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