European Journal of Paediatric Neurology 1999; 3:73-77
`
`ORIGINAL
`
`ARTICLE
`
`Home and hospital treatment of acute seizures
`in children with nasal midazolam
`
`PIERRE-YVES JEANNET,1 ELIANE ROULET,1 MALIN MAEDER-INGVAR/MARIO
`ANNE JUTZI, 1 THIERRY DEONNA 7
`I Department of Pediatrics, Neuropediatric Unit, 2Department of Neurology, Neurophysiology Unit,
`CHUV, Lausanne, Switzerland
`
`GEHRI,7
`
`Rectal diazepam is widely used in the treatment of acute seizures in children but has some disadvantages. Nasal/
`sublingual midazolam administration has been recently investigated for this purpose but never at home or in a general
`paediatric hospital. The aim of this open study was to determine the efficacy, the tolerance and the applicability of
`nasal midazolam during acute seizures in children both in hospital and at home. We included known epileptic
`children for treatment at home and all children with acute seizures in the hospital. In all, 26 children were enrolled,
`11 at home and 17 in the hospital (including two treated in both locations); only one had simple febrile seizure. They
`had a total of 125 seizures; 122 seizures (98%) stopped within 10 minutes (average 3.6 minutes). Two patients in the
`hospital did not respond and in three, seizures recurred within 3 hours. None had serious adverse effects. Parents had
`no difficulties administering the drug at home. Most of those who were using rectal diazepam found that nasal
`midazolam was easier to use and that postictal recovery was faster. Among 15 children who received the drug under
`electroencephalogram monitoring (six without clinical seizures), the paroxysmal activity disappeared in ten and
`decreased in three. Nasal midazolam is efficient in the treatment of acute seizures. It appears to be safe and most
`useful outside the hospital in severe epilepsies, particularly in older children because it is easy for parents to use.
`These data should be confirmed in a larger sample of children. Its usefulness in febrile convulsions also remains to be
`evaluated.
`Keywords: Acute seizures. Nasal midazolam.
`
`Introduction
`
`The treatment of acute seizures requires a drug that,
`is rapidly efficient and easily administered, even by
`non-medical professionals and the patient's rela-
`tives. Intrarectal diazepam has been successfully
`used for that purpose in children for several years
`in many countries. 1-3 This mode of administration
`has some disadvantages: diazepam has a tendency
`to accumulate if used repetitively; it can cause
`excitation or prolonged sedation; absorption from
`the rectum is variable; the drug is often rejected
`immediately after its administration; and it can be
`
`most impractical to administer in older children
`experiencing a generalized seizure. 4,s It can also be
`an embarrassment for older children if adminis-
`tered in public places, such as schools or camps.
`Given these disadvantages of rectal diazepam, new
`modes of treatment of acute seizures in children
`have
`recently been
`investigated such as
`the
`administration of nasal or sublingual midazo-
`lain. 6-9 This mode of administration of midazolam
`and its pharmacokinetics has already been exten-
`sively studied for sedation in children and has
`proved to be safe. 1°-13
`The efficacy of this new mode of administration
`in children presenting ongoing seizure in a regular
`
`Received 27.10.98. Revised 23.12.98. Accepted 30.12.98.
`Correspondence: Professor T Deonna, Neuropediatric Unit, Centre Hospitalier Universitaire Vaudois, CH-1011, Lausanne, Switzerland
`1090-379819910310073+5 $18.00
`© 1999 European Paediatric Neurology Society
`
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`74
`paediatric hospital as well as its applicability at
`home by the parents of epileptic children, remains
`to be shown. The purpose of this open study was to
`determine
`the efficacy, the
`tolerance and
`the
`applicability of nasal midazolam during acute
`seizures both in the hospital and at home.
`
`Patients and method
`We included all children aged from 1 month to 16
`years presenting with an acute seizure between
`November 1997 and July 1998 at
`the Centre
`Hospitalier Universitaire Vaudois
`(CHUV)
`in
`Lausanne, Switzerland. We also included
`three
`children from the Neonatology Unit with neonatal
`seizures.
`For the children at home, we enrolled chronic
`epileptic patients followed in the Neuropediatric
`Outpatient Clinic in the same hospital. The study
`was accepted by the hospital's ethical committee
`and written informed consent was obtained from
`the parents in this home treatment group.
`Some children were undergoing electroencepha-
`logram (EEG) monitoring while receiving nasal
`midazolam during
`their seizure. We also gave
`midazolam
`to some children without clinical
`seizures but who were given an EEG because of
`suspected epilepsy or as part of a control of their
`epilepsy, and whose tracing showed very frequent
`epileptic discharges. These particular children
`were not included further in the studied group
`but in all patients who received midazolam during
`EEG we noted how fast paroxysmal EEG activity
`disappeared or decreased and we looked for the
`presence of drug-induced beta rhythms as well as
`how much the child was sedated when he or she
`was conscious while receiving the drug.
`The dosage was 0.2 mg/kg of midazolam and we
`used
`the
`intravenous solution
`(5mg/ml). The
`solution was slightly hypotonic (215 mmol, com-
`pared with 285 mmol for isotonic saline), and its
`pH was 3.28. Half the volume was given in each
`nostril for about 4-5 seconds. A second dose could
`be given after 5 minutes if the seizure did not stop.
`Parents were instructed
`to prepare
`the correct
`amount of the drug in advance in a I ml syringe
`and to replace the syringe every month if it had not
`been used. 14
`Since many different people, both in the hospital
`and at home, were going to administer midazolam,
`and in order to simplify the protocol, we chose to
`give priority to nasal midazolam because it seemed
`easier to give in cases of generalized seizures. In a
`few cases, mostly when children were conscious,
`
`Original article: P-Y Jeannet et al.
`we gave it sublingually because it was reported to
`be better tolerated in this situation. 15
`
`Results (Table 1)
`In all, 26 children (13 males, 13 females) with
`seizures were enrolled, 11 at home and 17 in the
`hospital; two patients were treated in both places
`(Table1). They had a total of 125 seizures and
`received 128 doses of midazolam. Nasal midazo-
`lam was given to 24 patients, all with generalized
`or complex partial seizures. Two
`received
`it
`sublingually: the first (case 24) was conscious at
`the beginning of her seizure and the mother of the
`second patient felt more comfortable to give it in
`the mouth rather than the nose (case 5). Of the 17
`children with a seizure occurring in the hospital,
`nine had at least one seizure during EEG monitor-
`ing. The average age was 4.9 years (range 1 day-16
`years). A total of 17 (65%) patients were known
`epileptics undergoing regular anti-epileptic treat-
`ment; nine (35%) were having their first seizure;
`five (19%) received more than five doses; and two
`(8%) more than 20 doses (case numbers 18 and 21).
`These last two patients have severe refractory
`epilepsies.
`Efficacy
`Of 125 seizures, 122 (98%) stopped less than 10
`minutes after drug administration and lasted an
`average of 3.6 minutes (range 0.5-10min). All
`children receiving the drug at home did respond.
`Two patients in the hospital did not respond: the
`first (case 3) was admitted to our hospital with
`status epilepticus and had already received three
`different
`intravenous anti-epileptic drugs
`in a
`previous hospital. In the second patient (case 4),
`the seizure stopped within 30 seconds of mid-
`azolam administration, but recurred twice within
`10 minutes. The seizures were finally controlled
`with intravenous phenytoin.
`In three other patients seizures relapsed within a
`few hours: cases 9, 11 and 25. One of these patients
`(case 9) had a viral infection and presented with a
`generalized seizure in the emergency room while
`being afebrile. The seizure ceased within a minute
`of administration but recurred 3 hours later, and
`again was rapidly stopped with nasal midazolam
`without further relapse. The second patient (case
`11) had bilateral hippocampal dysplasia with
`frequent polymorphic seizures, despite vigabatrin
`and carbamazepine. On two occasions the seizures
`
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`Seizure type
`
`Sttrrge-Weber
`Acute HSV encephalitis
`Congenital hemiparesis
`(brain lesion)
`Infantile idiopathic convulsions
`Suspicion of Angelman
`syndrome
`Left sylvian stroke
`Asphyxia
`Cerebral haemorrhage
`Convulsion with viral infection,
`no fever
`Febrile convulsion
`Hippocampal dysplasia
`Idiopathic occipital epilepsy
`Primary generalized epilepsy
`Neonatal ischaemic
`encephalopathy
`Tuberous sclerosis
`Unknown syndrome
`Tuberous sclerosis
`
`Complex partial
`Complex partial
`Simple partial, then generalized
`Clusters of complex partial
`Polymorphic
`Polymorphic
`Polymorphic
`Polymorphic
`Tonic-clonic
`Tonic-clonic
`Polymorphic
`Simple partial (visual)
`Tonic-clonic
`Psychomotor status epilepticus
`Complex partial
`Complex partial
`Infantile spasms
`
`Severe myoclonic epilepsy of
`infancy
`Ischaemic cortical lesion
`congenital heart disease
`Vascular malformation
`Unknown
`Rett syndrome
`Unknown
`Ring chromosome 20
`Unknown syndrome
`Unknown
`
`Tonic-clonic
`Simple partial, then generalized
`Simple partial
`Complex partial
`Complex partial
`Simple partial, then generalized
`Complex partial
`Complex partial
`Complex partial
`
`75
`
`No. of
`doses ~
`
`15 (+2 at
`home)
`5
`2
`2
`1 (+2 at
`home)
`2
`1
`1
`2
`1
`3
`1
`1
`1
`1
`2
`1
`
`28
`2
`2
`29
`3
`2
`1
`14
`1
`128
`
`Original article: Nasal midazolam for acute seizures
`Table 1 Summary of cases treated with midazolam
`Case
`Age
`Sex
`Aetiology
`no.
`(years)
`Hospital
`I b
`2 c
`3
`4
`5 b
`6 c
`7
`8
`9
`10
`1V
`12 ¢
`13 ¢
`14 ¢
`15 c
`16 ¢
`17 c
`Home
`18
`19
`20
`21
`22
`23
`24
`25
`26
`TOTAL
`"A second dose was necessary to control patient's seizure in cases 21 and 22
`bReceived midazolam in hospital and at home
`CAt least one dose of rnidazolam was given under EEG monitoring. Seven additional children with frequent paroxysmal discharges but
`no clinical seizures were also given midazolam (see text)
`HSV, herpes simplex virus
`
`1
`1.5
`5.7
`1.2
`3.7
`5 days
`1 day
`10 days
`1.6
`1
`2.5
`12
`5.5
`3.9
`0.4
`3.5
`0.5
`
`7
`15.5
`6.1
`2.2
`8
`16
`14.5
`9.5
`4.2
`
`M
`M
`M
`M
`F
`M
`M
`M
`F
`F
`F
`F
`F
`M
`F
`F
`M
`
`M
`M
`F
`M
`F
`M
`F
`F
`F
`
`stopped within 2 minutes of nasal midazolam, but
`recurred after 1 and 2 hours. We thus decided to
`use rectal diazepam for this patient because of its
`longer duration of action. The third patient (case
`25) received 14 doses at home over 6 months. She
`had frequent complex partial seizures despite her
`treatment with carbamazepine and
`lamotrigine
`and, rarely, they occurred in clusters. On
`two
`occasions a seizure recurred within 3 hours of
`midazolam administration.
`
`Tolerance
`Of the 26 patients receiving a total of 128 doses, 24
`(92%) had no particular reaction when the drug
`was given through the nose which is not surprising
`since 23 of these were unconscious. Two (8%)
`fought and were agitated: the first (case 20) had
`frequent partial seizures without loss of conscious-
`ness, and refused further nasal application because
`she disliked
`the sensation and preferred rectal
`
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`76
`diazepam. Her mother tried the sublingual route,
`but the child did not like the taste and on another
`occasion she refused a sublingual mint-flavoured
`solution. The second patient (case 26) had complex
`partial seizures during which she was always very
`agitated even before she received any drug to stop
`the seizure. None had serious adverse effects such
`as respiratory depression or paradoxical reactions.
`One patient (case 24) who had complex partial
`seizures, complained of dizziness almost immedi-
`ately after the administration and refused to use
`sublingual midazolam again. Another patient (case
`18) with refractory epilepsy received five doses
`within 7 days and presented with a skin irritation
`around the nostrils which spontaneously disap-
`peared and did not recur despite further doses.
`Interestingly, two conscious children with simple
`partial seizures had no significant alteration of
`vigilance after administration of midazolam.
`
`Effect of nasal midazolam on paroxysmal
`EEG activity
`Of the 17 patients who received nasal midazolam
`during a seizure in the hospital, nine (53%) had at
`least one dose under EEG monitoring. Six other
`epileptic children with abnormal paroxysmal
`activity seen on the EEG, but no seizure, received
`midazolam. A total of 15 patients received nasal
`midazolam during EEG monitoring and in 10 of the
`15, the paroxysmal activity disappeared
`in less
`than 5 minutes after administration, and in three
`others
`it decreased markedly. In seven, drug-
`induced beta activity appeared within 1 to 6
`minutes of administration of the drug.
`
`Applicability at home
`Eleven patients received a total of 86 doses of
`intranasal midazolam during a seizure at home. No
`parent described any technical difficulties during
`administration. Nine patients were receiving rectal
`diazepam regularly prior to midazolam, and in
`seven (78%) of those children the parents thought
`that nasal midazolam was easier to use and that the
`child had a more rapid and easier recovery period.
`Two of
`those patients were adolescents. The
`parents of two children did not comment on the
`difference with rectal diazepam.
`
`Discussion
`This study shows the efficacy of intranasal admin-
`istration of midazolam in acute seizures, as 98%
`
`Original article: P-Y Jeannet et al.
`could be stopped within less than 10 minutes. One
`can argue whether at least some of those seizures
`would have stopped spontaneously without the
`drug. However, many of
`these children had
`chronic epilepsy with known prolonged seizures
`for which they had received rectal diazepam and
`many of the others had acute symptomatic seizures
`needing urgent treatment. In 10 of the 15 cases
`undergoing EEG monitoring, paroxysmal EEG
`stopped within 5 minutes and in seven beta activity
`appeared quickly after administration, demonstrat-
`ing a direct effect of the drug on brain activity. The
`appearance of beta activity on EEG within minutes
`of nasal or sublingual administration has been well
`documented in normal, healthy volunteers 16 but
`was not as constant in children after a seizure or
`after paroxysmal EEG activity had stopped, 6 as in
`our cases.
`The tolerance of nasal administration was good.
`Most patients had no adverse reaction when the
`drug was given. One conscious child complained
`of dizziness and did not want the drug any more.
`The skin irritation around the nostrils of another
`child who received many doses (more than 20) was
`of some concern, but the irritation disappeared
`after a few days and did not recur despite other
`doses of midazolam. The low pH of the solution
`(3.28) may explain this irritation.
`To our knowledge, this is the first study in which
`midazolam was administered by the nasal route to
`patients at home. The preparation in small syringes
`from the intravenous solution is not ideal and it
`would be preferable
`to have a
`ready-to-use
`preparation adapted to the child's weight. How-
`ever, no parents had
`technical difficulties
`in
`administering nasal midazolam. Most parents
`who had used rectal diazepam regularly for their
`epileptic child at home thought that nasal mid-
`azolam was preferable. They reported that it was
`easier to administer and that their child recovered
`faster after the seizure. This may be explained by
`the shorter half-life of midazolam over diazepam.
`This shorter duration of action may be a dis-
`advantage in some patients with severe seizures
`or instances of status epilepticus (three of our
`patients had recurrence of seizures within 1-3
`hours of nasal administration). However, further
`studies are needed to see whether nasal/sublin-
`gual midazolam can stop the repetition of seizures
`in children with chronic epilepsy or children
`whose seizures are infrequent but tend to occur
`in clusters. Recently a randomized, double-blind,
`parallel group placebo-control study of home-
`based treatment with rectal diazepam
`in acute
`repetitive seizures has also demonstrated
`its
`efficacy. 17
`
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`

`Original article: Nasal midazolam for acute seizures
`Will nasal or sublingual midazolam
`replace
`rectal diazepam in the treatment of acute seizures?
`A British study comparing both drugs is underway
`and seems to show that they are of equivalent
`efficacy. 9 Comparison will be difficult and requires
`a large number of cases of similar severity. If at
`least a similar efficacy can be confirmed, the ease of
`application of nasal midazolam will certainly be a
`great advantage
`and most useful
`in
`severe
`epilepsy, particularly
`in older children. In our
`study,
`two families with adolescent boys had
`experienced failure with rectal diazepam because
`it was difficult to undress
`them. A potentially
`useful application would be in conscious patients
`old enough to take midazolam themselves sublin-
`gually. We suggested this (outside the study) to a
`young adult woman with a visual aura and
`constant secondary generalization who used it on
`her own twice with success. She was, of course, not
`able to do the same with rectal diazepam, and finds
`this mode of treatment much more acceptable. This
`possibility
`of
`self-administration
`in
`selected
`instances should be further explored.
`During our study period, only one child with
`febrile seizure received nasal midazolam in the
`emergency room. All the other children with febrile
`convulsions had received rectal diazepam at home
`or
`in
`the ambulance.
`In children with
`febrile
`convulsions, nasal midazolam could be used
`if
`diarrhoea
`is present, whereas
`rectal diazepam
`might be a better choice in cases of nasal obstruc-
`tion or rhinitis. The usefulness of nasal midazolam
`in this common situation needs further evaluation.
`Acknowledgements
`We thank Professor Biollaz, Clinical Pharmacology
`Unit and Dr Stephane Gloor, Pharmacie Centrale,
`CHUV, for their help in this study.
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