkar 2013).

12. Dallas 2015 Proposed Consensus on Science statements In infants ≥ 36 weeks gestational age who have an Apgar score of zero after 10 minutes of effective resuscitation, what are the outcomes? For the critical outcome of death or moderate/severe neurodevelopmental impairment at ≥ 22 months of age, 6 studies (low quality evidence; downgraded for risk of bias, inconsistency, indirectness and imprecision) showed that this outcome occurred in 106 of 129 (85%) infants ≥ 36 weeks with an Apgar score of zero at 10 minutes of life (Casalaz 1998, Harrington 2007, Kasdorf 2014, Laptook 2009, Patel 2004, Sarkar 2013). For the critical outcome of death up to ≥22 months or moderate/ severe neurodevelopmental impairment, 3 studies performed after 2009 (moderate quality of evidence, downgraded for risk of bias) that included nested observational series in RCTs of therapeutic hypothermia and series of infants that received therapeutic hypothermia showed that this adverse outcome occurred in 68 of 90 (76%) infants with an Apgar score of zero at 10 minutes. Among the 44 survivors of these studies 22 (50%) survived without major or moderate disabilities. Among the 56 cooled infants in these studies, 15 (27%) survived without major or moderate disabilities (Kasdorf 2014, Laptook 2009, Sarkar 2013). No studies differentiated between severe and moderate disability.

13. Dallas 2015 Draft Treatment Recommendations We suggest that, in babies with an Apgar score of zero after 10 minutes of adequate resuscitation with effective ventilation, CC and IV epinephrine, if heart rate remains undetectable, it is reasonable to withdraw support; however, the decision to continue or withdraw resuscitative efforts should be individualized at the time of resuscitation. Variables to be taken into consideration may include availability of advanced neonatal care, including therapeutic hypothermia, specific circumstances prior to delivery (e.g., known timing of the insult) and wishes expressed by the family.

14. Dallas 2015 Knowledge Gaps The major flaws in the available scientific evidence regarding outcome of term neonates with asystole after 10 minutes of adequate resuscitation is the absence of data regarding: Number of infants born in the study centers or the transferring centers with asystole at 10 minutes who were not actively resuscitated Number of infants born in the study or the transferring centers with asystole at 10 minutes in whom ongoing DR resuscitation was attempted and was unsuccessful The quality and extent of resuscitation provided. A prospective international registry of infants with asystole/bradycardia after 10 minutes of adequate resuscitation that includes collection of relevant data with all needed information is needed to provide high-quality evidence to answer this prognostic question.

15. 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