Dear Editor,
We read with interest the randomized trial by Ostadmohammadi et al. comparing poractant alfa (Curosurf®) with bovine lipid extract surfactant (BLES®) for respiratory distress syndrome (RDS) in preterm neonates (1). The study suggested that Curosurf® may be more effective because it was associated with shorter neonatal intensive care unit (NICU) stays and a reduced need for redosing in preterm neonates with RDS. The authors address a clinically important and controversial topic. However, methodological limitations and potentially biased interpretations of previous studies discussed in the article limit the reliability of the findings. To strengthen the validity of future comparative studies, the limitations outlined below should be carefully considered and addressed.
One methodological limitation is the failure to follow the BLES® redosing protocol recommended by the manufacturer. Readministration of BLES® was restricted to a window of 12 to 72 hours after birth. However, the manufacturer recommends that BLES® may be readministered at any point within the first 5 days of life, with no required minimum interval after the first dose, whenever the neonate requires an FiO2 at least 10% greater than the level needed after the initial response to the first dose (2). Despite this recommendation, no additional doses were administered when the neonate had an FiO2 > 0.40 at 1 and 6 hours after the first dose. This limitation may have contributed to prolonged hypoxemia, which, in turn, could have increased the need for mechanical ventilation and prolonged hospitalization—factors subsequently interpreted as evidence of lower efficacy and higher associated costs.
Moreover, BLES® was administered in 2 equal aliquots, whereas Curosurf® was given as a single bolus. Although dose splitting is consistent with the manufacturer's recommendations, this difference in administration between the 2 surfactants may have influenced the outcomes. Dividing BLES® into 2 aliquots is an accepted practice and is most plausibly related to its larger administration volume rather than to any expected efficacy advantage. Although this rationale may be clinically reasonable, the practice differs from the standard single-bolus approach used for Curosurf®, and the resulting asymmetry in delivery technique introduces a comparability concern when efficacy outcomes are directly compared between the 2 agents. Dividing the bolus can interfere with the formation of a cohesive tracheal “plug,” which typically facilitates distal delivery of surfactant to the peripheral airways (3). Experimental studies have shown that dose fractionation may lead to greater retention of surfactant in the bronchi, reduced alveolar deposition, and an increased risk of airway obstruction (3). Therefore, this difference in dosing strategy could have adversely affected the performance of BLES®.
A retrospective study conducted in Iran in 2023 (4), which analyzed data from more than 13,000 surfactant-treated preterm neonates, demonstrated that BLES® had the best performance among neonates born at less than 32 weeks of gestation—the same population examined in the study by Ostadmohammadi et al. Notably, as in the study by Ostadmohammadi et al., the BLES® redosing rate in this retrospective study was approximately 1.4. However, NICU length of stay was shorter, with a reported mean of 17 days compared with 27 days in the Ostadmohammadi et al. study. In contrast to the differences observed with BLES®, no discrepancy in NICU length of stay was found for Curosurf®, with both studies reporting similar durations of approximately 20 to 21 days. As a retrospective comparison, these findings are inevitably subject to confounding due to differences in patient demographics, disease severity, and center-level institutional protocols and practices, which may themselves influence NICU length of stay. Nevertheless, because the divergence was confined to BLES® while the Curosurf® length of stay remained consistent across both studies, we consider this discrepancy relevant and unlikely to be explained by population-level differences alone. This discrepancy may highlight the importance of methodological factors that affect outcomes in neonates treated with BLES® surfactant.
In the Discussion section, the authors mentioned the lower incidence of severe airway obstruction episodes with Curosurf® than with BLES® in the controlled trial by Lemyre et al. in 2017. However, they did not mention a 3-fold increase in all-cause mortality in the Curosurf® group (9/42) compared with the BLES® group (3/45), which was considered concerning and warranted further investigation (5). Selective reporting of study data without acknowledging contradictory findings may lead to biased interpretation by readers. Furthermore, the Lemyre et al. study used a BLES® redosing protocol that diverged from the manufacturer's recommendation (5), whereas strict adherence to the BLES® redosing trigger has been shown to significantly reduce severe airway events and ventilation days (6). A more comprehensive study by Lemyre et al., published in 2022, reported no significant differences between the 2 agents in preterm neonates with a gestational age of less than 32 weeks (7).
Given the limitations of the Ostadmohammadi et al. study, its conclusions regarding the superior efficacy and lower cost of Curosurf® warrant reconsideration. These conclusions are based primarily on the duration of mechanical ventilation and length of hospital stay, which may reflect nonadherence to the recommended BLES® administration protocols. Moreover, the shorter NICU stay reported for patients treated with Curosurf® is inconsistent with findings from retrospective studies. A more rigorous investigation that addresses these methodological limitations is necessary to assess this claim accurately. Clarifying these issues would help readers better interpret the findings and reduce potential bias.
![Expression of Concern for Comparison of the Efficacy of Three Natural Surfactants (Curosurf, Survanta, and Alveofact) in the Treatment of Respiratory Distress Syndrome Among Neonates: A Randomized Controlled Trial [Iran J Pediatr. 2016;26(5): e5743]](https://brieflands.com/journals/ijp/articles/156756/figures/thumbnail.webp)
