Current UK ambulance service clinical practice guidelines (Association of Ambulance Chief Executives, 2013) include rectal (PR) and intravenous (IV) diazepam for use by paramedics to terminate seizures. The guidelines also advocate use of patient's own buccal midazolam (BM), but this is not currently carried out by UK paramedics (Association of Ambulance Chief Executives, 2013). Many patients with seizures will only require supportive care and limited intervention from the pre-hospital clinicians (Warden and Frederick, 2006). However, those patients who have complex, prolonged seizures or are found to be in status epilepticus, require drug therapy to terminate the seizure and prevent neurological insult (Warden and Frederick, 2006; Association of Ambulance Chief Executives, 2013). Before the guidelines were updated in 2013, paramedics were able to administer two doses of PR diazepam to account for difficulty in establishing IV access and facilitating prompt termination of seizures. Since the update in 2013, the second dose of PR diazepam was removed and emphasis was placed on early IV access and administration of IV diazepam. Diazepam is quickly able to cross the blood-brain barrier, but dosing may last just 30 minutes, resulting in the need for further drug administration. With repeat dosing, diazepam can accumulate and persist, sometimes causing unexpected side effects, including central nervous system (CNS) depression and impaired respiratory function (Aneja, 2012). Seizures are a common neurological emergency encountered in children and are associated with significant morbidity and mortality (Aneja, 2012). A primary goal of treatment is prompt seizure termination, and good evidence exists for the use of midazolam via the intranasal (IN) and buccal routes for the termination of paediatric seizures (Warden and Frederick, 2006; Aneja, 2012). The IN and buccal routes have proven effective, safe and are more socially acceptable than current PR diazepam (Scott et al, 1999).
Objective
The aim of this article is to review the evidence for the use of diazepam and midazolam, and to determine which anticonvulsant is the most appropriate for termination of paediatric seizures by paramedics.
Methodology
A literature search using PubMed was carried out, with the initial search criteria being ‘paediatric seizures AND midazolam AND diazepam’; this first search identified 45 papers. Pre-hospital data in this area of practice is extremely limited, so the search was not limited with terms such as ‘ambulance’ or ‘paramedic’. The search was limited to papers published in the last 5 years, which came to 20. Of the 20 papers, one was excluded due to non- English language, and a second was excluded because the full paper was not available. In total, 18 papers were selected for this review, with relevant citations from papers and PubMed also included.
Findings (including limitations)
Talukdar and Chakrabarty (2009) carried out a randomised controlled trial to compare BM with IV diazepam. One hundred and twenty cases that presented to the emergency department were treated randomly with either BM or IV diazepam, and successful control of seizure within five minutes was recorded as 85% for BM and 93.3% for IV diazepam, with no statistical difference. Mean time to control was significantly less with IV diazepam (p=<0.001); however, mean time to administration of medicine was significantly less for BM (p=<0.001). No significant side effects were noted, and it was concluded that BM is an effective alternative to IV diazepam, particularly when IV access is difficult to obtain.
In a systematic review in 2009, Sofou et al (2009) concluded similar findings—that BM is an effective anti-convulsant with a convenient route of administration—making it a suitable choice for first-line therapy when managing prolonged seizures in paediatric patients.
In 2010, Ashrafi et al (2010) evaluated the use of BM versus PR diazepam by randomised controlled trial in 98 paediatric patients. In the BM group, 42/49 (88%) had seizures controlled in less than 4 minutes from administration, and all patients were controlled within 5 minutes. In the PR diazepam group, just 24/49 (49%) were controlled in less than 4 minutes, and 40/49 within 5 minutes. Time to administration was significantly less in the BM group (p=<0.001). This study also considered parental satisfaction as an outcome measure; in the midazolam group 46/49 (94%) parents were satsified, compared with 7/49 (14%) in the diazepam group.
‘Seizures are a common neurological emergency encountered in children and are associated with significant morbidity and mortality’
‘After conducting this review, evidence for the safety and efficacy of an alternative to traditional diazepam is evident’
Holsti et al (2010) took a different approach and looked at IN midazolam and PR diazepam for home treatment. Home rescue kits were given to 358 patients to control their next seizure, and were randomised to receive either IN midazolam (0.2 mg/kg) or PR diazepam (0.3–0.5 mg/kg) for a seizure lasting longer than 5 minutes. The primary outcome measure was time of seizure duration after medication, with a total of 92 patients treated during the study period (50 midazolam, 42 diazepam). Median time of administration to seizure termination was non-significant, 3 minutes for the midazolam group and 4.3 minutes for the diazepam group, a difference of 1.3 minutes (p=0.09). However, carers reported the IN method of delivery to be much easier, and overall satisfaction was greater than in the diazepam group.
Gathwala et al (2012) reviewed IV administration of diazepam, midazolam and lorazepam for control of seizures. A sample of 120 children were randomised into three groups of 40, with a primary outcome measure of time to seizure termination. There was no significant difference in any of the three groups; however, patients receiving diazepam were more likely to require a second dose to control seizures. Ulgey et al (2012) suggest that the disadvantages of PR diazepam are outweighed by the simple, safe and effective administration of BM and IN midazolam. Evidence already presented has shown efficacy of midazolam in randomised controlled trials (Talukdar and Chakrabarty, 2009; Sofou et al, 2009; Ashrafi et al, 2010; Holsti et al, 2010; Gathwala et al, 2012; Ulgey et al, 2012), and for the pre-hospital provider who may not be confident with IV access or may find IV access difficult (Lammers et al, 2012), the buccal and IN routes of administration are very effective and practical.
Further hospital randomised controlled trial data concerning IN midazolam versus IV diazepam was provided by Thakker and Shanbag (2013). The mean time to initiating treatment was significantly less in the midazolam group (3.14 minutes) compared with the diazepam group (14.13 minutes). The same was seen for time to cessation of seizure activity: 6.67 minutes for midazolam and 17.18 minutes for diazepam. Diazepam was shown to terminate seizures more timely once administered, but was not significant. Again, midazolam via the IN route was shown to be safe and effective, and to facilitate prompt seizure cessation with no significant side effects. It is important to note that this study was only concerned with initial treatment options, and eight treatment failures were reported and additional drug administration was required to terminate seizure activity. Javadzadeh et al (2012) also demonstrated significance regarding suitability of IN midazolam as an alternative to IV diazepam. This randomised controlled trial looking at 60 patients contributed further evidence that IN midazolam can be rapidly administered, is effective at terminating seizure activity and has a proven safety record.
Tonekaboni et al (2012) conducted a randomised controlled trial of 92 patients comparing safety and efficacy of BM and IV diazepam. They were unable to demonstrate significance that one drug was better than the other, or indeed safer than the other. They did suggest that with a higher risk of respiratory depression following administration of IV diazepam, BM would be the safer choice for controlling seizures in children.
Evaluation
Good evidence exists regarding the efficacy and safety of midazolam for terminating seizures in children. Trials have compared midazolam via the IN and buccal routes against the traditional administration of diazepam via PR and IV routes (Talukdar and Chakrabarty, 2009; Sofou et al, 2009; Ashrafi et al, 2010; Holsti et al, 2010; Gathwala et al, 2012; Ulgey et al, 2012). The potential side effects of diazepam administration are well documented, and for pre-hospital providers the social aspect of delivering PR medication present a challenge, as does gaining IV access in children (Lammers et al, 2012). Much of the recent data exist from hospital studies—but in emergency department settings—and therefore it is reasonable to extrapolate results for application to the pre-hospital setting. Trials conducted do tend to be reported with relatively small samples, but results from more than one study have produced the same results for both midazolam and diazepam.
Ambulance clinical practice guidelines (Association of Ambulance Chief Executives, 2013) advocate that where possible clinicians should administer the patient's own BM, and the data from randomised controlled trials support this guidance. However, this is not available to all patients, and only certain advanced paramedics currently carry midazolam. Termination of seizure activity will undoubtedly help to reduce neurological insult. Where pre-hospital providers have long transfer times to definitive care, or work in isolation on fast response units, it would be logical to have medication available that is easy to administer and effective, in line with the published evidence base.
After conducting this review, evidence for the safety and efficacy of an alternative to traditional diazepam is evident. UK legislation (Misuse of Drugs Act 1971 (c.38)) has been changed to allow paramedics to carry and administer midazolam, and via the buccal or nasal route it is proven to be effective, easy to administer and has a faster onset of action. Therefore, it is a recommendation of this review to conduct a quality improvement project for the inclusion of midazolam for seizure termination, for all UK Paramedics.