SafeBoosC IIIv - Cerebral oximetry versus standard care in newborns receiving invasive mechanical ventilation – an RCT

Abstract

Background

Newborns in need of invasive mechanical ventilation are at high risk of a detrimental outcome,

not only due to the underlying condition, but also due to complications from the invasive

mechanical ventilation itself (1, 2). Such complications include pneumothorax, ventilation

associated pneumonia, and hyperventilation causing vasoconstriction of the cerebral vasculature

and possibly brain ischaemia (3). Summary data on outcomes is not easily available, but during

2019 death before discharge occurred in 41/500 (8.2%) newborns, born at more than 28 weeks of

gestation and in need of invasive mechanical ventilation during the neonatal period, in 10

neonatal units within the SafeBoosC consortium. A meta-analysis including 895 neonates from

23 non-randomised trials, undergoing surgery for non-cardiac congenital anomalies, found a

deficit in intelligence quotient of 0.5 standard deviations below the population average (4).

Additionally, data from a Danish national cohort, showed that 18% of children who underwent

invasive mechanical ventilation during the neonatal period, needed special educational support in

primary school, which is 2.5 times more often than normal (Wiingreen et al. unpublished data).

Thus, invasive mechanically ventilated newborns are a high-risk population. Given the instability

of the newborn’s pulmonary and circulatory physiology, it is possible that the addition of

measuring the oxygenation of the brain, by non-invasive near-infrared light technology (cerebral

oximetry) plus a treatment guideline, as an addition to the complex treatment and monitoring

regimes for these newborns, may increase the chance of surviving without neurodevelopmental

impairment.

Objectives

The objective of the SafeBoosC-IIIv trial is to evaluate cerebral oximetry added to usual care

versus usual care in newborns receiving invasive mechanical ventilation. The hypothesis for step

one is that the intervention will increase the number of hospital-free days within 90 days of

randomisation. The hypothesis for step two is that the intervention will decrease a composite

outcome of death or moderate to severe neurodevelopmental disability and/or increase the mean

PARCA-R non-verbal cognitive score at two years of corrected age.

Trial design

SafeBoosC-IIIv will be an investigator-initiated, multinational, randomised, pragmatic phase III

clinical trial. The trial will be conducted in two steps. In step one, 1,610 newborns will be

randomised, and the outcomes will be assessed 90 days after randomisation. Funding has been

obtained for step one. If further funding is obtained, we will continue to include newborns until a

total of 3,000 newborns are randomised and then follow them up at two years of corrected age

(step two). Randomisation will be performed in neonatal intensive care units across many

countries. Data managers, statisticians, and conclusion drawers will be blinded.

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Inclusion and exclusion criteria

Inclusion criteria will be:

Newborns with gestational age more than or equal to 28+0

Postnatal age less than 28 days

Expected to receive mechanical ventilation (invasive, i.e., not including CPAP or BiPAP)

for at least 24 hours, as judged by the physician intending to randomise

Parental informed consent unless the centre has chosen to use ‘opt-out’ or deferred

consent as consent method and a cerebral oximeter available so monitoring can be started

within six hours after initiation of invasive mechanical ventilation

Exclusion criteria will be:

Suspicion of or confirmed brain injury or disorder (e.g. perinatal asphyxia, cerebral

haemorrhage, cerebral malformation, genetic or metabolic disease)

Suspicion or diagnosis of congenital heart malformations likely to require surgery

Randomisation and interventions

Participants will be randomised through central web-based randomisation stratified by

neonatal intensive care unit; gestational age (lower gestational age (≤ 34 weeks) / higher

gestational age (> 34 weeks)), and surgery (newborns in need of invasive mechanical ventilation

due to a surgery (yes/no)) at the Copenhagen Trial Unit.

Participants in the experimental group will be monitored with cerebral oximetry, if possible

before or, as soon as possible and within six hours after initiation of invasive mechanical

ventilation. Cerebral oximetry will be continued until 1) the cardio-pulmonary function has been

stabilised as indicated by the need for respiratory and circulatory support and evaluated by the

responsible physician, 2) extubation, 3) until 28 days after birth, or 4) until death. Randomisation

will only direct the use of cerebral oximetry during the first invasive mechanical ventilation

episode. Cerebral oximetry will be used to minimise cerebral hypoxia by modifying clinical care

according to the SafeBoosC treatment guideline and monitoring as usual.

The control group will receive invasive mechanical ventilation without access to cerebral

oximetry (usual care).

Outcomes

The primary outcome for step one will be hospital-free days within 90 days of randomisation.

This outcome will be assessed by a blinded investigator.

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Based on a relative risk reduction of death of 5% and an absolute increase of 3 days in the

estimate of hospital-free days of the surviving participants (considered clinically relevant) with

an alpha of 0.05 and a power of 90% using the van Elteren test, we would need to include 1,610

participants.

There will be two co-primary outcomes for step two: 1) a composite of death or moderate-tosevere

neurodevelopmental disability and 2) non-verbal cognitive score of Parent Report of

Children’s Abilities-Revised (PARCA-R).

To test a reduction in death or moderate to severe neurodevelopment disability from 20% to 16%

between the experimental and control group, at an alpha-level of 2.5% and a power of 80%, a

total of 1,500 participants in each group, i.e. a total of 3,000, is needed. This corresponds to a

relative risk reduction of 20%.

Trial duration

Recruitment is expected to begin in December 2024 and expected to be completed within 24

months.