Current Literature In Clinical Science
What Should We Prescribe for Acute Seizures When There Is No Intravenous Access?
Efficacy of Nonvenous Medications for Acute Convulsive Seizures: A Network Meta-Analysis. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Neurology 28 Oct 2015. doi: 10.1212/WNL.0000000000002142 [Epub ahead of print]
OBJECTIVE: This is a network meta-analysis of nonvenous drugs used in randomized controlled trials (RCTs) for treatment of acute convulsive seizures and convulsive status epilepticus. METHODS: Literature was searched according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for RCTs examining treatment of acute convulsive seizures or status epilepticus with at least one of the study arms being a nonvenous medication. After demographic and outcome data extraction, a Bayesian network meta-analysis was performed and efficacy results were summarized using treatment effects and their credible intervals (CrI). We also calculated the probability of each route-drug combination being the most clinically effective for a given outcome, and provided their Bayesian hierarchical ranking. RESULTS: This meta-analysis of 16 studies found that intramuscular midazolam (IM-MDZ) is superior to other nonvenous medications regarding time to seizure termination after administration (2.145 minutes, 95% CrI 1.308-3.489), time to seizure cessation after arrival in the hospital (3.841 minutes, 95% CrI 2.697-5.416), and time to initiate treatment (0.779 minutes, 95% CrI 0.495-1.221). Additionally, intranasal midazolam (IN-MDZ) was adjudged most efficacious for seizure cessation within 10 minutes of administration (90.4% of participants, 95% CrI 79.4%-96.9%), and persistent seizure cessation for ≥1 hour (78.5% of participants, 95% CrI 59.5%-92.1%). Paucity of RCTs produced evidence gaps resulting in small networks, routes/drugs included in some networks but not others, and some trials not being connected to any network. CONCLUSIONS: Despite the evidence gaps, IM-MDZ and IN-MDZ exhibit the best efficacy data for the nonvenous treatment of acute convulsive seizures or status epilepticus.
Commentary For a long time clinicians and caregivers have been facing the question of what to do when a patient with epilepsy has breakthrough or cluster seizures outside of medical facilities— whether at home, day care, a store, school, or work. Although the caregiver’s knee-jerk response is frequently to call 911 to request immediate medical assistance, in many cases and situations necessary assistance can and has to be provided by a bystander or caregiver with limited or no training. This typically occurs in the case of patients with known and longstanding epilepsy who have frequent breakthrough seizures and who have been provided with nonvenous forms of benzodiazepines by their caregivers. Initially, several approaches were developed by physicians working with compounding pharmacies to provide patients with preparations of buccal midazolam, intranasal midazolam, or diazepam, or by prescribing intramuscular injections typically of the last two benzodiazepines. In the 1990s, rectal diazepam gel was added to the armamentarium of available treatments for acute repetitive Epilepsy Currents, Vol. 16, No. 3 (May/June) 2016 pp. 135–136 © American Epilepsy Society
seizures. While the availability of this treatment has altered the seizure management plans for many patients, its use remained controversial mainly because of social, but sometimes also legal, concerns (1). After all, how many patients feel comfortable being disrobed in public in order for someone, possibly a stranger, to administer rectally delivered treatment? Patients need other fast-acting treatments to abort seizures that carry less social stigma. Because of their pharmacokinetic properties and lipid solubility, benzodiazepines are the natural selection for further development. Diazepam and midazolam are very lipid soluble, which allows them to rapidly reach brain tissue but also causes them to be eliminated relatively rapidly. On the other hand, lorazepam is less lipid soluble, which delays its delivery to the receptor site in the brain but prolongs its redistribution. Despite these differences, all three pharmaceuticals have rapid onset of action, which is needed in the case of breakthrough or repetitive seizures in a nonmedical environment. So, here come the benzodiazepines. Several studies have evaluated their efficacy for the purpose of treating repetitive seizures and status epilepticus. We are all familiar with the 1998 study that showed intravenous lorazepam to be significantly superior to intravenous phenytoin for the treatment of convulsive status epilepticus (p = 0.002) and the 2001 study
135
Prescriptions for Seizure When Intravenous Access Is Lacking
that showed that more patients with out-of-hospital status responded to intravenous lorazepam or diazepam than placebo (p = 0.001) (2,3). In fact, these and other studies have shaped how we treat acute repetitive seizures and status epilepticus nowadays; every guideline and textbook now list benzodiazepines as the first-line therapy, and lorazepam and midazolam have Class I (level A) evidence for efficacy (4). Probably the most influential status epilepticus study since those two studies were published was the RAMPART study, which showed the noninferiority and superiority of intramuscular midazolam compared with standard treatment with intravenous lorazepam (p < 0.001) (5). Thus, while the need for benzodiazepine use in the setting of acute seizures is obvious and unquestionable, the choice of which preparation of which benzodiazepine to use in outpatient and nonvenous environments is difficult. This is because the available studies have typically compared intravenous medication utilization, which may have limited application in the field due to lack of intravenous access and other factors, including adequate training and availability of supplies. Faced with the probability of outpatient breakthrough seizures and status epilepticus, the managing physician needs to decide which nonvenous preparation of which benzodiazepine to use. Because direct evidence comparing every combination of various nonvenous treatments is scarce at best, methods to incorporate indirect comparisons need to be used to derive quality evidence. This is where the study by Arya et al. (6) comes into play. Before we discuss the results of the meta-analysis presented by these authors, we need to dive into the analytical methods that may or may not be familiar to practicing neurologists. The authors of this study were faced with the issue of comparing the efficacy of different drugs and routes of administration that needed to be reconciled when comparing studies. Thus, they used mixed (incorporating both direct and indirect comparisons) rather than fixed methods as this approach allowed them to accommodate for the possible differences between studies (7). To simplify, if one study compared intramuscular midazolam to intravenous lorazepam and another study compared intranasal midazolam to intravenous lorazepam, they were able not only to establish the relative efficacy of the two combinations of midazolam compared with intravenous lorazepam but also to compare them against each other. The results of their analyses are compelling— intramuscular and intranasal midazolam were significantly more efficacious and faster acting compared with other treatments, venous or otherwise (6). These results are important as they help providers select the best treatments for their patients from an array of rescue therapies that are in various stages of development—from the rectal diazepam gel that is currently the only Food and Drug Administration–approved therapy for the treatment of acute repetitive seizures to intranasal or intramuscular diazepam or midazolam or buccal midazolam. Other than rectal diazepam gel, those treatments are not yet approved for such use; however, they are currently available in compounding pharmacies and may soon be available in local pharmacies (8). But before we use these currently off-label therapies to develop the treatment plan for acute, repetitive, out-ofhospital seizures, we need to understand the efficacy and
136
potential risks of using benzodiazepines in this setting. While not trivial, the potential adverse events of benzodiazepines outweigh the danger of continued seizures and mainly include the risk of respiratory suppression/endotracheal intubation and hypotension in addition to less severe local reactions, for example, irritation due to intramuscular injection or effects on sinus mucosa with intranasal administration. Listing only a few potential adverse events may seem to some like sweeping the side effects of benzodiazepines under the carpet, but the risks need to be weighed against the risk of continuing seizures and status epilepticus, which we know carry ~30% risk of mortality if not rapidly controlled (9), and the risk of seizures extending into prolonged refractory status epilepticus, which has even higher rates of complications and death (10). Thus, for those patients who struggle with repetitive seizures and seizure flurries, there is a small light at the end of the long treatment tunnel—nonvenous medications other than rectal diazepam gel that are probably more efficacious and more socially acceptable. by Jerzy P. Szaflarski, MD, PhD References 1. Terry D, Paolicchi J, Karn M. Acceptance of the use of diazepam rectal gel in school and day care settings. J Child Neurol 2007;22:1135–1138. 2. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, SegAl MR, Lowenstein DH. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631–637. 3. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–798. 4. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, Laroche SM, Riviello JJ Jr, Shutter L, Sperling MR, Treiman DM, Vespa PM. Neurocritcal Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. 5. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591– 600. 6. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous medications for acute convulsive seizures: A network meta-analysis. Neurology 2015;85:1859–1868. 7. Jansen JP, Crawford B, Bergman G, Stam W. Bayesian meta-analysis of multiple treatment comparisons: An introduction to mixed treatment comparisons. Value Health 2008;11:956–964. 8. Agarwal SK, Cloyd JC. Development of benzodiazepines for outof-hospital management of seizure emergencies. Neurol Clin Pract 2015;5:80–85. 9. DeLorenzo RJ, Garnett LK, Towne AR, Waterhouse EJ, Boggs JG, Morton L, Choudhry MA, Barnes T, Ko D. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40:164–169. 10. Kilbride RD, Reynolds AS, Szaflarski JP, Hirsch LJ. Clinical outcomes following prolonged refractory status epilepticus (PRSE). Neurocrit Care 2013;18:374–385.
What Should We Prescribe for Acute Seizures When There Is No Intravenous Access?
Efficacy of Nonvenous Medications for Acute Convulsive Seizures: A Network Meta-Analysis. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Neurology 28 Oct 2015. doi: 10.1212/WNL.0000000000002142 [Epub ahead of print]
OBJECTIVE: This is a network meta-analysis of nonvenous drugs used in randomized controlled trials (RCTs) for treatment of acute convulsive seizures and convulsive status epilepticus. METHODS: Literature was searched according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for RCTs examining treatment of acute convulsive seizures or status epilepticus with at least one of the study arms being a nonvenous medication. After demographic and outcome data extraction, a Bayesian network meta-analysis was performed and efficacy results were summarized using treatment effects and their credible intervals (CrI). We also calculated the probability of each route-drug combination being the most clinically effective for a given outcome, and provided their Bayesian hierarchical ranking. RESULTS: This meta-analysis of 16 studies found that intramuscular midazolam (IM-MDZ) is superior to other nonvenous medications regarding time to seizure termination after administration (2.145 minutes, 95% CrI 1.308-3.489), time to seizure cessation after arrival in the hospital (3.841 minutes, 95% CrI 2.697-5.416), and time to initiate treatment (0.779 minutes, 95% CrI 0.495-1.221). Additionally, intranasal midazolam (IN-MDZ) was adjudged most efficacious for seizure cessation within 10 minutes of administration (90.4% of participants, 95% CrI 79.4%-96.9%), and persistent seizure cessation for ≥1 hour (78.5% of participants, 95% CrI 59.5%-92.1%). Paucity of RCTs produced evidence gaps resulting in small networks, routes/drugs included in some networks but not others, and some trials not being connected to any network. CONCLUSIONS: Despite the evidence gaps, IM-MDZ and IN-MDZ exhibit the best efficacy data for the nonvenous treatment of acute convulsive seizures or status epilepticus.
Commentary For a long time clinicians and caregivers have been facing the question of what to do when a patient with epilepsy has breakthrough or cluster seizures outside of medical facilities— whether at home, day care, a store, school, or work. Although the caregiver’s knee-jerk response is frequently to call 911 to request immediate medical assistance, in many cases and situations necessary assistance can and has to be provided by a bystander or caregiver with limited or no training. This typically occurs in the case of patients with known and longstanding epilepsy who have frequent breakthrough seizures and who have been provided with nonvenous forms of benzodiazepines by their caregivers. Initially, several approaches were developed by physicians working with compounding pharmacies to provide patients with preparations of buccal midazolam, intranasal midazolam, or diazepam, or by prescribing intramuscular injections typically of the last two benzodiazepines. In the 1990s, rectal diazepam gel was added to the armamentarium of available treatments for acute repetitive Epilepsy Currents, Vol. 16, No. 3 (May/June) 2016 pp. 135–136 © American Epilepsy Society
seizures. While the availability of this treatment has altered the seizure management plans for many patients, its use remained controversial mainly because of social, but sometimes also legal, concerns (1). After all, how many patients feel comfortable being disrobed in public in order for someone, possibly a stranger, to administer rectally delivered treatment? Patients need other fast-acting treatments to abort seizures that carry less social stigma. Because of their pharmacokinetic properties and lipid solubility, benzodiazepines are the natural selection for further development. Diazepam and midazolam are very lipid soluble, which allows them to rapidly reach brain tissue but also causes them to be eliminated relatively rapidly. On the other hand, lorazepam is less lipid soluble, which delays its delivery to the receptor site in the brain but prolongs its redistribution. Despite these differences, all three pharmaceuticals have rapid onset of action, which is needed in the case of breakthrough or repetitive seizures in a nonmedical environment. So, here come the benzodiazepines. Several studies have evaluated their efficacy for the purpose of treating repetitive seizures and status epilepticus. We are all familiar with the 1998 study that showed intravenous lorazepam to be significantly superior to intravenous phenytoin for the treatment of convulsive status epilepticus (p = 0.002) and the 2001 study
135
Prescriptions for Seizure When Intravenous Access Is Lacking
that showed that more patients with out-of-hospital status responded to intravenous lorazepam or diazepam than placebo (p = 0.001) (2,3). In fact, these and other studies have shaped how we treat acute repetitive seizures and status epilepticus nowadays; every guideline and textbook now list benzodiazepines as the first-line therapy, and lorazepam and midazolam have Class I (level A) evidence for efficacy (4). Probably the most influential status epilepticus study since those two studies were published was the RAMPART study, which showed the noninferiority and superiority of intramuscular midazolam compared with standard treatment with intravenous lorazepam (p < 0.001) (5). Thus, while the need for benzodiazepine use in the setting of acute seizures is obvious and unquestionable, the choice of which preparation of which benzodiazepine to use in outpatient and nonvenous environments is difficult. This is because the available studies have typically compared intravenous medication utilization, which may have limited application in the field due to lack of intravenous access and other factors, including adequate training and availability of supplies. Faced with the probability of outpatient breakthrough seizures and status epilepticus, the managing physician needs to decide which nonvenous preparation of which benzodiazepine to use. Because direct evidence comparing every combination of various nonvenous treatments is scarce at best, methods to incorporate indirect comparisons need to be used to derive quality evidence. This is where the study by Arya et al. (6) comes into play. Before we discuss the results of the meta-analysis presented by these authors, we need to dive into the analytical methods that may or may not be familiar to practicing neurologists. The authors of this study were faced with the issue of comparing the efficacy of different drugs and routes of administration that needed to be reconciled when comparing studies. Thus, they used mixed (incorporating both direct and indirect comparisons) rather than fixed methods as this approach allowed them to accommodate for the possible differences between studies (7). To simplify, if one study compared intramuscular midazolam to intravenous lorazepam and another study compared intranasal midazolam to intravenous lorazepam, they were able not only to establish the relative efficacy of the two combinations of midazolam compared with intravenous lorazepam but also to compare them against each other. The results of their analyses are compelling— intramuscular and intranasal midazolam were significantly more efficacious and faster acting compared with other treatments, venous or otherwise (6). These results are important as they help providers select the best treatments for their patients from an array of rescue therapies that are in various stages of development—from the rectal diazepam gel that is currently the only Food and Drug Administration–approved therapy for the treatment of acute repetitive seizures to intranasal or intramuscular diazepam or midazolam or buccal midazolam. Other than rectal diazepam gel, those treatments are not yet approved for such use; however, they are currently available in compounding pharmacies and may soon be available in local pharmacies (8). But before we use these currently off-label therapies to develop the treatment plan for acute, repetitive, out-ofhospital seizures, we need to understand the efficacy and
136
potential risks of using benzodiazepines in this setting. While not trivial, the potential adverse events of benzodiazepines outweigh the danger of continued seizures and mainly include the risk of respiratory suppression/endotracheal intubation and hypotension in addition to less severe local reactions, for example, irritation due to intramuscular injection or effects on sinus mucosa with intranasal administration. Listing only a few potential adverse events may seem to some like sweeping the side effects of benzodiazepines under the carpet, but the risks need to be weighed against the risk of continuing seizures and status epilepticus, which we know carry ~30% risk of mortality if not rapidly controlled (9), and the risk of seizures extending into prolonged refractory status epilepticus, which has even higher rates of complications and death (10). Thus, for those patients who struggle with repetitive seizures and seizure flurries, there is a small light at the end of the long treatment tunnel—nonvenous medications other than rectal diazepam gel that are probably more efficacious and more socially acceptable. by Jerzy P. Szaflarski, MD, PhD References 1. Terry D, Paolicchi J, Karn M. Acceptance of the use of diazepam rectal gel in school and day care settings. J Child Neurol 2007;22:1135–1138. 2. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, SegAl MR, Lowenstein DH. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631–637. 3. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–798. 4. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, Laroche SM, Riviello JJ Jr, Shutter L, Sperling MR, Treiman DM, Vespa PM. Neurocritcal Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. 5. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591– 600. 6. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous medications for acute convulsive seizures: A network meta-analysis. Neurology 2015;85:1859–1868. 7. Jansen JP, Crawford B, Bergman G, Stam W. Bayesian meta-analysis of multiple treatment comparisons: An introduction to mixed treatment comparisons. Value Health 2008;11:956–964. 8. Agarwal SK, Cloyd JC. Development of benzodiazepines for outof-hospital management of seizure emergencies. Neurol Clin Pract 2015;5:80–85. 9. DeLorenzo RJ, Garnett LK, Towne AR, Waterhouse EJ, Boggs JG, Morton L, Choudhry MA, Barnes T, Ko D. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40:164–169. 10. Kilbride RD, Reynolds AS, Szaflarski JP, Hirsch LJ. Clinical outcomes following prolonged refractory status epilepticus (PRSE). Neurocrit Care 2013;18:374–385.
