Fosphenytoin | clinical impact review Scope, aims, and objectives Status epilepticus (SE) is a serious, life-threatening condition that is often presented at casualty or emergency departments (ED). Phenytoin, a commonly used drug for the treatment of SE, is associated with poor solubility that complicates the use of the intravenous formulation. To overcome this limitation fosphenytoin, a water-soluble prodrug of phenytoin, was introduced in 1996. The objective of this review is to evaluate the evidence for the use of fosphenytoin in the treatment of SE. Methods The English language medical literature was reviewed for appropriate articles relating to fosphenytoin for the treatment of SE. The following databases were searched on January 5, 2005 using the search terms ‘fosphenytoin; status epilepticus AND guidelines’ for articles published between January 1990 and December 2004 (inclusive): • PubMed, www.ncbi.nlm.nih.gov/entrez • Database of Abstracts of Reviews of Effectiveness (DARE), NHS Economic Evaluations Database (NHSEED), Health Technology Assessment (HTA), www.york.ac.uk/inst/crd/darehp.htm • NHS HTA, www.ncchta.org • National Guidelines Clearinghouse, www.guideline.gov • National Institute for Health and Clinical Excellence (NICE), www.nice.org.uk • Cochrane Database of Systematic Reviews, www.cochrane.org • Clinical Evidence, www.clinicalevidence.com A total of 186 articles were identified and animal or in vitro studies were excluded. Table 1 summarizes the levels of evidence of articles identified from the search strategy (see Editorial Information on inside back cover). Table 1 | Evidence base included in the review Number of records Full papers Abstracts Category Initial search records excluded records included Additional studies identified Level 1 clinical evidence Level 2 clinical evidence Level ≥3 clinical evidence trials other than RCT case studies Economic evidence RCT, randomized controlled trial. 66 186 165 21 3 0 4 2 0 3 4 0 0 0 3 0 0 3 0 0 0 No systematic reviews were identified for the use of fosphenytoin in the treatment of SE, four papers were of level 2 evidence and there were eight papers and abstracts of level ≥3 evidence (including case studies). In addition, four articles relating to pharmacoeconomic outcomes with fosphenytoin were identified. Six additional articles were identified from a hand search of SE publications to ensure that relevant studies were not overlooked. Disease overview Epilepsy, the presence of unprovoked recurrent seizures, is a serious disorder that affects many patients worldwide. For example, in the USA alone it has a prevalence of approximately 6.6 per 1000, with about 2.5 million people affected by the condition. Up to 28% of patients with epilepsy require treatment in EDs annually (ACEP 2004). The economic burden of epilepsy is substantial with annual direct costs of treatment per patient reported to be $US329–2642 and $US1531–5065 in the USA and Italy, respectively (Jobst & Holmes 2004). In addition, the condition also imposes a costly societal burden on individuals, families, and dependents. The medical management of epilepsy is predominantly with the long-term use of oral antiepileptic drugs. However, parenterally administered drugs are necessary for the management of some conditions and emergency situations. One such epileptic condition is SE, which is a serious medical emergency familiar to EDs, acute medical wards, and intensive care units. Although there is no universally accepted definition of this life-threatening condition it has been defined in a number of incidence studies as ‘a clinical seizure lasting more than 30 min, or repeated seizures over a period of more than 30 min without intervening recovery of consciousness’ (Rosenow et al. 2002). Based on earlier animal studies, it has been postulated that the brain can compensate for the increased demands of SE for only 30 min and that the outcomes for patients (e.g. mortality) with a seizure duration less than 30 min are significantly better (P<0.001) compared with those over 30 min (DeLorenzo et al. 1999). In general, SE can be further classified, based on clinical and electrographic criteria, into generalized convulsive status epilepticus (GCSE) and nonconvulsive status epilepticus (NCSE). GCSE is the most common and easily recognized form of SE and is usually diagnosed by observation alone. It is characterized by unconsciousness, tonic-clonic muscle activity, urinary incontinence, and tongue biting. However, with prolonged seizure activity, these clinical characteristics become less apparent. The fundamental pathophysiology of SE involves a failure of inherent cellular mechanisms to prevent sustained seizure activity (Scott et al. 1998). The failure may be due to either ineffective inhibitory or excessive excitatory processes, although it is likely that several factors are involved in this poorly understood process (Lowenstein & Alldredge 1998). NCSE may account for 30–40% of all cases of SE, an incidence of approximately five to nine per 100 000 in the general population. It is characterized by continuous or near continuous focalized or generalized seizure activity detected by electroencephalogram (EEG) for at least 30 min without physical convulsions. NCSE carries an increased risk for evolving into refractory SE and is associated with a three-fold increase in long-term mortality compared with the © 2005 Core Medical Publishing Limited