Association of Administration of Surfactant Using Less Invasive Methods With Outcomes in Extremely Preterm Infants Less Than 27 Weeks of Gestation

Abstract

IMPORTANCEThe inclusion of less invasive surfactant administration (LISA) in the care of preterm infants has been found to be beneficial for respiratory outcomes. Recently, the OPTIMIST trial found higher mortality rates in the subgroup of infants born at 25 to 26 weeks' gestational age (GA) who received surfactant treatment while spontaneously breathing. OBJECTIVETo analyze outcomes among LISA-exposed, highly vulnerable babies born at less than 27 weeks' GA within the large-scale observational cohort of the German Neonatal Network. DESIGN, SETTING, AND PARTICIPANTSIn this cohort study of data from 68 tertiary level neonatal intensive care units in Germany of infants born between 22 weeks 0 days to 26 weeks 6 days of gestation between April 1, 2009, and December 31, 2020, short-term outcomes among infants receiving LISA vs infants not receiving LISA were compared. EXPOSURE Use of LISA within the first 72 hours of life. MAIN OUTCOMES AND MEASURESThe main outcomes were rates of LISA use, use of mechanical ventilation within the first 72 hours (considered failure of LISA), and association of LISA with outcomes, including death from all causes, bronchopulmonary dysplasia (BPD), death and BPD combined, pneumothorax, retinopathy of prematurity, intracerebral hemorrhage, and periventricular leukomalacia. To address potential confounding factors, multivariate logistic regression models were used. RESULTSA total of 6542 infants (3030 [46.3%] female and 3512 [53.7%] male; mean [SD] GA, 25.3(1.1) weeks; mean [SD] birth weight, 715 [180] g) were analyzed; 2534 infants (38.7%) received LISA, which was most frequently given quasi-prophylactically during delivery room management. Among the infants who received LISA, 1357 (53.6%) did not require mechanical ventilation in the first 72 hours compared with 331 infants (8.3%) of 4008 who did not receive LISA. In a multivariate logistic regression model that adjusted for GA, small-for-GA status, sex, multiple birth, inborn status, antenatal steroid use, and maximum fraction of inspired oxygen in the first 12 hours of life, LISA was associated with reduced risks of all-cause death (odds ratio [OR], 0.74; 95% CI, 0.61-0.90; P = .002), BPD (OR, 0.69; 95% CI, 0.62-0.78; P < .001), and BPD or death (OR, 0.64; 95% CI, 0.57-0.72; P < .001) compared with infants without LISA exposure. CONCLUSIONS AND RELEVANCEThe results of this long-term multicenter cohort study suggest that LISA may be associated with reduced risks of adverse outcomes in extremely preterm infants.

Can we balance early exogenous surfactant therapy and non-invasive respiratory support to optimise outcomes in extremely preterm infants? A nuanced review of the current literature

“…Although these differences did not reach statistical significance, they demand caution. Of note, in contrast, the recently published investigation of the GNN in 6542 preterm infants born at 22 0/6–26 6/7 weeks’ GA documented lower risks of all-cause death and BPD or death in LISA-treated infants in experienced centres 46. However, a previous GNN study found increased rates of focal intestinal perforation (FIP) in the LISA group, primarily in the most immature babies born at 22–24 weeks 41.…”

“…It is also reasonable to consider that targeting this intervention to those with surfactant deficiency would maximise the treatment effect and minimise exposure to the known short-term risks associated with the procedure, including laryngoscopy, bradycardia and hypoxaemia. The strategy of CPAP-assisted spontaneous breathing and early surfactant therapy via LISA—often within the first hour of life—is widespread in GNN centres and includes the tiniest babies 37 45 46. In ~60% of infants, this early treatment remains the only surfactant dose.…”

“…In ~60% of infants, this early treatment remains the only surfactant dose. A second dose is required in ~27%, a third in 8.5% and a fourth dose or more in ~4% of infants 46. The first RCT evaluating the benefits and harms of prophylactic LISA treatment in very immature preterm infants as well as forced expiratory volume in 1 s values at 5 years of age is underway (PRO-LISA trial (Propofol versus placebo (with rescue with ketamine) before less invasive surfactant administration: OPTIMIST: one of cOllaborative Paired Trials Investigating Minimally Invasive Surfactant Therapy), GNN).…”

“…It must be noted that OPTIMIST was closed prior to full enrolment due to the COVID-19 pandemic. The largest cohort studies comparing LISA with standard surfactant replacement therapy, published by the GNN, cover >2500 preterm infants ≤28 weeks’ GA managed with LISA 41 46. LISA was associated with reduced need for MV within the first 72 hours, reduced risk of mortality and BPD, as well as reduced risk of pneumothorax and most secondary outcomes 41 46.…”

“…The largest cohort studies comparing LISA with standard surfactant replacement therapy, published by the GNN, cover >2500 preterm infants ≤28 weeks’ GA managed with LISA 41 46. LISA was associated with reduced need for MV within the first 72 hours, reduced risk of mortality and BPD, as well as reduced risk of pneumothorax and most secondary outcomes 41 46. Data from these trials may indicate that these ‘lower-risk’ interventions can be broadly applied to improve outcomes.…”