A seizure lasting for more than 5 minutes or consecutive seizures with no return of consciousness are the definitions of convulsive status epilepticus (CSE)—an acute medical emergency with significant morbidity and a high mortality rate (Trinka et al, 2015; Grover et al, 2016; Neligan and Walker, 2016). This prolonged state of abnormal neurological activity is understood to be a result of either: failure of the mechanisms responsible for terminating the seizure; or the instigation of mechanisms leading to prolonged seizure activity (Trinka et al, 2015).
Depending on the duration and type of seizure, CSE is associated with injury, network disruption and neuronal death. It is also associated with significant systemic complications such as pulmonary aspiration, cardiac dysrhythmias, metabolic derangement and impaired ventilation (Millikan et al, 2009; Grover et al, 2016).
CSE accounts for approximately 10% of epilepsy-related deaths, but reports on its incidence and mortality vary considerably worldwide (Lv et al, 2017).
All treatment of CSE should take an algorithmic approach (Grover et al, 2016). Current guidelines developed by the National Institute for Health and Care Excellence (NICE) (2012) advocate the use of benzodiazepines in the early stages and this is reflected in prehospital and hospital guidelines around the world (Brophy et al, 2012; Queensland Ambulance Service, 2016; Brown et al, 2019).
In CSE, where benzodiazepines have failed, pharmacological therapy with non-benzodiazepines is indicated; a second-line medication seen in some prehospital settings and commonly found in hospital environments is phenytoin (NICE, 2012; Queensland Ambulance Service, 2016). However, prehospital guidelines for UK ambulance service paramedics limit treatment to benzodiazepines and offer no second-line therapy (Brown et al, 2019). The need for early pharmacological agents should exert pressure on prehospital medical advisory boards to investigate and consider second-line anti-epileptic drugs, such as phenytoin, for the administration by advanced paramedics attending high-acuity patients.
Phenytoin inhibits seizure activity by promoting sodium efflux from neurons and attempts to stabilise the threshold against excitability caused by overstimulation (Bullock, 2017). Phenytoin does not typically cause respiratory depression or central nervous system depression as frequently seen with benzodiazepines (Bullock, 2017).
It is commonly given as an infusion, with a maximum infusion rate of 50 mg phenytoin/minute with a dose of 15–18 mg/kg; its full anticonvulsant effect may not be seen for 30 minutes (NICE, 2012).
As a result of several factors including its side effect profile, the need for intravenous (IV) administration, its specific chemical properties and its prolonged mechanism of action, the use of phenytoin should be limited to a specific cohort of patients. It has previously only been administered by doctors (Emergency Medical Retrieval Service, 2018).
Literature review
Although phenytoin is common in emergency department management, prehospital research and published evidence of its use is limited. A literature search was conducted using PubMed and Google Scholar using the search terms ‘phenytoin’, ‘seizure’ or ‘convulsive’ and ‘prehospital’, ‘EMS’ or ‘ambulance’. The search was expanded to include additional articles such as those from emergency departments as the numbers of relevant studies were limited. Two literature reviews, a large, double-blind, randomised, phase 3 trial, and an additional literature review with an associated professional consensus piece were identified and critiqued.
A literature review by Billington et al (2016), Adult Status Epilepticus: a Review of the Prehospital and Emergency Department Management published in the Journal of Clinical Medicine, assessed the management of CSE in both prehospital and emergency department settings. This review advocates for prehospital providers, endorsing their ability to recognise, prioritise and treat CSE within the limitations of their protocols and guidelines. This review recommends that non-benzodiazepine anti-epileptic drugs are given within 20 minutes of seizure onset, with phenytoin as an initial second-line pharmacological intervention (Billington et al, 2016).
In the ‘prehospital phase’ of the article, Billington et al (2016) conclude that the future direction of prehospital care should examine different combinations of benzodiazepine and non-benzodiazepine anti-epileptic drugs with the outcome focusing on cessation of CSE before arrival at hospital. The authors also suggest that long-term longitudinal studies would be best to examine the impact of early anti-epileptic pharmacological therapy on mortality and morbidity (Billington et al, 2016).
The SAMUKeppra study was a large, double-blind, randomised, phase 3 trial with placebo control involving the addition of a second-line anti-epileptic drug to a benzodiazepine in the prehospital environment (Navarro et al, 2016) published in The Lancet Neurology. It randomised patients 1:1 to receive either clonazepam (a benzodiazepine) or clonazepam and levetiracetam (a benzodiazepine with a common second-line anti-epileptic drug with a similar mechanism of action to phenytoin but a lower evidence class) (Brophy et al, 2012; Schomer and Kapur, 2016).
The study was discontinued after no evidence was seen of a difference after 136 patients were randomised and interim results were published (Navarro et al, 2016). The study did show though that the IV injection of a second-line anti-epileptic drug in the prehospital setting was safe with no difference in circulatory or respiratory failures noted between control and study groups (Navarro et al, 2016).
SAMUKeppra was powered to determine if a second-line agent added to a benzodiazepine would result in earlier seizure cessation and, while this was not evident, several limitations restrict the study's usefulness in determining whether second-line agents have a role in prehospital care (Navarro et al, 2016). Billington et al (2016) concluded that the SAMUKeppra study provided data that were difficult to draw conclusions from and that future research should be based on studying different combinations of anti-epileptic drugs to maximise seizure termination in the prehospital setting.
Treatment of Convulsive Status Epilepticus by Grover et al (2016) is a 20-page review and professional consensus piece that analyses the current treatment and future vision of CSE management. The paper discusses second-line treatment options and outlines the published prospective randomised control studies from the previous 10 years, which is limited to six studies including a total of 501 patients. These studies investigate a range of second-line agents, including sodium valproate, phenytoin and levetiracetam (Grover et al, 2016). A summary of their findings led the authors to conclude that all three of these anti-epileptic drugs were approximately equal in efficacy and safety (Grover et al, 2016).
On an important side note, ketamine, which is being increasingly used prehospitally, is recognised as an agent of possible benefit in refractory status epilepticus. However, as only a handful of studies demonstrate its efficacy and safety, it is generally used only after attempts with second-line anti-epileptic drugs fail (Grover et al, 2016).
In 2015, an extensive review of the literature was undertaken and a paper was published, Clinical Decision Making in Seizures and Status Epilepticus, which focused on both pre- and in-hospital care (Teran et al, 2015). Clinical data presented in the article showed that without control of the seizure within 30 minutes of onset, permanent neuronal damage may occur despite efforts to maintain oxygenation, blood pressure and body temperature.
It also introduced the phenomenon of ‘pharmacoresistance’, which showed that early second-line anti-epileptic drug use is associated with easier and quicker seizure termination, with prolonged seizures becoming resistant to medication (Teran et al, 2015).
| Clinical condition | |||||
|---|---|---|---|---|---|
| Indication | For the management of convulsive status epilepticus (CSE) unresponsive to benzodiazepines | ||||
| Inclusion criteria | Previously received two doses of benzodiazepines during the current seizure event |
||||
| Exclusion criteria | Known hypersensitivity |
||||
| Cautions/need for further advice | Ensure all reversible causes including hypoxia and hypoglycaemia are managed as best as possible | ||||
| Drug details | |||||
| Name, form and strength of medicine | Phenytoin |
||||
| Route/method | Administer via a large vein through a large gauge intravenous (IV) catheter or patent intraosseous device |
||||
| Dosage | Weight-based calculation required, which is a potential source of medication error |
||||
| Weight | Dose | Weight | Dose | ||
| 35 kg | 700 mg | 70 kg | 1400 mg | ||
| 40 kg | 800 mg | 75 kg | 1500 mg | ||
| 45 kg | 900 mg | 80 kg | 1600 mg | ||
| 50 kg | 1000 mg | 85 kg | 1700 mg | ||
| 55 kg | 1100 mg | 90 kg | 1800 mg | ||
| 60 kg | 1200 mg | 95 kg | 1900 mg | ||
| 65 kg | 1300 mg | ≥100 kg | 2000 mg | ||
| NICE (2012) | |||||
| Frequency | Single episode of care | ||||
| Duration of treatment | Single episode of care, Infusion over 30 minutes or longer |
||||
| Side effects and adverse drug reactions | Alteration in respiratory function |
||||
| Follow-up | Ensure that the indication, dose administered and outcome are clearly documented |
||||
This review highlighted the paucity of randomised prospective studies into second-line anti-epileptic drugs. It also showed that prehospital providers nearly always arrive >5 minutes since seizure onset so prehospital providers should be initiating rapid treatment as ‘presumed CSE’ (Teran et al, 2015).
The study recognises that phenytoin is the most common recommended second-line therapy and, despite its limitations, is still a safe and regularly used agent (Teran et al, 2015).
Implications and recommendations
Although phenytoin is included in the guidelines for some physician-led critical care teams in the UK, the author found no published data regarding its level of use and whether physician-led teams are best placed to deliver the intervention (Emergency Medical Retrieval Service, 2018).
While phenytoin is an effective and commonly used second-line agent, there is a distinct lack of evidence showing its prehospital use. It would be reasonable to investigate phasing the introduction of phenytoin into practice while simultaneously running a well-designed research trial. The trial should involve trained advanced clinicians using randomisation, double-blinding and placebo control. This would allow the prehospital field the opportunity to guide worldwide research on second-line anti-epileptic drugs, as placebo control in hospital is no longer ethically endorsable because effective standard treatment is available to patients with CSE (Millum and Grady, 2013).
An add-on medication study design similar to SAMUKeppra could qualify as a phase IV trial and, while potentially exposing patients to risks from phenytoin, the benefits could change the course of seizure management prehospitally worldwide. This is particularly true for where transport times are long, extrication is difficult and when contact with prehospital providers is delayed.
The administration of phenytoin requires calculation, dilution and infusion rate setting; these skills are usually familiar only to advanced clinicians. There are multiple dangers regarding administration of prehospital phenytoin. Clinicians will need to understand the pharmacological principles behind phenytoin's effects including its ability to prolong the QT interval and cause cardiac dysrhythmias as well as significant education on its specific properties (Bullock, 2017). As it has a pH of 12, phenytoin is particularly capable of causing vessel damage; extravasation will lead to necrosis and other confounding factors (Teran et al, 2015). Phenytoin must be administered through a large, well-secured vessel or patent intraosseous access device (Teran et al, 2015).
Summary
Management of CSE will continue to present challenges to prehospital providers and, while evidence on phenytoin's use in the prehospital setting is limited, the evidence that does exist supports investigating the introduction of this (or a similar) agent into practice.
If prehospital medical directors promote the introduction of phenytoin to select patients, administered by advanced clinicians, this would be an excellent opportunity to provide much-needed clinical data and potentially reduce morbidity and mortality in CSE.
Prehospital providers will need extensive training and knowledge. Initially, administration of the medication should be done only by advanced clinicians and limited to patients enrolled in a suitably designed trial.