Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up

Abstract

IMPORTANCECompared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. OBJECTIVE To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. DESIGN, SETTING, AND PARTICIPANTSThis prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020.INTERVENTIONS Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. MAIN OUTCOMES AND MEASURESThe primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes.RESULTS A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center.CONCLUSIONS AND RELEVANCE Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk.

Cerebral Oxygenation and Metabolism After Hypoxia-Ischemia

“…HIE-associated seizures have typical onset and maximum seizure burden within 24 h after birth ( 61 ). Therapeutic hypothermia reduces seizure burden, but nearly half of the cooled babies still have seizures, and the odds of seizures during rewarming are higher ( 62 ). The incidence of seizures in preterm infants is much higher than term infants ( 63 ).…”

Biomarker und Neuromonitoring zur Entwicklungsprognose nach perinataler Hirnschädigung

“…B. für Früh- und Neugeborene mit zerebralen Anfällen und nach perinataler Asphyxie empfohlen. Die Ableitung sollte bis nach dem Ende der Aufwärmphase fortgeführt werden, da in dieser Phase noch prognostisch ungünstige, oft subklinische, Anfällen auftreten können [ 17 ]. Bei neonatalem Schlaganfall und Sinusvenenthrombose, aber auch bei unklaren neurologischen Symptomen empfiehlt sich der Einsatz ebenfalls.…”

Neonatal seizures: stepping outside the comfort zone

“…60) Of note, many studies reported a high incidence of seizures during cooling and rewarming periods in cooled HIE newborns. 24,6365) Interestingly, Chalak et al 66) found a higher seizure burden during rewarming and worse longterm outcomes at 2 years of age and highlighted the importance of continuous EEG 44,71) Two recent studies showed no significant difference between phenobarbital and levetiracetam as 1st line in treatment of electrical seizures 72,73) while, one study showed superiority of phenobarbital 44) Levetiracetam 1st or 2nd line of treatment Effects: better neurodevelopmental out come 44,74,75) ; antiepileptogenic effect 76) ; less reported adverse effects of pheno barbital 77) 35%-86% seizure control 78,79) Phenytoin 1st or 2nd line of treatment S/E: cardiac arrhythmia, hepatoxic 45% seizure control 80) Midazolam 2nd or 3rd line of treatment S/E: hypotension, respiratory depres sion…”

“…Abnormal outcome had been scored if TSB and MSB exceeding 40 and 13 minutes respectively Seizures burden alone is a predictor of poor outcome Prolonged or recurrent sei zures 67) Each 10minute increase in seizure burden is associated with a 5fold risk increase of epilepsy, while having more than 10 seizures increases the risk of epilepsy by 30fold compared to no seizures Seizure burden during re warming 66) High seizure burden during rewarming after 72 hours of cooling compared to 120 hours of cooling normal EEG findings were associated with poor response in an additional study, which also identified higher mean seizure score and higher degrees of brain magnetic resonance imaging injury (white matter, cortex, and watershed regions) were associated with a poor response to phenobarbital. 70) Briefly, the early declaration of this silent enemy is vital through the early use of EEG in any suspected or critically ill newborn with the aim of detecting any abnormal discharge and initiating antiepileptic drugs in curable doses that dampen the current and subsequent sparks.…”

“…Of note, many studies reported a high incidence of seizures during cooling and rewarming periods in cooled HIE newborns [ 24 , 63 - 65 ]. Interestingly, Chalak et al [ 66 ] found a higher seizure burden during rewarming and worse long-term outcomes at 2 years of age and highlighted the importance of continuous EEG monitoring during the rewarming period. In addition, a longer seizure duration is associated with a higher 1-year risk of epilepsy in children with perinatal asphyxia, and each 10-min increase in seizure burden is associated with a 5-fold increase in the risk of epilepsy, while having more than 10 seizures increases the risk of epilepsy by 30-fold compared to no seizures [ 67 ].…”