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Evidence‑based Neonatology Synopsis

PURPOSE practice changing original research articles and systematic

reviews. These articles are summarized and presented with
The main goal of evidence‑based neonatology synopsis is to a commentary of a clinical expert. Commentators are
inform and alert neonatal practitioners of the latest advances selected by the editorial team and invited to select articles
in neonatal literature. Our reviews focus on high quality, based on a prespecified criteria.

Effects of Targeting Higher vs Lower Arterial Oxygen

Saturations on Death or Disability in Extremely Preterm
Infants: The Canadian Oxygen Trial
Fahad Al Hazzani, Emad Khadawardi
Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. E-mail: [email protected]

CONTEXT Population
Inclusion
The goal of oxygen therapy is to deliver sufficient oxygen to
the tissues while minimizing oxygen toxicity and oxidative Infants with gestational ages of 23 weeks 0 days through
stress. It remains uncertain what values of arterial oxygen 27 weeks 6 days were eligible for enrollment during the first
saturations achieve this balance in immature infants, who 24 hours after birth.
are especially vulnerable to the harmful effects of oxygen.
Exclusion
Between 2005 and 2007, five randomized trials (Surfactant 1. Infant not considered viable
Positive Airway Pressure and Pulse Oximetry Trial 2. Persistent pulmonary hypertension
(SUPPORT), Benefits of Oxygen Saturation Targeting 3. Dysmorphic features or congenital malformations that
(BOOST) II Australia, BOOST‑NZ, BOOST II UK, and adversely affect life expectancy or neurodevelopment
Canadian oxygen trial (COT)) were initiated to resolve 4. Cyanotic heart disease
the long‑standing uncertainty of how to titrate oxygen 5. Infant was unlikely to be available for long‑term
therapy in extremely preterm infants.[1] All trials have been follow‑up.
conducted to test if targeting oxygen saturations in the lower
(85‑89%) vs the upper (91‑95%) part of the recommended Intervention
range confer advantages in regard to neurodevelopmental • Infants were placed on the modified Massimo pulse
outcome and severe retinopathy of prematurity (ROP) in oximeter. The oximeters were modified to display and
extremely premature infants. store oxygen saturations that were either 3% higher or
lower than the true values. True values were displayed if
MATERIALS AND METHODS
the measured values decreased below 84% or increased
The COT is a randomized and parallel double‑blind trial above 96%
that was conducted in 25 hospitals in Canada, the United • Caregivers were instructed to adjust the concentration
States, Argentina, Finland, Germany, and Israel. of oxygen to maintain saturation values between 88%
and 92%, which produced two treatment groups with
Enrollment began in December 2006 and ended in true target saturations of 85-89% or 91-95%
August 2010. Follow‑up assessments were performed • Alarms were triggered when the displayed saturations
between October 2008 and August 2012. decreased to 86% or increased to 94%

70 Journal of Clinical Neonatology | Vol. 2 | Issue 2 | April-June 2013

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• Study oximetry was continued until 36 weeks of Blinding

postmenstrual age even if an infant was not receiving The allocation remained unknown to the members of the
supplemental oxygen. Infants who were receiving any clinical and research teams and all staff at the coordinating
respiratory support including oxygen therapy at center.
35 weeks of postmenstrual age were monitored
with their assigned study oximeter until a postmenstrual RESULTS
age of 40 weeks. Study oximetry was stopped earlier if
infants were discharged home • Between December 2006 and August 2010, the study
• Between February 12 and June 26, 2009, a technician enrolled 1201 patients from 25 hospitals
from the coordinating center installed revised software • Primary outcome data were available for 95.5% of
on site in all study oximeters participants and are shown in Table 1
• All other aspects of respiratory management such as • The median of the individual study participants`
ventilatory rate and airway pressures were determined oxygen saturations on days with more than 12 hours of
by the clinicians caring for the infants. oxygen was:
• Lower saturation group: 90.9% (IQR 89.6‑92.5%)
Primary outcomes • Higher saturation group: 93.4% (IQR 92.7‑94.2%)
• Death • Targeting lower compared with higher oxygen
• Gross motor disability: Defined as a level of 2 or higher saturations had no significant effect on the rate of death
according to the Gross Motor Function Classification or disability at 18 months.
System • Subgroup analysis by oximeter software is shown in
• Cognitive or language delay defined as composite Table 2
cognitive or language score of less than 85 (1 SD below • Secondary outcomes:
the mean of 100) on the Bayley Scales of Infant and • Targeting lower compared with higher oxygen
Toddler Development, Third Edition saturations reduced the mean postmenstrual
• Severe hearing loss: Defined as the prescription of age at the last oxygen therapy from 36.2 to
hearing aids or cochlear implants 35.4 weeks (P = 0.03)
• There was no significant difference between the
• Bilateral blindness: Defined as a corrected visual acuity
groups in other outcome including ROP and
less than 20/200 in the better eye.
severe BPD.
Secondary outcomes
COMMENTARY
Prespecified neonatal outcomes included ROP, brain injury,
patent ductus arteriosus, necrotizing enterocolitis (NEC), The COT is a well designed and well performed multinational
bronchopulmonary dysplasia (BPD), and the duration of use randomized controlled trial. The median actual oxygen
of positive airway pressure and supplemental oxygen. saturations between the two groups were widely separated.
Halfway during the trial the pulse oximeter software was
Allocation updated to correct a 2% overestimation in the 87‑90%
A computer‑generated randomization scheme was produced saturation range.[2,3]
by an independent statistician at the coordinating center to
assign the infants to treatment groups in a 1:1 ratio. COT trial did not find a significant effect of targeting lower
compared with higher oxygen saturations on death and
Randomization was stratified by study center and balanced disability at 18 months. In addition, there was no significant
within randomly sized blocks of two or four patients. difference on the incidence of ROP and BPD.

Table 1: Primary outcome of death or disability

Outcome Target SO2 Target SO2 Unadjusted Adjusted OR
85‑89% 91‑85% OR OR (95% CI) P value
Composite: Death or disability 51.6 49.7 1.08 1.08 (0.85-1.37) 0.52
Death before 18 months 16.6 15.3 1.1 1.11 (0.8-1.54) 0.54
GMFC 2‑5 6.1 6.4 0.97 0.98 (057-1.67) 0.94
Cognitive or language delay 40 39.9 1.01 1.02 (0.78-1.34) 0.86
Severe hearing loss 3.7 2.5 1.53 1.53 (0.73-3.20) 0.26
Bilateral blindness 1.0 0.6 1.68 1.68 (0.4‑7.06) 1.53

Journal of Clinical Neonatology | Vol. 2 | Issue 2 | April-June 2013 71

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Table 2: Subgroup analysis by oximeter software

Outcome Target SO2 Target SO2 Unadjusted Adjusted OR
85‑89% 91‑85% OR OR (95% CI) P value
Death or disability 50.9 52.3 0.95 0.97 (0.68-1.39) 0.88
Original software
Death or disability 52.6 46.6 1.27 1.31 (0.91-1.88) 0.14
Revised software
Test of interaction 0.26
Death before 18 months 17.4 17.9 0.97 1.00 (0.63-1.59) 0.99
Original software
Death before 18 months 16.8 14.1 1.24 1.23 (0.75-2.01) 0.41
Revised software
Test of interaction 0.55

The findings of the COT trial are different from the findings prospective meta‑analysis is planned when follow‑up of
of the other oxygen trials. study infants has occurred in the last trial, the Neonatal
Oxygenation Prospective Meta‑analysis (NeOProM)
The support trial found that targeting lower (85‑89%) Collaboration.[6] Hopefully this meta‑analysis will help to
compared with higher (91‑95%) saturations resulted in answer the remaining questions raised by these studies.
significantly lower incidence of severe ROP and higher
mortality before discharge.[4] Abstracted from
Schmidt B, Whyte RK, Asztalos EV, Moddemann D,
The increased mortality with the lower SpO2 target was also Poets C, Rabi Y, et al. Canadian Oxygen Trial (COT)
observed in the BOOST II trial[5] conducted in Australia, Group. Effects of targeting higher vs lower arterial
New Zealand, and the UK. The increase mortality in the oxygen saturations on death or disability in extremely
lower saturation group was observed after the revised preterm infants: A randomized clinical trial. JAMA
software was implemented. As a result, this study was 2013;309:2111‑20.
stopped.
REFERENCES
What was the reason for the difference in mortality? 1. Schmidt B, Whyte RK, Asztalos EV, Moddemann D, Poets C, Rabi Y,
et al. Canadian Oxygen Trial (COT) Group. Effects of targeting
In the accompanying editorial in The Journal of the higher vs lower arterial oxygen saturations on death or disability
American Medical Association (JAMA), Bancalari and in extremely preterm infants: A randomized clinical trial. JAMA
2013;309:2111‑20.
Claure explained: “Although these 3 studies used a similar
2. Johnston ED, Boyle B, Juszczak E, King A, Brocklehurst P,
protocol to allow meta‑analysis, there were important Stenson BJ. Oxygen targeting in preterm infants using the Masimo
differences between them. One of these differences was SET Radical pulse oximeter. Arch Dis Child Fetal Neonatal Ed
the proportion of infants managed with the old or the 2011;96:F429‑33.
3. Bancalari E, Claure N. Oxygenation targets and outcomes in
revised version of the pulse oximeter software. Also, the
premature infants. JAMA 22;309:2161‑2.
3 studies included similar at‑risk populations but the
4. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR,
studies were conducted in different areas of the world et al. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD
and therefore differences in ethnicity could influence the Neonatal Research Network. Target ranges of oxygen saturation in
results. In addition, although the saturation targets were extremely preterm infants. N Engl J Med 2010;362:1959‑69.
5. Stenson BJ, Tarnow‑Mordi WO, Darlow BA, Simes J, Juszczak E,
the same in the 3 studies, the actual saturation ranges
Askie L, et al. BOOST II United Kingdom Collaborative Group,
these infants were exposed to may have been different. BOOST II Australia Collaborative Group, BOOST II New Zealand
COT achieved tighter compliance with the targets and a Collaborative Group. Oxygen saturation and outcomes in preterm
wider separation in saturation between the 2 groups than infants. N Engl J Med 2013;368:2094‑104.
6. Askie LM, Brocklehurst P, Darlow BA, Finer N, Schmidt B,
SUPPORT.”[3]
Tarnow‑Mordi W. NeOProM Collaborative Group. NeOProM:
Neonatal Oxygenation Prospective Meta‑analysis Collaboration
Since all five trials used a similar study design, a study protocol. BMC Pediatr 2011;11:6.

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