Treatment of generalized convulsive status epilepticus: An international survey in the East Mediterranean Countries

Treatment of generalized convulsive status epilepticus_ An international survey in the East Mediterranean Countriesjournal homepage: www.elsevier.com/locate/seizure
Treatment of generalized convulsive status epilepticus: An international survey in the East Mediterranean Countries Sahar Farhata,1, Wassim Nasreddinea,1, Taoufik Alsaadic, Adnan A Beydounb, Maher Arabid, Ahmad Beydouna,* a Comprehensive Epilepsy Program, Neurology Department, American University of Beirut Medical Center, Lebanon b American University of Beirut, Faculty of Medicine, Lebanon c American Center for Psychiatry & Neurology, Abu Dhabi, United Arab Emirates d Ibn Sina Hospital, Kuwait City, Kuwait
A R T I C L E I N F O
Keywords: Generalized convulsive status epilepticus ILAE survey treatment
A B S T R A C T
Purpose: Three Chapters of the Commission of the East Mediterranean Affairs (CEMA) of the ILAE conducted a survey to assess the availability of drugs used for the treatment of generalized convulsive status epilepticus (GCSE) across the CEMA countries and to evaluate the treatment choices of adult and pediatric neurologists for the treatment of this condition. Method: The web-based survey consisted of two similar vignettes of GCSE in a child and an adult. The questions evaluated the sequential drugs of choice based on drug availability and with the assumption that all drugs were at the disposition of the neurologists. The neurologists were also asked about the timing of introduction of anesthetic drugs and how they monitor patients in drug induced coma. Results: Our data showed that the availability of drugs differ substantially across CEMA countries. A benzo- diazepine and phenytoin/phenobarbital were the initial drugs of choice for the majority of adults and pediatric neurologists. In cases of refractory status, most neurologists would use a third agent before proceeding to treatment with an anesthetic agent. Although the vast majority would prefer to monitor patients in drug-induced coma with continuous EEG, only 38% are using this modality because of its unavailability at their institutions. Conclusions: Our data emphasize that an algorithm for the treatment of GCSE in the CEMA countries should be flexible and should propose different treatment options at each step of the protocol that are based on the best available data while taking into consideration the drug availability across the CEMA countries.
1. Introduction
Generalized convulsive status epilepticus (GCSE) is a medical and neurological emergency that requires immediate treatment in order to minimize morbidity and mortality [1]. Due to the difficulties in con- ducting clinical trials in GCSE, there is a paucity of evidence-based data to provide the clinician with treatment recommendations, especially for patients who fail treatment with the first- and second-line agents. A number of treatment guidelines and protocols for the management of GCSE have been published, partly evidence based, and when data are lacking, on consensus and/or expert opinion [2]. The value of adhering to a treatment protocol for the management of status epilepticus (SE) was shown in a number of studies. In a retrospective population-based study of 184 episodes of SE, it was reported that the initial treatment
was inadequate in 76% of cases, and that patients who received an adequate dose of AED treatment were significantly more likely to have an effective therapeutic response [3]. In another retrospective evalua- tion of 45 patients with SE, patients who were treated according to guidelines seized for a significantly shorter time (38 minutes) compared to those who did not (95 minutes) [4]. A recent retrospective study documented that the use of a clearly defined protocol resulted in fewer ICU admissions, adverse drug reactions and patients’ deaths. In addi- tion, a prospective cohort study of 100 adult patients showed that the main factor associated with termination of GCSE was adherence to protocol with an odds ratio of 11.1 [5]. Furthermore, it was associated with a significantly decreased rate of refractory SE beyond 60 min after initiation of treatment and a 3.8-fold reduction in the need for in- tubation [5].
https://doi.org/10.1016/j.seizure.2020.03.016 Received 21 November 2019; Received in revised form 25 March 2020; Accepted 27 March 2020
Corresponding author at: American University of Beirut Medical Center, Cairo Street, Hamra, Beirut, Lebanon E-mail address: [email protected] (A. Beydoun).
1 Authors with equal contribution.
Seizure: European Journal of Epilepsy 78 (2020) 96–101
1059-1311/ © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
2. Methods
Initially, each president of the CEMA chapters was asked about the availability in his/her country of the parenteral formulation of the various drugs used for the treatment of GCSE. A web-based survey was then made available and the presidents of the various CEMA chapters were asked to inform their members about the presence of this survey and to encourage them to participate. In addition, the survey was dis- tributed as a hard copy during an epilepsy meeting of the Emirate League Against Epilepsy. The survey was anonymous and consisted of two similar vignettes of GCSE in a child and an adult, with the adult and pediatric neurologists asked to fill in their responses for the adult and pediatric cases, respectively.
2.1. Case 1
A 28 years old man, not known to have epilepsy presented to the emergency department with generalized convulsive status epilepticus that started 10 min prior to his arrival.
2.2. Case 2
A 6 years old boy not known to have epilepsy presented to the emergency department with a non-febrile generalized convulsive status epilepticus that started 10 minutes prior to his arrival.
The various questions pertaining to those cases are shown in Table 1.
The survey questions were submitted to the IRB at the American University of Beirut Medical Center which approved the study and decided that the survey was anonymous and did not require any in- formed consents.
3. Results
One hundred and three adult neurologists and 31 pediatric neu- rologists from 12 CEMA countries responded to the survey. The vast majority of physicians (77%) reported epilepsy as their primary field of interest. The physicians were familiar with the treatment of SE with 38% and 60% having treated 1 to 5 and 6 or more patients with SE over the past year, respectively.
3.1. Availability of parenteral formulation of drugs in CEMA countries
Table 2 summarizes the availability of the parenteral forms of drugs used for the treatment of GCSE in the various CEMA countries. Phe- nytoin is available in all countries except Morocco whereas fo- sphenytoin is unavailable in all countries. As far as the benzodiaze- pines, diazepam is available in all countries whereas lorazepam and clonazepam are only available in four and three countries, respectively. Phenobarbital is available in all countries except Lebanon. Valproate is available in all countries except two (Tunisia and Morocco) whereas
levetiracetam is only available in six countries. The parenteral form of lacosamide was only available in two countries at the time of the survey (Kuwait and Lebanon). The anesthetic drugs are widely available with midazolam, ketamine and thiopental available in all countries while propofol and pentobarbital are available throughout except for the unavailability of propofol in Tunisia and pentobarbital in Kuwait (Table 2).
3.2. Initial drugs of choice
Based on the drugs available at their disposal, 52% of the adult neurologists chose diazepam as their initial drug of choice whereas 68% would have chosen lorazepam if all drugs were available at their dis- posal (Table 3A). For the second drug of choice, the majority of adult neurologists chose phenytoin whether based on the drugs at their dis- posal or if all drugs were available at their disposal (64% and 53% respectively). Valproate was chosen as the second drug of choice by 18% of physicians based on available drugs whereas 20% would have chosen levetiracetam if all drugs were available. If the GCSE persisted despite administration of the second drug, there was a wide variability in the choice of the third drug with midazolam, phenobarbital, valproate and propofol favored by 13-21% of the adult neurologists (Table 3A). Those percentages did not substantially differ if all drugs were available to the physicians.
Table 1 Survey questions for cases #1 and #2
Question1:
1a. What is your first drug of choice based on the drugs at your disposal? DZP, LZP, MDZ, CLZ, PHT, PB, VPA, LEV, LCS, PROP, PENT, THIO, KET
1b. What would be your first drug of choice assuming all drugs were available at your disposal? DZP, LZP, MDZ, CLZ, PHT, PB, VPA, LEV, LCS, PROP, PENT, THIO, KET
Question 2: 2a. What is your second drug of choice based on the drugs at your disposal?
DZP, LZP, MDZ, CLZ, PHT, PB, VPA, LEV, LCS, PROP, PENT, THIO, KET 2b. What would be your second drug of choice assuming all drugs were
available at your disposal? DZP, LZP, MDZ, CLZ, PHT, PB, VPA, LEV, LCS, PROP, PENT, THIO, KET
Question 3: 3a. What is your third choice based on the drugs at your disposal if the GCSE
persists after administration of your second drug? DZP, LZP, MDZ, CLZ, PHT, PB, VPA, LEV, LCS, PROP, PENT, THIO, KET
3b. What would be your third choice assuming all drugs were available at your disposal if the GCSE persists after administration of your second drug? DZP, LZP, MDZ, CLZ, PHT, PB, VPA, LEV, LCS, PROP, PENT, THIO, KET
Question 4: In case of refractory GCSE, you would consider using an anesthetic agent after failure of the: Second AED, third AED, fourth AED, fifth AED
Question 5: If you decide to use an anesthetic agent, what would be your drug of choice? DZP infusion, MDZ infusion, PROP, PENT, THIO, KET
Question 6: If the patient fails to respond to your anesthetic of first choice, what would be your next drug of choice? DZP infusion, MDZ infusion, PROP, PENT, THIO, KET
Question 7: When using your anesthetic agent, your target dose is based on reaching? Burst suppression, EEG seizure cessation, clinical seizure cessation
Question 8: Assuming that the GCSE is aborted with the anesthetic agent, how long would you keep the patient under anesthesia before tapering the dose? 12 hours, 24 hours, 48 hours, 72 hours
Question 9: 9a: If you decide to use an anesthetic agent, how are you monitoring the patient
at your institution? Continuous EEG monitoring, daily EEGs
9b: Ideally, how would you like to monitor patients under anesthetic-induced coma? Continuous EEG monitoring, daily EEGs
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Lorazepam was the first drug of choice chosen by 48% of the pe- diatric neurologists based on the drugs available at their disposal and by 77% if all drugs were available at their disposal (Table 3B). Phe- nobarbital was the second drug of choice as it was chosen by 42% and 35% based on the available drugs and if all drugs were available, re- spectively. Phenytoin was chosen as the second drug of choice by 32% of pediatric neurologists based on the available drugs whereas levetir- acetam would have been favored by 26% if all drugs were available at their disposal. In case the GCSE persisted despite administration of the second drug, there was again no clear consensus with phenytoin, valproate, phenobarbital and midazolam being the choice for 13-26% of the pediatric neurologists (Table 3B). If all drugs were available, the only substantial difference would have been for levetiracetam which would have been favored by 19% of the pediatric neurologists.
3.3. Timing of introduction of an anesthetic agent
For patients with refractory GCSE, 42% of adult neurologists would
use an anesthetic agent after failure of the second drug while 46% elected to do so after failure of the third drug (Table 4). When a deci- sion to use an anesthetic agent was made, 45% of adult neurologists elected midazolam infusion as their drug of choice (Table 5). If the first anesthetic agent failed to abort the GCSE, propofol was the second drug of choice for 45% of the adult neurologists (Table 5).
The pediatric neurologists were more reluctant in initiating treat- ment with an anesthetic agent with only 19% electing to do so after the failure of the first or the second drug while 48.4% would do so after the failure of the third drug (Table 4). Like the adult neurologists, the majority of pediatric neurologists (55%) chose midazolam as their an- esthetic of first choice, while thiopental was the second drug of choice
Table 2 Availability of the parenteral forms of drugs for the treatment of GCSE in the CEMA countries.
Country LZP DZP CLZ PHT FPHT PB LEV VPA LCS MDZ PROP PENT THIO KET
Egypt X O X O X O X O X O O O O O Iraq X O X O X O O O X O O O O O Jordan O O O O X O X O X O O O O O Kuwait X O X O X O O O O O O X O O Lebanon X O X O X X O O O O O O O O Morocco O O X X X O X X X O O O O O Qatar O O O O X O O O X O O O O O KSA O O X O X O O O X O O O O O Syria X O X O X O X O X O O O O O Tunisia X O O O X O X X X O X O O O UAE X O X O X O O O X O O O O O
LZP: Lorazepam, DZP: Diazepam, CLZ: Clonazepam, PHT: Phenytoin; FPHT: Fosphenytoin, PB: Phenobarbital, LEV: Levetiracetam, VPA: Valproate, LCS: Lacosamide, MDZ: Midazolam, PROP: Propofol, PENT: Pentobarbital, THIO: Thiopental, KET: Ketamine X=NO; O=YES
Table 3A Case 1 for adult neurologists.
First drug of choice Based on the drug at your disposal
All drugs are available at your disposal
DZP 51.5% 17.5% LZP 25.2% 68.0% PHT 12.6% 3.9% MDZ 5.8% 5.8% VPA 2.9% 0.0% LVT 1.9% 3.9% Second drug of choice Based on the drug at
your disposal All drugs are available at your disposal
PHT 64.1% 53.4% VPA 17.5% 16.5% LVT 6.8% 20.4% PB 4.9% 3.9% MDZ 3.9% 2.9% Propofol 1.0% 1.0% Pentobarbital 1.0% 1.0% Ketamine 1.0% 1.0% Third drug of choice Based on the drug at
your disposal All drugs are available at your disposal
MDZ 21.4% 19.4% PB 17.5% 16.5% VPA 16.5% 14.6% Propofol 12.6% 11.7% LVT 9.7% 13.6% Thiopental 8.7% 7.8% Pentobarbital 6.8% 5.8% PHT 2.9% 2.9% LCS 1.9% 5.8% Ketamine 1.9% 1.9%
Table 3B Case 2 for pediatric neurologists.
First drug of choice Based on the drug at your disposal
All drugs are available at your disposal
LZP 48.4% 77.4% DZP 32.3% 12.9% MDZ 9.7% 9.7% PB 9.7% 0.0% Second drug of choice Based on the drug at
your disposal All drugs are available at your disposal
PB 41.9% 35.4% PHT 32.2% 25.8% LVT 12.9% 25.8% MDZ 9.7% 12.9% VPA 3.2% 0.0% Third drug of choice Based on the drug at
your disposal All drugs are available at your disposal
PHT 25.8% 22.6% VPA 22.6% 22.6% PB 16.1% 12.9% MDZ 12.9% 9.7% LVT 9.7% 19.4% Thiopental 6.5% 6.5% LCS 3.2% 6.5% Pentobarbital 3.2% 0.0% Propofol 0.0% 0.0% Ketamine 0.0% 0.0%
Table 4 In case of refractory GCSE, you would consider using an anesthetic agent after failure of:
Adult neurologists Pediatric neurologists
The first drug 5.8% 3.2% The second drug 41.7% 16.1% The third drug 45.6% 48.4% The fourth drug 6.8% 32.3%
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for 36% if the patient failed to respond to the first drug (Table 5). Propofol was chosen as the anesthetic of first choice by only 7% of the pediatric neurologists (Table 5).
3.4. Target dose and duration of drug-induced coma
There was no clear consensus on the target dose of the anesthetic agent with 43.7% of adult neurologists titrating to reach burst sup- pression pattern while 32.0% and 24.3% would titrate the dose to reach EEG seizure cessation and clinical seizure cessation, respectively (Table 6). A similar lack of consensus was evident from the responses of the pediatric neurologists with 32.3%, 32.3% and 35.5% targeting the dose needed to reach burst suppression, EEG seizure cessation and clinical seizure cessation, respectively (Table 6).
The vast majority of adult and pediatric neurologists would keep the patient in drug-induced coma for more than 12 hours with 50.5% and 58.1% of adult and pediatric neurologists, respectively favoring a duration of 24 hours, while 31.3% and 19.4%, respectively would keep the patient in drug-induced coma for 48 hours prior to tapering the drug (Table 6).
3.5. Monitoring of patients in drug-induced coma
For patients treated with drug-induced coma, 62.5% of neurologists are monitoring the patients with daily EEGs. However, 97% of the neurologists would prefer using continuous EEG monitoring if available at their institution.
4. Discussion
The vast majority of adult and pediatric neurologists chose a ben- zodiazepine as their initial drug of choice, which is consistent with all published guidelines and protocols for the initial treatment of GCSE [1,2]. However, our results clearly show that although a substantial percentage of adults and pediatric neurologists are using diazepam as their first choice, most would have chosen lorazepam if that drug was at
their disposal. Indeed, the parenteral form of lorazepam is only cur- rently available in four of the 11 countries surveyed. This indicates that when a treatment protocol for the MENA region is developed, it is important to take this point into consideration and to develop a pro- tocol with alternative drug treatment based on the drug availability in our region. That lorazepam was considered the drug of choice in our study is consistent with the results of an international survey of 60 experts in the treatment of SE that revealed that 81-92% of respondents chose this drug as first line therapy for GCSE in children, adolescents and adults [7]. The choice of lorazepam probably reflects in part the impact of the results of the VA cooperative study in GCSE that showed that lorazepam administered at 0.1 mg/Kg was successful in aborting status in 65% of patients, compared to a success rate of 56% with a combination of 0.15 mg/Kg of diazepam, followed by 18 mg/Kg of phenytoin [8]. Two double-blind, prospective, multicenter studies compared the efficacy of lorazepam versus diazepam as the initial treatment in 78 adults with various types of SE [9] and in 273 children with GCSE [10]. In addition, a double-blind study compared the effi- cacy of intravenous lorazepam and diazepam versus placebo for the treatment of out of hospital GCSE in 205 adult patients [11]. Both adult trials showed a statistical trend favoring lorazepam over diazepam, whereas the efficacy of those two drugs was similar in the pediatric study. The pharmacokinetic advantages of lorazepam over diazepam include its lower volume of distribution and its longer distribution half- life while its disadvantage is its need for refrigeration compared to diazepam that can be used off the shelf [12].
Phenytoin was chosen as the preferred second drug by approxi- mately two thirds of adult neurologists while 42% of child neurologists favored phenobarbital and 32% chose phenytoin. If all drugs were at their disposal, phenytoin remained favored as the preferred second drug by more than 50% of adult neurologists. Those results are overall similar to those obtained in the international expert survey in which 80% of physicians chose phenytoin as their second drug of choice [7]. In our study, assuming all medications were at the disposal of physi- cians, the only substantial change affected levetiracetam that would have been the preferred second drug of 20% and 25% of adult and pediatric neurologists, respectively. According to the American Epi- lepsy Society (AES) guidelines, there is no evidence based preferred second therapy, with fosphenytoin, valproate…