1. Dallas 2015 TFQO: David Boyle COI #26 EVREV 1: David Boyle #COI#26 EVREV 1: Jane McGowan #370 Taskforce: Neonatal Ventilation Strategies in the DR (NRP 809)

2. Dallas 2015 COI Disclosure EVREV 1: Boyle, COI#26: No conflicts EVREV 2: McGowan, COI#370: No conflicts

3. Dallas 2015 2010 Treatment Recommendation To establish initial lung inflation in apneic newborn infants, initiation of intermittent positive-pressure ventilation at birth can be accomplished with either shorter or longer inspiratory times.

4. Dallas 2015 C2015 PICO Population: Term and preterm infants who do not establish spontaneous respirations at birth Intervention: Administration of one or more pressure-limited sustained lung inflations (lasting >5) seconds Comparison: Intermittent PPV with short inspiratory times Outcomes: Air leaks (9), overall mortality (9), BPD (8), establishment of FRC (8), mechanical ventilation in first 72 hr (8), time to HR >100 bpm (8), Apgar at 5 minutes (7), CPR in DR (6), intubation in DR (6)

5. Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions: Human and animal studies (RCTs and nonRCTs) comparing an initial sustained inflation (≥5 sec) immediately after birth to PPV Exclusions: Mechanical ventilation or other interventions prior to administration of a sustained inflation, an initial sustained inflation of less than 5 seconds, review articles, abstracts Number of Articles initially identified: 88 Number of articles included: 17 RCTs Human: 3 Animal: 9 Non-RCTs Human: 5

6. Dallas 2015 Inclusion/Exclusion & Articles Found Number in Evidence Profile tables: 5 Evidence Profile Tables include 3 human RCTs and 2 human cohort studies 9 animal studies and 3 human observational studies included in the worksheet provide biologic plausibility/context for this intervention

7. Dallas 2015 2015 Proposed Treatment Recommendations We suggest an initial sustained inflation (>5 seconds duration) should not be used as routine care for preterm infants without spontaneous respirations immediately after birth, but may be considered. (Weak recommendation, Moderate quality of evidence)

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 Lindner 1999, 9611999Non-RCT123 23 wks GANo Yes NoUnclear Lista 2011, 452011Non-RCT20828.1 (2.2) weeks GANo Yes Unclear Vyas 1981, 6351981Non-RCT931 to 43 weeks GANo RCT bias assessment StudyYearDesign Total Patients Population Industry Funding Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias Lindner 2005, 3032005RCT61 25-28+6 weeks GA NoLow High Low Harling 2005, F4062004RCT52<31 weeks GANoLowHigh UnclearLow Unclear Lista 2015, e4572015RCT291 25+0 to 28+6 wks GA NoLow HighLow

9. Dallas 2015 Mechanical ventilation <72 hours

10. Dallas 2015 Evidence profile table(s) Mechanical Ventilation <72 hours

11. Dallas 2015 BPD

12. Dallas 2015 Evidence profile table(s) BPD

13. Dallas 2015 Mortality

14. Dallas 2015 Evidence profile table(s) MORTALITY

15. Dallas 2015 Air Leaks

16. Dallas 2015 Evidence profile table(s) Air Leaks

17. Dallas 2015 Proposed Consensus on Science statements Regarding the administration of sustained inflation in newborn infants without spontaneous respirations: For the critical outcome of need for mechanical ventilation in the first 72 hours after birth, moderate quality evidence (downgraded for other considerations) from three RCTs enrolling 404 newborns showed significant benefit (Harling 2005 F406; Lindner 2005 303; Lista 2015 e457). In addition, very low quality evidence (downgraded for other considerations) from two cohort studies with a total of 331 patients also showed significant benefit (Lindner 1999 961, Lista 2011 45).

18. Dallas 2015 Proposed Consensus on Science statements For the critical outcome of BPD, moderate quality evidence (downgraded for moderate imprecision and other considerations) from three RCTs enrolling 404 patients showed no benefit (Harling 2005 F406; Lindner 2005 303; Lista 2015 e457). Very low quality evidence (downgraded for other considerations) from two cohort studies enrolling 331 patients showed significant benefit (Lindner 1999 961, Lista 2011 45).

19. Dallas 2015 Proposed Consensus on Science statements For the critical outcome of mortality, moderate quality evidence (downgraded for other considerations) from 3 RCTs enrolling 404 newborns, and very low quality evidence (downgraded for other considerations) from two cohort studies with a total of 331 patients showed no benefit (Harling 2005 F406; Lindner 2005 303; Lista 2015 e457; Lindner 1999 961, Lista 2011 45).

20. Dallas 2015 Proposed Consensus on Science statements For the critical outcome of air leak, low quality evidence (downgraded for imprecision and other considerations) from three RCTs enrolling 404 newborns (Harling 2005 F406; Lindner 2005 303; Lista 2015 e457) and very low quality of evidence (downgraded for imprecision and other considerations) from two cohort studies with a total of 331 patients (Lindner 1999 961, Lista 2011 45) showed no effect. For the important outcome of Apgar score, there was no difference between groups in any studies reviewed (Harling 2005 F406; Lindner 2005 303; Lindner 1999 961, Lista 2011 45).

21. Dallas 2015 Proposed Consensus on Science statements In a small case series of 9 asphyxiated term infants, a prolonged initial inflation of 5 seconds produced a 2-fold increase in functional residual capacity compared with historic controls (Vyas 1981 635). Very low quality evidence from one cohort study (Lindner 1999 961) demonstrated that the need for intubation in the delivery room was significantly lower in infants who received a sustained inflation compared to conventional management. No human studies evaluated time to HR >100 beats per minute, FiO2 in the delivery room, or need for chest compressions in the delivery room (i.e., “bystander CPR”).

22. Dallas 2015 Proposed Consensus on Science statements Animal studies of the effects of sustained inflation on alveolar recruitment have shown mixed results. Studies in preterm lambs (Sobotka 2011 56; Klingenberg 2013 F222) and preterm rabbits (te Pas 2009 295) showed more uniform lung inflation and better lung compliance if animals received a sustained inflation prior to initiation of mechanical ventilation; however, another study in preterm lambs, showed no benefit after an initial SI (Klopping-Ketelaars 1994 43), and an additional study showed that step-wise increases in PEEP resulted in better overall lung mechanics than treatment with an initial sustained inflation (Tingay 2014 288).

23. Dallas 2015 Proposed Consensus on Science statements Comparison across studies (RCTs and cohort) was complicated by variation across studies in the duration of the initial sustained inflation (from 5-20 seconds) as well as the initial peak inspiratory pressure (20-30 cm H2O). In addition, investigators used different interface devices to deliver the sustained inflations (endotracheal tube, face mask, nasopharyngeal tube). Three studies repeated the initial SI once (Lindner 1999 961, Lista 2011 451; Lista 2015 e457 ), one at a higher PIP (Lindner 1999 961); one study repeated the SI twice, increasing the PIP on second application (Lindner 2005 303). Therefore all studies were downgraded for “other considerations”. No studies compared the efficacy of a single sustained inflation to multiple sustained inflations.

24. Dallas 2015 Draft Treatment Recommendations We suggest an initial sustained inflation (>5 seconds duration) should not be used as routine care for preterm infants without spontaneous respirations immediately after birth, but may be considered. (Weak recommendation, Moderate quality of evidence)

25. Dallas 2015 Draft Treatment Recommendations Values and preferences statement : In making this recommendation we place a higher value on the lack of clarity of how to administer sustained inflations over the reduced need for intubation at 72 hours in the absence of long term benefits, including risk of bronchopulmonary dysplasia or overall mortality. Although the studies reviewed showed that administration of a sustained inflation reduced the need for mechanical ventilation in the first 72 hours of life, the use of SI did not change the incidence of important long-term outcomes related to lung function, including risk of bronchopulmonary dysplasia or overall mortality.

26. Dallas 2015 Knowledge Gaps Further studies are essential to determine the optimal pressure and duration of sustained inflation that would allow the establishment of FRC while minimizing the risk of barotrauma in the newly born infant, as well as the long-term morbidity. Randomized, controlled trials are needed to determine the optimal duration of initial sustained inflations, the appropriate peak inflation pressure, and the number of inflations that should be administered. Specific research required Larger studies in animal models-SI vs PPV, different durations of SI RCT of PPV vs SI using standard devices Further studies are need to determine the optimal pressure and duration of sustained inflation that would allow the establishment of FRC while minimizing the risk of barotrauma in the newly born infant. Early outcome measures, e.g., time to heart rate >100 beats per minute Population likely to benefit

27. Dallas 2015 Final Comments One additional human RCT is pending publication (ClinicalTrials.gov #NCT01739114); completed October 2014, estimated enrollment 186. One RCT identified (Pediatrics Aug--2007; 120 (2): 322-9. A randomized, controlled trial of delivery-room respiratory management in very preterm infants.. te Pas, Arjan B; Walther, Frans J) was excluded from the final analysis due to methodologic variability - use of different interface devices between control and experimental groups (NP tube and T-piece ventilator vs mask and self-inflating bag) as well as enrollment of subjects at multiple time points after delivery. DWB/JEM