Sustained Aeration of Infant Lungs Trial (SAIL)

This study is a 2-arm randomized, controlled, multi-center clinical trial to determine which of two strategies at birth are best to optimally aerate the lung of preterm infants. Specifically we will determine in 600 infants of 23-26 weeks gestational age (GA) requiring respiratory support at birth which of two lung opening strategies - either a standard PEEP/CPAP of 5-7 cm H2O in the delivery room (DR), as compared to early lung recruitment using Sustained Inflation (SI) in the DR, will result in a lower rate of the combined endpoint of death or bronchopulmonary dysplasia (BPD) at 36 weeks gestational age. Hypotheses: Early lung recruitment with SI superimposed upon standard PEEP/CPAP in the DR will reduce the need for mechanical ventilation in the first seven days of life, and reduce need for surfactant use; and A policy of DR SI on standard PEEP/CPAP recruitment will confer better outcomes at 36 weeks post-menstrual age (PMA) than standard PEEP/CPAP

The SAIL trial aims to provide evidence for changing policy or standard of care. The context of this trial is an unacceptable rate of poor long-term outcomes of preterm infants born as Extremely Low Gestational Age Newborns (ELGAN) <1000 g birthweight (BW), but especially for those born between 23-26 weeks' gestational age (GA). Such infants are the most vulnerable and immature in all organ systems, including the lungs and the brain. These infants are at high risk of death and bronchopulmonary dysplasia (BPD) during their initial hospitalization, neurodevelopmental impairment (NDI) and pulmonary problems in infancy and childhood. The SAIL trial focuses on facilitating the difficult transition of these most vulnerable infants from a liquid filled in-utero lung to an ex-utero air-filled lung. Sustained Inflation (SI) is a promising delivery room (DR) intervention, with evidence of short-term efficacy with minimal risk of additional harm beyond current standard accepted Newborn Resuscitation Program (NRP) Guidelines. This protocol proposes a fully informed consenting procedure. We propose to evaluate the impact of a SI in the DR on the need for mechanical ventilation in the first week of life which would also impact mortality rates and the incidence and severity of BPD.

Neonatal resuscitation, Extreme Low Gestational Age Newborn (ELGAN), Delivery Room, Continuous positive airway pressure (CPAP), Positive pressure ventilation (PPV), Sustained inflation

Control Arm-Respiratory support using Standard of Care positive-end expiratory pressure/continuous positive airway pressure (PEEP/CPAP) of 5-7 cm H2O compared to Sustained Inflation intervention

Administer delivery room respiratory support using a Sustained Inflation (SI) intervention and expiratory pressure/continuous positive airway pressure (PEEP/CPAP) of 5-7 cm H2O

Newborn Resuscitation Program (NRP) Guidelines using a standard PEEP/CPAP of 5-7 cm H2O as compared to the Sustained Inflation intervention

To determine in infants born at 23-26 weeks gestational age requiring respiratory support at birth, which of two treatment strategies when compared, results in a lower rate of the combined endpoint of death or bronchopulmonary dysplasia.

Duration of any chest drain in-situ post-DR during hospitalization - up to 36 weeks Post Menstrual Age (PMA)

Head ultrasound and/or MRI findings of intraventricular hemorrhage by all grades focusing on grades 3 and 4 by 48 hour and by day 10

Survival to Discharge Home Without BPD, Retinopathy of Prematurity (Grades 3 & 4), or Significant Brain Abnormalities on Head Ultrasound

Survival to discharge home without BPD, retinopathy of prematurity (grades 3 & 4), or significant brain abnormalities on head ultrasound with an expected discharge between 36-40 weeks PMA

Duration of respiratory support (ventilation, CPAP, supplemental oxygen) during hospitalization upto 36 weeks Post Menstrual Age (PMA)

Use of postnatal steroids for treatment of BPD during hospitalization up to 36 weeks Post Menstrual Age (PMA)

Inclusion Criteria: Gestational age (GA) at least 23 weeks but less than 27 completed weeks by best obstetrical estimate Requiring resuscitation/respiratory intervention at birth -"apneic, labored breathing, gasping" (as defined in NRP 2011 AAP 6th Edition p.45) Exclusion Criteria: Considered non-viable by the attending neonatologist Refusal of antenatal informed consent Known major anomalies, pulmonary hypoplasia Mothers who are unable to consent for their medical care and who do not have a surrogate guardian will not be approached for consent

Foglia EE, Kirpalani H, Ratcliffe SJ, Davis PG, Thio M, Hummler H, Lista G, Cavigioli F, Schmolzer GM, Keszler M, Te Pas AB. Sustained Inflation Versus Intermittent Positive Pressure Ventilation for Preterm Infants at Birth: Respiratory Function and Vital Sign Measurements. J Pediatr. 2021 Dec;239:150-154.e1. doi: 10.1016/j.jpeds.2021.08.038. Epub 2021 Aug 25.

Kirpalani H, Keszler M, Foglia EE, Davis P, Ratcliffe S. Considering the Validity of the SAIL Trial-A Navel Gazers Guide to the SAIL Trial. Front Pediatr. 2019 Nov 27;7:495. doi: 10.3389/fped.2019.00495. eCollection 2019.

Kirpalani H, Ratcliffe SJ, Keszler M, Davis PG, Foglia EE, Te Pas A, Fernando M, Chaudhary A, Localio R, van Kaam AH, Onland W, Owen LS, Schmolzer GM, Katheria A, Hummler H, Lista G, Abbasi S, Klotz D, Simma B, Nadkarni V, Poulain FR, Donn SM, Kim HS, Park WS, Cadet C, Kong JY, Smith A, Guillen U, Liley HG, Hopper AO, Tamura M; SAIL Site Investigators. Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial. JAMA. 2019 Mar 26;321(12):1165-1175. doi: 10.1001/jama.2019.1660.

Foglia EE, Te Pas AB. Sustained Lung Inflation: Physiology and Practice. Clin Perinatol. 2016 Dec;43(4):633-646. doi: 10.1016/j.clp.2016.07.002.

Foglia EE, Owen LS, Thio M, Ratcliffe SJ, Lista G, Te Pas A, Hummler H, Nadkarni V, Ades A, Posencheg M, Keszler M, Davis P, Kirpalani H. Sustained Aeration of Infant Lungs (SAIL) trial: study protocol for a randomized controlled trial. Trials. 2015 Mar 15;16:95. doi: 10.1186/s13063-015-0601-9.