JAMA Pediatrics Journal Club Slides:
Oxygen Saturation Target Range for
Extremely Preterm Infants
Manja V, Lakshminrusimha S, Cook DJ. Oxygen saturation target
range for extremely preterm infants: a systematic review and metaanalysis. JAMA Pediatr. Published online February 9, 2015.
doi:10.1001/jamapediatrics.2014.3307.
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Introduction
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Background
– Determining the optimal oxygen saturation (SpO2) target for extremely
preterm infants has been the focus of 5 randomized clinical trials (Surfactant,
Positive Pressure, and Oxygenation Randomized Trial [SUPPORT], Benefits
of Oxygen Saturation Targeting II [BOOST II] in the United Kingdom,
Australia, and New Zealand, and Canadian Oxygen Trial [COT]).
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Study Objective
– To assess whether targeting a lower SpO2 range (85%-89% restricted
oxygen) has an effect on mortality and severe disability, mortality alone,
bronchopulmonary dysplasia, neurodevelopmental outcome, hearing loss,
necrotizing enterocolitis, or severe retinopathy of prematurity compared with
targeting a higher SpO2 range (91%-95% liberal oxygen) after accounting for
the risk of bias of each included study as well as the quality of evidence for
each outcome.
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Study Design
– Meta-analysis and systematic review.
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Methods
Tools to Evaluate Studies
Heterogeneity Risk of Bias
Quality of Evidence
Tool
I2 index
Cochrane risk-of-bias tool
GRADE criteria
Categories
≤25% low,
≥75% high
Low bias
Unclear
High bias
High
Moderate
Low
Very low
Comments
and areas of
assessment
I2 > 50% with
χ2 P < .10
considered
significant
Sequence generation for
randomization
Blinding
Completeness of follow-up
Selective reporting
Publication bias
Other biases
Quality (design, execution, and
risk of bias)
Consistency (or heterogeneity)
Directness
Precision
Publication bias
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Methods
•
•
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Fixed-effect model assumes a common treatment effect and equal weight
is given to each subject (large study, proportionately larger weight in metaanalysis).
Random-effects model incorporates between-study variance. If a group of
studies is homogeneous, fixed-effect and random-effects study-specific
weights are equal. With increasing heterogeneity, the 2 weights will become
increasingly different.
Random-effects model was chosen to analyze results in this study because
– The goal was to estimate the mean effect in all studies and not let the
overall estimate be overly influenced by 1 study.
– These studies were performed by different researchers using similar
outlines but operating independently.
– These studies are not functionally equivalent due to variability in
patients, protocols (pulse oximeter algorithms).
– Random-effects model is more suitable to generalize results to a range
of clinical scenarios.
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Results
Main Outcomes
Outcome
Risk Ratio
(95% CI)
Participants,
No.
Heterogeneity
Quality of
Χ2 P Value I2, % Evidence
Death before hospital
discharge
1.18
(1.03-1.36)
3757
.68
0
Low
Death or severe disability at
18-24 months
1.02 (0.92-1.14)
2716
.29
20
Moderate
Death before 24 months
1.16 (0.98-1.37)
2783
.58
0
Moderate
Bronchopulmonary
dysplasia
0.95 (0.87-1.04)
2869
.73
0
Moderate
Necrotizing enterocolitis
1.24 (1.05-1.47)
4929
.65
0
Moderate
Neurodevelopmental
impairment
1.03 (0.73-1.45)
2252
.66
0
Moderate
Hearing loss
1.32 (0.78-2.21)
2237
.77
0
Moderate
Retinopathy of prematurity
0.72 (0.5-1.04)
4066
.01
78
Low
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Results
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Death before hospital discharge was statistically significantly higher in the
restricted oxygen group (risk ratio = 1.18; 95% CI, 1.03-1.36). This was not
a prespecified outcome in any of the studies.
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Necrotizing enterocolitis occured more frequently in the restricted oxygen
group (risk ratio = 1.24; 95% CI, 1.05-1.47).
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There was no significant difference in the outcomes of death or disability
before age 2 years, death before 24 months, bronchopulmonary dysplasia,
hearing loss, and retinopathy of prematurity.
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The quality of evidence was low for the outcomes of death before hospital
discharge and retinopathy of prematurity. It was moderate for all other
outcomes.
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Results
Distribution of Actual Median Oxygen Saturation:
Median Saturation Does Not Correlate with Mortality
19Lakshminrusimha
S, Manja V, Mathew B, Suresh GK. Oxygen targeting in preterm infants: a physiological interpretation.
J Perinatol. 2015;35(1):8-15.
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Comment
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This systematic review highlights the importance of assessing the risk of
bias in studies and of the level of confidence in the estimate of effect of
each outcome.
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Although SUPPORT, BOOST II, and COT were well-designed and mostly
well-executed studies, the significant overlap in oxygenation between the
intervention and comparator arms makes it difficult to conclude that the
results obtained were predominantly due to difference in oxygenation.
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Death before hospital discharge was not a prespecified outcome in any of
these trials. The confidence in this outcome is lower for this reason.
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Significant heterogeneity existed between studies for the outcome of
retinopathy of prematurity, resulting in lowering of the level of confidence for
the estimate of effect for this outcome.
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Conclusions
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This review illustrates the qualitative factors that need to be considered
before making treatment recommendations based on systematic reviews of
available literature.
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The assessment of quality of evidence can be subjective; however, using
GRADE, the rationale for the quality assessment is clearly stated and the
subjective nature of this process acknowledged.
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This review reveals that there continues to be significant uncertainty about
the optimal target range for SpO2 in extremely preterm infants. This is in
contrast to previous reviews, which did not consider the quality of evidence
in their final evaluation.
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Information from the planned prospective individual-patient meta-analysis
and practical considerations (difficulty in maintaining SpO2 in a narrow
range) should be included when making practice recommendations.
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Contact Information
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If you have questions, please contact the corresponding author:
– Satyan Lakshminrusimha, MD, Division of Neonatal-Perinatal
Medicine, Department of Pediatrics, Women and Children’s Hospital
of Buffalo, 219 Bryant St, Buffalo, NY 14222 (slakshmi@buffalo.edu).
Funding/Support
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This work was supported by grant 5 R01 HD072929 (optimal oxygenation
in neonatal lung injury) (Dr Lakshminrusimha).
Conflict of Interest Disclosures
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Dr Lakshminrusimha was a member of the speaker’s bureau for Ikaria
LLC. No other disclosures are reported.
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