Minimally Invasive Surfactant Therapy vs Sham Treatment and Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome—Reply

Abstract

To the Editor The OPTIMIST-A trial 1 found that minimally invasive surfactant therapy, compared with sham treatment, did not reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome. However, the incidence of bronchopulmonary dysplasia was significantly lower in the minimally invasive surfactant therapy group (relative risk, 0.83; 95% CI, 0.70-0.98).In addition, although there was no significant difference in death between groups, an exploratory analysis suggested an increased mortality risk associated with minimally invasive surfactant therapy in the gestational age stratum of 25 to 26 weeks. Because any signal of an increased risk of death raises a significant concern, the authors advised caution about the use of minimally invasive surfactant therapy in infants with gestational ages of 25 to 26 weeks.Nevertheless, subgroup analyses should be interpreted cautiously. 2 There was an imbalance in baseline variables between the groups in the 25 to 26 weeks' gestational age strata, which could have influenced the outcome of death. Within the gestational age stratum of 25 to 26 weeks, infants in the minimally invasive surfactant therapy group, compared with those receiving the control treatment, had a higher frequency of male sex (50% vs 37.9%, respectively), multiple birth (47.8% vs 34.5%), and no or incomplete exposure to antenatal corticosteroids (40% vs 26.4%).Although it is unclear why these imbalances occurred when randomization was stratified by gestational age, they may have resulted from premature trial termination. 3 An analysis performed after adjusting for these covariates was not significantly different; however, the event rate was lower and many covariates may not have been included in the regression analysis. In addition, the credibility of subgroup analyses depends on replication in other studies and biological plausibility supporting the subgroup effect. 2 A previous trial 4 and systematic review 5 did not show harm with the use of minimally invasive surfactant therapy in premature infants.Surfactant therapy is lifesaving, and giving it early via a thin catheter would be expected to be lifesaving rather than life-threatening. 4 In addition, this study 1 did not demonstrate any indication that death was directly attributable to the minimally invasive surfactant therapy intervention. Therefore, I believe the association of higher mortality risk in infants with gestational ages of 25 to 26 weeks who received minimally invasive surfactant therapy was likely attributable to chance rather than minimally invasive surfactant therapy itself.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update

“…The largest study (OPTIMIST) randomised 485 babies of 25–28 weeks with blinding of the intervention: LISA surfactant versus sham procedure at FiO 2 threshold 30%. Although there was no significant difference in the primary outcome of death or BPD, there was a significant reduction in BPD in survivors favouring the treated infants (37% vs. 45%) [73]. However, it is unclear if any differences can be attributed solely to the LISA method, as earlier compared to later surfactant in RDS is already known to be beneficial, and two-thirds of control infants received surfactant [73].…”

“…Although there was no significant difference in the primary outcome of death or BPD, there was a significant reduction in BPD in survivors favouring the treated infants (37% vs. 45%) [73]. However, it is unclear if any differences can be attributed solely to the LISA method, as earlier compared to later surfactant in RDS is already known to be beneficial, and two-thirds of control infants received surfactant [73]. The LISA technique has been widely adapted in many parts of Europe and in large cohort studies there are better clinical outcomes [74].…”

Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants

“…1,6 In light of these observations, more stringent BPD definitions based on a systematic assessment of the need for respiratory therapy using pulse oximetry became more widely used in more recent randomized clinical trials (RCTs) to improve the consistency of the diagnosis of BPD across neonatal units. [14][15][16][17] Two large RCTs 18,19 that were specifically designed to determine the effect of high-dose enteral DHA supplementation during the neonatal period on BPD outcomes in preterm infants who were born before 29 weeks' gestation used such a systematic physiological BPD definition at 36 weeks' PMA. Contrary to the aforementioned hypothesis, both trials reported an overall increase of BPD with the use of DHA but an inconsistent association with BPD-free survival in analysis by gestational age (GA) and mode of delivery.…”

Incorrect Wording

“…In the Reply Letter titled “Minimally Invasive Surfactant Therapy vs Sham Treatment and Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome—Reply,” published in the April 26, 2022, issue of JAMA , a sentence was incorrectly worded. In the second to last paragraph, the last sentence should have been “Beyond the surfactant received as part of the minimally invasive surfactant therapy intervention, in both groups any other surfactant therapy given followed accepted guidelines in relation to dosage, timing, and F io 2 threshold.” This article was corrected online.…”