www.elsevier.com/locate/ajem
`
`American Journal of Emergency Medicine (2006) 24, 343 – 346
`
`Therapeutics
`
`Intranasal midazolam therapy for pediatric
`B
`status epilepticus
`
`Timothy R. Wolfe MD*, Thomas C. Macfarlane MD
`
`Department of Emergency Medicine, Jordan Valley Hospital, West Jordan, UT 84088, USA
`
`Received 5 November 2005; accepted 7 November 2005
`
`Abstract 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.
`D 2006 Elsevier Inc. All rights reserved.
`
`1. Introduction
`
`The cumulative lifetime incidence of epilepsy is 3%,
`with half of
`these cases beginning in childhood [1].
`Approximately 10% to 20% of childhood epilepsy is
`refractory to medications, resulting in frequent breakthrough
`seizure episodes [1]. Most of these seizures are brief and
`resolve without treatment. However, if they persist for more
`than 5 minutes, prompt intervention is recommended [2].
`Early antiepileptic intervention in an actively seizing patient
`
`B
`
`Financial disclosure: Dr Wolfe is the medical director and a
`shareholder in Wolfe Tory Medical, a company that manufactures MAD
`mucosal atomization devices for nasal medication delivery. He has not
`participated with nor influenced any of the research studies presented in
`this document.
`* Corresponding author. 1119 East Alpine Place, Salt Lake City, UT
`84105, USA. Tel.: +1 801 910 8518 (office), +1 801 583 1540 (home);
`fax: +1 801 281 0708 (office), +1 801 583 1540 (home).
`E-mail address: wolfeman@csolutions.net (T.R. Wolfe).
`
`0735-6757/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
`doi:10.1016/j.ajem.2005.11.004
`
`reduces seizure duration, decreasing both morbidity and
`mortality [3,4]. Because most episodes of prolonged seizure
`activity begin outside the hospital, parents and caretakers
`need simple, safe, and effective treatment options to ensure
`early intervention. Currently, diazepam and lorazepam are
`the most widely used medications for
`the emergent
`management of seizures in both adults and children [5-7].
`Diazepam must be given intravenously (IV) or rectally
`because absorption is slow and erratic if given via the
`intramuscular route [8,9]. Lorazepam may be administered
`via the IV, intramuscular, or transmucosal route [10,11].
`Outside the hospital, where IV and intramuscular therapy
`may be difficult or impossible, transmucosal rectal diaze-
`pam has emerged as the primary treatment option for
`breakthrough seizures. Unfortunately, compared with the IV
`formulation, rectal diazepam has a slower onset of action
`and is less effective at controlling seizures [8,12-15]. Rectal
`drug administration is also less socially acceptable than
`other
`routes, making medication compliance an issue
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`344
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`T.R. Wolfe, T.C. Macfarlane
`
`Table 1 Average wholesale prices for benzodiazepines commonly used to treat seizures
`
`Medication
`
`Diastat
`
`Diazepam
`
`Midazolam
`
`Lorazepam
`
`Packaging
`AWP
`
`10 mg (twin pack—2 doses)
`$117.43 per dose
`
`5 mg/mL (2-mL vial)
`$2.53
`
`5 mg/mL (2-mL vial)
`$3.20
`
`2 mg/mL (1-mL vial)
`$6.43
`
`AWP, average wholesale price.
`
`[16-18]. Finally, because of patent protection, the commer-
`cially available rectal diazepam product
`(Diastat-Xcel
`pharmaceuticals, San Diego, Calif) is considerably more
`expensive than generic formulations of other commonly
`used benzodiazepines, making affordability difficult for
`some families (see Table 1).
`Transmucosal delivery of generic benzodiazepines via
`the nasal mucosa offers an attractive and cost-effective
`alternative in the out-of-hospital setting. Midazolam and
`lorazepam easily cross the nasal mucosa and the blood brain
`barrier, resulting in a rapid rise in both the plasma and the
`cerebrospinal fluid concentrations [11,13,19]. Numerous
`studies now demonstrate the efficacy and safety of
`intranasal benzodiazepines for seizure treatment, both
`within the hospital, prehospital, extended care, and home
`settings [15-18,20-25]. The following discussion will
`review the concept of intranasal medication delivery and
`the literature that supports hospital and home-based
`management of seizures with intranasal benzodiazepines.
`
`2. Discussion
`
`Transmucosal intranasal benzodiazepine delivery for the
`treatment of breakthrough seizures offers several advantages
`over transmucosal rectal delivery. First of all, intranasal
`benzodiazepine delivery is easily understood and mastered
`by the lay public and does not carry the social
`taboos
`associated with rectal drug delivery [16-18,25]. Secondly,
`the nasal mucosa provides a large (180 cm2), highly
`vascular absorptive surface sitting adjacent
`to the brain
`[26]. This vascular plexus and the adjacent olfactory mucosa
`provide direct routes for benzodiazepine absorption into the
`blood stream and the cerebral spinal fluid [27,28]. In fact,
`within a few minutes of delivery, serum levels of intranasal
`midazolam are comparable with injectable levels [13]. In
`contrast, rectal administration of benzodiazepines results in
`substantially lower blood levels than IV administration
`[8,12]. The result is higher blood levels, faster onset of
`action, and more effective seizure control with intranasal
`than with rectally administered benzodiazepines [8,12-15].
`However,
`to achieve optimal results using intranasal
`benzodiazepine delivery,
`it
`is important
`to use highly
`concentrated medications delivered as a thin layer over the
`mucosa. Too much medication will run out of the nose or
`down the back of
`the throat, rendering it
`ineffective.
`Therefore, volumes more than about 1/2 mL per nostril
`are not optimally absorbed [29]. Absorption can be further
`enhanced if half the medication is placed into each nostril,
`
`cutting the volume per nostril in half while doubling the
`surface area available for absorption. The method chosen to
`deliver the medication to the nasal mucosa is also important.
`Covering a large mucosal surface area with a thin layer of
`medication will
`result
`in better drug absorption than
`administration of large droplets to a small surface area
`[27]. Nasal medication bioavailability increases as the drug
`delivery system is changed from a drop form to a spray form
`to an atomized form [28,30].
`Three randomized controlled trials and 1 prehospital
`observational trial exist, comparing rectal diazepam to either
`buccal
`(oral
`transmucosal) or
`intranasal midazolam
`[15,24,31,32]. Scott et al [32] conducted a randomized
`controlled trial comparing buccal midazolam to rectal
`diazepam in epileptic students in an extended care school.
`A school nurse administered medication to all students who
`suffered continuous seizures for more than 5-minutes.
`Patients with persistent seizures for an additional 10 minutes
`were treated at
`the on-call physician’s discretion. Oral
`transmucosal midazolam was effective in 75% of cases
`(30 of 40 seizures), whereas rectal diazepam was effective in
`59% (23/39) ( P = non significant). There were no adverse
`cardiorespiratory effects in either group. Although these
`differences did not achieve statistical significance, the trend
`toward a better outcome along with the more socially
`acceptable delivery of oral transmucosal medication led the
`school to change its preferred treatment to the oral trans-
`mucosal route. Camfield et al [31] found similar efficacy in
`their randomized trail comparing these 2 routes and drew
`identical conclusions — oral transmucosal midazolam was
`preferred over rectal diazepam because of ease of use and
`social acceptability. The third randomized controlled trial,
`conducted by Fisgin et al, compared intranasal (rather than
`buccal) transmucosal midazolam to rectal diazepam [15]. In
`this study, midazolam aborted 20 (87%) of 23 seizures and
`rectal diazepam 13 (60%) of 22 seizures ( P b .05). These
`results were statistically significant in favor of the intranasal
`route when compared with the rectal route. Again, as in
`previous studies, no clinically important adverse events
`were identified in the 2 groups. The final study was
`conducted in a prehospital ambulance setting [24]. In this
`study, the entire emergency medical system converted from
`rectal diazepam to intranasal midazolam for treatment of
`pediatric seizures. The authors compared effectiveness and
`complication data before and after the change. The rates of
`prehospital seizure control (100% vs 78%), need for need
`for emergent intubation (0% vs 33%), and need for hospital
`admission (40% vs 89%) were all substantially less in the
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`Intranasal midazolam for seizures
`
`345
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`intranasal midazolam group compared with the rectal
`diazepam group. All
`these authors conclude that
`trans-
`mucosal midazolam is more convenient, easier to use, just
`as safe, and is more socially acceptable than rectal
`diazepam. Furthermore, when given via the intranasal route,
`midazolam is more effective than rectal diazepam.
`The above evidence clearly suggests that
`intranasal
`midazolam is superior to rectal midazolam for seizure therapy
`in children. However, IV benzodiazepines are first-line
`therapy in most hospitals — how does intranasal midazolam
`compare to IV benzodiazepines? Two randomized controlled
`trials comparing intranasal midazolam to IV diazepam
`answer this question [22,23]. Lahat et al [22] compared
`intranasal midazolam to IV diazepam in children seizing
`10 minutes or longer. Patients were randomized to receive
`diazepam, 0.3mg/kg IV, or midazolam 0.2 mg/kg intranasal-
`ly. Nasal midazolam stopped 23 (88%) of 26, whereas
`24 (92%) of 26 were controlled with IV diazepam ( P = non
`significant). The mean time from patient arrival to seizure
`cessation was 6.1 minutes with midazolam and 8.0 minutes
`with diazepam. The authors conclude that intranasal mid-
`azolam was as safe and effective as IV diazepam, but the
`overall
`time to cessation of seizures after arrival at the
`hospital was faster with intranasal midazolam because of the
`time required to establish an IV line in the diazepam group. A
`similar study was conducted by Mahmoudian and Zadeh
`[23]. These authors compared the efficacy of intranasal
`midazolam (0.2 mg/kg) to IV diazepam (0.2 mg/kg) in
`70 patients (ages 2 to 15 years) presenting to the emergency
`department with seizure activity. Both methods were equally
`effective, and no adverse effects occurred in either group.
`These authors conclude that nasal midazolam should be
`used not only in medical centers but also in general
`practitioners’ offices as well as at home by families of
`seizure-prone children after appropriate instruction.
`Perhaps the greatest benefit of intranasal midazolam will
`be for the treatment of seizures in the prehospital, home or
`extended care setting. Wilson et al [17] sent
`intranasal
`midazolam home with families of children suffering
`epilepsy and found that 33 (83%) of 40 who used it found
`it effective and 83% (20/24) preferred using transmucosal
`midazolam to rectal diazepam. Harbord et al [18] reported
`experience using intranasal midazolam for home treatment
`of 54 seizures in 22 children. These authors found it to be
`89% effective, with no evidence of respiratory compromise.
`Ninety percent of families found no difficulty with nasal
`medication administration. Of the 15 parents with previous
`rectal diazepam experience, 13 thought intranasal delivery
`was easier and 14 preferred it to the rectal route. Jeannet et al
`[25] used intranasal midazolam both on the medical wards
`and as home therapy. Their experience with 26 children
`suffering 125 seizures note a 98% effectiveness in less than
`10 minutes, with no serious adverse effects. When compared
`with rectal diazepam, they report that the intranasal route
`was both easier to use and that postictal recovery was faster.
`
`Scheepers et al [16] report their experience with intranasal
`medication delivery in an extended care facility caring for
`adolescents and adults with severe epileptic disorders. Of
`84 uses, they found this route to be effective in 79 (94%). In
`the 5 instances when it was not effective, 3 of the 5 doses
`were delivered intraorally rather than intranasally.
`All these reports confirm that intranasal midazolam is
`safe and effective for treating seizures in the hospital,
`prehospital, and outpatient settings. Compared with the
`current bstandardQ of rectal diazepam, intranasal midazolam
`is preferred because of its superior efficacy, ease of use,
`reduced postictal period, and more dignified route of
`administration. These findings all suggest that intranasal
`midazolam should replace rectal diazepam as the preferred
`method for treating prolonged seizures in patients without
`IV access in place.
`In conclusion, intranasal midazolam offers a simple, safe,
`and effective way to treat prolonged seizures. This therapy
`is proven to effectively terminate and control most acute
`seizures. It is as effective as IV diazepam and more effective
`than rectal diazepam. Parents, caregivers, paramedics,
`nurses, and physicians can easily learn intranasal midazolam
`delivery. It is as safe as traditional rectal and IV delivery
`methods, and it is more dignified than rectal diazepam.
`Emergency physicians who manage epileptic children
`should consider intranasal midazolam as viable method to
`control breakthrough seizures at home, in the prehospital
`setting, and in the emergency department.
`
`References
`
`In: Behrman RE, editor.
`[1] Johnston MV. Seizures in childhood.
`Nelson textbook of pediatrics. Philadelphia7 W.B. Saunders; 2004.
`p. 1994 - 2009.
`[2] Lowenstein DH. Status epilepticus: an overview of the clinical
`problem. Epilepsia 1999;40(Suppl 1):S3 - S8.
`[3] Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of
`lorazepam, diazepam, and placebo for the treatment of out-of-hospital
`status epilepticus. N Engl J Med 2001;345:631 - 7.
`[4] Bassin S, Smith TL, Bleck TP. Clinical review: status epilepticus. Crit
`Care 2002;6:137 - 42.
`[5] DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective,
`population-based epidemiologic study of status epilepticus in Rich-
`mond, Virginia. Neurology 1996;46:1029 - 35.
`[6] Gilbert DL, Gartside PS, Glauser TA. Efficacy and mortality in
`treatment of refractory generalized convulsive status epilepticus in
`children: a meta-analysis. J Child Neurol 1999;14:602 - 9.
`[7] Pang T, Hirsch LJ. Treatment of convulsive and nonconvulsive status
`epilepticus. Curr Treatm Opt Neurol 2005;7:247 - 59.
`[8] Magnussen I, Oxlund HR, Alsbirk KE, Arnold E. Absorption of
`diazepam in man following rectal and parenteral administration. Acta
`Pharmacol Toxicol (Copenh) 1979;45:87 - 90.
`[9] Hung OR, Dyck JB, Varvel J, Shafer SL, Stanski DR. Comparative
`absorption kinetics of intramuscular midazolam and diazepam. Can J
`Anaesth 1996;43:450 - 5.
`lorazepam in childhood serial
`[10] Yager JY, Seshia SS. Sublingual
`seizures. Am J Dis Child 1988;142:931 - 2.
`[11] Wermeling DP, Miller JL, Archer SM, Manaligod JM, Rudy AC.
`Bioavailability and pharmacokinetics of lorazepam after intranasal,
`
`AQUESTIVE EXHIBIT 1110 Page 0003
`
`

`

`346
`
`T.R. Wolfe, T.C. Macfarlane
`
`intravenous, and intramuscular administration. J Clin Pharmacol 2001;
`41:1225 - 31.
`[12] Dhillon S, Oxley J, Richens A. Bioavailability of diazepam after
`intravenous, oral and rectal administration in adult epileptic patients.
`Br J Clin Pharmacol 1982;13:427 - 32.
`[13] Knoester PD, Jonker DM, Van Der Hoeven RT, et al. Pharmacoki-
`netics and pharmacodynamics of midazolam administered as a
`concentrated intranasal spray. A study in healthy volunteers. Br J
`Clin Pharmacol 2002;53:501 - 7.
`[14] Remy C, Jourdil N, Villemain D, Favel P, Genton P. Intrarectal
`diazepam in epileptic adults. Epilepsia 1992;33:353 - 8.
`[15] Fisgin T, Gurer Y, Tezic T, et al. Effects of intranasal midazolam and
`rectal diazepam on acute convulsions in children: prospective
`randomized study. J Child Neurol 2002;17:123 - 6.
`[16] Scheepers M, Scheepers B, Clarke M, Comish S, Ibitoye M. Is
`intranasal midazolam an effective rescue medication in adolescents
`and adults with severe epilepsy? Seizure 2000;9:417 - 22.
`[17] Wilson MT, Macleod S, O’Regan ME. Nasal/buccal midazolam use in
`the community. Arch Dis Child 2004;89:50 - 1.
`[18] Harbord MG, Kyrkou NE, Kyrkou MR, Kay D, Coulthard KP. Use of
`intranasal midazolam to treat acute seizures in paediatric community
`settings. J Paediatr Child Health 2004;40:556 - 8.
`[19] Malinovsky JM, Lejus C, Servin F, et al. Plasma concentrations of
`midazolam after i.v., nasal or rectal administration in children. Br J
`Anaesth 1993;70:617 - 20.
`[20] Fisgin T, Gurer Y, Senbil N, et al. Nasal midazolam effects on
`childhood acute seizures. J Child Neurol 2000;15:833 - 5.
`[21] Kutlu NO, Yakinci C, Dogrul M, Durmaz Y. Intranasal midazolam for
`prolonged convulsive seizures. Brain Dev 2000;22:359 - 61.
`[22] Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison
`of intranasal midazolam with intravenous diazepam for treating febrile
`
`seizures in children: prospective randomised study. BMJ 2000;
`321:83 - 6.
`[23] Mahmoudian T, Zadeh MM. Comparison of intranasal midazolam
`with intravenous diazepam for treating acute seizures in children.
`Epilepsy Behav 2004;5:253 - 5.
`[24] Holsti M, Sill BL, Firth SD, Joyce SM, Filloux F, Furnival RA.
`Prehospital
`intranasal versed for pediatric seizures, American
`Academy of Pediatrics National Meeting, San Francisco 2004;
`[Abstract presentation].
`[25] Jeannet PY, Roulet E, Maeder-Ingvar M, Gehri M, Jutzi A, Deonna T.
`Home and hospital treatment of acute seizures in children with nasal
`midazolam. Eur J Paediatr Neurol 1999;3:73 - 7.
`[26] Stanley TH. Anesthesia for the 21st century. BUMC Proceedings
`2000;13:7 - 10.
`[27] Chien YW, Su KSE, Chang SF. Chapter 1: anatomy and physiology
`of the nose. Nasal systemic drug delivery. New York7 Dekker; 1989.
`p. 1 - 26.
`[28] Henry RJ, Ruano N, Casto D, Wolf RH. A pharmacokinetic study of
`midazolam in dogs: nasal drop vs. atomizer administration. Pediatr
`Dent 1998;20:321 - 6.
`[29] Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids
`for pain management in adults. Acta Anaesthesiol Scand 2002;46:
`759 - 70.
`[30] Mygind N, Vesterhauge S. Aerosol distribution in the nose. Rhinology
`1978;16:79 - 88.
`[31] Camfield PR. Buccal midazolam and rectal diazepam for treatment of
`prolonged seizures in childhood and adolescence: a randomised trial.
`J Pediatr 1999;135:398 - 9.
`[32] Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal
`diazepam for treatment of prolonged seizures in childhood and
`adolescence: a randomised trial. Lancet 1999;353:623 - 6.
`
`AQUESTIVE EXHIBIT 1110 Page 0004
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