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`Comparison of intranasal midazolam with
`intravenous diazepam for treating febrile seizures
`in children: prospective randomised study
`
` 
`Eli Lahat, Michael Goldman, Joseph Barr, Tzvi Bistritzer and Matithyahu
`Berkovitch
` 
`BMJ
` 2000;321;83-86
`doi:10.1136/bmj.321.7253.83
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`
`Comparison of intranasal midazolam with intravenous
`diazepam for treating febrile seizures in children:
`prospective randomised study
`Eli Lahat, Michael Goldman, Joseph Barr, Tzvi Bistritzer, Matithyahu Berkovitch
`
`Papers
`
`Editorial by Koren
`
`Pediatric Neurology
`Unit, Assaf Harofeh
`Medical Center,
`Zerifin 70300, Israel
`Eli Lahat
`senior clinical lecturer
`
`Department of
`Pediatrics, Assaf
`Harofeh Medical
`Center
`Michael Goldman
`tutor
`Tzvi Bistritzer
`senior lecturer
`
`Pediatric Intensive
`Care Unit, Assaf
`Harofeh Medical
`Center
`Joseph Barr
`lecturer
`
`Pediatric Clinical
`Pharmacology Unit,
`Assaf Harofeh
`Medical Center
`Matithyahu
`Berkovitch
`lecturer
`
`Correspondence to:
`E Lahat
`shiri@gezernet.co.il
`
`BMJ 2000;321:83–6
`
`Abstract
`Objective To compare the safety and efficacy of
`midazolam given intranasally with diazepam given
`intravenously in the treatment of children with
`prolonged febrile seizures.
`Design Prospective randomised study.
`Setting Paediatric emergency department in a general
`hospital.
`Subjects 47 children aged six months to five years
`with prolonged febrile seizure (at least 10 minutes)
`during a 12 month period.
`Interventions Intranasal midazolam (0.2 mg/kg) and
`intravenous diazepam (0.3 mg/kg).
`Main outcome measures Time from arrival at
`hospital to starting treatment and cessation of
`seizures.
`Results Intranasal midazolam and intravenous
`diazepam were equally effective. Overall, 23 of 26
`seizures were controlled with midazolam and 24 out
`of 26 with diazepam. The mean time from arrival at
`hospital to starting treatment was significantly shorter
`in the midazolam group (3.5 (SD 1.8) minutes, 95%
`confidence interval 3.3 to 3.7) than the diazepam
`group (5.5 (2.0), 5.3 to 5.7). The mean time to control
`of seizures was significantly sooner (6.1 (3.6), 6.3 to
`6.7) in the midazolam group than the diazepam
`group (8.0 (0.5), 7.9 to 8.3). No significant side effects
`were observed in either group.
`Conclusion Seizures were controlled more quickly
`with intravenous diazepam than with intranasal
`midazolam, although midazolam was as safe and
`effective as diazepam. The overall time to cessation of
`seizures after arrival at hospital was faster with
`intranasal midazolam than with intravenous
`diazepam. The intranasal route can possibly be used
`not only in medical centres but in general practice
`and, with appropriate instructions, by families of
`children with recurrent febrile seizures at home.
`
`Introduction
`Convulsions triggered by fever (febrile seizures) are the
`most common type of seizures in childhood, with a
`prevalence of 3›4%.1 Acute onset of febrile seizures
`requires prompt medical attention, ventilation support,
`and appropriate oxygenation until they either stop
`spontaneously or are controlled by drugs.
`Diazepam is the most widely used drug for the
`acute management of all types of seizures in both
`adults and children.2 However, it has a short duration
`of action, should be given intravenously or rectally
`(since its absorption is slow if given intramuscularly),
`and tends to accumulate if repeated doses are given,
`with the possible rare complication of brain stem
`depression leading to bradypnoea or even respiratory
`arrest. The introduction of an intravenous line may be
`
`BMJ VOLUME 321 8 JULY 2000 bmj.com
`
`difficult, particularly in children with generalised tonic›
`clonic febrile seizures.3 4 Diazepam may also be given
`rectally to control seizures, which is as effective as intra›
`venous diazepam.5 A literature review in 1990
`identified only three cases of reversible respiratory
`depression in 843 patients with seizures.6
`Midazolam, the first water soluble benzodiazepine,
`is widely accepted as a parenteral anxiolytic and
`premedicant.7 Its safety and efficacy as an anticonvul›
`sant drug given intramuscularly have been shown in
`several studies in animals and humans (adults and chil›
`dren).3 4 8 9
`Midazolam given intranasally as an anaesthetic
`agent has been shown to be safe and effective in
`children undergoing various diagnostic studies and
`minor surgical procedures.10–13 Intransal midazolam
`also suppresses epileptic activity and improves the
`background of electroencephalograms in children
`with epilepsy.14
`We recently showed that intranasal midazolam is
`safe and effective for the management of acute seizures
`In the present study, we aimed to
`in children.15
`compare midazolam given intranasally with diazepam
`given intravenously for the treatment of febrile seizures
`in children.
`
`Subjects and methods
`Our study was performed at the Pediatric Emergency
`Department of Assaf Harofeh Medical Center in Zeri›
`fin, Israel, a general hospital affiliated with a university.
`Over 12 months, all children between the ages of six
`months and five years who presented with febrile
`seizures (tonic, clonic, or tonic›clonic) lasting for at
`least 10 minutes were eligible for inclusion in our
`study. Febrile seizures were diagnosed retrospectively
`on the basis of clinical data (history, physical findings,
`and cerebrospinal fluid results). We excluded children
`with established intravenous lines or those who had
`received anticonvulsants before admission. We chose
`10 minutes of ongoing motor seizure as the entry cri›
`terion, as most emergency physicians would initiate
`anticonvulsive treatment after that time.3 We estimated
`that upon arrival at the hospital children would have
`had seizures for at least 10 minutes as that is the least
`time it would take to reach the hospital from the near›
`est cities.
`After seizures were controlled in the children, their
`parents were asked to sign a consent form giving per›
`mission to enrol them in our study. The hospital’s eth›
`ics committee approved the study on the understand›
`ing that, because midazolam is rapidly taken up by the
`intranasal route, there would be no significant delay in
`treating patients randomised to receive this drug, and
`that if this treatment failed an intravenous line would
`immediately be introduced.
`
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`Children with febrile seizures received routine life
`support on admission to hospital. We randomly
`assigned 100 episodes of febrile seizure to treatment
`with either
`intranasal midazolam 0.2 mg/kg or
`intravenous diazepam 0.3 mg/kg, the maximum dose
`being 10 mg. Randomisation was performed in
`advance with a random number table by a hospital
`pharmacist not involved in the study, and treatment
`allocations were sealed in opaque envelopes. Investiga›
`tors were blind to these allocations.
`Midazolam solution (5 mg/ml) was dripped by
`syringe into both nostrils in equal doses, and an intra›
`venous line was immediately introduced. We recorded
`the following times: arrival at hospital, treatment with
`intranasal midazolam, intravenous access, cessation of
`seizures, and recurrence. Treatment was considered
`successful if the seizure ceased within five minutes. Sei›
`zures that stopped between five and 10 minutes after
`treatment were defined as successful but delayed
`control of seizure. Seizures that did not stop within 10
`minutes after treatment were defined as treatment fail›
`ures, and intravenous diazepam 0.3 mg/kg was given.
`Seizures that were controlled with midazolam or
`diazepam but recurred within 60 minutes were defined
`as recurrent seizures.
`During seizure activity and for 60 minutes after
`control, the children were followed by continuous car›
`diorespiratory and pulse oximetry monitors. Vital
`signs were recorded every 15 minutes. During seizure
`activity, high flow oxygen was provided through a
`mask. All the children were admitted to the paediatric
`ward for 24 hour observation after cessation of
`seizures.
`The results are presented as means (standard
`deviations) and 95% confidence intervals for continu›
`ous data and proportions for nominal data. We
`compared the two groups by independent sample t test
`or Fisher’s exact test. We estimated the duration of sei›
`zure after arrival at hospital between the two groups
`from survival curves produced by using the Kaplan›
`Meier method and the log rank statistics.
`
`Results
`Overall, 53 children were eligible for our study. We
`excluded nine children owing to spontaneous cessa›
`tion of seizure: five (one with bacterial meningitis) were
`randomised to receive intranasal midazolam, and four
`(one with viral meningitis) were randomised to receive
`intravenous diazepam (fig1).
`Intranasal midazolam was given for 26 episodes of
`febrile seizures
`in 21 children and intravenous
`diazepam for 26 episodes in 23 children. Overall, 40
`children had one seizure and four children had three
`recurrent seizures. On each occasion these children
`were rerandomised to either treatment group.
`Table 1 summarises the patients’ clinical character›
`istics. No statistically significant differences were found
`between the groups. Table 2 presents the results of
`treatment. The drugs were equally effective at
`stopping seizures. Overall, 23 of 26 seizures
`responded to initial
`treatment with intranasal
`midazolam and 24 of 26 responded to intravenous
`diazepam. Five treatment failures occurred, three in
`the midazolam group (all with upper respiratory tract
`infection) and two in the diazepam group. Two of the
`
`Eligible patients
`(n=53)
`
`Randomisation
`
`Intranasal midazolam
`(n=21)
`
`Intravenous diazepam
`(n=23)
`
`Did not receive midazolam
`(n=5)
`
`Did not receive diazepam
`(n=4)
`
`Follow up (n=21)
`Time intervals between
`arrival at hospital, receiving
`midazolam, and cessation
`of seizures (n=21)
`
`Follow up (n=23)
`Time intervals between
`arrival at hospital, receiving
`diazepam, and cessation
`of seizures (n=23)
`
`Withdrawn (n=3)
`Intervention ineffective (n=3)
`
`Withdrawn (n=1)
`Intervention ineffective (n=1)
`
`Completed trial
`(n=21)
`
`Completed trial
`(n=23)
`
`Fig 1 Flow of subjects through trial
`
`in the midazolam group were
`seizures
`three
`controlled with intravenous diazepam and one with
`intravenous phenobarbital after intravenous diazepam
`failed. Two seizures in the diazepam group were con›
`trolled with intravenous phenobarbital. Statistically
`significant differences were found between the time of
`treatment and control of seizures. Time from arrival at
`hospital to treatment was faster in the midazolam
`group. Seizures were controlled faster in the diazepam
`group, and the time from arrival at hospital to control
`of seizure was faster in the midazolam group. Survival
`analysis showed a significant difference between the
`time to cessation of seizures after arrival at hospital in
`the two groups (fig 2). Two children with recurrent sei›
`zures, one in each group,
`failed to respond to
`midazolam and diazepam. Both were successfully
`controlled with intravenous phenobarbital.
`signs of
`None of
`the children had clinical
`respiratory distress, bradycardia, or other side effects.
`Electrocardiograms, blood pressure, and the results of
`pulse oximetry were normal in all children during sei›
`zure activity and 60 minutes after cessation of seizures.
`
`Table 1 Clinical characteristics of study groups. Values are
`numbers of children unless stated otherwise
`
`Median age (months) (range)
`Boys
`Girls
`Previous febrile seizures
`Recurrent febrile seizures
`Cause of febrile seizures:
`Upper respiratory tract infection
`Acute otitis media
`Bronchopneumonia
`Clinical dysentry (shigellosis)
`Others
`
`Intranasal
`midazolam
`(n=21)
`16 (6›38)
`13
`8
`17
`4
`
`Intravenous
`diazepam
`(n=23)
`18 (6›40)
`12
`11
`17
`6
`
`10
`6
`3
`3
`4
`
`10
`4
`4
`5
`3
`
`84
`
`AQUESTIVE EXHIBIT 1139 Page 0003
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`Papers
`
`Intranasal midazolam
`
`Intravenous diazepam
`
`1.2
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Non-responses (%)
`
`continuously monitored by electroencephalography)
`was absorbed rapidly through the nasal mucosa, and
`that it could suppress epileptic activity and improve the
`background for electroencephalography.14 None of the
`19 children included in this study had apnoea or
`bradycardia.
`We recently showed that intranasal midazolam is
`effective in the management of acute seizures in
`children.15 In 19 out of 20 children, control of seizures
`was achieved within 3.5 (SD 0.8) minutes of starting
`midazolam. None of the children had clinical signs of
`respiratory distress or bradycardia.
`To our knowledge, no controlled studies have com›
`pared the efficacy of
`intranasal midazolam with
`intravenous diazepam for the management of febrile
`seizures. We found that seizures were controlled faster
`with intravenous diazepam than with intranasal mida›
`zolam but that midazolam was as safe and effective as
`diazepam. The time to cessation of seizure was shorter
`with intranasal midazolam.
`A potential weakness of our definition of efficacy as
`being control of seizures under five minutes is the
`possibility of
`spontaneous
`cessation of
`seizures
`irrespective of
`treatment within this
`time. We
`attempted to minimise this limitation by choosing
`ongoing seizure for at least 10 minutes as our entry
`criterion to the study, assuming that the chance for
`spontaneous cessation of such prolonged seizures is
`low.
`Although upper respiratory tract infection might
`help absorption by increasing blood flow to the nasal
`mucous membrane, the presence of nasal secretions
`could dilute the midazolam solution and interfere with
`its contact with the absorbing surface. Most of the chil›
`dren in our
`study had upper
`respiratory tract
`infections, but this only affected the absorption of
`midazolam and subsequent seizure control in three
`episodes.
`Acute seizures have been treated with oral
`diazepam and lorazepam, sublingual lorazepam, rectal
`solutions of lorazepam and diazepam, and diazepam
`suppositories.25–28 Giving the drugs orally or sublin›
`gually is frequently difficult and hazardous when
`children are convulsing, and absorption of diazepam
`and lorazepam tablets and rectal lorazepam solution
`are relatively slow.29 Rectal diazepam can be given
`safely in a prehospital environment by medical and
`non›medical staff, as a means of providing immediate
`treatment for prolonged seizures. This may shorten the
`duration of seizures and simplify the management of
`these patients in the emergency department.5 Because
`our study was designed to investigate an alternative
`means of treating prolonged febrile seizures in an
`emergency setting, we chose to compare intranasal
`midazolam with intravenous
`rather
`than rectal
`diazepam, as the rectal route is not always reliable
`
`Table 2 Duration of time intervals (in minutes) for giving drug, seizure control, and
`response to treatment in study groups. Values are means (SDs) and 95% confidence
`intervals
`
`Time to giving drug after arrival at hospital
`Time of cessation of seizure after giving drug
`Time to cessation of seizure after arrival at hospital
`P<0.001 for all groups.
`
`Intranasal midazolam
`3.5 (1.8) (3.3 to 3.7)
`3.1 (2.2) (2.9 to 3.3)
`6.1 (3.6) (6.3 to 6.7)
`
`Intravenous diazepam
`5.5 (2.0) (5.3 to 5.7)
`2.5 (1.9) (2.4 to 2.6)
`8.0 (4.1) (7.9 to 8.3)
`
`AQUESTIVE EXHIBIT 1139 Page 0004
`
`85
`
`0
`
`5
`
`6
`
`7
`
`10
`11
`Time (minutes)
`Fig 2 Time from arrival at hospital to cessation of seizures in
`children receiving intranasal midazolam 0.2 mg/kg or intravenous
`diazepam 0.3 mg/kg, presented as survival data
`
`8
`
`9
`
`Discussion
`Midazolam given intranasally is as safe and effective as
`diazepam given intravenously in the management of
`febrile seizures
`in children. Midazolam, a 1,4›
`benzodiazepine agent of the group of 1,2›unrelated
`benzodiazepines, is a water soluble compound. It has
`been extensively used in anaesthetic practice since
`1982, and its pharmacology and pharmacokinetics are
`well known.16 The drug is hydrophilic at its prepared
`pH of 3.5 and is therefore reliably absorbed intramus›
`cularly. At physiological pH, its ring structure closes, it
`becomes highly lipophilic, readily crosses the blood›
`brain barrier, and enters the central nervous system,
`with rapid clinical effects.17 18 The elimination half›life
`of midazolam is usually between 1.5 and 3.5 hours.16
`Several
`studies have found it effective as an
`anticonvulsant—it inhibited convulsions in mice to a
`greater extent
`than diazepam.8 9 Midazolam given
`intramuscularly was effective in controlling convul›
`sions in pigs, but its onset of action was not as fast as
`when given intravenously.19 The activity of interictal
`spike waves in adults with epilepsy was successfully
`abolished with intramuscular midazolam and intra›
`venous diazepam.9
`The safety and efficacy of midazolam has been
`shown by several clinical studies in epileptic adults and
`children,3 4 9 and continuous infusion of midazolam
`has successfully controlled status epilepticus in adults
`and children.20–22 Midazolam given intravenously or
`intramuscularly is not associated with respiratory
`changes, although there are reported associations with
`hypertension, bradycardia, and hypoxia in adults and
`children. These changes were, however, mild and tran›
`sient. No patient had to be intubated or mechanically
`ventilated.22 23
`intranasal
`the popularity of
`As a result of
`midazolam as a sedative agent for minor surgical inter›
`ventions and diagnostic procedures, there is consider›
`able information on its use in young children. The
`elimination half›life of intranasal midazolam at a dose
`of 0.2 mg/kg is similar to that when the drug is given
`intravenously,24 and no significant complications have
`been reported when it is given by the intranasal route.
`Therefore, it seemed pertinent to investigate the use of
`intranasal midazolam in the management of acute sei›
`zures, especially in children, where the introduction of
`an intravenous line is frequently unsuccessful.
`One study found that intranasal midazolam given
`to epileptic children without clinical seizures (who were
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`
`What is already known on this topic
`
`Midazolam given intranasally is a safe and effective treatment for
`prolonged febrile seizures in children
`What this study adds
`
`Control of seizures in children is faster with intravenous diazepam
`than with intranasal midazolam, but the time to cessation of seizures
`after arrival of a child at hospital is faster with intranasal midazolam
`
`Intranasal midazolam may be used in general practice and, with
`appropriate instructions, by the parents of children with recurrent
`febrile seizures at home
`
`owing to variable bioavailability and wide range of
`serum concentrations.30 31 Rectal diazepam in the form
`of a gel was recently introduced as another effective
`and well
`tolerated treatment
`for acute repetitive
`seizures, which can be administered at home by trained
`caregivers.32
`In conclusion, intranasal midazolam could be pro›
`vided not only
`in medical
`centres but, with
`appropriate instruction, by the parents of children
`with febrile seizures at home. Further studies are, how›
`ever, needed on a larger series of children with various
`types of seizures.
`
`Contributors: EL had the original idea for, and coordinated, the
`study. MG, JB, and TB coordinated the study and helped with
`data analysis. MB helped with the analysis and, with EL,
`prepared the paper. EL will act as guarantor for the paper.
`Funding: None.
`Competing interests: None declared.
`
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`Am 1989;36:375›82.
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`3 Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenchlager
`DW, Waisman Y. A prospective,
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`19 Orebaugh SZ, Bradford SM. Intravenous vs intramuscular midazolam in
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`(15 March 2000)
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`AQUESTIVE EXHIBIT 1139 Page 0005
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`BMJ VOLUME 321 8 JULY 2000 bmj.com
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`General practice
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`Downloaded from on 4 January 2006 bmj.com
`
`
`
`What is already known on this topic
`
`Sociocultural factors are believed to play a part in women’s decisions
`making about infant feeding
`
`No previous study has examined how infant feeding is portrayed in the
`British media
`What this study adds
`
`Breast and bottle feeding are portrayed very differently by the mass
`media
`
`Bottle feeding is shown more often than breast feeding and is
`presented as being less problematic
`
`Bottle feeding is associated with “ordinary” families whereas breast
`feeding is associated with middle class or celebrity women
`
`Health professionals and policy makers should be aware of patterns in
`media coverage and the cultural background within which women
`make decisions about infant feeding
`
`entire press sample, we found no explicit references to
`the health benefits of breast feeding.
`Media coverage implies that breast feeding is prob›
`lematic,
`funny, and embarrassing, and that
`it
`is
`associated with middle class or celebrity women. In
`contrast, bottle feeding is socially integrated, highly vis›
`ible, unproblematic, and associated with “ordinary”
`families. The health benefits of breast feeding and the
`risks of formula feeding were largely absent in routine
`media coverage.
`Discussion
`
`The mass media do not promote a positive image of
`breast feeding, even though it is the method of infant
`feeding associated with the most health benefits. Media
`coverage may, of course, reflect the reality of what is
`publicly visible—that is, that many women do not breast
`feed in public—and attention to problems may prepare
`women for the realities of breast feeding. These limited
`portrayals, however, may also help perpetuate a lack of
`acceptance of breast feeding in public. They may also
`sustain ideas that breast feeding is a difficult activity,
`likely to fail, or that it is an option only for certain types
`of women. Although some people argue that we live in
`a culture that makes breast feeding “compulsory,” this
`does not seem to be the case as far as mass media rep›
`resentation is concerned. On the contrary, bottle feed›
`ing seems to be normalised and represented as the
`obvious choice.
`We chose to analyse the coverage of infant feeding
`by the media for one month only, and it may be useful
`to compare the portrayal of breast and bottle feeding
`over a longer time frame. This would enable compari›
`son between routine coverage and special initiatives
`(for example, breastfeeding awareness week). It may
`also be valuable to extend the sampling to include chil›
`dren’s programming to explore messages reaching
`young people. Examining the decision making
`processes of media staff could facilitate a greater
`awareness of obstacles to portraying breast feeding and
`identify areas for intervention. The study of women’s
`responses to media representations could inform
`future campaigns and interventions. It is important
`
`that clinicians, health educators, and policymakers are
`aware of patterns of media coverage and the complex
`cultural background within which women are making
`choices about infant feeding. The media may have pro›
`found implications for how women decide to feed their
`babies and thus for the health of the next generation.
`
`Contributors: LH, the principal researcher on the project,
`formulated the study goals, gathered and analysed the data, and
`wrote the paper. JK formulated the study goals, analysed the
`data, and wrote the paper. JG formulated the study goals and
`provided expertise on infant feeding. Serena Patterson and
`Yvonne Wayne helped code the television programmes. LH and
`JK will act as guarantors for the paper.
`Funding: The study “infant feeding in the media: an analysis
`of representation and influence” was funded by the Economic
`and Social Research Council (grant No R000222785).
`Competing interests: None declared.
`
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