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

^a Department of Pediatrics and Child Health, Faculty of Medicine, Makerere University, Kampala, Uganda
^b London School of Hygiene and Tropical Medicine, London, United Kingdom
^c Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California

	ABSTRACT

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OBJECTIVE. Our goal was to compare the efficacy 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 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 benefits were limited to children without malaria.

Key Words: midazolam • diazepam • seizures • Ugandan • children

Abbreviations: ACU—acute care unit • RR—relative risk • CI—confidence interval • IQR—interquartile range

Prolonged seizures are responsible for 15% of visits to pediatric emergency departments in sub-Saharan Africa.^1–3 The cause of seizures in Africa differs from that in developed countries, because infectious diseases that are unique to the tropics are common underlying factors, in addition to simple febrile convulsions and epilepsy.^4,5 In malaria-endemic areas, falciparum malaria remains the leading cause of seizures in children who present to emergency departments.⁶ In children with cerebral malaria, seizures have been shown to increase the risks for death and neurologic sequelae.^7,8 Seizures that last for >5 minutes are termed prolonged.⁹ Unlike brief seizures, those that are prolonged are associated with an increased risk for poor outcome^10,11; therefore, prolonged seizures warrant urgent treatment that is focused on early and safe seizure termination, prevention of recurrence, and identification and treatment of precipitating conditions and secondary complications.¹²

In most of sub-Saharan Africa, diazepam remains the first-line treatment for seizures in children.¹³ Although this drug is fairly efficacious, 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 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 efficacious 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 efficacy, at least in developed countries, ease of administration, and safety. To evaluate further the use of buccal midazolam in Africa, we compared the efficacy and safety of buccal midazolam with rectal diazepam in Kampala, Uganda.

	METHODS

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Study Design
We conducted a single-blind, randomized clinical trial to compare the efficacy 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 fulfilled 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 confirm genuine convulsive activity, examined the patient's airway for gastric contents, and screened the patient for enrollment. If the patient qualified for enrollment, then a parent or legal guardian was briefly 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 patient's 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 riboflavin, giving it a yellow tinge, for rectal diazepam. The volumes of placebos were equivalent to those of study drugs. The concentration of riboflavin 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 10°C and emptied and refilled 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.^22–24 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 patient's assigned treatment code. Both drugs were administered at 0.5 mg/kg (2.5 mg for 3–11 months of age; 5 mg for ages 1–4 years; 7.5 mg for ages 5–9 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 flushed 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 films 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 confirmation. 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, defined as a persistent decrease in oxygen saturation to <92% or a decrease in respiratory effort sufficient to warrant assisted breathing. This approach 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 significance 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 used to compare medians, and the ² test was used to assess the relative risk (RR) for treatment failure.

	RESULTS

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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 37.5°C. 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).

View larger version (9K): [in this window] [in a new window]   FIGURE 1 Study profile. a Some patients had more than 1 reason for exclusion.

View larger version (14K): [in this window] [in a new window]   FIGURE 2 Distribution of clinical diagnosis in the 2 treatment groups.

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: 0.63–3.57; 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

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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, defined 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 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 benefit of midazolam was confined 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 efficacy over rectal diazepam for control of prolonged seizures.²¹ It was of interest to determine whether the efficacy benefits 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 efficacious, 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 significantly 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 the time to recurrence in patients who received midazolam was significantly 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.^31–33

The benefits 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 efficacy 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 efficacies of rectal diazepam and buccal midazolam were remarkably similar in Uganda and Great Britain.²¹

	CONCLUSIONS

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Our results suggest that buccal midazolam offers a promising alternative to rectal diazepam for the treatment of seizures in African children. Midazolam offers benefits over diazepam in ease of use, improved efficacy 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 benefits, 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 Nuffield 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.

	FOOTNOTES

 
Accepted May 29, 2007.

Address correspondence to Arthur Mpimbaza, MMed, Makerere University, Department of Pediatrics and Child Health, Faculty of Medicine, PO Box 7072, Kampala, Uganda. E-mail: arthurwakg{at}yahoo.com

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

This trial has been registered at www.controlled-trials.com (identifier ISRCTN13964268).

Dr Mpimbaza contributed to study design and coordination, collected data, supervised patient enrollment and follow-up, 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.

	REFERENCES

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mpimbaza, A. Articles by Byarugaba, J. Search for Related Content PubMed PubMed Citation Articles by Mpimbaza, A. Articles by Byarugaba, J. Related Collections Neurology & Psychiatry

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