MANUSCRIPT CITATION

Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS, Tsai CH, Lin HC. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193(1):86-95. PMID: 26351971

REVIEWED BY

Kent Willis, MD
Neonatal-Perinatal Medicine Fellow
Department of Pediatrics, Division of Neonatology
The University of Tennessee Health Science Center

Mark Weems, MD
Assistant Professor
Department of Pediatrics, Division of Neonatology
The University of Tennessee Health Science Center

TYPE OF INVESTIGATION

Prevention

QUESTION

In very low birthweight infants with severe respiratory distress syndrome, does the administration of budesonide-surfactant compared with surfactant alone significantly decrease the incidence of bronchopulmonary dysplasia or death at 36 weeks’ postmenstrual age?

METHODS

• Design: Multinational, multicenter, randomized controlled trial
• Allocation: Concealed
• Blinding: Blinded (Site PI not blinded)
• Follow-up period:
  • Primary: Death or NICU discharge
  • Secondary: Two to Three years of age.
• Setting: Three tertiary neonatal centers in the United States and Taiwan
• Patients:
  • Included:
    • Birthweight less than 1500 g.
    • Radiographic evidence of severe respiratory distress syndrome (RDS)
    • Mechanical ventilation.
    • Fraction of inspired oxygen (FiO₂) at least 0.5.
    • Absence of severe congenital anomalies or lethal cardiopulmonary disorder
  • Excluded:
    • Known severe congenital anomaly.
    • Known lethal cardiopulmonary disorder.
    • Age greater than 4 hours of life.
    • Birthweight less than 500 g.
    • Died before 8 hours of life.
• Intervention: Intervention infants received surfactant (100 mg/kg) mixed with budesonide (0.25 mg/kg), and the control infants received only surfactant. This was repeated every 8 hours until the infant required an FiO₂ < 0.3, was extubated, or 6 doses had been given.
• Outcomes: The primary outcome was the incidence of a combination of death or moderate to severe bronchopulmonary dysplasia (BPD). BPD was defined as:
  • Continued respiratory distress since birth and a requirement for supplemental oxygen with a FiO₂ > 0.21 at 36 weeks’ postmenstrual age.
  • Post hoc analysis was performed using the NICHD definition of BPD: oxygen support at 28 days with stratification to mild, moderate, and severe BPD at 36 weeks postmenstrual age.
  • Secondary outcomes:
    • Interleukins (IL)-1, 6 and 8 levels measured in tracheal aspirates at 12 h, 24 h, 3-5 d, and 7-10 d from the first 40 infants.
    • Follow up outcomes:
      • Severity of neuromotor dysfunction.
      • Presence of neurodevelopmental impairment
• Analysis and Sample Size: To demonstrate a 20 % difference in the prevalence of BPD or death (60 % in the control arm versus 40 % in the intervention arm), the authors estimated, after allowing for 5% of Type I error and 10% of Type II error, 130 infants would be required in each study arm. They therefore aimed to recruit 140 infants to each intervention. 131 infants were randomized to the intervention group and 134 to the control group.
• Patient follow-up: From 1215 VLBW infants assessed for eligibility, 858 were eligible, 287 infants met the entrance criteria, and 265 infants were randomized. 22 infants were excluded prior to randomization because 9 died < 8 h of life, 2 had a birthweight < 500 g and 11 rejected consent. All of the randomized infants were followed to completion of the primary outcome. 192 (85 %) of the 226 surviving infants were assessed at 2-3 years of age.

MAIN RESULTS

Infants in the intervention group had a significantly reduced incidence of BPD or death (42 versus 66%) yielding a risk ratio of 0.58 (95 % CI 0.44-77, P < 0.001) and a number needed to treat of 4.1 (95 % CI 2.8-7.8). Post hoc analysis using the NICHD definition, adjusted for prenatal steroids, Apgar score and chorioamnionitis, demonstrated an odds ratio for the primary outcome of 0.37 (95% CI 0.22-0.54, P < 0.01). Use of the NICHD definition is important, as it clarifies that the treatment effect focuses on infants with moderate to severe BPD. Baseline characteristics and primary outcomes are presented in Table 1.

The intervention was associated with less IL-1, 6 and 8 in tracheal aspirates at 12 h of life and less IL-8 at 3-5 d. The authors also report the intervention was associated with significantly fewer doses of surfactant administered, lower FiO₂ and oxygen index during the first day of life, lower mean airway pressure during the first three days of life, and less diagnosis of significant patent ductus arteriosus. There was no difference in duration of intermittent mandatory ventilation.

CONCLUSION

The authors conclude the intratracheal administration of surfactant-budesonide compared with surfactant alone significantly decreases the incidence of BPD or death in very low birthweight infants with severe respiratory distress syndrome without immediate adverse effect.

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COMMENTARY

The magic bullet that prevents bronchopulmonary dysplasia (BPD) in very low birthweight infants without increasing long-term side effects remains elusive. Because pulmonary inflammation is likely critical to the pathogenesis of BPD, numerous investigators have attempted to prevent the development of BPD with a wide variety of postnatal corticosteroid regimens(1). Unfortunately, systemic corticosteroids have been linked to increased risk of adverse neurodevelopmental outcomes(2). Inhaled corticosteroids combine more direct action on lung tissue with less systemic effect, but inhaled corticosteroids have also failed to reduce BPD(3,4).

Adding budesonide to surfactant potentiates the delivery of corticosteroid to the peripheral lung tissue(5). The authors posit that delivering this combination therapy early in the course of illness may unlock the minimum required anti-inflammatory stimuli necessary to prevent BPD while avoiding adverse outcomes. A paucity of data makes assessing the impact of the specific surfactant preparation used in this study difficult. This would likely be worthwhile to explore in future research.

Yeh et al. found a significant reduction in the incidence of BPD or death after administration of budesonide-surfactant as compared to surfactant alone. The effect can be attributed to a reduction in BPD alone without a significant effect on mortality. While not powered to examine neurodevelopmental outcomes, it is encouraging that the surviving infants exhibited no trend towards adverse outcome at 2-3 years old. Both findings were confirmed by meta-analysis(7) with the group’s prior pilot study(6). The major limitation of this study is the high incidence of BPD in the control group (50%). In a population with a lower prevalence of BPD, the relative risk reduction and number needed to treat are likely to be many fold different.

Many infants experienced significant intervention prior to randomization that could alter the magnitude of the treatment effect and thus the number needed to treat, such as mechanical ventilation and oxygen administration. While randomization prevents the introduction of significant bias in this study, earlier surfactant administration may potentiate the budesonide effect when compared to other strategies shown to reduce BPD(8). The role of budesonide-surfactant administration should be reevaluated in conjunction with other current treatment strategies known to prevent BPD. This would reassure clinicians that budesonide-surfactant therapy continues to offer benefit in the context of current clinical practice.

In the end, Yeh et al. represents a potentially powerful intervention to reduce the risk of BPD. Considering the less than satisfactory results achieved by previous corticosteroid delivery methods, this is a significant achievement. However, the previous failure of postnatal corticosteroid administration, has created a paradox that is difficult to overcome. Clinicians continue to use corticosteroids in infants with moderate to severe BPD despite known risks, while at the same time demanding a high bar of evidence be achieved before altering current management. Before budesonide-surfactant can become the standard of care, further large trials are required in populations with a lower prevalence of BPD. We advocate for a multicenter trial in conjunction with non-invasive respiratory management that is powered to evaluate neurodevelopmental outcomes.

REFERENCES

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6. Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, et al. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics. 2008 May;121(5):e1310–8.
7. Venkataraman R, Kamaluddeen M, Hasan SU, Robertson HL, Lodha A. Intratracheal Administration of Budesonide-Surfactant in Prevention of Bronchopulmonary Dysplasia in Very Low Birth Weight Infants: A Systematic Review and Meta-Analysis. Pediatric Pulmonology. 6 ed. 2017 Jul;52(7):968–75.
8. Polin RA, Carlo WA, Committee on Fetus and Newborn, American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Vol. 133, Pediatrics. 2014. pp. 156–63.