Higher Versus Lower Noninvasive PEEP for Very Preterm Infants at Birth – A Randomized Controlled Trial

Background: Noninvasive continuous positive airway pressure (CPAP) is the recommended first-line respiratory support for very preterm infants after birth to reduce mechanical ventilation associated lung injury and bronchopulmonary dysplasia. The most effective positive end expiratory pressure (PEEP) to prevent CPAP failure is unknown.<br><br>Methods: We conducted this multicenter randomized controlled trial at twelve tertiary neonatal intensive care units in Germany and Switzerland. Infants of 26 weeks 0 days to 29 weeks 6 days´ gestation with written informed consent prior to birth were eligible. Infants with severe congenita anomalies affecting breathing control, gas exchange and/or hemodynamics or decision not to provide full life support before study entry were ineligible.Immediately after birth, infants were assigned to receive higher (6-8cmH2O, intervention group) or lower (3-5cmH2O, control group) PEEP during CPAP support.&nbsp; Randomization was stratified by gestational age (26 + 0/7 – 27 + 6/7 or 28 + 0/7 – 29+6/7). The primary outcome was CPAP failure within the first 120 hours after birth defined by at least meeting one of the following criteria: Intubation and mechanical ventilation &gt;1 hour, FiO2 ≥0.5 for more than one hour, pCO2 ≥70mmHg in two consecutive blood gas analyses &gt;2 hours apart and the analysis was based on the intention to treat principle. The trial was registered with the German Clinical Trial Registry, DRKS.de, Identifier: 00019940.<br><br>Findings: Between June 2020 and August 2024, a total of 216 infants were enrolled at 11 of 12 participating centers.107 infants were randomized to the higher PEEP group and 109 infants to lower PEEP with available primary outcome data for 105 and 108, respectively. The median GA was 28.4 weeks (interquartile range (IQR), 27.4 – 29.3) with a median birthweight of 1070 grams (IQR, 845 – 1260). CPAP failure occurred in 32/105 (30.5%) during higher and 37/108 (34.3%) with lower PEEP (risk ratio (RR) 0.95; 95%-confidence interval [CI], 0.79 – 1.14, p=0.56). There were no differences in in-hospital mortality (3.7% vs. 0.9%; RR, 1.03 [95% CI, 0.99 – 1.07]), any intraventricular hemorrhage (13.5% vs. 8.3%; RR, 1.06 [95% CI, 0.96 – 1.16]), bronchopulmonary dysplasia (32.0% vs. 30.6%; RR, 1.02 [95% CI, 0.85 – 1.23]) or any further secondary outcomes, adverse and serious adverse events.<br><br>Interpretation: The application of higher compared to lower PEEP levels after birth did not significantly affect the rate of CPAP-failure. Both applied PEEP ranges appear to be equally safe in terms of adverse and serious adverse effects. Future trials should be larger scaled and expanded to the most immature preterm infants to further assess potential benefits or harms of different PEEP levels during primary nasal CPAP respiratory support.