`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`J. Paediatr. Child Health
`
`(2004)
`
`
`40
`, 556–558
`
`Use of intranasal midazolam to treat acute seizures in
`paediatric community settings
`
`1
`MG Harbord,
`
`2
` NE Kyrkou,
`
`3
` MR Kyrkou,
`
`4
` D Kay,
`
` and KP Coulthard
`
`5
`
`2
`1
`School of Disability Studies, Flinders University,
`Paediatrics and Child Health, Flinders Medical Centre,
`Departments of
`5
`4
`3
`Bedford Park,
`Child and Youth Health,
`Education and Children’s Services, Adelaide and
`Pharmacy Department, Women’s and
`Children’s Hospital, North Adelaide, South Australia, Australia
`
`Objectives:
`To evaluate the acceptability of intranasal midazolam (INM) in acute seizure management in the community.
`Methods:
`Parents and staff in residential and educational settings were trained in first aid and seizure management and the
`administration of INM. Feedback was obtained from those who had given INM over the 30-month period September
`2000–March 2003.
`Results:
`Intranasal midazolam was administered to 22 children for a total of 54 seizures (range 1–6 seizures each). The
`dose was 0.2–0.3 mg/kg rounded down to 1 or 2 of the 5 mg in 1-mL plastic ampoules, with the anticonvulsant instilled into
`the child’s nose directly from the plastic ampoule. Seizures were effectively stopped on 48 occasions, i.e. 89%, while no
`respiratory arrests occurred. Thirty carers had given INM to a convulsing child and 27 (90%) reported no difficulty in
`administering it. Fifteen people had also previously administered rectal diazepam and INM was considered easier to
`administer than rectal diazepam by 13 while a preference to use INM rather than rectal diazepam was indicated by 14.
`Conclusion:
`This study has shown that INM is an acceptable treatment option as a first aid response for acute seizures. We
`believe that INM should be considered as the preferred alternative in the community setting, as it is easier to administer and
`is more dignified for the patient than rectal diazepam.
`
`Key words:
`
`children; community; midazolam; seizure.
`
`Tonic clonic status epilepticus is a medical emergency that is
`defined as prolonged or recurrent seizure activity persisting for
`1
`30 min or more.
` It occurs in 5% of adults and 10–25% of
`1
`children with epilepsy.
`The mortality rate of this condition in childhood is 3–6%
`while permanent neurologic sequelae, i.e. neurologic deficits or
`intellectual disability occurs in up to 30%, with the highest risk
`2
` Brain imaging studies with
`occurring in younger children.
`MRI have demonstrated regions of focal cerebral oedema
`3
` Although
`occurring soon after an episode of status epilepticus.
`the oedema resolved, changes of atrophy and gliosis subse-
`quently appeared in the same regions.
`Urgent treatment is required for status epilepticus as neuro-
`logic complications are directly related to the duration of the
`1
`seizure.
` In addition the sooner that treatment is commenced,
`4
`the more likely it is that it will be effective. Lowenstein
`showed that treatment of prolonged seizures within 30 min of
`onset was associated with an 80% response rate to first line
`anticonvulsants, compared with less than a 40% response rate if
`the seizure had persisted for more than 2 h.
`Since most generalized tonic clonic seizures usually last less
`5
`6
`than a few minutes, Holmes
` and Lowenstein
` have proposed
`an operational definition of status epilepticus as continuous
`seizures lasting more than 5 min, or two or more discrete
`seizures not separated by complete recovery of consciousness.
`It therefore seems desirable that once a seizure has continued
`for more than 5 min, then treatment should be commenced with
`a quick acting anticonvulsant.
`In the community setting the current options for acute
`seizure management are limited to waiting for an ambulance to
`arrive or giving rectal diazepam. Rectal diazepam has been
`
`used for the prehospital acute treatment of seizures for over
`7
`20 years.
` It is usually effective, but concerns have been raised
`about the physical difficulty of administering rectal medication
`to a convulsing patient, as well as the ethical considerations in
`regard to maintaining privacy and the potential for allegations
`5
`of sexual abuse.
`Interest has recently been raised in using intranasal mida-
`zolam (INM), which has an equally rapid onset of activity
`compared with rectal diazepam, but is easier and more socially
`8
` Midazolam is now available in a
`acceptable to administer.
`plastic ampoule at a strength of 5 mg in 1 mL, which enables
`nasal instillation of the midazolam directly from the ampoule.
`
`OBJECTIVES
`
`The aims of this study were to evaluate the acceptance of INM
`for acute seizure management in the community when given by
`parents, carers, teachers and first aiders.
`
`METHODS
`
`Consecutive children with epilepsy from the first author’s
`epilepsy clinic at Flinders Medical Centre, Adelaide, South
`Australia (SA) and his private practice were approached for
`involvement in the study between September 2000 and March
`2003. The inclusion criteria were an age between 4 and
`18 years and at least one primary or secondarily generalized
`tonic clonic seizure lasting two or more minutes. Parents were
`informed about the availability of INM and those who elected
`
`Correspondence: Dr M Harbord, Department of Paediatrics and Child Health, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
`Fax: +61 8 8204 3945; email: michael.harbord@flinders.edu.au
`Accepted for publication 7 April 2004.
`
`AQUESTIVE EXHIBIT 1142 Page 0001
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Intranasal midazolam and acute seizures
`
`557
`
`to be trained were enrolled in the study. The child’s teacher and
`care worker were also invited to be trained as well, with
`parental permission. The study was approved by the Ethics
`Committee of the South Australian Department of Education
`and Children’s Services, while parents of all children gave
`informed consent.
`A standardized management procedure was developed for
`directly giving INM using the 5 mg in 1-mL plastic ampoule,
`i.e. without the need for drawing the dose up into a syringe
`first. Although various intranasal administration devices are
`available, we opted to use the plastic ampoules on the grounds
`of cost and stability of the drug in the ampoule. Preparations
`were made to give INM if a generalized tonic clonic seizure
`had lasted more than 3 min, which is similar to the method used
`in a recent comparative trial of buccal midazolam and rectal
`9
`diazepam by Scott.
` The children were moved onto their backs
`for instillation of the midazolam, with 1–3 drops squeezed
`gently from the ampoule into each nostril until the ampoule was
`empty, i.e. 15–16 drops in all. This took 30–60 s and they were
`immediately rolled onto their sides into the recovery position
`once the dose had been given.
`The prescribed dose was 0.2 mg – 0.3 mg/kg, which was
`rounded down to one or two of the 5 mg ampoules. In general
`children aged 4–10 years had one ampoule and those older than
`10 had two ampoules. All children had been given an interictal
`test dose of INM in a hospital outpatient clinic prior to its use
`in the community, to ensure that there were no side-effects of
`respiratory depression with the dose prescribed. Feedback
`about the use of INM was then obtained by a questionnaire,
`coupled with direct interviews of parents and carers in the
`outpatients clinic.
`
`RESULTS
`
`No family refused to be involved in the study. Over the
`30-month study period training was given to 43 parents,
`41 teachers and 30 care workers. INM was administered to
`22 children for 54 Seizures (range 1–6) at home or school. The
`clinical and demographic information about the children and
`their epilepsy is listed in Table 1. Seizures were effectively
`stopped in 48 episodes (89%) meaning that further administra-
`tion of an anticonvulsant by an ambulance officer or in hospital
`was not required.
`In two of four children whose seizures did not respond to
`INM a successful response did occur on subsequent occasions
`when the dose was increased to 0.3 mg/kg with two rather than
`one of the 5 mg ampoules used. Although shallow breathing
`was reported in one case, no respiratory arrests occurred.
`Questionnaires were completed by all those who had given
`INM, i.e. 30 parents, school assistants and teachers. Twenty-
`seven (90%) reported no difficulty in administering the
`medication.
`Fifteen people also had experience administering INM and
`rectal diazepam (either as a suppository or rectal solution) with
`
`Table 1
`Clinical and demographic features of 22 children administered
`intranasal midazolam
`
`Age range
`Males
`Intellectual disability
`Aetiology of epilepsy syndrome
`Symptomatic
`Idiopathic
`
`4–18 years
`10 (45%)
`20 (91%)
`
`13
`9
`
`13 considering INM easier to administer than rectal diazepam.
`A preference to use INM instead of rectal diazepam was
`reported by 14.
`Once they had been trained to give INM, 80% of people
`preferred to use it rather than wait for an ambulance, with
`100% of parents, 79% of teachers and 58% of school assistants
`expressing this intention. The most frequent comments about
`the use of INM were that it was less intrusive, gave greater
`privacy and was more suitable for use in the community
`compared with rectal diazepam.
`
`DISCUSSION
`
`This study has shown that INM is an acceptable anticonvulsant
`for acute seizure treatment in the community setting. The
`technique for administering INM was considered to be easier
`than for rectal diazepam and less intrusive. It was also per-
`ceived that INM was more effective than rectal diazepam,
`although this was not objectively evaluated in the study.
`There is a steadily growing volume of literature on the use of
`10
`INM to treat seizures. Lahat
` compared the safety and effi-
`ciency of INM with IV diazepam in children presenting to the
`emergency department with prolonged febrile seizures, which
`had lasted at least 10 min. Both INM and IV diazepam were
`equally effective, but the authors noted that the mean time to
`control the seizures was shorter in the midazolam group, as
`there was no delay in having to obtain intravenous access
`before administering the drug.
`11
`12
`Kutlu
` and Fisgin
` found that INM at a dose of 0.2–
`0.3 mg/kg effectively stopped seizures in over 80% of children
`13
` reported that the
`within 5–8 min. In a later study Fisgin
`response rate to INM for seizures lasting more than 5 min was
`14
` found
`87%, compared with 60% for rectal diazepam. Conroy
`that only three of 13 children whose seizure had lasted more
`than 30 min responded to INM 0.2 mg/kg compared with five
`of five children whose seizure duration was 10 min or less.
`8
`Jeannet
` reported the use of INM in 26 children who had
`acute seizures, either when in hospital (17 children) or at home
`(11 children). The dose was 0.2 mg/kg and the midazolam had
`been drawn up beforehand in a 1-mL syringe. All the seizures
`treated at home responded within 10 min and no serious
`adverse side-effects occurred, with two children being adminis-
`tered the INM on over 25 occasions. Parents of nine children
`had previously used rectal diazepam at home, and for seven of
`these children their parents considered that INM was easier to
`use and that their children had recovered more rapidly.
`15
`Wilson
` reported a telephone survey of 40 parents whose
`children had been administered nasal or buccal midazolam at
`home for prolonged seizures. Midazolam was considered effec-
`tive for 33 children (83%). Rectal diazepam had previously
`been used for seizures in 24 children and parents expressed a
`preference for using midazolam in 20 of these. Reasons for
`preferring midazolam included that it was more dignified and
`socially appropriate, it was easier to administer in wheelchair
`users and a response occurred more quickly than with rectal
`diazepam.
`Some anticipated problems with INM did not eventuate. No
`difficulties were encountered with airway obstruction during
`the brief period of 30–60 s during which the children were on
`their back for INM administration.
`Training emphasized that the children must be turned onto
`their side into the recovery position once the dose has been
`given. INM was well absorbed despite some children having a
`runny nose. Occasionally nasal irritation was reported when the
`trial dose was given in the waking state, but this was not a
`
`AQUESTIVE EXHIBIT 1142 Page 0002
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`558
`
`MG Harbord
`
`.
`et al
`
`problem in clinical use as the children were unconscious during
`the generalized seizures.
`16
`Midazolam appears to be better tolerated than diazepam.
`A recent comparative study of IV or IM midazolam with IV or
`rectal diazepam by ambulance paramedics in New South Wales
`found that respiratory depression was significantly less fre-
`17
`quent with midazolam.
` No episodes of apnoea occurred
`secondary to INM administration in the current study but the
`authors consider that it is desirable to give a test dose of INM
`in the hospital or clinic prior to its use in the community.
`Carers and parents frequently commented that INM was
`easier to administer and was more dignified for the child,
`particularly for adolescents. This issue has previously been
`raised in the 1995 Australian Position Statement on Rectal
`18
`Diazepam
` in which it was recognized that the physical
`difficulty of rectal diazepam administration and issues of
`privacy, dignity and consent limited enthusiasm for its use in
`adolescents and adults.
`Once they had been trained to give INM, parents and
`caregivers showed a willingness to treat seizures rather than
`just wait for an ambulance to arrive. This study has shown that
`INM is an acceptable treatment option as a first aid response for
`acute seizures. We believe that INM should be considered as
`the preferred alternative to rectal diazepam in the community
`setting.
`
`ACKNOWLEDGEMENT
`
`The authors thank Ms Kylie Bailey for assistance in collecting
`data.
`
`REFERENCES
`
`1 Shorvon S. Tonic clonic status epilepticus.
`56
` 1993;
`: 125–34.
`Psych.
`2 Pellock JM. Status epilepticus in children: update and review.
`9
` 1994;
` (Suppl.): S527–S535.
`J. Child Neurol.
`
`J. Neurol. Neurosurg.
`
`NEJM
`
` 1998;
`
`3 Meierkord H, Wieshmann U, Niehaus L, Lehmann R. Structural
`consequences of status epilepticus demonstrated with serial mag-
`96
`netic resonance imaging.
` 1997;
`: 127–32.
`Acta Neurol. Scand.
`4 Lowenstein DH, Alldredge BK. Status epilepticus at an urban
`43
`public hospital in the 1980s.
` 1993;
`: 483–8.
`Neurology
`5 Holmes GL. Buccal route for benzodiazepines in treatment of
`353
`seizures?
` 1999;
`: 608.
`Lancet
`6 Lowenstein DH, Alldredge BK. Status Epilepticus.
`338
`: 970–6.
`7 Knudsen FV. Plasma diazepam in infants after rectal administra-
`tion in solution and by suppository.
` 1977;
`Acta Paediatr. Scand.
`66
`: 563–76.
`8 Jeannet P, Roulet E, Maeder-Ingvar M, Gehri M, Jutzi A,
`Deanna T. Home and hospital treatment of acute seizures in
`children with nasal midazolam.
` 1999;
`Eur. J. Paediatr. Neurol.
`3
`: 73–7.
`9 Scott RC, Besag FMC, Neville BGR. Buccal midazolam and
`rectal diazepam for treatment of prolonged seizures in childhood
`353
`and adolescence: a randomised trial.
` 1999;
`: 623–6.
`Lancet
`10 Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Com-
`parison of intra nasal midazolam with intravenous diazepam for
`treating febrile seizures in children: prospective randomised study.
`321
` 2000;
`: 83–6.
`BMJ
`11 Kutlu NO, Yakinci C, Dogrul M, Durmaz Y. Intranasal mida-
`22
`zolam for prolonged convulsive seizures.
` 2000;
`:
`Brain Dev.
`359–61.
` Nasal midazolam effects on
`12 Fisgin T, Gurer Y, Senbil N
`et al.
`15
`childhood acute seizures.
` 2000;
`: 833–5.
`J. Child Neurol.
`13 Fisgin T, Gurer Y, Tezic T
` Effects of intranasal midazolam
`et al.
`and rectal diazepam on acute convulsions in children: prospective
`17
`randomised study.
` 2002;
`: 123–6.
`J. Child Neurol.
`14 Conroy S, Morton R, Dixon H, Porter A, Choonara I. A pros-
`pective study of intranasal Midazolam for children with acute
`4
`seizures.
` 2000;
`: 52–7.
`Paediatr. Perinat. Drug Ther.
`15 Wilson MT, MacLeod S, O’Regan ME. Nasal/buccal midazolam
`89
`use in the community.
` 2004;
`: 50–1.
`Arch. Dis. Child
`16 Koren G. Intranasal midazolam for febrile seizures.
`BMJ
`321
`: 64–5.
`17 Rainbow J, Browne GJ, Lam LT. Controlling seizures in the
`pre-hospital setting: diazepam or midazolam?
`J. Paediatr.
`38
` 2002;
`: 582–6.
`Child Health
`18 Somerville ER, Antony JH. Position statement on the use of rectal
`163
`diazepam in epilepsy.
` 1995;
`: 268–9.
`Med. J. Aust.
`
` 2000;
`
`AQUESTIVE EXHIBIT 1142 Page 0003
`
`