Elsevier

The Lancet

Volume 378, Issue 9803, 5–11 November 2011, Pages 1627-1634
The Lancet

Articles
Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial

https://doi.org/10.1016/S0140-6736(11)60986-0Get rights and content

Summary

Background

Surfactant is usually given to mechanically ventilated preterm infants via an endotracheal tube to treat respiratory distress syndrome. We tested a new method of surfactant application to spontaneously breathing preterm infants to avoid mechanical ventilation.

Method

In a parallel-group, randomised controlled trial, 220 preterm infants with a gestational age between 26 and 28 weeks and a birthweight less than 1·5 kg were enrolled in 12 German neonatal intensive care units. Infants were independently randomised in a 1:1 ratio with variable block sizes, to standard treatment or intervention, and randomisation was stratified according to centre and multiple birth status. Masking was not possible. Infants were stabilised with continuous positive airway pressure and received rescue intubation if necessary. In the intervention group, infants received surfactant treatment during spontaneous breathing via a thin catheter inserted into the trachea by laryngoscopy if they needed a fraction of inspired oxygen more than 0·30. The primary endpoint was need for any mechanical ventilation, or being not ventilated but having a partial pressure of carbon dioxide more than 65 mm Hg (8·6 kPa) or a fraction of inspired oxygen more than 0·60, or both, for more than 2 h between 25 h and 72 h of age. Analysis was by intention to treat. This study is registered, number ISRCTN05025922.

Findings

108 infants were assigned to the intervention group and 112 infants to the standard treatment group. All infants were analysed. On day 2 or 3 after birth, 30 (28%) infants in the intervention group were mechanically ventilated versus 51 (46%) in the standard treatment group (number needed to treat 6, 95% CI 3–20, absolute risk reduction 0·18, 95% CI 0·30–0·05, p=0·008). 36 (33%) infants in the intervention group were mechanically ventilated during their stay in the hospital compared with 82 (73%) in the standard treatment group (number needed to treat: 3, 95% CI 2–4, p<0·0001). The intervention group had significantly fewer median days on mechanical ventilation, (0 days. IQR 0–3 vs 2 days, 0–5) and a lower need for oxygen therapy at 28 days (30 infants [30%] vs 49 infants [45%], p=0·032) compared with the standard treatment group. We recorded no differences between groups for mortality (seven deaths in the intervention group vs five in the standard treatment group) and serious adverse events (21 vs 28).

Interpretation

The application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving continuous positive airway pressure reduces the need for mechanical ventilation.

Funding

German Ministry of Research and Technology, University of Lübeck, and Chiesi Pharmaceuticals.

Introduction

Continuous positive airway pressure (CPAP) and non-invasive ventilation are used in adults and children to avoid endotracheal intubation.1, 2, 3 Preterm infants are frequently treated with surfactant for respiratory distress syndrome.4 Surfactant is usually given via the endotracheal tube during mechanical ventilation. Therefore, preterm infants who are stabilised after birth without intubation are not treated with surfactant, which is a disadvantage of CPAP.

An approach of intubation, surfactant application during brief mechanical ventilation, and extubation before nasal CPAP has previously been used.5, 6, 7, 8, 9, 10 A meta-analysis of the use of this technique reported a reduced need for mechanical ventilation but increased surfactant use.11 The method still requires sedation, intubation, and short mechanical ventilation, and because similar outcomes have been reported for infants treated with CPAP alone,2, 9, 12 the technique of intubation, surfactant, and extubation has not been widely used.

A method of surfactant application without endotracheal intubation and mechanical ventilation has become widespread in German neonatal intensive care units. Surfactant is given to spontaneously breathing preterm infants on CPAP via a thin catheter placed in the trachea only for the time needed to give the surfactant (webvideo 1).13, 14 Observational, multicentre data suggest that this method might reduce the need for mechanical ventilation.15 However, the safety and efficacy of this method have not been tested in a randomised controlled trial.

We postulated that the application of surfactant to spontaneously breathing preterm infants would reduce the percentage of infants who subsequently need mechanical ventilation.

Section snippets

Study design and patients

The Avoiding Mechanical Ventilation (AMV) trial was a multicentre, randomised, controlled parallel-group study done at 12 neonatal intensive care units (level three) in Germany between October, 2007, and January, 2010. The protocol was approved by the ethics committee of each participating centre and done in accordance with good clinical practice guidelines and all applicable regulatory rules. Preterm infants with a gestational age from 26 weeks to 28 weeks plus 6 days, and with a birthweight

Results

Figure 1 shows the trial profile. Between Oct, 8, 2007, and Aug 1, 2009, 403 infants were eligible for the study in 12 centres. 220 infants (55%) were enrolled and analysed (figure 1). No significant differences were reported between included and excluded infant's birthweight, gestational age, bronchopulmonary dysplasia or death (data not shown). The trial was completed as planned; the last patient was discharged in January, 2010. 112 infants were randomly assigned to receive standard treatment

Discussion

Findings from this study have shown that the application of surfactant to spontaneously breathing preterm infants is feasible and reduces the need for subsequent mechanical ventilation. This effect was apparent in our primary analysis, which was designed to account for the variability of each gestational age group, but was even more pronounced in the subgroup of infants who were stabilised with CPAP after birth.

Infants with established respiratory distress syndrome who received animal-derived

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