Fosphenytoin | clinical impact review Table 3 | Summary of antiepileptic drugs used for the treatment of status epilepticus (adapted from Manno 2003; Sirven & Waterhouse 2003) Drug (route) Benzodiazepines Diazepam (iv, rectal) Lorazepam (iv) Midazolam (iv, im) Hydantoins Fosphenytoin (iv) Phenytoin (iv) Barbiturates Phenobarbital (iv) Pentobarbital (iv) General anesthetic Propofol (iv) Potential AEs Advantages Disadvantages Respiratory depression, hypotension, decreased level of consciousness Respiratory depression, hypotension, decreased level of consciousness Respiratory depression, hypotension, decreased level of consciousness Most rapidly acting (10–20 s) Stable in liquid form at room temperature Rectal administration commonly used for children Long duration of action (4–6 h) May be least respiratory depressant in class Rapid acting (<1 min) Hypotension, cardiac arrhythmias, pruritus Potentially fewer AEs Faster infusion rate than phenytoin Hypotension, QT interval prolongation, PGS, venous irritation, phlebitis Low cost Effective in longer-term seizure recurrence Hypotension, respiratory depression, decreased level of consciousness Hypotension, respiratory depression, decreased level of consciousness Hypotension, respiratory depression, acidosis, lipemia Long acting Shorter half-life than phenobarbital Rapid onset of action Rapid recovery Short duration of action (<20 min) Second-line drug required Refrigerated storage Delay in brain uptake (2 min to maximal effect) Short duration of action Second-line drug required Minimal CV effects CV monitoring AEs High acquisition cost AE profile (infusion rate, CV monitoring) Long half-life More hypoventilation, more hypotension than benzodiazepines or phenytoin More hypoventilation, more hypotension than benzodiazepines or phenytoin AE profile in children AE, adverse event; CV, cardiovascular; im, intramuscular; iv, intravenous; PGS, purple glove syndrome. in medical schools and private practice) evaluated current treatment preferences for GCSE. Of the 106 respondents 76% initially treated patients with intravenous lorazepam, while 95% would use phenytoin or fosphenytoin if seizures continued for 10 min following initial benzodiazepine treatment (Claassen et al. 2003). Fosphenytoin was more popular with respondents than phenytoin (65 versus 31%, respectively). Phenytoin and fosphenytoin have also been recommended for second-line treatment in general guidelines for treating GCSE (Lowenstein & Alldredge 1998; Appleton et al. 2000; Rosenow et al. 2002). Phenytoin can be used as an initial treatment for cessation of seizure activity, for maintaining a prolonged antiseizure effect following effective treatment with a benzodiazepine, or when benzodiazepines are ineffective. Its mode of action is to limit the repetitive firing of action potentials by slowing the rate of recovery of voltage-activated sodium channels. Parenteral sodium phenytoin is formulated with 40% propylene glycol and 10% ethanol in water for injection adjusted to pH 12 with sodium hydroxide. The recommended starting dose for intravenous phenytoin is 20 mg/kg (via a large vein) given at a maximal rate of 50 mg/min to achieve therapeutic serum concentrations of 10–20 mg/L. Therefore it 68 would take nearly 30 min to give the required dose to a patient weighing 70 kg, which is undesirable given that the aim of SE treatment is the prompt termination of seizure activity. The recommended dose for children is 18 mg/kg infused over 20 min (maximum infusion rate 1 mg/kg per min), which is similarly inappropriate (Appleton et al. 2000). In addition, adverse effects following use of intravenous phenytoin in SE can be common and are cardiovascular-related: hypotension, QT prolongation, and cardiac dysrhythmias may occur and these are direct effects of the active ingredient and excipients, plus local venous irritation and pain may occur. Propylene glycol in the formulation contributes to the hypotension and cardiac arrhythmias observed with the rapid infusion of phenytoin (Fischer et al. 2003). One of the most poorly understood and potentially serious local complications of intravenous phenytoin administration is the purple glove syndrome, which is characterized by progressive limb edema, discoloration, and pain. In the only reported systematic study of this syndrome, the incidence of purple glove syndrome was 5.9% (nine of 152) in patients receiving intravenous phenytoin (O’Brien et al. 1998). Thus, while the efficacy of phenytoin for the treatment of acute seizures and SE is well established (Treiman et al. 1998), its © 2005 Core Medical Publishing Limited