Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. 
A David Edwards, Peter Brocklehurst, Alistair J Gunn, et al.  BMJ 2010;340:c363.  full free article

Objective To determine whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcome at 18 months of age.

Design A meta-analysis was performed using a fixed effect model. Risk ratios, risk difference, and number needed to treat, plus 95% confidence intervals, were measured.

Data sources Studies were identified from the Cochrane central register of controlled trials, the Oxford database of perinatal trials, PubMed, previous reviews, and abstracts.

Review methods Reports that compared whole body cooling or selective head cooling with normal care in neonates with hypoxic-ischaemic encephalopathy and that included data on death or disability and on specific neurological outcomes of interest to patients and clinicians were selected.

Results We found three trials, encompassing 767 infants, that included information on death and major neurodevelopmental disability after at least 18 months’ follow-up. We also identified seven other trials with mortality information but no appropriate neurodevelopmental data. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability in the three trials with 18 month outcomes (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, P=0.002; risk difference –0.11, 95% CI –0.18 to –0.04), with a number needed to treat of nine (95% CI 5 to 25). Hypothermia increased survival with normal neurological function (risk ratio 1.53, 95% CI 1.22 to 1.93, P<0.001; risk difference 0.12, 95% CI 0.06 to 0.18), with a number needed to treat of eight (95% CI 5 to 17), and in survivors reduced the rates of severe disability (P=0.006), cerebral palsy (P=0.004), and mental and the psychomotor developmental index of less than 70 (P=0.01 and P=0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected. Mortality was significantly reduced when we assessed all 10 trials (1320 infants; relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005; risk difference –0.07, 95% CI –0.12 to –0.02), with a number needed to treat of 14 (95% CI 8 to 47).

Conclusions In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia is associated with a consistent reduction in death and neurological impairment at 18 months.  

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Comments:   This study reports the the combined neurologic outcome outcome data of 3 large multi-center randomized, controlled trials of moderate hypothermia for hypoxic ischemic encephalopathy.  The trials studied included the Cool Cap Study, The NICHD trial, and the TOBY trial.  Combining the data from these 3 trials clearly shows a decreased risk of death or neurologic disability in babies at 18 months who underwent this treatment.  I don't believe that we need any further studies to validate the efficacy of this treatment.  In light of these results, it would probably be unethical to conduct further trials of hypothermia for neonatal encephalopathy if they included a control group that were not offered this treatment.  Future studies to determine the optimal temperature, duration or mode (total body or head cooling) of hypothermia are still needed.  It would also be desirable to look at longer term outcomes (perhaps at school age) for these patients. 

Considering the evidence presented in this paper, I would like to propose 2 questions for discussion:

1) Should all level IIIB and IIIC NICUs develop the capability to provide therapeutic hypothermia to babies with neonatal encephalopathy?

2) Should all hospitals that deliver babies but don't have hypothermia available, develop a plan  to provide timely transfer to a center that can provide this treatment? 

What do you think?    Is hypothermia treatment for neonatal encephalopathy finally ready for "prime time"?  

Andy Kairalla MD