Randomised controlled trial of weaning strategies for preterm infants on nasal continuous positive airway pressure

Nasal continuous positive airway pressure (NCPAP) is effective at preventing intubation in preterm infants [1, 2] and preventing extubation failure in infants after mechanical ventilation [3]. Subsequently, various strategies have been trialled for the withdrawal of NCPAP in preterm infants [4]. Trials have compared a gradual reduction of NCPAP pressure versus increasing duration of time off; [5, 6] and also initially weaning pressure to 4-6cmH₂O and then comparing attempts to take infants off NCPAP (‘abrupt weaning’) versus increasing duration of time off (‘gradual weaning’), with or without the addition of low flow nasal cannula [7]. This later study reported a decreased length of stay for babies randomised to a weaning strategy where NCPAP is simply stopped when infants met predefined stability criteria.

However, NCPAP has side effects including gaseous distension of the bowel, nasal trauma, and nasal deformity if NCPAP use is prolonged [8]. Heated, humidified high flow nasal cannula (HFNC) using flow rates greater than 1 L/min [9] are being used as an alternative to NCPAP. Surveys in Australia and the United Kingdom document its widespread use as an alternative to NCPAP, weaning off CPAP and post extubation [10, 11]. Trials comparing use of HFNC versus NCPAP for facilitating extubation in preterm infants report similar efficacy for prevention of extubation failure [12, 13] and reduced nasal trauma with HFNC [14]. Previous research reported that use of HFNC in preterm infants for weaning from NCPAP is associated with an increased exposure to oxygen and longer duration of respiratory support. [15] However, HFNC flow was restricted to 2 L/min and infants weaned from NCPAP were on a relatively high fraction inspired oxygen (FiO₂ ≤ 0.3) so may have had relatively severe lung disease.

This is a pilot study designed to inform the optimal comparisons for a larger trial. The primary aim of a larger trial will be to determine the optimal method for weaning infants born <30 weeks gestation from NCPAP to reduce duration of respiratory support and time to full suck feeds. The secondary aims are to determine the efficacy of abrupt versus gradual weaning from NCPAP; and the efficacy of use of HFNC versus no HFNC for weaning infants from NCPAP.

Ninety infants were born <30 weeks gestational age October 2010 and June 2012. Sixty eligible infants were enrolled and randomised, 15 to each group. Reasons for non-enrolment are reported in Fig. 1. All infants received the allocated treatment and were analysed by intention to treat. The groups were well balanced for perinatal and clinical characteristics after randomisation (Table 1). Infants randomised had a mean gestation 27.5 weeks (range 24.0–29.9) and birth weight 989 g (574–1617). They were aged 28 days (range 2–76) with mean postmenstrual age 31 weeks (27–37) and weight 1237 g (662–1890) and were similar between groups. Infants were on mean FiO₂ 0.21 (range 21–23), pressure 5 cmH₂0 (5–5), on NCPAP for 19 h (5–24) and tolerated 5 h (0–15) off NCPAP and were similar between groups.

This study was a pilot designed to determine the optimal comparisons for a larger trial. None of the strategies resulted in a significant effect on the prespecified primary outcomes including incidence of CLD, duration of respiratory support, days to full suck feeds or hospital stay although the study is underpowered to find a difference. However, there were significant differences between groups in days of NCPAP and infants withdrawn from treatment due to parental concern. The group abruptly weaning infants to HFNC had the shortest duration of NCPAP. The group abruptly weaned without use of HFNC had the highest withdrawal rate. In combined group analysis, infants on HFNC had a significant reduction in days NCPAP. Use of HFNC may be an efficient method for weaning infants from NCPAP even though it did not reduce the overall duration of respiratory support, days to full suck feeds or duration of hospital stay. In combined group analysis, abruptly weaning infants reduced the duration of HFNC required. This suggests the best strategy for weaning infants from NCPAP is to place them on HFNC when they are at a predefined level of pressure support. Although abrupt weaning was also associated with a reduced duration of NCPAP, corrected gestational age off NCPAP and duration of pressure support, this did not reach our predefined significance level for secondary outcomes.

HFNC delivers continuous distending pressure [16]. The delivered continuous distending pressure is higher in smaller infants (<1500 g) [17], at higher flow rates [17‐20], using prongs with a larger outer diameter [19], and when the infant’s mouth is closed [19]. Previous research that assessed use of HFNC in preterm infants for weaning from NCPAP reported use of HFNC was associated with an increased exposure to oxygen and longer duration of respiratory support. [15] However, in that study HFNC flow used prongs with an outer diameter of 0.3 cm and flow was restricted to 2 L per minute. In addition, infants were weaned from NCPAP when on a relatively high fraction inspired oxygen (≤0.3) suggesting the infants had more severe lung disease and were on a higher level of respiratory support. In contrast, our study weaned infants on NCPAP at 5cmH₂O, the majority of whom were in air, and used HFNC with an outer diameter of 0.2 cm and commenced at 6 L/min. The efficiency of HFNC in this study may be due to the use of higher flow rates for weaning infants from lower levels of respiratory support.

Two recent trials comparing use of HFNC versus NCPAP for facilitating extubation in preterm infants report similar efficacy for prevention of extubation failure [12, 13] and reduced nasal trauma with HFNC [14]. It is noteworthy that these trials did not report routine mouth closure techniques for infants allocated NCPAP. Mouth open is associated with loss of pharyngeal pressure support and potentially efficacy of NCPAP [21]. A third trial comparing HFNC versus NCPAP applied immediately post extubation or early as initial non-invasive support for respiratory dysfunction, reported similar efficacy including no difference in early failure or need for intubation [22]. Infants on HFNC had an increased duration of pressure support although there was no difference in duration of oxygen, bronchopulmonary dysplasia or duration of hospitalisation. These trials and the current study suggest HFNC has similar efficacy to NCPAP for infants in need of lower levels of respiratory support. A previous trial that assessed a practice of abrupt weaning versus gradual weaning from NCPAP when infants met prespecified stability criteria, reported that abrupt weaning from NCPAP was associated with a shorter duration of oxygen and time on respiratory support. [7] However, the trial had substantial differences in baseline characteristics including gender and condition at birth suggesting the results should be treated with caution. Our trial had a similar set of ‘stability’ and ‘failure’ criteria. However, abrupt weaning without HFNC was associated with a significantly increased rate of parental withdrawal and no significant benefits. The reason for withdrawal of all infants was dissatisfaction with weaning method. Parents reported feeling their infant was ‘failing the weaning process’ when attempting to abruptly cease NCPAP. The analyses from our trial suggest a strategy of abrupt wean with use of HFNC may be the most efficient and acceptable to parents. Given this is a small pilot study caution is advised in interpreting the findings.

Given HFNC has been demonstrated to reduce nasal trauma [14, 22], a trial of abrupt weaning of NCPAP with HFNC versus gradual weaning of NCPAP may be difficult to justify for infants on lower level respiratory support. Further research is required to further define the role of HFNC for primary respiratory support of newborn infants and infants being extubated from mechanical ventilation.

Use of high flow nasal cannula was effective at weaning infants from NCPAP. Further trials are required to determine if use of HFNC for weaning can reduce the duration of pressure support or reduce time to full suck feeds. A strategy of weaning NCPAP to a predefined level and then stopping NCPAP completely without use of high flow nasal cannula was associated with increased rate of withdrawal at parent request so may not be acceptable in all settings.