Dallas : CPAP and IPPV In spontaneously breathing preterm infants with respiratory distress requiring respiratory support in the delivery room, does the use of CPAP compared with intubation and IPPV improve outcome ? TFQO: B Stenson #274 EVREV 1: Tetsuya Isayama #113 EVREV 2: Ben Stenson #274 Taskforce: NRP

Dallas 2015 COI Disclosure B Stenson COI#274 Commercial/industry Nil relevant to this review Potential intellectual conflicts nil Tetsuya Isayama COI#113 Commercial/industry nil Potential intellectual conflicts nil

Dallas CoSTR “Spontaneously breathing preterm infants who have respiratory distress may be supported with CPAP or intubation and mechanical ventilation. The most appropriate choice may be guided by local expertise and preferences.”

Dallas 2015 C2015 PICO Population:Spontaneously breathing preterm infants with respiratory distress in the delivery room Intervention:CPAP Comparison:Intubation and IPPV Outcomes: Death or BPD -8, Death -9, BPD-7 Air leak -5, severe IVH-7, NEC -7, severe ROP - 7

Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions/Exclusions Inclusion - Randomized controlled trials with the intervention allocated in the first 15 minutes after birth Exclusion – Randomized trials with later treatment allocation Lower levels of evidence Number of Articles initially identified, and number finally Included in Evidence Profile tables Found in Medline 469, Embase 679, Cochrane RCTs identified, RCTs - 3 included Other 3 RCTs were excluded because they were published only as abstracts. non-RCTs n/a

Dallas Proposed Treatment Recommendations For spontaneously breathing preterm infants with respiratory distress requiring respiratory support in the delivery room we suggest initial use of CPAP rather than intubation and IPPV (weak recommendation, moderate quality of evidence).

Dallas 2015 Risk of Bias in studies RCT bias assessment Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias Study Year Design Total Patients Population Industry Funding Morley 2008RCT wkGA with RD NoneLow HighLow Finer 2010RCT wkGANoneLow HighLow Unclear Dunn 2011RCT wkGANoneLow HighLow Unclear No blinding was done in all 3 trials but all outcomes assessed were objective. Two trials (Finer 2010 and Dunn 2011) included all infants at birth. Finer 2010 used different extubation criteria between the 2 groups.

Dallas 2015 Key data from key studies Death or BPD Death BPD

Dallas 2015 Key data from key studies Severe IVH NEC Air leak

Dallas 2015 Evidence profile table Quality assessmentEvent ratesEffect Quality Importan ce Study# & Design Risk of bias Inconsis tency Indirect ness Impreci sion OtherNCPAP Intubate & IPPV Relative (95% CI) Absolute (95% CI) Death or bronchopulmonary dysplasia (BPD) 3 RCT not serious 1 not serious serious 2 none 493/1193 (41.3%) 531/1165 (45.6%) RR 0.91 (0.83 to 1) 41 fewer per 1000 (0 fewer−77 fewer) ◯ MODERA TE CRITICAL (8) Bronchopulmonary dysplasia (BPD) 3 RCT not serious 1 not serious serious 2 none 370/1070 (34.6%) 384/1018 (37.7%) RR 0.92 (0.82 to 1.03) 30 fewer per 1000 (11 more−68 fewer) ◯ MODERA TE CRITICAL (7) Death 3 RCT not serious 1 not serious serious 2 none 123/1193 (10.3%) 147/1165 (12.6%) RR 0.82 (0.66 to 1.03) 23 fewer per 1000 (4 more−43 fewer) ◯ MODERA TE CRITICAL (9) Three RCTs (Morley 2008, Finer 2010, and Dunn 2011) were included. 1.Interventions were not blinded but outcomes were objective. 2.The 95%CI included the null or minimal (negligible) harm (RR )

Dallas 2015 Evidence profile table Quality assessmentEvent ratesEffect Quality Importan ce Study# & Design Risk of bias Inconsi stency Indirect ness Impreci sion OtherNCPAP Intubate & IPPV Relative (95% CI) Absolute (95% CI) Severe intraventricular hemorrhage (Severe IVH) 3 RCT not serious 1 serious 2 not serious very serious 4 none 125/1167 (10.7%) 112/1134 (9.9%) RR 1.09 (0.86 to 1.39) 9 more per 1000 (14 fewer−39 more) ◯◯◯ VERY LOW CRITICAL (7) Air leak 3 RCT not serious 1 serious 3 not serious serious 5 none 85/1192 (7.1%) 67/1165 (5.8%) RR 1.24 (0.91 to 1.69) 14 more per 1000 (5 fewer−40 more) ◯◯◯ LOW IMPORTANT (5) Severe retinopathy of prematurity (Severe ROP) 2 RCT not serious 1 not serious very serious 4 none 80/703 (11.4%) 72/656 (11.0%) RR 1.03 (0.77 to 1.39) 3 more per 1000 (25 fewer−43 more) ◯◯◯ LOW CRITICAL (7) Necrotizing enterocolitis (NEC) 3 RCT not serious 1 not serious serious 5 none 113/1183 (9.6%) 92/1148 (8.0%) RR 1.19 (0.92 to 1.55) 15 more per 1000 (6 fewer−44 more) ◯◯◯ MODERA TE CRITICAL (7) Three RCTs (Morley 2008, Finer 2010, and Dunn 2011) were included, except for severe ROP in which two RCTs (Finer 2010 and Dunn 2011) were included. 1.Interventions were not blinded but outcomes were objective. 2.I-square = 52% 3.I-squared = 75%. Air leak was increased in the CPAP group in one trial (Morley 2008). In this trial the initial CPAP was at 8cmH2O and the criteria for intubation was an oxygen requirement of 60%. 4.The 95% CI were wide and included both clinically important benefit (RR 1.1) 5.The 95%CI included the null or minimal (negligible) harm (RR )

Dallas 2015 Proposed Consensus on Science statements For the critical composite outcome of “death or bronchopulmonary dysplasia” we have identified moderate quality evidence (downgraded for imprecision) from 3 RCTs (Morley , Finer , Dunn 2011 e1069) enrolling 2358 preterm infants born at < 30 weeks gestation in the first 15 minutes after birth showing modest potential benefit to starting treatment with CPAP (R.R. 0.91, 95% CI 0.83 – 1.00). For the critical outcome of “death” we have identified moderate quality evidence (downgraded for imprecision) from the same 3 RCTs (Morley , Finer , Dunn 2011 e1069) showing modest potential benefit to starting treatment with CPAP (R.R. 0.82, 95% CI 0.66 – 1.03). For the critical outcome of “bronchopulmonary dysplasia” we have identified moderate quality evidence (downgraded for imprecision) from the same 3 RCTs (Morley , Finer , Dunn 2011 e1069) showing modest potential benefit to starting treatment with CPAP (R.R. 0.92, 95% CI 0.82 – 1.03).

Dallas 2015 Proposed Consensus on Science statements For the critical outcome of “air leak” we have identified low quality evidence (downgraded for inconsistency and imprecision) from the same 3 RCTs (Morley , Finer , Dunn 2011 e1069) showing no benefit to starting treatment with CPAP (R.R 1.24, 95% CI 0.91 – 1.69). For the critical outcome of “severe intraventricular haemorrhage” we have identified very low quality evidence (downgraded for inconsistency and very serious imprecision) from the same 3 RCTs (Morley , Finer , Dunn 2011 e1069) showing no benefit to starting treatment with CPAP (R.R 1.09, 95% CI 0.86 – 1.39).

Dallas 2015 Proposed Consensus on Science statements For the important outcome of “necrotizing enterocolitis” we have identified moderate quality evidence (downgraded for imprecision) from the same 3 RCTs (Morley , Finer , Dunn 2011 e1069) showing no benefit to starting treatment with CPAP (R.R % CI 0.92 – 1.55). For the important outcome of “severe retinopathy of prematurity” we have identified low quality evidence (downgraded for very serious imprecision) from 2 RCTs (Finer , Dunn 2011 e1069) enrolling 1359 infants showing no benefit to starting treatment with CPAP (R.R % CI ).

Dallas 2015 Draft Treatment Recommendations For spontaneously breathing preterm infants with respiratory distress requiring respiratory support in the delivery room we suggest initial use of CPAP rather than intubation and IPPV (weak recommendation, moderate quality of evidence). Values and preference statement: In making this suggestion we recognize that the absolute reduction in risk of adverse outcome associated with starting with CPAP is small and that infants recruited to the trials had a high rate of treatment with antenatal steroids but we favor the less invasive approach. The balance of risks and benefits of this approach in infants who have not received antenatal steroids is unknown.

Dallas 2015 Knowledge Gaps A further trial of CPAP versus intubation and IPPV in high risk preterm infants at lower gestations is required to determine the risks and benefits more clearly. It is not clear whether there is a significant effect on mortality. The confidence intervals for the other morbidities of prematurity leave open the possibility that any benefit in relation to bronchopulmonary dysplasia might still be balanced by a small increase in risk of severe intraventricular haemorrhage or necrotizing enterocolitis. The utility of using an INSURE approach to facilitate early stabilization on CPAP soon after birth has been compared with CPAP alone in at least 2 trials and this should be the subject of a future worksheet.

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