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Randomized Controlled Trial
. 2019 Mar 26;321(12):1165-1175.
doi: 10.1001/jama.2019.1660.

Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial

Haresh Kirpalani  1 , Sarah J Ratcliffe  2 , Martin Keszler  3 , Peter G Davis  4 , Elizabeth E Foglia  5 , Arjan Te Pas  6 , Melissa Fernando  7 , Aasma Chaudhary  8 , Russell Localio  7 , Anton H van Kaam  9 , Wes Onland  9 , Louise S Owen  10   11   12 , Georg M Schmölzer  13 , Anup Katheria  14 , Helmut Hummler  15   16 , Gianluca Lista  17 , Soraya Abbasi  18 , Daniel Klotz  19 , Burkhard Simma  20 , Vinay Nadkarni  21 , Francis R Poulain  22 , Steven M Donn  23 , Han-Suk Kim  24 , Won Soon Park  25 , Claudia Cadet  26 , Juin Yee Kong  27 , Alexandra Smith  28 , Ursula Guillen  29 , Helen G Liley  30 , Andrew O Hopper  31 , Masanori Tamura  32 ; SAIL Site Investigators
Affiliations
Randomized Controlled Trial

Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial

Haresh Kirpalani et al. JAMA. .

Abstract

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations.

Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants.

Design, setting, and participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes.

Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211).

Main outcome and measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours.

Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups.

Conclusions and relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions.

Trial registration: clinicaltrials.gov Identifier: NCT02139800.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kirpalani reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and a donation of face masks from Fisher-Paykel during the conduct of the study. Drs Ratcliffe, Keszler, Katheria, Poulain, and Smith reported receiving grants from the NICHD during the conduct of the study. Dr Davis reported receiving grants from the Australian National Health and Medical Research Council during the conduct of the study. Dr Localio reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and grants from the NIH, Patient-Centered Outcomes Research Institute, American College of Physicians, and the US Department of Education outside the submitted work. Drs Owen, Schmölzer, Abbasi, and Kong reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Recruitment, Randomization, and Retention
In the antenatal consent procedure, the informed-consent rate was 48% of women assessed for potential eligibility (626 of 1302 screened). Three hundred infants from 269 mothers for whom consent was given antenatally were assessed for eligibility. Of the infants delivered within the gestational age inclusion dates, but who could not be randomized (n = 65), most being infants with adequate respiration (n = 52). In centers undergoing a deferred-consent procedure, of 246 infants assessed for eligibility having met inclusion criteria, 18 had adequate respiration at birth and were not randomized.
Figure 2.
Figure 2.. Adjusted Comparisons of Prespecified Secondary Safety Outcomes and Adverse Events by Group
These prespecified markers of harm were chosen a priori by the executive committee and the data and safety monitoring committee together. Results expressed as adjusted risk differences (95% CIs), calculated using marginal probabilities from the adjusted generalized estimating equation models. Covariates adjusted for were gestational age, site, infant sex, maternal corticosteroid use, initial heart rate, small for gestational age, and consent type used, as well as for the correlation between infants from multiple births. Fio2 indicates fraction of inspired oxygen; and IVH, intraventricular hemorrhage.
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