A randomised controlled trial comparing two methods of providing volume targeted ventilation in preterm infants :volume guarantee versus volume-controlled ventilation, The VoluVent Trial

Abstract

Background: Many preterm infants require mechanical ventilation via an endotracheal tube for the treatment of neonatal respiratory distress (RDS). A side effect of mechanical ventilation is lung injury. VTV aims to reduce lung injury by controlling the tidal volumes delivered to the infant by the ventilator. Many VTV modes are widely in use but have not been compared using clinically relevant outcomes. Aim: This was the first trial to compare two modes of VTV in preterm infants with RDS. We aimed to compare volume-controlled ventilation (VCV) with volume guarantee (VG) using clinically relevant outcomes. Hypothesis: We hypothesised that, in preterm infants with RDS, the time taken to be ready for extubation would be shorter in the VG group compared with VCV. The initial sample size calculation indicated that 102 infants were needed to show a 33% reduction in the time taken to be ready for extubation with a significance level of 0.05 and a power of 80%. Methods: This single centre, randomised controlled pilot trial was undertaken in a tertiary neonatal unit from July 2013 – December 2015. Infants were stratified into two groups according to gestational age at birth (<28 weeks’ gestation and 28 – 33+6 weeks’ gestation). The primary outcome was the duration of time from starting the trial mode until being ready for extubation. Readiness for extubation was defined using pre-determined ‘success’ criteria. Secondary outcomes included important clinical outcomes. After four months the consent method was changed from prospective to deferred parental consent. A trial oversight review of data from the first 50 infants identified that the primary outcome data were not likely to be normally distributed. The statistical analysis plan was therefore updated prior to any data analysis. We planned to present data as descriptive summary statistics including survival probabilities, hazard ratios (HRs) and odds ratios (ORs). In addition, using early phase trials statistical methods, a difference of 15% between groups in the numbers of infants reaching the ‘success’ criteria at 48 hours would indicate a potentially significant difference between groups. iv An ancillary study was undertaken using mechanistic data downloaded from ventilators to validate one of the ‘success’ criteria (mean airway pressure). Results: One hundred and thirteen infants were enrolled. One infant was subsequently withdrawn due to a diagnosis consistent with exclusion criteria. The median time to ‘success’ criteria was 23 hours (95% CI 10.78 – 35.22 hours) in the VG group and 36 hours (95% CI 18.03 – 53.97) in the VCV group. The HR was 0.93 (95% CI 0.63 – 1.37). Thirty four infants in the VG group and 33 infants in the VCV group had met the ‘success’ criteria by 48 hours. Subgroup analyses showed that, in infants born at 28 – 33+6 weeks’ gestation, the median time to reach the primary outcome faster in the VG group. The pneumothorax rates and duration of ventilation were lower in the VG group. The use of deferred consent appeared to be more acceptable to parents and led to an improvement in the recruitment rate. The ancillary study showed very good correlation between the mean airway pressure values recorded manually once every hour and the values downloaded with every breath. This validated the use of manual recordings of mean airway pressure as part of the primary outcome. Conclusions: There was a clinical important difference between VG and VCV in the time taken for infants to be ready for extubation. This difference favoured VG but a larger trial is needed to show a definitive result. This trial also highlights current gaps in knowledge regarding short-term clinical outcomes and the use of VTV modes in different subgroups of infants. Deferred consent appears to be acceptable to parents of newborn infants but qualitative research is needed to explore this further. This thesis describes The VoluVent Trial (ISRCTN 04448562), the first clinical trial to compare two types of volume-targeted ventilation (VTV) in preterm infants. One of the known side effects of mechanical ventilation is lung injury. VTV aims to minimise ventilator-associated lung injury and different types of VTV are used widely. However, there is no evidence to confirm whether one type of VTV is better than another for preterm infants