Effects of Targeting Higher VS Lower Arterial Oxygen Saturations on Death or Disability in Extremely Preterm Infants: The Canadian Oxygen Trial.

CONTEXT

The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in immature infants, who are especially vulnerable to the harmful effects of oxygen.

Between 2005 and 2007, five randomized trials (Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT), Benefits of Oxygen Saturation Targeting (BOOST) II Australia, BOOST-NZ, BOOST II UK, and Canadian oxygen trial (COT)) were initiated to resolve the long-standing uncertainty of how to titrate oxygen therapy in extremely preterm infants.[1] All trials have been conducted to test if targeting oxygen saturations in the lower (85-89%) vs the upper (91-95%) part of the recommended range confer advantages in regard to neurodevelopmental outcome and severe retinopathy of prematurity (ROP) in extremely premature infants.

MATERIALS AND METHODS

The COT is a randomized and parallel double-blind trial that was conducted in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel.

Enrollment began in December 2006 and ended in August 2010. Follow-up assessments were performed between October 2008 and August 2012.

Population

Inclusion

Infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days were eligible for enrollment during the first 24 hours after birth.

Exclusion

Infant not considered viable

Persistent pulmonary hypertension

Dysmorphic features or congenital malformations that adversely affect life expectancy or neurodevelopment

Cyanotic heart disease

Infant was unlikely to be available for long-term follow-up.

Intervention

Infants were placed on the modified Massimo pulse oximeter. The oximeters were modified to display and store oxygen saturations that were either 3% higher or lower than the true values. True values were displayed if the measured values decreased below 84% or increased above 96%

Caregivers were instructed to adjust the concentration of oxygen to maintain saturation values between 88% and 92%, which produced two treatment groups with true target saturations of 85-89% or 91-95%

Alarms were triggered when the displayed saturations decreased to 86% or increased to 94%

Study oximetry was continued until 36 weeks of postmenstrual age even if an infant was not receiving supplemental oxygen. Infants who were receiving any respiratory support including oxygen therapy at 35 weeks of postmenstrual age were monitored with their assigned study oximeter until a postmenstrual age of 40 weeks. Study oximetry was stopped earlier if infants were discharged home

Between February 12 and June 26, 2009, a technician from the coordinating center installed revised software on site in all study oximeters

All other aspects of respiratory management such as ventilatory rate and airway pressures were determined by the clinicians caring for the infants.

Primary outcomes

Death

Gross motor disability: Defined as a level of 2 or higher according to the Gross Motor Function Classification System

Cognitive or language delay defined as composite cognitive or language score of less than 85 (1 SD below the mean of 100) on the Bayley Scales of Infant and Toddler Development, Third Edition

Severe hearing loss: Defined as the prescription of hearing aids or cochlear implants

Bilateral blindness: Defined as a corrected visual acuity less than 20/200 in the better eye.

Secondary outcomes

Prespecified neonatal outcomes included ROP, brain injury, patent ductus arteriosus, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and the duration of use of positive airway pressure and supplemental oxygen.

Allocation

A computer-generated randomization scheme was produced by an independent statistician at the coordinating center to assign the infants to treatment groups in a 1:1 ratio.

Randomization was stratified by study center and balanced within randomly sized blocks of two or four patients.

Blinding

The allocation remained unknown to the members of the clinical and research teams and all staff at the coordinating center.

RESULTS

Between December 2006 and August 2010, the study enrolled 1201 patients from 25 hospitals

Primary outcome data were available for 95.5% of participants and are shown in Table 1

Table 1

Primary outcome of death or disability

The median of the individual study participants` oxygen saturations on days with more than 12 hours of oxygen was:

Lower saturation group: 90.9% (IQR 89.6-92.5%)

Higher saturation group: 93.4% (IQR 92.7-94.2%)

Targeting lower compared with higher oxygen saturations had no significant effect on the rate of death or disability at 18 months.

Subgroup analysis by oximeter software is shown in Table 2

Table 2

Subgroup analysis by oximeter software

Secondary outcomes:

Targeting lower compared with higher oxygen saturations reduced the mean postmenstrual age at the last oxygen therapy from 36.2 to 35.4 weeks (P = 0.03)

There was no significant difference between the groups in other outcome including ROP and severe BPD.

COMMENTARY

The COT is a well designed and well performed multinational randomized controlled trial. The median actual oxygen saturations between the two groups were widely separated. Halfway during the trial the pulse oximeter software was updated to correct a 2% overestimation in the 87-90% saturation range.[23]

COT trial did not find a significant effect of targeting lower compared with higher oxygen saturations on death and disability at 18 months. In addition, there was no significant difference on the incidence of ROP and BPD.

The findings of the COT trial are different from the findings of the other oxygen trials.

The support trial found that targeting lower (85-89%) compared with higher (91-95%) saturations resulted in significantly lower incidence of severe ROP and higher mortality before discharge.[4]

The increased mortality with the lower SpO2 target was also observed in the BOOST II trial[5] conducted in Australia, New Zealand, and the UK. The increase mortality in the lower saturation group was observed after the revised software was implemented. As a result, this study was stopped.

What was the reason for the difference in mortality?

In the accompanying editorial in The Journal of the American Medical Association (JAMA), Bancalari and Claure explained: “Although these 3 studies used a similar protocol to allow meta-analysis, there were important differences between them. One of these differences was the proportion of infants managed with the old or the revised version of the pulse oximeter software. Also, the 3 studies included similar at-risk populations but the studies were conducted in different areas of the world and therefore differences in ethnicity could influence the results. In addition, although the saturation targets were the same in the 3 studies, the actual saturation ranges these infants were exposed to may have been different. COT achieved tighter compliance with the targets and a wider separation in saturation between the 2 groups than SUPPORT.”[3]

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 Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration.[6] Hopefully this meta-analysis will help to answer the remaining questions raised by these studies.

Abstracted from

Schmidt B, Whyte RK, Asztalos EV, Moddemann D, Poets C, Rabi Y, et al. Canadian Oxygen Trial (COT) Group. Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: A randomized clinical trial. JAMA 2013;309:2111-20.