What is the role of ketamine in the management of status epilepticus?

Introduction
Status epilepticus (SE) is a syndrome of clinical or subclinical seizures which lasts at least 5 minutes and is associated with an overall morality of 20%.1,2 Mortality worsens with longer seizure duration, and current data indicate worsening outcomes with seizures lasting longer than 30 minutes. Refractory SE (RSE) is defined as continuous seizure activity that is not controlled by first-line and second-line antiepileptic drugs (AEDs). Super-refractory SE (SRSE) is defined as status epilepticus not controlled by third-line agents or SE which continues for 24 hours or longer after the administration of anesthesia. Guideline recommendations for the management of SE are well established; however, less data is available for managing RSE and SRSE.

Status epilepticus affects approximately 120,000 to 180,000 people annually in the United States.1,2 Refractory SE is estimated to occur in 9% to 43% of all SE cases and SRSE is even more rare with no well-designed studies determining a true incidence. One study estimated that there is a 17.3% mortality rate associated with RSE and another showed a 43.3% mortality rate associated with SRSE. The most common causes of SE and RSE are AED non-compliance, metabolic derangements, and central nervous system (CNS) infection. This contrasts with SRSE which is most often associated with encephalitis.

The pathophysiology of SE is mediated by 2 main receptors, gamma-aminobutyric acid (GABA), which is inhibitory, and N-methyl-D-aspartate (NMDA), which is excitatory.1,2 Current therapies such as benzodiazepines (BZDs), propofol, and barbiturates, target GABA to increase inhibitory effects and serve as seizure abortifacients. Ketamine is an NMDA antagonist which works on the NMDA receptor to blunt excitatory impulses associated with seizure disorders. Ketamine’s theoretical benefit in patients with SE is through suppression of excitatory pathways via NMDA antagonism. It is often given in tandem with BZD receptor targeting agents so patients will have concomitant GABA activation and glutamate suppression, restoring the balance of neurologic signaling.

Guideline recommendations
The most recent Neurocritical Care Society guideline was published in 2012.3 The management of status epileptics is broken down into emergent, urgent, and refractory treatments. In the emergent and urgent settings, the recommended therapies include BZDs and AEDs. Benzodiazepines serve as seizure abortifacients and AEDs are used to prevent additional seizures. If patients do not respond to adequate doses of initial therapies, they are considered to be in RSE. Medications used in the management of RSE and SRSE include propofol, pentobarbital/thiopental, continuous midazolam infusions, and additional AED doses.

The guideline makes brief mention of ketamine when discussing alternative therapies for RSE.3 Ketamine is listed as an emerging therapy with limited data on safety and efficacy for RSE. The guideline cites 9 articles, 2 of which are case series, as a basis for its recommendations. Comments included in the guideline are “intravenous drip” and “potential neurotoxicity”. The general recommendation is to reserve the use of ketamine for patients in RSE who did not respond to recommended RSE AEDs.

Clinical evidence
There is limited quality evidence associated with the use of ketamine in the management of SE. Most of the available evidence discusses its use in the management of RSE and SRSE with no current randomized controlled trials (RCTs) published on the topic; however, observational studies and a systematic review of these studies provide the best available evidence.

Attempts have been made to gather a higher quality of evidence. The best example is the KETASER01 trial, which was terminated early due to low enrollment.4 This was a multicenter, randomized, controlled, open-label trial that aimed to assess the efficacy of ketamine compared to other anesthetics in the management of convulsive RSE in children. Per protocol, patients who did not respond to first and second-line medications were randomized to either the experimental ketamine arm or one of the control arms of midazolam, propofol, or thiopental. These patients were analyzed for electroencephalogram (EEG) resolution of SE up to 24 hours after withdrawal of therapy. The investigators predicted a necessary sample size of 57 patients to detect a 25% higher success rate in the experimental arm. After a 5-year recruitment period, only 10 children were enrolled, and the investigators terminated the study. The investigators postulate that the failure to recruit patients was due to the following main factors: an overly rigid protocol, involvement of too many specialist providers, and the study being non-profit. The protocol standardized second-line agents to ensure true RSE, but this ultimately resulted in the exclusion of 12 patients. In addition, 42 patients received an anesthetic prior to admission to participating centers and were, therefore, excluded, further limiting the trial participants. By analyzing the downfalls of the KETASER01 trial, further studies may be able to design a trial which can assess the most effective agents for children and adults in these rare, but life-threatening, syndromes.

Systematic reviews
In 2018, Rosati et al published a systematic review of the efficacy and safety of ketamine for RSE treatment.5 Included articles had ketamine efficacy and safety as the primary outcome in SE, both in pediatric and adult populations. Excluded articles were preclinical studies, editorials, letters, and non-English publications. Data extracted included study type and design; patient demographics and number of patients; type of SE; etiology of SE; dose, timing, duration, and route of ketamine; prior and concomitant therapies; outcome defined as electrographic SE control; and adverse effects.

Included evidence consisted of 27 case reports and 14 case series all of which were retrospective in nature.5 The evidence for the adult population included 8 different case series and 16 case reports (n=219) of patients with RSE largely due to infection or anoxia. Ketamine was most often used to treat non-convulsive SE with mean duration of ketamine therapy being widely varied from 12 hours to 5 months. In all cases, ketamine was administered as a continuous infusion after conventional anesthetics with dosage ranging from 0.07 to 15 mg/kg/hour. A total of 156 of 222 (70.3%) RSE episodes were controlled with ketamine administration, confirmed via continuous EEG. Documented adverse effects included shock, sepsis, renal failure, pneumonia, acidosis, cerebellar atrophy, and cardiac arrest. The evidence for ketamine in pediatric patients included 4 case series and 11 case reports (n=29) with 46 total RSE episodes. Children ages ranged from 2 months to 18 years. Patients were treated with ketamine after receipt of conventional anesthetics, with midazolam being the most frequently administered. The duration of ketamine infusions ranged from 1 to 21 days and dosing ranged from 0.04 to 10 mg/kg/hour. Overall, ketamine was effective at seizure cessation in 28 of 46 (61%) episodes of pediatric RSE. The only adverse events reported were a slight increase in saliva secretion and transient, mild, increase in liver enzymes. Endotracheal intubation was avoided in 10 total patients.

Observational studies
In 2020, Alkhachroum and colleagues performed a retrospective study to examine the efficacy of ketamine infusions for the treatment of SRSE and the relationship of high-dose ketamine on systemic and brain physiologic measures.6 This study identified 261 adult patients with SRSE admitted to the neurologic intensive care unit at Columbia University Medical Center. A total of 68 patients were started on ketamine for SRSE based on the discretion of the treating physician. Patients received concomitant midazolam infusions. Patients were monitored with continuous EEG from initiation of ketamine to 24 hours post-infusion. Patients also had their mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) monitored for assessment of ketamine safety. The main outcome measured was seizure control within 24 hours of ketamine initiation defined as complete seizure cessation or more than 50% reduction of seizure burden. Relevant secondary outcomes included seizure control after ketamine discontinuation, in-hospital mortality, discharge disposition, and hospital length of stay. Baseline characteristics of patients receiving ketamine were age 53 ± 19 years with 46 (68%) women and 39 (57%) patients with focal seizure type. The average length of stay was 31 ± 34 days, and in-hospital mortality occurred in 31 (46%) patients. A total of 55 (81%) patients had at least a 50% decrease in seizure burden within 24 hours of ketamine initiation and 43 (63%) had complete seizure cessation. Of those with seizure cessation on ketamine, 18 (41%) patients died. On average, 2 concurrent anesthetics were used for SRSE with propofol being the most common second agent and midazolam used for all patients receiving ketamine. Midazolam was administered as a continuous infusion and the average dose was 1.0 ± 0.8 mg/kg/hour at the time of ketamine initiation. On average, midazolam started 0.4 (0.1 to 1.0) days prior to the addition of ketamine. Ketamine was administered as a continuous infusion with the average dose being 2.2 ± 1.8 mg/kg/hour. Higher doses of ketamine (odds ratio [OR] 1.39; 95% confidence interval [CI], 1.38 to 1.4) and longer administration time (OR 0.9; 95% CI, 0.8 to 1) were associated with a stable mean MAP and decreased vasopressor use. There was no effect observed with ketamine dosing and duration and ICP, CBF, and CPP.

Jacobwitz and colleagues performed a retrospective, single-center cohort study of neonatal patients receiving ketamine for RSE.7 The electronic medical record from a standalone children’s hospital was used to identify patients. Patients were included if they received ketamine for seizures and were monitored via continuous EEG during admission in the neonatal, cardiac, or pediatric intensive care units. Patients were excluded if the ketamine infusion was ordered but not administered because the patient died, or seizures terminated. Seizures were classified via continuous EEG and classified as SE, RSE, new-onset RSE, and febrile-infection related epilepsy syndrome (FIRES) per consensus definitions. Safety was assessed via chart review and was classified as ketamine-related if occurring during the infusion or within 12 hours of the last ketamine administration (bolus or infusion). The electronic medical record (EMR) review identified 69 patients receiving ketamine for SE. The median age at SE onset was 0.7 (interquartile range [IQR] 0.15 to 7.2) years. Seventeen (25%) patients had underlying diagnosed epilepsy at baseline and were on an average of 3 AEDs. Seven (10%) patients had a prior episode of SE with 5 (71%) of those patients experiencing RSE which was treated with anesthetic medications. RSE occurred in 25 (36%) patients and SRSE occurred in 29 (42%) patients. All patients received antiseizure therapies prior to ketamine, with a median of 3 (IQR 2-4) agents used. Ketamine was the first-used anesthetic in 38 (55%) patients and 4 (11%) patients received an additional anesthetic due to continuous seizures while on ketamine. The median duration of ketamine infusion was 85.7 hours (IQR 49.7 to 128.0). Ketamine infusions reduced seizure burden in 19 (28%) patients and terminated seizures in 32 (46%) patients. This effect was most pronounced in those patients with non-convulsive seizures. Hypertension was the most common adverse effect associated with ketamine infusion occurring in 3 (4%) patients, 2 of which had to receive antihypertensives for control. Delirium occurred in 1 (1%) patient who received ketamine which was treated with quetiapine. There were no concerns for elevated ICP in any subjects.

Conclusions
Ketamine is a reasonable medication to consider in the setting of RSE or SRSE in combination with midazolam continuous infusions. Evidence highlighted in this review does suggest that ketamine in combination with midazolam can reduce seizure activity in both adults and pediatric populations. Although the current evidence supporting the use of ketamine is low quality and small quantity, given the nature of the conditions being treated there is justification for ketamine use. As discussed, properly designed studies comparing ketamine to other third-line agents in this setting would help to elucidate the efficacy and safety of ketamine; however, there are unique challenges in study design and recruitment which must be overcome.

Adverse effects associated with ketamine outweigh the risk of adverse effects related to persistent seizures in patients with RSE or SRSE, which may include death. A potential benefit of ketamine compared with other third-line therapies is its sympathomimetic properties, which allows it to act as a pressor-sparing agent. Due to this, its use may be more compelling in those select patients who need additional hemodynamic support or are receiving multiple vasopressors. This contrasts significantly with other agents used in RSE and SRSE, such as propofol, which are associated with hypotension. In addition, ketamine may be beneficial since it is rarely associated with respiratory depression. One concern with ketamine use is the potential for increased ICP; however, this has not been demonstrated in currently available RSE or SRSE literature.

References

  1. Nelson SE, Varelas PN. Status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum (Minneap Minn). 2018;24(6):1683-1707. doi:10.1212/CON.0000000000000668
  2. Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015;14(6):615-624. doi:10.1016/S1474-4422(15)00042-3
  3. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23. doi:10.1007/s12028-012-9695-z
  4. Rosati A, L’Erario M, Bianchi R, et al. KETASER01 protocol: What went right and what went wrong. Epilepsia Open. 2022;7(3):532-540. doi:10.1002/epi4.12627
  5. Rosati A, De Masi S, Guerrini R. Ketamine for refractory status epilepticus: a systematic review. CNS Drugs. 2018;32(11):997-1009. doi:10.1007/s40263-018-0569-6
  6. Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Ketamine to treat super-refractory status epilepticus. Neurology. 2020;95(16):e2286-e2294. doi:10.1212/WNL.0000000000010611
  7. Jacobwitz M, Mulvihill C, Kaufman MC, et al. Ketamine for management of neonatal and pediatric refractory status epilepticus. Neurology. 2022;99(12):e1227-e1238. doi:10.1212/WNL.0000000000200889

Prepared by:
Mark Pulver, PharmD
PGY1 Pharmacy Practice Resident

December 2023

The information presented is current as November 1, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.