Childhood Outcomes after Hypothermia for Neonatal Encephalopathy

Abstract

BACKGROUND We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. METHODS In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. RESULTS Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P = 0.06); death occurred in 27 (28%) and 41 (44%) (P = 0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P = 0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P = 0.87). Attention–executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P = 0.19), and visuospatial dysfunction occurred in 4% and 3% (P = 0.80). CONCLUSIONS The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.)

Cerebral Oxygen Metabolism in Neonatal Hypoxic Ischemic Encephalopathy during and after Therapeutic Hypothermia

“…17 However, the rate of mildly abnormal outcome (33.3%) was higher compared with literature and the rate of abnormal outcome (1 death, 11.1%) was lower than reported trials. 5,17 This discrepancy is most likely due to the small sample size included in this particular study, as the overall outcome of neonatal HIE treated with TH at our institution is similar to published data. Due to the low number of patients, scores can only be used to describe individuals but predictive modeling will be implemented for a planned larger cohort.…”

“…4 Although early studies showed that TH decreased rates of both mortality and disability, recently published long-term outcomes have demonstrated significance only for decreased mortality rates. 5 In addition, a recent meta-analysis advocated refinement of patient selection and TH duration whereas others have suggested that currently excluded neonates be considered in future trials. 6,7 Thus a need for further optimization of TH remains.…”

How Long is Too Long for Cerebral Cooling after Ischemia in Fetal Sheep?

“…1 Follow-up studies of large randomized trials have shown that infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia showed a reduction in death, cerebral palsy and disability, and improved neurocognitive functioning that persisted into middle childhood. [1][2][3][4] The major challenge for the future is that current protocols for therapeutic hypothermia are partially neuroprotective, with a number needed to treat of eight. 1 In part, partial protection is likely related to the formidable clinical difficulties involved in starting hypothermia within the optimal window of opportunity.…”

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

“…Despite its relatively high incidence among newborns with cerebral injury, limited therapies are available for its prevention and treatment 2, 3. Furthermore, unlike the aging adult brain, neuronal death in the immature CNS is not only a pathological cellular event of brain injury but also a biological process required for early normal brain development 4.…”