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Post-Hypothermia Rewarming Period Associated With Worse Outcomes in Neonatal Encephalopathy

An abnormal composite outcome of death or disability at age 18 to 22 months was found in 46% of those who had seizures during rewarming compared with 25% of those without seizures at rewarming.

Neonates with hypoxic ischemic encephalopathy who underwent hypothermia demonstrated higher odds of developing electrographic seizures during the rewarming epoch compared with the preceding epoch. These seizures were thus associated with an increased risk for death or disability at ages 18-22 months.

Led by Lina F. Chalak, MD, MSCS, professor of psychiatry, University of Texas Southwestern, a total of 120 newborns were randomized to either 72 hours of cooling (group A; n = 66) or 120 hours (group B; n = 54) and were followed for 2 years. Serial amplitude electroencephalography (aEEG) was recorded during hypothermia rewarming and focused on 4, 12-hour epochs before and after the initiation of rewarming.

In total, 23% (n = 28) had electrographic seizures at rewarming, 6 of which had clinical manifestations that required phenobarbital treatment. Within each group, more infants had seizures during the rewarming epoch compared with its immediately preceding epoch (group A epoch 2 vs 1: 17 [27%] vs 9 [14%]; group B epoch 4 vs 3: 11 [21%] vs 5 [10%]; P <.05). The adjusted OR for having a seizure during rewarming was 2.7 (95% CI, 1.0-0.5) for group A and 3.2 (95% CI, 0.9-11.6) for group B.

There was high agreement between the 2 central readers on the presence of seizures (k, 0.99; 95% CI, 0.98-1.00). According to the investigators, this was the largest study to date to systematically assess electrographic seizures during preceding and rewarming phases in hypothermia therapy for asphyxiated neonates.

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"Strengths include the prospective study design, predefined outcomes, masked central aEEG readers with a high concordance rate in readings, and the standardized study protocols, including assessments at age 18 and 22 months by certified examiners masked to trial group assessment," the study authors concluded. "In addition to the standard 72-hour duration of hypothermia, this study suggests that monitoring should be continued during rewarming until normothermia is completed and seizure control is assured."

There were no differences in the number of infants with seizures during rewarming at 72 (n = 17 [27%]) or 120 hours (11 [21%]; all P <.11). Seizure severity score also did not differ. Models adjusted for the depth of hypothermia (33.5 C° vs 32.0 C°) did not alter these associations.

In total 46% (n = 13) of neonates who had seizures during rewarming had an abnormal composite outcome of death or disability, compared with 25% (n = 20) of those without seizures at rewarming (P <.001). Death prior to 18 to 22 months occurred in 6 infants with seizures during rewarming and in 8 without rewarming seizures. Those who had seizures during rewarming had similar baseline characteristics to those without, except for a higher incidence of outborn birth and abnormal background aEEG.

At ages 18-22 months, death or disability outcome was different among those who did and did not have seizures throughout the rewarming phase (relative risk, 1.7 [95% CI, 1.25-2.37]). These results remained significant after adjusting for clinical encephalopathy and prior seizures needing anticonvulsants, as well as for any center association.

A suppressed background, which included burst suppression, low voltage, and flat tracing, was recorded in 15 of the 28 infants who had seizures compared with 18 of 87 in the group that did not have seizures (OR, 5.9 [95% CI, 2.3-14.8]; P <.001). Despite no significant differences in overall percentage of MRI abnormalities, those with rewarming seizures had a twice higher incidence of basal ganglia-thalamic vs white matter injury pattern compared with those without seizures at rewarming.

The study authors also concluded that the "study findings of higher odds of seizures during rewarming associated with higher risk of abnormal outcomes at age 18 to 22 months support the American Clinical Neurophysiology Society’s Guidelines of continuous electroencephalography monitoring of neonates with suspected perinatal asphyxia at high risk."

Chalak LF, Pappas A, Tan S, et al. Association of increased seizures during rewarming with abnormal neurodevelopmental outcomes at 2-year follow-up. JAMA Neurol. Published online October 18, 2021. doi:10.1001/jamaneurol.2021.3723