Attention to basic life-support issues (airway, breathing, and circulation) is central to the management of generalized convulsive status epilepticus. While the rapid termination of this condition is often the best way to deal with airway problems, emergent endotracheal intubation may be necessary for the patient unable to ventilate adequately or if treatment to terminate status epilepticus causes respiratory depression. Blind nasotracheal intubation is preferable for patients able to move air spontaneously, since neuromuscular junction blockade is not required. If laryngoscopic intubation is required in a patient with suspected intracranial hypertension, premedicate the patient with lidocaine (lignocaine) 1 mg/kg or thiopental (thiopentone) 3 mg/kg to blunt the increase in intracranial pressure associated with laryngoscopy.
During the first 30 to 60 min of status epilepticus most patients are hypertensive; after this, blood pressure usually declines to normal or hypotensive values. Many drugs used to terminate status epilepticus can induce hypotension, and so the clinician should always be ready to support the circulation with fluids and vasopressors.
Since hypoglycemia may be associated with status epilepticus, either as an etiology or as a consequence of prolonged seizure activity with autonomic failure, the blood glucose should be rapidly determined. Since the techniques employed for bedside determination lose accuracy outside the normal range, 'borderline' hypoglycemic values should be treated (along with thiamine administration). Non-ketotic hyperglycemia frequently presents with epilepsia partialis continua, which does not typically respond to antiseizure agents, but which usually remits with rehydration and control of the blood sugar.
Therapy for status epilepticus involves three principles: terminate the condition, prevent its recurrence, and manage its complications. The recently completed United States Department of Veterans Affairs study of status epilepticus compared four treatment regimens for generalized convulsive status epilepticus (lorazepam, diazepam followed by phenytoin, phenytoin alone, and phenobarbital (phenobarbitone) alone). This study showed that lorazepam 0.1 mg/kg terminated 63 per cent of generalized convulsive status epilepticus episodes and was marginally superior to the other treatment arms. In another important preliminary result, about 20 per cent of patients remained in electrical status epilepticus after their clinical seizure activity stopped. This reinforces the clinical suspicion of non-convulsive status epilepticus in patients who do not begin to awaken within 15 to 20 min after the apparent termination of their seizures.
Recommended lorazepam doses vary from 0.05 to 0.2 mg/kg (up to 8 mg in adults) administered at a rate of 0.04 mg/kg/min. Increasing the dose above 8 mg does not appear to improve the response rate. If this drug fails, phenytoin is frequently chosen as a second-line agent. However, the aggregate response rate to all second-line drugs in the Department of Veterans Affairs study was about 9 per cent, and the response to third-line drugs was 3 per cent. This suggests that additional conventional treatments have limited utility after the first choice fails. If phenytoin is used, it should be given in an initial dose of 20 mg/kg, at a rate of up to 1 mg/kg/min (maximum rate, 50 mg/min). This process generally takes over 30 min to complete, during which the majority of patients who failed lorazepam will continue in status epilepticus.
At this juncture, the patient is refractory to standard therapy and one might use one of the 'definitive' treatments. These more aggressive treatments should be given in intensive care units, since the patients require ventilatory support and frequently need hemodynamic support as well. EEG monitoring is also necessary, since these drugs typically abolish clinical evidence of seizure activity before achieving electrographic control.
We use either midazolam or propofol at this juncture. Midazolam therapy starts with a loading dose of 0.2 mg/kg and an initial maintenance dose of 0.1 mg/kg/h. The maintenance dose is titrated to produce clinical and electrographic suppression of seizures, rather than a burst-suppression EEG pattern. This agent is effective in over 90 per cent of cases of refractory status epilepticus pooled from three centers, but produces substantial tachyphylaxis. When the infusion rate reaches 2.0 mg/kg/h, we arbitrarily change to another drug, usually pentobarbital. This is often required in those situations in which the patient has a prolonged stimulus for epileptogenesis, such as encephalitis. Typical doses for propofol in status epilepticus range from 2 to 15 mg/kg/h; we also use a loading dose of 2 mg/kg. The costs of these doses for either drug are quite high, and often approximately equal. The caloric content of propofol, which is administered in a lipid solution, is about 1.1 kcal/ml.
Recommendations for pentobarbital loading doses vary from 5 to 12 mg/kg, with maintenance doses beginning at about 1 mg/kg/h. An EEG goal of burst suppression is traditional, but since there is no clear evidence to support this, we now choose seizure suppression instead. A pentobarbital dose adequate to produce burst suppression is often necessary to suppress all seizures, and there are several examples of seizures arising from a background of this pattern. Thus intermittent sampling of the EEG to insure that this pattem is present is not sufficient to be certain that no seizures are occurring. The extent to which occasional seizures produce further brain damage in this setting is unknown.
Adverse effects of pentobarbital include hypotension (from both venodilation and diminished myocardial contractility), immune suppression, poikilothermia, interference with the clearance of pulmonary secretions, and loss of gastrointestinal motility. Almost all adult patients will require pulmonary artery catheterization to provide the information necessary for the management of fluids and vasoactive drugs. Total parenteral nutrition may be required. Pulmonary embolism prophylaxis is necessary, and gastric mucosal protection (H2 blockade or sucralfate) is advisable.
The optimal duration of these therapies is uncertain. To prevent recurrence of refractory status epilepticus, we typically institute a regimen of phenytoin and high-dose phenobarbital (aiming for a phenobarbital serum concentration of 50-100 pg/ml or higher) before withdrawing the agent being used for definitive control of status epilepticus. These choices are modified on the basis of the patient's history. This withdrawal of therapy is attempted once or twice daily, and requires both EEG and clinical absence of seizures to be considered successful.
Many other agents have been reported to be useful in terminating status epilepticus, but none have been demonstrated to be superior to those discussed herein.
Complications of status epilepticus include neuronal damage, rhabdomyolysis, hyperthermia, and cerebral edema. The only current approach to neuronal damage is to prevent it by rapid termination of status epilepticus, but excitatory amino acid antagonists are one of a number of promising neuroprotective treatments currently under study. Rhabdomyolysis from sustained muscular overactivity may be sufficient to produce renal damage; it may be preventable if treated early with volume expansion and alkalinization with sodium bicarbonate. Hyperthermia usually resolves after status epilepticus is controlled, but may contribute to neuronal damage prior to this point. External cooling is usually sufficient to control it once status epilepticus is terminated. Cerebral edema due to status epilepticus is vasogenic in experimental models, and may be managed with steroids and mannitol in the rare cases in which it produces symptoms. However, if marked edema is present, the likelihood that both status epilepticus and the edema reflect an underlying pathological process should be considered.
One change in drug therapy will most likely occur in the very near future; intravenous phenytoin will probably be replaced by fosphenytoin in most centers. This phenytoin prodrug is converted to phenytoin within about 20 min of administration. Its major advantage in status epilepticus will be the increased safety of its administration; in contrast with phenytoin, no adverse effects occur if it is extravasated. It can be administered more rapidly that phenytoin (up to 150 mg/min of phenytoin equivalent), and may be used either intravenously or subcutaneously. In studies to date, fosphenytoin does not appear to produce hypotension at the same frequency or severity as the intravenous formulation of phenytoin.
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