Dallas 2015 TFQO: S. Velaphi EVREV 1: N. Singhal COI #213 EVREV 2: S. Velaphi COI #242 EVREV 3: H. Ersdal – COI # 76 Taskforce: NLS Prognosis: In newborn infants >34weeks gestation that are receiving positive pressure ventilation at birth (Pop.), does presence of heart rate with no spontaneous breathing or Apgar score of 1, 2 or 3 at >5 minutes (Pr) predict death and/ or neurological outcome (O ). [NRP 860]

Dallas 2015 COI Disclosure Commercial/ industry or Potential Intellectual Conflicts EVREV 1. N Singhal, COI #213- None EVREV 2. S Velaphi, COI #242- None EVREV 3. H Ersdal, COI # 76- None

Dallas Treatment Recommendation Topic not reviewed in 2010

Dallas 2015 C2015 PICO ---  PPO Population: Newborn infants at >34 weeks gestation receiving positive pressure ventilation (Pop) Predictor: No spontaneous breathing with heart rate or Apgar score 1, 2 or 3 at >5 minutes of life (Pr) Outcomes: Death (9-critical), cerebral palsy (8- important), developmental disability (7-important) (O)

Dallas 2015 Inclusion/Exclusion & Articles Found Search Strategy ((Resuscitation AND Apgar score) OR Apgar score OR (Positive pressure ventilation AND Apgar score) OR (Resuscitation AND spontaneous breathing) OR spontaneous breathing OR (positive pressure ventilation AND spontaneous breathing)) AND (mortality OR death OR cerebral palsy OR developmental disability) NOT (case report OR letter OR comment OR editorial OR review) AND (Humans[Mesh] AND infant, newborn[MeSH]). Total retrieved: 532 Inclusions Criteria Newborn, Spontaneous respiration/breathing and/or Apgar score at >5 minutes, Positive pressure ventilation, Resuscitation, Death, Cerebral palsy or Disability at ≥12 m Exclusion Criteria Animal studies, Case reports, Editorials, Letters, Comments, Reviews, Non-English Articles Finally Included in Evidence Profile tables: RCTs # 2; non-RCTs # 6

Dallas Proposed Treatment Recommendations In babies >34 weeks gestation receiving positive pressure ventilation, absence of spontaneous breathing despite presence of heart rate or an Apgar score 1 to 3 at ≥20 minutes of age are strong predictors of mortality or significant morbidity. In settings where resources are limited we suggest that it may be reasonable to stop assisted ventilation in babies with no spontaneous breathing despite presence of heart rate or Apgar score 1-3 at ≥20 minutes (weak recommendation, very low quality of evidence).

Dallas 2015 Risk of Bias in studies Non-RCT bias asssesment StudyYearDesign Total Patients PopulationCountry Industry Funding Eligibility Criteria Exposure/Outc ome Confounding Follow up Ekert 1997 Retrosp. 178Term, FU- 12mCanadaNoLow High Koppe 1984 Retrosp. 54>37w, FU- 5yNetherlandsNoLow HighLow Laptook 2009 Prospect. 188 ≥36w, FU m, coolingUSANoLow Natarajan 2013 Prospect. 174 ≥36w, FU- 6-7y, cooling USANoLowHighLow Nelson 1981 Retrosp. 390Pre/Term, FU-7yUSANoHighLowHighLow Scott 1976 Retrosp w, FU- 3- 7y UK NoHighLowHighLow Shah 2006 Retrosp.375 Term, FU m CanadaNo Low Steiner 1975 Retrosp.22FU-4.5UKNo High Low

Dallas 2015 Key data from key studies: Death/CP/Disability Author, YearApgar score min Apgar score Apgar score Apgar score 20min Nelson 1981, % Mortality 57% CP Laptook 2009, % Mortality 50% Disability 47% Mortality 63% Disability 39% Mortality 38% Disabilty - Natarajan 2013, 98 (Control) 63% Mortality 75% Mort./ CP 75% Mort/LIQ 57% Mortality 86% Mort./ CP 86% Mort/LIQ 62% Mortality 86% Mort./ CP 86% Mort/LIQ - Natarajan 2013, 98 (Hypothermia) 67% Mortality 67% Mort./ CP 67% Mort/LIQ 43% Mortality 83% Mort./ CP 86% Mort/LIQ 27% Mortality 33% Mort./ CP 33% Mort/LIQ -

Dallas 2015 Key data from key studies: Death/CP/Disability Author, YearOnset of breathing 1-9 Onset of breathing min Onset of breathing >20 min Onset of breathing >30 min Steiner (n=27) 5% Mortality (at 1-15min) No deaths (at 16-28min) --100% Mortality Scott (n=33) - 52% Mortality 26% CP Koppe (n=54) 20% Mortality 10% Disability (at <15 min) 29% Mortality 20% Disability (at min) - 77% Mortality 67% Disability Ekert (n=178) 42% Death/ Disability 56% Death/ Disability 88% Death/ Disability - Shah (n=302) - OR (CI )

Dallas 2015 Evidence Profile Table (Apgar Score) Quality assessment№ of patients ImpactQualityImportance № of studies Study design Risk of biasInconsistencyIndirectness Imprecisio n Other considerations absence of spontaneou s breathing in presence of heart rate or Apgar score of 1, 2 or 3 at >5 minutes presence of spontaneous breathing or Apgar score >3 Mortality or Deaths and Apgar score 0-3 at 20 minutes 1 observational studies serious 1 not seriousserious 1 not seriousnone 59/100 (59.0%) 12.8/100 (12.8%) Death rate in neonates with Apgar scores 0- 3 was 59%, compared to 23.2% and 2.4% in those with Apgar score 4-6 and 7-10 respectively at 20 minutes. ⨁ ◯◯◯ VERY LOW CRITICAL Mortality or Death at 6-7 years and Apgar score 1, 2, or 3 at 10 minutes 1randomised trials not serious serious 2 serious 3 none 31/60 (51.7%) 21/89 (23.6%) Mortality rate was 37.5% in the cooled group (induced hypothermia) compared to 61% in the control group in infants with Apgar scores of 1, 2 or 3 at 10 minutes. ⨁⨁ ◯◯ LOW CRITICAL Mortality at months and Apgar score 1, 2, or 3 at 10 minutes 1randomised trials not serious serious 2 serious 3 none29/65 (44.6%) 18/98 (18.4%)Death rates were 7/11, 8/15 and 15/39 with Apgar score of 1, 2 and 3 respectively compared to 11/42, 3/20, 4/23 and 0/13 with Apgar scores of 4, 5, 6 and 7-10 respectively at 10 minutes. ⨁⨁ ◯◯ LOW CRITICAL

Dallas 2015 Evidence Profile Table (Apgar score) (2) Quality assessment№ of patients ImpactQualityImportance № of studies Study design Risk of biasInconsistencyIndirectnessImprecision Other considerati ons absence of spontaneo us breathing in presence of heart rate or Apgar score of 1, 2 or 3 at >5 minutes presence of spontaneo us breathing or Apgar score >3 Cerebral Palsy at 6-7 years- Apgar score 1, 2 and 3 at 10 minutes 1 randomised trials not serious serious 1 serious 2 none 11/29 (37.9%) 9/68 (13.2%) Cerebral palsy occurred in 3/15 (20%) of the cooled group (induced hypothermia) compared to 8/14 (57%) in the control group in infants with Apgar scores of 1, 2 and 3 at 10 minutes. ⨁⨁ ◯◯ LOW CRITICAL Moderate to severe disability at months with Apgar score 1, 2 and 3 at 10 minutes 1 randomised trials not serious serious 1 serious 2 none 16/36 (44.4%) 21/80 (26.3%) ⨁⨁ ◯◯ LOW CRITICAL Moderate to severe disability at 6-7 years with Apgar score 1, 2 and 3 at 10 minutes 1randomised trials not serious serious 1 serious 2 none14/29 (48.3%) 19/68 (27.9%) Moderate to severe disability occurred in 33% of the cooled group (induced hypothermia) compared to 64% in the control group in infants with Apgar score 1, 2 or 3 at 10 minutes ⨁⨁ ◯◯ LOW CRITICAL

Dallas 2015 Evidence Profile Table (Breathing) Quality assessment№ of patients ImpactQualityImportance № of studies Study design Risk of bias Inconsisten cy IndirectnessImprecision Other consideration s absence of spontaneous breathing in presence of heart rate or Apgar score of 1, 2 or 3 at >5 minutes presence of spontaneous breathing or Apgar score >3 Mortality and no spontaneous breathing for >20 or 30 minutes 2 observation al studies serious 2 not seriousserious 2 serious 1 none 17/33 (52%) of infants with onset of cpontaneous breathing at >20 minutes (Scott 712, 1976) and 10/13 (77%) in infants with onset of breathing after >30 minutes (Koppe, 193, 1984) ⨁ ◯◯◯ VERY LOW CRITICAL Cerebral palsy or abnormal neurological outcome and spontaneous breathing >20 or 30 minutes 3 observation al studies serious 2 not seriousserious 2 serious 1 none 35% had cerebral palsy and % had abnormal neurological outcome ⨁ ◯◯◯ VERY LOW CRITICAL Death and/ or moderate to severe disability and no spontaneous breathing >20 or 30 minutes 2 observation al studies serious 3 not serious serious 1 noneTime to spontaneous respiration >20 minutes is associated with 88% mortality and/or moderate to severe disability (Ekert 613, 1997), time to spontaneous breathing at>30 minutes is a predictor of death and/ or moderate to severe disability with OR ( ). ⨁ ◯◯◯ VERY LOW CRITICAL

Dallas 2015 Consensus on Science statements (1) Apgar score at 20 minutes For all the outcomes, we could not find studies that reported on individual Apgar scores (1, 2 or 3) beyond 10 minutes. One very low quality study (downgraded for indirectness) reported on Apgar scores at 20 minutes but included patients with Apgar score of 0 (Nelson 1981, 36). This study reported that in babies weighing >2500 grams with Apgar score of 0- 3 at 20 minutes the mortality was 59% and 57% of patients developed cerebral palsy.

Dallas 2015 Consensus on Science statements Apgar score at 10 minutes For the critical outcome of death we identified low quality evidence (downgraded for imprecision) from 2 randomized studies (Laptook 2009, 1619; Natarajan 2013, F473), one study (Laptook 2009, 1619) reporting mortality of 64%, 47% and 39% for Apgar score of 1, 2 and 3 respectively, with OR – 1.42 ( ) at months. Other study (Natarajan 2013, 473) reported outcomes at 6-7 years, babies with Apgar scores of 1, 2 and 3 had a mortality rate of 67%, 43% and 27% respectively if were managed with induced hypothermia and 63%, 57% and 62% for those not cooled.

Dallas 2015 Consensus on Science statements Apgar score at 10 minutes For the critical outcome of death and/or cerebral palsy (CP) we identified low quality evidence (downgraded for imprecision) from 1 randomized study (Natarajan 2013, F473) reporting at 6-7 years of life that 67%, 83% and 33% of babies with Apgar score of 1, 2 and 3 respectively had the outcome of death/ CP if managed with induced hypothermia, and 75%, 86% and 86% if not managed with hypothermia.

Dallas 2015 Consensus on Science statements Apgar score at 10 minutes For the critical outcome of moderate/ severe disability we identified low quality evidence (downgraded for imprecision) from 2 randomized (Laptook 2009, 1619; Natarajan 2013, F473) one (Laptook 2009, 1619) reporting the outcome in 50%, 63% and 38% for Apgar score of 1, 2 and 3 respectively, with OR – 1.30 ( ) at months., the other study (Natarajan 2013, 473) reporting at 6-7 years of life that 100%, 75% and 9% of babies with Apgar score of 1, 2 and 3 respectively had moderate/ severe disability if managed with induced hypothermia, and 67%, 67% and 71% if not managed with hypothermia.

Dallas 2015 Consensus on Science statements No spontaneous respiration For the critical outcome of death we identified very low quality evidence (downgraded for imprecision) from 2 observational studies (Scott 1976, 712; Koppe 1984, 193) that time to spontaneous respiration for more than 30 minutes was associated with 52-77% mortality For the critical outcome of cerebral palsy or abnormal neurological findings we identified very low quality evidence (downgraded for imprecision) (Steiner 1975, 696; Scott 1976, 712; Koppe 1984, 193) that time to respiration more than 30 minutes was associated with 35% of cerebral palsy and % abnormal neurological findings

Dallas 2015 Consensus on Science statements No spontaneous respiration For the critical outcome of death and/ or moderate to severe disability we identified very low quality evidence (downgraded for imprecision) from 2 observational studies (Ekert 1997, 613; Shah 2006, 729) that time to spontaneous respiration of minutes and >20 minutes was associated with this outcome in 56% and 88% of patients respectively (Ekert 1997, 613) and time to spontaneous breathing at ≥30 minutes was a predictor of this outcome – OR ( ).

Dallas Proposed Treatment Recommendations In babies >34 weeks gestation receiving positive pressure ventilation, absence of spontaneous breathing despite presence of heart rate or an Apgar score 1 to 3 at ≥20 minutes of age are strong predictors of mortality or significant morbidity. In settings where resources are limited we suggest that it may be reasonable to stop assisted ventilation in babies with no spontaneous breathing despite presence of heart rate or Apgar score 1 to 3 at ≥20 minutes (weak recommendation, very low quality of evidence).

Dallas 2015 Knowledge Gaps No studies identified from low-resource settings Outcome of babies with delayed onset of breathing who are managed with induced hypothermia in low resource settings Outcome of babies with gasping or irregular breathing and a heart activity at 20 minutes of life

Dallas 2015 COI Disclosure (specific to this systematic review) Commercial/industry List here Potential intellectual conflicts List here Essential slide if no simultaneous projection. Estimated time <30 sec

Dallas CoSTR Please provide the Consensus on Science and Treatment Recommendation published in the 2010 International Consensus on CPR and ECC Science with Treatment Recommendations (paste from SEERs) if this topic was reviewed in If topic not reviewed, indicate no review in Essential slide. Paste from SEERs or CoSTR. Estimated time <30 sec

Dallas 2015 C2015 PICO Population: Intervention: Comparison: Outcomes Essential slide. Paste from SEERs. Estimated time <30 sec

Dallas 2015 Inclusion/Exclusion & Articles Found List Inclusions/Exclusions Criteria Insert Number of Articles Finally Evaluated Essential slide. Paste (as picture or text) from SEERs. Estimated time <30 sec

Dallas Proposed Treatment Recommendations Insert draft Treatment Recommendations from SEERs (including direction, strength of evidence grade and quality of evidence): eg. We recommend against X in comparison to Y for OHCA (strong recommendation, high quality of evidence). Values and preferences statement: In making this recommendation we place a higher value on not allocating resources to an ineffective intervention over any yet to be proven benefit for critical or important outcomes. For weak recommendation would use the word “suggest” instead of “recommend”. Recommendations can obviously be for or against routine or specific use. Essential slide. Paste from SEERs. Estimated time <30 sec This is going to help the audience evaluate your presentation and decide if the data supports it or not. Paste from SEERs

Dallas 2015 Risk of Bias in studies Essential slide(s). Either paste summary of bias assessments here (estimated time 30 sec), or use one slide for the bias assessment for each study included in your evidence profile tables (estimated time 5 sec per slide). Paste from SEERs.

Dallas 2015 Key data from key studies Optional slide(s). May use up to 3 slides (with <30 seconds each) to cover key data (given restrictions imposed by total time available to present topic). May refer to more than one citation per slide if necessary. Data could be pasted from SEERs. Reference P: I: C: O:

Dallas 2015 Evidence profile table(s) Essential slide. Estimated time <60 sec. One of up to 3 (maximum) Evidence Profile slides (in standard format) for all outcomes designated as “critical”. May refer to more than one question per slide if necessary. Could be pasted from word, GuidelineDevelopment.org or SEERs.

Dallas 2015 Proposed Consensus on Science statements Insert Summary statement(s) from SEERs* For the important outcome of “survival to hospital discharge” we have identified moderate quality evidence (downgraded for indirectness) from two RCTs enrolling 421 patients showing no benefit (OR % CI 0.33 – 2.01). We did not identify any evidence to address the critical outcome of “neurologically intact survival”. Essential slide (minimum of one slide). Estimated time <60 sec. Insert Summary statement(s) from SEERs.

Dallas 2015 Draft Treatment Recommendations Insert draft Treatment Recommendations from SEERs (including direction, strength of evidence grade and quality of evidence): eg. We recommend against X in comparison to Y for OHCA (strong recommendation, high quality of evidence). Values and preferences statement: In making this recommendation we place a higher value on not allocating resources to an ineffective intervention over any yet to be proven benefit for critical or important outcomes. For weak recommendation would use the word “suggest” instead of “recommend”. Recommendations can obviously be for or against routine or specific use. Essential slide (one or two slides only). Estimated time <60 sec. Insert draft Treatment recommendations from SEERs.

Dallas 2015 Knowledge Gaps (eg. ETT vs BVM) Other specific worksheets that would be helpful Relationship with training to ETT success Specific research required Adult ETT vs BVM Essential slide (one slide only). Estimated time <30 sec

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 Essential slide (one slide only). Estimated time <30 sec

Dallas 2015 Evidence profile table(s)