Comparing delivery room oxygen for preterms: An IPD–NMA Review

[EBNEO]

Dr Kiran Shrivastava from Mumbai and Dr Abdul Razak from Australia review Sotiropoulos JX et al's #EBNEO June Article of the month: 

"Sotiropoulos JX, Oei JL, Schmölzer GM, Libesman S, Hunter KE, Williams JG, Webster AC, Vento M, Kapadia V, Rabi Y, Dekker J, Vermeulen MJ, Sundaram V, Kumar P, Kaban RK, Rohsiswatmo R, Saugstad OD, Seidler AL. Initial Oxygen Concentration for the Resuscitation of Infants Born at Less Than 32 Weeks’ Gestation: A Systematic Review and Individual Participant Data Network Meta-Analysis. JAMA Pediatr. 2024 Aug 1;178(8):774-783. doi: 10.1001/jamapediatrics.2024.1848. PMID: 38913382; PMCID: PMC11197034"

READ HERE!

Hear it discussed on the Incubator Podcast as well!

Acta Commentary:

Acta Paediatrica - 2024 - Shrivastava - EBNEO Commentary Comparing delivery room oxygen for preterms An IPD NMA Review.pdf

The Individual Participant Data and Network Meta-analysis (IPD-NMA) examined 11 of 13 eligible studies, including data from 1003 babies, to address a critical question in neonatal care: What is the optimal initial oxygen concentration for resuscitating preterm infants born at less than 32 weeks' gestation?

The authors categorised initial oxygen concentrations into three groups: low (21%–30%), intermediate (50%–65%), and high (90%–100%). They found that high initial oxygen concentrations were associated with a reduction in death compared to low and intermediate concentrations. Furthermore, they observed no differences in secondary outcomes, except for higher oxygen saturation within 5 min in the high oxygen group compared to the low oxygen group.1

These findings stand in contrast to previously conducted meta-analyses, which showed no significant effect of initial oxygen concentration on mortality. These earlier analyses typically compared low versus high oxygen concentrations based on an arbitrary distinction classifying infants exposed to intermediate oxygen as part of the high oxygen group. This categorisation likely diluted the apparent lower effect of high oxygen on mortality, ultimately leading to conclusions of no significant difference.2-4 In contrast, the IPD-NMA categorises oxygen exposure more precisely, revealing a significant reduction in mortality with high oxygen compared to both low and intermediate exposures.

The striking impact of brief differences in initial oxygen exposure on such a critical outcome might prompt immediate consideration of this approach in clinical practice. However, it is essential to carefully weigh the certainty of this evidence, which remains low to very low. This lower certainty is driven by several factors, most notably statistical heterogeneity. In NMA, prediction intervals serve as a measure of heterogeneity and are based on the posterior distribution of analysis. They tell us that, with 95% certainty, the effect of a new trial would fall within this range. The authors point out that the lower mortality seen with high oxygen levels becomes nonsignificant as the prediction intervals cross the null, suggesting significant heterogeneity and reducing our confidence in the result.

This statistical heterogeneity may, at least in part, be influenced by differences in how oxygen was titrated in the included trials (clinical heterogeneity). Most trials employed slow titration, while others used fast titration, and one trial even increased oxygen concentration from 0.21 to 1.0 rapidly. Such variations in oxygen delivery methods likely contributed to the observed heterogeneity.1 Additionally, the trials enrolled infants over a span of the last two decades and involved populations from different countries, further contributing to the variability. Beyond heterogeneity, other factors, such as the lack of blinding in many trials and the relatively low numbers of participants leading to imprecise estimates, also diminish confidence in the findings and raise questions about their overall reliability.

While this type of IPD-NMA provides more credible evidence compared to traditional pairwise meta-analyses, the above-mentioned concerns urge caution among neonatal care providers. Should we adopt this evidence from a meta-analysis of heterogenous trials examining 1003 infants, or should we wait for more homogenous clinical trials with larger populations, such as the TORPIDO (Targeted Oxygen saturation in Respiratory care of premature Infants at Delivery: effects on Outcome) trial (1470 participants) and the HILO (higher versus lower oxygen) trial (1200 participants)?5, 6 This is just the beginning of our journey to determine the best approach to oxygen use in preterm resuscitation. Ongoing studies like OPTISTART (Optimisation of Saturation Targets And Resuscitation) may further illuminate how to optimise oxygen therapy after birth for these vulnerable infants.7