- Email: [email protected]
Therapeutic Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy: Electrographic Seizures and Magnetic Resonance Imaging Evidence of Injury
Therapeutic Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy: Electrographic Seizures and Magnetic Resonance Imaging Evidence of Injury Preethi Srinivasakumar, MD1,*, John Zempel, MD, PhD2, Michael Wallendorf, PhD3, Russell Lawrence, MD1, Terrie Inder, MD1, and Amit Mathur, MD1 Objective To evaluate the electrographic seizure burden in neonates with hypoxic ischemic encephalopathy (HIE) treated with or without therapeutic hypothermia and stratified results by severity of HIE and severity of injury as assessed by magnetic resonance imaging (MRI). Study design Between 2007 and 2011, video-electroencephalography (EEG) monitoring was initiated in neonates with moderate to severe HIE. Seizure burden (in seconds) was calculated, and brain MRI scans were quantitatively scored. Data were analyzed by ANOVA, the Student t test, and the c2 test. Results Sixty-nine neonates with moderate or severe HIE were prospectively enrolled, including 51 who received therapeutic hypothermia and 18 who did not. The mean duration of video-EEG monitoring was longer in the therapeutic hypothermia group (72 34 hours vs 48 34 hours; P = .01). The therapeutic hypothermia group had a lower electrographic seizure burden (log units) after controlling for injury, as assessed by MRI (2.9 0.6 vs 6.2 0.9; P = .003). A reduction in seizure burden was seen in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80). Among neonates with injury assessed by MRI, seizure burden was lower in those with mild (P = .0004) and moderate (P = .02) injury, but not in those with severe injury (P = .90). Conclusion Therapeutic hypothermia was associated with reduced electrographic seizure burden in neonatal HIE. This effect was detected on video-EEG in infants with moderate HIE, but not in those with severe HIE. When stratified by injury as assessed by MRI, therapeutic hypothermia was associated with a reduced seizure burden in infants with mild and moderate injury, but not in those with severe injury. (J Pediatr 2013;-:---).
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eonatal seizures are associated with an increased incidence of brain injury and long-term neurodevelopmental delay.1,2 Between 20% and 50% of neonates with neonatal seizures experience later epilepsy.3 Approximately 50%75% of neonatal seizures at term are attributable to hypoxic ischemic encephalopathy (HIE).4 Clinical assessment5 and amplitude-integrated electroencephalography (aEEG)6-8 might not accurately quantify seizure burden. Evaluation with a multichannel electroencephalography (EEG) video study remains the gold standard for accurate identification and quantification of seizures. Along with seizure monitoring by video-EEG in HIE, delineation of the nature and extent of cerebral injury is important to the clinical management and prognosis of neonates with HIE, and is best done with magnetic resonance imaging (MRI).9 Seizures in neonates in the setting of hypoxia-ischemia are independently associated with brain injury and worse neurodevelopmental outcomes, and these trends are independent of the severity of brain injury as assessed by MRI.2,5 The use of moderate therapeutic hypothermia to treat neonates with HIE is increasing. A meta-analysis of 3 trials including 767 neonates showed that moderate therapeutic hypothermia in neonates with HIE was associated with consistently reduced rates of mortality and neurologic impairment at age 18 months.8 Multiple pathways attenuating the secondary phase of energy failure mediate the improved outcomes after therapeutic hypothermia in HIE.10 In a biphasic model of neuronal death after hypoxic-ischemic injury, the cascade of events during secondary energy failure was associated with seizures.11 There is also evidence linking therapeutic hypothermia with reduced brain injury as assessed by MRI.9 Data on the impact of therapeutic hypothermia on seizure burden in neonatal HIE are limited, however. The present study evaluated the impact of therapeutic hypothermia on electrographic seizure burden in neonates with moderate to severe HIE, stratified by the severity of HIE on presentation as assessed by video-EEG From the Departments of Pediatrics, Neurology, and Biostatistics, Washington University in St Louis, St and by the presence and severity of brain injury as assessed by MRI. Louis, MO 1
2
3
aEEG EEG HIE MRI
Amplitude-integrated electroencephalography Electroencephalography Hypoxic ischemic encephalopathy Magnetic resonance imaging
*Present address: Division of Neonatology, Department of Pediatrics, Akron Children’s Hospital–Mahoning Valley, Boardman, OH. Funded by Thrasher Foundation. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.01.041
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Methods Between 2007 and 2011, neonates born at $36 weeks gestational age with clinical evidence of moderate to severe HIE12 with or without seizures, aged #24 hours, and managed with or without therapeutic hypothermia were prospectively enrolled for continuous video-EEG monitoring. This singlecenter study was conducted at St Louis Children’s Hospital after approval from the Washington University Human Research Protection Office. Informed written consent was obtained from at least 1 parent for each neonate enrolled. Exclusion criteria included birth at <36 weeks gestational age, age >24 hours, presence of congenital anomalies of the central nervous system, moribund status with no planned escalation of care, and receipt of neuromuscular blockade. At the start of the study, neonates born at $36 weeks gestational age who presented with moderate to severe HIE were eligible for video-EEG monitoring.10 After the institution of therapeutic hypothermia in 2008, the eligibility criteria for therapeutic hypothermia were expanded to include all of the following: $36 weeks gestational age at birth, moderate to severe HIE9 with or without seizures, and any of the following: 10-minute Apgar score <5, prolonged resuscitation at birth (eg, chest compressions and/or intubation or mask ventilation at 10 minutes), severe acidosis (pH < 7.1) on cord or neonate blood gas analysis within 60 minutes of birth, or base deficit (>12 mmol/L) on cord or neonate blood gas analysis within 60 minutes of birth. Infants were recruited into a study protocol, and eligibility criteria and management did not change over time. The CritiCool and Pediatric CureWrap system (Mennen Medical Corp, Southampton, Pennsylvania) was used to provide servo-controlled hypothermia. Neonates in the therapeutic hypothermia group were cooled to a core (rectal) temperature of 33.5 C for 72 hours and then rewarmed gradually over 24 hours. All neonates underwent conventional multichannel video-EEG recordings using a 10-20 system of electrode placement. Scalp electrodes were placed at Fp1, Fp2, F3, F4, Fz, C3, C4, Cz, P3, P4, Pz, T7 (T3), T8 (T4), P7 (T5), P8 (T6), O1, and O2 locations to record EEG activity from frontal, central, parietal, temporal, and occipital areas. The entire video-EEG recording from each neonate was independently reviewed by an epileptologist blinded to the clinical course. An electrographic seizure was defined as a sudden and repetitive, evolving stereotypic EEG waveform with a definite start and end lasting for at least 10 seconds on at least 1 channel.13 Electrographic status epilepticus was defined as continuous14 or cumulative15 electrographically documented seizure activity lasting for at least one-half of each 1-hour period. Seizure burden was defined as total duration of electrographic seizures in seconds. Video-EEG monitoring was started as soon as feasible after admission to the neonatal intensive care unit and was continued for up to 4 days in the therapeutic hypothermia group and for up to 3 days in the no therapeutic hypothermia group. 2
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All clinical and electrographic seizures were treated based on a standard antiseizure protocol that included specific indications for treatment and standard antiseizure medications. Phenobarbital 20 mg/kg was the first-line antiseizure medication, followed by a second dose if needed. Fosphenytoin 20 mg/kg was the second-line antiseizure agent, followed by midazolam if necessary. Timing and dose of all antiseizure medications administered were recorded. Conventional (T1- and T2-weighted) and diffusion MRI of the brain performed between day of life 4 and 10 were reviewed. In neonates with injury detected on MRI, the severity of injury was classified as mild, moderate, or severe based on a standard quantitative scoring method16 by 2 blinded independent reviewers experienced in interpreting neonatal brain MRI images. Continuous variables are described using mean SD and median and IQR, and categorical variables are described using frequencies. Seizure burden data (in seconds) was log transformed to stabilize the variance. For comparison of log-transformed seizure burden in the 2 groups, ANOVA was applied to the log-transformed data. The c2 test was used for categorical variables. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina). All tests were 2-sided, and a P value <.05 was considered statistically significant.
Results Continuous EEG and MRI data were available for 69 of 74 neonates with moderate to severe HIE, including 51 (74%) in the therapeutic hypothermia group and 18 (26%) in the no therapeutic hypothermia group (Figure 1). The majority of infants in the study cohort who did not undergo therapeutic hypothermia (11 of 18) were born before the institution of therapeutic hypothermia in 2008. The other 7 of these 18 infants were born after therapeutic hypothermia was clinically available, but were outside the 6-hour window of eligibility for this therapy. Characteristics of neonates in the therapeutic hypothermia and no therapeutic hypothermia groups are shown in Table I. The therapeutic hypothermia and no therapeutic hypothermia groups were comparable in terms of gestational age, birth weight, sex distribution, inborn versus outborn status, 5-minute Apgar score, cord blood/first arterial blood gas pH, and age at the start of video-EEG monitoring. None of the neonates in either group had an axillary maximum temperature exceeding 37.6 C during the first 7 days of life. The duration of video-EEG monitoring was longer in the therapeutic hypothermia group compared with the no therapeutic hypothermia group (72 334 vs 48 34 hours; P = .01) (Table I). Electrographic seizures were documented in 19 of the 51 neonates (37%) in the therapeutic hypothermia group and in 16 of 18 (88%) in the no therapeutic hypothermia group. Electrographic status epilepticus was detected in 5 of 19 neonates with seizures Srinivasakumar et al
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Figure 1. Flow diagram of the study cohort. TH, therapeutic hypothermia. Moderate and severe HIE are defined in accordance with Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria.10
(26%) in the therapeutic hypothermia group, compared with 3 of 16 (19%) in the no therapeutic hypothermia group. All 8 of these neonates had severe injury as assessed by MRI. A reduction in electrographic seizure burden (log units) was noted in the therapeutic hypothermia group compared with the no therapeutic hypothermia group (2.9 0.6 vs 6.2 0.9; P = .003) (Figure 2 and Table II). Further analysis revealed an association between therapeutic hypothermia and a reduced seizure burden in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80) (Table II). Among neonates with brain injury as assessed by MRI, this reduced electrographic seizure burden was significant only in those with mild (P = .0004) or moderate (P = .02) injury, and was not significant in those with severe injury (P = .90) (Figure 2). The 2 groups were comparable with respect to antiseizure medication use before and during video-EEG monitoring, total phenobarbital dose and age at first phenobarbital administration, total number of antiseizure medications used, and plasma levels of phenobarbital. The mean doses of fosphenytoin and midazolam were slightly higher in the no therapeutic hypothermia group, although the difference did not reach statistical significance (Table II).
Discussion This study supports the report by Low et al17 of an association between therapeutic hypothermia and a reduction in electrographic seizure burden in neonates with moderate HIE but not in those with severe HIE. Our findings further demonstrate that this reduction is limited to infants with mild to moderate injury and is not seen in those with severe injury as assessed by MRI. The longterm benefit of this seizure reduction with therapeutic hypothermia remains unclear. In an animal model, Wirrell et al18 showed that seizures superimposed on hypoxiaischemia increased neuronal cell death; however, they subsequently reported that this neuronal cell death in their model occurred in the setting of higher brain temperatures in the animal with seizures.19 In other animal models, therapeutic hypothermia has been associated with reductions in both the duration20 and amplitude21 of electrographic seizures. Studies in human neonates with HIE have also suggested that the severity and duration of seizures are independently associated with brain injury.2,22
Table I. Clinical characteristics of the study cohort Measure
Therapeutic hypothermia (n = 51)
No therapeutic hypothermia (n = 18)
P value
Gestational age, weeks, mean SD Birth weight, g, mean SD Sex, male:female, n 5-minute Apgar score Cord blood/first arterial blood pH, mean SD Inborn:outborn, n Age at start of video-EEG monitoring, h, mean SD Duration of video-EEG monitoring, h, mean SD
39 2 3160 655 29:22 4 7.05 0.1 30:21 13 11 72 34
38 2 3315 980 11:7 5 7.10 0.2 9:9 19 13 48 34
.80 .40 .70 .80 .06 .40 .10 .01*
*P value significant, c2 test.
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Figure 2. Boxplot comparing electrographic seizure burden (log units) in neonates with and without TH, stratified by severity of brain injury as assessed by MRI. > denotes the mean; —, the median.
Data on the potential mechanisms behind the antiseizure effect of therapeutic hypothermia are limited. In a rat model of cerebral ischemia, hypothermia inhibited the release of excitotoxic glutamate,23 which may suppress seizure activity. Hypothermia also may inhibit oxidative injury24 and result in attenuation of the secondary phase of neuronal injury, when seizures are more likely to occur. In addition, little is known about the potential interactions between antiepileptic drugs and hypothermia in HIE. Barks et al25 reported that early phenobarbital administration augments the neuroprotection offered by therapeutic hypothermia in a rodent model of HIE. Hypothermia is also known to prolong the half-life of phenobarbital,26 although our monitoring of drug levels detected no difference between the 2 study groups. Clinical observation and aEEG monitoring are known to underestimate seizures. Previous clinical trials of therapeutic hypothermia have used clinical27 and/or aEEG monitoring,8 and none has included full-montage video-EEG recording. Clinical estimation of seizure burden is unreliable, as has been demonstrated by several groups.28,29 Although better
than clinical monitoring, aEEG has a limited ability to detect short seizures, seizures that do not generalize, and low-voltage seizures.7 In the present study, we used full-montage videoEEG to monitor seizure activity and relied solely on EEGdocumented seizures to estimate seizure burden. On subanalysis, we found that seizure burden was reduced only in hypothermic neonates with moderate HIE, and not those with severe HIE. Five of 12 neonates with severe HIE who underwent therapeutic hypothermia had subclinical status epilepticus, and all five neonates had severe brain injury as assessed by MRI. The status epilepticus resulting from severe and extensive brain injury in these neonates likely will not readily respond to antiseizure medications or hypothermia. Low et al,17 using full-montage video-EEG, also found that therapeutic hypothermia provided a benefit, with reduced electrographic seizure burden, only in neonates with moderate HIE. A meta-analysis of data from 3 hypothermia trials found that the primary outcome of death and disability at 18 months was significantly reduced by cooling in neonates with moderate HIE, but not in those with severe HIE.8 In
Table II. Characteristics of seizure burden in the study cohort Measure Electrographic seizure burden (log) Severity of HIE, mean SD All Moderate Severe Severity of MRI-detected injury, mean SD Mild Moderate Severe Other measures Total number of antiseizure medications Phenobarbital dose, mg/kg, mean SD Plasma phenobarbital level, mg/mL, mean SD Fosphenytoin dose, mg/kg, mean SD Midazolam dose, mg/kg/d, mean SD Age at initial phenobarbital dose, h, mean SD Phenobarbital use before monitoring, n/N
Therapeutic hypothermia (n = 51)
No therapeutic hypothermia (n = 18)
P value
2.9 0.6 2.2 0.6 7.6 2.5
6.2 0.9 7.0 1.0 8.4 3.8
.003* .0001* .80
1.6 0.9 3.9 1.7 8.8 1.5
4.9 0.2 6.2 0.9 8.9 0.7
.0004* .02* .90
1-3 25 20 26 29 20 5 0.23 17 4.5 6/51
1-3 23 17 27 23 22 4 0.35 19 4 7/18
NS .60 .90 .90 .80 .50 .90
NS, not significant. *P value significant, ANOVA.
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contrast, Simbruner et al30 reported that hypothermia is strongly neuroprotective even in severe HIE. Thus, although therapeutic hypothermia may not significantly reduce the seizure burden in neonates with severe HIE, it may have benefits beyond seizure-mediated effects. Longitudinal neurodevelopmental follow-up data are needed to examine this issue in more depth. The duration of video-EEG monitoring was significantly longer in the therapeutic hypothermia group compared with the no therapeutic hypothermia group, because EEG monitoring was continued during the rewarming period. Thus, there was more opportunity to capture electrographic seizures in the therapeutic hypothermia group. Even with the longer monitoring time, the therapeutic hypothermia group had a significantly lower seizure burden than the no therapeutic hypothermia group, further strengthening our findings. This study has some limitations. Infants were not prospectively randomized into groups with and without therapeutic hypothermia; rather, the infants without therapeutic hypothermia either were born before the initiation of clinical therapeutic hypothermia or were admitted beyond the 6-hour eligibility window. This might have introduced biases in enrollment. However, because all infants in the study were enrolled as part of a study protocol, other than the introduction of therapeutic hypothermia, there were no differences in the management protocol for neonatal HIE throughout the study period. In conclusion, our findings demonstrate that therapeutic hypothermia is associated with reduced electrographic seizure burden in neonates with moderate HIE but not in those with severe HIE, and in neonates with mild or moderate brain injury but not in those with severe injury, as assessed by MRI. n We thank Anthony Barton for data acquisition and Barbara Smith and the other EEG technicians at St Louis Children’s Hospital for ensuring timely placement and maintenance of EEG leads through the monitoring period. Submitted for publication Jul 12, 2012; last revision received Dec 20, 2012; accepted Jan 22, 2013. Reprint requests: Preethi Srinivasakumar, MBBS, MD, Division of Neonatology, Department of Pediatrics, Akron Children’s Hospital–Mahoning Valley, 6505 Market St, Boardman, OH 44512. E-mail: psrinivasakumar@ chmca.org
References 1. Levene M. The clinical conundrum of neonatal seizures. Arch Dis Childhood Fetal Neonatal Ed 2002;86:F75-7. 2. Miller SP, Weiss J, Barnwell A, Ferriero DM, Latal-Hajnal B, FerrerRogers A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542-8. 3. Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991;32:69-76. 4. Volpe J. Neurology of the newborn. Philadelphia: Elsevier Health Sciences; 2008. 5. Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr 2009;155:318-23. 6. Shellhaas RA, Barks AK. Impact of amplitude-integrated electroencephalograms on clinical care for neonates with seizures. Pediatr Neurol 2012;46:32-5.
7. Rennie JM, Chorley G, Boylan GB, Pressler R, Nguyen Y, Hooper R. Non-expert use of the cerebral function monitor for neonatal seizure detection. Arch Dis Child Fetal Neonatal Ed 2004;89:F37-40. 8. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340:c363. 9. Rutherford M, Pennock J, Schwieso J, Cowan F, Dubowitz L. Hypoxicischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child Fetal Neonatal Ed 1996;75:F145-51. 10. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Eng J Med 2005;353:1574-84. 11. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99:248-56. 12. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976; 33:696-705. 13. Clancy RR, Legido A. The exact ictal and interictal duration of electroencephalographic neonatal seizures. Epilepsia 1987;28:537-41. 14. Scher MS, Aso K, Beggarly ME, Hamid MY, Steppe DA, Painter MJ. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91:128-34. 15. Ortibus EL, Sum JM, Hahn JS. Predictive value of EEG for outcome and epilepsy following neonatal seizures. Electroencephalogr Clin Neurophysiol 1996;98:175-85. 16. Bednarek N, Mathur A, Inder T, Wilkinson J, Neil J, Shimony J. Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy. Neurology 2012;78:1420-7. 17. Low E, Boylan GB, Mathieson SR, Murray DM, Korotchikova I, Stevenson NJ, et al. Cooling and seizure burden in term neonates: an observational study. Arch Dis Child Fetal Neonatal Ed 2012;97: F267-72. 18. Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001;50: 445-54. 19. Yager JY, Armstrong EA, Jaharus C, Saucier DM, Wirrell EC. Preventing hyperthermia decreases brain damage following neonatal hypoxicischemic seizures. Brain Res 2004;1011:48-57. 20. Azzopardi D, Brocklehurst P, Edwards D, Halliday H, Levene M, Thoresen M, et al. The TOBY study. Whole-body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr 2008;8:17. 21. Tooley JR, Satas S, Porter H, Silver IA, Thoresen M. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 2003;53:65-72. 22. Younkin DP, Delivoria-Papadopoulos M, Maris J, Donlon E, Clancy R, Chance B. Cerebral metabolic effects of neonatal seizures measured with in vivo 31P NMR spectroscopy. Ann Neurol 1986;20:513-9. 23. Nakashima K, Todd MM. Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke 1996;27: 913-8. 24. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 1995;65:1704-11. 25. Barks JD, Liu YQ, Shangguan Y, Silverstein FS. Phenobarbital augments hypothermic neuroprotection. Pediatr Res 2010;67:532-7. 26. Filippi L, la Marca G, Cavallaro G, Fiorini P, Favelli F, Malvagia S, et al. Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia. Epilepsia 2011;52:794-801. 27. Kwon JM, Guillet R, Shankaran S, Laptook AR, McDonald SA, Ehrenkranz RA, et al. Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental
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outcome: secondary analyses of data from the Neonatal Research Network hypothermia trial. J Child Neurol 2011;26:322-8. 28. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008;93:F187-91.
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Vol. -, No. 29. Yap V, Engel M, Takenouchi T, Perlman JM. Seizures are common in term infants undergoing head cooling. Pediatr Neurol 2009;41: 327-31. 30. Simbruner G, Mittal RA, Rohlmann F, Muche R. neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics 2010;126:e771-8.
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eonatal seizures are associated with an increased incidence of brain injury and long-term neurodevelopmental delay.1,2 Between 20% and 50% of neonates with neonatal seizures experience later epilepsy.3 Approximately 50%75% of neonatal seizures at term are attributable to hypoxic ischemic encephalopathy (HIE).4 Clinical assessment5 and amplitude-integrated electroencephalography (aEEG)6-8 might not accurately quantify seizure burden. Evaluation with a multichannel electroencephalography (EEG) video study remains the gold standard for accurate identification and quantification of seizures. Along with seizure monitoring by video-EEG in HIE, delineation of the nature and extent of cerebral injury is important to the clinical management and prognosis of neonates with HIE, and is best done with magnetic resonance imaging (MRI).9 Seizures in neonates in the setting of hypoxia-ischemia are independently associated with brain injury and worse neurodevelopmental outcomes, and these trends are independent of the severity of brain injury as assessed by MRI.2,5 The use of moderate therapeutic hypothermia to treat neonates with HIE is increasing. A meta-analysis of 3 trials including 767 neonates showed that moderate therapeutic hypothermia in neonates with HIE was associated with consistently reduced rates of mortality and neurologic impairment at age 18 months.8 Multiple pathways attenuating the secondary phase of energy failure mediate the improved outcomes after therapeutic hypothermia in HIE.10 In a biphasic model of neuronal death after hypoxic-ischemic injury, the cascade of events during secondary energy failure was associated with seizures.11 There is also evidence linking therapeutic hypothermia with reduced brain injury as assessed by MRI.9 Data on the impact of therapeutic hypothermia on seizure burden in neonatal HIE are limited, however. The present study evaluated the impact of therapeutic hypothermia on electrographic seizure burden in neonates with moderate to severe HIE, stratified by the severity of HIE on presentation as assessed by video-EEG From the Departments of Pediatrics, Neurology, and Biostatistics, Washington University in St Louis, St and by the presence and severity of brain injury as assessed by MRI. Louis, MO 1
2
3
aEEG EEG HIE MRI
Amplitude-integrated electroencephalography Electroencephalography Hypoxic ischemic encephalopathy Magnetic resonance imaging
*Present address: Division of Neonatology, Department of Pediatrics, Akron Children’s Hospital–Mahoning Valley, Boardman, OH. Funded by Thrasher Foundation. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.01.041
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Methods Between 2007 and 2011, neonates born at $36 weeks gestational age with clinical evidence of moderate to severe HIE12 with or without seizures, aged #24 hours, and managed with or without therapeutic hypothermia were prospectively enrolled for continuous video-EEG monitoring. This singlecenter study was conducted at St Louis Children’s Hospital after approval from the Washington University Human Research Protection Office. Informed written consent was obtained from at least 1 parent for each neonate enrolled. Exclusion criteria included birth at <36 weeks gestational age, age >24 hours, presence of congenital anomalies of the central nervous system, moribund status with no planned escalation of care, and receipt of neuromuscular blockade. At the start of the study, neonates born at $36 weeks gestational age who presented with moderate to severe HIE were eligible for video-EEG monitoring.10 After the institution of therapeutic hypothermia in 2008, the eligibility criteria for therapeutic hypothermia were expanded to include all of the following: $36 weeks gestational age at birth, moderate to severe HIE9 with or without seizures, and any of the following: 10-minute Apgar score <5, prolonged resuscitation at birth (eg, chest compressions and/or intubation or mask ventilation at 10 minutes), severe acidosis (pH < 7.1) on cord or neonate blood gas analysis within 60 minutes of birth, or base deficit (>12 mmol/L) on cord or neonate blood gas analysis within 60 minutes of birth. Infants were recruited into a study protocol, and eligibility criteria and management did not change over time. The CritiCool and Pediatric CureWrap system (Mennen Medical Corp, Southampton, Pennsylvania) was used to provide servo-controlled hypothermia. Neonates in the therapeutic hypothermia group were cooled to a core (rectal) temperature of 33.5 C for 72 hours and then rewarmed gradually over 24 hours. All neonates underwent conventional multichannel video-EEG recordings using a 10-20 system of electrode placement. Scalp electrodes were placed at Fp1, Fp2, F3, F4, Fz, C3, C4, Cz, P3, P4, Pz, T7 (T3), T8 (T4), P7 (T5), P8 (T6), O1, and O2 locations to record EEG activity from frontal, central, parietal, temporal, and occipital areas. The entire video-EEG recording from each neonate was independently reviewed by an epileptologist blinded to the clinical course. An electrographic seizure was defined as a sudden and repetitive, evolving stereotypic EEG waveform with a definite start and end lasting for at least 10 seconds on at least 1 channel.13 Electrographic status epilepticus was defined as continuous14 or cumulative15 electrographically documented seizure activity lasting for at least one-half of each 1-hour period. Seizure burden was defined as total duration of electrographic seizures in seconds. Video-EEG monitoring was started as soon as feasible after admission to the neonatal intensive care unit and was continued for up to 4 days in the therapeutic hypothermia group and for up to 3 days in the no therapeutic hypothermia group. 2
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All clinical and electrographic seizures were treated based on a standard antiseizure protocol that included specific indications for treatment and standard antiseizure medications. Phenobarbital 20 mg/kg was the first-line antiseizure medication, followed by a second dose if needed. Fosphenytoin 20 mg/kg was the second-line antiseizure agent, followed by midazolam if necessary. Timing and dose of all antiseizure medications administered were recorded. Conventional (T1- and T2-weighted) and diffusion MRI of the brain performed between day of life 4 and 10 were reviewed. In neonates with injury detected on MRI, the severity of injury was classified as mild, moderate, or severe based on a standard quantitative scoring method16 by 2 blinded independent reviewers experienced in interpreting neonatal brain MRI images. Continuous variables are described using mean SD and median and IQR, and categorical variables are described using frequencies. Seizure burden data (in seconds) was log transformed to stabilize the variance. For comparison of log-transformed seizure burden in the 2 groups, ANOVA was applied to the log-transformed data. The c2 test was used for categorical variables. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina). All tests were 2-sided, and a P value <.05 was considered statistically significant.
Results Continuous EEG and MRI data were available for 69 of 74 neonates with moderate to severe HIE, including 51 (74%) in the therapeutic hypothermia group and 18 (26%) in the no therapeutic hypothermia group (Figure 1). The majority of infants in the study cohort who did not undergo therapeutic hypothermia (11 of 18) were born before the institution of therapeutic hypothermia in 2008. The other 7 of these 18 infants were born after therapeutic hypothermia was clinically available, but were outside the 6-hour window of eligibility for this therapy. Characteristics of neonates in the therapeutic hypothermia and no therapeutic hypothermia groups are shown in Table I. The therapeutic hypothermia and no therapeutic hypothermia groups were comparable in terms of gestational age, birth weight, sex distribution, inborn versus outborn status, 5-minute Apgar score, cord blood/first arterial blood gas pH, and age at the start of video-EEG monitoring. None of the neonates in either group had an axillary maximum temperature exceeding 37.6 C during the first 7 days of life. The duration of video-EEG monitoring was longer in the therapeutic hypothermia group compared with the no therapeutic hypothermia group (72 334 vs 48 34 hours; P = .01) (Table I). Electrographic seizures were documented in 19 of the 51 neonates (37%) in the therapeutic hypothermia group and in 16 of 18 (88%) in the no therapeutic hypothermia group. Electrographic status epilepticus was detected in 5 of 19 neonates with seizures Srinivasakumar et al
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Figure 1. Flow diagram of the study cohort. TH, therapeutic hypothermia. Moderate and severe HIE are defined in accordance with Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria.10
(26%) in the therapeutic hypothermia group, compared with 3 of 16 (19%) in the no therapeutic hypothermia group. All 8 of these neonates had severe injury as assessed by MRI. A reduction in electrographic seizure burden (log units) was noted in the therapeutic hypothermia group compared with the no therapeutic hypothermia group (2.9 0.6 vs 6.2 0.9; P = .003) (Figure 2 and Table II). Further analysis revealed an association between therapeutic hypothermia and a reduced seizure burden in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80) (Table II). Among neonates with brain injury as assessed by MRI, this reduced electrographic seizure burden was significant only in those with mild (P = .0004) or moderate (P = .02) injury, and was not significant in those with severe injury (P = .90) (Figure 2). The 2 groups were comparable with respect to antiseizure medication use before and during video-EEG monitoring, total phenobarbital dose and age at first phenobarbital administration, total number of antiseizure medications used, and plasma levels of phenobarbital. The mean doses of fosphenytoin and midazolam were slightly higher in the no therapeutic hypothermia group, although the difference did not reach statistical significance (Table II).
Discussion This study supports the report by Low et al17 of an association between therapeutic hypothermia and a reduction in electrographic seizure burden in neonates with moderate HIE but not in those with severe HIE. Our findings further demonstrate that this reduction is limited to infants with mild to moderate injury and is not seen in those with severe injury as assessed by MRI. The longterm benefit of this seizure reduction with therapeutic hypothermia remains unclear. In an animal model, Wirrell et al18 showed that seizures superimposed on hypoxiaischemia increased neuronal cell death; however, they subsequently reported that this neuronal cell death in their model occurred in the setting of higher brain temperatures in the animal with seizures.19 In other animal models, therapeutic hypothermia has been associated with reductions in both the duration20 and amplitude21 of electrographic seizures. Studies in human neonates with HIE have also suggested that the severity and duration of seizures are independently associated with brain injury.2,22
Table I. Clinical characteristics of the study cohort Measure
Therapeutic hypothermia (n = 51)
No therapeutic hypothermia (n = 18)
P value
Gestational age, weeks, mean SD Birth weight, g, mean SD Sex, male:female, n 5-minute Apgar score Cord blood/first arterial blood pH, mean SD Inborn:outborn, n Age at start of video-EEG monitoring, h, mean SD Duration of video-EEG monitoring, h, mean SD
39 2 3160 655 29:22 4 7.05 0.1 30:21 13 11 72 34
38 2 3315 980 11:7 5 7.10 0.2 9:9 19 13 48 34
.80 .40 .70 .80 .06 .40 .10 .01*
*P value significant, c2 test.
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Figure 2. Boxplot comparing electrographic seizure burden (log units) in neonates with and without TH, stratified by severity of brain injury as assessed by MRI. > denotes the mean; —, the median.
Data on the potential mechanisms behind the antiseizure effect of therapeutic hypothermia are limited. In a rat model of cerebral ischemia, hypothermia inhibited the release of excitotoxic glutamate,23 which may suppress seizure activity. Hypothermia also may inhibit oxidative injury24 and result in attenuation of the secondary phase of neuronal injury, when seizures are more likely to occur. In addition, little is known about the potential interactions between antiepileptic drugs and hypothermia in HIE. Barks et al25 reported that early phenobarbital administration augments the neuroprotection offered by therapeutic hypothermia in a rodent model of HIE. Hypothermia is also known to prolong the half-life of phenobarbital,26 although our monitoring of drug levels detected no difference between the 2 study groups. Clinical observation and aEEG monitoring are known to underestimate seizures. Previous clinical trials of therapeutic hypothermia have used clinical27 and/or aEEG monitoring,8 and none has included full-montage video-EEG recording. Clinical estimation of seizure burden is unreliable, as has been demonstrated by several groups.28,29 Although better
than clinical monitoring, aEEG has a limited ability to detect short seizures, seizures that do not generalize, and low-voltage seizures.7 In the present study, we used full-montage videoEEG to monitor seizure activity and relied solely on EEGdocumented seizures to estimate seizure burden. On subanalysis, we found that seizure burden was reduced only in hypothermic neonates with moderate HIE, and not those with severe HIE. Five of 12 neonates with severe HIE who underwent therapeutic hypothermia had subclinical status epilepticus, and all five neonates had severe brain injury as assessed by MRI. The status epilepticus resulting from severe and extensive brain injury in these neonates likely will not readily respond to antiseizure medications or hypothermia. Low et al,17 using full-montage video-EEG, also found that therapeutic hypothermia provided a benefit, with reduced electrographic seizure burden, only in neonates with moderate HIE. A meta-analysis of data from 3 hypothermia trials found that the primary outcome of death and disability at 18 months was significantly reduced by cooling in neonates with moderate HIE, but not in those with severe HIE.8 In
Table II. Characteristics of seizure burden in the study cohort Measure Electrographic seizure burden (log) Severity of HIE, mean SD All Moderate Severe Severity of MRI-detected injury, mean SD Mild Moderate Severe Other measures Total number of antiseizure medications Phenobarbital dose, mg/kg, mean SD Plasma phenobarbital level, mg/mL, mean SD Fosphenytoin dose, mg/kg, mean SD Midazolam dose, mg/kg/d, mean SD Age at initial phenobarbital dose, h, mean SD Phenobarbital use before monitoring, n/N
Therapeutic hypothermia (n = 51)
No therapeutic hypothermia (n = 18)
P value
2.9 0.6 2.2 0.6 7.6 2.5
6.2 0.9 7.0 1.0 8.4 3.8
.003* .0001* .80
1.6 0.9 3.9 1.7 8.8 1.5
4.9 0.2 6.2 0.9 8.9 0.7
.0004* .02* .90
1-3 25 20 26 29 20 5 0.23 17 4.5 6/51
1-3 23 17 27 23 22 4 0.35 19 4 7/18
NS .60 .90 .90 .80 .50 .90
NS, not significant. *P value significant, ANOVA.
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contrast, Simbruner et al30 reported that hypothermia is strongly neuroprotective even in severe HIE. Thus, although therapeutic hypothermia may not significantly reduce the seizure burden in neonates with severe HIE, it may have benefits beyond seizure-mediated effects. Longitudinal neurodevelopmental follow-up data are needed to examine this issue in more depth. The duration of video-EEG monitoring was significantly longer in the therapeutic hypothermia group compared with the no therapeutic hypothermia group, because EEG monitoring was continued during the rewarming period. Thus, there was more opportunity to capture electrographic seizures in the therapeutic hypothermia group. Even with the longer monitoring time, the therapeutic hypothermia group had a significantly lower seizure burden than the no therapeutic hypothermia group, further strengthening our findings. This study has some limitations. Infants were not prospectively randomized into groups with and without therapeutic hypothermia; rather, the infants without therapeutic hypothermia either were born before the initiation of clinical therapeutic hypothermia or were admitted beyond the 6-hour eligibility window. This might have introduced biases in enrollment. However, because all infants in the study were enrolled as part of a study protocol, other than the introduction of therapeutic hypothermia, there were no differences in the management protocol for neonatal HIE throughout the study period. In conclusion, our findings demonstrate that therapeutic hypothermia is associated with reduced electrographic seizure burden in neonates with moderate HIE but not in those with severe HIE, and in neonates with mild or moderate brain injury but not in those with severe injury, as assessed by MRI. n We thank Anthony Barton for data acquisition and Barbara Smith and the other EEG technicians at St Louis Children’s Hospital for ensuring timely placement and maintenance of EEG leads through the monitoring period. Submitted for publication Jul 12, 2012; last revision received Dec 20, 2012; accepted Jan 22, 2013. Reprint requests: Preethi Srinivasakumar, MBBS, MD, Division of Neonatology, Department of Pediatrics, Akron Children’s Hospital–Mahoning Valley, 6505 Market St, Boardman, OH 44512. E-mail: psrinivasakumar@ chmca.org
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