MANUSCRIPT CITATION

• Chalak LF, Pappas A, Tan S, Das A, Sánchez PJ, Laptook AR, Van Meurs KP, Shankaran S, Bell EF, Davis AS, Heyne RJ, Pedroza C, Poindexter BB,  Schibler K, Tyson JE, Ball MB, Bara R, Grisby C,  Sokol GM,  D’Angio CT, Hamrick SEG, Dysart KC, Cotton CM, Truog WE, Watterberg KL, Timan CJ, Garg M, Carlo WA, Higgins RD,  for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association between increased seizures during rewarming after hypothermia for neonatal hypoxic ischemic encephalopathy and abnormal neurodevelopmental outcome at 2-year follow up: A nested multisite cohort study. JAMA Neurol. 2021;78(12):1484–1493. PMID: 34882200

REVIEWED BY

Ashajyothi M Siddappa, MD
Staff Neonatologist, Hennepin Healthcare, Minneapolis, Minnesota, USA

CORRESPONDING AUTHOR

Ashajyothi Mooganayakanakote Siddappa, MD
Neonatologist
Department of Pediatrics
Assistant Professor
University of Minnesota
Phone 612-873-2064/Fax 612-904-4284
Ashajyothi.Mooganayakanakotesiddappa@hcmed.org

 TYPE OF INVESTIGATION

A prespecified nested cohort prospective study

QUESTION

In neonates receiving induced hypothermia treatment for 72 hours or 120 hours for hypoxemic-ischemic encephalopathy, would electrographic seizures during the rewarming period, compared to preceding period, be associated with abnormal neurodevelopmental outcomes at 18-22 months of age.

METHODS

Design: This was a prospective study of infants enrolled in the multicenter Optimizing Cooling Neonatal Research Network trial at the Eunice Kennedy Shriver NICHD, USA, from December 2011 to December 2013.

Allocations: NICHD study centers

Blinding: Staff involved in reading amplitude-integrated electroencephalographs (aEEGs) were blinded

Follow up period: 18-22 months of age

Participants: Neonates older than 36 weeks of gestation who were enrolled in Optimized Cooling trial were included in the Systematic Monitoring of EEG in Asphyxiated Newborns During Rewarming After Hypothermia Therapy (SMART) study after separate written consent was obtained. Of the 364 infants enrolled in the NICHD Optimizing Cooling study, 120 infants took part in the SMART study:  66 were in group A and were cooled for 72 hours and 54 infants were in group B and were cooled for 120 hours.

Intervention

Infants who underwent induced hypothermia treatment for neonatal hypoxemic ischemia were monitored for electrographic seizure during rewarming period and for neurodevelopmental outcomes at 2 years of age. Group A infants were cooled for 72 hours, and group B infants were cooled for 120 hours. In both groups, aEEGs were recorded 12 hours before rewarming (Epoch1, 60-72 hours in group A, Epoch 3, 108-120 hours in group B) and 12 hours during rewarming (Epoch 2, 72-84 hours in group A, Epoch 4, 120-132 hours in group B). At 18-22 months of age, 112 subjects were followed up to see if they had died or had moderate or severe disability, according to the Bayley Scales of Infant Development, Third Edition, and the Gross Motor Function Classification System.

Primary outcome

Electrographic seizures using aEEG analysis between the two consecutive 12-hour intervals before and during rewarming.

Secondary outcome

To evaluate two duration of cooling and assess death or moderate or severe disability at 18 to 22 months of age using the Bayley Scales of Infant Development, Third Edition and the Gross Motor Function Classification System. To examine differences during rewarming in the seizure severity score and background patterns.

Analysis and sample size

The characteristics of infants who took part in the Optimized Cooling trial but did not participate in the SMART study were compared with those who did take part in Group A (72 hours) and Group B (120 hours). The chi-square test or Fisher’s exact tests were used for the categorical variables and t-tests or Wilcoxon nonparametric tests were used for continuous variables. Data on different depths of hypothermia (33.5 °C vs 32.0 °C) were pooled based on the time of rewarming, as the rate of rewarming was same for all of the infants. The models were also adjusted for the depth of hypothermia (33.5 °C vs 32.0 °C) using sensitivity analysis. Serial aEEGs were compared in the 12 hours before rewarming and for 12 hours during rewarming for evidence of electrographic seizure activity. Odds ratios (ORs) and 95% confidence interval (CIs) were evaluated after adjusting for center, prior seizures, depth of cooling, and severity of encephalopathy.

MAIN RESULTS

– 120 of the 364 infants in the Optimized Cooling trial were enrolled in the SMART study from December 2011 to December 2014.

– 66 infants were placed in group A and received 72 hours of cooling and 54 infants were placed in group B and received 120 hours of cooling.

– 112 infants completed the neurodevelopmental assessments at 2 years of age.

-The maternal characteristics of the SMART patients were comparable with those in the overall Optimized Cooling cohort. The maternal and neonatal characteristics of neonates enrolled in the SMART study were comparable between groups A and B.

-There were similar allocations of infants with moderate and severe encephalopathy as well as temperature depth, in the SMART study. This reflected the effectiveness of the Optimized Cooling randomization process.

– 28 (23%) of 120 infants had electrographic seizures during rewarming.

– 6 (21%) of 28 infants with electrographic seizures during rewarming had clinical manifestations that required phenobarbital treatment.

– 19 (68%) of the 28 infants had a prior seizure either before or during maintenance of hypothermia therapy.

– The onset of new rewarming seizures were noted in 8 (12%) of the 66 infants in group A and 7 (13%) of the 54 infants in group B.

– A larger number of infants in each group had more seizures during the rewarming epoch than the immediately preceding epoch: for Group A this was 17 (27%) in epoch 2 versus 9 (14%) epoch 1 and for Group B this was 11(21%) in epoch 4 versus 5(10%) in epoch 3 (P < .05).

-There was high agreement regarding the presence of seizures between the two central aEEG readers (κ, 0.99; 95% CI, 0.98-1.00).

-The adjusted OR (95% CI) for having a seizure during rewarming was 2.7 (1.0-0.5) for group A and 3.2 (0.9-11.6) for group B. Analysis of the rewarming period, namely 72 vs 120 hours, showed no differences in the number of infants with seizures: 17(27%) for72 hours vs 11 (21%) for 120 hours (P =0.11). There were no differences in the seizure severity score.

-These associations were not altered after the models were adjusted for the depth of hypothermia (33.5 vs 32.0 °C) and they did not occur at any particular time during the rewarming phase.

– At 18-22 months of age there was an abnormal composite outcome of death or disability in 13 neonates (46%) who had seizures during the rewarming period, compared to 20 (25%) who did not (P < 0.001).

– There were 14 deaths before 18 to 22months of age: 6 infants who had seizures during rewarming and 8 who did not.

-A suppressed background, namely burst suppression, low voltage, and flat tracing, occurred in 15 of the 28 infants who had seizures during rewarming and 18 of the 87 who did not have seizures (OR, 5.9; 95% CI, 2.3-14.8; P < 0.001).

-Infants who had seizures during rewarming had a higher incidence of magnetic resonance imaging (MRI) abnormalities, namely basal ganglia and thalamic versus white matter injury patterns, compared with those without seizures during rewarming.

– The composite death or disability outcome at 18 to 22 months of age was different in infants who had seizures during rewarming compared to those who did not (relative risk, 1.7; 95% CI, 1.25-2.37). This remained significant, even after adjusting for clinical encephalopathy and prior seizures that required anticonvulsants and for any association with the center where the treatment was provided.

CONCLUSION

This study showed  a high incidence of electrographic seizures during rewarming in infants undergoing hypothermia for HIE and that these seizures were associated with an increase in the relative risk of disability and death at 2 years of age.

COMMENTARY

Neonatal HIE contributes to neonatal mortality and neurodevelopmental disability in infants born at term or near term.¹Studies have shown that in neonates with HIE, induced hypothermia  decreases the incidence of mortality and moderate to severe neurodevelopmental disability  at 18-24 months of age.^{2, 3} Inducing hypothermia for 72 hours is currently the standard treatment for infants with moderate to severe neonatal HIE.⁴ The current SMART study includes a cohort of 120 of the 364 infants enrolled in the Optimizing Cooling trial: 66 infants received 72 hours (standard care) and 54 received 120 hours of therapeutic hypothermia.

Of these 120 infants, 28 (23%) had electrographic seizures during rewarming and that 19/28 (68%) infants had seizures before or during maintenance of hypothermia therapy. It appears that of these 28 infants, 13 infants had seizures during 12 hours prior to rewarming and during rewarming, 15 infants  had seizures during rewarming phase that were not previously documented. Perhaps importantly, the authors did not report whether neurodevelopmental outcomes differed between those that presented with seizures during rewarming were different from those that had seizures prior to rewarming and during rewarming. It is possible that the outcomes of those that had seizures both prior to and during rewarming would differ from those with seizures during rewarming alone.

The authors did not state whether treating electrographic seizures and clinical seizures during rewarming were associated with any difference in the injuries seen on the MRI scans and abnormal neurodevelopment. This information could help us to understand whether these seizures exacerbated the injuries or merely reflected severe injuries in particular infants. This information would have an impact on how aggressively seizures during the rewarming period should be treated.

aEEG can be a good screening tool for diagnosing seizures in neonates, sensitivity and specificity improves with a raw trace. aEEG recordings could miss shorter seizures due to time compression, focal seizures are often unnoticed due to the limited number of electrodes and EEG artifacts occur frequently despite the filtering process. Using aEEG for treatment decision could lead to wrong diagnosis and overtreatment, which could be harmful to the developing brain. The American Clinical Neurophysiology Society (ACNS) and the International League Against Epilepsy (ILAE) guidelines recommend using conventional EEGs as the gold standard method for diagnosing neonatal seizures. However, aEEGs use has clinical value in NICU but does not replace the standard conventional EEGs and latter should have been carried out to confirm seizures during rewarming phase, as the aim of the SMART study was to monitor seizure activity. It is important to use conventional EEG during maintenance period of hypothermia therapy and during rewarming phase. This provides critical information for healthcare staff and parents, as it accurately records seizure activity and can be used to correlate these findings with neurodevelopmental outcomes.

The strengths of the study include the prospective study design, standardized protocols and neurodevelopmental follow up at 18-22 months of age. This study emphasizes importance of monitoring for electrographic seizures in infants during rewarming phase after hypothermia treatment and the importance of thorough neurodevelopmental follow -up.

REFERENCES

1. Ferriero DM. Neonatal brain injury. N Engl J Med 2004; 351(19):1985–95.

2. Shankaran S, Laptook AR, Ehrenkranz RA, et al. National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84

3. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. New England Journal of Medicine. 2012; 366(22):2085–92. https://doi.org/10.1056/NEJMoa1112066 PMID: 22646631.

4. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischemic encephalopathy. Cochrane Database Syst Rev. 2013:CD003311.

CONFLICT OF INTEREST

No conflict of interest to disclose

FUNDING

No funding was available