Midazolam for Seizures ====================== þ Midazolam IM for Seizures - 0.2 mg/kg - 14 mg for standard adult Clin Neuropharmacol 1992 Feb;15(1):44-49 The use of intramuscular midazolam for acute seizure cessation or behavioral emergencies in patients with traumatic brain injury. Wroblewski BA, Joseph AB Greenery Rehabilitation Center, Brighton, MA 02135. Brain-injured patients involved in rehabilitation programs are susceptible to the occurrence of acute seizures or severe behavioral episodes. Effective pharmacological management in this setting should ideally include rapid onset without severe adverse effects. Previous treatments have generally included intramuscular diazepam or lorazepam, as well as intramuscular antipsychotic drugs. These options have proved problematic due to poor absorption, slow onset of activity, or potential for unacceptable side effects. We report 10 cases involving the use of intramuscular midazolam, a rapid-acting, short half-life benzodiazepine, in treating acute seizures or behavioral problems. We conclude that this drug demonstrates great promise for the rapid, effective treatment of these conditions without significant adverse effects and deserves further study in these areas. Neurologia 1994 Mar;9(3):109-111 Treatment of status epilepticus with midazolam: report of four cases. [Article in Spanish] Galdames Poblete D, Silva-Rosas C, Aguilera Olivares L Departamento de Neurologia y Neurocirugia, Hospital Clinico de la Universidad de Chile. Midazolam is a water-soluble benzodiazepine imide that has been used in recent years to manage status epilepticus (SE). We describe four patients with SE refractory to conventional treatment, whose seizures were controlled with midazolam administered intramuscularly in two cases and intravenously in the remaining two. Given the pharmacokinetic traits of this drug, the intramuscular route offers great advantages. Midazolam also produces fewer side effects than do other benzodiazepines, suggesting the possibility of its use as a first line treatment for SE and frequent epileptic seizures. Ann Emerg Med 1996 Sep;28(3):377 Out-of-hospital midazolam for status epilepticus. [LETTER] (5 mg IM Versed given after 5mg IV x 2 Valium failed to stop seizure and IV became dislodged.)+ LeDuc TJ, Goellner WE, el-Sanadi N Chamberlain JM, Altieri MA, Futterman C, et al. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children Pediatr Emerg Care 1997; 13:92-4 OBJECTIVE: To compare treatment of ongoing seizures using intramuscular (IM) midazolam versus intravenous (IV) diazepam. DESIGN: Controlled clinical trial. PATIENTS: Children with motor seizures of at least 10 minutes' duration. MAIN OUTCOME MEASURES: Time to cessation of seizures. RESULTS: Twenty-four patients were enrolled (13 midazolam, 11 diazepam). Initial treatment with either midazolam or diazepam was successful in 22 of the 24 patients. One patient in each group failed therapy and eventually required endotracheal intubation and general anesthesia for convulsive status epilepticus lasting more than one hour. Patients in the midazolam group received medication sooner (3.3 +/- 2.0 vs 7.8 +/- 3.2 minutes, P = 0.001) and had more rapid cessation of their seizures (7.8 +/- 4.1 vs 11.2 +/- 3.6, P = 0.047) than patients randomized to receive diazepam. CONCLUSIONS: IM midazolam is an effective anticonvulsant for children with motor seizures. Compared to IV diazepam, IM midazolam results in more rapid cessation of seizures because of more rapid administration. The IM route of administration may be particularly useful in physicians' offices, in the prehospital setting, and for children with difficult IV access. ------------- IM midazolam is standard in South Australia prehospital care and other Australian state ambulance services. WA has the longest experience and has had no reported problems. Hugh Grantham Med Dir SAAS South Australia ------------- Simon Brown Staff Specialist, Emergency Medicine Royal Hobart Hospital Tasmania, Australia. **EXTRACT FOLLOWS** The intravenous administration of a rapidly acting anticonvulsant (usually a benzodiazepine) is considered the treatment of choice to arrest a seizure. However, an intravenous line can be difficult to insert into a convulsing child. The intramuscular and rectal routes are alternative but pharmacokinetically slower means of anticonvulsant administration. Nevertheless, given the time taken to insert an intravenous line the seizure may actually terminate more quickly with IM or PR treatment. Intramuscular administration of diazepam is not recommended for the treatment of seizures as its absorption is slow and erratic. A solution of diazepam for intravenous use (diazepam compounded with 40% propylene glycol and 10% ethyl alcohol) given undiluted rectally in a dose of about 0.5 mg/kg is often effective in stopping convulsions in children. It has been recommended as an "ideal alternative" in patients without intravenous access [1]. When given in this fashion to non-convulsing subjects diazepam is rapidly absorbed, with "therapeutic" serum concentrations occurring within 5 to 10 minutes, peak levels at 16 to 20 minutes [2] and a bioavailability of about 80% [3]. The largest studies of clinical efficacy of rectal diazepam in children [4,5] found that seizure cessation occurred within 5 minutes in 70% and 80% respectively. For ethical reasons control groups were not included. It is therefore possible that the true response rates (as opposed to spontaneous seizure cessation) were closer to 46% and 57% respectively, these being the response rates in those children whose convulsions had lasted for greater than 15 minutes prior to treatment. Diazepam precipitates in aqueous solutions and thus rectal absorption is poor if suspended in water [6]. No published studies were found [Medline search] demonstrating adequate rectal absorption of diazepam lipid emulsion (e.g. Diazemuls™) even though this preparation is commonly used rectally. Hence for the purposes of this study we will be using undiluted diazepam solution (in propylene glycol and alcohol) for rectal administration. Midazolam is a water soluble benzodiazepine which is rapidly absorbed after IM injection with a time to maximum serum concentration ranging from 10 to 30 minutes and an absolute bioavailability of 87 ñ 18% in non-convulsing adult patients [7]. It has been recognised as an effective anticonvulsant and clinical trials have demonstrated its efficacy and safety in adult patients when used intravenously as first line management of seizures [8,9]. Its successful intravenous use in 24 children (aged 2 months to 12 years) with refractory status epilepticus using a bolus of 0.15 mg/kg, followed by an infusion of 1 ug/kg/min has also been described [10]. Repeated doses of intravenous diazepam, phenobarbital and phenytoin had been given prior to the midazolam, but despite this there were no significant adverse effects and no child required intubation or ventilation. Intramuscular midazolam has been shown in a trial to be safe and effective in both children and adults (38 patients aged from 15 months to 89 years [11]). Actual doses administered ranged from 0.07-0.21 mg/kg (average 0.12 mg/kg) and the time to cessation of fitting in the group with prolonged fits (15 patients) averaged 2 minutes 41 seconds (range 25 seconds to 6 minutes 7 seconds). Only three patients (all adults) "failed" and in these cases the doses of midazolam were low at 0.12, 0.12 and 0.07 mg/kg. All subsequently responded to intravenous benzodiazepine. No adverse effects were reported in any patients. Lahat et al. [12] administered IM midazolam at a dose of 0.2 mg/kg to 48 children aged 4 months to 14 years (69 epileptic episodes) without adverse effect. Seizure control occurred by 5 minutes in 83%, and 10 minutes in all but 5%. The results were not broken down according to seizure duration. We hypothesise that midazolam given intramuscularly at a dose of 0.2 mg/kg will prove a more rapid and effective means of terminating seizures than rectal diazepam 0.5 mg/kg. Not only may it be a more efficacious anticonvulsant in its own right [10], but it may also undergo particularly rapid absorption from muscle in convulsing patients as a result of increased muscle blood flow. Because PR diazepam is more difficult to administer than IM midazolam, the time taken to give the drug may also be shorter. 1. Barkin R. Old routes for new drugs (Editorial). Journal of Emergency Medicine. 1990 Mar-Apr; 8 (2): 205. 2. Seigler RS. The administration of rectal diazepam for acute management of seizures. Journal of Emergency Medicine. 1990 Mar-Apr; 8 (2): 155-159. 3. Agurell S, Berlin A, Ferngren H, Hellstrom B. Plasma levels of diazepam after parenteral and rectal administration in children. Epilepsia. 1975; 19:277-283. 4. Sykes RM, Okonofua JA. Rectal diazepam solution in the treatment of convulsions in the children's emergency room. Ann Trop Paediatr. 1988 Dec; 8 (4): 259-61. 5. Knudsen FU. Rectal administration of diazepam in solution in the acute treatment of convulsions in infants and children. Archives of Disease in Childhood. 1979; 54 (11):855-7. 6. Moolenar F, Bakker S, Visser J et al. Biopharmaceutics of rectal administration of drugs in man:IX. Comparative biopharmaceutics of diazepam after single rectal, oral, IM, and intravenous administration in man. International Journal of Biopharmaceutics. 1980; 5: 127-37. 7. Bell DM, Richards G, Dhillon S etal. A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy. Epilepsy Res 1991 Nov-Dec; 10: 183-190. 8. Galvin GM, Jelinek GA. Midazolam: an effective intravenous agent for seizure control. Archives of Emergency Medicine 1987 Sep; 4 (3): 169-72. 9. Galvin GM, Jelinek GA. Successful treatment of 75 patients in status epilepticus with intravenous midazolam. Emergency Medicine 1992 Mar; 4: 11-12. 10. Rivera R, Segnini M, Baltodano A, Perez V. Midazolam in the treatment of status epilepticus in children. Critical Care Medicine 1993 Jul; 21 (7): 955-7. 11. McDonagh TJ, Jelinek GA, Galvin GM. Intramuscular midazolam rapidly terminates seizures in children and adults. Emergency Medicine 1992 Jun; 4: 77-81. 12. Lahat E, Aladjem M, Eshel G etal. Midazolam in Treatment of Epileptic Seizures. Paediatr Neurol 1992 May-Jun; 8 (3):215-6. Midazolam ========= I was able to find only one reference to the use of ET midazolam and that was in an animal model (1). On the other hand, midazolam has been used, quite sucessfully, by the IM route in status and may be a better option particularly for those situations in the field where paralysis is not available and intubation difficult (2,3). Although lorazepam is most commonly used intravenously, it is well absorbed by the IM route as well and has been used this way, anecdotally, for status. I am not aware of any studies directly comparing the effectiveness of lorazepam vs midazolam for status but, at least theoretically, the former has the advantage of a much longer half-life which allows time for subsequently IV administered anticonvulsants (phenytoin) to kick in. Admittedly, the more rapid therapeutic effectiveness of fosphenytoin compared to phenytoin may make this distinction unimportant. H. Louzon MD (1) Jaimovich DG, Osborne JS 3d, Shabino CL Comparison of intravenous and endotracheal administration of midazolam and the effect on pulmonary function and histology in the lamb model. Ann Emerg Med 1992 May;21(5):480-5 OBJECTIVES: To determine the effect of endotracheal administration of midazolam on pulmonary function and histology in lambs. DESIGN: Prospective, randomized, controlled study. SETTING: Laboratory of the UpJohn Pharmaceutical Company. TYPES OF PARTICIPANTS: Twenty male and female lambs weighing 10 to 20 kg. INTERVENTIONS: The animals were anesthetized and placed on controlled ventilation. The animals were divided into four groups. The first two groups received endotracheal midazolam 0.1 and 0.2 mg/kg. The other two groups received IV midazolam 0.1 and 0.2 mg/kg. The endotracheal group had a catheter placed through the endotracheal tube, and midazolam was rapidly injected through the catheter followed by a 2-mL normal saline flush. Two rapid insufflations were administered, and the animals were then returned to the ventilator. Serum midazolam levels were drawn at one, two, five, ten, 15, and 20 minutes after both IV and endotracheal administration. Heart rate, respirations, SaO2 by oximetry, peak and mean airway pressure, compliance, airway resistance, and end-tidal CO2 were measured throughout the experiment. Lung sections were taken from control and treated animals receiving 0.1 and 0.2 mg/kg endotracheal midazolam, respectively. Sample lung sections were taken at 24, 48, and 120 hours after endotracheal midazolam administration. MEASUREMENTS AND MAIN RESULTS: There were no statistical or clinically significant differences for pulmonary function between endotracheally and IV-administered midazolam. Histologic examination of the lungs at 24, 48, and 120 hours after endotracheal midazolam showed no pathologic changes in the control and study animals. Acceptable serum midazolam levels were achieved endotracheally with no clinically deleterious effects. CONCLUSION: Endotracheal midazolam showed no significant deleterious effect on pulmonary function or histology in the lamb model. (2) Galdames Poblete D, Silva-Rosas C, Aguilera Olivares L [Treatment of status epilepticus with midazolam: report of four cases] Neurologia 1994 Mar;9(3):109-11 Midazolam is a water-soluble benzodiazepine imide that has been used in recent years to manage status epilepticus (SE). We describe four patients with SE refractory to conventional treatment, whose seizures were controlled with midazolam administered intramuscularly in two cases and intravenously in the remaining two. Given the pharmacokinetic traits of this drug, the intramuscular route offers great advantages. Midazolam also produces fewer side effects than do other benzodiazepines, suggesting the possibility of its use as a first line treatment for SE and frequent epileptic seizures. (3) Mayhue FE IM midazolam for status epilepticus in the emergency department. Ann Emerg Med 1988 Jun;17(6):643-5 A 71-year-old man presented with a continuous generalized tonic-clonic seizure of 80 minutes duration. Multiple attempts to establish an IV line failed. Ten milligrams of midazolam hydrochloride was administered IM and was followed by prompt termination of seizure activity. This report discusses the pharmacokinetic and anticonvulsant properties of midazolam as an alternative to diazepam for the initial treatment of status epilepticus. -------------- From: Garry Wilkes Brown A.F.T., Wilkes G.J. The Emergency Department Management of Status Epilepticus. Emerg Med 1994;6:49-61. :-) This is a different Brown to Simon Brown who has also done some preliminary work looking at good comparative study in children addressing the same issue. 54. Galvin GM, Jelinek GA. Midazolam: An effective intravenous agent for seizure control. Arch Emerg Med 1987;4:169-172. 55. Galvin GM, Jelinek GA. Successful treatment of 75 patients in status epilepticus with intravenous midazolam. Emergency Medicine 1992;4:11-12. 56. Kumar A, Bleck T. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 1992;20:483-488. 57. McDonagh TJ, Jelinek GA, Galvin GM. Intramuscular midazolam rapidly terminates seizures in children and adults. Emergency Medicine 1992;4:77-81. the final one is the one you are referring to. The study was quite good as the set up at Fremantle hospital is quite unique as it then stood. The ambulance entrance was one floor below the ED which meant a trolley ride up the corridor, in the lift, up a floor, down the corridor, around the corner, up to the ED (past the waiting room and the pan room), in to the department and then to the resus bay at the end. Quite a protracted trip really! The ambulance was met at the bay by a doctor with a syringe full of midazolam and a stop watch. If the seizure had not ceased by 6 minutes midazolam was given IV. As it turned out it took almost that long to get the IV in with the patient stationary in a bed anyway. Almost all of the patients (about 40 from memory) had stopped ceasing by that time despite fitting for at least 20 minutes before arrival. No patient needed ventilation even though some were sedated for a while. This study has been used to validate the safety of IM use which has now been adopted by most ambulance services in Australia. ------------