|Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data
|Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D
This review concluded that, for infants with hypoxic-ischaemic encephalopathy, cooling was associated with a reduction in death and neurological impairments at 18 months. Although this reduction was consistent across all trials, the potential for missed trials, poor reporting of the review process, and the small sample sizes for most analyses, means the results should be viewed with some caution.
To evaluate whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcomes at 18 months of age.
PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and the Oxford Database of Perinatal Trials were searched to July 2009; search terms were reported. Bibliographies of previous reviews and abstracts (source not specified) were also searched, and trialists contacted.
Studies conducted in neonates with hypoxic-ischaemic encephalopathy that compared whole body or head cooling with normal care, and reported mortality, disability and/or neurological outcomes, were eligible for inclusion. Randomised controlled trials, with a minimum of 18 months follow-up, were used to evaluate neurological outcomes.
Most included studies used whole body cooling achieved using varying methods, all but one study cooled for 72 hours, and the core temperature achieved ranged from 33 degrees C to 36.5 degrees C. The infants were at least 36 weeks gestation, and allocation to treatment occurred within six hours of birth.
Studies were selected by the study group; inclusion was based on consensus.
Assessment of study quality
Study quality was assessed in terms of randomisation, allocation concealment, blinding, and completeness of follow-up. The assessment of study quality for six of the trials appears to be that of a prior Cochrane review.
The number of reviewers performing the quality assessment was not reported.
Event rates for death and severe disability (alone and composite), survival with normal neurological function, major neurodevelopmental disability, cerebral palsy, severe neuromotor delay in survivors, blindness, and deafness were extracted. Risk ratios (RR) and 95% confidence intervals (CI) were calculated.
The number of reviewers performing the data extraction was not reported.
Methods of synthesis
Pooled risk ratios and risk differences (RD) and 95% confidence intervals were calculated using a fixed-effect meta-analysis; the number-needed-to-treat (NNT) was also calculated. Heterogeneity was assessed using the X2 and I2 statistics. Subgroup analyses were conducted to investigate the impact of the severity of encephalopathy.
Results of the review
Ten randomised controlled trials (RCTs) were identified (n=1,320 infants; range 19 to 325); follow-up ranged from four days to 24 months. Three RCTs reported neurological outcomes up to 18 months (n=767 infants; range 208 to 325); of these 767 infants, none were cared for by caregivers blinded to allocation, and 746 infants were assessed at 18 months by blinded outcome assessors. Of the six RCTs assessed by the Cochrane review (see Other Publications of Related Interest), one was considered to have inadequate allocation concealment. The methodological quality of the other four RCTs was considered appropriate.
Overall (10 RCTs), cooling significantly reduced mortality (RR 0.78, 95% CI 0.66 to 0.93; RD -0.07, 95% CI -0.12 to -0.02; NNT 14, 95% CI 8 to 47).
At 18 months (three RCTs), the risk of death/disability was significantly reduced with cooling (RR 0.81, 95% CI 0.71 to 0.93; RD -0.11, 95% CI -0.18 to -0.04; NNT 9, 95% CI 5 to 25), more so in infants with moderate (RR 0.73, 95% CI 0.58 to 0.92) than severe (RR 0.87, 95% CI 0.75 to 1.01) encephalopathy. Cooling also significantly reduced the incidence of mortality (RR 0.78, 95% CI 0.66 to 0.93), severe disability in survivors (RR 0.71, 95% CI 0.56 to 0.91), cerebral palsy (RR 0.69, 95% CI 0.54 to 0.89), severe neuromotor delay (RR 0.73, 95% CI 0.56 to 0.95), severe neurodevelopmental delay (RR 0.71, 95% CI 0.54 to 0.92), and blindness (RR 0.56, 95% CI 0.33 to 0.96), but not deafness. Survival with normal neurological function was significantly increased with cooling (RR 1.53, 95% CI 1.22 to 1.93). No significant heterogeneity was observed for any outcome.
In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia was associated with a consistent reduction in death and neurological impairments at 18 months.
The review addressed a clear research question supported by appropriate inclusion criteria. Several relevant sources were searched and attempts were made to locate unpublished studies. It was unclear whether language restrictions were applied, so relevant trials may have been missed. Study selection was conducted in duplicate, but it was unclear whether similar methods to reduce error and bias during data extraction and the quality assessment were employed.
Although relevant criteria were reported for the assessment of trial quality, it seems that the authors did not conduct the assessment on all included trials, and the results were poorly reported. The authors acknowledged that there was clinical heterogeneity between trials, but there was no statistical heterogeneity observed and the direction of effect was the same in all trials for most outcomes. Most of the pooled results on which the conclusions were based were informed by only three of the ten included trials.
Although there was consistency in the direction of effect across trials, the potential for missed non-English trials, the poor reporting of the review process, and the small sample sizes for most analyses, means the results should be viewed with some caution.
Implications of the review for practice and research
Practice: The authors stated that until further evidence becomes available, decision on whether to treat infants with severe encephalopathy by cooling should be made on an individual basis.
Research: The authors advised continued follow-up of the children in the trials included in the meta-analysis to determine whether benefits of cooling persist into later childhood.
One author was supported by the Health Research Council of New Zealand.
Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340:c363
Other publications of related interest
Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub2.
Subject indexing assigned by NLM
Developmental Disabilities /mortality /prevention & control; Humans; Hypothermia, Induced /methods; Hypoxia-Ischemia, Brain /mortality /therapy; Infant; Infant, Newborn; Nervous System Diseases /mortality /prevention & control; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.