Is it time to ditch Phenytoin?

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By Gabriel Jones, Consultant EM.

Epilepsy is common, with a prevalence of approximately 1% in adults (1,2). Annual costs are estimated to be 1.6 billion pounds (3,4). Status epilepticus (SE) is a neurological emergency which still has a significant mortality (4-32%) (5,6,7). The current definition is a seizure lasting longer than five minutes or two seizures without a return of consciousness between seizures (8).

Until recent years, the management of SE has changed little. The established consensus being initial treatment with repeated Benzodiazepines (BZD) followed by a second line agent. A third line drug or General Anaesthetic (GA) may follow. In the United Kingdom (UK) and abroad this has conventionally equated to Lorazepam (LOR) then Phenytoin (PHT)9 which is in keeping with National Institute for Health and Clinical Excellence (NICE) guidance (7). Whilst most emergency physicians will be familiar with using Phenytoin, the evidence for its use is largely based on low quality data some 20 years old (10).

PHT has a potentially dangerous side effect profile including respiratory depression, hypotension, toxicity in overdose, numerous interactions and contraindications including pregnancy (7,10). We all read the recent RCEM safety alert. In addition, PHT infusion is slow, requires a filtered giving set, electrocardiogram monitoring and subsequent drug level monitoring. The NICE 2014 Evidence Update Advisory Group suggested a safer alternative to Phenytoin is needed (11).

So what are the options?

With the advent of newer Anti-Epileptic Drugs (AEDs), clinicians are increasingly considering alternative agents to manage SE (9). Sodium Valproate (VPA) is considered to be effective but is not without risk (12,13). Levetiracetam (LEV) is currently licensed for monotherapy and adjunctive treatment of focal seizures and is widely regarded as safe (14). It has an acceptable side effect profile including haemodynamic stability and no known drug interactions due to its minimal protein binding (15,16). LEV can be administered rapidly and does not require subsequent serum level monitoring making it an attractive emergency drug for the management of SE. Already LEV is the first AED of choice for many intensive care units, particularly specialist neurosurgical units. So why are we still exposing our patients to a single dose of a dangerous drug in the emergency department when we know our intensive care colleagues are likely to take a very different approach?

So what is the evidence for the use of Keppra?

The 2004 NICE clinical guidance 137 and subsequent 2012 (7), 2014 (11) updates do not include any studies that evaluate Levetiracetam use in SE. The Cochrane review 2014, Anticonvulsant therapy for SE (20), concluded that, ‘beyond initial treatment with a benzodiazepine, there is uncertainty as to the effectiveness of other AEDs versus each other’.

The only study that included LEV found it to be as effective as LOR as a first-line agent. There are several more recent small prospective studies that compare LEV to PHT but most were conducted in the Indian subcontinent. They do not demonstrate a difference in efficacy and none were powered for equivalence or non inferiority. There are of course numerous case series that document the use of LEV in SE and suggest a similar efficacy to other AEDs.

Synthesis of what little data is available is inherently difficult because the outcome measure seizure cessation is inconsistently defined. Most prospective studies defined this as an assessment at 30 minutes; (18,23,28) however, there was a range from 331 minutes to 24 hours. Some studies gave no detail. Redecker et al.(39) recently published an analysis of efficacy of four AEDs based on four different efficacy criteria. Unsurprisingly, there was huge variation in reported efficacy highlighting the need for standardisation of outcome data. There is no strong evidence to identify LEV as either more or less effective than PHT or any other AED. We should, however, put this in the context of only weak evidence for current practice.

Given the apparently excellent safety profile that LEV offers, one could argue that the exact efficacy may not be important. If this safety profile is confirmed, it may be reasonable to accept the current limited published efficacy data. If LEV is approximately as effective, but much safer, quicker and easier to administer than the current available alternatives, this could justify its full endorsement within current practice.

 

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