You are on page 1of 9

Comparison of Buccal Midazolam With Rectal Diazepam in the Treatment of Prolonged Seizures in Ugandan Children: A Randomized Clinical Trial

Arthur Mpimbaza, Grace Ndeezi, Sarah Staedke, Philip J. Rosenthal and Justus Byarugaba Pediatrics 2008;121;e58 DOI: 10.1542/peds.2007-0930

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/121/1/e58.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

ARTICLE

Comparison of Buccal Midazolam With Rectal Diazepam in the Treatment of Prolonged Seizures in Ugandan Children: A Randomized Clinical Trial
Arthur Mpimbaza, MMeda, Grace Ndeezi, MMeda, Sarah Staedke, MDb, Philip J. Rosenthal, MDc, Justus Byarugaba, MMeda
a

Department of Pediatrics and Child Health, Faculty of Medicine, Makerere University, Kampala, Uganda; bLondon School of Hygiene and Tropical Medicine, London, United Kingdom; cDepartment of Medicine, San Francisco General Hospital, University of California, San Francisco, California

Financial Disclosure: Both study drugs were donated by Roche Products Limited, Nairobi, Kenya.

ABSTRACT
OBJECTIVE. Our goal was to compare the efcacy and safety of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children. METHODS. This was a single-blind, randomized clinical trial in which 330 patients were
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-0930 doi:10.1542/peds.2007-0930
This trial has been registered at www.controlled-trials.com (identier ISRCTN13964268). Dr Mpimbaza contributed to study design and coordination, collected data, supervised patient enrollment and followup, and analyzed and interpreted data; Dr Byarugaba contributed to study design, supervised coordination of the study, enrollment, and clinical care of the patients, and interpreted data; Dr Ndeezi contributed to study design and coordination, supervised enrollment and follow-up of the patients, and interpreted data; Dr Staedke contributed to study design, analysis, and data interpretation; and Dr Rosenthal contributed to study design and coordination, analysis, and data interpretation. All authors contributed to the writing of the manuscript. Key Words midazolam, diazepam, seizures, Ugandan, children Abbreviations

randomly assigned to receive buccal midazolam or rectal diazepam. The trial was conducted in the pediatric emergency unit of the national referral hospital of Uganda. Consecutive patients who were aged 3 months to 12 years and presented while convulsing or who experienced a seizure that lasted 5 minutes were randomly assigned to receive buccal midazolam plus rectal placebo or rectal diazepam plus buccal placebo. The primary outcome of this study was cessation of visible seizure activity within 10 minutes without recurrence in the subsequent hour.
RESULTS. Treatment failures occurred in 71 (43.0%) of 165 patients who received rectal

diazepam compared with 50 (30.3%) of 165 patients who received buccal midazolam. Malaria was the most common underlying diagnosis (67.3%), although the risk for failure of treatment for malaria-related seizures was similar: 35.8% for rectal diazepam compared with 31.8% for buccal midazolam. For children without malaria, buccal midazolam was superior (55.9% vs 26.5%). Respiratory depression occurred uncommonly in both of the treatment arms.
CONCLUSION. Buccal midazolam was as safe as and more effective than rectal diazepam

for the treatment of seizures in Ugandan children, although benets were limited to children without malaria.

ACUacute care unit 15% of visits to pediatric emergency RRrelative risk 13 The cause of seizures in Africa differs from departments in sub-Saharan Africa. CI condence interval that in developed countries, because infectious diseases that are unique to the tropics IQRinterquartile range are common underlying factors, in addition to simple febrile convulsions and epiAccepted for publication May 29, 2007 lepsy.4,5 In malaria-endemic areas, falciparum malaria remains the leading cause of Address correspondence to Arthur Mpimbaza, MMed, Makerere University, Department of seizures in children who present to emergency departments.6 In children with Pediatrics and Child Health, Faculty of cerebral malaria, seizures have been shown to increase the risks for death and Medicine, PO Box 7072, Kampala, Uganda. 7,8 Seizures that last for 9 5 minutes are termed prolonged. neurologic sequelae. E-mail: arthurwakg@yahoo.com Unlike brief seizures, those that are prolonged are associated with an increased risk PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2008 by the for poor outcome10,11; therefore, prolonged seizures warrant urgent treatment that is American Academy of Pediatrics focused on early and safe seizure termination, prevention of recurrence, and iden12 tication and treatment of precipitating conditions and secondary complications. In most of sub-Saharan Africa, diazepam remains the rst-line treatment for seizures in children.13 Although this drug is fairly efcacious, inexpensive, readily available, and easy to administer via the rectal route when intravenous access is not available, rectally administered diazepam results in variable plasma concentrations and fails to terminate 30% of seizures.14 An advantage of rectal administration of diazepam is that the risk for respiratory depression, the

ROLONGED SEIZURES ARE responsible for

e58

MPIMBAZA et al

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

principal concern with intravenous administration of the drug, is low15; however, because of the tendency of diazepam to accumulate in adipose tissue, repeated doses of rectal diazepam can cause marked respiratory depression.16,17 This is of particular concern in units without infrastructure to provide ventilatory support. An additional concern is that a combination of diazepam, in multiple doses, and phenobarbital has been associated with an increased risk for mortality from respiratory depression in children with cerebral malaria.17 Midazolam, an inexpensive benzodiazepine with anticonvulsive activity, can be administered via multiple routes, including topical application in the buccal cavity.18 Buccal midazolam has been found to be as effective as rectal diazepam in control of seizures in developed countries.19,20 Recently, in a randomized, controlled trial, buccal midazolam was as safe as and more efcacious than rectal diazepam for the treatment of seizures in children who presented to hospitals in Great Britain.21 Potential advantages of buccal midazolam over rectal diazepam include improved efcacy, at least in developed countries, ease of administration, and safety. To evaluate further the use of buccal midazolam in Africa, we compared the efcacy and safety of buccal midazolam with rectal diazepam in Kampala, Uganda. METHODS Study Design We conducted a single-blind, randomized clinical trial to compare the efcacy and safety of buccal midazolam versus rectal diazepam. Study Site and Population The study was conducted between November 2005 and June 2006 in the acute care unit (ACU), the pediatric emergency unit of Mulago Hospital, the national referral hospital in Kampala, Uganda. In Kampala, malaria is mesoendemic (25% palpable spleen rate, 25% parasitemia rate), occurring perennially with peaks during 2 rainy seasons (A. Talisuna, MBchB, MSc, PhD, personal communication, 1994). The ACU is the emergency unit for review and admission of acutely ill children up to the age of 12 years. The unit admits between 30 and 70 patients daily. Consecutive patients who were aged 3 months to 12 years and presented to the ACU while convulsing or who experienced a seizure that lasted 5 minutes while in the unit were screened for enrollment. Patients were enrolled when they fullled the following criteria: (1) 3 months to 12 years of age; (2) no documented evidence of having received intravenous diazepam or intravenous phenobarbital within 24 hours before presentation; (3) documented seizure persisting at the time of administration of study drug; and (4) provision of informed consent to continue participation in the study. In view of ethical and practical limitations, informed consent was waived on emergency presentation. Written consent to continue participation in the study was subsequently sought from parents or legal guardians as

soon as was practically possible after initial evaluation and treatment. The study was approved by the Uganda National Council for Science and Technology and the institutional review boards of Makerere University, Kampala, and the University of California, San Francisco; it was overseen by a data and safety monitoring board that consisted of 2 pediatricians and 1 pharmacist, all in Kampala. The study was reviewed on 3 occasions. Study Procedures Screening and subsequent enrollment of patients was done consecutively. A child with a suspected seizure was transferred to a resuscitation room, where the study doctor rapidly assessed the patient to conrm genuine convulsive activity, examined the patients airway for gastric contents, and screened the patient for enrollment. If the patient qualied for enrollment, then a parent or legal guardian was briey informed of the study procedures. If they agreed to proceed, then the patient was randomly assigned to 1 of 2 treatment arms: rectal diazepam and buccal placebo or rectal placebo and buccal midazolam. For randomization, a person independent of the study used a computer to generate a list of sequential random treatment codes, representing each treatment arm, using variable blocks of 4 or 6. Each assigned treatment code and the corresponding sequential study treatment number were written on a piece of paper in the order of the randomization list and placed in an opaque envelope that was labeled with the treatment number, sealed, and placed in a box for the nurse who was responsible for treatment allocation. Investigators were not aware of a patients treatment allocation. Two placebos were designed (Department of Pharmacy, Faculty of Medicine, Makerere University) to have a color that matched the study drug; normal saline for buccal midazolam and distilled water colored with riboavin, giving it a yellow tinge, for rectal diazepam. The volumes of placebos were equivalent to those of study drugs. The concentration of riboavin administered was below its recommended daily dietary allowance. Study drugs and placebos were prepackaged by a pharmacist who was not involved with patient care and kept in 2 boxes that corresponded to the 2 treatment arms: each included study drug and placebo, separated into aliquots for 4 different age-based dosing categories. Although the study team was not aware which treatment a patient received, they were aware of the treatment code to which a patient was assigned, potentially introducing bias, so we considered this to be a single-blind trial. Boxes were stored at 5 to 10C and emptied and relled every 7 days. Diazepam and rectal placebo were packaged in 2-mL glass syringes, whereas midazolam and buccal placebo were packaged in 2-mL plastic syringes. Both midazolam and diazepam are stable under these conditions for up to 1 month.2224 When a patient was due to receive treatment, the study nurse opened the top randomization envelope, noted the treatment code, and selected age-based dosages from the box with the patients assigned treatment code. Both drugs were administered at 0.5 mg/kg (2.5 mg for 311
PEDIATRICS Volume 121, Number 1, January 2008 e59

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

FIGURE 1 Study prole. a Some patients had more than 1 reason for exclusion.

months of age; 5 mg for ages 1 4 years; 7.5 mg for ages 59 years; and 10 mg for ages 10 12 years). Treatment was administered simultaneously by 2 study nurses. For buccal treatments, a syringe was placed between the teeth and cheek, the drug or placebo was administered, and the cheek was gently massaged. For rectal treatments, the drug or placebo was administered via a tube inserted 3 to 4 cm into the rectum and the tube was ushed with air to ensure complete delivery of the drug. The buttocks were then held together for 5 minutes to prevent expulsion. During a seizure, oxygen was administered by nasal prongs. Peripheral oxygen saturation and blood pressure were recorded on study drug administration and at 5, 10, 20, 40, and 60 minutes thereafter. All children in the study had a random blood sugar level determined with a glucometer (Sensorex Apex Biotechnology Corp, Hsinchu, Taiwan) during the course of study drug administration. Two thick blood lms were prepared, 1 stained with Field stain and read in the ACU laboratory by the laboratory technologist on duty and the other stained with Giemsa and read subsequently by an experienced malaria microscopist for conrmation. Patients were followed up for 24 hours after study drug administration or until cessation of the study as a result of loss to follow-up or death. Outcome Measurements The primary study outcome was cessation of visible seizure activity within 10 minutes, without recurrence in the subsequent hour. When the convulsion persisted beyond 10 minutes or recurred within 1 hour, the child was categorized as having treatment failure and treated with intravenous diazepam. Secondary outcome measures included proportion with cessation of convulsions within 10 minutes, time to cessation of convulsion within 10 minutes, proportion with seizure recurrence in subsequent hour and within 24 hours after initial control, and time to recurrence within the respective time periods. We also assessed the risk for respiratory depression, dened as a persistent decrease in oxygen saturation to 92% or a decrease in respiratory effort sufcient to warrant assisted breathing. This approach
e60 MPIMBAZA et al

was consistent with the hospitals policies for assisted ventilation. Sample Size On the basis of a similar study conducted in Great Britain,19 we estimated that the proportion of patients whose seizure would not successfully terminate within 10 minutes would be 41% after rectal diazepam compared with 25% after buccal midazolam. With these estimates, a study with a sample size of 176 patients in each arm was required to show a 16% difference between the 2 treatment groups with 90% power and a 2-tailed signicance of 5%. Data Analysis Data were analyzed as intention to treat. Data were entered on standardized case record forms and doubly entered into EpiInfo 6.04 (Centers for Disease Control and Prevention, Atlanta, GA). SPSS 12 (SPSS Inc, Chicago, IL) and Stata 8.0 (Stata Corp, College Station, TX) were used for data analysis. The Mann-Whitney test was

TABLE 1 Baseline Characteristics of Enrolled Children


Characteristic Demographics Male, n (%) Age, median (IQR), mo Clinical features Axillary temperature, mean SD, C No. of convulsions before treatment, median (IQR)a Classication of convulsion, n (%) Febrile ( 37.5C ) Generalized Focal Laboratory results Positive blood-smear result for malaria parasites, n (%) Random blood sugar level, N Median (IQR), mg/dL
a During

Rectal Diazepam Buccal Midazolam (N 165) (N 165) 82 (49.7) 18.0 (11.536.0) 38.2 1.15 2 (14) 84 (50.9) 17.0 (10.530.0) 38.2 1.16 3 (14)

115 (69.7) 134 (81.2) 31 (18.8) 106 (64.2) 162 117 (83.0152.7)

121 (73.3) 135 (81.8) 30 (18.2) 116 (70.3) 160 106 (80.1165.5)

24 hours before enrollment.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

120 100 No. of patients


80 91

Diazepam Midazolam

TABLE 2 Risk for Treatment Failure


Outcome All patients Treatment failure, n (%) Patients with malaria, N Treatment failure, n (%) Patients without malaria, N Treatment failure, n (%)
a RR: b RR:

Rectal Diazepam (N 165) 71 (43.0) 106 38 (35.8) 59 33 (55.9)


.016. .002.

Buccal Midazolam (N 165) 50 (30.3) 116 37 (31.8) 49 13 (26.5)

80 60 40
25 23 34 10 8 30

.016a .534 .002b

20 0

9 7

7 6

1.42 (95% CI: 1.06 1.90); P 2.11 (95% CI: 1.26 3.54); P

on ia

ar ia

git is

m ala

ps y

m al

Ot h

ile

in

er s

r ia

ve re

Ce re

ommended that the study be halted when 330 patients had been enrolled. Secondary Outcome For initial cessation of seizures, 114 (69.1%) seizures terminated within 10 minutes in the diazepam arm compared with 125 (75.8%) in the midazolam arm (RR: 0.91; 95% CI: 0.80 1.04; P .175). The median time to cessation of the seizure was 4.4 minutes (interquartile range [IQR]: 2.72 6.58) for rectal diazepam and 4.8 minutes (IQR: 3.02 6.52; P .518) for buccal midazolam (Table 3). Of the 114 children whose seizure was initially controlled within 10 minutes by rectal diazepam, 20 (17.5%) experienced a seizure recurrence in the subsequent hour compared with 10 (8%) of 125 children in the buccal midazolam arm (RR: 2.19; 95% CI: 1.07 4.50; P .026). Of children who experienced a seizure recurrence within 1 hour after initial control, the median time to recurrence was 20 minutes (IQR: 11.0 47.2) for rectal diazepam and 25 minutes (IQR: 2.75 36.7) for buccal midazolam (P .492). Considering the risk for seizure recurrence after initial control during the 24 hours after treatment, 51 (46.3%) who were treated with rectal diazepam recurred versus 47 (39.1%) who were treated with buccal midazolam. The median time to recurrence within 24 hours differed signicantly between the 2 treatment arms: 1.8 hours (IQR: 0.933.48) for rectal diazepam and 5.11 hours (IQR: 1.08 10.0; P

M en

eu m

br al

FIGURE 2 Distribution of clinical diagnosis in the 2 treatment groups.

used to compare medians, and the 2 test was used to assess the relative risk (RR) for treatment failure. RESULTS Patient Recruitment and Baseline Characteristics Of 525 patients screened, 195 (37.1%) were excluded (Fig 1). The most common reason for exclusion was termination of seizure before enrollment. Baseline characteristics of study patients were similar in the 2 treatment arms (Table 1). The majority (94.8%) of children enrolled in the study were between the ages of 3 months and 5 years. Of the 330 patients enrolled, 304 (92.1%) presented with a history of fever as reported by the parent or guardian and 236 (71.5%) had a documented temperature 37.5C. Considering the nature of convulsions, 269 (81.5%) were generalized and 61 (18.5%) were focal. Of the generalized convulsions, 249 (92.5%) were tonic-clonic, 18 (6.9%) were tonic, and 3 patients experienced myoclonic jerks. Severe malaria (excluding cerebral malaria) was the most frequent clinical diagnosis, followed by cerebral malaria, bacterial meningitis, pneumonia, and epilepsy (Fig 2). Primary Outcome Comparing the 2 treatment arms, 71 (43.0%) patients who received rectal diazepam experienced treatment failure compared with 50 (30.3%) who received buccal midazolam (RR: 1.42; 95% condence interval [CI]: 1.06 1.90; P .016; Table 2). When we considered only those with malaria, the risk for treatment failure did not differ between the 2 treatment arms (35.8% vs 31.8%; RR: 1.12; 95% CI: 0.78 1.62; P .534). For those without malaria, the risk for treatment failure was signicantly higher when the patient had received rectal diazepam (55.9%) compared with buccal midazolam (26.5%; RR: 2.11; 95% CI: 1.26 3.54; P .002). On the last interim review, when 300 patients had been enrolled, the data and safety monitoring board identied a signicant difference between treatment arms and rec-

Se

Pn

Ep

TABLE 3 Secondary Outcomes After Treatment


Outcome Initial 10 min Stopped convulsing, n (%) Time to stop convulsing, median (IQR), min 1 h after control in rst 10 min, N Recurred in next 1 h, n (%) Time to recur within 1 h, N Median (IQR), min 24 h after control in rst 10 minb Recurred in next 24 h, N n (%) Time to recur within 24 h, N Median (IQR), h
a RR: b

Rectal Diazepam Buccal Midazolam (N 165) (N 165) 114 (69.1) 4.35 (2.726.58) 114 20 (17.5) 20 20.0 (11.047.2) 110 51 (46.3) 51 1.81 (0.563.48)

125 (75.8) .175 4.75 (3.026.52) .518 125 10 (8) 10 25.0 (2.7536.7)

.026a .492

120 47 (39.1) .270 47 5.11 (1.0810.3) .001c

2.19 (95% CI: 1.07 4.50); P .026. 9 patients who received phenobarbitone 1 hour after seizure control were excluded c Mann-Whitney test.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

PEDIATRICS Volume 121, Number 1, January 2008

e61

.001) for buccal midazolam. This difference was signicant even for children with malaria: 2.10 hours (IQR: 0.76 3.40) for rectal diazepam versus 5.18 hours (IQR: 0.6311.2; P .028) for buccal midazolam. After treatment, parents were asked which route of treatment administration they preferred; 184 (56%) favored the buccal route compared with 111 (34%) who favored the rectal route. The remaining parents did not mind which route was used. Safety Only 4 (1.2%) children experienced respiratory depression. These patients included 2 in the diazepam group (1 who had cerebral malaria and died after seizure cessation and 1 who had meningitis and recovered after resuscitation and treatment with antibiotics) and 2 patients in the buccal midazolam arm (1 who had status epilepticus with raised intracranial pressure and had a full recovery after treatment with mannitol and antibiotics and 1 who had severe malaria and also fully recovered). Adverse Events One patient, a 2-year-old girl who was admitted with severe malaria and multiple convulsions, developed aphasia 12 hours after receiving buccal midazolam. This event was considered to be unlikely to be related to the midazolam treatment, given that aphasia is a known complication of multiple convulsions. Another patient, who received buccal midazolam in addition to oral phenobarbitone, experienced intense pruritus that resolved on oral antihistamines. The pruritus was deemed possibly related to midazolam treatment. Deaths Twenty children died during the course of the study, 12 of 165 in the rectal diazepam arm and 8 of 165 in the buccal midazolam arm (RR: 1.5; 95% CI: 0.633.57; P .356). Severe malaria accounted for 10 (50%) of the deaths; 8 of the children who died had cerebral malaria, and 2 had severe malaria complicated by severe anemia and multiple convulsions. Severe malnutrition and septicemia each accounted for 3 (15%) of the deaths. Two (10%) children died of pneumonia; both of these children had HIV and had clinical evidence of severe immune suppression. Meningitis accounted for the remaining 2 (10%) deaths. DISCUSSION In this study of treatment for prolonged seizures in African children, patients who received buccal midazolam were more likely than those who received rectal diazepam to have successful control of seizures, dened as cessation of convulsive activity within 10 minutes, without recurrence in the subsequent hour. In subgroup analysis, the risk for treatment failure differed only in children who did not have a diagnosis of malaria. The risk for respiratory depression was minimal and similar in both treatment arms, although this risk might be greater with multiple doses of either
e62 MPIMBAZA et al

drug. In summary, in this study of an urban African population, buccal midazolam was superior to rectal diazepam for treatment of children with prolonged convulsions, but the benet of midazolam was conned to children with convulsions that were not associated with malaria. Our study provides a useful summary of causes of prolonged seizures in African children. Malaria was by far the most common problem underlying presentation with prolonged seizures, with prevalence similar to that seen in other hospital-based studies of seizures from Nigeria and Kenya.1,25 Our study population seems to be representative of sub-Saharan Africa but very different from that in Great Britain, in which buccal midazolam was shown to have superior efcacy over rectal diazepam for control of prolonged seizures.21 It was of interest to determine whether the efcacy benets of buccal midazolam applied also to Africa, where the need for simple therapies for seizures is particularly great, because intravenous therapy is routinely unavailable. It is encouraging that buccal midazolam was highly efcacious, because this regimen offers simple administration, relatively low cost, lack of need for refrigeration, and low risk for respiratory depression. Indeed, buccal midazolam provides a more socially acceptable route of drug administration than rectal diazepam and avoids the need for intravenous access,26,27 which is often unavailable in many district hospitals in Africa and can be challenging to establish in a convulsing child; therefore, the buccal route of administration offers an appealing alternative for seizure control in the community and also in situations in which establishing intravenous access is problematic or not possible. Additional options for anticonvulsant therapy in Africa include intramuscular paraldehyde and intranasal lorazepam. A recent study showed that intranasal lorazepam was as effective as intramuscular paraldehyde in stopping seizures in Malawi28; however, both of these agents have important drawbacks, including high cost and need for refrigeration of parenteral lorazepam and risk for sterile abscesses with intramuscular paraldehyde.16,29 Considering available options, buccal midazolam seems to be the superior simple therapy for prolonged seizures in African children. An effective anticonvulsant should rapidly control seizures and also prevent recurrent seizure activity12; therefore, we judged treatment success on the basis of both rapid seizure termination and persistence of anticonvulsive effects. It is interesting that the effects of rectal diazepam and buccal midazolam differed primarily not in their initial effects but in prevention of seizure recurrences in the subsequent 1 hour after initial control. The number of seizures that failed to stop in the initial 10 minutes was higher in patients who received diazepam, but this difference was not statistically significant. The regimens differed more greatly in the risk for seizure recurrence in the subsequent hour, with the risk for recurrence with rectal diazepam signicantly higher than that with buccal midazolam, which was similar to that in other studies.21 Over 24 hours, the risk for seizure recurrence was similar with midazolam or diazepam, but

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

the time to recurrence in patients who received midazolam was signicantly longer. The difference between diazepam and midazolam was likely attributable to the shorter duration of action of diazepam in the brain (active half-life of diazepam: 1 hour),30 which is explained by the rapid decline in diazepam brain concentration levels during the redistribution of diazepam from cerebral gray matter into white matter, brainstem, and body fat.14,16 The active half-life of midazolam is 2 to 3 hours in healthy children and 5 hours in very ill children.3133 The benets of buccal midazolam were pronounced in children who did not have malaria diagnosed at the time of presentation with seizures, but there was no difference in efcacy in children who had convulsions associated with malaria. These results suggest that the cause of convulsions in severe malaria differs from that in other conditions.34 Indeed, after omission of children with malaria, the efcacies of rectal diazepam and buccal midazolam were remarkably similar in Uganda and Great Britain.21 CONCLUSIONS Our results suggest that buccal midazolam offers a promising alternative to rectal diazepam for the treatment of seizures in African children. Midazolam offers benets over diazepam in ease of use, improved efcacy over 1 hour, and a more prolonged anticonvulsive effect. For children with malaria-related seizures, midazolam remains a suitable alternative to diazepam considering its ease of use and that the underlying diagnosis may not be known at the time of treatment. Thus, in addition to its immediate benets, buccal midazolam may be a more effective bridge to long-acting agents in children who need prolonged anticonvulsant therapy. ACKNOWLEDGMENTS This investigation received support from the Fogarty International Center of the National Institutes of Health (grant D43 TWO1506). Financial support was also provided by the Nufeld Foundation, United Kingdom. Dr Rosenthal is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. The sponsors of this study had no role in study design or collection, analysis, or interpretation of data or in the writing of the report. We thank the study clinical team, Aggrey Dhabangi, Jolly Rubambarama, Julian Eyotaru, Florence Pido, Rose Nakikwaku, and Maria Rutaro, and the laboratory team, Maxwell Kilama, Regina Nakafeero, and Felix Jurua. We also thank Grant Dorsey for providing methodologic and statistical guidance and all of the families and children who participated in this study. Finally, we thank Prof Richard Odome Odoi (Head Department of Pharmacy Medical School, Makerere University), Paul Musoke, and Benjamin Mwesigwe, who designed and prepared the placebos that were used in the study. REFERENCES
1. Waruiru CM, Newton CR, Forster D, et al. Epileptic seizures and malaria in Kenyan children. Trans R Soc Trop Med Hyg. 1996;90:152155 2. Iloeje SO. Paediatric neurologic emergencies at the University

3.

4. 5.

6. 7.

8. 9. 10.

11. 12.

13.

14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

24. 25.

of Nigeria Teaching Hospital, Enugu. West Afr J Med. 1997;16: 80 84 Mulowoza M. Knowledge, Attitudes and Practices About Convulsions Among Carers of Children Presenting to Mulago Hospital [dissertation]. Kampala, Uganda: Makerere University; 2004 Birbeck GL. Neurologic disease in a rural Zambian hospital. Trop Doct. 2001;31:82 85 Ofovwe GE, Ibadin MO, Okunola PO, Ofoegbu B. Pattern of emergency neurologic morbidities in children. J Natl Med Assoc. 2005;97:488 492 Ogutu BR, Newton CR. Management of seizures in children with falciparum malaria. Trop Doct. 2004;34:7175 Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med. 1989;71:441 459 Brewster DR, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in children. Lancet. 1990;336:1039 1043 Lowenstein DH, Bleck T, Macdonald RL. Its time to revise the denition of status epilepticus. Epilepsia. 1999;40:120 122 Metsaranta P, Koivikko M, Peltola J, Eriksson K. Outcome after prolonged convulsive seizures in 186 children: low morbidity, no mortality. Dev Med Child Neurol. 2004;46:4 8 Scott RC. The acute management of seizures in childhood. Hosp Med. 2004;65:748 752 Bleck TP. Management approaches to prolonged seizures and status epilepticus. Epilepsia. 1999;40(suppl 1):S59 S63; discussion S64 S66 Idro R, Aketch S, Gwer S, Newton CR, Maitland K. Research priorities in the management of severe Plasmodium falciparum malaria in children. Ann Trop Med Parasitol. 2006;100:95108 Ogutu BR, Newton CR, Crawley J, et al. Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions. Br J Clin Pharmacol. 2002; 53:49 57 Appleton R, Sweeney A, Choonara I, Robson J, Molyneux E. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol. 1995;37: 682 688 Scott RC, Neville BG. Pharmacological management of convulsive status epilepticus in children. Dev Med Child Neurol. 1999; 41:207210 Crawley J, Waruiru C, Mithwani S, et al. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet. 2000;355:701706 Wallace SJ. Nasal benzodiazepines for management of acute childhood seizures? Lancet. 1997;349:222 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;353:623 626 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;44:771776 McIntyre J, Robertson S, Norris E, et al. Safety and efcacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet. 2005;366:205210 Pramar YV, Loucas VA, el-Rachidi A. Stability of midazolam hydrochloride in syringes and i.v. uids. Am J Health Syst Pharm. 1997;54:913915 Smith FM, Nuessle NO. Stability of diazepam injection repackaged in glass unit-dose syringes. Am J Hosp Pharm. 1982;39: 16871690 Gottwald MD, Akers LC, Liu PK, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med. 1999;17:333337 Asindi AA, Ekanem EE, Ibia EO, Nwangwa MA. Upsurge of

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

PEDIATRICS Volume 121, Number 1, January 2008

e63

26. 27. 28.

29. 30.

malaria-related convulsions in a paediatric emergency room in Nigeria: consequence of emergence of chloroquineresistant Plasmodium falciparum. Trop Geogr Med. 1993;45: 110 113 Reading R. Managing medication in schools. Arch Dis Child. 2005;90:12531255 Wilson MT, Macleod S, ORegan ME. Nasal/buccal midazolam use in the community. Arch Dis Child. 2004;89:50 51 Ahmad S, Ellis JC, Kamwendo H, Molyneux E. Efcacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial. Lancet. 2006;367:15911597 Goyal M, Wiznitzer M. Emergency management of seizures in children. Lancet. 2006;367:15551556 Greenblatt DJ, Divoll M. Diazepam versus lorazepam: relation-

31. 32.

33.

34.

ship of drug distribution to duration of clinical action. Adv Neurol. 1983;34:487 491 Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet. 1998;35:37 47 Byatt CM, Lewis LD, Dawling S, Cochrane GM. Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit. Br Med J (Clin Res Ed). 1984;289:799 800 de Wildt SN, de Hoog M, Vinks AA, van der Giesen E, van den Anker JN. Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med. 2003;31:19521958 Wattanagoon Y, Srivilairit S, Looareesuwan S, White NJ. Convulsions in childhood malaria. Trans R Soc Trop Med Hyg. 1994; 88:426 428

e64

MPIMBAZA et al

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

Comparison of Buccal Midazolam With Rectal Diazepam in the Treatment of Prolonged Seizures in Ugandan Children: A Randomized Clinical Trial Arthur Mpimbaza, Grace Ndeezi, Sarah Staedke, Philip J. Rosenthal and Justus Byarugaba Pediatrics 2008;121;e58 DOI: 10.1542/peds.2007-0930
Updated Information & Services including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/121/1/e58.full.ht ml This article cites 33 articles, 8 of which can be accessed free at: http://pediatrics.aappublications.org/content/121/1/e58.full.ht ml#ref-list-1 This article has been cited by 3 HighWire-hosted articles: http://pediatrics.aappublications.org/content/121/1/e58.full.ht ml#related-urls This article, along with others on similar topics, appears in the following collection(s): Neurology & Psychiatry http://pediatrics.aappublications.org/cgi/collection/neurology _and_psychiatry Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

References

Citations

Subspecialty Collections

Permissions & Licensing

Reprints

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on October 24, 2012

You might also like