Intranasal midazolam or lorazepam for acute seizure treatment - abstracted references:
(2000). "Intranasal midazolam effectively treats febrile seizures in children." Bmj 321(7253): D.
Ahmad, S., J. C. Ellis, et al. (2006). "Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial." Lancet 367(9522): 1591-7.
BACKGROUND: In sub-Saharan Africa, rectal diazepam or intramuscular paraldehyde are commonly used as first-line anticonvulsant agents in the emergency treatment of seizures in children. These treatments can be expensive and sometimes toxic. We aimed to assess a drug and delivery system that is potentially more effective, safer, and easier to administer than those presently in use. METHODS: We did an open randomised trial in a paediatric emergency department of a tertiary hospital in Malawi. 160 children aged over 2 months with seizures persisting for more than 5 min were randomly assigned to receive either intranasal lorazepam (100 microg/kg, n=80) or intramuscular paraldehyde (0.2 mL/kg, n=80). The primary outcome measure was whether the presenting seizure stopped with one dose of assigned anticonvulsant agent within 10 min of administration. The primary analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00116064. FINDINGS: Intranasal lorazepam stopped convulsions within 10 min in 60 (75%) episodes treated (absolute risk 0.75, 95% CI 0.64-0.84), and intramuscular paraldehyde in 49 (61.3%; absolute risk 0.61, 95% CI 0.49-0.72). No clinically important cardiorespiratory events were seen in either group (95% binomial exact CI 0-4.5%), and all children finished the trial. INTERPRETATION: Intranasal lorazepam is effective, safe, and provides a less invasive alternative to intramuscular paraldehyde in children with protracted convulsions. The ease of use of this drug makes it an attractive and preferable prehospital treatment option.
Anderson, M., P. Tambe, et al. (2012). "Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers." Eur J Clin Pharmacol 68(2): 155-159.
PURPOSE: To investigate the plasma-concentration profile of lorazepam when administered by the intranasal and buccal routes to determine their utility for the treatment of prolonged seizures. METHODS: On two occasions separated by at least 7 days washout, 12 healthy adult male volunteers received 2 mg of lorazepam via the intranasal or buccal route. Blood samples were collected at time periods from 0 to 48 h, and pharmacokinetic parameters were determined. RESULTS: Lorazepam was well absorbed from both administration routes; however, there was a more pronounced lag phase with the buccal route and absorption was more rapid from the intranasal route. CONCLUSIONS: Intranasal lorazepam has more favourable pharmacokinetics than buccal lorazepam when considering the need for the rapid blood concentrations required for seizure termination. Further clinical evaluation of this route is required.
Armijo, J. A., J. L. Herranz, et al. (2004). "[Intranasal and buccal midazolam in the treatment of acute seizures]." Rev Neurol 38(5): 458-68.
AIMS. There are several personal and social problems involved in the administration of rectal diazepam that make it unsuitable for use in public places and by non medical workers, in children and especially in teenagers and adults. Intranasal and oral midazolam could be an alternative to rectal diazepam. We review the efficacy and safety of these ways of administering midazolam, which is already used in some countries as a sedative and as an anticonvulsive drug, despite the fact that it has not yet received authorisation. DEVELOPMENT. Intranasal midazolam (INM) was first used as a sedative in dental extractions, echocardiography, endoscopies or surgery, especially in children. After proving its efficacy electroencephalographically in patients with seizures, it started to be used to interrupt acute seizures. In three randomised trials, the efficacy of intranasal and oral midazolam in hospitalised patients was similar to, and even higher than, that of intravenous or rectal diazepam, with a similar speed of action and safety; no studies have been conducted, however, in the extra hospital milieu and its risk of respiratory depression may be like that of other benzodiazepines. One of the problems of using the parenteral solution for intranasal administration is the irritation that is produced by its acidic pH and the relatively large volume that has to be administered. These problems could be reduced by using aerosols containing a solution of midazolam in cyclodextrin, which accomplishes a greater concentration with a pH that is less acidic. Oral administration can be used in patients with nasal secretions or intense movements of the head. CONCLUSIONS. Intranasal or oral midazolam can improve the treatment of acute seizures in the hospital milieu and, more especially, in the extra hospital milieu when patients are attended by non medical staff. There is a need, however, for trials that prove its efficacy and safety in this situation.
Arya, R., S. Gulati, et al. (2011). "Intranasal versus intravenous lorazepam for control of acute seizures in children: A randomized open-label study." Epilepsia.
Purpose: Intravenous lorazepam is considered the drug of first choice for control of acute convulsive seizures. However, resource or personnel constraints necessitate the study of alternative routes and medications. This study compared the efficacy and adverse effects of intranasal versus intravenous lorazepam in children aged 6-14 years who presented with acute seizures. Methods: This was a randomized open-label study conducted at an Indian hospital from August 2008 to April 2009. One hundred forty-one consecutive children aged 6-14 years who presented convulsing to the emergency room were included. After stabilization, the children were randomized to receive either intravenous or intranasal lorazepam (0.1 mg/kg, maximum 4 mg). The primary outcome measure was clinical seizure remission within 10 min of drug administration. The study was registered with clinicaltrials.gov (NCT00735527). Key Findings: Seventy patients were randomized to receive intravenous and 71 to receive intranasal lorazepam. The patients in the two groups were comparable at baseline. Clinical seizure remission within 10 min of drug administration was found in 80% of the intravenous group as compared to 83.1% of intranasal group. The lower limit of 95% confidence interval for effect size was approximately -9.7%, with an a priori cutoff for noninferiority of -10%. Significance: Intranasal administration of lorazepam is not found to be inferior to intravenous administration for termination of acute convulsive seizures in children.
Bancke, L. L., H. A. Dworak, et al. (2015). "Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers." Epilepsia 56(11): 1723-1731.
OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults. METHODS: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded. RESULTS: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (Cmax ), with all doses demonstrating rapid median time to Cmax (Tmax ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation. SIGNIFICANCE: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.
Beran, R. G. (2008). "An alternative perspective on the management of status epilepticus." Epilepsy Behav.
The definition of status epilepticus (SE) has been reduced from 30minutes to 5minutes and this article questions if treatment should not be offered before reaching that window. After provision of first aid, benzodiazepines (BDZ) are the initial form of intervention, with either nasal or buccal midazolam being favored for nonprofessionals. Proper patient supervision, including admission to an intensive care unit for more difficult patients, is endorsed, and the need to warn nonprofessionals of the potential risk of respiratory depression is imperative. The article criticizes the use of phenytoin as the antiepileptic medication (AEM) with which to load patients, as it is no longer a first-line AEM, and argues in favor of using a first-line AEM such as valproate or carbamazepine, or preferably the AEM that previously proved efficacious in a patient with known epilepsy who was noncompliant. Alternative routes of administration of AEMs are discussed, and the use of blood level monitoring, as an adjunct to management, to protect against further episodes of SE, is supported. Touched on in this article are the use of some of the newer AEMs in the management of SE and exploration of treatment strategies that acknowledge that treatment must also include patient education that incorporates techniques to enhance compliance.
Bhattacharyya, Kalra, et al. (2006). "Intranasal midazolam vs rectal diazepam in acute childhood seizures." Pediatr Neurol 34(5): 355-9.
One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.
Brigo, F., R. Nardone, et al. (2015). "Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis." Epilepsy Behav.
BACKGROUND: Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment of early SE instead of intravenous applications. The aim of this review was to determine if nonintravenous MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE seizures in children and adults. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for randomized controlled trials comparing non-IV MDZ with DZP (by any route) in patients (all ages) with early SE defined either as seizures lasting >5min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15min of drug administration, serious adverse effects, time interval to drug administration, and time from arrival in the emergency department to seizure cessation. Outcomes were assessed using a random-effects Mantel-Haenszel meta-analysis to calculate risk ratio (RR), odds ratio (OR) and mean difference with 95% confidence intervals (95% CIs). RESULTS: Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure) were included. One thousand five hundred seventy-three patients were younger than 16years. For seizure cessation, non-IV MDZ was as effective as DZP (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in adverse effects was found between non-IM MDZ and DZP by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (338 seizures; mean difference: -3.67min; 95% CIs: -5.98 to -1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: -3.56min; 95% CIs: -5.00 to -2.11). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (812 seizures; mean difference: 0.56min; 95% CIs: 0.15 to 0.98min). Not all studies reported information on time intervals. Comparison by each way of administration failed to find a significant difference in terms of clinical seizure cessation and occurrence of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11 to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP. CONCLUSIONS: Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and probably also in adults. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily result in higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have a higher efficacy than rectal DZP in seizure control. This article is part of a Special Issue entitled Status Epilepticus.
Caron, E., C. E. Wheless, et al. (2015). "The charges for seizures in the pediatric emergency room: a single center study." Pediatr Neurol 52(5): 517-520.BACKGROUND: The direct charges for emergency department visits resulting from recurrent seizures are significant, and home intervention with abortive medications can be cost-saving. Over a 1-year period, we evaluated children with seizures who were seen in the emergency department, stabilized, and released. The information is necessary to assess the pharmacoeconomic advantages of at-home interventions for seizure emergencies. METHODS: We did a retrospective chart review of 90 patients and divided them into febrile versus nonfebrile seizures and existing versus new-onset seizure disorder. The hospital accounting department performed a charge analysis. RESULTS AND CONCLUSION: The total charges for all 90 patients treated for seizures in the emergency department were $219,945. The minimum was $370, for a patient with no history of febrile seizures. The maximum was $17,126, for a patient with a nonfebrile seizure and a history of seizures. This information allows a comparison with the cost of preventive medications, such as diazepam rectal gel or intranasal midazolam.
de Haan, G. J., P. van der Geest, et al. (2010). "A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations." Epilepsia 51(3): 478-482.
Rectal diazepam is established as a standard rescue or emergency treatment for seizure or status epilepticus; however, the rectal route of administration has not been universally accepted. To determine if an alternative route of administration of a benzodiazepine was equally effective, we compared a novel midazolam HCl concentrated nasal spray (MDZ-n) with diazepam rectal solution (DZP-r) in the treatment of prolonged seizures in a residential epilepsy center. In 21 adult patients with medically refractory epilepsy, 124 seizure-exacerbations were treated by their caregivers, alternatively with 10 mg DZP-r and 10 mg concentrated MDZ-n, two or three treatments with each medication for each patient. No difference was demonstrated in efficacy or time to effect between the two drugs. Common treatment emerging adverse effects were drowsiness for both drugs in more than 50% of the administrations, and short-lasting local irritation after 29% of MDZ-n. No severe adverse events occurred. The nasal spray was preferred to the rectal solution by 16 of 21 caregivers and patients conjointly. MDZ-n was equal to DZP-r with respect to efficacy and side effects in the suppression of seizure exacerbations. The majority of patients and caregivers preferred the nasal spray over the rectal formulation.
Fisgin, T., Y. Gurer, et al. (2000). "Nasal midazolam effects on childhood acute seizures." J Child Neurol 15(12): 833-5.
Sixteen children, aged from 2 months to 14 years, with a diagnosis of acute seizures and seen at Dr. Sami Ulus Child Health and Disease Center, were included in this study. Midazolam (5 mg/mL) 0.2 mg/kg was administered intranasally in 30 seconds by an injector. The heart rate, respiratory rate, blood pressure, and oxygen saturation were recorded at 0, 5, and 10 minutes after administration. The seizures of three (18.7%) patients terminated within 1 minute, of seven (43.7%) patients in 1 to 2 minutes, and of three (18.7%) patients in 2 to 5 minutes. However, three (18.7%) patients did not respond to treatment. As a result, it was concluded that intranasal midazolam administration is easy and effective. The half-life of midazolam is shorter than diazepam, and midazolam has fewer complications when compared with diazepam. It is easier to use in nasal drop and spray forms.
Fisgin, T., Y. Gurer, et al. (2002). "Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study." J Child Neurol 17(2): 123-6.
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.
Fujita, H., H. Muranaka, et al. (2001). "[Intranasal midazolam for prevention of status epilepticus]." No To Hattatsu 33(3): 283-4.
Gilat, Kadar, et al. (2005). "Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: an electrographic, behavioral, and histological study in freely moving rats." Toxicol Appl Pharmacol 209(1): 74-85.
Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 +/- 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 +/- 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.
Gilat, E., M. Goldman, et al. (2003). "Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig." Arch Toxicol 77(3): 167-72.
Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2x LD(50,) 56 micro g/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4 (1 mg/kg im) were administered. Within 3-8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389+/-181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949+/-466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216+/-185 s) or 30 min (308+/-122 s) following the onset of EGSA ( P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.
Gizurarson, S., F. K. Gudbrandsson, et al. (1999). "Intranasal administration of diazepam aiming at the treatment of acute seizures: clinical trials in healthy volunteers." Biol Pharm Bull 22(4): 425-7.
Intranasal administration of diazepam may be a practical alternative to the conventional acute medication of seizures, such as status epilepticus. Nine healthy students participated in an open crossover study on intranasal versus intravenous administration of diazepam (2 mg). Blood samples were collected, pharmacodynamic tests were performed, and the volunteers filled out questionnaire. Peak concentration was achieved after 18+/-11 min and the bioavailability was 50.4+/-23.3%. A pharmacodynamic effect was observed after about 5 min, but the dose, even for i.v. administration, was too low to generate a strong measurable effect. The results indicate that intranasally administered diazepam may be an effective alternative to i.v. administration in relief of seizures, e.g. in an acute situation when a physician or nurse is not available on location.
Goyal and Wiznitzer (2006). "Emergency management of seizures in children." Lancet 367(9522): 1555-6.
Harbord, M. G., N. E. Kyrkou, et al. (2004). "Use of intranasal midazolam to treat acute seizures in paediatric community settings." J Paediatr Child Health 40(9-10): 556-8.
OBJECTIVES: To evaluate the acceptability of intranasal midazolam (INM) in acute seizure management in the community. METHODS: Parents and staff in residential and educational settings were trained in first aid and seizure management and the administration of INM. Feedback was obtained from those who had given INM over the 30-month period September 2000-March 2003. RESULTS: Intranasal midazolam was administered to 22 children for a total of 54 seizures (range 1-6 seizures each). The dose was 0.2-0.3 mg/kg rounded down to 1 or 2 of the 5 mg in 1-mL plastic ampoules, with the anticonvulsant instilled into the child's nose directly from the plastic ampoule. Seizures were effectively stopped on 48 occasions, i.e. 89%, while no respiratory arrests occurred. Thirty carers had given INM to a convulsing child and 27 (90%) reported no difficulty in administering it. Fifteen people had also previously administered rectal diazepam and INM was considered easier to administer than rectal diazepam by 13 while a preference to use INM rather than rectal diazepam was indicated by 14. CONCLUSION: This study has shown that INM is an acceptable treatment option as a first aid response for acute seizures. We believe that INM should be considered as the preferred alternative in the community setting, as it is easier to administer and is more dignified for the patient than rectal diazepam.
Hardmeier, M., R. Zimmermann, et al. (2012). "Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers." Clin Pharmacol Ther 91(5): 856-862.
The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation containing the absorption-enhancer chitosan were studied in 12 healthy volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the beta2 band (18-25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum-effect (E(max)) model indicated disequilibrium between plasma and effect-site concentrations, with equilibration half-lives of 2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out-of-hospital emergency settings with no immediate i.v. access.
Harnden, A. (2001). "Intranasal midazolam for treating febrile seizures in children. Caution is required in applying hospital based evidence to primary care population." Bmj 322(7278): 108.
Henney, H. R., 3rd, M. R. Sperling, et al. (2014). "Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults." Epilepsy Res 108(7): 1204-1211.
Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-infinity and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 +/- 106 and 328 +/- 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability to that of diazepam-RG. The intranasal formulation may provide caregivers and patients with a more socially acceptable and convenient alternative rescue therapy in the acute treatment of seizure clusters.
Hirsch, L.J., Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. N Engl J Med, 2012. 366(7): p. 659-60.
Holsti, M., B. L. Sill, et al. (2007). "Prehospital intranasal midazolam for the treatment of pediatric seizures." Pediatr Emerg Care 23(3): 148-53.
BACKGROUND: The local emergency medical services (EMS) council implemented a new pediatric treatment protocol using a Mucosal Atomization Device (MAD) to deliver intranasal (IN) midazolam for seizure activity. METHODS: We sought to compare outcomes in seizing pediatric patients treated with IN midazolam using a MAD (IN-MAD midazolam) to those treated with rectal (PR) diazepam, 18 months before and after the implementation of the protocol. RESULTS: Of 857 seizure patients brought by EMS to our emergency department (ED), 124 patients (14%) had seizure activity in the presence of EMS and were eligible for inclusion in this study. Of the 124 patients eligible for this study, 67 patients (54%) received no medications in the prehospital setting, 39 patients (32%) were treated with IN-MAD midazolam, and 18 patients (15%) were treated with PR diazepam. Median seizure time noted by EMS was 19 minutes longer for PR diazepam (30 minutes) when compared with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated with PR diazepam in the prehospital setting were significantly more likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence interval [CI], 1.6-43.7), ED intubation (OR, 12.2; CI, 2.0-75.4), seizure medications in the ED to treat ongoing seizure activity (OR, 12.1; CI, 2.2-67.8), admission to the hospital (OR, 29.3; CI, 3.0-288.6), and admission to the pediatric intensive care unit (OR, 53.5; CI, 2.7-1046.8). CONCLUSIONS: The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.
Holsti, M, et al: Intranasal midazolam versus rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med 2010;164(8):747-753.
Objective: To compare intranasal midazolam using a Mucosal Atomization Device (IN-MMAD) with rectal diazepam (RD) for the home treatment of seizures in children with epilepsy.Methods: 358 pediatric epilepsy subjects were prospectively enrolled from July 2006 through September 2008. Caretakers were randomized to use either 0.2 mg/kg of IN- child’s next seizure lasting longer than five minutes. Outcome data were summarized using medians and interquartile ranges (IQR) in minutes. Results: 92 caretakers administered a study medication to their child during a seizure (50 IN-MMAD, 42 RD). Groups were similar with regard to age, gender, daily anti-epileptic medications, and caretakers’ past experience with RD. Median IQR for seizure time before medication administration was IN-MMAD: 6.0 (4.8, 10.0) and RD: 6.0 (5.0, 10.0), time from drug administration to seizure cessation was IN-MMAD: 3.0 (1.0, 10.1) and RD: 4.3 (2.0, 14.5), and total seizure time was IN-MMAD: 12.0 (7.0, 21.0) and RD: 14.3 (7.5, 30.0). No differences were found between treatment groups with regard to repeat/prolonged seizures, need for emergency services, respiratory depression, emergency room visits, or hospitalization. Using a ten-point scale, caretakers report that IN-MMAD was easier to administer (9.2, CI: 8.9, 9.6 vs. 8.0, CI: 7.2, 8.7). Overall satisfaction with medication was higher in the IN-MMADÒ group (8.3, CI: 7.6, 9.0 vs. 7.2, CI: 6.4, 8.0).Conclusions: IN-MMAD was as effective as RD, as a “rescue medication” in terminating seizures at home in pediatric epilepsy patients. Ease of administration and overall satisfaction were higher with IN-MMAD compared to RD.
Humphries, L. K. and L. S. Eiland (2013). "Treatment of acute seizures: is intranasal midazolam a viable option?" J Pediatr Pharmacol Ther 18(2): 79-87.
Seizures in the pediatric population commonly occur, and when proper rescue medication is not administered quickly, the risk of neurologic compromise emerges. For many years, rectal diazepam has been the standard of care, but recent interest in a more cost-effective, safe alternative has led to the investigation of intranasal midazolam for this indication. Although midazolam and diazepam are both members of the benzodiazepine class, the kinetic properties of these 2 anticonvulsants vary. This paper will review available data pertaining to the efficacy, safety, cost, and pharmacokinetics of intranasal midazolam versus rectal diazepam as treatment for acute seizures for children in the prehospital, home, and emergency department settings.
Full article link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668946/
Inokuchi, R., N. Ohashi-Fukuda, et al. (2015). "Comparison of intranasal and intravenous diazepam on status epilepticus in stroke patients: a retrospective cohort study." Medicine (Baltimore) 94(7): e555.
Administering diazepam intravenously or rectally in an adult with status epilepticus can be difficult and time consuming. The aim of this study was to examine whether intranasal diazepam is an effective alternative to intravenous diazepam when treating status epilepticus. We undertook a retrospective cohort study based on the medical records of 19 stroke patients presenting with status epilepticus to our institution. We measured the time between arrival at the hospital, the intravenous or intranasal administration of diazepam, and the seizure termination. Intranasal diazepam was administered about 9 times faster than intravenous diazepam (1 vs 9.5 minutes, P = 0.001), resulting in about 3-fold reduction in the time to termination of seizure activity after arrival at the hospital (3 minutes compared with 9.5 minutes in the intravenous group, P = 0.030). No adverse effects of intranasal diazepam were evident from the medical records. Intranasal diazepam administration is safer, easier, and quicker than intravenous administration.
Javadzadeh, M., K. Sheibani, et al. (2012). "Intranasal midazolam compared with intravenous diazepam in patients suffering from acute seizure: A randomized controlled trial." Iran J Pediatr 22(1): 1-8.
Objective: Acute seizure attack is a stressful experience both for health care personnel and parents. These attacks might cause morbidity and mortality among patients, so reliable methods to control the seizure preferably at home should be developed. This study was performed to measure the time needed to control seizure attacks using intranasal midazolam compared to the common treatment (intravenous diazepam) and to evaluate its probable side effects. Methods: This study was conducted as a not blind randomized clinical trial among 60 patients coming to Imam Ali Hospital, Zahedan, Iran. The patients were 2 months to 15 years old children coming to our emergency department suffering from an acute seizure episode. Intranasal midazolam was administered 0.2 mg/kg equally dropped in both nostrils for case group and intravenous diazepam was administered 0.3mg/kg via IV line for control group. After both treatments the time needed to control the seizure was registered by the practitioner. Pulse rate and O saturation were recorded at patients’ entrance and in minutes 5 and 10 after drug administration. Findings: The time needed to control seizure using intranasal midazolam (3.16±1.24) was statistically shorter than intravenous diazepam (6.42±2.59) if the time needed to establish IV line in patients treated by intravenous diazepam is taken into account (P<0.001). The readings for O saturation or heart rate did not indicate a statistically significant difference between two groups of patients either at entrance or 5 and 10 minutes after drug administration. Conclusion: Considering the shorter time needed to control acute seizure episodes compared to intravenous diazepam and its safety record, intranasal midazolam seems to be a good candidate to replace diazepam, as the drug of choice, in controlling this condition.
Full article link:
Full article link: http://ijp.tums.ac.ir/index.php/ijp/article/view/1270
Jeannet, P. Y., E. Roulet, et al. (1999). "Home and hospital treatment of acute seizures in children with nasal midazolam." Eur J Paediatr Neurol 3(2): 73-7.
Rectal diazepam is widely used in the treatment of acute seizures in children but has some disadvantages. Nasal/sublingual midazolam administration has been recently investigated for this purpose but never at home or in a general paediatric hospital. The aim of this open study was to determine the efficacy, the tolerance and the applicability of nasal midazolam during acute seizures in children both in hospital and at home. We included known epileptic children for treatment at home and all children with acute seizures in the hospital. In all, 26 children were enrolled, 11 at home and 17 in the hospital (including two treated in both locations); only one had simple febrile seizure. They had a total of 125 seizures; 122 seizures (98%) stopped within 10 minutes (average 3.6 minutes). Two patients in the hospital did not respond and in three, seizures recurred within 3 hours. None had serious adverse effects. Parents had no difficulties administering the drug at home. Most of those who were using rectal diazepam found that nasal midazolam was easier to use and that postictal recovery was faster. Among 15 children who received the drug under electroencephalogram monitoring (six without clinical seizures), the paroxysmal activity disappeared in ten and decreased in three. Nasal midazolam is efficient in the treatment of acute seizures. It appears to be safe and most useful outside the hospital in severe epilepsies, particularly in older children because it is easy for parents to use. These data should be confirmed in a larger sample of children. Its usefulness in febrile convulsions also remains to be evaluated.
Johnson, T. (2001). "Intranasal midazolam for treating febrile seizures in children. Caution is advised in interpreting trial conclusions." Bmj 322(7278): 107.
Kay, L., P. S. Reif, et al. (2015). "Intranasal midazolam during presurgical epilepsy monitoring is well tolerated, delays seizure recurrence, and protects from generalized tonic-clonic seizures." Epilepsia.
OBJECTIVE: To evaluate the tolerability and efficacy of the ictal and immediate postictal application of intranasal midazolam (in-MDZ) in adolescents and adults during video-electroencephalography (EEG) monitoring. METHODS: Medical records of all patients treated with in-MDZ between 2008 and 2014 were reviewed retrospectively. For each single patient, the time span until recurrence of seizures was analyzed after an index seizure with and without in-MDZ application. To prevent potential bias, we defined the first seizure with application of in-MDZ as the in-MDZ index seizure. The control index seizure was the preceding, alternatively the next successive seizure without application of in-MDZ. RESULTS: In total, 75 epilepsy patients (mean age 34 +/- 14.7 years; 42 male, 33 female) were treated with in-MDZ (mean dose 5.1 mg). Adverse events were observed in four patients (5.3%), and no serious adverse events occurred. The median time after EEG seizure onset before administration of in-MDZ was 2.17 min (interquartile range [IQR] 03.82; range 0.13-15.0 min). Over the next 12 h after in-MDZ, the number of seizures was significantly lower (p = 0.031). The median seizure-free interval was significantly longer following treatment with in-MDZ (5.83 h; IQR 6.83, range 0.4-23.87) than it was for those with no in-MDZ treatment (2.37 h; IQR 4.87, range 0.03-21.87; p = 0.015). Conversely, the likelihood of the patient developing a subsequent seizure was four times higher (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.30-14.47) in the first hour and decreased gradually after 12 h (OR 1.5, 95% CI 1.06-2.12). The occurrence of generalized tonic-clonic seizures was lower in the in-MDZ group in the 24-h observation period (OR 4.67, 95% CI 1.41-15.45; p = 0.009). SIGNIFICANCE: Ictal and immediate postictal administration of in-MDZ was well tolerated and not associated with serious adverse events. We demonstrated a significant reduction of subsequent seizures (all seizure types) for a 12 h period and of generalized tonic-clonic seizures for 24 h following in-MDZ.
Kendall, J. L., M. Reynolds, et al. (1997). "Intranasal midazolam in patients with status epilepticus." Ann Emerg Med 29(3): 415-7.
The patient in status epilepticus presents many challenges to the emergency physician. IV access is frequently difficult to achieve, and prolonged attempts at access can jeopardize the patient and endanger the caregiver. We present two cases in which the administration of intranasal midazolam appeared to successfully terminate status epilepticus. No adverse effects were noted. Studies are needed to clarify the safety, optimal dosing, and clinical utility of this treatment modality.
Koekkoek, J. A., M. S. Boddaert, et al. (2014). "[Gliomas: fighting until the end against epilepsy; administration of antiepileptic drugs in the end-of-life phase]." Ned Tijdschr Geneeskd 158(1): A6924.
In patients with high-grade glioma seizures occur relatively frequently during the end-of-life phase. At some point, the use of oral anti-epileptic drugs is no longer possible due to swallowing difficulties caused by advanced tumour progression. We have established a draft guideline and propose that anti-epileptic drugs be prescribed by alternative routes of administration in the end-of-life phase in glioma patients with known epilepsy who develop swallowing difficulties. Buccal clonazepam would be our drug of first choice as a maintenance treatment in addition to intranasal midazolam for the acute management of seizures. Adequate treatment of epileptic seizures, particularly during the end-of-life phase, can help to maintain quality of life as long as possible in patients with high-grade glioma.
Koren, G. (2000). "Intranasal midazolam for febrile seizures. A step forward in treating a common and distressing condition." Bmj 321(7253): 64-5.
Kutlu, N. O., M. Dogrul, et al. (2003). "Buccal midazolam for treatment of prolonged seizures in children." Brain Dev 25(4): 275-8.
Midazolam is a relatively new anticonvulsive agent in the benzodiazepine group. It has a short onset of duration and is practical for use, providing several alternatives such as intravenous, intramuscular, and intranasal routes. The buccal route could be an alternative choice for seizure control in an emergency setting. However, no sufficient reports are available on buccal midazolam administration. The present study was designated to examine the efficacy of buccal midazolam in children at different ages with seizures of more than 5 min duration. Nineteen previously unreported children, aged from 1 month to 15 years, were treated with a 0.3 mg/kg dose of buccal midazolam; 13 had prolonged seizures, and six had status epilepticus, with a duration of 5-45 min (mean 22 min). Sixteen of 19 seizures (84.2%) stopped within 10 min of buccal midazolam being given. The drug efficacy in patients with status epilepticus was 50%. However, all patients with convulsions shorter than 30 min showed a perfect response (100%). Convulsion episodes stopped within 3.89+/-2.22 min (median time 3 min). Seizure duration was correlated with cessation of seizure (r=0.76, P<0.001). No clinically important side effects were seen in any patient. On the basis of this experience, we concluded that a 0.3 mg/kg dose of buccal administration of midazolam might offer an effective treatment in all ages of children.
Kutlu, N. O., C. Yakinci, et al. (2000). "Intranasal midazolam for prolonged convulsive seizures." Brain Dev 22(6): 359-61.
In order to determine the efficiency of intranasal midazolam in prolonged convulsive episodes, we conducted a prospective study in children with various types of seizures. Nine patients (six boys, three girls; age range 6 months to 9 years) with prolonged convulsions lasting more than 10 min were treated with intranasal midazolam, 0.3 mg/kg. The success rate was 100% with only one case requiring a second dose. Estimated duration of seizures was 12-30 min (mean 18.6) while mean time elapsed until cessation of seizures was 139.6 s (range 60-480). No significant adverse effects were noted except for one patient who had seizures secondary to serious CNS infection and respiratory depression after intranasal midazolam.
Kyrkou, Harbord, et al. (2006). "Community use of intranasal midazolam for managing prolonged seizures." J Intellect Dev Disabil 31(3): 131-8.
Background Until a few years ago, rectal diazepam (RD) was the only option available to parents and carers managing prolonged seizures. However, its use in the community was limited due to the requirement for privacy, and because education staff in South Australia are not permitted to carry out invasive procedures.Method Following a literature review, a seizure management training package was developed to enhance the implementation of a trial treatment protocol for the administration of intranasal midazolam (INM). Parents, carers and education staff were later surveyed about their experiences and perceptions.Results Intranasal midazolam was administered to 131 people (51 children and 80 adults), with 96.9% control of seizures, and only one minor adverse event. Parents expressed a preference for INM over RD because of the shorter time it took to take effect and wear off, and the ability to administer it in public if necessary.Conclusion Intranasal midazolam is a safe and practical alternative to rectal diazepam for managing prolonged seizures in the community.
Lagae, L. (2014). "Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures." Epileptic Disord 16 Suppl 1: 44-49.
An historical overview is provided regarding the use of benzodiazepines for the treatment of acute prolonged convulsive seizures. It is clear that intravenous benzodiazepines remain a first step for the in-hospital treatment of prolonged seizures or status epilepticus. However, in the community, in a pre-hospital situation, intravenous administration is not possible. In recent years, it was shown that rectal, buccal, intranasal, and intramuscular administration of benzodiazepines is very effective as a first and safe treatment step. In many cases, rectal diazepam is not socially acceptable anymore, and therefore more emphasis is now put on buccal, intranasal, and intramuscular administration. At present, based on the available data, midazolam is the product of choice for the acute treatment of prolonged convulsive seizures.
Lahat, E., M. Goldman, et al. (2000). "Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study." Bmj 321(7253): 83-6.
Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomised study. Setting: Paediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7. 9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.
Lahat, E., M. Goldman, et al. (1998). "Intranasal midazolam for childhood seizures." Lancet 352(9128): 620.
Lahat, E., M. Goldman, et al. (1998). "Intranasal midazolam for childhood seizures [letter]." Lancet 352(9128): 620.
Lissauer, S., J. Kenny, et al. (2015). "Buccal, intranasal or intravenous lorazepam for the treatment of acute convulsions in childen in Malawi: An open randomized trial." African Journal o f Emergency Medicine 5: 120-126.
Introduction: Acute convulsions in children are a common emergency worldwide. Benzodiazepines are the recommended first line treatment. Intravenous lorazepam is inexpensive, long acting and the first line drug in resource-rich settings. However, comparable efficacy by other routes of administration is unknown. We wished to compare the efficacy of lorazepam by the buccal, intranasal or intravenous route in the treatment of acute seizures in Malawian children. Methods: A prospective, open-label, randomised, non-inferiority trial was performed in children aged 2 months to 14 years presenting to the Queen Elizabeth Central Hospital in Blantyre, Malawi with acute seizures lasting longer than 5 min. Children were randomly assigned to receive lorazepam, 0.1 mg/kg, by the buccal, intranasal or intravenous route. The primary endpoint was seizure cessation within 10 min of drug administration. Results: There were 761 seizures analysed, with 252 patients in the buccal, 245 in the intranasal and 264 in the intravenous groups. Intravenous lorazepam stopped seizures within 10 min in 83%, intranasal lorazepam in 57% (RR 2.46, CI 1.82–3.34), and the buccal route in 46% (RR 3.14, CI 2.35–4.20; p= 0.001) of children. There were no significant cardio-respiratory events and no difference in mortality or neurological deficits. The study was halted after an interim analysis showed that the primary endpoint had exceeded the protocol-stopping rule. Conclusions: Intravenous lorazepam effectively treats most childhood seizures in this setting. Intranasal and buccal routes are less effective but may be useful in prehospital care or when intravenous access cannot be obtained. Further studies comparing intranasal lorazepam to other benzodiazepines, or alternative doses by a nonintravenous route are warranted.
Mahmoudian, T. and M. M. Zadeh (2004). "Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children." Epilepsy Behav 5(2): 253-5.
Midazolam, a water-soluble benzodiazepine, is usually given intravenously in status epilepticus. The aim of this study was to determine whether intranasal midazolam is as safe and effective as intravenous diazepam in the treatment of acute childhood seizures. Seventy children aged 2 months to 15 years with acute seizures (febrile or afebrile) admitted to the pediatric emergency department of a general hospital during a 14-month period were eligible for inclusion. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.2 mg/kg were administered after intravenous lines were established. Intranasal midazolam and intravenous diazepam were equally effective. The mean time to control of seizures was 3.58 (SD 1.68) minutes in the midazolam group and 2.94 (SD 2.62) in the diazepam group, not counting the time required to insert the intravenous line. No significant side effects were observed in either group. Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Intranasal midazolam can possibly be used not only in medical centers, but also in general practice and at home after appropriate instructions are given to families of children with recurrent seizures.
McGlone, R. and M. Smith (2001). "Intranasal midazolam. An alternative in childhood seizures." Emerg Med J 18(3): 234.
McMullan, J., C. Sasson, et al. (2010). "Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis." Acad Emerg Med 17(6): 575-582.
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.
Neff, C., S. M. Joyce, et al. (2006). "Efficacy and safety of intranasal midazolam administration by EMS personnel for seizures and sedation." NAEMSP Winter abstracts.
O'Regan, M. E., J. K. Brown, et al. (1996). "Nasal rather than rectal benzodiazepines in the management of acute childhood seizures?" Dev Med Child Neurol 38(11): 1037-45.
Benzodiazepines are routinely used by the rectal route for the treatment of acute epileptic seizures: if a benzodiazepine was absorbed from nasal administration this could provide a more acceptable alternative to rectal administration. Nineteen children (age range 7 months to 14 years) with intractable epilepsy were chosen. The EEG's showed unequivocal epileptic activity persisting during the recording. The midazolam was dripped slowly into the anterior nares. Fifteen had a positive response, a dramatic improvement in their EEG or cessation of fits. Drug induced beta activity occurred in 14 children. The mean time to appearance of beta activity was 111.5 secs (SD = 95.3 secs). The reduction in spike count pre and post midazolam was statistically significant (p 0.01). The improvement in EEG background was also statistically significant. Midazolam is absorbed via the i.n. route. With the dosages used it suppressed epileptic activity and produced an improvement in EEG background. The children and parents found the method acceptable. This is the first study to use the i.n. route for anti-convulsant drugs.
O'Regan, M. E., J. K. Brown, et al. (1996). "Nasal rather than rectal benzodiazepines in the management of acute childhood seizures? [see comments]." Dev Med Child Neurol 38(11): 1037-45.
Benzodiazepines are routinely used by the rectal route for the treatment of acute epileptic seizures: if a benzodiazepine was absorbed from nasal administration this could provide a more acceptable alternative to rectal administration. Nineteen children (age range 7 months to 14 years) with intractable epilepsy were chosen. The EEG's showed unequivocal epileptic activity persisting during the recording. The midazolam was dripped slowly into the anterior nares. Fifteen had a positive response, a dramatic improvement in their EEG or cessation of fits. Drug induced beta activity occurred in 14 children. The mean time to appearance of beta activity was 111.5 secs (SD = 95.3 secs). The reduction in spike count pre and post midazolam was statistically significant (p < 0.01). The improvement in EEG background was also statistically significant. Midazolam is absorbed via the i.n. route. With the dosages used it suppressed epileptic activity and produced an improvement in EEG background. The children and parents found the method acceptable. This is the first study to use the i.n. route for anti-convulsant drugs.
Perez, A., R. Clark, et al. (2000). "Out-of-hospital management of patients who are having seizures: Is there a need for an alternative to intravenous therapy? (abstract)." Ann Emerg Med 36(4): S38, abstract 144.
Phillips, B. and R. Appleton (2001). "Intranasal midazolam for treating febrile seizures in children. Safety is as important as efficacy." Bmj 322(7278): 107-8.
Rey, E., J. M. Treluyer, et al. (1999). "Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes." Clin Pharmacokinet 36(6): 409-24.
All benzodiazepines enter cerebral tissue rapidly. However, the duration of action is short for diazepam ( 2 hours) and midazolam (3 to 4 hours) and longer for clonazepam (24 hours) and lorazepam (up to 72 hours), and is not correlated with the plasma concentration-time profiles of these drugs. Although a relationship between the plasma concentration of diazepam, lorazepam and midazolam and their pharmacodynamic effect has been demonstrated in healthy individuals, some caution is warranted as the clinical relevance of these data has not been clearly established. The physicochemical properties of benzodiazepines (lipid solubility and protein binding) regulate their rate and extent of entry into the brain and cerebrospinal fluid. However, the duration of the pharmacological activity of benzodiazepines may be in part related to the affinity of these compounds for the benzodiazepine receptors in the brain: midazolam, clonazepam and lorazepam have higher affinities than diazepam. In the emergency setting, the intravenous route is the most suitable, delivering adequate quantities of benzodiazepines as fast as possible. However, when intravenous administration is not available, rectal administration of a solution is a convenient method for diazepam, midazolam being the only one of these drugs that should be given intramuscularly. The assessment of the efficacy of benzodiazepines in the management of acute seizures and status epilepticus is mainly based on nonrandomized uncontrolled trials. According to the route of administration, the efficacy was 28.6 to 100% (intrarectal) and 54 to 100% (intravenous) for diazepam, 82 to 100% (intravenous) for lorazepam, and 79% (intranasal), 93 to 100% (intramuscular) and 100% (intravenous) for midazolam. Although diazepam was initially chosen for the management of refractory status epilepticus, the longer duration of action of lorazepam and clonazepam may favour the use of these 2 drugs. However, double-blind evaluations are necessary to determine which drug is best.
Scheepers, M., B. Scheepers, et al. (2000). "Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy?" Seizure 9(6): 417-22.
The aim of this study was to determine whether intranasal midazolam is a safe and effective rescue medication in adolescent and adult patients with severe epilepsy. This field trial was designed to test the feasibility of the use of intranasal midazolam as an alternative to rectal diazepam in a cohort of patients with severe epilepsy who require rescue medication as part of their treatment. A dose of intranasal midazolam (5 mg if the patient weighed less than 50 kg and 10 mg if the patient weighed over 50 kilograms) was prescribed for those who had previously responded to other rescue medication. Midazolam was prescribed buccally if excessive head movement accompanied seizures. The protocol reverted to the usual rescue medication if there was no response to midazolam within 10 minutes. Vital signs were monitored for half an hour following the administration of the treatment. Twenty-two patients received 84 treatment episodes and 79 of these were considered clinically effective. Five treatment failures were recorded, three due to poor technique in delivering the midazolam. Two patients were successfully retried on midazolam and a third is awaiting a retrial of this drug. The two other treatment failures received the drug buccally. In the first patient the clinical opinion was that this was possibly a psychogenic non-epileptic seizure. The other patient responded initially, but within an hour had another seizure requiring further rescue treatment. No significant adverse effects were reported. Our study shows that intranasal midazolam, when used appropriately, is an effective treatment in those who require rescue treatment. There are clear advantages in the use of midazolam over diazepam in the treatment of acute seizures. These include the favourable pharmacokinetic and pharmacodynamic properties of midazolam as well as the potential of a more acceptable and dignified administration route.
Scheepers, M., B. Scheepers, et al. (1998). "Midazolam via the intranasal route: an effective rescue medication for severe epilepsy in adults with learning disability." Seizure 7(6): 509-12.
People with a learning disability are often disadvantaged due to the nature of their disability. Up to a third are likely to have concomitant epilepsy which adds to the health loss experienced by this group. It is important to manage their epilepsy in such a way as to limit the debilitating effects of both the illness and the medication. Rectal diazepam remains the gold standard rescue medication for prolonged, recurrent seizures or seizures associated with hypoxia. Some of the drawbacks are highlighted in this paper and we go on to explore a novel means of treating these seizures. Midazolam, via the intranasal route, has been used extensively in children, mostly as a sedative but also in the treatment of epilepsy. We present two cases, both are adults with a learning disability, who have benefited significantly from the use of intranasal midazolam. Ongoing research into the safe use of this form of treatment, training of staff and carers and the impact on the individual is being conducted.
Scott, R. C., F. M. Besag, et al. (2001). "Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam." Bmj 322(7278): 107.
Scott, R. C., B. G. Neville, et al. (1997). "Nasal rather than rectal benzodiazepines in the management of acute childhood seizures? [letter; comment]." Dev Med Child Neurol 39(2): 137-8.
Silbergleit, R., V. Durkalski, et al. (2012). "Intramuscular versus intravenous therapy for prehospital status epilepticus." N Engl J Med 366(7): 591-600.
BACKGROUND: Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route. METHODS: This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points. RESULTS: At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups. CONCLUSIONS: For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, ClinicalTrials.gov NCT00809146.).
Sharma, R. and R. Harish (2013). "Comparative study of the efficacy of intranasal midazolam vs intravenous midazolam in convulsing neonates and children." RRJMHS 2(4): 54-57. (click for link to free article)
To compare the efficacy of intranasal midazolam in relation to intravenous midazolam for control of seizures. To observe variability if any amongst the two groups in terms of heart rate, respiratory rate, blood pressure and oxygen saturation. A Prospective Randomized study conducted on 100 patients of 0-19 years of age hospitalized in emergency ward and NICU in a convulsing state. They were divided into two groups. GP-I was given intranasal midazolam @ 0.3 mg/ kg and GP-II was given intravenous midazolam @ 0.3 mg/ kg. Outcome was measured in terms of: Time taken from physician contact to drug administration. Time taken from drug administration to cessation of seizures. Mean time from physician contact to drug administration was significantly shorter with intranasal midazolam as compared to intravenous midazolam viz [ 0.40+ 0.10min vs 1.06+0.40+min) [p< 0.05 ].Mean time from drug administration to cessation of seizures was comparable in both the groups 1.0 + 0.31 min and 1.0+0.32 min (p> 0.05). However this difference was statistically insignificant. The readings for oxygen saturation and vital parameters did not show a statistically significant difference amongst the groups. Seizure control was more prompt with intranasal midazolam as compared to intravenous midazolam. As time needed for drug administration was lesser. Intranasal midazolam is a rapid, efficacious, easy to administer and socially more acceptable route of drug administration. It can be used not only in hospital setting but also for home management of seizures after proper instructions to parents.
Sperling, M. R., K. F. Haas, et al. (2014). "Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy." Epilepsia 55(10): 1544-1550.
OBJECTIVE: To determine the feasibility of administering a diazepam nasal spray formulation (diazepam-NS) to adults with epilepsy during a generalized tonic-clonic seizure or in the postictal period following a tonic-clonic or other seizure type, to assess pharmacokinetics and to assess tolerability. METHODS: An open-label study was conducted in patients admitted to the epilepsy monitoring unit. Eligible patients received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma diazepam concentrations were measured serially up to 12 h postdose, and maximum observed plasma concentration (Cmax ); time to maximum concentration (Tmax ); and the area under the plasma concentration-time curve for time zero to last sampling time (AUC0-12 ) were estimated and dose-normalized. Pharmacodynamic assessments included Kaplan-Meier analysis to determine the time-to-next seizure. Safety and tolerability were assessed. RESULTS: Of the 78 patients who consented, 30 had treatment and pharmacokinetic data. Ten patients were treated during a convulsive tonic-clonic seizure, seven within 5 min following the last clonic jerk, and 13 in the postictal period >/=5 min after a tonic-clonic or following other seizure-types. Diazepam median Tmax was 45 min. Dose-normalized mean Cmax and AUC0-12 values of diazepam were comparable among patients regardless of the timing of diazepam-NS administration in relation to seizure. Of those treated, 65% were seizure-free during the 12-h observation period and 35% had post-dose seizures. Treatment was well tolerated, with no unexpected safety findings: 74% had mild and 25% had moderate adverse events. Nasopharyngeal signs were resolved by 12 h postdose. SIGNIFICANCE: Diazepam can be delivered in effective therapeutic concentrations by a nasal spray device during the convulsive phase of tonic-clonic seizures or in the postictal periods following tonic-clonic or other seizure types.
Thakker, A. and P. Shanbag (2012). "A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures." J Neurol.
The objective of this study is to compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of acute childhood seizures. A randomized controlled study was conducted in a pediatric emergency department in a tertiary general hospital. Fifty children aged from 1 month to 12 years presenting with acute seizures of at least 10 min duration were enrolled during a 12 month period. Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg) were administered. The main outcome measures were interval between arrival at hospital and starting treatment and interval between arrival at hospital and cessation of seizures. Intranasal midazolam and intravenous diazepam were equally effective. Overall 18 of 27 seizures were controlled with midazolam and 15 of 23 with diazepam. The mean interval between arrival at hospital and starting treatment was significantly shorter in the midazolam group [3.37 min (SD 2.46)] as compared to the diazepam group [14.13 min (SD 3.39)]. The mean interval between cessation of seizures and arrival at hospital was significantly shorter in the midazolam group [6.67 min (SD 3.12)] as compared to the diazepam group [17.18 min (SD 5.09)]. The mean interval between control of seizures and administration of the drug was shorter in the diazepam group [2.67 min (SD 2.31)] as compared to the midazolam group [3.01 min (SD 2.79)]. No significant side effects were observed in either group. Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Midazolam was as safe and effective as diazepam. The overall interval between arrival at hospital and cessation of seizures was shorter with intranasal midazolam than with intravenous diazepam. The intranasal route can be possibly used not only in medical centres, but with appropriate instruction by the parents of children with acute seizures at home.
Veldhorst-Janssen, N. M. (2013). Intranasal delivery of rapid acting drugs: Studies of pharmacokinetics, effect, tolerability and satisfaction, Universitaire Pers Maastricht. PhD Thesis: 141: Patient satisfaction with intranasal midazolam versus rectal diazepam as fast-working recue medication in epilepsy.
Walker, Dm, et al. (2006). "Update on the acute management of status epilepticus in children." Curr Opin Pediatr 18(3): 239-244.
PURPOSE OF REVIEW: Status epilepticus is the most common neurologic emergency in children. The understanding of its less recognizable forms, its pharmacologic management, the role of electroencephalography and the long-term morbidity and mortality as a result of status epilepticus are consistently evolving. This review frames the current understanding of several issues as they apply to acute management in the emergency department. RECENT FINDINGS: Researchers are working to define less recognizable forms of status epilepticus such as nonconvulsive, autonomic and psychogenic. Buccal and intranasal forms of midazolam are emerging as suitable alternatives to rectal diazepam in the initial treatment of status epilepticus. Valproic acid, chloral hydrate and newer-generation antiepileptics are being proposed as safe and effective alternatives to the traditional drugs used to treat status epilepticus. The role of electroencephalography in diagnosis is being elucidated. Risk factors for neurologic sequelae and mortality after status epilepticus remain an area of research with conflicting findings and no real consensus. SUMMARY: The understanding of different types of status epilepticus, the options for pharmacologic treatment, the tools for diagnosis and the morbidity and mortality of the disease are still evolving. As a result, several areas for further research remain that will help clinicians in their approach to this complex condition.
Wallace, S. J. (1997). "Nasal benzodiazepines for management of acute childhood seizures?" Lancet 349(9047): 222.
Wassner, E., B. Morris, et al. (2001). "Intranasal midazolam for treating febrile seizures in children. Buccal midazolam for childhood seizures at home preferred to rectal diazepam." Bmj 322(7278): 108.
Wilson, M. T., S. Macleod, et al. (2004). "Nasal/buccal midazolam use in the community." Arch Dis Child 89(1): 50-1.
A telephone survey was carried out to evaluate the effectiveness and convenience of nasal/buccal midazolam in terminating prolonged seizures in the community. A total of 33/40 (83%) families who had used it found it effective and easy to use; 20/24 (83%) preferred using midazolam to rectal diazepam.
Wolfe, T.R., T Macfarlane. (2006). "Intranasal midazolam therapy for pediatric status epilepticus." Am J Emerg Med 24(3): 343-6.
Prolonged seizure activity in a child is a frightening experience for families as well as care providers. Because duration of seizure activity impacts morbidity and mortality, effective methods for seizure control should be instituted as soon as possible, preferably at home. Unfortunately, parenteral methods of medication delivery are not available to most caregivers and rectal diazepam, the most commonly used home therapy, is expensive and often ineffective. This brief review article examines recent research suggesting that there is a better way to treat pediatric seizures in situations where no intravenous access is immediately available. Intranasal midazolam, which delivers antiepileptic medication directly to the blood and cerebrospinal fluid via the nasal mucosa, is safe, inexpensive, easy to learn by parents and paramedics, and provides better seizure control than rectal diazepam.
Wolfe, T. R. and E. D. Barton (2003). "Reducing needlestick risk: Nasal drug delivery in EMS." J Emerg Med Serv JEMS 28(12): 52-63.
Wolfe, T. R. and T. Bernstone (2004). "Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases." J Emerg Nurs 30(2): 141-7.