Controlling seizures in children: diazepam or midazolam? Systematic review

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1 Hong Kong Journal of Emergency Medicine Controlling seizures in children: diazepam or midazolam? Systematic review D Doshi Introduction: Diazepam is commonly used to treat acute childhood seizures, but difficulty gaining intravenous access and variability of absorption after rectal administration can limit its efficacy. Midazolam is a water soluble benzodiazepine that has a rapid onset of action after intranasal or buccal administration and provides an alternative to diazepam in the control of acute childhood seizures. Methods: A literature search was performed to identify papers comparing the efficacy and tolerability of midazolam and diazepam in the management of childhood seizures. Results: Intranasal or buccal midazolam are at least as effective as rectal or intravenous diazepam in controlling acute childhood seizures. In all robust studies reporting a significant difference, time to gain seizure control was shorter in patients treated with midazolam than those treated with diazepam, predominantly due to shorter drug administration time. The incidence of seizure recurrence was lower in patients treated with midazolam than diazepam. Respiratory depression was uncommon in both groups. Conclusion: Intranasal or buccal midazolam provides a safe, effective and acceptable alternative to intravenous or rectal diazepam in the management of acute childhood seizures. (Hong Kong j.emerg.med. 2010;17: ) Keywords: Benzodiazepines, buccal administration, rectal administration Introduction The incidence of epilepsy in developed societies has been estimated to range from 40 to 70 cases per 100,000 persons per year. 1-4 In the UK, the overall Correspondence to: Deepak Doshi, FCEM, MRCSEd(A&E), DCH Royal Manchester Children's Hospital, Emergency Department, Manchester M13 9WL, United Kingdom drdeepdoshi@yahoo.com incidence is 66.3 cases per 100,000 persons per year. 5 Almost half of these cases occur in children. 6 Most childhood seizures are brief and resolve without treatment but in those that do not, early use of effective medication that reduces seizure duration has been shown to decrease morbidity and mortality. 7 However, approximately 10% to 20% of seizures are refractory to currently used medication. 6 Diazepam is a benzodiazepine that has been extensively used in the management of epileptic seizures for four

2 Doshi/Controlling seizures in children 197 decades. 8 It has a rapid onset of action (usually 3-5 minutes) and a short duration of action (20-30 minutes). 9 Rectal diazepam is generally regarded as the gold-standard of prehospital management of acute childhood seizures. 10 Because diazepam accumulates in fat stores, repeated doses can lead to a prolonged period of sedation. 10 Cardio-respiratory depression and hypotension can also occur. 6 Administration of rectal diazepam can be embarrassing and awkward and absorption is variable. 11 First pass metabolism can lead to significant drug inactivation before therapeutic effects are achieved. 12 Midazolam is an imidazobenzodiazepine with sedative, amnesic, anxiolytic, muscle relaxant and anticonvulsant properties. 13 It is more potent than diazepam and has a rapid onset of action (2-3 minutes). 14 Midazolam can be administered intravenously, intramuscularly, rectally, buccally or intranasally. For acute childhood seizures, intranasal and buccal routes provide rapid absorption into the systemic circulation over a large surface area and are less invasive than rectal anticonvulsant administration. 15,16 Midazolam's short half-life also means it has a lower potential than diazepam for drug accumulation and prolonged sedation. 11,13,16 This clinical topic review aims to compare the efficacy and tolerability of diazepam and midazolam in the control of paediatric seizures. Literature review Search strategy The following listed were accessed through Athens login via the Dialog Datastar interface. Science Direct, Proquest and ejournals were accessed and searched directly (Figure 1). Figure 1. Literature search flow chart.

3 198 Hong Kong j. emerg. med. Vol. 17(2) Apr 2010 MEDLINE 1950 to date The search was conducted on 15 October Search terms were chosen based on previous Best Evidence Topics: Midazolam OR Diazepam OR Benzodiazepine OR Fit OR Seizure OR Convulsion OR Epilepsy. Terms were exploded to maximise the chance of success. Results were limited to English, as translation facilities were not available, and limited to children for relevance to the chosen topic. The search returned 332 results. The titles and abstracts of these were reviewed to identify journal articles relevant to the clinical review topic. A total of 21 relevant articles were selected for analysis. EMBASE 1974 to date Search terms similar to those for the MEDLINE search were chosen. Duplicates were removed from the two databases. The search returned 1030 results. Two new articles were found. On review, one was considered relevant to the search and was added to the analysis. COCHRANE The search was conducted on 15 October Search terms were similar to those for the MEDLINE search. The search returned 43 hits, one of which was considered relevant. Cross references All selected articles, reviews and letters to the editors were reviewed for relevant cross references. Two case reports were added to the review and two articles related to the pharmacology of benzodiazepines were studied. Web resources The following web resources were accessed: Emedicine ( Google ( BestBETs ( Bandolier ( OMNI ( NeLH ( CINAHL ( Epilepsy action ( Textbooks and other materials The following textbooks were accessed: Nelson textbook of pediatrics (17th edition) Emergency medicine: a comprehensive study guide (6th edition) National Institute for Health and Clinical Excellence (NICE) guidelines. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care Scottish Intercollegiate Guidelines Network (SIGN) guidelines. Diagnosis and management of epilepsies in children and young people Advanced Pediatric Life Support (APLS) manual Review process Relevant journal articles were obtained through a number of public, medical and university libraries, the Royal College of Surgeons of Edinburgh and the Information Manager of Manchester Royal Infirmary Emergency Department. Each paper was graded according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Grey literature Several authors involved in the study of midazolam versus diazepam were contacted and two ongoing studies were identified: one in Kenya Medical Research Institute, Kilifi, headed by Simon Muchohi; and another in Salt Lake City, USA, headed by Maija Holsti. Data collection for the latter was designed to compare intranasal midazolam with diazepam. The International Clinical Trials Registry Platform ( and The National Research Register ( were searched for any unpublished trials. No study was found. Inclusion and exclusion criteria All studies in which drugs were administered were included, even when drug administration occurred at the beginning of the seizure. No differentiation was made between first episode or repeated seizures. Studies of patients with status epilepticus were excluded from this review. Level 3 and 4 studies were excluded after analysis, due to the poor quality of evidence.

4 Doshi/Controlling seizures in children 199 Results A total of 24 papers comparing midazolam with diazepam in acute childhood seizures were found. Two of the papers were level 3, one was a retrospective study, while eleven papers were level 4 case reports or uncontrolled cohort studies and these were not included due to their poor quality of evidence. The results of the remaining 10 papers are summarised (Tables 1-3). Discussion An ideal anticonvulsant should be safe, effective, easy to administer, rapid-acting and cost-effective. Diazepam has been used in the management of epilepsy and other convulsive syndromes for the past four decades and controls seizures in 60-80% of the cases. 27 However, orally administered preparations of diazepam are too slow acting for acute use and intramuscular formulations have variable absorption. 28,29 In acute seizures, therefore, intravenous or rectal preparations of diazepam are usually used, but gaining intravenous access in convulsing children is difficult and rectal drug administration may be embarrassing. Of the four randomised, controlled trials reviewed that compared buccal midazolam with rectal diazepam, Mpimbaza et al and McIntnyre et al found that significantly more children achieved seizure control within 10 minutes when treated with midazolam than with diazepam, while Baysun et al and Scott et al found no difference between treatments Seizure recurrence was significantly less common in children treated with midazolam than diazepam, in the two studies reporting on it. 17,18 In all studies, respiratory depression was uncommon in either treatment group Three studies were reviewed that compared intranasal midazolam with rectal diazepam Bhattacharyya et al and Fisgin et al found that more children achieved seizure control within 10 minutes with midazolam than diazepam, although in the Bhattacharyya et al study, the difference was not statistically significant; and in the Holsti et al study, seizure control within 10 minutes was not reported. 21,22 The time to seizure cessation was significantly shorter in patients treated with midazolam than diazepam, in the two studies reporting on it. 22,23 The Bhattacharyya et al study examined the time to drug administration and found it to be significantly shorter in the midazolam group. 22 No significant difference was found in the rate of seizure recurrence within one hour. 21 Holsti et al showed that respiratory depression was significantly less common in children treated with midazolam than diazepam. 21 In the other studies, respiratory depression was uncommon in either group. 22,23 Three studies in this review compared intranasal midazolam with intravenous diazepam Lahat et al and Mittal et al found that the mean time to seizure cessation was significantly lower in children treated with midazolam than diazepam. 25,26 Although Mahmoudian et al found that seizures were controlled an average of 40 seconds faster with diazepam treatment, they did not include the time taken to gain intravenous access, 24 and therefore does not reflect the clinical reality of the situation. The other studies both reported that drug administration was significantly faster in children treated with midazolam, 25,26 suggesting that the difference in the results between these studies may be due to these methodological differences. No significant adverse events, including respiratory depression, were reported in these studies Overall, this literature review has demonstrated that midazolam is at least as effective as diazepam in controlling acute childhood seizures. Seizure control was gained as rapidly or significantly more rapidly in children treated with midazolam than those treated with diazepam in all studies except one, and this study was flawed as it did not take into account the time required to gain intravenous access in order to administer diazepam. 24 Notably, the time required to administer midazolam, by either the intranasal or intramuscular route, was significantly faster than the time required to administer intravenous diazepam in all studies that examined it. 22,25,26,32 Diazepam rectal preparation of 10 mg in 2.5 ml costs 1.96 whereas the cost of 10 mg midazolam, prepared in 1 ml solution for buccal administration (Epistatus), marketed by special products company in the UK, is

5 200 Hong Kong j. emerg. med. Vol. 17(2) Apr 2010 Table 1. Buccal midazolam versus rectal diazepam Author, date Patient group Study type and Outcomes Key results Study weaknesses and country evidence level Mpimbaza 330 children Prospective, Treatment failure Significantly lower Study terminated at 330 et al, 2008 (3 months to 12 single-blind, (persistence of in BM group patients as a significant Uganda 17 years) presenting to randomised, seizure beyond (30.3% vs. 43%; difference was paediatric ED with controlled trial 10 min or recurrence p=0.016) discovered convulsion or seizure within 1 hour) lasting >5 min Level 1 Recurrence of Significantly lower in seizure within 1 hour BM group (8% BM vs. BM plus rectal placebo vs. 17.5% RD; p=0.026) RD plus buccal placebo Respiratory Uncommon (2 patients depression in each group) McIntyre 219 seizure episodes in Prospective, Treatment success Significantly higher Data from one hospital et al, children randomised, (cessation of seizure in BM group (33% was incomplete UK 18 ( 6 months) multicentre, within 10 min vs. 14%; p<0.001) presenting to hospital controlled trial without recurrence Children given diazepam with active seizures within 1 hour and before they arrived at and no IV access Level 1 without respiratory hospital were excluded, depression) resulting in selection BM vs. RD Recurrence of Significantly lower bias seizure within 1 hour in BM Group (41% vs. 65%; p=0.02) No blinding Respiratory No significant depression difference (5% BM vs. 6% RD) Baysun 43 children (2 months Prospective, Cessation of seizure No significant Small sample size et al, 2005 to 12 years) presenting randomised, within 10 min difference (78% Turkey 19 to paediatric ED with controlled study BM vs. 85% RD; Recurrence of seizure acute convulsions p>0.05) activity not reported Level 1 Respiratory 1 patient in the BM vs. RD depression RD group No blinding Scott 79 seizure episodes Prospective, Cessation of seizure No significant Small sample size et al, 1999 of >5 min in 28 young randomised within 10 min difference (75% BM UK 20 people at a residential trial vs. 59% RD; p=0.16) Recurrence of seizure centre Median time from No significant activity not reported Level 1 drug administration difference (6 min BM vs. RD to cessation of seizure BM vs. 8 min RD; No blinding p=0.31) Cardiorespiratory AEs No clinically important AEs AEs=adverse events; BM=buccal midazolam; ED=emergency department; RD=rectal diazepam

6 Doshi/Controlling seizures in children 201 Table 2 Intranasal midazolam versus rectal diazepam Author, date Patient group Study type and Outcomes Key results Study weaknesses and country level of evidence Holsti 57 children (<18 Retrospective Presence of seizure Significantly lower in Small sample size et al, 2007 years) with seizure cohort study in ED IN-M group (38% USA 21 activity >5 min in vs. 72%; p value Retrospective data the presence of Level 2 not reported) collection means emergency medical Total seizure duration Significantly lower in some data were services who received IN-M group (25 min incomplete prehospital treatment vs. 45 min; p<0.001) Respiratory Significantly lower in No randomisation Prehospital IN-M vs. complications IN-M group prehospital RD controls Median total Significantly lower in Seizure recurrence hospital charges IN-M group ($1459 not reported vs. $6980; p<0.0001) Bhattacharyya 188 seizure episodes in Prospective, Cessation of seizure No significant No blinding et al, children (3 months randomised, within 10 min difference (96.7% India 22 to 12 years) controlled trial IN-M vs. 88.5% RD; p=0.06) IN-M vs. RD Level 1 Mean seizure Significantly shorter cessation time in IN-M group (116.7 seconds vs seconds; p=0.005) Drug administration Significantly shorter time in IN-M group (50.6 seconds vs seconds; p=0.002) Recurrence of seizure No significant within 1 hour difference (3% IN-M vs. 6.25% RD) Respiratory AEs Decrease in mean respiratory rate and SaO 2 noted in RD group only AEs of vomiting and Significantly lower in excessive drowsiness IN-M group (0% vs. 10.4%; p=0.009) Fisgin 45 children (1 month Prospective, Cessation of seizure Significantly higher Small sample size et al, 2002 to 13 years) admitted randomised, within 10 min in IN-M group Turkey 23 to paediatric ED with controlled (87% vs. 60%; Seizure recurrence acute convulsions study p>0.05) not reported lasting 5 min AEs 1 patient with Level 1 tachypnoea and IN-M vs. RD 1 with tachycardia in IN-M group AEs=adverse events; ED=emergency department; IN-M=intranasal midazolam; RD=rectal diazepam

7 202 Hong Kong j. emerg. med. Vol. 17(2) Apr 2010 Table 3. Intranasal midazolam versus intravenous diazepam Author, date Patient group Study type and Outcomes Key results Study weaknesses and country evidence level Mahmoudian 70 children (2 months Prospective, Mean time to Significantly longer Mean time to cessation and Zadeh, to 15 years) with acute randomised, cessation of in IN-M group of seizures did not 2004 seizures admitted to controlled trial seizures (3.58 min vs. include time taken to Iran 24 paediatric ED 2.94 min; p=0.007) gain IV access for Level 1 Cessation of No significant IV-D group so does IN-M vs. IV-D seizure within difference (100% not reflect total 10 min both groups) seizure activity time AEs No significant AEs Seizure recurrence not reported No blinding Lahat 47 children (6 months Prospective, Time from arrival Significantly shorter Small sample size et al, 2000 to 5 years) with febrile randomised, to treatment in IN-M group Israel 25 seizures lasting controlled trial (3.5 min vs. 5.5 min; No blinding 10 min admitted to p value not reported) paediatric ED Level 1 Time to cessation Significantly shorter Seizure recurrence not of seizures in IN-M group reported IN-M vs. IV-D (6.1 min vs. 8.0 min; p value not reported) Treatment success No significant (seizures controlled difference (88.5% within 5 min) IN-M vs. 92.3% IV-D; p value not reported) AEs No significant AEs Mittal 125 children enrolled Prospective, Mean time from Significantly shorter Two variables were et al, 2006 for seizure episodes randomised, arrival at hospital to in IN-M group studied - seizures and India 26 (n=76) or various controlled trial drug administration (2.34 min vs. procedures; paper is invasive/non-invasive 4.61 min; p<0.001) unclear whether procedures (n=49) Level 1 Mean time to Significantly longer results include all seizure cessation in IN-M group patients or seizure IN-M vs. IV-D for after drug (2.97 min vs. patients only seizure control or administration 1.92 min; p<0.001) sedation Small sample size Mean time to seizure Significantly shorter cessation after in IN-M group No blinding arrival at hospital (5.25 min vs min; p<0.001) Seizure recurrence Cardiorespiratory No significant changes not reported AEs in cardiorespiratory parameters in either group AEs=adverse events; ED=emergency department; BM=buccal midazolam; IN-M=intranasal midazolam; IV-D=intravenous diazepam

8 Doshi/Controlling seizures in children 203 priced at 6.76 ( Epistatus comes in a vial of 10 mg x 4 doses. An oral syringe is supplied with the bottle of Epistatus for ease of administration. One half of the prescribed dose can be administered on one side between the gum and cheek or into one nostril, and the other half on the other side. Midazolam is not licensed in the UK for use in controlling seizures in children. A survey of five European hospitals, which analyzed 2262 prescriptions administered to 624 children, found that almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. On the whole, over half of the patients (421; 67%) received an unlicensed or off label prescription. 33 NICE guidelines for the treatment of prolonged and repeated seizures in the community recommend that buccal midazolam should be used according to an agreed protocol drawn up by the specialist and only used following training (www. nice.org.uk). There are several NHS (National Health Service) trusts in the UK which have drawn up protocol for the use of buccal midazolam by clinicians, families and/or carers. On the basis of available evidence from this clinical topic review and in accordance with the NICE and APLS guidelines, I have suggested a protocol for the use of midazolam in controlling seizures in children (Appendix). It is, however, important to note that midazolam is not currently licensed for this use in the UK and therefore local consensus from the specialist team and ethics committee should be sought prior to its use. Conclusion In conclusion, intranasal or buccal midazolam provides a safe, effective and convenient alternative to intravenous or rectal diazepam in the management of acute childhood seizures. References 1. MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 2000;123(Pt 4): Goodridge DM Shorvon SD. Epileptic seizures in a population of I: Demography, diagnosis and classification, and role of the hospital services. BMJ 1983; 287(6393): Goodridge DM, Shorvon SD. Epileptic seizures in a population of II: Treatment and prognosis. BMJ 1983;287(6393): Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through Epilepsia 1975;16(1): Reading R, Haynes R, Beach R. Deprivation and incidence of epilepsy in children. Seizure 2006;15(3): Johnston M. Seizures in childhood. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics, 17th ed. Philadelphia: WB Saunders; p Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345(9): Erratum in: N Engl J Med 2001;345(25): Martin J. Acute repetitive seizures and seizure emergencies: weighing your treatment options. Epilepsy.com. [published 2005 Mar 3]. [cited 2009 Nov 28]. Available from: 9. Bebin EM. Additional modalities for treating acute seizures in children: overview. J Child Neurol 1998;13 Suppl 1: S23-6; discussion S Eriksson K, Kalviainen R. Pharmacologic management of convulsive status epilepticus in childhood. Expert Rev Neurother 2005;5(6): Wallace SJ. Nasal benzodiazepines for management of acute childhood seizures? Lancet 1997;349(9047): De Boer AG, De Leede LG, Breimer DD. Drug absorption by sublingual and rectal routes. Br J Anaesth 1984;56(1): Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet 1998;35(1): Pieri L. Preclinical pharmacology of midazolam. Br J Clin Pharmacol 1983;16 Suppl 1:17S-27S. 15. Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med 2006;24 (3): Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics, and efficacy; in insomnia and anesthesia. Pharmacotherapy 1985;5(3): Mpimbaza A, Ndeezi G, Staedke S, Rosenthal P, Byarugaba J. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 2008;121(1):e McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005;366(9481): Baysun S, Aydin OF, Atmaca E, Gurer YK. A comparison of buccal midazolam and rectal diazepam for the acute treatment of seizures. Clin Pediatr (Phila) 2005;44(9):771-6.

9 204 Hong Kong j. emerg. med. Vol. 17(2) Apr 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(9153): Holsti M, Sill BL, Firth SD, Filloux FM, Joyce SM, Furnival RA. Prehospital intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care 2007; 23(3): Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol 2006;34(5): Fisgin T, Gurer Y, Tezic T, Senbil N, Zorlu P, Okuyaz C, et al. Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol 2002;17(2): Mahmoudian T, Zadeh MM. Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav 2004;5(2): 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(7253): Mittal P, Manohar R, Rawat AK. Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Indian J Pediatr 2006;73(11): Walker M. Status epilepticus: an evidence based guide. BMJ 2005;331(7518): Hung OR, Dyck JB, Varvel J, Shafer SL, Stanski DR. Comparative absorption kinetics of intramuscular midazolam and diazepam. Can J Anaesth 1996;43(5 Pt 1): Magnussen I, Oxlund HR, Alsbirk KE, Arnold E. Absorption of diazepam in man following rectal and parenteral administration. Acta Pharmacol Toxicol (Copenh) 1979;45(2): Warden CR, Frederick C. Midazolam and diazepam for pediatric seizures in the prehospital setting. Prehosp Emerg Care 2006;10(4): Rainbow J, Browne GJ, Lam LT. Controlling seizures in the prehospital setting: diazepam or midazolam? J Paediatr Child Health 2002;38(6): Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997;13(2): Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ 2000;320(7227): Appendix 1. Emergency treatment of convulsion in children.