Midazolam, Ketamine, and Propofol: While We Slept, Others Worked on Anesthetizing Infusions for Refractory Status Epilepticus

Abstract

Management of Refractory Status Epilepticus: An International Cohort Study (MORSE CODe) Analysis of Patients Managed in the ICU

Chiu WT, Campozano V, Schiefecker A, Rodriguez DR, Ferreira D, Headlee A, Zeidan S, Grinea A, Huang YH, Doyle K, Shen Q, Gómez D, Hocker SE, Rohaut B, Sonneville R, Hong C-T, Demeret S, Kurtz P, Maldonado N, Helbok R, Fernandez T, Claassen J. Neurology. 2022;99(11):e1191-e1201. doi:10.1212/WNL.0000000000200818

Background and Objectives:

Status epilepticus that continues after the initial benzodiazepine and a second anticonvulsant medication is known as refractory status epilepticus (RSE). Management is highly variable because adequately powered clinical trials are missing. We aimed to determine whether propofol and midazolam were equally effective in controlling RSE in the intensive care unit, focusing on management in resource-limited settings.

Methods:

Patients with RSE treated with midazolam or propofol between January 2015 and December 2018 were retrospectively identified among 9 centers across 4 continents from upper-middle-income economies in Latin America and high-income economies in North America, Europe, and Asia. Demographics, Status Epilepticus Severity Score, etiology, treatment details, and discharge modified Rankin Scale (mRS) were collected. The primary outcome measure was good functional outcome defined as a mRS score of 0-2 at hospital discharge.

Results:

Three hundred eighty-seven episodes of RSE (386 patients) were included, with 162 (42%) from upper-middle-income and 225 (58%) from high-income economies. Three hundred six (79%) had acute and 79 (21%) remote etiologies. Initial RSE management included midazolam in 266 (69%) and propofol in 121 episodes (31%). Seventy episodes (26%) that were initially treated with midazolam and 42 (35%) with propofol required the addition of a second anesthetic to treat RSE. Baseline characteristics and outcomes of patients treated with midazolam or propofol were similar. Breakthrough (odds ratio [OR] 1.6, 95% CI 1.3-2.0) and withdrawal seizures (OR 2.0, 95% CI 1.7-2.5) were associated with an increased number of days requiring continuous intravenous anticonvulsant medications (cIV-ACMs). Prolonged EEG monitoring was associated with fewer days of cIV-ACMs (1-24 hours OR 0.5, 95% CI 0.2-0.9, and >24 hours OR 0.7, 95% CI 0.5-1.0; reference EEG <1 hour). This association was seen in both, high-income and upper-middle-income economies, but was particularly prominent in high-income countries. One hundred ten patients (28%) were dead, and 80 (21%) had good functional outcomes at hospital discharge.

Discussion:

Outcomes of patients with RSE managed in the intensive care unit with propofol or midazolam infusions are comparable. Prolonged EEG monitoring may allow physicians to decrease the duration of anesthetic infusions safely, but this will depend on the implementation of RSE management protocols. Goal-directed management approaches including EEG targets may hold promise for patients with RSE.

Ketamine for Management of Neonatal and Pediatric Refractory Status Epilepticus

Jacobwitz M, Mulvihill C, Kaufman MC, Gonzalez AK, Resendiz K, MacDonald JM, Francoeur C, Helbig I, Topjian AA, Abend NS. Neurology. 2022;99(12):e1227-e1238. doi:10.1212/WNL.0000000000200889

Background and Objectives:

Few data are available regarding the use of anesthetic infusions for refractory status epilepticus (RSE) in children and neonates, and ketamine use is increasing despite limited data. We aimed to describe the impact of ketamine for RSE in children and neonates.

Methods:

Retrospective single-center cohort study of consecutive patients admitted to the intensive care units of a quaternary care children’s hospital treated with ketamine infusion for RSE.

Results:

Sixty-nine patients were treated with a ketamine infusion for RSE. The median age at onset of RSE was 0.7 years (interquartile range 0.15-7.2), and the cohort included 13 (19%) neonates. Three patients (4%) had adverse events requiring intervention during or within 12 hours of ketamine administration, including hypertension in 2 patients and delirium in 1 patient. Ketamine infusion was followed by seizure termination in 32 patients (46%), seizure reduction in 19 patients (28%), and no change in 18 patients (26%).

Discussion:

Ketamine administration was associated with few adverse events, and seizures often terminated or improved after ketamine administration. Further data are needed comparing first-line and subsequent anesthetic medications for treatment of pediatric and neonatal RSE.

Commentary

Refractory status epilepticus (RSE) is defined as seizures that persist despite treatment with a benzodiazepine followed by an appropriately selected and dosed anti-seizure medication (ASM). Refractory status epilepticus develops in about 23% to 43% of SE patients, causes death in 17% to 39% of adults (a lower rate in children), and leads to a return to baseline neurological status in a minority of, and longer hospital stays and a need for rehabilitation in many, patients. ¹ The American Epilepsy Society published a comprehensive review on the treatment of RSE in 2020. ¹

To reduce complications from RSE, clinicians often select a continuous intravenous anesthetizing ASM (CIV ASM) as the third drug. ² Continuous intravenous anesthetizing ASMs in current use are midazolam, pentobarbital, and propofol, but there have been several newer reports on the use of ketamine. The desire to quickly stop RSE is understandable, but there are 2 questions to consider when considering a CIV ASM. Firstly, is there conclusive evidence that the common practice of using CIV ASMs as the third treatment for RSE yields better short-term and long-term outcomes and fewer harms than adding a second nonsedating ASM? Secondly, which CIV ASM is most effective in stopping seizures in the intensive care unit (ICU) and has better long-term outcomes and fewer harms than the others?

There is conflicting literature addressing the first question. ¹ Several studies found that the use of CIV ASMs were unnecessary or caused increased risk of death or infection. ^{3 -7} In contrast, one group reported that “therapeutic coma” was associated with longer hospitalizations but not with increased mortality. ⁸ The two highlighted studies do not address this question, but they do provide new information to address the second question.

The MORSE CODe retrospective, observational study at 9 centers involved both high-income and upper-middle-income countries. ⁹ Investigators reviewed medical records and included adults who had been admitted to ICUs and received treatment with midazolam or propofol. The hypothesis was that midazolam and propofol were equally effective at controlling RSE in the ICU. Control of convulsive SE was defined as cessation of clinical generalized or focal tonic–clonic seizures. If EEG was available, seizure control was also defined as cessation of “nonconvulsive,” and presumably electrographic (subclinical), seizures. Baseline predictors of outcome used the Status Epilepticus Severity Score (STESS). A response was defined as seizure-freedom within 24 hours of starting CIV ASM. A “breakthrough seizure” was a clinical or electrographic seizure occurring >6 hours after starting the CIV ASM. Outcomes were determined at the time of hospital discharge using the modified Rankin Scale (mRS) and were dichotomized as good (mRS = 0-2) and poor (mRS = 3-6).

In 387 episodes of RSE, 69% were treated with midazolam and 31% with propofol as the first CIV ASM. ⁹ The need for a second CIV ASM was similar for both treatment groups at about 1/4 to 1/3 of patients. Long-term EEG was recorded in half of RSE episodes. Patients with higher STESS underwent longer-duration EEG recording. Median maximum doses of midazolam and propofol were 0.5 mg/kg/h and 2.2 mg/kg/h, respectively (N.B., the report appears to contain an error in how the propofol dose was converted from μ/kg/min to mg/kg/h). Patients treated with propofol had a higher risk of requiring a second CIV ASM (midazolam), especially if they had convulsive RSE. Long-term EEG was more frequently available in high-income countries. Breakthrough and anesthesia-withdrawal seizures occurred in comparable numbers of episodes initially treated with midazolam and with propofol. One or more vasopressors were required in 61% of midazolam and 54% of propofol cases. Lactic acidosis, rhabdomyolysis, hyperkalemia, and hypertriglyceridemia occurred with similar frequencies in both midazolam and propofol-treated patients, but all except hypertriglyceridemia were significantly more common in upper-middle-income than in high-income countries. A good outcome occurred in 21% of patients treated with midazolam and 25% with propofol. Death occurred in 28% of patients, but the rate was higher in upper-middle-income than in high-income countries.

The second highlighted report consisted of a single-center retrospective study of 69 children who received ketamine for RSE. ¹⁰ The median age was 0.7 years (interquartile range 0.15-7.2) and 19% were neonates aged 0 to 30 days. Preexisting epilepsy occurred in 25%, and they were taking a median of 3 ASMs at baseline. Seven of the 69 children had prior SE; 5 had prior RSE or super RSE of whom 1 had febrile infection-related epilepsy syndrome (FIRES). ¹⁰ Preexisting neurological problems occurred in 30% and congenital malformations in 35%. Acute neurological injury was present in one-third of the children, including hypoxic-ischemic encephalopathy, stroke, and traumatic brain injury.

Not only did many of these young children have background medical complexity, but they also had more severity. Refractory status epilepticus occurred in only 36%, while super RSE existed in 42% and prolonged super RSE in 22% of the patients. Five had new-onset RSE of whom 4 had FIRES. Patients received a median of 3 ASMs prior to receiving ketamine. The first CIV ASM was ketamine in 55% and midazolam in 45%. Propofol use was not reported (likely due to the increased risk of propofol infusion syndrome in children). When second or third anesthetics were required, ketamine, midazolam, and pentobarbital were used. Inhalation isoflurane was required as the fourth anesthetic ASM in 3 cases. Ketamine was given via a median of 4 boluses in the first 24 hours followed by infusion starting at 1 mg/kg/h. Maximum infusion rates ranged from 1 to 7 mg/kg/h. Median time from SE onset to first administration of ketamine was 20 hours. The median duration of ketamine infusion was 85.7 hours.

Treatment was followed by EEG-determined seizure termination in 46%, seizure reduction in 28%, and no change in 26% of patients. Seizure termination was significantly more likely when ketamine was given as the first anesthetic than when given after midazolam had been used first and failed. There was no difference between neonates and children in the seizure termination rate after ketamine. Clinical outcomes were measured only at the end of the hospitalization: 30% of patients had died, 35% had new or worse epilepsy, and 22% still had seizures upon discharge. Adverse effects included 1 patient with delirium, 3 with hypertension, and 3 with hypotension. Overall, this study ¹⁰ involved an uncontrolled series of markedly ill, young children: 99% had seizures refractory to multiple ASMs before ketamine and two-thirds had super RSE or prolonged super RSE. In-hospital adverse effects were judged to be few and manageable. Ketamine provided seizure improvement in 3-quarters of the patients.

In conclusion, neither study addressed whether it is better to use a second nonsedating ASM or to go straight to a CIV ASM in early RSE. Nevertheless, the first study ⁹ indicates that propofol and midazolam are similarly effective and have no substantial differences in adverse effects or short-term outcomes for the treatment of adults with RSE. The second study ¹⁰ adds important data in neonates and younger children to the world literature to suggest that ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, can be effectively and safely used to treat adults and children with RSE as the first CIV ASM. ^1,2 Unfortunately, long-term patient outcomes were not reported in either study.

David G. Vossler, MD
Department of Neurology, University of Washington System