A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet?

Abstract

Background: The objective of this study was to systematically review randomized trials assessing therapeutic hypothermia as a treatment for term neonates with hypoxic ischemic encephalopathy.

Methods: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL databases, reference lists of identified studies, and proceedings of the Pediatric Academic Societies were searched in July 2006. Randomized trials assessing the effect of therapeutic hypothermia by either selective head cooling or whole body cooling in term neonates were eligible for inclusion in the meta-analysis. The primary outcome was death or neurodevelopmental disability at >or= 18 months.

Results: Five trials involving 552 neonates were included in the analysis. Cooling techniques and the definition and severity of neurodevelopmental disability differed between studies. Overall, there is evidence of a significant effect of therapeutic hypothermia on the primary composite outcome of death or disability (RR: 0.78, 95% CI: 0.66, 0.92, NNT: 8, 95% CI: 5, 20) as well as on the single outcomes of mortality (RR: 0.75, 95% CI: 0.59, 0.96) and neurodevelopmental disability at 18 to 22 months (RR: 0.72, 95% CI: 0.53, 0.98). Adverse effects include benign sinus bradycardia (RR: 7.42, 95% CI: 2.52, 21.87) and thrombocytopenia (RR: 1.47, 95% CI: 1.07, 2.03, NNH: 8) without deleterious consequences.

Conclusion: In general, therapeutic hypothermia seems to have a beneficial effect on the outcome of term neonates with moderate to severe hypoxic ischemic encephalopathy. Despite the methodological differences between trials, wide confidence intervals, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging. Further research is necessary to minimize the uncertainty regarding efficacy and safety of any specific technique of cooling for any specific population.

Figure 1

Primary outcome: death or neurodevelopmental disability at 18 to 22 months. Forest plot displays relative risk of death or neurodevelopmental disability at 18 to 22 months for all included studies and separately for selective head cooling and whole body cooling studies. There is a significant benefit of therapeutic hypothermia on the composite outcome of death or disability (RR: 0.78, 95% CI: 0.66, 0.92, NNT: 8, 95% CI: 5, 20). The squares represent the point estimate of treatment effect of each study with a horizontal line extending on either side of the square representing the 95% confidence interval. The diamonds represent the overall and subgroup relative risk estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% confidence interval of the relative risk. The vertical midline of the forest plot corresponding to a relative risk of 1 represents a "no effect" line. Gunn et al 1998 and Gluckman et al 2005 assessed death or severe disability, Shankaran et al 2005 reported on death or moderate or severe disability as described in the results.

Figure 2

Secondary outcome: mortality. Forest plot displays relative risk of death for all included studies and separately for selective head cooling and whole body cooling studies. There is a significant benefit of therapeutic hypothermia on the single outcome of mortality (RR: 0.75, 95% CI: 0.59, 0.96, NNT: 11, 95% CI: 6, 100). The squares represent the point estimate of treatment effect of each study with a horizontal line extending on either side of the square representing the 95% confidence interval. The diamonds represent the overall and subgroup relative risk estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% confidence interval of the relative risk. The vertical midline of the forest plot corresponding to a relative risk of 1 represents a "no effect" line.

Figure 3

Secondary outcome: neurodevelopmental disability at 18 to 22 months. Forest plot displays relative risk of neurodevelopmental disability at 18 to 22 months for all included studies and separately for selective head cooling and whole body cooling studies. There is a significant benefit of therapeutic hypothermia on the single outcome of neurodevelopmental disability at 18 to 22 months (RR: 0.72, 95% CI: 0.53, 0.98, NNT: 9, 95% CI: 5, 100). The squares represent the point estimate of treatment effect of each study with a horizontal line extending on either side of the square representing the 95% confidence interval. The arrowheads indicate a wide confidence interval that is compressed to fit the scale. The diamonds represent the overall and subgroup relative risk estimate of the studies presented in the meta-analysis. The widths of the diamonds represent the 95% confidence interval of the relative risk. The vertical midline of the forest plot corresponding to a relative risk of 1 represents a "no effect" line. Gunn et al 1998 and Gluckman et al 2005 assessed severe disability, Shankaran et al 2005 reported on moderate or severe disability as explained in the results.