Abstract Summary: Intranasal Benzodiazepines for seizure control

ABSTRACT SUMMARY:

Intranasal Benzodiazepines for seizure control

Contents Bibliography:

Title:

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.

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.

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.

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.

Holsti, M., B.L. Sill, S.D. Firth, S. M. Joyce, F. Filloux, R. A. Furniva. (2004). “Prehospital Intranasal Versed for Pediatric Seizures.” Abstract presentation, American Acadamy of Pediatrics, San Francisco, CA, October 2004.

Kutlu, N. O., M. Dogrul, et al. (2003). "Buccal midazolam for treatment of prolonged seizures in children." Brain Dev 25(4): 275-8.

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.

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.

Kutlu, N. O., C. Yakinci, et al. (2000). “Intranasal midazolam for prolonged convulsive seizures.” Brain Dev 22(6): 359-61.

Wilson, M. T., S. Macleod, et al. (2004). "Nasal/buccal midazolam use in the community." Arch Dis Child 89(1): 50-1.

Fisgin, T., Y. Gurer, et al. (2000). “Nasal midazolam effects on childhood acute seizures.” J Child Neurol 15(12): 833-5.

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.

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.

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.

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 randomized 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.

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.

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.

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.

Holsti, M., B.L. Sill, S.D. Firth, S. M. Joyce, F. Filloux, R. A. Furniva. (2004). “Prehospital Intranasal Versed for Pediatric Seizures” Abstract presentation, AAP San Francisco, CA, October 2004.

Background: Seizures are the most frequent non-traumatic diagnosis for children transported by Emergency Medical Services (EMS). In July of 2003, the Salt Lake County EMS Council implemented a new pediatric treatment protocol utilizing Intranasal Versed (IN-V) for seizure activity. We sought to prospectively compare pediatric patient outcomes with IN-V to the previous intravenous or rectal Valium EMS protocol for seizures. Methods: Cohort study following two treatment groups of all EMS-transported pediatric seizure patients to Primary Children’s Medical Center Emergency Department (ED), from March 1, 2002 through October 31, 2003. Charts will be reviewed through July 1, 2004. Clinical outcomes for those treated with Valium or IN-V by EMS personnel for witnessed seizure activity were compared. Results: Of 340 ED seizure patients brought by EMS, 163 without witnessed seizure activity by EMS personnel, 108 interhospital transfers, and 1 with incomplete records were excluded. Sixty-six included children had a median age of 3.5 years, 52% were female, and 73% had a history of previous seizures. EMS personnel gave anti-epileptic medication to only 38% of children with witnessed seizures, both before (17/45) and after (8/21) implementation of the IN-V protocol. Children treated with IN-V required less bag-valve-mask ventilation (0%, 0/10 vs. 31%, 5/16; p=0.12) and endotracheal intubation (0%, 0/10 vs. 33%, 6/18; p=0.06) than those treated with Valium. IN-V patients were less likely to have further seizures in the prehospital (0%, 0/10 vs. 22%, 4/18; p=0.26) and in the ED setting (60%, 6/10 vs. 78%, 14/18; p=0.40). Finally, IN-V treated children were less likely to require hospitalization (40%, 4/10 vs. 89%, 16/18; p=0.01) than those treated with Valium. Conclusion: Prehospital EMS treatment of pediatric seizures with IN-V is associated with lower rates of respiratory support, repeat seizures, and hospital admission than with prehospital Valium. IN-Versed may be a more effective prehospital treatment for pediatric seizures than Valium.

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.

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 favorable pharmacokinetic and pharmacodynamic properties of midazolam as well as the potential of a more acceptable and dignified administration route.

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.

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.

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.

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.

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 care givers and the impact on the individual is being conducted.

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.

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.