Nuñez-Ramiro A, Benavente-Fernández I, Valverde E, Cordeiro M, Blanco D, Boix H, Cabañas F, Chaffanel M, Fernández-Colomer B, Fernández-Lorenzo JR, Kuligowski J, Loureiro B, Moral-Pumarega MT, Pavón A, Sánchez-Illana A, Tofé I, Hervás D,García-Robles A, Parra-Llorca A, Cernada M, Martinez-Rodilla J, Lorente-Pozo S,Llorens R, Marqués R, Vento M; on behalf of the Hypotop Study Group. Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial. Neonatology. 2019;116(1):76-84. PMID: 31091527.
Kathleen E. Hannan MD
University of Colorado
Megan J. Kirkley MD, MPH
University of Colorado
TYPE OF INVESTIGATION
In a population of neonates with moderate to severe hypoxic ischemic encephalopathy (HIE), does body cooling plus topiramate therapy compared to body cooling alone lead to reduced seizure activity during hospitalization?
- Design: Randomized, controlled, double-blinded study
- Allocation: Randomization was performed using sealed envelopes. Topiramate and placebo vials both contained 30mL of solution.
- Blinding: EEG registries were evaluated by 2 blinded expert neonatologists following a pre-established scoring system. MRI interpretation was centralized and performed by 2 expert blinded radiologists.
- Follow-up period: Infants were followed during their hospitalization, survival was assessed through 168 hours after initiation of hypothermia and seizure activity was assessed through 96 hours after initiation of hypothermia.
- Setting: This study was performed in multiple centers in Spain where therapeutic hypothermia was available.
- Eligible patients included newborn infants with perinatal asphyxia evolving to HIE and requiring cooling therapy.
- Inclusion criteria: infants with gestational age ≥ 36 weeks and birthweight >2000g, with pH≤7.0 and/or base deficit ≥16mmol/L in umbilical cord or the worst blood gas determination performed during the first 60 minutes after birth. If blood gas pH was 7.01 to 7.15, base deficit was between -10 and -15.9 mmol/L, or was not available, at least one criterioncompatible with perinatal hypoxia ischemia (non-reassuring fetal status during fetal heart monitoring or sentinel event including cord prolaspe, placental abruption, uterine rupture, severe maternal or fetal hemorrhage or birth dystocia) or other objective piece of perinatal evidence (APGAR ≤5 at 10 minutes of life or needing positive pressure ventilation with mask or tracheal tube at 10 minutes of life) were required.
- Infants were excluded if they were less than 36 weeks gestational age, needed acute surgery before discharge, had severe congenital malformations and/or chromosome abnormalities, or parents refused consent.
- Intervention: Therpeutic hyopthermia with the use of topiramate compared to therapeutic hypothermia without the use of topiramate (placebo).
- Outcomes: The primary outcome for this study was seizure activity during hospitalization. Secondary outcomes included mortality during hospital stay, severity of brain damage assessed with MRI, oxidative stress, topiramate side effects and pharmacokinetics, and evaluation of energy-related metabolites.
- Analysis and Sample Size: The sample for this study included an identified 180 eligible patients, with 110 patients undergoing randomization. Ultimately 42 completed the placebo arm and 49 completed the topiramate arm.
- Patient follow-up: % included in analysis
- Among patients who were randomized, 79% received the placebo and 86% received topiramate, all of whom were followed to hospital discharge.
No differences were noted between the topiramate group and placebo group in terms of neonatal characteristics, APGAR scores, resuscitation maneuvers, or clinical status upon arriving to the NICU.
As summarized in Table 1, the authors found no difference in seizure prevalence in 4 different timeframes from the initiation of therapeutic hypothermia in the placebo group versus the topiramate group. Although p-values were not provided, comparisons for all time groups were noted to be non-significant.
|Time elapsed from beginning of hypothermia (hours)||Seizure prevalence in placebo group (n=52)||Seizure prevalence in topiramate group (n=54)||Significance|
|0-24||22 (42%)||14 (25.9%)||ns|
|24-48||6 (12%)||8 (14.8%)||ns|
|48-72||3 (6.4%)||3 (5.8%)||ns|
|72-96||2 (4.4%)||3 (5.9%)||ns|
Table 1. Time from beginning hypothermia and seizure prevalence in placebo vs topiramate groups
Mortality during hospitalzation was not significantly different between the placebo and topiramate groups (placebo 19.2% vs topiramate 9.2%, p=0.123). MRI was performed in 78.8% of patients in the placebo group and 88.9% of patients in the topiramate group. Abnormal MRI findings were present in 58.5% of patients in the placebo group compared to 56.3% of patients in the topiramate group, with no statistically significant difference in prevalence of abnormal findings or degree of severity of findings. Multiple serum biochemical markers were compared between the two groups, and no differences were found for lactate levels, pyruvate levels, plasma succinate and malate metabolic profiles, and urine lipid peroxidation biomarker levels. When examining pharmocokinetic outcomes, all patients receiving topiramate were within the published safety ranges. Therapeutic levels of topiramate were achieved in 36.9% at 24 hours, 75.5% at 48 hours, 77% at 72 hours, and 78.2% at 96 hours.
The authors conclude that topiramate reduced seizure activity and mortality, despite these findings not reaching statistical significance. The authors suggest that there is a need for follow-up studies with higher loading and maintenance doses of topiramate given that only ~3/4 of patients who received topiramate were in the therapeutic range at 48 hours of hypothermia.
Therapeutic hypothermia decreases mortality and improves neurodevelopmental outcomes in infants with moderate to severe hypoxic-ischemic encephalopathy (1-3). However, as morbidity in HIE remains high, adjuvant therapies that further improve outcomes are needed. One area of focus is reducing seizures, as studies suggest increased seizure burden is associated with worse neurodevelopmental outcomes(4).
This study seeks to address whether adding topiramate to therapeutic hypothermia reduces seizure burden compared to therapeutic hypothermia alone. The authors found no statistically significant difference in prevalence of seizures at any of the time frames measured between those who received topiramate and those who did not, however, overall seizure prevalence for the entire study time was not presented. The secondary outcome of mortality was also not statistically significantly different between groups.
There are several strengths to this study. First, the design being a randomized, controlled, double-blinded study limits bias and allows easier comparison between the study and control groups. The authors also discuss several different important outcomes, including seizure incidence, duration, and type, MRI findings, and drug levels and pharmacokinetics.
The authors also acknowledge several important limitations of this study. The study was not powered to detect a difference in mortality, thus the strong trend toward decreased mortality must be interpreted with caution.
Secondly, they discuss that the dose of topiramate used was low compared to other studies and acknowledge that a substantial number of infants did not reach therapeutic drug levels in the first 48 hours of hypothermia. The authors chose the lower drug doses in order to avoid toxicity or unknown side-effects, although with using the lower drug dose they may have been unable to detect the effects of a therapeutic level of the drug. Despite this, the authors state the intent to study side effects of the medication but do not present data on side effects in either the manuscript or supplemental materials.
Regarding the primary outcome, the authors highlight that seizure burden in the first 24 hours was reduced from 42% to 25%. Though this would seem to satisfy the absolute risk reduction of 15% specified by their power calculations (a reduction in seizure incidence from 40% to 25%), this difference was not statistically significant. Furthermore, they report that topiramate was only at a therapeutic level in 37% of infants by this 24-hour time point, making it difficult to ascribe the lower rate of seizure activity to the medication.
The description of how the primary outcome of seizure burden was determined remains somewhat nebulous. The methods discuss using “aEEG/multichannel EEG during hospital stay” and that conventional EEG and consultation with an electrophysiologist or pediatric neurologist were performed at the request of the neonatologist, indicating that most infants did not receive full EEGs. Further, the results presented indicate that aEEG was used to assess incidence, duration, and type of seizure. This is problematic because aEEG interpretation varies widely and is not always a reliable and sensitive marker of true epileptic activity (5). It has become common practice at many centers for infants undergoing therapeutic hypothermia to receive full EEG continuously during hypothermia for more accurate diagnosis of seizures, which limits the study’s generalizability.
Overall, this RCT provides limited evidence on the effectiveness of topiramate in conjunction with therapeutic hypothermia compared to therapeutic hypothermia alone. More work is needed to fully evaluate efficacy and safety of topiramate when patients achieve therapeutic levels during the most vulnerable time in the course of recovery from hypoxic-ischemic encephalopathy.
- Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy : multicentre randomised trial. The Lancet 2005; 365: 663–670.
- Jacobs S, Berg M, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy ( Review ). Cochrane Database of Systematic Reviews 2013; 1.
- Kharoshankaya L, Stevenson NJ, Livingstone V, Murray DM, Murphy BP, Ahearne CE, et al. Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Developmental Medicine & Child Neurology 2016; 58(12), 1242–1248.
- Shellhaas RA, Soaita AI, Clancy RR. Sensitivity of Amplitude-Integrated Electroencephalography for Neonatal Seizure Detection. Pediatrics 2007; 120(4), 770–777.
- Tyson JE, Mcdonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright L, et al. Whole-Body Hypothermia for Neonates with Hypoxic–Ischemic Encephalopathy. N Engl J Med 2005; 353: 1574–1584.