Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome

Background: Non-invasive respiratory support is increasingly used for the management of respiratory dysfunction in preterm infants. This approach runs the risk of under-treating those with respiratory distress syndrome (RDS), for whom surfactant administration is of paramount importance. Several techniques of minimally invasive surfactant therapy have been described. This review focuses on surfactant administration to spontaneously breathing infants via a thin catheter briefly inserted into the trachea.

Objectives: Primary objectives In non-intubated preterm infants with established RDS or at risk of developing RDS to compare surfactant administration via thin catheter with: 1. intubation and surfactant administration through an endotracheal tube (ETT); or 2. continuation of non-invasive respiratory support without surfactant administration or intubation. Secondary objective 1. To compare different methods of surfactant administration via thin catheter Planned subgroup analyses included gestational age, timing of intervention, and use of sedating pre-medication during the intervention.

Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 30 September 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials.

Selection criteria: We included randomised trials comparing surfactant administration via thin catheter (S-TC) with (1) surfactant administration through an ETT (S-ETT), or (2) continuation of non-invasive respiratory support without surfactant administration or intubation. We also included trials comparing different methods/strategies of surfactant administration via thin catheter. We included preterm infants (at < 37 weeks' gestation) with or at risk of RDS.

Data collection and analysis: Review authors independently assessed study quality and risk of bias and extracted data. Authors of all studies were contacted regarding study design and/or missing or unpublished data. We used the GRADE approach to assess the certainty of evidence.

Main results: We included 16 studies (18 publications; 2164 neonates) in this review. These studies compared surfactant administration via thin catheter with surfactant administration through an ETT with early extubation (Intubate, Surfactant, Extubate technique - InSurE) (12 studies) or with delayed extubation (2 studies), or with continuation of continuous positive airway pressure (CPAP) and rescue surfactant administration at pre-specified criteria (1 study), or compared different strategies of surfactant administration via thin catheter (1 study). Two trials reported neurosensory outcomes of of surviving participants at two years of age. Eight studies were of moderate certainty with low risk of bias, and eight studies were of lower certainty with unclear risk of bias. S-TC versus S-ETT in preterm infants with or at risk of RDS Meta-analyses of 14 studies in which S-TC was compared with S-ETT as a control demonstrated a significant decrease in risk of the composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.48 to 0.73; risk difference (RD) -0.11, 95% CI -0.15 to -0.07; number needed to treat for an additional beneficial outcome (NNTB) 9, 95% CI 7 to 16; 10 studies; 1324 infants; moderate-certainty evidence); the need for intubation within 72 hours (RR 0.63, 95% CI 0.54 to 0.74; RD -0.14, 95% CI -0.18 to -0.09; NNTB 8, 95% CI; 6 to 12; 12 studies, 1422 infants; moderate-certainty evidence); severe intraventricular haemorrhage (RR 0.63, 95% CI 0.42 to 0.96; RD -0.04, 95% CI -0.08 to -0.00; NNTB 22, 95% CI 12 to 193; 5 studies, 857 infants; low-certainty evidence); death during first hospitalisation (RR 0.63, 95% CI 0.47 to 0.84; RD -0.02, 95% CI -0.10 to 0.06; NNTB 20, 95% CI 12 to 58; 11 studies, 1424 infants; low-certainty evidence); and BPD among survivors (RR 0.57, 95% CI 0.45 to 0.74; RD -0.08, 95% CI -0.11 to -0.04; NNTB 13, 95% CI 9 to 24; 11 studies, 1567 infants; moderate-certainty evidence). There was no significant difference in risk of air leak requiring drainage (RR 0.58, 95% CI 0.33 to 1.02; RD -0.03, 95% CI -0.05 to 0.00; 6 studies, 1036 infants; low-certainty evidence). None of the studies reported on the outcome of death or survival with neurosensory disability. Only one trial compared surfactant delivery via thin catheter with continuation of CPAP, and one trial compared different strategies of surfactant delivery via thin catheter, precluding meta-analysis.

Authors' conclusions: Administration of surfactant via thin catheter compared with administration via an ETT is associated with reduced risk of death or BPD, less intubation in the first 72 hours, and reduced incidence of major complications and in-hospital mortality. This procedure had a similar rate of adverse effects as surfactant administration through an ETT. Data suggest that treatment with surfactant via thin catheter may be preferable to surfactant therapy by ETT. Further well-designed studies of adequate size and power, as well as ongoing studies, will help confirm and refine these findings, clarify whether surfactant therapy via thin tracheal catheter provides benefits over continuation of non-invasive respiratory support without surfactant, address uncertainties within important subgroups, and clarify the role of sedation.