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[JAMA发表述评]:极早产婴儿气道内联合使用布地奈德和表面活性物质
2025年01月23日 研究点评, 进展交流 [JAMA发表述评]:极早产婴儿气道内联合使用布地奈德和表面活性物质已关闭评论

Editorial 

November 11, 2024

Intratracheal Budesonide Combined With Surfactant in Extremely Preterm Infants

Erik A. Jensen

JAMA. Published online November 11, 2024. doi:10.1001/jama.2024.19641

Infants born extremely premature (those with gestational ages of less than 28 weeks at delivery) are at risk of both acute and subsequent chronic respiratory insufficiency due in part to absent or inadequate production of pulmonary surfactant. More than 90% of extremely preterm infants have clinical or radiographic evidence of acute surfactant deficiency, referred to as neonatal respiratory distress syndrome, within the first hours or days after birth.1 Approximately half of these infants go on to develop a chronic respiratory disease of prematurity known as bronchopulmonary dysplasia (BPD).2 This condition is one of the most consequential complications of preterm birth and is the second most common chronic pediatric lung illness after asthma; in the US more than 12 000 preterm infants are affected each year.2,3 BPD is associated with significant impairments in pulmonary and cardiac health, poor longitudinal growth, neurodevelopmental disability, and early mortality in childhood.4In the most severely affected patients, these health consequences can persist through adult years.4 BPD is typically defined as requiring treatment with supplemental oxygen or positive airway pressure at a postmenstrual age of 36 weeks.5 In addition to surfactant insufficiency, proinflammatory exposures, including prenatal and postnatal infection, supplemental oxygen, and mechanical ventilation, combined with abnormal postinjury lung repair, are believed to contribute to the underlying disease pathobiology.6

The prevalence of BPD has increased in recent decades, due in part to increased survival of infants born extremely premature and because few pharmacological therapies exist that have high-quality evidence to support routine use to prevent the disease.6,7 Randomized clinical trials conducted in the 1980s and early 1990s demonstrated that administration of exogenous surfactant via endotracheal tube increased survival and reduced acute pulmonary morbidity in infants with neonatal respiratory distress syndrome when compared with mechanical ventilation alone, but that it did not reduce the risk of BPD.8 Subsequent trials showed that prophylactic intubation combined with surfactant therapy increased the risk of death or BPD at 36 weeks’ postmenstrual age when compared with initial stabilization via noninvasive continuous positive airway pressure (CPAP).8 More recently, the OPTIMIST-A trial showed a reduction in BPD in extremely preterm infants with respiratory distress syndrome who were supported by noninvasive CPAP and were randomized to receive surfactant therapy administered via thin endotracheal catheter vs sham therapy.9 However, a subgroup analysis raised the possibility of increased mortality with minimally invasive surfactant therapy among the study participants born at the youngest eligible gestational ages.9

Because of their potent anti-inflammatory properties, corticosteroids have also been extensively investigated to prevent and treat respiratory disease in preterm infants. Randomized clinical trials of systemic glucocorticoids initiated during the first postnatal week have shown reduced risk of BPD but increased risk of gastrointestinal perforation and cerebral palsy.7 These worrisome adverse effects associated with systemic administration of glucocorticoids have prompted hope that direct intrapulmonary administration will confer similar beneficial respiratory effects without the same undesirable consequences. This hope was not realized with the administration of inhaled glucocorticoids. The NEUROSIS randomized clinical trial showed that administration of inhaled budesonide to extremely preterm infants beginning within the first 24 hours after birth reduced the risk of BPD but increased the risk of mortality.10 Consequently, many clinicians agree that prophylactic administration of systemic or inhaled glucocorticoids should be avoided in preterm infants during the first postnatal week.11 However, the pooled results of several small randomized clinical trials have shown a nearly 2-fold reduction in the risk of BPD, without apparent serious systemic adverse effects, when the glucocorticoid budesonide is combined with surfactant and instilled intratracheally in extremely preterm infants with respiratory distress syndrome.12 Based on these results, some centers have adopted intratracheal budesonide into routine practice, while other clinicians and investigators have called for larger confirmatory trials.11

In this issue of JAMA, Manley and colleagues13 report the results of a large, international randomized clinical trial that compared intratracheal budesonide combined with surfactant with surfactant monotherapy. The study was conducted in 1059 infants born at less than 28 weeks’ gestation in whom there was a clinical decision to administer surfactant within the first 48 hours after birth. Participants were recruited from 21 centers in 4 countries. Surfactant with or without budesonide was instilled either through an in situ endotracheal tube or via thin catheter in infants receiving noninvasive respiratory support. Infants treated with a single open-label dose of surfactant prior to enrollment were eligible if the treating clinician chose to administer additional surfactant therapy. The primary trial outcome was survival without BPD, assessed at a postmenstrual age of 36 weeks 0 days to 36 weeks 6 days. Infants receiving a fraction of inspired oxygen (Fio2) of less than 0.30 via low-flow nasal cannula at 36 weeks’ postmenstrual age underwent a standardized oxygen reduction challenge to determine BPD status.

In this trial, the use of budesonide plus surfactant did not increase survival without BPD (adjusted risk difference, 2.7%; 95% CI, −2.1% to 7.4%). Risks of the individual components of the primary outcome, BPD among survivors to 36 weeks’ postmenstrual age (adjusted risk difference, −2.7%; 95% CI, −8.4% to 3.1%) and survival to 36 weeks alone (adjusted risk difference, 1.4%; 95% CI, −2.9% to 5.7%) were also not significantly different between the treatment groups. Examination of multiple secondary outcomes assessed throughout the initial hospitalization showed little evidence of benefit or harm from intratracheal budesonide.

This is a sobering result. Confirmation of the large treatment effects observed in earlier and smaller trials of intratracheal budesonide would have been a breakthrough in the long-standing effort to substantively reduce the rates of BPD in extremely preterm infants. This result also provides another reminder of the importance of large multicenter trials in neonatology to define the risks and benefits of incompletely tested interventions and to understand the generalizability of results obtained from initial, smaller studies. One essential question is whether there are systematic differences between the trial conducted by Manley et al13 and prior studies that explain the stark differences in results. The largest previous randomized trial of intratracheal budesonide plus surfactant, reported by Yeh et al14 in 2016, enrolled 265 very low-birth-weight infants and demonstrated a greater than 40% relative reduction in the composite outcome of death or BPD (relative risk, 0.58; 95% CI, 0.44-0.77). Eligibility for the trial by Yeh et al was restricted to infants with a birth weight of less than 1500 g who were receiving invasive ventilation with Fio2 of 0.50 or greater and had radiographic evidence of severe respiratory distress syndrome within the first 4 hours after birth.14 These criteria likely skew the study population toward infants who, on average, had more severe initial respiratory disease, and it is possible that such infants garner greater benefit from intratracheal budesonide. In a post hoc analysis, Manley et al13 found a potential treatment advantage among study participants who were receiving Fio2 of 0.50 or greater immediately prior to the first trial intervention. In this subgroup, there was a statistically significant increase in survival without BPD in infants randomized to receive budesonide plus surfactant vs surfactant alone (20.2% vs 12.3%; adjusted risk difference, 10.2%; 95% CI, 1.5%-18.8%). No treatment effect was observed among infants receiving lower amounts of supplemental oxygen (adjusted risk difference, 0.4%; 95% CI, −5.1% to 5.8%). The authors rightly note that these results should be interpreted cautiously. The analysis was performed at editorial request and was not prespecified. Formal interaction testing yielded a P = .07, providing only weak evidence of a potential subgroup difference. Finally, the 95% CI around the estimated treatment effect is wide, and only 36 infants receiving Fio2 of 0.50 or greater at initial intervention survived without BPD, limiting the statistical power for this comparison.

The timing of the initial study intervention also differed between the trial conducted by Manley et al13 and that conducted by Yeh et al.14 The median postnatal age at enrollment in the study by Manley et al13 was approximately 5 hours compared with a mean age of approximately 2 hours in the study by Yeh et al.14 Randomized trials conducted in the 1990s and early 2000s showed that administration of surfactant within the first 1 to 2 postnatal hours in infants receiving invasive ventilation, compared with delayed selective administration in those with worsening respiratory distress syndrome, may reduce the risk of neonatal mortality and combined BPD or death in infants born at less than 30 weeks’ gestation.8 Whether earlier administration of intratracheal budesonide yields similar effects is not yet known. However, greater reductions in administered Fio2 and mean airway pressure have been observed within 1 hour after treatment in infants randomized to receive budesonide plus surfactant vs surfactant alone.14

Clinicians and investigators will rightfully examine these and other potential differences in search of explanations for the discrepant findings between the present and prior trials of intratracheal budesonide. The Budesonide in Babies (BiB) trial conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network will provide additional important information on the safety and efficacy of intratracheal budesonide combined with surfactant in extremely preterm infants.15 This trial examined the same dose of budesonide as the trial by Manley et al13 and used similar eligibility criteria, with the exception that infants previously treated with open-label surfactant were not eligible to participate in the BiB trial. Once available, the large collective amount of data provided by these trials should enable informative individual participant data meta-analyses and examination of potential treatment harms and benefits in key patient subgroups. At present, however, it remains unclear which, if any, infants should be routinely treated with intratracheal budesonide.

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