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If there is failure to respond to lorazepam, an intravenous infusion of phenytoin or fosphenytoin should be commenced. It is essential to liaise with the anaesthetic services at this stage to make them aware of the situation and the possibility that ICU transfer may be required. Fosphenytoin has the advantage over phenytoin of faster administration and less risk of hypotension. Both should be administered at a dose of 20 mg/kg. There has been a tendency among physicians to use lower doses of phenytoin due to fears of toxicity. However, the risk of phenytoin toxicity at this dose is low and is outweighed by the risks of ongoing SE in those who are under-treated. Epileptic patients who go into SE and who are already taking phenytoin as part of their regimen should be treated with full loading doses initially while the baseline phenytoin level is awaited (if available). If this level is in the medium-to-high range, the succeeding doses of the drug should be reduced.

The rate of infusion should not exceed 50 mg/min, which is equivalent to a 1500-mg infusion given over approximately 30 minutes. It is prudent to reduce this to 30 mg/min in the elderly. For neonates the rate of infusion should not exceed 1 mg/kg/min. The drug should be administered in normal saline to avoid precipitation and other drugs should not be added to the infusion, for the same reason. Owing to its high pH, it may also cause thrombophlebitis (which in severe cases may result in the so-called 'purple glove' syndrome). Phenytoin causes relatively little cerebral or respiratory depression. However, hypotension and cardiac arrhythmia can occur and patients should have their blood pressure and pulse monitored during and after treatment. The risk of severe hypotension or cardiac arrhythmia is low and does not appear to significantly differ from the risks associated with either benzodiazepines or phenobarbital [100]. If there are concerns over the safety of phenytoin use, a good alternative appears to be intravenous valproate. It has the advantage of rapid administration, lower risk of adverse effects and may also offer the benefits of neuroprotection (see below).

It is worth noting that in certain circumstances, it may be reasonable to administer a second-line agent even if the SE is terminated by the initial treatment with lorazepam. This usually arises in the setting of irritative structural lesion, such as a tumour or acute stroke, where the risk of recurrent seizure is high and there is a desire for rapid titration of maintenance AED.

Alternative second-Line or Third-Line Therapeutic strategies for status Epilepticus

These agents should be considered when phenytoin is contraindicated or when the patient continues to seize after its administration (i.e. as a third-line agent). Although there are few data available, it is the authors' opinion that the majority of patients who fail to respond to the combination of benzodiazepine and phenytoin in adequate doses are probably unlikely to respond to a third-line agent and will require intubation and treatment with an anaesthetic agent, as discussed below.

Valproate

Most of the available data on the efficacy of intravenous sodium valproate in treating SE come from non-comparative case series [101-106]. In these studies, the efficacy is reported at between 58% and 100%, as both a first- and second-line agent and in all clinical forms of status, including complex partial SE. However, a recent randomized unblinded study that compared valproate to phenytoin in 68 patients found valproate to be superior at aborting SE as both a first-line (66% vs. 42%) and second-line (79% vs. 25%) agent [107]. There was a suggestion of a synergistic effect with other drugs when valproate was given as the second, third or fourth agent. The drug also has the advantage over phenytoin of better safety, serious side-effects being virtually unheard of in reports. Side-effects that have been reported in occasional patients include respiratory depression, tremor and transient disturbance of liver function tests. It may be given as a rapid intravenous infusion of up to 6 mg/kg/min to a maximum dose of 45 mg/kg, most reports using 20-30 mg/kg at a rate of about 3 mg/kg/min (approximately 2000 mg over 10 min for the average adult). Clearly, large-scale randomized comparative trials are warranted to further clarify the role of the drug in the management of SE.

Levetiracetam

Anecdotal evidence is also beginning to emerge on the use of oral or nasogastric levetiracetam as a treatment for SE [108-111]. Two retrospective case series from the same group have reported that 33-43% of patients with SE of different aetiologies and seizure types responded to levetiracetam, having failed standard SE regimens [109, 111]. The authors noted that although doses between 1000 and 9000 mg/day were given, all responders did so at less than 3000 mg/day and when the drug was commenced within 4 days of the onset of SE. A further case series reported that six patients, refractory to at least two prior AEDs, responded to oral levetiracetam within 96 h at doses up to 3000 mg/day [108]. No significant adverse reactions were reported. Levetiracetam may also be given via nasogastric tube in comatose patients, although absorption may be variable. Levetiracetam can now also be administered intravenously and thus represents an alternative to phenytoin in the acute setting. There are few data currently available on its efficacy. The main advantages of levetiracetam in the setting of SE are ease of administration, rapid titration, easy transition to use as a maintenance anti-epileptic drug (AED) and few drug-drug interactions. Further data are clearly needed before its use can be recommended.

Phenobarbital

Phenobarbital, also known as phenobarbital, is the traditional agent of choice after phenytoin has proven ineffective in the setting of SE. Phenobarbital requires less dilution and can be given as a slow i.v. push over 10 minutes. Phenobarbital is sedating, although not sufficient to induce a burst-suppression EEG pattern when a 20-mg/kg loading dose is administered. Patients need intubation after a loading dose. The drug has a very long half-life of 3-7 days and accumulates in tissues; hence, patients often require a long waking-up period after significant doses are administered. Phenobarbital rarely causes idiosyncratic reactions, but rashes, hepatic dysfunction and aplastic anaemia have been reported.

Topiramate

Evidence supporting the use of topiramate in SE comes from a small number of case series where it has been used in the setting of refractory SE in both children and adults [112-117]. All patients reported thus far appear to have had a favourable response to topiramate in this setting, despite different aetiologies and seizure types, and no serious adverse reactions have been reported. Its multiple mechanisms of action make it a good candidate drug for SE, with the potential for additive effects with other agents. Again, however, prospective clinical trial data are lacking. The drug is typically given in this setting as a suspension, via nasogastric tube in the comatose patient, at doses between 300 and 1600 mg/day. Topiramate is currently not available as an intravenous drug.

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