Articles

Safety and efficacy of buccal midazolam versus rectal

diazepam for emergency treatment of seizures in children:
a randomised controlled trial
John McIntyre, Sue Robertson, Elizabeth Norris, Richard Appleton,William P Whitehouse, Barbara Phillips, Tim Martland, Kathleen Berry,
Jacqueline Collier, Stephanie Smith, Imti Choonara

Summary
Background Rectal diazepam and buccal midazolam are used for emergency treatment of acute febrile and afebrile Lancet 2005; 366: 205–10
(epileptic) seizures in children. We aimed to compare the safety and efficacy of these drugs. See Comment page 182
Academic Division of Child
Methods A multicentre, randomised controlled trial was undertaken to compare buccal midazolam with rectal Health, University of
diazepam for emergency-room treatment of children aged 6 months and older presenting to hospital with active Nottingham, Derbyshire
Children’s Hospital, Uttoxeter
seizures and without intravenous access. The dose varied according to age from 2·5 to 10 mg. The primary endpoint Road, Derby DE22 3DT, UK
was therapeutic success: cessation of seizures within 10 min and for at least 1 hour, without respiratory depression (J McIntyre FRCPCH,
requiring intervention. Analysis was per protocol. S Robertson RSCN,
Prof I Choonara MD); Emergency
Department, Alder Hey
Findings Consent was obtained for 219 separate episodes involving 177 patients, who had a median age of 3 years Children’s Hospital, Liverpool,
(IQR 1–5) at initial episode. Therapeutic success was 56% (61 of 109) for buccal midazolam and 27% (30 of 110) for UK (E Norris RSCN,
rectal diazepam (percentage difference 29%, 95% CI 16–41). Analysing only initial episodes revealed a similar result. B Phillips FRCPCH); Department
of Paediatric Neurology, Alder
The rate of respiratory depression did not differ between groups. When centre, age, known diagnosis of epilepsy, use
Hey Children’s Hospital,
of antiepileptic drugs, prior treatment, and length of seizure before treatment were adjusted for with logistic Liverpool, UK
regression, buccal midazolam was more effective than rectal diazepam. (R Appleton FRCPCH);
Department of Child Health,
University of Nottingham,
Interpretation Buccal midazolam was more effective than rectal diazepam for children presenting to hospital with
Nottingham, UK
acute seizures and was not associated with an increased incidence of respiratory depression. (W P Whitehouse FRCPCH);
Department of Paediatric
Introduction infections.13 Intranasal midazolam has also been used Neurology, Royal Manchester
Children’s Hospital,
Tonic-clonic seizures requiring emergency drug for children with epilepsy14 and might be easier to
Manchester, UK
treatment are a common problem in children, and administer and more effective than rectal diazepam.15,16 (T Martland MRCPCH);
convulsive status epilepticus causes significant mortality Midazolam can also be given via the buccal or Emergency Department,
and morbidity.1 Immediate management of a continuing sublingual route. Buccal midazolam is well absorbed17 Birmingham Children’s
Hospital, Birmingham, UK
seizure follows the basic principles of emergency care and might be easier for carers to administer. It stopped (K Berry FRCPCH); School of
with the role of drug treatment being to terminate the 30 of 40 seizures in 14 children with severe epilepsy and Nursing, University of
seizure promptly and safely. Ideally, a drug would be easy seems at least as effective as rectal diazepam for acute Nottingham, Nottingham, UK
to give, effective, and safe, and would have a long-lasting seizures.18 It has proved effective across a range of ages.19 (J Collier PhD); and Emergency
Department, Queens Medical
antiseizure (anticonvulsant) action.2 Benzodiazepines are The purpose of this study was to compare the efficacy Centre, Nottingham, UK
often used as first-line drugs,3 but a systematic review and safety of buccal midazolam with rectal diazepam for (S Smith BM)
reported little supporting evidence for their use.4 treatment of children presenting to the hospital Correspondence to:
Intravenous lorazepam, successfully used in status emergency room with an acute seizure. Dr John McIntyre
epilepticus both in the emergency room for children5 john.mcintyre@nhs.net

and out of hospital for adults,6 might be associated with Methods

less respiratory depression and a longer duration of
action than diazepam.7 However, intravenous access can
be a problem out of hospital or in small children. In
these situations, rectal diazepam is the established first-
line drug and is effective in 60–80% of patients,8,9 but
with a risk of seizure recurrence10 and respiratory
depression.11 Intranasal midazolam has been used to
treat acute seizures, but in a prospective study, it
effectively controlled the seizure within 15 min in only
ten of 20 children.12 For febrile seizures, intranasal
midazolam controlled seizures in 23 of 26 children and
seems as effective as intravenous diazepam, but
treatment failures arose with upper respiratory tract
Trial design and participants
Eligible children were those aged 6 months and older,
who presented to the emergency room of one of the four
participating hospitals (Alder Hey Children’s Hospital,
Liverpool; Derbyshire Children’s Hospital; Queen’s
Medical Centre Nottingham; and Birmingham Children’s
Hospital) still having a seizure, who did not already have
established intravenous access. Children who had chronic
epilepsy or who had been given prehospital emergency or
rescue treatment were not excluded from the trial. It was
anticipated that most seizures would be generalised tonic-
clonic and it was not intended to include those patients
with partial or non-convulsive seizures.

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 Articles
Weekly blocks of treatment of either buccal
midazolam or rectal diazepam were randomly selected
for each of the four participating centres. The
randomisation sequence was generated by the research
nurse from a table of random numbers and allocated by
the same nurse who communicated it directly with staff
in the emergency departments. Determining in
advance a schedule for each centre allowed a smooth
transition between treatment weeks. A similar
approach by randomising days has proved acceptable
and appropriate when the treatments used are not new
untested drugs.7 We also hoped that this approach
would reduce confusion for staff in the emergency
room and would keep the time taken for treatment to be
given to a minimum. Allocation was not concealed
from attending staff.
This study was approved by the Trent Regional
Multicentre Research Ethics Committee. Informed
consent cannot be obtained from parents while their
child is in a tonic-clonic seizure. Furthermore, prior
consent for many children would neither be feasible
nor justified. Therefore, parents or patients were
informed as soon as practicably possible after treatment
and consent sought to use their data in the study. To
improve awareness of the study in the local
populations, interviews with the local press and radio
stations were given in some centres. Furthermore, local
epilepsy nurses were asked to discuss the study with
those families whose children were known to attend the
hospitals and emergency rooms with acute seizures
frequently. In view of the complex ethical issues around
consent in emergency situations, an anonymous follow-
up questionnaire was designed and sent to
participating families, with approval from the ethics
committee. The questionnaire was semi-structured and
asked for views on the information sheets and the
consent form. It also had free text boxes for responses
about their reasons for giving consent. Collection of
responses is continuing, and we hope to report on this
issue separately.
Procedures
The dose of buccal midazolam or rectal diazepam to be
administered was determined by the child’s age and
was designed to give about 0·5 mg per kg (2·5 mg for
children aged 6–12 months; 5 mg for 1–4 years, 7·5 mg
for 5–9 years, and 10 mg for 10 years and older). This
pragmatic approach was taken to reflect clinical
practice, since in an emergency room estimated
weights are more likely to be used rather than
attempting accurate weighing of a child undergoing a
seizure. Both treatment groups would therefore be
expected to have similar variation around the estimated
0·5 mg per kg dose.
The intravenous preparation of midazolam
hydrochoride, filtered through a needle or straw, was
administered into the buccal cavity between the gum
206
and cheeks. Because the routes of administration were
different for each drug, those administering the
treatment and assessing the outcome were aware of the
specific drug used. An approach by which all children
received a buccal and rectal preparation, only one of
which was active, was considered inappropriate because
of introducing an additional treatment delay and
resulting in the rectal administration of placebo to
more than 100 children.
The primary outcome measure, therapeutic success,
was the cessation of visible signs of seizure activity
within 10 min of administration of the randomised
drug without respiratory depression and without
another seizure within 1 h. All three of these clinically
determined measures, reflecting the context in which
decision-making in the emergency room usually takes
place, are reported. Respiratory depression was defined
as a fall in oxygen saturation or decrease in respiratory
effort sufficient to require assisted breathing either via
face-mask inflation or intubation after administration
of the drug.
If the child was still having a seizure at 10 min and
intravenous access had been established, then
intravenous lorazepam (100 g per kg) was
administered and any additional medication given
based on each participating hospital’s protocols or
guidelines. The requirement of lorazepam or another
anticonvulsant drug at this stage was classified as a
treatment failure.
The time of administration of all medications and
start and termination of seizures were recorded.
Observations of oxygen saturation, respiratory rate, and
supportive interventions were recorded at 5, 15, and
40 min. The total number of seizures within the first
6 h and first 24 h were also recorded. Seizure duration
before treatment in the emergency room was recorded
from the report of the child’s parents or carers.
After analysis of the completed data forms, a final
diagnosis was allocated in one of four categories:
seizure with fever (38ºC) and not receiving oral
maintenance antiepileptic drugs; seizure with fever and
receiving such drugs; seizure without fever and
receiving such drugs; and other.
Statistical analysis
By use of two-tailed tests, it was calculated that
107 episodes would be needed in each treatment group
to detect a difference in efficacy of 15% (between 79%
and 94%) as defined by effective seizure cessation after
buccal midazolam or rectal diazepam (90% power, 5%
significance level), on the basis of previous data.11,20 The
trial design allowed for entry of a patient more than
once because of the potential delay in treatment if
clinicians had to check for prior participation. The
results are therefore reported for both the total episodes
and for the first presenting episode of a patient to avoid
the bias of a patient with multiple entries.
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 Articles

Number of times entered into trial These sponsors of the study had no role in study design,
1 2 3 4 5 6 Total
data collection, data analysis, data interpretation, or
writing of the report. The corresponding author had full
AHCH 106 17 4 3 2 1 133
DCH 26 6 4 1 .. .. 37 access to all the data in the study and had final
BCH 30 2 2 .. .. .. 34 responsibility for the decision to submit for publication.
QMC 15 .. .. .. .. .. 15
Total 177 (81%) 25 (11%) 10 (5%) 4 (2%) 2 (1%) 1 (1%) 219
Results
Data are number or number (%). AHCH=Alder Hey Children’s Hospital. DCH=Derbyshire Study recruitment was from October, 2000, to February,
Children’s Hospital. BCH=Birmingham Children’s Hospital. QMC=Queen’s Medical 2004. Appointment of a research nurse coordinator in
Centre.
Derbyshire Children’s Hospital and a research nurse at
Table 1: Recruitment from the different centres Alder Hey Children’s Hospital enabled recruitment to
start at an early stage in these centres. Consent was
obtained for 219 separate episodes (123 [56%] male)
To detect a 9% difference in the onset of respiratory involving 177 patients (98 [55%] male; table 1). Of the
depression, 110 episodes in each treatment group would 42 patients recruited more than once, seven were
be needed with a baseline value of 9% for diazepam11 recruited again within a week and four within a month,
and 0% for midazolam (no rates for midazolam were the remainder being separated by more than 2 months.
available from previous studies). Each entry was double- During the recruitment phase (roughly 172 weeks)
checked and entered into a database (SPSS version 11.0). centres recruited more than one patient in 40 weeks
Logistic regression analysis was used for the (about 6% of the total centre weeks available), which
multivariate analysis of the efficacy of the two suggests that substantial clustering was unlikely. 109
treatments. Analysis was done at seizure level, and (50%) episodes involved 92 patients treated with buccal
centre was adjusted for in the logistic regression midazolam and 110 (50%) involving 85 patients treated
analysis. Analysis was per protocol. with rectal diazepam.
The age distribution at initial episode was skewed
Role of the funding source towards young preschool children (median 3 years; IQR
Funding for a full time equivalent research nurse over 1–5 years, range 7 months to 15 years). For both initial
two years with travelling expenses was provided by and all presenting episodes, most children were aged
SEARCH. Additional support to complete the trial was between 1 and 4 years (109 [62%] and 135 [62%],
provided by the Derbyshire Children’s Research Fund respectively). 14 infants (6%) were aged between 6 and
and Alder Hey Children’s Hospital Research Funds. 12 months, 50 children (23%) between 5 and 9 years,

46 episodes excluded: AHCH DCH QMC BCH

5 consent declined
4 protocol violation 231 episodes screened Data incomplete
30 intravenous lorazepam
7 rectal paraldehyde

AHCH DCH QMC BCH

133 37 15 34
episodes episodes episodes episodes
randomised randomised randomised randomised
(106 patients) (26 patients) (15 patients) (30 patients)

61 assigned 72 assigned 13 assigned 24 assigned 9 assigned 6 assigned 26 assigned 8 assigned

buccal rectal buccal rectal buccal rectal buccal rectal
midazolam diazepam midazolam diazepam midazolam diazepam midazolam diazepam

109 110
buccal rectal
midazolom diazepam
treatment treatment
episodes episodes

Figure: Trial profile

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Buccal midazolam Rectal diazepam was administered; 35 of these patients were

(109 episodes, (110 episodes, subsequently treated with buccal midazolam and 33 with
92 initial episodes) 85 initial episodes) rectal diazepam (28 and 22 of 50, respectively, for initial
Male episodes only).
All episodes 59 (54%) 64 (58%)
The distribution of final diagnoses for episodes was as
Initial episodes 52 (57%) 46 (54%)
Admission temperature (ºC) follows: 56 (26%) had seizure with fever and were not
All episodes 37·3 (36·2–38·5) 37·1 (36·3–38·1) receiving antiepileptic drugs; 22 (10%) had seizure with
Initial episodes 37·3 (36·3–38·2) 37·6 (36·3–38·5) fever and were receiving these drugs; 93 (42%) had
Age (years)
All episodes 2 (1–5) 3 (1–6)
seizure without fever and were receiving these drugs (54
Initial episodes 2 (1–5) 3 (1–6) [31%], 13 [7%], and 57 [32%], respectively, for initial
Previous seizures episodes only). Of the episodes categorised “other”,
All episodes 78 (72%) 79 (72%) 24 children had no history of previous seizures or known
Initial episodes 61 (66%) 55 (65%)
Receiving antiepileptic drugs
underlying medical condition.
All episodes 52 (48%) 63 (57%) The figure summarises presenting episodes and
Initial episodes 37 (40%) 42 (49%) randomisation at the four centres. In three centres,
Episodes with prehospital emergency treatment documentation was available from the study period on
All episodes 35 (32%) 33 (30%)
Initial episodes 28 (30%) 22 (26%)
admissions. 30 episodes were initially treated with
Seizure duration before treatment (mins) lorazepam, indicating that intravenous access was
All episodes 30 (10–49) 41 (10–61) already established at time of admission, and seven were
Initial episodes 30 (14–45) 37 (10–60) treated with rectal paraldehyde. At Birmingham
Data are number (%) or median (IQR). Children’s Hospital, the data were incomplete. However,
a retrospective review of a sample of 200 admissions did
Table 2: Baseline characteristics
not identify any missed cases.
Documentation in five episodes suggests a seizure type
and the remaining 20 (9%) were 10 years and older (the (focal or part) that might have been inappropriate to enrol
numbers were 13 [7%], 37 [21%], and 18 [10%], in this study. However, the treating clinician followed the
respectively, for initial episodes only). In 157 (72%) study protocol and these episodes have been included in
episodes, patients had previously had seizures and 115 the analysis on an intention-to-treat basis.
(53%) were receiving antiepileptic drugs (102 [58%] and Table 2 shows the baseline characteristics of the two
98 [55%], respectively, for initial episodes only). groups. Table 3 summarises the treatment outcomes for
Admission temperature was 38ºC or more in 77 (35%) the two groups. Therapeutic success—cessation of
episodes and less than 38ºC in 142 (65%) episodes (66 seizure within 10 min of drug administration without
[37%] and 111 [63%], respectively, for initial episodes respiratory depression and without another seizure
only). In 68 episodes (31%), a prehospital emergency within 1 h—was higher for those receiving buccal
treatment (67 rectal diazepam, one rectal paraldehyde) midazolam than for those receiving rectal diazepam. For
initial episodes, therapeutic success was similarly higher
Buccal midazolam Rectal diazepam Percentage in those receiving buccal midazolam. For all episodes,
(109 episodes) (110 episodes) difference (95% CI) when centre, age, diagnosis of epilepsy, presence of
Therapeutic success (%) fever, use of antiepileptic drugs, prior treatment, and
All episodes 61 (56%) 30 (27%) 29% (16 to 41)
duration of seizure before treatment were adjusted for in
Initial episodes 49 (53%) 24 (28%) 25% (11 to 39)
Time (mins) to stop seizing after treatment (median, IQR) logistic regression, buccal midazolam was more effective
All episodes 8 (5–20)* 15 (5–31)* than rectal diazepam (p0·001; odds ratio 4·1, 95% CI
Initial episodes 10 (5–22)† 15 (6–32)† 2·2–7·6). This finding was similar when only initial
Stopped seizing within 10 min (%)
All episodes 71 (65%) 45 (41%) 24% (11 to 37)
admissions were analysed (p=0·008, 3·5, 1·8–7·0).
Initial episodes 56 (60%) 36 (42%) 18% (4 to 33) For all episodes, median time after treatment until the
Given intravenous lorazepam (%) seizure stopped was 8 min (IQR 5–20) for buccal
All episodes 36 (33%) 63 (57%) 24% (12 to 37) midazolam and 15 min (5–31) for rectal diazepam
Initial episodes 33 (36%) 47 (55%) 19% (5 to 35)
Seizure stopped, then further seizure‡
(p=0·01, hazard ratio 0·7, 95% CI 0·5–0·9).
All episodes 10 (14%) (n=71) 15 (33%) (n=45) 19% (4 to 36) For initial episodes only, the median time after
Initial episodes 7 (13%) (n=56) 12 (34%) (n=31) 22% (4 to 40) treatment until the seizure stopped was 10 min (IQR
Respiratory depression (%) 5–22) for buccal midazolam and 15 min (6–33) for rectal
All episodes 5 (5%) 7 (6%) 2 (–4 to 8)
Initial episodes 4 (4%) 6 (7%) 3% (–4 to 10)
diazepam (p=0·03, hazard ratio 0·7, 95% CI 0·5–0·96).
Including all episodes, more children had stopped
Data are number (%) unless otherwise indicated. *p=0·01, hazard ratio 0·7 (95% CI 0·5–0·9). †p=0·03, hazard ratio seizing within 10 min after receiving buccal midazolam
0·7 (0·5–0·96). ‡Seizure stopped within 10 min, but further seizure within 1 h requiring treatment.
compared with rectal diazepam (p0·001), a finding
Table 3: Outcome after treatment also true for initial episodes only. For both total episodes
and initial episodes only, fewer children were given

208 www.thelancet.com Vol 366 July 16, 2005


lorazepam for continuing seizure activity after buccal
midazolam than after rectal diazepam. Some seizures
had stopped by 10 min but recurred within the first hour
and required treatment; this was less likely for those
given buccal midazolam than for those given rectal
diazepam (p=0·02 for both initial episodes only and for
all episodes).
Of the 12 children in whom respiratory depression was
recorded, five had not previously had seizures and five
were known to have epilepsy and to have been taking at
least one antiepileptic drug. Of the 67 treated with rectal
diazepam by a carer or paramedic before admission, five
(7%) developed respiratory depression. Five children
required intubation, two after buccal midazolam and
three after rectal diazepam, and were subsequently
admitted to intensive care for continuing management
of their seizures.
Discussion
Our results show that buccal midazolam is more
effective than rectal diazepam for treatment of children
with seizures in a hospital emergency department, and
does not appear to increase the risk of respiratory
depression. Intravenous access is not always possible
for administration of emergency anticonvulsant
treatment for the children having a seizure, and an
effective and safe alternative is frequently required.
Traditionally, this has been the rectal route for
diazepam and more recently the buccal or intranasal
route for midazolam.
Safe, effective, and long-lasting antiseizure
(anticonvulsant) activity is an important characteristic
of any drug for emergency treatment of seizures.2 In
this study, our primary outcome measure therefore
included these elements: cessation of visible signs of
seizure activity within 10 min of the drug
administrations, without respiratory depression
requiring medical intervention, and without another
seizure within the hour. Diazepam is widely used as an
emergency treatment for seizures. Rectal diazepam is
well absorbed and has a rapid onset of action but is
rapidly redistributed and can accumulate with repeated
doses.21 Previous studies have generally shown a rapid
initial response in 60–80% of patients, but with a risk of
early recurrence of seizures of up to 30%.8,10,18,22 We
recorded a lower rate of rectal diazepam successfully
terminating seizures within 10 min (41% of patient
episodes) despite using a recommended dose regimen.
This could be partly explained by the tightly defined
endpoint in our study. Furthermore, prehospital
treatment with rectal diazepam by carers and
paramedics is increasingly widespread, as was seen in
roughly a third of children in our study. Many children
would have been given rectal diazepam before arriving
in the emergency room, and those likely to respond
would have stopped having a seizure before admission
and would not have been eligible for this study.
www.thelancet.com Vol 366 July 16, 2005
Articles
Midazolam has also been used for the emergency
treatment of seizures. Transmucosal midazolam is
rapidly effective,17,23 and in previous studies buccal
administration has terminated seizures within 10 min of
administration in 75–84%18,19 and in 2–20 minutes in
87% of patients in the out-of-hospital environment.24 In
our study, buccal midazolam ended seizures more
rapidly than rectal diazepam (p=0·01) and stopped
seizures within 10 min in more children. Furthermore,
fewer patients required intravenous lorazepam, and of
those whose seizures had stopped within 10 min, fewer
seizures restarted within the hour. This study confirms
the rapid clinical effect of buccal midazolam, but has
also identified important clinical advantages over rectal
diazepam in both speed of onset and duration of action.
Respiratory depression associated with seizures is
probably multifactorial, and the emergency treatment
will be just one of these factors. It is not surprising that
the reported incidence of systemic complications after
rectal diazepam for acute seizures, especially respiratory
depression, varies widely, in different study populations.
In a review of 843 administrations of rectal diazepam that
included prehospital use,25 only three systemic
complications were recorded, two (0·4%) of which were
respiratory depression. In a hospital-based study of all
children treated for acute seizures,11 the overall incidence
of respiratory depression attributed to diazepam
(intravenous or rectal) was 9%, and 8% for rectal
diazepam. Midazolam, like other benzodiazepines,
might also be expected to cause cardiorespiratory
depression; however, in clinical practice such effects are
either uncommon or rarely reported.
The overall frequency of respiratory depression in our
study (as defined in the methods) was 5·5% and similar
for both drugs. This is less than the 9% reported in a
previous and similar hospital-based study.11 This
difference could reflect a real reduction since the
recommendations introduced in 2000 provided a clear
algorithm with distinct 10-min intervals between the
steps in drug administration.3 The smaller than expected
total numbers make it difficult to rule out a true
difference in rates of respiratory depression, but if a
difference does exist it is likely to be small and might
only be detected by a much larger study.
The need to treat acute seizures promptly when
intravenous access is unavailable demands
consideration of administration and acceptability of any
alternative routes. Rectal administration can be difficult
to arrange in schools and respite care facilities or other
out-of-hospital environments, and absorption is
variable.26 Intranasal midazolam is effective,13,14,27 but it
can be less reliable in the presence of concurrent upper
respiratory tract infection.12 Pharmacokinetic data and
acceptability to patients indicate that the buccal or
sublingual route is a suitable alternative.23,28 However, in
acute seizures it might not be possible to easily or safely
lower the jaw to open the oral cavity, and therefore the
209
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sublingual route is probably best avoided. Despite some
initial reservations, anecdotal comments from staff in
the emergency room involved in this study suggest that
the buccal route was easy to use. No adverse events were
reported during the study period in relation to the route
of administration. The use of the buccal route by non-
trained carers in non-hospital situations will be the topic
of future work.
Evidence to support decision making in emergency
situations is vital but designing studies to secure it is
challenging. Some of the issues highlighted in this
study include the shortage of robust prior data to power
and design the study, obtaining consent in an
emergency situation involving children, and ensuring
the statistical analysis is not undermined by multiple
entries or clustering. Nevertheless, this study shows
that these challenges can be met and that learning
points for paediatric clinical trials in emergency
situations can be shared.
Contributors
J McIntyre, R Appleton, I Choonara, W Whitehouse, T Martland,
K Berry, B Phillips, and S Smith were clinical leads in the participating
centres and were involved in the study design. S Robertson coordinated
and maintained the database and, with Elizabeth Norris, collected the
data. J Collier, J McIntyre, and S Robertson analysed the data. All
investigators contributed to the writing of the final draft of the report.
Conflict of interest statement
We declare that we have no conflict of interest.
Acknowledgments
This study was funded by SEARCH, Derbyshire Children’s Research
Fund, and Alder Hey Children’s Hospital Research Fund. We thank all
the staff in the Emergency Rooms at the participating hospitals,
particularly Kirsty Soames and Gareth Evans.
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