大塚頌子. 日本における小児てんかん重積状態の年間発生率に関する検討：第1報. 厚生労働科学研究費補助金 効果的医療技術の確立推進臨床研究事業「小児のけいれん重積に対する薬物療法のエビデンスに関する臨床研究」平成15年度総括・分担研究報告書. 2004:13-5.
大塚頌子. 日本におけるてんかん重積状態の疫学調査：第2報. 厚生労働科学研究費補助金 効果的医療技術の確立推進臨床研究事業「小児のけいれん重積に対する薬物療法のエビデンスに関する臨床研究」平成15年度総括・分担研究報告書. 2005:9-11.
大澤真木子ら. けいれん重積症，発作頻発状態におけるミダゾラム静注の有用性について（後方視的多施設共同研究）．厚生労働科学研究費補助金事業「小児のけいれん重積に対する薬物療法のエビデンスに関する臨床研究」平成14年度総括・分担研究報告書. 2003:55-62.
山野恒一ら. 後方視的症例研究による小児のけいれん重積に対するリドカインの効果に関する研究．厚生労働科学研究費補助金事業「小児のけいれん重積に対する薬物療法のエビデンスに関する臨床研究」平成14年度総括・分担研究報告書. 2003:75-6.
R J DeLorenzo, W A Hauser, A R Towne, J G Boggs, J M Pellock, L Penberthy, L Garnett, C A Fortner, D Ko
A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia.
Neurology. 1996 Apr;46(4):1029-35.
Abstract/Text
This report presents the initial analysis of a prospective, population-based study of status epilepticus (SE) in the city of Richmond, Virginia. The incidence of SE was 41 patients per year per 100,000 population. The frequency of total SE episodes was 50 per year per 100,000 population. The mortality rate for the population was 22%, 3% for children and 26% for adults. Evaluation of the seizure types for adult and pediatric patients demonstrated that both partial and generalized SE occur with a high frequency in these populations. Based on the incidence of SE actually determined in Richmond, Virginia, we project 126,000 to 195,000 SE events with 22,200 to 42,000 deaths per year in the United States. The majority of SE patients had no history of epilepsy. These results indicate that SE is a common neurologic emergency.
B S Meldrum, R W Horton
Physiology of status epilepticus in primates.
Arch Neurol. 1973 Jan;28(1):1-9.
Abstract/Text
B S Meldrum, R A Vigouroux, J B Brierley
Systemic factors and epileptic brain damage. Prolonged seizures in paralyzed, artificially ventilated baboons.
Arch Neurol. 1973 Aug;29(2):82-7.
Abstract/Text
B K Alldredge, A M Gelb, S M Isaacs, M D Corry, F Allen, S Ulrich, M D Gottwald, N O'Neil, J M Neuhaus, M R Segal, D H Lowenstein
A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
N Engl J Med. 2001 Aug 30;345(9):631-7. doi: 10.1056/NEJMoa002141.
Abstract/Text
BACKGROUND: It is uncertain whether the administration of benzodiazepines by paramedics is an effective and safe treatment for out-of-hospital status epilepticus.
METHODS: We conducted a randomized, double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus. Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was given if needed.
RESULTS: Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent) than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as compared with the placebo group. The rates of respiratory or circulatory complications (indicated by bag valve-mask ventilation or an attempt at intubation, hypotension, or cardiac dysrhythmia) after the study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for the diazepam group, and 22.5 percent for the placebo group (P=0.08).
CONCLUSIONS: Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.
S Shinnar, A T Berg, S L Moshe, R Shinnar
How long do new-onset seizures in children last?
Ann Neurol. 2001 May;49(5):659-64.
Abstract/Text
Although there are data on the duration of seizures in patients with refractory epilepsy, little is known about the duration of seizures in nonrefractory epilepsy populations. In a prospective study, seizure duration was determined in 407 children with a first unprovoked seizure using a structured interview and review of medical and ambulance records. Analysis focused on the distribution of seizure duration and on the conditional probability that a seizure would stop once it had already lasted for a specified time. Seizures lasted > or = 5 minutes in 50% of cases, > or = 10 minutes in 29%, > or = 20 minutes in 16%, and > or = 30 minutes in 12%. Seizure duration data were best fit as the sum of two exponential distributions, one with a mean of 3.6 minutes accounting for 76% of cases and the other with a mean of 31 minutes accounting for 24% of cases. The longer a seizure lasted, the less likely it was to stop within the next few minutes. In the 182 children with 2 or more seizures, the durations of the first and second seizures were highly correlated (r = 0.395, p < 0.0001). We conclude that the distribution of seizure duration in children with a first unprovoked seizure differs markedly from that observed in patients with refractory epilepsy. A subgroup of patients are predisposed to prolonged seizures. The data suggest that, once a seizure lasts for more than 5-10 minutes, it is unlikely to stop spontaneously within the next few minutes, and intervention is therefore indicated. These findings also support the continued use of the current definition of status epilepticus as a seizure lasting for 30 minutes or longer for epidemiologic studies.
Eugen Trinka, Hannah Cock, Dale Hesdorffer, Andrea O Rossetti, Ingrid E Scheffer, Shlomo Shinnar, Simon Shorvon, Daniel H Lowenstein
A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus.
Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121. Epub 2015 Sep 4.
Abstract/Text
The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.
Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
Takashi Ichiyama, Hironori Matsufuji, Naoko Suenaga, Miki Nishikawa, Takashi Hayashi, Susumu Furukawa
[Low-dose therapy with carbamazepine for convulsions associated with mild gastroenteritis].
No To Hattatsu. 2005 Nov;37(6):493-7.
Abstract/Text
We investigated the effect of carbamazepine on convulsions associated with mild gastroenteritis. Sixteen infants and young children (aged 9 months to 3 years) who experienced repetitive convulsions associated with mild gastroenteritis were admitted to our hospital. We treated the sixteen affected patients with 5 mg/kg of carbamazepine once per day until the diarrhea had stopped. Thirteen of the sixteen patients were subjected to intravenous and/or suppository administration of diazepam (0.3-0.5 mg/kg/time), and one patient suppository administration of 0.5 mg/kg diazepam and 5.7 mg/kg phenobarbital before the administration of carbamazepine. In all patients who were given diazepam and/or phenobarbital, the convulsions recurred after the administration of these medicines. The convulsions occurred 2 to 8 times (mean, 4.1 times) before the administration of carbamazepine. Fifteen of the sixteen patients had no seizures after the administration of carbamazepine. One patient had one convulsion 15 min after the administration of carbamazepine. All patients were treated with 5 mg/kg of carbamazepine once per day until the diarrhea had stopped, i.e. for 2 to 9 days (mean, 6.4 days). Low dose therapy with carbamazepine once per day is thus effective for convulsions associated with mild gastroenteritis.
小俣卓ら．軽症胃腸炎に伴うけいれんに対するフェノバルビタールの有用性．脳と発達 2004;36:S302.
I E Leppik, A T Derivan, R W Homan, J Walker, R E Ramsay, B Patrick
Double-blind study of lorazepam and diazepam in status epilepticus.
JAMA. 1983 Mar 18;249(11):1452-4.
Abstract/Text
Lorazepam was compared with diazepam for the treatment of status epilepticus in a double-blind, randomized trial. Seventy-eight patients with 81 episodes were enrolled. Patients received one or two doses of either 4 mg of lorazepam or 10 mg of diazepam intravenously. Seizures were controlled in 89% of the episodes treated with lorazepam and in 76% treated with diazepam. The times for onset of action of the medications did not differ significantly. Adverse effects occurred in 13% of the lorazepam-treated patients and in 12% of the diazepam-treated patients. Respiratory depression and arrest, the most frequent adverse effects, were treated symptomatically; no adverse sequelae were noted.
Jason McMullan, Comilla Sasson, Arthur Pancioli, Robert Silbergleit
Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis.
Acad Emerg Med. 2010 Jun;17(6):575-82. doi: 10.1111/j.1553-2712.2010.00751.x.
Abstract/Text
BACKGROUND: Rapid treatment of status epilepticus (SE) is associated with better outcomes. Diazepam and midazolam are commonly used, but the optimal agent and administration route is unclear.
OBJECTIVES: The objective was to determine by systematic review if nonintravenous (non-IV) midazolam is as effective as diazepam, by any route, in terminating SE seizures in children and adults. Time to seizure cessation and respiratory complications was examined.
METHODS: We performed a search of PubMed, Web of Knowledge, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, American College of Physicians Journal Club, Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, and International Pharmaceutical Abstracts for studies published January 1, 1950, through July 4, 2009. English language quasi-experimental or randomized controlled trials comparing midazolam and diazepam as first-line treatment for SE, and meeting the Consolidated Standards of Reporting Trials (CONSORT)-based quality measures, were eligible. Two reviewers independently screened studies for inclusion and extracted outcomes data. Administration routes were stratified as non-IV (buccal, intranasal, intramuscular, rectal) or IV. Fixed-effects models generated pooled statistics.
RESULTS: Six studies with 774 subjects were included. For seizure cessation, midazolam, by any route, was superior to diazepam, by any route (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.27 to 1.82). Non-IV midazolam is as effective as IV diazepam (RR = 0.79; 95% CI = 0.19 to 3.36), and buccal midazolam is superior to rectal diazepam in achieving seizure control (RR = 1.54; 95% CI = 1.29 to 1.85). Midazolam was administered faster than diazepam (mean difference = 2.46 minutes; 95% CI = 1.52 to 3.39 minutes) and had similar times between drug administration and seizure cessation. Respiratory complications requiring intervention were similar, regardless of administration route (RR = 1.49; 95% CI = 0.25 to 8.72).
CONCLUSIONS: Non-IV midazolam, compared to non-IV or IV diazepam, is safe and effective in treating SE. Comparison to lorazepam, evaluation in adults, and prospective confirmation of safety and efficacy is needed.
(c) 2010 by the Society for Academic Emergency Medicine.
James M Chamberlain, Pamela Okada, Maija Holsti, Prashant Mahajan, Kathleen M Brown, Cheryl Vance, Victor Gonzalez, Richard Lichenstein, Rachel Stanley, David C Brousseau, Joseph Grubenhoff, Roger Zemek, David W Johnson, Traci E Clemons, Jill Baren, Pediatric Emergency Care Applied Research Network (PECARN)
Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial.
JAMA. 2014 Apr 23-30;311(16):1652-60. doi: 10.1001/jama.2014.2625.
Abstract/Text
IMPORTANCE: Benzodiazepines are considered first-line therapy for pediatric status epilepticus. Some studies suggest that lorazepam may be more effective or safer than diazepam, but lorazepam is not Food and Drug Administration approved for this indication.
OBJECTIVE: To test the hypothesis that lorazepam has better efficacy and safety than diazepam for treating pediatric status epilepticus.
DESIGN, SETTING, AND PARTICIPANTS: This double-blind, randomized clinical trial was conducted from March 1, 2008, to March 14, 2012. Patients aged 3 months to younger than 18 years with convulsive status epilepticus presenting to 1 of 11 US academic pediatric emergency departments were eligible. There were 273 patients; 140 randomized to diazepam and 133 to lorazepam.
INTERVENTIONS: Patients received either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam intravenously, with half this dose repeated at 5 minutes if necessary. If status epilepticus continued at 12 minutes, fosphenytoin was administered.
MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was cessation of status epilepticus by 10 minutes without recurrence within 30 minutes. The primary safety outcome was the performance of assisted ventilation. Secondary outcomes included rates of seizure recurrence and sedation and times to cessation of status epilepticus and return to baseline mental status. Outcomes were measured 4 hours after study medication administration.
RESULTS: Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, -11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, -9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%).
CONCLUSIONS AND RELEVANCE: Among pediatric patients with convulsive status epilepticus, treatment with lorazepam did not result in improved efficacy or safety compared with diazepam. These findings do not support the preferential use of lorazepam for this condition.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621478.
Geeta Gathwala, Mayank Goel, Jagjit Singh, Kundan Mittal
Intravenous diazepam, midazolam and lorazepam in acute seizure control.
Indian J Pediatr. 2012 Mar;79(3):327-32. doi: 10.1007/s12098-011-0505-y. Epub 2011 Jun 29.
Abstract/Text
OBJECTIVE: To evaluate the safety and efficacy of three benzodiazepine drugs: Lorazepam, Midazolam and Diazepam, when given parenterally in the control of acute seizure.
METHODS: One hundred and twenty children of either sex in the age group 6 month to 14 years brought convulsing to the pediatric emergency services, were enrolled in the study. These were randomised to three equal groups of 40 patients each; Group A-received diazepam, Group B-received midazolam, Group C-received lorazepam. End of seizure episode (clinically) was defined as cessation of visible epileptic phenomenon or return of purposeful response to external stimuli within 15 min of drug administration. A stopwatch was used to measure various time intervals accurately. The patient's vitals were monitored and recorded in a predesigned performa. The primary outcome was the time to seizure cessation and secondary outcome was the side effects of the drugs. Data obtained was analysed statistically using student's t-test and chi-square test.
RESULTS: Mean duration to clinical seizure cessation was comparable among the three groups. For diazepam group it was 84.94 ± 38.56 s, for midazolam group it was 92.69 ± 25.97 s, for lorazepam group it was 91.12 ± 23.58 s. Number of patients with any abnormality in seizure cessation were significantly higher in diazepam group [11/40 (27.5%)] when compared to the midazolam [4/40 (10%)] and lorazepam group [2/40 (5%)]. Number of patients requiring 2nd dose to control seizures was significantly higher [4/40 (10%)] in diazepam group when compared to lorazepam group [0/40 (0%)] but diazepam and midazolam and midazolam and lorazepam were comparable in this aspect.All the three drugs were comparable in terms of side effects except excessive somnolence which was significantly higher in diazepam group.
CONCLUSIONS: All the three groups were comparable in terms of time to clinical seizure cessation, seizure recurrence and uncontrolled seizures after drug administration. However, number of patients requiring second dose to control seizures were significantly higher in diazepam group when compared to lorazepam group. Excessive somnolence and sedation occurred more frequently with diazepam.
R E Garr, R E Appleton, W J Robson, E M Molyneux
Children presenting with convulsions (including status epilepticus) to a paediatric accident and emergency department: an audit of a treatment protocol.
Dev Med Child Neurol. 1999 Jan;41(1):44-7.
Abstract/Text
All children who presented in a convulsion, including convulsive status epilepticus, to the accident and emergency department over a 12-month period and who required treatment, were reviewed retrospectively to identify the effectiveness and safety of a specific treatment protocol. This protocol recommends the initial use of one, or if necessary, two doses of rectal or intravenous diazepam (0.4 mg/kg) followed by the simultaneous administration of phenytoin (18 mg/kg) and rectal paraldehyde (0.4 mL/kg), with instructions for maximum doses and timings of administration. Eighty-one evaluable children (52 male) were audited. The mean age of the study population was 4.1 (range 0.1 to 14.9) years. Overall, the presenting convulsion was successfully terminated in 76 children (94%) within the accident and emergency department. In 69 children (85% of the entire study population) this was after a single dose of diazepam (rectal in 41 and intravenous in 28). In only an additional two children did the presenting convulsion stop after a second dose of diazepam. In five of the 10 children (50%) who received paraldehyde and phenytoin as a combination, the convulsion stopped. Nine patients (11%) required admission to the intensive-care unit, five because of persisting convulsive activity, and four because of respiratory depression. The results of this retrospective audit suggest that the current treatment protocol appears to be effective and relatively safe in treating acute convulsions, including convulsive status epilepticus. The audit is to be repeated prospectively to either confirm or refute these findings before recommending any changes to the protocol.
Shin-Ichiro Hamano, Kenji Sugai, Masuo Miki, Toshiyuki Tabata, Takako Fukuyama, Makiko Osawa
Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus.
J Neurol Sci. 2019 Jan 15;396:150-158. doi: 10.1016/j.jns.2018.09.035. Epub 2018 Oct 4.
Abstract/Text
BACKGROUND: No dosing regimen has been established for the initial treatment of pediatric status epilepticus with intravenous midazolam. We therefore evaluated the efficacy, safety, and pharmacokinetics of bolus and continuous midazolam infusion.
METHODS: This open-label, prospective, multicenter study involved 34 Japanese children with status epilepticus unresponsive to diazepam. An initial bolus of 0.15 mg/kg midazolam was given, with additional doses of 0.1-0.3 mg/kg up to a cumulative dose of 0.6 mg/kg. A continuous infusion was initiated at 0.1 mg/kg/h (maximum 0.4 mg/kg/h) for patients at high risk of recurrence or in whom seizure reduction was achieved, and continued for 24 h after seizure cessation. Seizure cessation was assessed based on clinical observation (disappearance of motor symptoms regardless of recovery of consciousness), rather than the disappearance of electroencephalography abnormalities.
RESULTS: The seizure cessation rate with bolus midazolam was 88%. The cumulative dose was ≤0.3 mg/kg in 90% of patients who responded to bolus administration. Adverse events were observed in three patients; one had mild respiratory depression that required supplemental oxygen and bag-valve-mask ventilation. Elimination half-life was 0.999 ± 0.241 h in seven patients. Total body clearance ranged from 423 to 1220 mL/h/kg in older children but was notably higher in a 10-month-old infant (2010 mL/h/kg).
CONCLUSIONS: The efficacy and safety of midazolam were demonstrated in children with status epilepticus, suggesting that intravenous midazolam is suitable as first-line treatment.
Copyright © 2018 Elsevier B.V. All rights reserved.
Bibek Talukdar, Biswaroop Chakrabarty
Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial.
Brain Dev. 2009 Nov;31(10):744-9. doi: 10.1016/j.braindev.2008.11.006. Epub 2008 Dec 27.
Abstract/Text
A study was done to examine the efficacy of buccal midazolam in controlling convulsion in children by comparing it with intravenous diazepam, a standard mode of treating convulsions. One hundred and twenty cases presenting with convulsions to emergency were treated randomly with either buccal midazolam (in a dose of 0.2mg/kg) or intravenous diazepam (in a dose of 0.3mg/kg). Partial seizures, generalized tonic, clonic and tonic-clonic convulsions were included irrespective of duration or cause. One episode per child only was included. The frequency of overall control of convulsive episodes within 5 min were 85% and 93.3% in buccal midazolam and intravenous diazepam groups, respectively; the difference was, however, not statistically significant (p=0.142). The mean time needed for controlling the convulsive episodes after administration of the drugs was significantly less with intravenous diazepam (p=<0.001). The mean time for initiation of treatment was significantly less with buccal midazolam (p=<0.001). The mean time for controlling the convulsive episodes after noticing these first were significantly less with buccal midazolam than with intravenous diazepam (p=0.004) that is likely to be due to longer time needed for initiating treatment with intravenous diazepam in preparing the injection and establishing an IV line. There was no significant side effect in both the groups. The findings suggest that buccal midazolam can be used as an alternative to intravenous diazepam especially when getting an IV line becomes difficult. In situations where establishing an IV line is a problem, buccal midazolam may be the first choice.
C Remy, N Jourdil, D Villemain, P Favel, P Genton
Intrarectal diazepam in epileptic adults.
Epilepsia. 1992 Mar-Apr;33(2):353-8.
Abstract/Text
Intrarectally (i.r.) administered diazepam (DZP) solution at doses of 20 and 30 mg in the treatment of serial seizures was studied in 39 adult patients with refractory partial epilepsy. Patients were randomly distributed into two groups (20 mg, n = 21; 30 mg, n = 18). Plasma levels of DZP were assessed over 24 h following i.r. injection. The efficacy of i.r. DZP in the treatment of serial seizures in adults was confirmed; onset of effect was noted approximately 10 min after the injection, and the effective dose was 0.50 mg/kg. Tolerance and acceptability were good. Intrarectal injection of DZP can be performed even by unskilled personnel and may be recommended in patients with serial seizures in the hope of preventing development of status epilepticus.
R A Dieckmann
Rectal diazepam for prehospital pediatric status epilepticus.
Ann Emerg Med. 1994 Feb;23(2):216-24.
Abstract/Text
STUDY OBJECTIVES: To compare the feasibility, effectiveness, and safety of rectal diazepam and intravenous diazepam in the treatment of pediatric prehospital status epilepticus.
DESIGN AND SETTING: Retrospective analysis of a 30-month consecutive sample of ambulance-transported children in a large urban emergency medical service region.
TYPE OF PARTICIPANTS: Study group included 324 patients with seizure who were less than 18 years of age; 36 had status epilepticus, of whom 16 received rectal diazepam and 15 received IV diazepam.
INTERVENTIONS: For children with status epilepticus, paramedics administered the 5-mg/mL IV solution of diazepam by one of two routes: rectally either through a 5F feeding tube with an attached syringe or by lubricated tuberculin syringe inserted 4 to 5 cm into the rectum at a one-time dose of 0.2 to 0.5 mg/kg or intravenously using a one-time dose of 0.1 to 0.3 mg/kg. Cardiopulmonary status was carefully monitored in the field and emergency department.
MEASUREMENTS AND MAIN RESULTS: Thirteen of 16 children (81%) who received rectal diazepam stopped seizing after a single dose ranging from 0.16 to 0.57 mg/kg. Convulsions recurred before arrival at the ED in four of the 13 (30.8%). All of three patients who did not respond to rectal diazepam initially were 3 to 5 years old and had serious underlying comorbidity; two required endotracheal intubation in the ED and multiple anticonvulsants to terminate the seizure. No child treated with rectal diazepam required prehospital endotracheal intubation. All children who received IV diazepam stopped seizing after one dose ranging from 0.04 to 0.33 mg/kg. Convulsions recurred before arrival at the ED in nine of 15 children (60%); two required prehospital endotracheal intubation for profound respiratory depression.
CONCLUSION: Rectal diazepam is a simple, effective, and safe method of prehospital management of pediatric status epilepticus. Compared with IV diazepam, rectal diazepam is easier to administer, especially in infants and toddlers; is equally efficacious; and is less likely to produce respiratory depression. Although respiratory depression is rare with rectal diazepam, prehospital personnel must be prepared to provide definitive respiratory support. Short duration of action is an important limitation of both treatments.
R C Scott, F M Besag, B G Neville
Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial.
Lancet. 1999 Feb 20;353(9153):623-6. doi: 10.1016/S0140-6736(98)06425-3.
Abstract/Text
BACKGROUND: Convulsive status epilepticus is the most common neurological medical emergency and has high morbidity and mortality. Early treatment before admission to hospital is best with an effective medication that can be administered safely. We aimed to find out whether there are differences in efficacy and adverse events between buccal administration of liquid midazolam and rectal administration of liquid diazepam in the acute treatment of seizures.
METHODS: At a residential school with on-site medical facilities 42 young people with severe epilepsy were enrolled. Continuous seizures of more than 5 min duration were randomly treated with buccal midazolam or rectal diazepam. If the seizure did not stop within 10 min additional medication chosen by the attending physician was administered. We monitored oxygen saturation and blood pressure for 30 min after treatment. The main outcome measures were efficacy, time from arrival of the nurse to drug administration, time from drug administration to end of seizure, and incidence of adverse cardiorespiratory events.
FINDINGS: Buccal midazolam was used to treat 40 seizures in 14 students, and rectal diazepam 39 seizures in 14 students. Midazolam stopped 30 (75%) of 40 seizures and diazepam 23 (59%) of 39 (p=0.16). The median time from arrival of the nurse to administration of medication was 2 min. Time from administration to end of seizure did not differ significantly between the two treatments. No clinically important adverse cardiorespiratory events were identified in the two groups. Buccal midazolam was universally acceptable to the nursing and care staff.
INTERPRETATION: Buccal midazolam is at least as effective as rectal diazepam in the acute treatment of seizures. Administration via the mouth is more socially acceptable and convenient and may become the preferred treatment for long seizures that occur outside hospital.
Tunç Fişgin, Yavuz Gurer, Tahsin Teziç, Nesrin Senbil, Pelin Zorlu, Cetin Okuyaz, Deniz Akgün
Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study.
J Child Neurol. 2002 Feb;17(2):123-6.
Abstract/Text
In this study, the effects and side effects of rectal diazepam and intranasal midazolam were compared in the treatment of acute convulsions in children to develop a practical and safe treatment protocol. In the diazepam group, the seizures of 13 (60%) patients terminated in 10 minutes; however, 9 (40%) patients did not respond. In the midazolam group, 20 (87%) patients responded in 10 minutes, but 3 (13%) patients did not respond. Regarding the anticonvulsant effect, midazolam was found to be more effective than diazepam, and the difference was statistically significant (P < .05). The necessity of a second drug for the seizures that did not stop with the first drug was higher in the diazepam group than the midazolam group, and the difference was statistically significant (P < .05). We conclude that as an antiepileptic agent, intranasal midazolam is more effective than rectal diazepam. After administration, we did not observe any serious complications. Further investigations are necessary; however, intranasal administration is easy, so if the nasal drop and spray forms used in some European countries and the United States are available worldwide, it will be very useful for physicians in the emergency room.
J M Chamberlain, M A Altieri, C Futterman, G M Young, D W Ochsenschlager, Y Waisman
A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children.
Pediatr Emerg Care. 1997 Apr;13(2):92-4.
Abstract/Text
OBJECTIVE: To compare treatment of ongoing seizures using intramuscular (IM) midazolam versus intravenous (IV) diazepam.
DESIGN: Controlled clinical trial.
PATIENTS: Children with motor seizures of at least 10 minutes' duration.
MAIN OUTCOME MEASURES: Time to cessation of seizures.
RESULTS: Twenty-four patients were enrolled (13 midazolam, 11 diazepam). Initial treatment with either midazolam or diazepam was successful in 22 of the 24 patients. One patient in each group failed therapy and eventually required endotracheal intubation and general anesthesia for convulsive status epilepticus lasting more than one hour. Patients in the midazolam group received medication sooner (3.3 +/- 2.0 vs 7.8 +/- 3.2 minutes, P = 0.001) and had more rapid cessation of their seizures (7.8 +/- 4.1 vs 11.2 +/- 3.6, P = 0.047) than patients randomized to receive diazepam.
CONCLUSIONS: IM midazolam is an effective anticonvulsant for children with motor seizures. Compared to IV diazepam, IM midazolam results in more rapid cessation of seizures because of more rapid administration. The IM route of administration may be particularly useful in physicians' offices, in the prehospital setting, and for children with difficult IV access.
K Minagawa, H Miura, S Mizuno, H Shirai
Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions.
Brain Dev. 1986;8(1):53-9.
Abstract/Text
To determine the optimum dosage schedule for intermittent rectal diazepam in suppository form for the prevention of recurrent febrile convulsions, we studied the pharmacokinetics of diazepam administered in repeated rectal doses. The plasma concentration-time data for diazepam on twice repeated rectal dosing with 0.5 mg/kg at 8-hour intervals in six infants showed that therapeutic plasma levels could be attained within 30 minutes and maintained for the first 24 hours. Most of the observed plasma diazepam levels were found to be within +/- one standard deviation of the values calculated from the pharmacokinetic parameters in six other infants with single rectal dosing. Computer-simulated plasma level profile suggested that plasma diazepam levels may reach the toxic range after administration of five or more doses. Twice repeated rectal dosing with 0.5 mg/kg of diazepam in suppository form at 8-hour intervals during the febrile period may be a rational approach for the prevention of recurrent febrile convulsions.
D M Treiman, P D Meyers, N Y Walton, J F Collins, C Colling, A J Rowan, A Handforth, E Faught, V P Calabrese, B M Uthman, R E Ramsay, M B Mamdani
A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
N Engl J Med. 1998 Sep 17;339(12):792-8. doi: 10.1056/NEJM199809173391202.
Abstract/Text
BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled.
RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days.
CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.
James M Chamberlain, Jaideep Kapur, Shlomo Shinnar, Jordan Elm, Maija Holsti, Lynn Babcock, Alex Rogers, William Barsan, James Cloyd, Daniel Lowenstein, Thomas P Bleck, Robin Conwit, Caitlyn Meinzer, Hannah Cock, Nathan B Fountain, Ellen Underwood, Jason T Connor, Robert Silbergleit, Neurological Emergencies Treatment Trials, Pediatric Emergency Care Applied Research Network investigators
Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
Lancet. 2020 Apr 11;395(10231):1217-1224. doi: 10.1016/S0140-6736(20)30611-5. Epub 2020 Mar 20.
Abstract/Text
BACKGROUND: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.
METHODS: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.
FINDINGS: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.
INTERPRETATION: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.
FUNDING: National Institute of Neurological Disorders and Stroke, National Institutes of Health.
Copyright © 2020 Elsevier Ltd. All rights reserved.
D M Shaner, S A McCurdy, M O Herring, A J Gabor
Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin.
Neurology. 1988 Feb;38(2):202-7.
Abstract/Text
In a randomized, nonblinded clinical trial, 36 consecutive patients with generalized convulsive status epilepticus were treated with either combination diazepam and phenytoin (DZ/DPH) or phenobarbital (PB). Phenytoin was added to the PB regimen if seizures persisted for 10 minutes after beginning therapy. The cumulative convulsion time (total time spent in active convulsive movements) was shorter for the PB group than for the DZ/DPH group (median, 5 versus 9 minutes, p less than 0.06); the response latency (elapsed time from initiation of therapy to the end of the last convulsion) was also shorter for the PB group (median, 5.5 versus 15 minutes, p less than 0.10). The median cumulative convulsion time is between 0 and 14 minutes shorter for the PB regimen than for the DZ/DPH regimen (95% confidence interval). Similarly, the median response latency for the PB regimen is between 1 minute longer and 20 minutes shorter than that for the DZ/DPH regimen (95% confidence interval). The frequencies of intubation, hypotension, and arrhythmias were similar in the two groups. Eleven of 18 patients in the PB group responded to phenobarbital monotherapy. We conclude that the PB regimen is rapidly effective, comparable in safety, and enjoys certain practical advantages in comparison with the DZ/DPH regimen.
R J DeLorenzo, E J Waterhouse, A R Towne, J G Boggs, D Ko, G A DeLorenzo, A Brown, L Garnett
Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus.
Epilepsia. 1998 Aug;39(8):833-40.
Abstract/Text
PURPOSE: Convulsive status epilepticus (CSE) is a major medical and neurological emergency that is associated with significant morbidity and mortality. Despite this high morbidity and mortality, most acute care facilities in the United States cannot evaluate patients with EEG monitoring during or immediately after SE. The present study was initiated to determine whether control of CSE by standard treatment protocols was sufficient to terminate electrographic seizures.
METHODS: One hundred sixty-four prospective patients were evaluated at the Medical College of Virginia/VCU Status Epilepticus Program. Continuous EEG monitoring was performed for a minimum of 24 h after clinical control of CSE. SE and seizure types were defined as described previously. A standardized data form entry system was compiled for each patient and used to evaluate the data collected.
RESULTS: After CSE was controlled, continuous EEG monitoring demonstrated that 52% of the patients had no after-SE ictal discharges (ASIDS) and manifested EEG patterns of generalized slowing, attenuation, periodic lateralizing epileptiform discharges (PLEDS), focal slowing, and/or burst suppression. The remaining 48% demonstrated persistent electrographic seizures. More than 14% of the patients manifested nonconvulsive SE (NCSE) predominantly of the complex partial NCSE seizure (CPS) type (2). These patients were comatose and showed no overt clinical signs of convulsive activity. Clinical detection of NCSE in these patients would not have been possible with routine neurological evaluations without use of EEG monitoring. The clinical presentation, mortality, morbidity, and demographic information on this population are reported.
CONCLUSIONS: Our results demonstrate that EEG monitoring after treatment of CSE is essential to recognition of persistent electrographic seizures and NCSE unresponsive to routine therapeutic management of CSE. These findings also suggest that EEG monitoring immediately after control of CSE is an important diagnostic test to guide treatment plans and to evaluate prognosis in the management of SE.
H Meierkord, B Will, D Fish, S Shorvon
The clinical features and prognosis of pseudoseizures diagnosed using video-EEG telemetry.
Neurology. 1991 Oct;41(10):1643-6.
Abstract/Text
A total of 110 patients underwent diagnostic evaluation for attacks of uncertain origin by means of video-EEG telemetry and had a diagnosis of pseudoseizures confirmed. Eighty-six patients (78%) were female, mean age of onset 25 years, and mean duration of attacks was 3 years. Many of the patients had erroneously been thought to be suffering from epilepsy. The attacks could be divided into two broad categories: attacks of collapse (one-third) and attacks with prominent motor activity (two-thirds). In some patients, the attacks were associated with incontinence and injury. The differential diagnosis and clinical features of the attacks are described. Additional psychiatric features were present in 52 (47%) patients. Follow-up (for a median 5 years; range, 1 to 14 years) showed that 40% of these patients stopped having pseudoseizures. This favorable outcome was associated with being female, leading an independent life, a formal psychological approach to therapy and counseling, and the absence of coexisting epilepsy, but not with the duration of pseudoepilepsy, prior episodes of pseudostatus, the coexistence of overt psychiatric disease, or the clinical features of the attacks.
Martin Holtkamp, Jalal Othman, Katharina Buchheim, Hartmut Meierkord
Diagnosis of psychogenic nonepileptic status epilepticus in the emergency setting.
Neurology. 2006 Jun 13;66(11):1727-9. doi: 10.1212/01.wnl.0000218299.15988.9d.
Abstract/Text
Episodes of psychogenic nonepileptic status epilepticus (PNESE) characterized by pronounced generalized motor features were compared with those of refractory generalized convulsive status epilepticus. Patients with PNESE were younger, had port systems implanted more frequently, received higher doses of benzodiazepines until seizure termination or respiratory failure, and had lower serum creatine kinase levels.
