Effect of Phenobarbitone on Amplitude-Integrated Electroencephalography in Neonates with Hypoxic-Ischemic Encephalopathy during Hypothermia Original Paper Neonatology 2020;117:721–728 Effect of Phenobarbitone on Amplitude-Integrated Electroencephalography in Neonates with Hypoxic-Ischemic Encephalopathy during Hypothermia Poorva Deshpande a, b Amish Jain a, b Patrick J. McNamara a, c aDivision of Neonatology, Hospital for Sick Children, Toronto, ON, Canada; bDepartment of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; cDepartment of Physiology, University of Toronto, Toronto, ON, Canada Received: January 28, 2020 Accepted: September 1, 2020 Published online: January 7, 2021 Poorva Deshpande Department of Paediatrics, Staff Neonatologist Room 19-231, Mount Sinai Hospital, 600 University Avenue Toronto, ON M5G 1X5 (Canada) poorva.deshpande @ sinaihealth.ca © 2021 The Author(s) Published by S. Karger AG, Basel karger@karger.com www.karger.com/neo DOI: 10.1159/000511540 Keywords Hypoxic-ischemic encephalopathy · Amplitude-integrated electroencephalography · Phenobarbitone · Hypothermia · Neonates Abstract Background: Phenobarbitone induces suppression of cere- bral electrical activity on amplitude-integrated electroen- cephalography (aEEG) in neonates with hypoxic-ischemic encephalopathy (HIE); however, its effect during therapeutic hypothermia (TH) has not been well characterized. Objec- tive: To evaluate the effect of phenobarbitone on aEEG in neonates with HIE undergoing TH. Methods: Thirty-five neo- nates born at ≥350 weeks gestational age (GA), who received phenobarbitone as first-line antiepileptic drug during TH for ≥ Sarnat stage II HIE with aEEG recordings were retrospec- tively studied. Background pattern, upper and lower margin voltages were characterized for a 30-min period before and 30–60 min after phenobarbitone administration. Primary outcome was presence of severely abnormal aEEG pattern after phenobarbitone administration. Results: Mean (±SD) GA and median birth weight were 38.2 ± 1.9 weeks and 3.1 (2.5–3.9) kg, respectively. Phenobarbitone (10–20 mg/kg), administered at median age 16.8 h, was associated with background pattern worsening in 19/29 (65.5%) cases. Se- vere background patterns were more prevalent in post- ver- sus pre-phenobarbitone tracings (21/29 [72%] vs. 11/29 [38%]; p = 0.01). Presence of severe pattern versus either continuous normal voltage or discontinuous normal voltage pattern post-phenobarbitone, (20/25 [80%] vs. 3/8 [38%]; p = 0.036) was associated with death or moderate-to-severe injury on MRI brain. Median time to trace recovery, when measurable, was 4 h (45 min–72 h). Conclusions: Phenobar- bitone induces significant suppression on aEEG in infants with HIE undergoing TH. Development of severe aEEG back- ground patterns after phenobarbitone may unmask a popu- lation at greater risk of abnormal outcome. © 2021 The Author(s) Published by S. Karger AG, Basel Background Amplitude-integrated EEG (aEEG) is commonly em- ployed in neonatal intensive care units (NICUs) to mon- itor background cortical activity, seizure management, This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for com- mercial purposes requires written permission. Deshpande/Jain/McNamaraNeonatology 2020;117:721–728722 DOI: 10.1159/000511540 and aid prognostication in infants with hypoxic-ischemic encephalopathy (HIE) [1–11]. Previously, presence of a severely abnormal aEEG background pattern at <6 h of age was considered to be a strong predictor for adverse neurodevelopmental outcome [2, 4]. Therapeutic hypo- thermia (TH), however, has shown to delay the overall recovery of aEEG in HIE patients, with recent studies demonstrating persistence of aEEG abnormalities ≥24 h of age and time to normalization of trace being better pre- dictors of adverse outcomes [12–14]. Antiepileptic drugs (AED), such as phenobarbitone being the commonest first-line agent, are frequently used for seizure management in infants with moderate and se- vere HIE and are well known to induce aEEG suppression [15–17]. In clinical practice, trends in aEEG characteris- tics are often used as an ancillary tool to refine prognosis. Hence, accurate documentation of the degree and/or du- ration of drug-induced aEEG suppression may help clini- cians differentiate these “iatrogenic” effects from HIE-re- lated suppression and potentially avoid misinterpreta- tions. Although the suppressive effects of phenobarbitone on neonatal aEEG have been described under normothermic conditions, its impact and clinical relevance in the pres- ence of TH remains unknown [16–18]. Therefore, the primary aim of this study was to characterize the effect of phenobarbitone on aEEG background pattern in infants with moderate and severe HIE undergoing TH. Second- ary aims were to assess the effect of phenobarbitone on aEEG voltage, investigate the time to trace recovery and to study the association between aEEG suppression fol- lowing phenobarbitone and severity of HIE. We hypoth- esized that during hypothermia, phenobarbitone causes suppression of aEEG background in >50% of tracings. Methods Study Design This retrospective cohort study was conducted at the NICU of the Hospital for Sick Children, Toronto, over a 2-year period when aEEG recordings were archived and phenobarbitone was the first-line AED used. The study was approved by the Institu- tional Research Ethics Board and parental consent requirement was waived. Inclusion and Exclusion Criteria All infants with Sarnat stage II (moderate) or III (severe) HIE, born at gestational age ≥350 weeks, who received treatment with intravenous phenobarbitone for clinical or electrical sei- zures while undergoing TH, and had aEEG recorded during phe- nobarbitone administration were considered for inclusion. Only the first episode of seizure treatment after admission to our unit was considered for analysis. Infants who may have had a prior phenobarbitone dose in the community before admission were included. Infants who received AEDs other than phenobarbi- tone, including lorazepam as first treatment after admission, and those who had seizures after completion of rewarming were excluded. Tracings with impedance >10 ohms or where time of phenobarbitone administration was not marked were also ex- cluded. Study Setting Our center is an outborn quaternary NICU, where infants with suspected HIE are referred from community hospitals after initial stabilization. When appropriate, TH is commenced pre-transfer either by the community physicians or the neonatal transport team or in the NICU after admission, in all cases according to our stan- dardized guideline. Typically, TH is commenced at age <6 h and continued for 72 h. All infants undergoing TH also receive aEEG monitoring for the duration of treatment, starting soon after ad- mission until completion of rewarming or death/withdrawal of life sustaining treatment, whichever occurred earlier. During the study period, aEEG was recorded using single-channel Olympic CFM 6000 monitor (Natus Medical Incorporated, San Carlos, CA, USA) with electrodes at P3-P4 location or BRM2 BrainZ monitor (BrainZ Instruments, New Zealand) with electrodes at C3-C4 and P3-P4 locations, using hydrogel electrodes, and archived electron- ically on our hospital’s server. Phenobarbitone, given intravenous- ly at a dose of 10, 15, or 20 mg/kg over 20 min was our first-line AED and the timing was marked on the aEEG monitor by the bed- side nurse. The decision to treat, whether for a clinical and/or elec- trical seizure, as well as the choice of dose of phenobarbitone, was at the attending physician’s discretion. Conventional 1-h EEG was obtained at some point during the infant’s admission period. For Table 1. National Institute of Child Health and Human Development (NICHD) scoring system for classifying brain injury on MRI for infants with HIE Score Injury pattern observed on brain MRI 0 No injury seen 1A Minimal cerebral lesions without involvement of BGT, ALIC, or PLIC, and no watershed area infarction 1B More extensive cerebral lesions but without BGT, PLIC, or ALIC involvement or watershed area infarction 2A Any BGT, ALIC, or PLIC involvement or watershed area infarction, but without any other cerebral lesions 2B Any BGT, ALIC, or PLIC involvement or watershed area infarction, and additional cerebral lesions 3 Cerebral hemispheric devastation HIE, hypoxic-ischemic encephalopathy; BGT, basal ganglia or thalamus; ALIC, anterior limb of the internal capsule; PLIC, posterior limb of the internal capsule. Phenobarbitone and aEEG in Hypothermia 723Neonatology 2020;117:721–728 DOI: 10.1159/000511540 the study period, full montage continuous EEG monitoring was undertaken only for patients with intractable seizures needing midazolam infusion, in consultation with our institute’s pediatric neurology team. Brain MRI was performed between days 3 and 5 after birth for all surviving infants treated with TH for HIE and reported by our institute’s pediatric neuroradiologists. Data Collection Patients who underwent TH for HIE were identified from our unit’s computerized database, and their health records were re- viewed to determine eligibility. Clinical data were collected for de- mographics and perinatal history, Sarnat stage of HIE, timing of TH initiation and rewarming, presence of liver dysfunction, phe- nobarbitone dose and age at administration, concomitant use of opioid sedatives and outcomes (mortality and results of brain MRI, whenever available). Only the first episode of phenobarbitone ad- ministration after admission to the NICU and initiation of aEEG monitoring was included for analysis. Assessment of aEEG Tracings for a duration of 30 min prior to (baseline) and be- tween 30 and 60 min after phenobarbitone administration were reviewed and categorized by one of the 2 investigators (PD and AJ), who had >7 years of clinical experience in interpreting neona- tal aEEG. For consistency between the 2 aEEG devices, only the P3-P4 traces were used for trace analysis. For each time period, the worst background pattern and lowest upper margin voltages (UMV) and lower margin voltages (LMV) were recorded. The UMV and LMV were determined visually by drawing a line across the uppermost and lowermost dense part of the tracing, respec- (n = 102) admissions with HIE for TH (n = 35) infants included (n = 1) unknown time of phenobarbitone administration (n = 3) received other AEDs prior to phenobarbitone (n = 1) Jet ventilation artifact (n = 21) no aEEG monitoring during phenobarbitone treatment (n = 3) seizures after rewarming (n = 1) impedance>10 ohms (n = 2) flat trace prior to phenobarbitone (n = 65) seizures (n = 29) infants included for background pattern comparison pre and post phenobarbitone (n = 1) UMV and LMV not interpretable (n = 4) background pattern not interpretable (n = 32) infants included for UMV and LMV comparison pre and post phenobarbitone Fig. 1. Eligibility and analysis criteria. HIE, hypoxic-ischemic encephalopathy; TH, therapeutic hypothermia; aEEG, amplitude-integrated electroencephalography; AEDs, anti-epileptic drugs; FT, flat trace; LMV, lower mar- gin voltage; UMV, upper margin voltage. Deshpande/Jain/McNamaraNeonatology 2020;117:721–728724 DOI: 10.1159/000511540 tively. Whenever background pattern changed after phenobarbi- tone, tracings were further reviewed either until it recovered to baseline status or until completion of rewarming, whichever oc- curred first. For the former, time to trace recovery was calculated. Definitions Background pattern was categorized according to the classifi- cation previously described by Hellström-Westas [19]. Continu- ous normal voltage (CNV) was considered a normal background, discontinuous normal voltage (DNV) as moderately abnormal, and burst suppression (BS), continuous low voltage (CLV), or flat trace (FT) as severely abnormal. UMV was categorized as > 25 µV, 10–25 µV, 5–10 µV, or <5 µV, and LMV as >5 µV, 3–5µV, or <2 µV. A “clinically significant” change after phenobarbitone was de- fined a priori based on (i) background pattern: CNV to any other pattern or DNV to BS/CLV/FT or BS/CLV to FT or (ii) changes in UMV: 10–25 µV to <10 µV or >5 µV to <5 µV or (iii) changes in LMV: >5 µV to <5 µV or 3–5µV to <2 µV. Brain MRI findings were scored from 0 to 3, as per the National Institute of Child Health and Human Development system (Table  1) [20]. For this study, adverse outcome was defined as death or moderate-to-severe in- jury on MRI (score ≥2 A). Furthermore, liver dysfunction was de- fined as alanine transferase >52 Units/L and/or aspartate transfer- ase >70 Units/L as per our laboratory normal values. Study Outcomes Presence of new-onset, severely abnormal background patterns af- ter phenobarbitone was considered the primary outcome. Secondary outcomes included: (i) changes in UMV and LMV after phenobarbi- tone compared to baseline, (ii) time to trace recovery, where applicable, (iii) association between pre- and post-phenobarbitone aEEG charac- teristics and death or moderate-to-severe injury on brain MRI. Statistical Analysis Data are described as frequency (percentage), mean (standard deviation), or median (range), as appropriate. The frequency of aEEG patterns pre- and post-phenobarbitone as well as their as- sociation with adverse outcome of death or moderate-to-severe MRI injury was analyzed using Fisher’s exact test. Time to trace recovery was described in hours and compared between infants with Sarnat stage II versus stage III HIE, with or without liver dys- function and phenobarbitone dose <20 mg/kg versus 20 mg/kg using Wilcoxon signed-rank test. Furthermore, interobserver reli- ability was tested on 20 tracings (10 pre- and 10 post-phenobarbi- tone) from 10 randomly selected subjects using Cohen’s kappa sta- tistic, which was 0.92 and 0.93, for categorization of background pattern and LMV, respectively. Table 2. Perinatal and clinical characteristics of the study cohort (n = 35) Female gender 16 (46%) Gestational age, weeks 38.2±1.9 Birth weight, g 3,085 (2,510, 3,900) Known sentinel eventα 10 (29%) History of fetal distressβ 28 (80%) Caesarean delivery 23 (66%) Intubation at birth 32 (91%) Chest compressions 19 (54%) Apgar score at 5 min 3 (0, 9) Cord pH 6.9±0.2 Base deficit −16.9±6.9 Persistent pulmonary hypertension 5 (14%) Hypotension – requiring treatment 16 (46%) Prior phenobarbitone before admission 20 (57%) Clinical seizures only 10 (29%) Dose of phenobarbitone for the episode studied 20, mg/kg 24 (69%) 15, mg/kg 1 (3%) 10, mg/kg 10 (29%) Age at phenobarbitone administration, h 16.8 (5.8, 62.9) Liver dysfunction 22 (63%) Severe injury on MRI 16 (46%) Mortality 10 (29%) Data are presented as percentage, mean ± SD, or median (range) as appropriate. α  Include placental abruption, prolonged labor, and shoulder dystocia. β Defined as documentation of fetal heart decelerations, tachycardia, or abnormal variability. γ  Rest were either electrical or electroclinical. CNV 7 DNV 11 BS 8 CLV 3 FT 2 FT 6 CLV 4 BS 13 DNV 8 CNV 0 4 3 1 5 1 4 5 2 1 1 2 2 Pre- phenobarbitone background pattern BS DNV CNV CLV FT Fig. 2. Changes in aEEG background pattern before and after phe- nobarbitone in 31 infants. Background pattern could not be deter- mined in 4 infants due to prolonged seizure activity prior to phe- nobarbitone administration. aEEG, amplitude-integrated electro- encephalography; CNV, continuous normal voltage; DNV, discontinuous voltage; BS, burst suppression; CLV, continuous low voltage; FT, flat trace. Phenobarbitone and aEEG in Hypothermia 725Neonatology 2020;117:721–728 DOI: 10.1159/000511540 Results A total of 35 infants with HIE, 18 with Sarnat stage III and 17 with stage II, satisfied the inclusion criteria (Fig. 1). The cohort characteristics are listed in Table 2. Two infants demonstrated FT even before phenobarbi- tone, and were not included in further analysis. Four tracings had pre-seizure recording duration <15 min, where background pattern could not be ascertained, in- cluding 1, where LMV and UMV could not be ascer- tained. In comparison to baseline, post-phenobarbi- tone tracings demonstrated higher frequency of severe- ly abnormal patterns and UMV and LMV below pre-defined thresholds (Table  3). None of the traces demonstrated CNV pattern after phenobarbitone ad- ministration (Table  3). A clinically significant change Table 3. Characteristics of background aEEG traces at baseline and post-phenobarbitone aEEG characteristics Baseline N (%) Post-phenobarbitone N (%) p value Background patternα Severely abnormal trace (BS/CLV/FT)β 11/29 (38) 21/29 (72) 0.004 Continuous 7/29 0/29 0.01 Discontinuous 11/29 (38) 13/29 (24) 0.6 Upper margin <10 µVγ 10/32 (31) 16/32 (50) 0.2 Upper margin <5 µVγ 2/32 (6) 10/32 (31) 0.001 Lower margin <5 µVγ 24/32 (75) 32/32 (100) 0.005 Lower margin <3 µVγ 9/32 (28) 22/32 (69) 0.005 aEEG, amplitude-integrated electroencephalography; BS, burst suppression; CLV, continuous low voltage; FT, flat trace. Valies in italics indicate p < 0.05. α Pre-phenobarbitone background pattern could not be ascertained for 4 infants due to presence of seizures at onset of aEEG recording. β Excluding 2 infants with baseline flat trace. γ Pre-phenobarbitone upper and lower margin voltage could not be classified for 1 infant due to seizures at onset of aEEG recording. DNV Upper margin 10–25 µV CF M , µ V 100 50 25 10 5 0 Phenobarbitone Burst suppression pattern Upper margin 5–10 µV Lower margin 4–5 µV ED 04:00 01/20/10 05:00 06:00WED Lower margin 2–3 µV Burst suppression pattern Upper margin 5–10 µV Fig. 3. Example of an aEEG tracing illustrating effect of phenobar- bitone administration to an infant with HIE and seizures while receiving therapeutic hypothermia. The left side of the tracing shows a discontinuous background pattern (UMV between 10 and 25 μV and LMV at 4–5 μV) with repetitive seizures. The dotted line in the middle part of the tracing indicates intravenous administra- tion of phenobarbitone at 20 mg/kg over 20 min. Following this, the background changed to a BS pattern with a drop of both UMV and LMV to 5–10 μV and 2–3 μV respectively. aEEG, amplitude- integrated electroencephalography; HIE, hypoxic-ischemic en- cephalopathy; UMV, upper margin voltage; LMV, lower margin voltage; BS, burst suppression; DNV, discontinuous normal volt- age. Deshpande/Jain/McNamaraNeonatology 2020;117:721–728726 DOI: 10.1159/000511540 in background pattern was seen in 19/29 (65%) (Fig. 2, 3) and in UMV and/or LMV in 14/32 (44%) infants. There was no difference within the subgroups of infants with clinical and electrical seizures with respect to clin- ically significant change in the background (7/19 vs. 3/10, p = 1) or any clinically significant change (7/25 vs. 3/7, p = 0.7). Fourteen of the 19 traces recovered to baseline status prior to exposure to any further AED. The median (range) time to trace recovery was 4 (0.75–72) hours. Four traces remained suppressed until the end of aEEG recording and 1 infant was given another AED before trace recov- ery. Time to trace recovery did not differ between infants with Sarnat stage II versus III HIE (4.38 [1–72] vs. 3 [0.75–9] hours; p = 0.40), with versus without liver dys- function (2.75 [1–9] vs. 5.7 [0.75–72] hours; p = 0.22), or phenobarbitone dose <20 mg/kg versus 20 mg/kg (1.8 [0.75–72] vs. 5.67 [2–10] hours; p = 0.10). For 6 infants, where the study episode was the only exposure to pheno- barbitone and therefore not proceeded by any AED in the community, median (range) time to trace recovery was 4 (2–10) hours. Death or moderate-to-severe MRI injury occurred more frequently in those with severely abnormal post- phenobarbitone background pattern versus CNV/DNV (20/25 [80%] vs. 3/8 [38%]; p = 0.036). No association was seen between adverse outcome and pre-phenobarbitone severely abnormal background pattern versus CNV/ DNV (8/11 [72%] vs. 11/18 [61%]; p = 0.7). Discussion In this study, we found that phenobarbitone treatment for seizures in neonates with HIE undergoing TH is char- acterized by important changes in various clinically rel- evant aEEG parameters including background pattern and voltage margins. We also provide data on time to trace recovery, where applicable, that clinicians may be able to apply while interpreting aEEG in the context of HIE and TH. Furthermore, we found an association be- tween aEEG patterns 30–60 min post-treatment but not pre-treatment, with adverse outcome of death or moder- ate-to-severe brain injury. Although the suppressive effect of AEDs on neonatal aEEG have previously been described, to the best of our knowledge there is no previous report on the effect of phenobarbitone on neonatal aEEG in the setting of TH studied in the clinical context [16, 18]. Shany et al. [17] described the suppressive effects of commonly used AEDs from 191 aEEG tracings in 77 neonates, who received treatment for seizures. While 75% of patients had a diag- nosis of HIE, none received TH. Each repeat AED expo- sure was considered as a separate episode. The authors reported worsening in background pattern, UMV, and LMV in up to 12, 35, and 32% tracings, respectively. Overall, mean (range) time to trace recovery was 2.5 (0.25–15) hours and 2.7 h for phenobarbitone. Data spe- cifically from the HIE subgroup or clinical outcomes were not evaluated. Although there are differences in the pop- ulation and AEDs used by Shany et al. [17], we noted a comparatively higher frequency of post-treatment sup- pressed tracings and slightly longer median time to trace recovery; however, trace recovery was noted in only half of the traces in our cohort. The mechanism behind suppression after phenobarbi- tone in the setting of HIE and TH may likely be because of the following reasons: first, the severity of suppression may relate to the severity of brain injury; specifically, it is plausible that treatment with AEDs may unmask a sub- population with increased risk of brain injury. This hy- pothesis is supported by our finding of an association of adverse clinical outcome and abnormal tracing only after but not before phenobarbitone administration. Second, it may be related to seizure burden, which could not be ad- dressed in our study. Although it may be plausible that severe HIE or a high seizure burden may increase the sen- sitivity of the brain to the suppressive effect of phenobar- bitone, our findings do not explain the mechanism be- hind these hypotheses. Finally, although we do not have data on plasma phenobarbitone levels, pharmacokinetic studies have demonstrated no change in phenobarbitone clearance in hypothermia versus normothermia [21, 22]. In fact, a study using simulated pharmacodynamic mod- eling found phenobarbitone treatment to be associated with reduced rate of transition in aEEG pattern from CNV to DNV [21]. Phenobarbitone clearance may also be impacted by liver dysfunction; however, a lack of as- sociation between hepatic dysfunction and trace suppres- sion in our study also suggests a likely lack of role of dif- fering pharmacokinetic profile. Our observations, how- ever, are based on a small sample size and need further validation. Strengths of our study include strict eligibility criteria, well-defined population, and minimizing the confound- ing influence of multiple drugs and escalating dosage. Limitations include retrospective design and small sample size, which prevented us from accounting for the indepen- dent effect of confounders such as severity of HIE, seizure burden, dose of phenobarbitone, and concomitant use of Phenobarbitone and aEEG in Hypothermia 727Neonatology 2020;117:721–728 DOI: 10.1159/000511540 opioids. Second, we were unable to correlate degree of aEEG suppression with plasma phenobarbitone levels due to limited and variable testing. Furthermore, though we did not use automated quantification of aEEG upper and lower margins, the categorization of margins we used makes the results clinically applicable. Finally, although we found an association between severity of aEEG sup- pression and adverse short-term outcomes, long-term neurodevelopmental outcome data are lacking. In conclusion, a significant number of infants who re- ceive phenobarbitone for seizures while undergoing TH for moderate-to-severe HIE may demonstrate clinically significant suppression in aEEG characteristics after treatment, including new-onset severely abnormal back- ground patterns. Presence of severely abnormal aEEG patterns 30–60 min post-phenobarbitone may be a better indicator of risk of adverse outcome of death or moder- ate-to-severe injury on MRI brain than aEEG pattern pri- or to treatment. A larger prospective study that includes information on drug levels may provide more mechanis- tic insights. Clinicians should consider the potential sup- pressive effect of phenobarbitone on aEEG during deci- sion-making and prognostication. Statement of Ethics This research was approved by the Institutional Research Eth- ics Board of the Hospital for Sick Children (REB# 1000032663). Parental consent was not required due to the retrospective nature of the study. 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