Oxygen Saturation and Outcomes in Preterm Infants The BOOST II United Kingdom, Australia, and New Zealand Collaborative Groups.

CONTEXT

The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used.[1]

Five randomized, masked trials with similar protocols were conducted in the United States, Australia, New Zealand, Canada, and the United Kingdom involving infants born before 28 weeks’ gestation. Investigators are evaluating the effects of targeting a range of oxygen saturation of 85-89%, as compared with a range of 91-95% on survival and neurodevelopmental outcomes at 18 months to 2 years after the expected delivery date.

In all five trials, Masimo Radical pulse oximeters were used to measure oxygen saturation.

MATERIALS AND METHODS

The BOOST II collaborative groups conducted three international randomized, controlled trials in the UK, Australia, and New Zealand from March 2006 to December 2010

The planned study sample size was 1200 infants each for UK and Australian trial and 340 infants for the New Zealand trial

The short-term outcomes were reported on May 2013.

Long-term outcomes (at 2 years) are not reported yet.

Population

Inclusion

Infants were eligible for enrolment if they were less than 28 weeks gestation and born within the past 24 hours.

Exclusion

Infant unlikely to survive

Major congenital abnormality

Infant would not be available for follow-up.

Intervention

Infants were randomly assigned to treatment with the use of an oxygen-saturation target of 85-89% (lower target group) or 91-95% (higher target group)

To mask the intervention, the study oximeters were modified internally so that readings of 85-95% showed oxygen saturation that was either 3 percentage points higher or 3 percentage points lower than the actual value.

To achieve the intended oxygen-saturation range in either group, clinical staff members targeted displayed readings in the range of 88-92%

Only study oximeters were used from the time of randomization until 36 weeks, unless infants died or were discharged home

Approximately halfway through the trials, between December 2008 and May 2009, oximeters in the United Kingdom and Australian trials were changed to the new calibration algorithm, and the new algorithm was used for all infants who were subsequently enrolled. The New Zealand trial oximeters were not changed because recruitment had nearly finished.

Primary outcomes

Death

Severe neurosensory disability at 18 months to 2 years of age, corrected for prematurity.

Secondary outcomes

Retinopathy of prematurity

NEC

Intraventricular hemorrhage

Patent ductus arteriosus

Bronchopulmonary dysplasia.

Allocation

Randomization was performed centrally by computer and separately for each trial

In the United Kingdom, a minimization procedure was used to balance study-group assignment according to sex, gestational age, and center

In Australia and New Zealand, randomization was stratified according to sex, gestational age, center, single birth or multiple births, and whether birth took place in the hospital where enrolment took place.

RESULTS

During the trials, investigators in the United Kingdom found that standard Masimo Radical oximeters returned fewer oxygen-saturation values in the range of 870-90% than expected. This reduced the frequency of displayed oxygen-saturation values ranging from 87% to 90% and caused values ranging from 87% to 96% to read 1-2% higher

Masimo supplied software with a revised calibration algorithm

A total of 2448 infants were enrolled in the three trials (973 in the United Kingdom, 1135 in Australia, and 340 in New Zealand)

Of these infants, 1261 (51.5%) were treated with the use of the original oximeter-calibration algorithm and 1187 (48.5%) with the use of the revised algorithm

Baseline demographic and clinical characteristics were similar in the two target groups, among the three trials, and in the two algorithm groups.

Primary outcome

The current publication reported the outcome for all infants until hospital discharge. The rate of long-term neurodevelopmental disability is expected to be published later

Among the 1187 infants for whom the revised oximeter-calibration algorithm was used, those in the lower-target group had a higher rate of death than those in the higher-target group before hospital discharge [Tables 1 and 2], hence the trial was stopped early

Table 1

Death before hospital discharge

Table 2

Death at gestational age of 36 weeks

Among the 1261 infants for whom the original oximeter-calibration algorithm was used, there were no significant between group differences in outcomes at hospital discharge

In all data combined, there was no significant difference in rate of death in the lower target group, as compared with the higher target group

There were more deaths in the lower target group, but no single cause dominated the difference.

Secondary outcome

Infants in the lower target group had a reduced rate of treatment for retinopathy of prematurity

Infants in the lower target group had an increased rate of NEC requiring surgery or causing death

Fewer infants in the lower target group were treated with oxygen at 36 weeks in the three trials

There was no significant difference in the rate of BPD, PDA, IVH and other brain injury between the two groups.

COMMENTARY

Oxygen saturation and outcomes in preterm infants (BOOST II) trial is a multinational randomized controlled trial that was performed in parallel with the other oxygen trials using the same protocol, to evaluate the effect of targeting lower (85-89%) compared with higher (91-95%) oxygen saturations on death and disability at 2 years on infants born before 28 weeks. At the time these trials were conducted, there was no evidence that targeting lower oxygen saturations will increase mortality.

BOOST II recruited around 2448 infants, 1187 were treated with the use of a revised algorithm. During the course of the trial, the calibration of the Masimo radical pulse oximeters was revised due to issues with fewer oxygen retention values in the range of 87-90% providing an incorrect reading by 1-2% higher.[2] After revising the algorithm, the difference in mortality start to be clear between the two groups (more mortality in lower target group) and that lead the data and safety monitoring committee to stop enrolment in the study.

The current publication of the BOOST II trials provide short-term outcome data till hospital discharge; while long-term outcomes of the study at 2 years follow-up is still awaited.

In this study, targeting lower oxygen saturations resulted in higher rate of NEC requiring surgery and a lower rate of retinopathy of prematurity. Other secondary outcomes showed no difference between the two groups.

The results of the BOOST II trial are similar to the results of the SUPPORT trial.[3] However, the COT did not show a significant effect on mortality with targeting lower oxygen saturations.[4]

Since all five trials used a similar study design, a prospective meta-analysis is planned when follow-up of study infants has occurred in the last trial, the NeOProM Collaboration.[5]

Given the increased mortality observed at lower oxygen-saturation ranges in BOOST II and SUPPORT trials, it now appears prudent to aim to maintain an oxygen-saturation level in the 90-95% range. Yet, such an approach may result in an increased incidence of retinopathy of prematurity.[6]

Abstracted from

Stenson BJ, Tarnow-Mordi WO, Darlow BA, Simes J, Juszczak E, Askie L, et al. BOOST II United Kingdom Collaborative Group, BOOST II Australia Collaborative Group, BOOST II New Zealand Collaborative Group. Oxygen saturation and outcomes in preterm infants. N Engl J Med 2013;368:2094-104.