Managing status epilepticusBMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7240.953 (Published 08 April 2000) Cite this as: BMJ 2000;320:953
New drug offers real advantages
Status epilepticus is a medical emergency familiar to accident and emergency departments, acute medical wards, and intensive care units. It is defined as a continuous seizure lasting for at least 30 minutes,1 or two or more discrete seizures between which the patient does not recover consciousness, and in the 15-30 patients per 100 000 per year who present in status epilepticus mortality may be as high as 10%. The longer seizures persist the more difficult they are to control and the higher the mortality,2 with an increase in neuronal damage and chronic epilepsy. Until recently phenytoin has been the drug of choice for managing prolonged seizures, but it has to be given intravenously and major side effects are common. Fosphenytoin is a prodrug of phenytoin, recently licensed in the United Kingdom, that seems to offer several advantages over its parent.
Status epilepticus is challenging to treat and may be difficult to diagnose. In early status epilepticus patients usually have visible tonic-clonic seizures, although motor-convulsive activity can decline. Diagnosis may require electroencephalographic monitoring, because some patients have seizure discharge without detectable motor activity. An electroencephalogram is also invaluable to exclude “pseudostatus epilepticus,” which is seen more commonly in specialist neurological practice. Early treatment of status epilepticus means easier control, and basic life-support measures should not be ignored. Initial treatment of the patient should include the appropriate management of airway, breathing, and circulation and measurement of glucose and blood gases. Metabolic causes of seizures should be reversed as a priority. Emergency departments should have established protocols for dealing with this medical emergency.
If control of status epilepticus is delayed epileptic activity may outstrip metabolic capacity and glucose delivery, and metabolic and hypoxic-ischaemic brain and systemic injury may occur.3 The seizures compromise cerebral vascular autoregulation, which in turn compromises hypothalamic autonomic regulation, and raised intracranial pressure may supervene. Complications such as cardiovascular collapse, arrhythmias, aspiration pneumonia, acute lung injury, and pulmonary hypertension may compromise cerebral oxygen delivery further. Metabolic derangement and cerebral and systemic acidosis with hyperpyrexia, rhabdomyolysis, and disseminated intravascular coagulation may cause multiple organ failure. Revealed seizures are then unusual.
Drug treatment divides into four stages2: that of premonitory, early, established, or refractory status epilepticus. Parenteral dosing with diazepam, lorazepam, or midazolam is preferred at the premonitory stage. Lorazepam is often preferred as it has a long duration of anticonvulsive effect and the best parenchymal distribution. Adverse events include a risk of respiratory arrest, hypotension, and impaired consciousness.1
Early management should include a prompt decision to use a long term parenteral anticonvulsant. Most patients in status epilepticus or who require a longer term anticonvulsant after acute presentation are treated with phenytoin. The pharmacology of phenytoin is complex but well understood. Given adequate loading (18 mg/kg intravenously at 50 mg/min) and an adequate continuing dose, seizures are often successfully controlled. Phenytoin is effective when coadministered with diazepam in treating status epilepticus, controlling 60% to 80% of seizures.4 Brain concentrations of phenytoin peak at 10 minutes and are three to four times those in plasma after injection. Phenytoin has a pH of 12, so intramuscular dosage is inappropriate. Local reactions to phenytoin occur often and thrombophlebitisnecessitates frequent changes of cannulas and makes central administration the preferred route.
Fosphenytoin has been used for some years in the United States and can be administered intravenously or intramuscularly. Studies have found it to be as effective as phenytoin in treating status epilepticus, with several advantages over its parent drug. In one series of 81 patients with generalised convulsive status epilepticus treated with fosphenytoin 76 became seizure free.5 Another showed that 37 of 40 patients treated with fosphenytoin were seizure free within 30 minutes.6 Intravenous fosphenytoin is tolerated at infusion rates up to three times faster than those for phenytoin, and therapeutic concentrations are established within 10 minutes.7–10
Intramuscular administration of fosphenytoin has benefits: rapid and complete absorption, no requirement for cardiac monitoring, and a low incidence of side effects.11 12 Patients with neurological or neurosurgical disorders which affect conscious levels, or patients for which the gastrointestinal route is not available, would be well suited to the use of intramuscular fosphenytoin. Side effects are similar to those of parenteral phenytoin: nystagmus, dizziness, pruritus, paraesthesias, headache, somnolence, and ataxia.12
Refractory status is characterised by seizure activity for about an hour in which the patient has not responded to therapy. General anaesthesia is recommended to abolish electroencephalographic and seizure activity and prevent further cerebral damage. Agents of choice for refractory status epilepticus are the newer agent propofol and older thiopentone, whose disadvantages include a tendency to accumulate in fatty tissues, an active metabolite, haemodynamic instability, long recovery time after infusion, and the need for bloodconcentration monitoring.
Continued seizure activity in status epilepticus is associated with neuronal damage. The aim should be to halt this activity urgently. The ideal drug should be 100% effective,administered quickly without compromising conscious level or producing cardiovascular or airway reflex effects, and have no harmful effects. For status epilepticus fosphenytoin is safe and effective in the emergency initiation and maintenance of anticonvulsant treatment and may usefully complement current practices for early control of seizures.
MTEH has received a fee for speaking on status epilepticus and fosphenytoin at a studyday organised by Parke Davis.