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 intramuscularly. 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 convulsions 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 intravenous 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 transient. No patient had to be intubated or mechanically ventilated.22,23
As a result of the popularity of intranasal midazolam as a sedative agent for minor surgical interventions and diagnostic procedures, there is considerable 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 seizures, 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 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 compared 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 midazolam 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 children 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 sublingually 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 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 provided not only in medical centres but, with appropriate instruction, by the parents of children with febrile seizures at home. Further studies are, however, needed on a larger series of children with various types of seizures.
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