Feasibility Study Evaluating Therapeutic Hypothermia for Refractory Status Epilepticus in Children

Abstract

Pediatric refractory status epilepticus (RSE) is a neurological emergency with significant morbidity and mortality, which lacks consensus regarding diagnosis and treatment(s). Therapeutic hypothermia (TH) is an effective treatment for RSE in preclinical models and small series. In addition, TH is a standard care for adults after cardiac arrest and neonates with hypoxic-ischemic encephalopathy. The purpose of this study was to identify the feasibility of a study of pediatric RSE within a research group (Pediatric Neurocritical Care Research Group [PNCRG]). Pediatric intensive care unit (PICU) admissions at seven centers were prospectively screened from October 2012 to July 2013 for RSE. Experts within the PNCRG estimated that clinicians would be unwilling to enroll a child, unless the child required at least two different antiepileptic medications and a continuous infusion of another antiepileptic medication with ongoing electrographic seizure activity for ≥2 hours after continuous infusion initiation. Data for children meeting the above inclusion criteria were collected, including the etiology of RSE, history of epilepsy, and maximum dose of continuous antiepileptic infusions. There were 8113 PICU admissions over a cumulative 52 months (October 2012–July 2013) at seven centers. Of these, 69 (0.85%) children met inclusion criteria. Twenty children were excluded due to acute diagnoses affected by TH, contraindications to TH, or lack of commitment to aggressive therapies. Sixteen patients had seizure cessation within 2 hours, resulting in 33 patients who had inadequate seizure control after 2 hours and a continuous antiepileptic infusion. Midazolam (21/33, 64%) and pentobarbital (5/33, 15%) were the most common infusions with a wide maximum dose range. More than one infusion was required for seizure control in four patients. There are substantial numbers of subjects at clinical sites within the PNCRG with RSE that would meet the proposed inclusion criteria for a study of TH. The true feasibility of such a study depends on the sample size necessary to achieve therapeutic effects on justifiable clinical outcomes.

Introduction

Status epilepticus is a neurological emergency defined as a clinical and/or electrographic seizure lasting for 5 minutes or more or recurrent seizures without full recovery to baseline between seizures (Brophy et al., 2012). The incidence of status epilepticus ranges from 10 to 38 per 100,000 per year for children, with the highest incidence in children <1 year of age (DeLorenzo et al., 1996; Coeytaux et al., 2000). Mortality rates for pediatric status epilepticus of 3–11% have been reported (Riviello and Holmes, 2004; Chin et al., 2006). There is no consensus definition for refractory status epilepticus (RSE), although it is generally defined as status epilepticus, which does not respond to standard medical therapy (e.g., at least two antiepileptic medications) (Brophy et al., 2012). RSE occurs in ∼33–39% of children with status epilepticus and has a mortality rate of 13–33% (Sahin et al., 2001; Lambrechtsen and Buchhalter, 2008; Saz et al., 2011; Barberio et al., 2012).

Therapeutic hypothermia (TH) has been used in a number of pediatric disorders, including traumatic brain injury (Hutchison et al., 2008; Adelson et al., 2013), perinatal hypoxic-ischemic encephalopathy (Gluckman et al., 2005; Shankaran et al., 2008), and cardiac arrest (Doherty et al., 2009; Fink et al., 2010; Moler et al., 2015). TH has been shown in preclinical models to decrease seizure frequency, seizure severity, and mitigate cell death (Liu et al., 1993; Lundgren et al., 1994; Schmitt et al., 2006; Yu et al., 2011; Kowski et al., 2012). In humans, the use of TH in RSE has been limited to small case series, including four adults who were treated with TH for up to 60 hours (Corry et al., 2008). In children, a number of case reports and case series totaling 13 patients with RSE treated with TH for up to 5 days resulted in decreased seizures or resolution of RSE (Vastola et al., 1969; Orlowski et al., 1984; Elting et al., 2010; Lin et al., 2012; Shein et al., 2012; Guilliams et al., 2013).

The Pediatric Neurocritical Care Research Group (PNCRG) is a multi-institutional and a multinational research network that conducts research aimed at optimizing functional outcomes for critically ill children with neurological conditions. PNCRG includes academic children's hospitals located in the United States, Canada, Europe, and Asia and provides resources such as broad-based patient populations ideal for randomized controlled trials. We hypothesize that TH may be a useful adjuvant in the therapy of RSE. To plan an interventional trial of the effect of TH on seizure burden during RSE, specific data identifying the patient cohort from PNCRG sites are needed. The objective of this study was to identify a cohort of pediatric patients with RSE within potential clinical sites that would be eligible for such a study.

Materials and Methods

This feasibility study was ruled exempt from institutional review board approval at each individual clinical site. All patients admitted to the pediatric intensive care unit (PICU) with RSE from October 2012 to July 2013 at four clinical sites were prospectively screened, with an additional three clinical sites screening from April 2013 to July 2013. For this feasibility study, RSE was defined as inadequate seizure control after receiving (i) at least two different intermittently dosed antiepileptic medications (AEDs) and (ii) require a continuous infusion of an AED or anesthetic with (iii) ongoing electrographic seizure activity for ≥2 hours after initiation of continuous AED infusion. This a priori definition was derived by polling members of the research group for their willingness to consider enrolling a subject in a novel interventional trial. In addition to the above criteria, patients were also considered as possible subjects if they required continuous electroencephalographic (cEEG) monitoring and invasive mechanical ventilation based on the bedside clinician's judgment. Again, it was believed that these criteria would be minimally necessary by the members of the research group in an a priori discussion. Patients were initially identified by centers if they were placed on cEEG monitoring and were receiving a continuous infusion of an AED. Patients were considered excluded from this feasibility study if they had (i) an acute diagnosis of conditions known to be affected by TH (traumatic brain injury, cardiac arrest, perinatal hypoxic-ischemic encephalopathy, acute ischemic stroke, and hepatic encephalopathy), (ii) previous enrollment in a trial evaluating the use of TH, (iii) uncontrollable coagulopathy or refractory severe bleeding, (iv) platelet count of less than 100,000 or known platelet dysfunction, or (v) a lack of commitment to aggressive therapies.

From subjects who met inclusion/exclusion criteria, data were collected, including demographics, etiology of status epilepticus, medical history, and maximum dose of continuous AED infusion.

Results

During the screening period (spanning a cumulative 52 months), there were a total of 8113 admissions to the respective PICUs, of which 69 patients (0.85%) met the putative inclusion/exclusion criteria. Twenty children were excluded—with the majority (15/20, 75%) having an acute diagnosis of traumatic brain injury, cardiac arrest, or acute ischemic stroke. In addition, 16 children had cessation of seizures within 2 hours. Thus, 33 patients continued to exhibit inadequate seizure control for 2 hours after initiation of a continuous AED infusion therapy. The primary etiology of RSE is depicted in Table 1. Over half (18/33, 55%) of patients with RSE had a known history of epilepsy.

Table 1.

Primary Etiology of Refractory Status Epilepticus

	Refractory status epilepticus ≥2 h (N = 33), n (%)
Central nervous system infection	10 (30)
Epilepsy	13 (39)
Hypoxic-ischemic encephalopathy (pediatric)	1 (3)
Inborn error of metabolism	4 (12)
Autoimmune	1 (3)
Congenital heart disease	1 (3)
Unknown^a	3 (9)

Unable to identify etiology of refractory status epilepticus after a standard evaluation was completed.

Medications administered to the children meeting inclusion/exclusion criteria varied widely. Midazolam was the most common continuous AED infusion used in 21/33 (64%) of patients with a dose range of 0.12–3 mg/kg/h. Five patients were treated with pentobarbital infusions (dose range of 1–5 mg/kg/h). More than one continuous AED infusion was required for four patients (three patients: midazolam, pentobarbital; one patient: midazolam, pentobarbital, ketamine). There were three patients with missing data regarding continuous infusions and could not be evaluated for this analysis.

Discussion

TH is an intriguing therapeutic option for children with RSE, and there is currently insufficient evidence within the literature to even plan for an interventional study. Our study is the first to evaluate the first step in such a process—to determine if there is sufficient need in large academic centers, where a study such as this would be attempted. We found that more than one patient for every 2 months would be eligible at the enrolling centers using our criteria. Based on the enrollment data from the Hypothermia Pediatric Head Injury Trial (Hutchison et al., 2008), Cool Kids trial (Adelson et al., 2013), and Therapeutic Hypothermia after Pediatric Cardiac Arrest trial (Moler et al., 2015), which were all studies randomizing patients to hypothermia treatment, we expect that the recruitment would be ∼50–60% of eligible patients. With this information, it is possible to calculate the number of clinical sites that would be necessary to enroll subjects in future trials, which is dependent on the sample size needed to determine a sufficient clinical effect.

In any study of RSE, development of a consensus definition of the ictal event(s) is (are) a necessary first step. Overall, RSE itself lacks such a consensus (Bleck, 2005; Brophy et al., 2012; Fernandez and Claassen, 2012). We chose our definition for this feasibility study in an attempt to balance the possible beneficial effects of TH with its risks. Specifically, our group believed that it would be essential for a child to fail several conventional therapies for seizure management before an experimental therapy, such as TH, would be considered by most clinicians. To that end, we arrived at the inclusion criteria for this study. It is likely that a future interventional study may have slightly more conservative (i.e., more therapies had failed) or liberal (i.e., earlier use of TH) approaches. However, we conducted this feasibility study to determine if a population of children exists within our centers that might benefit from TH.

Another consideration for planning such a clinical study is defining a clinical protocol. Numerous AED have been reported efficacious for the treatment of RSE, and no single algorithm or combination of therapies has proven to be superior, which is supported by the lack of Class I treatment recommendations in the most recently published guidelines (Brophy et al., 2012). Our study demonstrates that a wide variety of agents, including benzodiazepines and barbiturates, as well as intermittently administered medications, are used in this complex patient population. Current therapies for RSE include administration of a number of medications that decrease neuronal excitability, including benzodiazepines, barbiturates, phenytoin, and many others. Combinations of these agents are often used, with the addition of continuous infusions of benzodiazepines, ketamine, propofol, and/or barbiturates (Riviello and Holmes, 2004; Brophy et al., 2012; Fernandez and Claassen, 2012; Tasker and Vitali, 2014). These medications carry significant risk of cardiovascular instability—necessitating the use of vasoactive agents in 30–77% of patients with RSE (Claassen et al., 2002). Using a novel therapeutic strategy, such as TH, may reduce the dose of antiepileptic agents required to control RSE and therefore avoid the untoward side effects of these medications. Guilliams et al. (2013) reported decreased vasoactive agents required during TH in 3/5 patients, which they attributed to lower pentobarbital doses. Long-term exposure to barbiturates is also associated with adverse neurodevelopmental outcomes (Ries, 2003; Maitre et al., 2013). If TH offers seizure control while minimizing the exposure to medications with long-lasting developmental implications, this could be a significant advance for the treatment of RSE patients.

There is significant preclinical data to support the use of TH as a treatment for RSE, although the mechanism of action has yet to be fully elucidated. In rodents that were treated with TH after traumatic brain injury (33.0–33.6°C and 34.0–35.0°C, respectively), post-traumatic seizures occurred less frequently compared to normothermia (Atkins et al., 2010; D'Ambrosio et al., 2013). In two models of status epilepticus, the frequency of epileptic discharges was significantly reduced in animals treated with hypothermia (29.0–33.0°C) compared to normothermia (Schmitt et al., 2006) and did not reoccur with rewarming from 20°C (Kowski et al., 2012). Status epilepticus resulted in neuronal damage and ischemia in normothermic animals, which was significantly decreased in animals treated with TH to 28°C and 32.5°C (Liu et al., 1993; Lundgren et al., 1994). Similarly, in a pediatric model of status epilepticus, hypothermia (32–34°C) significantly reduced neuronal necrosis and apoptosis (Yu et al., 2011). TH to 30°C also resulted in decreased brain edema and a better cognitive function following status epilepticus induced by kainic acid injection (Wang et al., 2011).

Unfortunately, TH is not without its own adverse effects. These have previously been well described in other disease processes and include the following: arrhythmia, electrolyte imbalance, infection, coagulopathy, and hypotension with rewarming. Corry et al. (2008) described four adults treated with TH for RSE, in which two developed arrhythmia, two had electrolyte imbalance, two had infection, and three exhibited coagulopathy. Two case reports included one adult with infection (Zhumadilov et al., 2014) and one adult with bradycardia and supratherapeutic coagulopathy while on warfarin (Bennett et al., 2014). No specific adverse effects due to TH were mentioned in three series totaling five children (Vastola et al., 1969; Orlowski et al., 1984; Elting et al., 2010), while Shein et al. (2012) reported only bradycardia, which preceded TH, and Lin et al. (2012) found mild electrolyte imbalance in one of two patients that was clinically insignificant. In the largest pediatric series, Guilliams et al. (2013) reported three of five patients with mild electrolyte imbalance, two with infection and one with coagulopathy. Although the adverse effects of TH are generally mild and tolerable, they would certainly need to be evaluated in the pediatric RSE population.

We recommend that an interventional trial would need to have a clearly defined patient population and standardization of AED administration to optimally evaluate both the beneficial as well as adverse effects of the TH intervention. Based on data from three large pediatric randomized controlled trials, which have previously evaluated TH (Hypothermia Pediatric Head Injury Trial, Cool Kids, Therapeutic Hypothermia after Pediatric Cardiac Arrest), patients can be cooled to 32–34°C using surface cooling measures in 2.4–3.9 hours from initiation of intervention (Hutchison et al., 2008; Adelson et al., 2013; Moler et al., 2015). A future Phase I/II trial could evaluate safety and efficacy of TH, where efficacy is measured by seizure frequency and duration. Incidence of arrhythmia, electrolyte imbalance, infection, coagulopathy, and hypotension with rewarming could be evaluated for safety. If TH proved safe and efficacious, then a Phase III trial could be designed to evaluate outcomes such as mortality and neurological morbidity, including the development of epilepsy (Lambrechtsen and Buchhalter, 2008; Novy et al., 2010). Timing of outcome evaluation would need to be determined. In a review of pediatric status epilepticus, 43 studies reported mortality rates from the time of hospital discharge to 30 years (Raspall-Chaure et al., 2006), and Martinos et al. (2013) reported that 70% of children with status epilepticus were available for a 12-month neurobehavioral follow-up. This is compared with 100% of patients available for a 3-month mortality rate evaluation in the Cool Kids trial (Adelson et al., 2013) and 97% of patients available for a 12-month neurobehavioral outcome testing in the Therapeutic Hypothermia after Pediatric Cardiac Arrest trial (Moler et al., 2015).

We chose to exclude subjects who had RSE secondary to etiologies, where TH has either been proven efficacious or has been tested extensively. These conditions include traumatic brain injury, cardiac arrest, and acute ischemic stroke, which were relatively common at the clinical sites (15/69, 22%). There is existing evidence that these pediatric conditions are affected by TH (Gluckman et al., 2005; Hutchison et al., 2008; Shankaran et al., 2008; Doherty et al., 2009; Fink et al., 2010; Adelson et al., 2013), which may have important clinical effects. Of course, a group of clinicians attempting to design a future study of TH in RSE could choose to include these subjects. However, we believe that the potential confounding of including such subjects in future studies would be a significant limitation within that particular study design.

Extrapolation of these data yields a cohort of approximately seven patients per year per clinical site with uncontrolled RSE after 2 hours of initiation of a continuous AED infusion that could be eligible for an interventional TH trial. These data will aid in study design and appropriate recruitment of participating centers. Conveniently, the PNCRG network includes many sites (>40 institutions at present) that are facile with the use of TH, both on and off study protocols (Hypothermia Pediatric Head Injury Trial, Cool Kids, Therapeutic Hypothermia after Pediatric Cardiac Arrest), and are well versed in screening, recruiting, enrolling, and implementing temperature intervention in a timely manner. In adults, there is currently a similar Phase 3 trial being conducted in France, which is actively enrolling patients with an expected completion date of April 2015 (Evaluation of Therapeutic Hypothermia in Convulsive Status Epilepticus in Adults in Intensive Care [HYBERNATUS], www.clinicaltrials.gov; NCT 01359332).

Limitations of this study include the limited data collection. Although data were collected over a relatively short time period, only the months of August and September were omitted, which may not greatly affect the representation of potential seasonal variation encountered in RSE, specifically related to infectious etiologies. Data collection occurred in centers representing varied areas of North America with only the southeast and northwest of the United States not included. Centers in these areas of the country are members of PNCRG and could readily participate in future collaborations.

Conclusion

There is an adequate cohort of patients within the PNCRG network with RSE that require cEEG monitoring and mechanical ventilation, without contraindications to TH, to pursue future studies of TH for the treatment of RSE in children.

Footnotes

Acknowledgements

The authors thank the PNCRG steering committee, including Drs. Mark Wainwright and Jose Pineda, for their collaboration and expert review for this study.

Author Disclosure Statement

No competing financial interests exist.

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