In a challenge to existing recommendations, researchers say delivery room resuscitation with high initial levels of oxygen for very preterm infants could reduce their odds of death.
This is according to the findings of their systematic review and individual participant data network meta-analysis. However, they stressed that more research is needed to confirm this, reports Medpage Today.
Using data from 12 randomised trials and more than 1 000 infants younger than 32 weeks’ gestational age showed that a high initial fractional inspired oxygen (FiO2) of 90% or greater was associated with a 55% reduction in mortality (OR 0.45, 95% credible interval [CrI] 0.23-0.86), compared with a low FiO2 of 30% or less, though with low certainty of evidence.
Furthermore, that high initial FiO2 was also associated with a lower odds of mortality versus an intermediate FiO2 of 50% to 65% (OR 0.34 95% CrI 0.11-0.99), this time with very low certainty of evidence, reported James Sotiropoulos, MD, of the University of Sydney in Australia, and colleagues.
The findings diverge from current recommendations and suggest that “further evaluation of high initial FiO2 is required”, the researchers wrote in JAMA Paediatrics.
“While promising and potentially practice-changing, these findings will need to be confirmed in future larger studies,” Sotiropoulos said.
The number needed to treat to prevent one additional death was 16 for the high-versus-low oxygen comparison, and 11 for the high-versus-intermediate comparison.
“Ensuring very premature infants get the right treatment from the beginning sets them up to lead healthy lives,” he said. “The goal is to find the right balance – how do we give enough oxygen to prevent death and disability, but not damage vital organs.”
Historically, an FiO2 of 100% had been used for all infants requiring resuscitation at birth, the study authors said, but more recent data showing room air to be associated with reduced mortality in term and near-term infants shifted practice.
“This spurred changes to international treatment recommendations in 2010 to recommend the judicious use of blended oxygen for preterm infants despite there being no conclusive evidence for this vulnerable population,” wrote Sotiropoulos and colleagues.
For preterm infants, a group that often requires oxygen supplementation to prevent hypoxia, those guidelines favour starting at low oxygen concentrations (FiO2 21% to 30%) and then titrated to reach oxygen saturation (SpO2) targets of 80% to 85% at 5 minutes and 85% to 95% at 10 minutes of life, they noted.
Still, the researchers encouraged caution when interpreting their results, given the large body of evidence detailing potential harms at higher oxygen concentrations.
“Excessive oxygen exposure may increase the formation of harmful reactive oxygen species, causing irreversible organ and tissue damage,” they wrote.
“For this reason, benefits of higher oxygen must be balanced with potential risks of hyperoxia. Without careful monitoring of the evolution of SpO2 and titration of FiO2, the excessive use of high concentrations of oxygen may be harmful. Our findings do not support the historic practice of administering a static concentration of 100% oxygen; rather, they suggest that high initial FiO2 that is then titrated down to the lowest effective dose of oxygen is probably superior to starting with low FiO2 and then titrating up.”
For their study, Sotiropoulos and colleagues included 12 randomised trials conducted from 2005 to 2019 that compared two or more initial oxygen concentrations for delivery room resuscitation, ultimately including 1 055 infants under 32 weeks’ gestational age with individual patient data.
Ten of the trials were conducted in high-income countries and two in middle-income countries, and trials featuring low or intermediate initial FiO2 were permitted if the delivered oxygen concentration were titrated based on clinical status.
Of the included infants, 48% were girls, with a median gestational age of 28 weeks. Average birth weight was 1.1 kg, nearly two-thirds were delivered via C-section, 17% were from multiple-birth pregnancies, and 10% were small for gestational age. Most received low oxygen (n=507), followed by high oxygen (n=378) or intermediate oxygen (n=170).
The primary outcome was mortality, and across the 11 studies (n=1,003) that contributed to this endpoint, deaths occurred in 12%.
The investigators reported that “there was no evidence of differential effects of treatment across gestational ages or according to infant sex (post hoc, primary outcome only) when examining treatment-covariate interactions”, but noted limited power to detect such interactions.
For the secondary outcomes of chronic lung disease, severe intraventricular haemorrhage, and retinopathy of prematurity, they found no differences between the different initial oxygen concentrations (based on 11 trials).
Nine studies provided data on oxygen saturation outcomes and showed that infants receiving higher initial oxygen concentrations had a more than threefold greater odds of achieving an SpO2 of at least 80% at 5 minutes compared with the lower initial oxygen (OR 3.67, 95% CrI 1.15-12.21). Mean difference in SpO2 at 5 minutes was 9.02 (95% CrI 2.08-16.31) favouring high versus low initial oxygen.
Limitations included a high risk of bias in the studies (in three studies for the primary outcome), mostly due to a lack of blinding, and low certainty evidence on account of the few mortality events. Sotiropoulos and co-authors also noted that few infants were born younger than 24 weeks’ gestation, limiting the generalisability for this group.
Study details
Initial Oxygen Concentration for the Resuscitation of Infants Born at Less Than 32 Weeks’ Gestation
James Sotiropoulos, Ju Lee Oei, Anna Lene Seidler et al.
Published in JAMA Paediatrics on 24 June 2024
Key Points
Question Is low, intermediate, or high initial oxygen for delivery resuscitation best to prevent adverse outcomes in preterm infants born at less than 32 weeks’ gestation?
Findings In this systematic review and individual participant data network meta-analysis of 12 randomised clinical trials including 1055 infants, resuscitation with high initial oxygen compared to low initial oxygen reduced the odds of mortality (low certainty of evidence).
Meaning These findings challenge current treatment recommendations that suggest the use of lower initial oxygen.
Abstract
Importance
Resuscitation with lower fractional inspired oxygen (FiO2) reduces mortality in term and near-term infants but the impact of this practice on very preterm infants is unclear.
Objective
To evaluate the relative effectiveness of initial FiO2 on reducing mortality, severe morbidities, and oxygen saturations (SpO2) in preterm infants born at less than 32 weeks’ gestation using network meta-analysis (NMA) of individual participant data (IPD).
Data Sources
MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov, and WHO ICTRP from 1980 to October 10, 2023.
Study Selection
Eligible studies were randomised clinical trials enrolling infants born at less than 32 weeks’ gestation comparing at least 2 initial oxygen concentrations for delivery room resuscitation, defined as either low (≤0.3), intermediate (0.5-0.65), or high (≥0.90) FiO2.
Data Extraction and Synthesis
Investigators from eligible studies were invited to provide IPD. Data were processed and checked for quality and integrity. One-stage contrast-based bayesian IPD-NMA was performed with noninformative priors and random effects and adjusted for key covariates.
Main Outcomes and Measures
The primary outcome was all-cause mortality at hospital discharge. Secondary outcomes were morbidities of prematurity and SpO2 at 5 minutes.
Results
IPD were provided for 1055 infants from 12 of the 13 eligible studies (2005-2019). Resuscitation with high (≥0.90) initial FiO2 was associated with significantly reduced mortality compared to low (≤0.3) (odds ratio [OR], 0.45; 95% credible interval [CrI], 0.23-0.86; low certainty) and intermediate (0.5-0.65) FiO2 (OR, 0.34; 95% CrI, 0.11-0.99; very low certainty). High initial FiO2 had a 97% probability of ranking first to reduce mortality. The effects on other morbidities were inconclusive.
Conclusions and Relevance
High initial FiO2 (≥0.90) may be associated with reduced mortality in preterm infants born at less than 32 weeks’ gestation compared to low initial FiO2 (low certainty). High initial FiO2 is possibly associated with reduced mortality compared to intermediate initial FiO2 (very low certainty) but more evidence is required.
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