MANUSCRIPT CITATION

Cummings JJ, Gerday E, Minton S, et al. Aerosolized Calfactant for Newborns with Respiratory Distress: A Randomized Trial. Pediatrics. 2020 Nov;146(5):e20193967. doi: 10.1542/peds.2019-3967. Epub 2020 Oct 15. PMID 33060258

REVIEWED BY

Kirsten Glaser, MD
Division of Neonatology, Department of Women’s and Children’s Health
University of Leipzig Medical Center, Leipzig, Germany

Clyde J. Wright, MD
Section of Neonatology, Department of Pediatrics
University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO

TYPE OF INVESTIGATION

Prevention, treatment

QUESTION

In (P) spontaneously breathing preterm and term infants presenting with RDS on nCPAP, high-flow nasal cannula, or noninvasive ventilation, does (I) administration of aerosolized calfactant (C) compared to usual care, determined by providers, (O) reduce the need for intubation and instillation of liquid surfactant within (T) the first 4 days of life?

METHODS

• Design: Prospective, multicenter, randomized, unblinded comparison trial. Trial registration number NCT03058666.
• Allocation: Separate randomization at each site. Allocation concealed. Alternating assignment in blocks of 2 and 4, not revealed to investigators.
• Blinding: Unblinded.
• Follow-up period: First 28 days of life (or until death or until hospital discharge).
• Setting: 22 level III or IV neonatal intensive care units in the United States.
• Patients:
  • Inclusion criteria:
    • Cohort 1: Preterm and term infants > 1h and < 12h of life presenting with RDS requiring nCPAP, high-flow nasal cannula, or noninvasive ventilation; entry requirement initially defined as FiO₂25 to 0.40 (until fourth month of the trial, afterwards no minimum FiO₂ requirement defined).
    • Cohort 2: Preterm and term infants < 24h of life who received liquid surfactant by 1h of age and were extubated to nasal respiratory support afterwards.
    • Written informed consent from parent(s) or guardian.
  • Exclusion criteria:
    • Congenital anomaly limiting care or requiring surgery
    • Hypotension with metabolic acidosis (base deficit > 10 mEq/L)
    • Hypoxemia (O₂ saturation < 88%) or hypercapnia (PaCO₂ ³ 60 mm Hg) unresponsive to intervention
    • Intraventricular hemorrhage > grade 2
    • Perinatal hypoxia-ischemia (5-minute Apgar score < 5 and/or umbilical cord pH < 7.0 and/or base deficit ³ 16 mmol/L) with acute hypoxic encephalopathy
• Intervention:
  • Aerosol group: Administration of 6mL/kg body weight of aerosolized calfactant suspension (bovine surfactant; 210 mg phospholipids/kg body weight) using a modified nebulizer with pacifier interface at a continuous, not synchronized rate of 0.20 ±02 mL/min.
  • Control group: Standard therapy per clinician judgement including endotracheal surfactant instillation.
• Outcomes:
  • Primary outcome: Endotracheal intubation and surfactant instillation within the first 4 days of age – upon individual clinical decision. No criteria set in the study protocol defining treatment failure and indication for intubation and endotracheal surfactant.
  • Secondary outcomes: Respiratory support at day 3, 7, and 28 or at hospital discharge. Any adverse event during aerosol delivery, pneumothorax or other lung air leak, pulmonary hemorrhage, pneumonia, intraventricular hemorrhage > grade 2, need for patent ductus arteriosus treatment, hypotension requiring treatment, necrotizing enterocolitis ³ stage 2, neutropenia, sepsis.
• Analysis and Sample Size:
  • Sample size was determined targeting a 20% decrease in the need of intubation and liquid surfactant instillation within the first 4 days of life.
  • Calculation was based upon an estimated rate of intubation of 60% in standard care infants as adapted from a previous study of supraglottic surfactant administration.
  • A minimum of 229 infants per group was calculated (α = 0.05, β = 0.80).
  • Primary outcome was analyzed following intention-to-treat and as-treated principles.
  • Logistic regression controlled for gestational age, birth weight, age when randomly assigned, sex, delivery mode, and antenatal steroids.
  • Post-hoc analyses for overtreatment or undertreatment bias was done.
• Patient follow-up: Of 772 infants eligible, 457 were randomly assigned. 230 patients were allocated to the aerosol group and 227 to standard care, determined by providers. 5 babies in the intervention group and 1 baby in the control group were inadvertently treated with the respective other regimen.

MAIN RESULTS

Randomized infants had similar baseline characteristics (table 1). 66% of infants in the aerosol group received one dose, 19% received two, and 15% received three doses of aerosolized calfactant. The number of treatments was not influenced by gestational age or birth weight.

^a Data are missing for 19 infants in the usual care group; the percentage shown is based on n = 208.

Primary outcome: The need for endotracheal intubation and surfactant instillation within the first 4 days of life was significantly reduced in infants in the aerosol group upon intent-to-treat analysis (26% vs. 50%; RR 0.51, 90% CI 0.41 – 0.63, p < 0.0001) (table 2), with a number needed to treat of 5 to prevent one intubation. This remained true after adjustment for stratification risk factors.

Secondary outcomes: Both groups did not differ in terms of respiratory support on days 3, 7, and 28. Nor did they differ in terms of other secondary outcomes.

CONCLUSION

Administration of aerosolized calfactant to preterm and term infants presenting with RDS on nasal respiratory support was shown to be feasible and safe, and reduced the need for intubation and liquid surfactant instillation during first 4 days of life compared to standard care, determined by providers. Avoidance of any endotracheal manipulation make this application an attractive route of surfactant administration.

COMMENTARY

Although almost 60 years have passed since the initial report of treating RDS with aerosolized surfactant (1), clinicians remain without an effective delivery system. A truly non-invasive approach of surfactant delivery could decrease many of the risks of exposure to mechanical ventilation, including lung injury, and bronchopulmonary dysplasia (2-7). Recently, Cummings et al reported the largest RCT (with 457 neonates randomized) to date comparing nebulized surfactant to standard therapy for babies with RDS (8). In this pragmatic clinical trial, administration of nebulized surfactant was shown to reduce the need for liquid surfactant treatment, cutting rates of intubation in half (from ~50% to ~25%), with a number needed to treat of 5 to prevent one intubation. These promising results demonstrate that the modified nebulizer with pacifier interface could effectively and safely administer surfactant to neonates with signs of RDS. Of note, respiratory support at days 3, 7, and 28 did not differ among both groups.

In this study, the authors have taken advantage of a “pragmatic” study design. Specifically, the trial did not include criteria dictating intubation and liquid surfactant administration following randomization. This allowed clinicians – rather than study protocols – to decide who received liquid surfactant following randomization. There are multiple benefits to this pragmatic design. It could be argued that by incorporating natural variations in clinical practice the study findings would be more likely to be replicated when applied to real-life clinical practice. Additionally, the authors state that by leaving the decision of who to treat with liquid surfactant to the practitioner results in ethically compliant practice.

In addition to these benefits, there are potential limitations to this practical design. By not strictly “treatment failure” or “surfactant therapy criteria”, the unblinded design could have introduced variability in practice and contributed to differences in outcomes found between treatment arms. Clinicians could have been biased to anticipate a beneficial effect of aerosolized surfactant – this bias potentially resulting in a delay in treatment with liquid surfactant in infants allocated to the aerosol group. This could have manifested as differences between groups in the level of non-invasive respiratory support and oxygen requirement at the time of liquid surfactant administration, however these data are not available.  Of note, treatment with liquid surfactant occurred later in the group following aerosolized surfactant (~24 h) when compared to standard therapy (~10 h), indicating a delay in treatment. Whether this delay, and other potential differences, have clinical implications is unknown and should be addressed in future trials.

This trial constitutes another important step forward in the management of RDS. A truly non-invasive surfactant administration would have broad application and wide-ranging benefits (2). Specifically, trials targeting less mature neonates at very high risk of injury following intubation and mechanical ventilation are eagerly anticipated. By demonstrating safety and feasibility, this trial sets the stage for a more intensive investigation of aerosolized surfactant to treat RDS.

REFERENCES

1. Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Microaerosol Administration of Synthetic Beta-Gamma-Dipalmitoyl-L-Alpha-Lecithin in the Respiratory Distress Syndome: A Preliminary Report. Can Med Assoc J 1964; 90:55-7
2. Barkhuff WD, Soll RF. Novel Surfactant Administration Techniques: Will They Change Outcome? Neonatology 2019; 115 4:411-22.
3. Berggren E, Liljedahl M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al. Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome. Acta Paediatr 2000; 89 4:460-4.
4. Finer NN, Merritt TA, Bernstein G, Job L, Mazela J, Segal R. An open label, pilot study of Aerosurf(R) combined with nCPAP to prevent RDS in preterm neonates. J Aerosol Med Pulm Drug Deliv 2010; 23 5:303-9.
5. Minocchieri S, Berry CA, Pillow JJ, CureNeb Study T. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2019; 104 3:F313-F9.
6. Sood BG, Cortez J, Kolli M, Sharma A, Delaney-Black V, Chen X. Aerosolized surfactant in neonatal respiratory distress syndrome: Phase I study. Early Hum Dev 2019; 134:19-25.
7. Sood BG, Thomas R, Delaney-Black V, Xin Y, Sharma A, Chen X. Aerosolized Beractant in neonatal respiratory distress syndrome: A randomized fixed-dose parallel-arm phase II trial. Pulm Pharmacol Ther 2021; 66:101986.
8. Cummings JJ, Gerday E, Minton S, Katheria A, Albert G, Flores-Torres J, et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics 2020; 146 5.